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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) Once Daily Monotherapy to Methotrexate (MTX) Monotherapy in MTX-Naïve Subjects with Moderately to Severely Active Rheumatoid Arthritis

Summary
EudraCT number	2015-003334-27
Trial protocol	SK SI ES GR LT BE CZ IE LV PL GB PT HU FI RO HR BG IT
Global end of trial date	11 Nov 2022

Results information
Results version number	v1(current)
This version publication date	07 Jul 2023
First version publication date	07 Jul 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

M13-545

ISRCTN number

US NCT number

NCT02706873

WHO universal trial number (UTN)

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB

Public contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Scientific contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Nov 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Nov 2022

Was the trial ended prematurely?

Main objective of the trial

The objectives of Period 1 were the following: ● To compare the safety and efficacy of upadacitinib 7.5 mg once daily (QD) monotherapy (for participants in Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy versus weekly methotrexate monotherapy for the treatment of signs and symptoms of RA in methotrexate-naïve adults with moderately to severely active RA; ● To compare the efficacy of upadacitinib 15 mg QD monotherapy and upadacitinib 30 mg QD monotherapy versus weekly methotrexate monotherapy for prevention of structural progression in methotrexate-naïve adults with moderately to severely active RA. The objective of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 7.5 mg QD (for participants in Japan only), 15 mg QD, and 30 mg QD in adults with RA who have completed Period 1.

Protection of trial subjects

Subject read and understood the information provided about the study and gave written permission.

Background therapy

Subjects should continue on their stable doses of NSAIDs, paracetamol, oral corticosteroids (equivalent to prednisone ≤ 10 mg/day), or inhaled corticosteroids with no change in dose or frequency. If not taking any of the above at Baseline, these must not be initiated except where permitted by protocol-defined rescue therapy. Those who do not achieve ≥ 20% improvement in both TJC and SJC compared with Baseline at two consecutive visits from Week 12 to 24 were offered rescue therapy with background RA medications: NSAIDs, corticosteroids and/or low-potency analgesics. Rescue therapy for participants who do not achieve clinical remission (CR) based on Clinical Disease Activity Index (CDAI) (CDAI score ≤ 2.8) at Week 26 includes: ● If ≥ 20% improvement in both TJC and SJC compared with Baseline was achieved the Investigator will optimize (initiate or increase) background RA medications: NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local injections), low-potency analgesics and conventional synthetic disease-modifying anti-rheumatic drug(s) (csDMARDs) (only 1 of the following: sulfasalazine, hydroxychloroquine or chloroquine). ● If ≥ 20% improvement in both TJC and SJC compared with baseline was not achieved subjects originally assigned to methotrexate will be re-randomized in a 1:1 ratio to receive blinded upadacitinib 15 mg or 30 mg QD (participants in Japan will be randomized 1:1:1 to receive upadacitinib 7.5 mg, 15 mg, or 30 mg QD) while continuing methotrexate treatment. Participants originally assigned to upadacitinib will add methotrexate 10 mg/week (7.5 mg for Japan) to upadacitinib. From Week 36 to Week 40 subjects who do not achieve ≥ 20% improvement in both TJC and SJC compared with Baseline at two consecutive visits starting at Week 36 will be rescued with optimizing background RA medications: NSAIDs, corticosteroids, low-potency analgesics and csDMARDs (1 of the following: sulfasalazine, hydroxychloroquine or chloroquine).

Evidence for comparator

Actual start date of recruitment

23 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 45

Country: Number of subjects enrolled

Australia: 19

Country: Number of subjects enrolled

Belarus: 5

Country: Number of subjects enrolled

Belgium: 15

Country: Number of subjects enrolled

Bosnia and Herzegovina: 17

Country: Number of subjects enrolled

Brazil: 43

Country: Number of subjects enrolled

Bulgaria: 36

Country: Number of subjects enrolled

Canada: 13

Country: Number of subjects enrolled

Chile: 38

Country: Number of subjects enrolled

China: 3

Country: Number of subjects enrolled

Colombia: 12

Country: Number of subjects enrolled

Croatia: 2

Country: Number of subjects enrolled

Czechia: 19

Country: Number of subjects enrolled

Estonia: 4

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Guatemala: 56

Country: Number of subjects enrolled

Hong Kong: 2

Country: Number of subjects enrolled

Hungary: 18

Country: Number of subjects enrolled

Ireland: 2

Country: Number of subjects enrolled

Israel: 10

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Japan: 138

Country: Number of subjects enrolled

Kazakhstan: 7

Country: Number of subjects enrolled

Latvia: 3

Country: Number of subjects enrolled

Lithuania: 7

Country: Number of subjects enrolled

Mexico: 78

Country: Number of subjects enrolled

New Zealand: 16

Country: Number of subjects enrolled

Poland: 20

Country: Number of subjects enrolled

Portugal: 11

Country: Number of subjects enrolled

Puerto Rico: 3

Country: Number of subjects enrolled

Romania: 2

Country: Number of subjects enrolled

Russian Federation: 38

Country: Number of subjects enrolled

Slovakia: 19

Country: Number of subjects enrolled

Slovenia: 4

Country: Number of subjects enrolled

South Africa: 16

Country: Number of subjects enrolled

Spain: 38

Country: Number of subjects enrolled

Switzerland: 4

Country: Number of subjects enrolled

Taiwan: 7

Country: Number of subjects enrolled

Tunisia: 9

Country: Number of subjects enrolled

Turkey: 10

Country: Number of subjects enrolled

Ukraine: 49

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

United States: 124

Worldwide total number of subjects

1002

EEA total number of subjects

231

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

798

From 65 to 84 years

203

85 years and over

Subject disposition

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Recruitment details

Participants were randomized at 236 sites in 43 countries. The study included 2 periods and a Japan sub-study. The global study analysis included participants from Japan, but excluded the upadacitinib 7.5 mg group. The Japan sub-study included all participants from Japan, including the upadacitinib 7.5 mg treatment group.

Screening details

Participants were randomized in a 1:1:1 ratio to Groups 1, 3, and 4 below, except for participants in Japan who were randomized in a 1:2:1:1 ratio to Groups 1, 2, 3, and 4. Randomization was stratified by geographic region. Efficacy analyses were conducted separately for the Japan sub-study.

Period 1 title

Period 1 (Week 1 to Week 48)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Sponsor personnel with direct oversight conduct and management of the trial, the Investigator, study site personnel, and the subject were blinded to each subject's treatment throughout Period 1. When the last subject completed the last visit of Period 1 (Week 48), study drug assignment in both periods was unblinded to the Sponsor and sites, and subjects were dispensed study drug in an open-label fashion until the completion of Period 2.

Are arms mutually exclusive

Yes

Methotrexate

Arm description

Group 1 participants received up to 20 mg methotrexate orally per week (15 mg/week in China and Japan) and placebo to upadacitinib once a day (QD) for 48 weeks during Period 1. Participants who did not achieve Clinical Remission (CR) based on clinical disease activity index (CDAI) score (CDAI ≤ 2.8) and did not achieve a ≥ 20% improvement from Baseline in both tender joint count (TJC) and swollen joint count (SJC) at Week 26 were re-randomized in a 1:1 ratio to receive rescue therapy with upadacitinib 15 mg or 30 mg QD (or in a 1:1:1 ratio to receive upadacitinib 7.5 mg, 15 mg, or 30 mg QD for participants in Japan) in addition to methotrexate.

Arm type

Active comparator

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Methotrexate starting at 10 mg/week [7.5 mg/week for patients in China and Japan] and titrated up to a maximum of 20 mg/week [15 mg/week for patients in Japan] through week 8, as tolerated). Methotrexate dose increment was 5 mg/4 weeks with a minimum of 15 mg/week as the final dose, if intolerance of 20 mg/week was documented.

Investigational medicinal product name

Placebo to upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Taken orally once a day

Upadacitinib 7.5 mg

Arm description

Group 2 participants (Japan only) received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants who did not achieve CR based on CDAI and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 received rescue treatment with methotrexate 7.5 mg/week in addition to continuing to receive upadacitinib 7.5 mg QD through Week 48.

Arm type

Experimental

Investigational medicinal product name

Placebo to methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to methotrexate taken orally once a week.

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

ABT-494

Other name

RINVOQ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 7.5 mg taken orally once a day.

Upadacitinib 15 mg

Arm description

Group 3 participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants who did not achieve CR based on CDAI and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 received rescue treatment with methotrexate 10 mg/week (7.5 mg for China and Japan) in addition to continuing to receive upadacitinib 15 mg QD through Week 48.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

ABT-494

Other name

RINVOQ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 15 mg taken orally once a day.

Investigational medicinal product name

Placebo to methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to methotrexate taken orally once a week.

Upadacitinib 30 mg

Arm description

Group 4 participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants who did not achieve CR by CDAI and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 received rescue treatment with methotrexate 10 mg/week (7.5 mg for China and Japan) in addition to continuing to receive upadacitinib 30 mg QD through Week 48.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

ABT-494

Other name

RINVOQ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 30 mg taken orally once a day.

Investigational medicinal product name

Placebo to methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to methotrexate taken orally once a week.

Number of subjects in period 1	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Started	315	55	317	315
Received Study Drug	314	55	317	314
Global Analysis Population	314	0 ^[1]	317	314
Japan Sub-study	28 ^[2]	55	27 ^[3]	28 ^[4]
Completed Week 24 Study Drug	268	51	290	282
Received Rescue Therapy at Week 26	37 ^[5]	3 ^[6]	19 ^[7]	9 ^[8]
Completed	256	51	277	271
Not completed	59	4	40	44
Consent withdrawn by subject	22	-	12	20
Other	5	1	2	3
Adverse event	15	3	18	11
Lost to follow-up	4	-	6	5
Lack of efficacy	12	-	2	4
Not dosed	1	-	-	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants in the upadacitinib 7.5 mg treatment group were not included in the Global Analysis Population.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The methotrexate treatment group included 28 subjects from Japan.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The upadacitinib 15 mg treatment group included 27 subjects from Japan.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The upadacitinib 30 mg treatment group included 28 subjects from Japan.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Rescue therapy at Week 26 was offered to subjects who did not achieve CR based on CDAI and who did not achieve a ≥ 20% improvement in both TJC and SJC compared with Baseline.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Rescue therapy at Week 26 was offered to subjects who did not achieve CR based on CDAI and who did not achieve a ≥ 20% improvement in both TJC and SJC compared with Baseline.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Rescue therapy at Week 26 was offered to subjects who did not achieve CR based on CDAI and who did not achieve a ≥ 20% improvement in both TJC and SJC compared with Baseline.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Rescue therapy was offered to subjects who did not achieve CR based on CDAI and who did not achieve a ≥ 20% improvement in both TJC and SJC compared with Baseline.

Period 2 title

Period 2 (Week 48 to Week 260)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Methotrexate

Arm description

Participants received up to 20 mg methotrexate orally per week (15 mg/week in China and Japan) and placebo to upadacitinib QD for 48 weeks during Period 1. Participants who did not achieve CR based on CDAI score (CDAI ≤ 2.8) and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 were re-randomized in a 1:1 ratio to receive rescue therapy with upadacitinib 15 mg or 30 mg QD (or in a 1:1:1 ratio to receive upadacitinib 7.5 mg, 15 mg, or 30 mg QD for participants in Japan) in addition to methotrexate. In Period 2 (Weeks 48 to 260) participants continued to receive the treatment they were assigned at the end of Period 1.

Arm type

Active comparator

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Placebo to upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Taken orally once a day

Upadacitinib 7.5 mg

Arm description

Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants who did not achieve CR based on CDAI and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 received rescue treatment with methotrexate 7.5 mg/week in addition to continuing to receive upadacitinib 7.5 mg QD. In Period 2 participants continued to receive the treatment they were assigned at the end of Period 1.

Arm type

Experimental

Investigational medicinal product name

Placebo to methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to methotrexate taken orally once a week.

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

ABT-494

Other name

RINVOQ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 7.5 mg taken orally once a day.

Upadacitinib 15 mg

Arm description

Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants who did not achieve CR based on CDAI and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 received rescue treatment with methotrexate 10 mg/week (7.5 mg for China and Japan) in addition to continuing to receive upadacitinib 15 mg QD. In Period 2 participants continued to receive the treatment they were assigned at the end of Period 1.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

ABT-494

Other name

RINVOQ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 15 mg taken orally once a day.

Investigational medicinal product name

Placebo to methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to methotrexate taken orally once a week.

Upadacitinib 30 mg

Arm description

Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants who did not achieve CR by CDAI and did not achieve a ≥ 20% improvement from Baseline in both TJC and SJC at Week 26 received rescue treatment with methotrexate 10 mg/week (7.5 mg for China and Japan) in addition to continuing to receive upadacitinib 30 mg QD. In Period 2 participants continued to receive the treatment they were assigned at the end of Period 1. Starting with Protocol Amendment 6 participants were switched to receive open-label upadacitinib 15 mg QD.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

ABT-494

Other name

RINVOQ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 30 mg taken orally once a day.

Investigational medicinal product name

Placebo to methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to methotrexate taken orally once a week.

Number of subjects in period 2 ^[9]	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Started	253	50	275	268
Received Study Drug	242	48	273	260
Completed	163	40	217	187
Not completed	90	10	58	81
Consent withdrawn by subject	32	5	23	27
Coronavirus Disease of 2019 (COVID-19) Infection	-	-	-	3
Other	14	1	11	17
Adverse event	16	4	11	26
COVID-19 Logistic Restrictions	-	-	2	1
Lost to follow-up	17	-	10	6
Lack of efficacy	11	-	1	1

Notes
[9] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Nine participants who completed Period 1 opted not to enter Period 2.

Baseline characteristics

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Reporting group title

Methotrexate

Reporting group description

Reporting group title

Upadacitinib 7.5 mg

Reporting group description

Reporting group title

Upadacitinib 15 mg

Reporting group description

Reporting group title

Upadacitinib 30 mg

Reporting group description

Reporting group values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg	Total
Number of subjects	315	55	317	315	1002
Age categorical
Units: Subjects
< 40 years	51	5	60	34	150
40 – 65 years	206	25	204	213	648
≥ 65 years	58	25	53	68	204
Age continuous
Units: years
arithmetic mean (standard deviation)	53.3 ( 12.89 )	59.7 ( 13.8 )	51.9 ( 12.58 )	54.9 ( 12.58 )	-
Gender categorical
Units: Subjects
Female	241	36	241	241	759
Male	74	19	76	74	243
Ethnicity
Units: Subjects
Hispanic or Latino	102	0	107	107	316
Not Hispanic or Latino	213	55	210	208	686
Race
Units: Subjects
White	257	0	256	255	768
Black or African American	12	0	8	13	33
American Indian/Alaska Native	2	0	8	7	17
Native Hawaiian or other Pacific Islander	2	0	3	1	6
Asian	37	55	35	34	161
Multiple	5	0	7	5	17
Geographic Region
Units: Subjects
North America	46	0	48	46	140
South/Central America	90	0	91	91	272
Western Europe	37	0	36	37	110
Eastern Europe	86	0	87	87	260
Asia-Japan	28	55	27	28	138
Asia - China	1	0	1	1	3
Asia - Other	3	0	4	2	9
Other	24	0	23	23	70
Duration of Rheumatoid Arthritis Diagnosis
Data are reported for the full analysis set (FAS; N = 314, 55, 317, and 314 participants in each treatment group respectively).
Units: years
arithmetic mean (standard deviation)	2.6 ( 5.14 )	2.3 ( 5.77 )	2.9 ( 5.38 )	2.8 ( 5.63 )	-
Tender Joint Count
A total of 68 joints were assessed for the presence or absence of tenderness. Data are reported for the full analysis set (N = 314, 55, 317, and 314 participants in each treatment group respectively).
Units: joints
arithmetic mean (standard deviation)	26.4 ( 16.15 )	18.0 ( 11.75 )	25.4 ( 14.42 )	25.2 ( 14.99 )	-
Swollen Joint Count
A total of 66 joints were assessed for the presence or absence of swelling. Data are reported for the full analysis set (N = 314, 55, 317, and 314 participants in each treatment group respectively).
Units: joints
arithmetic mean (standard deviation)	16.9 ( 10.58 )	14.7 ( 8.24 )	16.9 ( 10.35 )	15.7 ( 9.71 )	-
Patient's Assessment of Pain
Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale (VAS) from 0 to 100 mm. A score of 0 mm indicates "no pain" and a score of 100 mm indicates "worst possible pain." Data are reported for the full analysis set with available data (N = 314, 55, 317, and 311 participants in each treatment group respectively).
Units: mm
arithmetic mean (standard deviation)	65.7 ( 21.46 )	64.1 ( 21.20 )	68.4 ( 20.60 )	65.3 ( 25.51 )	-
Patient's Global Assessment of Disease Activity
The participant was asked to rate their current RA disease activity over the past 24 hours on a 100 mm VAS, where 0 mm indicates very low disease activity and 100 mm indicates very high disease activity. Data are reported for the full analysis set with available data (N = 314, 55, 317, and 311 participants in each treatment group respectively).
Units: mm
arithmetic mean (standard deviation)	65.8 ( 21.45 )	64.1 ( 21.36 )	66.6 ( 22.01 )	64.9 ( 21.63 )	-
Physician's Global Assessment of Disease Activity
The physician rated the participant's current global RA disease activity (independently from the participant's assessment) on a VAS scale from 0 to 100 mm, where 0 mm indicates very low disease activity and 100 mm indicates very high disease activity. Data are reported for the full analysis set with available data; N = 299, 54, 301, and 304 participants in each treatment group respectively).
Units: mm
arithmetic mean (standard deviation)	68.7 ( 16.45 )	63.3 ( 19.34 )	67.1 ( 17.00 )	65.3 ( 16.60 )	-
Health Assessment Questionnaire - Disability Index (HAQ-DI)
The HAQ-DI is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 (no disability) to 3 (very severe disability). Data are reported for the FAS with available data (N = 314, 55, 317, and 311 participants in each groop respectively).
Units: units on a scale
arithmetic mean (standard deviation)	1.6 ( 0.67 )	1.3 ( 0.62 )	1.6 ( 0.67 )	1.5 ( 0.66 )	-
High-sensitivity C-reactive Protein (hsCRP)
Data are reported for the full analysis set (N = 314, 55, 317, and 314 participants in each groop respectively).
Units: g/L
arithmetic mean (standard deviation)	21.2 ( 22.05 )	18.5 ( 17.55 )	23.0 ( 27.37 )	19.4 ( 22.59 )	-
Disease Activity Score 28 Based on CRP (DAS28[CRP])
The DAS28(CRP) is a composite index used to assess RA disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. Data are reported for the FAS with available data (N = 314, 55, 317, and 311 participants in each groop respectively).
Units: units on a scale
arithmetic mean (standard deviation)	5.9 ( 0.97 )	5.5 ( 0.90 )	5.9 ( 0.97 )	5.8 ( 1.02 )	-
Modified Total Sharp Score (mTSS)
The mTSS measures the level of joint damage from radiographs of the hands and feet, calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score and ranges from 0 (normal) to 448 (worst). Data are reported for the FAS with available data (N = 309, 55, 309, and 309 participants in each groop respectively).
Units: units on a scale
arithmetic mean (standard deviation)	13.3 ( 30.55 )	15.9 ( 39.10 )	18.1 ( 38.15 )	17.2 ( 38.25 )	-

End points

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Reporting group title

Methotrexate

Reporting group description

Reporting group title

Upadacitinib 7.5 mg

Reporting group description

Reporting group title

Upadacitinib 15 mg

Reporting group description

Reporting group title

Upadacitinib 30 mg

Reporting group description

Reporting group title

Methotrexate

Reporting group description

Reporting group title

Upadacitinib 7.5 mg

Reporting group description

Reporting group title

Upadacitinib 15 mg

Reporting group description

Reporting group title

Upadacitinib 30 mg

Reporting group description

Primary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis

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End point title

Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis ^[1]

End point description

The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission, based on a Disease Activity Score 28 (DAS28)-CRP score of < 2.6 at Week 24. The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28 score less than 2.6 indicates clinical remission. Participants who prematurely discontinued from study drug prior to Week 24 or for whom DAS28 data were missing at Week 24 were considered non-responders.

End point type

Primary

End point timeframe

Week 24

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[2]	317 ^[3]	314 ^[4]
Units: percentage of participants
number (confidence interval 95%)	18.5 (14.2 to 22.8)	48.3 (42.8 to 53.8)	50.0 (44.5 to 55.5)

Notes
[2] - Full analysis set
[3] - Full analysis set
[4] - Full analysis set

Analysis of DAS28(CRP) Clinical Remisison

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.001 ^[6]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

29.8

Confidence interval

level

95%

sides

2-sided

lower limit

22.8

upper limit

36.8

Notes
[5] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for United States (US)/Food and Drug Administration (FDA), EU/EMA and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[6] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of DAS28(CRP) Clinical Remisison

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.001 ^[8]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

31.5

Confidence interval

level

95%

sides

2-sided

lower limit

24.5

upper limit

38.5

Notes
[7] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for United States (US)/Food and Drug Administration (FDA), EU/EMA and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[8] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Primary: Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis

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End point title

Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis ^[9]

End point description

The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 50% response (ACR50) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity (PhGA); • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

End point type

Primary

End point timeframe

Baseline and Week 12

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[10]	317 ^[11]	314 ^[12]
Units: percentage of participants
number (confidence interval 95%)	28.3 (23.4 to 33.3)	52.1 (46.6 to 57.5)	56.4 (50.9 to 61.9)

Notes
[10] - Full analysis set
[11] - Full analysis set
[12] - Full analysis set

Analysis of ACR50 Response at Week 12

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.001 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

23.7

Confidence interval

level

95%

sides

2-sided

lower limit

16.3

upper limit

31.1

Notes
[13] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, EU/EMA and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[14] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of ACR50 Response at Week 12

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.001 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

20.6

upper limit

35.4

Notes
[15] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, EU/EMA and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[16] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Primary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis

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End point title

Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis ^[17]

End point description

The primary endpoint for Japan/Pharmaceuticals and Medical Devices Agency (PMDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

End point type

Primary

End point timeframe

Baseline and Week 12

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[18]	317 ^[19]	314 ^[20]
Units: percentage of participants
number (confidence interval 95%)	54.1 (48.6 to 59.7)	75.7 (71.0 to 80.4)	77.1 (72.4 to 81.7)

Notes
[18] - Full analysis set
[19] - Full analysis set
[20] - Full analysis set

Analysis of ACR20 Response At Week 12

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.001 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

21.6

Confidence interval

level

95%

sides

2-sided

lower limit

14.3

upper limit

28.8

Notes
[21] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, EU/EMA and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[22] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of ACR20 Response at Week 12

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

< 0.001 ^[24]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

22.9

Confidence interval

level

95%

sides

2-sided

lower limit

15.7

upper limit

30.1

Notes
[23] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, EU/EMA and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[24] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Primary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis

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End point title

Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis ^[25]

End point description

The second primary endpoint for Japan/PMDA was change from baseline in mTSS at Week 24. The mTSS measures the level of joint damage from radiographs of the hands and feet and was assessed by two independent, blinded readers. Joint erosion was assessed in 16 joints in each hand/wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst). JSN was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst). The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst). A change from Baseline greater than 0 indicates progression. Linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing.

End point type

Primary

End point timeframe

Baseline to Week 24

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	264 ^[26]	279 ^[27]	270 ^[28]
Units: units on a scale
least squares mean (confidence interval 95%)	0.67 (0.43 to 0.90)	0.14 (-0.09 to 0.37)	0.07 (-0.16 to 0.31)

Notes
[26] - Full analysis set participants with available data at Baseline
[27] - Full analysis set participants with available data at Baseline
[28] - Full analysis set participants with available data at Baseline

Analysis of Change in mTSS at Week 24

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

543

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.001 ^[30]

Method

ANCOVA

Parameter type

Least Squares (LS) Mean Difference

Point estimate

-0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.85

upper limit

-0.2

Notes
[29] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[30] - Analysis of covariance (ANCOVA) model with treatment, geographic region as fixed factors and baseline value as the covariate.

Analysis of Change in mTSS at Week 24

Statistical analysis description

For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

534

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

< 0.001 ^[32]

Method

ANCOVA

Parameter type

Least Squares (LS) Mean Difference

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-0.91

upper limit

-0.27

Notes
[31] - The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
[32] - Analysis of covariance (ANCOVA) model with treatment, geographic region as fixed factors and baseline value as the covariate.

Secondary: Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis

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End point title

Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis ^[33]

End point description

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity. Multiple imputation was used for missing post-baseline data.

End point type

Secondary

End point timeframe

Baseline to Week 24

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	312 ^[34]	317 ^[35]	310 ^[36]
Units: score on a scale
least squares mean (confidence interval 95%)	-2.15 (-2.31 to -1.99)	-3.07 (-3.21 to -2.92)	-3.34 (-3.49 to -3.19)

Notes
[34] - Full analysis set participants with available data at Baseline
[35] - Full analysis set participants with available data at Baseline
[36] - Full analysis set participants with available data at Baseline

Analysis of Change in DAS28(CRP) at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

629

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

< 0.001 ^[38]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.92

Confidence interval

level

95%

sides

2-sided

lower limit

-1.12

upper limit

-0.71

Notes
[37] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[38] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Analysis of Change in DAS28(CRP) at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

622

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

< 0.001 ^[40]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

-0.99

Notes
[39] - TThe overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[40] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis

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End point title

Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis ^[41]

End point description

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from Baseline in the overall score indicates improvement. Multiple imputation was used for missing data.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	313 ^[42]	317 ^[43]	310 ^[44]
Units: score on a scale
least squares mean (confidence interval 95%)	-0.60 (-0.67 to -0.52)	-0.87 (-0.94 to -0.80)	-0.91 (-0.98 to -0.84)

Notes
[42] - Full analysis set participants with available data at Baseline
[43] - Full analysis set participants with available data at Baseline
[44] - Full analysis set participants with available data at Baseline

Analysis of Change in HAQ-DI at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

630

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

< 0.001 ^[46]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

-0.17

Notes
[45] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[46] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Analysis of Change in HAQ-DI at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

623

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

< 0.001 ^[48]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

-0.21

Notes
[47] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[48] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Secondary: Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis

Top of page

End point title

Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis ^[49]

End point description

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[50]	317 ^[51]	314 ^[52]
Units: percentage of participants
number (confidence interval 95%)	33.4 (28.2 to 38.7)	60.3 (54.9 to 65.6)	65.6 (60.4 to 70.9)

Notes
[50] - Full analysis set
[51] - Full analysis set
[52] - Full analysis set

Analysis of ACR50 Response at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

< 0.001 ^[54]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

26.8

Confidence interval

level

95%

sides

2-sided

lower limit

19.3

upper limit

34.3

Notes
[53] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[54] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of ACR50 Response at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

< 0.001 ^[56]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

32.2

Confidence interval

level

95%

sides

2-sided

lower limit

24.8

upper limit

39.6

Notes
[55] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[56] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis

Top of page

End point title

Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis ^[57]

End point description

The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity. Participants who prematurely discontinued from study drug prior to Week 24 or for whom DAS28 data were missing at Week 24 were considered non-responders.

End point type

Secondary

End point timeframe

Week 24

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[58]	317 ^[59]	314 ^[60]
Units: percentage of participants
number (confidence interval 95%)	32.2 (27.0 to 37.3)	59.9 (54.5 to 65.3)	65.0 (59.7 to 70.2)

Notes
[58] - Full analysis set
[59] - Full analysis set
[60] - Full analysis set

Analysis of LDA at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[61]

P-value

< 0.001 ^[62]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

27.8

Confidence interval

level

95%

sides

2-sided

lower limit

20.3

upper limit

35.2

Notes
[61] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[62] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of LDA at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[63]

P-value

< 0.001 ^[64]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

32.8

Confidence interval

level

95%

sides

2-sided

lower limit

25.4

upper limit

40.2

Notes
[63] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[64] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis

Top of page

End point title

Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis ^[65]

End point description

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement. Multiple imputation was used for missing data.

End point type

Secondary

End point timeframe

Baseline to Week 24

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	313 ^[66]	315 ^[67]	312 ^[68]
Units: score on a scale
least squares mean (confidence interval 95%)	6.97 (6.03 to 7.91)	10.70 (9.76 to 11.63)	11.39 (10.42 to 12.36)

Notes
[66] - Full analysis set participants with available data at Baseline
[67] - Full analysis set participants with available data at Baseline
[68] - Full analysis set participants with available data at Baseline

Analysis of Change in SF-36 PCS at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[69]

P-value

< 0.001 ^[70]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

3.72

Confidence interval

level

95%

sides

2-sided

lower limit

2.42

upper limit

5.03

Notes
[69] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[70] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Analysis of Change in SF-36 PCS at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

625

Analysis specification

Pre-specified

Analysis type

superiority ^[71]

P-value

< 0.001 ^[72]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

4.42

Confidence interval

level

95%

sides

2-sided

lower limit

3.12

upper limit

5.72

Notes
[71] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[72] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Secondary: Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis

Top of page

End point title

Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis ^[73]

End point description

No radiographic progression is defined as a change from Baseline in mTSS ≤ 0. The mTSS measures the level of joint damage from radiographs of the hands and feet. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. Joint erosion severity was assessed in 16 joints in each hand and wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst). Joint space narrowing (JSN) was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst). The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst). Linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing.

End point type

Secondary

End point timeframe

Week 24

Notes
[73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	264 ^[74]	279 ^[75]	270 ^[76]
Units: percentage of participants
number (confidence interval 95%)	77.7 (72.6 to 82.7)	87.5 (83.6 to 91.3)	89.3 (85.6 to 93.0)

Notes
[74] - Full analysis set participants with available data at Baseline
[75] - Full analysis set participants with available data at Baseline
[76] - Full analysis set participants with available data at Baseline

Analysis of No Radiographic Progression at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

543

Analysis specification

Pre-specified

Analysis type

superiority ^[77]

P-value

= 0.002 ^[78]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

9.8

Confidence interval

level

95%

sides

2-sided

lower limit

3.5

upper limit

16.2

Notes
[77] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[78] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of No Radiographic Progression at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

534

Analysis specification

Pre-specified

Analysis type

superiority ^[79]

P-value

< 0.001 ^[80]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

11.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.4

upper limit

17.8

Notes
[79] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes. The nominal p-value is reported.
[80] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis

Top of page

End point title

Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis ^[81]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

Notes
[81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	312 ^[82]	317 ^[83]	310 ^[84]
Units: score on a scale
least squares mean (confidence interval 95%)	-1.85 (-2.00 to -1.69)	-2.73 (-2.87 to -2.58)	-2.85 (-3.00 to -2.70)

Notes
[82] - Full analysis set participants with available data at Baseline
[83] - Full analysis set participants with available data at Baseline
[84] - Full analysis set participants with available data at Baseline

Analysis of Change in DAS28 (CRP) at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

629

Analysis specification

Pre-specified

Analysis type

superiority ^[85]

P-value

< 0.001 ^[86]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.88

Confidence interval

level

95%

sides

2-sided

lower limit

-1.09

upper limit

-0.67

Notes
[85] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[86] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Analysis of Change in DAS28 (CRP) at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

622

Analysis specification

Pre-specified

Analysis type

superiority ^[87]

P-value

< 0.001 ^[88]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.01

Confidence interval

level

95%

sides

2-sided

lower limit

-1.21

upper limit

-0.8

Notes
[87] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[88] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis

Top of page

End point title

Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis ^[89]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

Notes
[89] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	313 ^[90]	317 ^[91]	310 ^[92]
Units: score on a scale
least squares mean (confidence interval 95%)	-0.49 (-0.55 to -0.42)	-0.83 (-0.90 to -0.76)	-0.86 (-0.93 to -0.79)

Notes
[90] - Full analysis set participants with available data at Baseline
[91] - Full analysis set participants with available data at Baseline
[92] - Full analysis set participants with available data at Baseline

Analysis of Change in HAQ-DI at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

630

Analysis specification

Pre-specified

Analysis type

superiority ^[93]

P-value

< 0.001 ^[94]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

-0.25

Notes
[93] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[94] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Analysis of Change in HAQ-DI at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

623

Analysis specification

Pre-specified

Analysis type

superiority ^[95]

P-value

< 0.001 ^[96]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

-0.28

Notes
[95] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[96] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis

Top of page

End point title

Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis ^[97]

End point description

The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity. Participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

Notes
[97] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[98]	317 ^[99]	314 ^[100]
Units: percentage of participants
number (confidence interval 95%)	28.3 (23.4 to 33.3)	53.3 (47.8 to 58.8)	54.8 (49.3 to 60.3)

Notes
[98] - Full analysis set
[99] - Full analysis set
[100] - Full analysis set

Analysis of LDA at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[101]

P-value

< 0.001 ^[102]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

17.6

upper limit

32.4

Notes
[101] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[102] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of LDA at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[103]

P-value

< 0.001 ^[104]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

26.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

33.9

Notes
[103] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[104] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis

Top of page

End point title

Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis ^[105]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

Notes
[105] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	311 ^[106]	315 ^[107]	311 ^[108]
Units: score on a scale
least squares mean (confidence interval 95%)	5.74 (4.84 to 6.64)	9.99 (9.11 to 10.88)	10.08 (9.19 to 10.98)

Notes
[106] - Full analysis set participants with available data at Baseline
[107] - Full analysis set participants with available data at Baseline
[108] - Full analysis set participants with available data at Baseline

Analysis of Change in SF-36 PCS at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

626

Analysis specification

Pre-specified

Analysis type

superiority ^[109]

P-value

< 0.001 ^[110]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

4.25

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

5.5

Notes
[109] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[110] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Analysis of Change in SF-36 PCS at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

622

Analysis specification

Pre-specified

Analysis type

superiority ^[111]

P-value

< 0.001 ^[112]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

4.34

Confidence interval

level

95%

sides

2-sided

lower limit

3.09

upper limit

5.59

Notes
[111] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes. The nominal p-value is reported.
[112] - ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.

Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 24 - Global Analysis

Top of page

End point title

Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 24 - Global Analysis ^[113]

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[113] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[114]	317 ^[115]	314 ^[116]
Units: percentage of participants
number (confidence interval 95%)	58.6 (53.2 to 64.0)	78.9 (74.4 to 83.4)	78.0 (73.4 to 82.6)

Notes
[114] - Full analysis set
[115] - Full analysis set
[116] - Full analysis set

Analysis of ACR20 Response at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[117]

P-value

< 0.001 ^[118]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

20.3

Confidence interval

level

95%

sides

2-sided

lower limit

13.2

upper limit

27.3

Notes
[117] - The nominal p-value is reported.
[118] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of ACR20 Response at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[119]

P-value

< 0.001 ^[120]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

19.4

Confidence interval

level

95%

sides

2-sided

lower limit

12.3

upper limit

26.5

Notes
[119] - The nominal p-value is reported.
[120] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis

Top of page

End point title

Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis ^[121]

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[121] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[122]	317 ^[123]	314 ^[124]
Units: percentage of participants
number (confidence interval 95%)	18.5 (14.2 to 22.8)	44.5 (39.0 to 49.9)	49.7 (44.2 to 55.2)

Notes
[122] - Full analysis set
[123] - Full analysis set
[124] - Full analysis set

Analysis of ACR70 Response at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[125]

P-value

< 0.001 ^[126]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

19.1

upper limit

Notes
[125] - The nominal p-value is reported.
[126] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of ACR70 Response at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[127]

P-value

< 0.001 ^[128]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

31.2

Confidence interval

level

95%

sides

2-sided

lower limit

24.2

upper limit

38.2

Notes
[127] - The nominal p-value is reported.
[128] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis

Top of page

End point title

Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis ^[129]

End point description

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 12

Notes
[129] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

End point values	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	314 ^[130]	317 ^[131]	314 ^[132]
Units: percentage of participants
number (confidence interval 95%)	14.0 (10.2 to 17.9)	32.5 (27.3 to 37.6)	36.9 (31.6 to 42.3)

Notes
[130] - Full analysis set
[131] - Full analysis set
[132] - Full analysis set

Analysis of ACR70 Response at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

631

Analysis specification

Pre-specified

Analysis type

superiority ^[133]

P-value

< 0.001 ^[134]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

18.5

Confidence interval

level

95%

sides

2-sided

lower limit

12.1

upper limit

24.9

Notes
[133] - The nominal p-value is reported.
[134] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Analysis of ACR70 Response at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

628

Analysis specification

Pre-specified

Analysis type

superiority ^[135]

P-value

< 0.001 ^[136]

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

22.9

Confidence interval

level

95%

sides

2-sided

lower limit

16.4

upper limit

29.5

Notes
[135] - The nominal p-value is reported.
[136] - Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).

Secondary: Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study

Top of page

End point title

Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[137]	55	27 ^[138]	28 ^[139]
Units: percentage of participants
number (confidence interval 95%)	57.1 (38.8 to 75.5)	85.5 (76.1 to 94.8)	85.2 (71.8 to 98.6)	78.6 (63.4 to 93.8)

Notes
[137] - Japan sub-study full analysis set
[138] - Japan sub-study full analysis set
[139] - Japan sub-study full analysis set

Analysis of ACR20 Response at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[140]

P-value

= 0.004

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

28.3

Confidence interval

level

95%

sides

2-sided

lower limit

7.7

upper limit

48.9

Notes
[140] - For the Japan sub-study, no multiplicity adjustments were applied and only nominal p-values were provided for all efficacy analyses.

Analysis of ACR20 Response at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[141]

P-value

= 0.022

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

5.3

upper limit

50.7

Notes
[141] - For the Japan sub-study, no multiplicity adjustments were applied and only nominal p-values were provided for all efficacy analyses.

Analysis of ACR20 Response at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[142]

P-value

= 0.086

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

21.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

45.2

Notes
[142] - For the Japan sub-study, no multiplicity adjustments were applied and only nominal p-values were provided for all efficacy analyses.

Secondary: Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study

Top of page

End point title

Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: • Physician global assessment of disease activity; • Patient global assessment of disease activity; • Patient assessment of pain; • Health Assessment Questionnaire - Disability Index (HAQ-DI); • High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[143]	55 ^[144]	27 ^[145]	28 ^[146]
Units: percentage of participants
number (confidence interval 95%)	21.4 (6.2 to 36.6)	60.0 (47.1 to 72.9)	66.7 (48.9 to 84.4)	71.4 (54.7 to 88.2)

Notes
[143] - Japan sub-study full analysis set
[144] - Japan sub-study full analysis set
[145] - Japan sub-study full analysis set
[146] - Japan sub-study full analysis set

Analysis of ACR50 Response at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

38.6

Confidence interval

level

95%

sides

2-sided

lower limit

18.6

upper limit

58.5

Analysis of ACR50 Response at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

45.2

Confidence interval

level

95%

sides

2-sided

lower limit

21.8

upper limit

68.6

Analysis of ACR50 Response at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

27.4

upper limit

72.6

Secondary: Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study

Top of page

End point title

Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study

End point description

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[147]	55 ^[148]	27 ^[149]	28 ^[150]
Units: percentage of participants
number (confidence interval 95%)	0.0 (0.0 to 0.0)	34.5 (22.0 to 47.1)	51.9 (33.0 to 70.7)	64.3 (46.5 to 82.0)

Notes
[147] - Japan sub-study full analysis set
[148] - Japan sub-study full analysis set
[149] - Japan sub-study full analysis set
[150] - Japan sub-study full analysis set

Analysis of ACR70 Response at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

34.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

47.1

Analysis of ACR70 Response at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

51.9

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

70.7

Analysis of ACR70 Response at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

64.3

Confidence interval

level

95%

sides

2-sided

lower limit

46.5

upper limit

Secondary: Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study

Top of page

End point title

Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[151]	55 ^[152]	27 ^[153]	28 ^[154]
Units: score on a scale
least squares mean (confidence interval 95%)	-1.42 (-1.82 to -1.03)	-2.86 (-3.14 to -2.58)	-3.28 (-3.68 to -2.89)	-3.34 (-3.74 to -2.95)

Notes
[151] - Japan sub-study full analysis set participants with available data at Baseline
[152] - Japan sub-study full analysis set participants with available data at Baseline
[153] - Japan sub-study full analysis set participants with available data at Baseline
[154] - Japan sub-study full analysis set participants with available data at Baseline

Analysis of Change in DAS28 (CRP) at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[155]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-1.43

Confidence interval

level

95%

sides

2-sided

lower limit

-1.92

upper limit

-0.95

Notes
[155] - ANOVA model with Baseline value as covariate.

Analysis of Change in DAS28 (CRP) at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[156]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-1.86

Confidence interval

level

95%

sides

2-sided

lower limit

-2.42

upper limit

-1.3

Notes
[156] - ANOVA model with Baseline value as covariate.

Analysis of Change in DAS28 (CRP) at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[157]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-1.92

Confidence interval

level

95%

sides

2-sided

lower limit

-2.48

upper limit

-1.36

Notes
[157] - ANOVA model with Baseline value as covariate.

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study

Top of page

End point title

Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[158]	55 ^[159]	27 ^[160]	28 ^[161]
Units: score on a scale
least squares mean (confidence interval 95%)	-0.20 (-0.37 to -0.04)	-0.75 (-0.86 to -0.63)	-0.95 (-1.12 to -0.78)	-0.95 (-1.12 to -0.79)

Notes
[158] - Japan sub-study full analysis set participants with available data at baseline
[159] - Japan sub-study full analysis set participants with available data at baseline
[160] - Japan sub-study full analysis set participants with available data at baseline
[161] - Japan sub-study full analysis set participants with available data at baseline

Analysis of Change in HAQ-DI at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[162]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-0.75

upper limit

-0.34

Notes
[162] - ANOVA model with Baseline value as covariate.

Analysis of Change in HAQ-DI at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[163]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

-0.51

Notes
[163] - ANOVA model with Baseline value as covariate.

Analysis of Change in HAQ-DI at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[164]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

-0.51

Notes
[164] - ANOVA model with Baseline value as covariate.

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study

Top of page

End point title

Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study

End point description

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[165]	55 ^[166]	27 ^[167]	28 ^[168]
Units: score on a scale
least squares mean (confidence interval 95%)	2.87 (0.56 to 5.18)	8.84 (7.18 to 10.50)	10.79 (8.48 to 13.09)	9.63 (7.13 to 12.13)

Notes
[165] - Japan sub-study full analysis set participants with available data at baseline
[166] - Japan sub-study full analysis set participants with available data at baseline
[167] - Japan sub-study full analysis set participants with available data at baseline
[168] - Japan sub-study full analysis set participants with available data at baseline

Analysis of Change in SF-36 PCS at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[169]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

5.97

Confidence interval

level

95%

sides

2-sided

lower limit

3.15

upper limit

8.8

Notes
[169] - ANOVA model with Baseline value as covariate.

Analysis of Change in SF-36 PCS at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[170]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

7.92

Confidence interval

level

95%

sides

2-sided

lower limit

4.66

upper limit

11.19

Notes
[170] - ANOVA model with Baseline value as covariate.

Analysis of Change in SF-36 PCS at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[171]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

6.76

Confidence interval

level

95%

sides

2-sided

lower limit

3.33

upper limit

10.2

Notes
[171] - ANOVA model with Baseline value as covariate.

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study

Top of page

End point title

Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study

End point description

The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity. Participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[172]	55 ^[173]	27 ^[174]	28 ^[175]
Units: percentage of participants
number (confidence interval 95%)	17.9 (3.7 to 32.0)	69.1 (56.9 to 81.3)	77.8 (62.1 to 93.5)	78.6 (63.4 to 93.8)

Notes
[172] - Japan sub-study full analysis set
[173] - Japan sub-study full analysis set
[174] - Japan sub-study full analysis set
[175] - Japan sub-study full analysis set

Analysis of LDA at Week 12

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

51.2

Confidence interval

level

95%

sides

2-sided

lower limit

32.5

upper limit

Analysis of LDA at Week 12

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

59.9

Confidence interval

level

95%

sides

2-sided

lower limit

38.8

upper limit

81.1

Analysis of LDA at Week 12

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

60.7

Confidence interval

level

95%

sides

2-sided

lower limit

39.9

upper limit

81.5

Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study

Top of page

End point title

Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study

End point description

The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. Participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

End point type

Secondary

End point timeframe

Week 24

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	28 ^[176]	55 ^[177]	27 ^[178]	28 ^[179]
Units: percentage of participants
number (confidence interval 95%)	17.9 (3.7 to 32.0)	67.3 (54.9 to 79.7)	70.4 (53.1 to 87.6)	82.1 (68.0 to 96.3)

Notes
[176] - Japan sub-study full analysis set
[177] - Japan sub-study full analysis set
[178] - Japan sub-study full analysis set
[179] - Japan sub-study full analysis set

Analysis of CR at Week 24

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

49.4

Confidence interval

level

95%

sides

2-sided

lower limit

30.6

upper limit

68.3

Analysis of CR at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

52.5

Confidence interval

level

95%

sides

2-sided

lower limit

30.2

upper limit

74.8

Analysis of CR at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

64.3

Confidence interval

level

95%

sides

2-sided

lower limit

44.2

upper limit

84.3

Secondary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study

Top of page

End point title

Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study

End point description

The mTSS measures the level of joint damage from radiographs of the hands and feet. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. Joint erosion was assessed in 16 joints in each hand/wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst). JSN was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst). The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst). A change from Baseline greater than 0 indicates progression. Linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

End point type

Secondary

End point timeframe

Baseline to Week 24

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	26 ^[180]	51 ^[181]	26 ^[182]	24 ^[183]
Units: score on a scale
least squares mean (confidence interval 95%)	2.64 (1.19 to 4.09)	0.95 (-0.09 to 1.98)	0.24 (-1.21 to 1.69)	0.19 (-1.31 to 1.70)

Notes
[180] - Japan sub-study full analysis set participants with available data at Baseline
[181] - Japan sub-study full analysis set participants with available data at Baseline
[182] - Japan sub-study full analysis set participants with available data at Baseline
[183] - Japan sub-study full analysis set participants with available data at Baseline

Analysis of Change in mTSS at Week 24

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.063 ^[184]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-3.47

upper limit

0.09

Notes
[184] - ANOVA model with Baseline value as covariate.

Analysis of Change in mTSS at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022 ^[185]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.45

upper limit

-0.35

Notes
[185] - ANOVA model with Baseline value as covariate.

Analysis of Change in mTSS at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022 ^[186]

Method

ANOVA

Parameter type

LS Mean Difference

Point estimate

-2.45

Confidence interval

level

95%

sides

2-sided

lower limit

-4.54

upper limit

-0.35

Notes
[186] - ANOVA model with Baseline value as covariate.

Secondary: Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study

Top of page

End point title

Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study

End point description

End point type

Secondary

End point timeframe

Week 24

End point values	Methotrexate	Upadacitinib 7.5 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Number of subjects analysed	26 ^[187]	51 ^[188]	26 ^[189]	24 ^[190]
Units: percentage of participants
number (confidence interval 95%)	46.2 (27.0 to 65.3)	82.4 (71.9 to 92.8)	80.8 (65.6 to 95.9)	79.2 (62.9 to 95.4)

Notes
[187] - Japan sub-study full analysis set participants with available data at Baseline
[188] - Japan sub-study full analysis set participants with available data at Baseline
[189] - Japan sub-study full analysis set participants with available data at Baseline
[190] - Japan sub-study full analysis set participants with available data at Baseline

Analysis of No Radiographic Progression at Week 24

Comparison groups

Upadacitinib 7.5 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

36.2

Confidence interval

level

95%

sides

2-sided

lower limit

14.4

upper limit

Analysis of No Radiographic Progression at Week 24

Comparison groups

Upadacitinib 15 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

34.6

Confidence interval

level

95%

sides

2-sided

lower limit

10.2

upper limit

Analysis of No Radiographic Progression at Week 24

Comparison groups

Upadacitinib 30 mg v Methotrexate

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

Chi-squared

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

7.9

upper limit

58.1

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug to 30 days after last dose, up to 264 weeks; AEs are reported for Weeks 1 to 24, Weeks 1 to 260, and After Switch for participants switched from upadacitinib 30 mg QD to 15 mg QD after implementation of Protocol Amendment 6.

Adverse event reporting additional description

In Weeks 1 to 24 all participants received monotherapy. For Weeks 1 to 260 and After Switch, AEs are reported for the following: Monotherapy: includes events through the end of study or until rescue treatment was initiated. All upadacitinib: includes any exposure to upadacitinib, alone or in addition to methotrexate or csDMARD after rescue.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Weeks 1-24: Methotrexate Monotherapy

Reporting group description

Participants received up to 20 mg methotrexate orally per week (15 mg/week in China and Japan) and placebo to upadacitinib QD for 24 weeks during Period 1.

Reporting group title

Weeks 1-24: Upadacitinib 7.5 mg Monotherapy

Reporting group description

Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 24 weeks in Period 1.

Reporting group title

Weeks 1-24: Upadacitinib 15 mg Monotherapy

Reporting group description

Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 24 weeks in Period 1.

Reporting group title

Weeks 1-24: Upadacitinib 30 mg Monotherapy

Reporting group description

Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 24 weeks in Period 1.

Reporting group title

Weeks 1-260: Methotrexate Monotherapy

Reporting group description

Participants received up to 20 mg methotrexate orally per week (15 mg/week in China and Japan) for 260 weeks. Includes events up until the addition of upadacitinib for participants who were rescued at Week 26.

Reporting group title

Weeks 1-260: Upadacitinib 7.5 mg Monotherapy

Reporting group description

Participants received 7.5 mg upadacitinib monotherapy once a day for 260 weeks. Includes events up until the addition of methotrexate or addition of background csDMARD for participants who received rescue.

Reporting group title

Weeks 1-260: Upadacitinib 15 mg Monotherapy

Reporting group description

Participants received 15 mg upadacitinib monotherapy once a day for 260 weeks. Includes events up until the addition of methotrexate or addition of background csDMARD for participants who received rescue.

Reporting group title

Weeks 1-260/Switch: Upadacitinib 30 mg Monotherapy

Reporting group description

Participants received 30 mg upadacitinib monotherapy once a day for 260 weeks or until implementation of Protocol Amendment 6 (December 2019) when they were switched to upadacitinib 15 mg. Includes events up until the addition of methotrexate or addition of background csDMARD for participants who received rescue, or up until the switch to upadacitinib 15 mg.

Reporting group title

Weeks 1-260: Any Upadacitinib 7.5 mg

Reporting group description

Participants originally randomized to upadacitinib 7.5 mg received upadacitinib 7.5 mg QD for up to 260 weeks, including events after the addition of rescue therapy. Participants originally randomized to methotrexate and rescued at Week 26 to methotrexate plus upadacitinib 7.5 mg received upadacitinib 7.5 mg QD from Week 26 to Week 260.

Reporting group title

Weeks 1-260: Any Upadacitinib 15 mg

Reporting group description

Participants originally randomized to upadacitinib 15 mg received upadacitinib 15 mg QD for up to 260 weeks, including events after the addition of rescue therapy. Participants originally randomized to methotrexate and rescued at Week 26 to methotrexate plus upadacitinib 15 mg received upadacitinib 15 mg QD from Week 26 to Week 260.

Reporting group title

Weeks 1-260/Switch: Any Upadacitinib 30 mg

Reporting group description

Participants originally randomized to upadacitinib 30 mg received upadacitinib 30 mg QD for up to 260 weeks or until implementation of Protocol Amendment 6 (December 2019)when they were switched to upadacitinib 15 mg, including events after the addition of rescue therapy. Participants originally randomized to methotrexate and rescued at Week 26 to methotrexate plus upadacitinib 30 mg received upadacitinib 30 mg QD from Week 26 to Week 260 or until implementation of Protocol Amendment 6 when they were switched to methotrexate plus upadacitinib 15 mg. Includes events up until the switch to upadacitinib 15 mg.

Reporting group title

After Switch: Upadacitinib 15 mg Monotherapy

Reporting group description

Participants who were receiving upadacitinib 30 mg QD monotherapy in Period 2 were switched to upadacitinib 15 mg QD monotherapy after implementation of Protocol Amendment 6 (December 2019) up to Week 260.

Reporting group title

After Switch: Any Upadacitinib 15 mg

Reporting group description

Participants who were receiving any upadacitinib 30 mg QD (monotherapy or in combination with methotrexate or csDMARD after rescue) in Period 2 were switched to upadacitinib 15 mg QD (monotherapy or in combination with methotrexate or csDMARD if rescued) after implementation of Protocol Amendment 6 (December 2019) up to Week 260.

Weeks 1-24: Methotrexate Monotherapy

Weeks 1-24: Upadacitinib 7.5 mg Monotherapy

Weeks 1-24: Upadacitinib 15 mg Monotherapy

Weeks 1-24: Upadacitinib 30 mg Monotherapy

Weeks 1-260: Methotrexate Monotherapy

Weeks 1-260: Upadacitinib 7.5 mg Monotherapy

Weeks 1-260: Upadacitinib 15 mg Monotherapy

Weeks 1-260/Switch: Upadacitinib 30 mg Monotherapy

Weeks 1-260: Any Upadacitinib 7.5 mg

Weeks 1-260: Any Upadacitinib 15 mg

Weeks 1-260/Switch: Any Upadacitinib 30 mg

After Switch: Upadacitinib 15 mg Monotherapy

After Switch: Any Upadacitinib 15 mg

Total subjects affected by serious adverse events

subjects affected / exposed

13 / 314 (4.14%)

5 / 55 (9.09%)

16 / 317 (5.05%)

20 / 314 (6.37%)

49 / 314 (15.61%)

13 / 55 (23.64%)

68 / 317 (21.45%)

71 / 314 (22.61%)

15 / 56 (26.79%)

88 / 335 (26.27%)

79 / 332 (23.80%)

28 / 181 (15.47%)

35 / 218 (16.06%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

ADENOCARCINOMA GASTRIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

ADENOCARCINOMA OF COLON

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ADENOCARCINOMA METASTATIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

ANGIOFIBROMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

B-CELL LYMPHOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BASAL CELL CARCINOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BENIGN OVARIAN TUMOUR

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BLADDER CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

BLADDER NEOPLASM

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BOWEN'S DISEASE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BREAST CANCER METASTATIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CERVIX CARCINOMA STAGE 0

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BREAST CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ENDOMETRIAL ADENOCARCINOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

FIBROMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTRIC CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LUNG ADENOCARCINOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

LIPOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

LEIOMYOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LUNG SQUAMOUS CELL CARCINOMA METASTATIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MALIGNANT PALATE NEOPLASM

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MALIGNANT MELANOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

METASTATIC NEOPLASM

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

NEUROENDOCRINE TUMOUR

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

METASTASES TO BONE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

NON-SMALL CELL LUNG CANCER METASTATIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

OVARIAN GERM CELL TERATOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

OVARIAN CANCER

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PAPILLARY THYROID CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PROSTATE CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RENAL CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RENAL CELL CARCINOMA STAGE I

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SEBACEOUS CARCINOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SQUAMOUS CELL CARCINOMA OF LUNG

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SQUAMOUS CELL CARCINOMA OF SKIN

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SQUAMOUS CELL CARCINOMA OF THE TONGUE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

UTERINE CANCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

UTERINE CARCINOMA IN SITU

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

DEEP VEIN THROMBOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

2 / 314 (0.64%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

EMBOLISM ARTERIAL

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HYPERTENSION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PERIPHERAL ARTERIAL OCCLUSIVE DISEASE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PERIPHERAL ARTERY STENOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PERIPHERAL ISCHAEMIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SHOCK HAEMORRHAGIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pregnancy, puerperium and perinatal conditions

ABORTION SPONTANEOUS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

CHEST DISCOMFORT

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

CHEST PAIN

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

2 / 335 (0.60%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

DEATH

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

MULTIPLE ORGAN DYSFUNCTION SYNDROME

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUDDEN DEATH

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Reproductive system and breast disorders

BENIGN PROSTATIC HYPERPLASIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BREAST HYPOPLASIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CERVIX HAEMORRHAGE UTERINE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CERVICAL DYSPLASIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

2 / 317 (0.63%)

0 / 314 (0.00%)

0 / 56 (0.00%)

2 / 335 (0.60%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

ENDOMETRIAL HYPERPLASIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MENOMETRORRHAGIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

OVARIAN CYST

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PROSTATITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

OVARIAN CYST RUPTURED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

ACUTE RESPIRATORY FAILURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

0 / 335 (0.00%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

ASTHMATIC CRISIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ASTHMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 2

0 / 0

1 / 1

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

2 / 314 (0.64%)

0 / 56 (0.00%)

1 / 335 (0.30%)

2 / 332 (0.60%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

PLEURAL EFFUSION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

PLEURISY

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMOTHORAX

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

PNEUMOTHORAX SPONTANEOUS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PULMONARY EMBOLISM

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

3 / 314 (0.96%)

0 / 55 (0.00%)

2 / 317 (0.63%)

3 / 314 (0.96%)

0 / 56 (0.00%)

2 / 335 (0.60%)

3 / 332 (0.90%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

1 / 3

0 / 0

2 / 2

1 / 3

0 / 0

2 / 2

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

PULMONARY FIBROSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RESPIRATORY FAILURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

DEPRESSION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

MENTAL DISORDER DUE TO A GENERAL MEDICAL CONDITION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

BLOOD CREATINE PHOSPHOKINASE INCREASED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HEPATIC ENZYME INCREASED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

TRANSAMINASES INCREASED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

WHITE BLOOD CELL COUNT INCREASED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

ANKLE FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CONTUSION

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CORNEAL LACERATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CONCUSSION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

FEMORAL NECK FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

FEMUR FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

1 / 55 (1.82%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 56 (1.79%)

2 / 335 (0.60%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

FOOT FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HIP FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

HUMERUS FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

JOINT DISLOCATION

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

2 / 314 (0.64%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

LIMB CRUSHING INJURY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LOWER LIMB FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MENISCUS INJURY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

PATELLA FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

POST LUMBAR PUNCTURE SYNDROME

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

POST PROCEDURAL FISTULA

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RADIUS FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

0 / 335 (0.00%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

ROAD TRAFFIC ACCIDENT

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUBDURAL HAEMATOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

TENDON RUPTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

THORACIC VERTEBRAL FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

UPPER LIMB FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

WRIST FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Congenital, familial and genetic disorders

HAEMORRHAGIC ARTERIOVENOUS MALFORMATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

ACUTE CORONARY SYNDROME

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ANGINA PECTORIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

0 / 335 (0.00%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

ACUTE MYOCARDIAL INFARCTION

subjects affected / exposed

2 / 314 (0.64%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

2 / 314 (0.64%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

0 / 335 (0.00%)

2 / 332 (0.60%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 2

0 / 0

0 / 1

0 / 2

0 / 0

0 / 2

0 / 0

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

ARTERIOSPASM CORONARY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ATRIAL FIBRILLATION

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

2 / 314 (0.64%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

CARDIAC ARREST

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

CARDIAC FAILURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

CARDIAC FAILURE CONGESTIVE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

2 / 317 (0.63%)

0 / 314 (0.00%)

0 / 56 (0.00%)

2 / 335 (0.60%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

CARDIAC TAMPONADE

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CARDIO-RESPIRATORY ARREST

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

CARDIOVASCULAR DISORDER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

METABOLIC CARDIOMYOPATHY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

MYOCARDIAL INFARCTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

2 / 314 (0.64%)

0 / 55 (0.00%)

2 / 317 (0.63%)

1 / 314 (0.32%)

0 / 56 (0.00%)

2 / 335 (0.60%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

1 / 2

0 / 1

0 / 0

1 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

MYOCARDIAL FIBROSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

MYOCARDIAL ISCHAEMIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

0 / 335 (0.00%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

0 / 3

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

SINUS NODE DYSFUNCTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PERICARDITIS

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUPRAVENTRICULAR TACHYCARDIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

TACHYCARDIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

CAROTID ARTERIOSCLEROSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HYPOXIC-ISCHAEMIC ENCEPHALOPATHY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

MONOPARESIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CAROTID ARTERY DISEASE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SCIATICA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SPONDYLITIC MYELOPATHY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MYELOPATHY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

VERTEBROBASILAR INSUFFICIENCY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

TRANSIENT ISCHAEMIC ATTACK

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 314 (0.32%)

1 / 55 (1.82%)

3 / 317 (0.95%)

1 / 314 (0.32%)

1 / 56 (1.79%)

3 / 335 (0.90%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

1 / 3

0 / 1

1 / 3

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SYNCOPE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

ANAEMIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

IRON DEFICIENCY ANAEMIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

CATARACT

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

CATARACT DIABETIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

IRIDOCYCLITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MACULAR HOLE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

VITREOUS HAEMORRHAGE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

VITREORETINAL TRACTION SYNDROME

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

ABDOMINAL PAIN

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ABDOMINAL WALL HAEMATOMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ANAL FISTULA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ASCITES

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COLITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CONSTIPATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DUODENAL ULCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DIVERTICULAR PERFORATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

FOOD POISONING

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTRIC ULCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTRIC ULCER HAEMORRHAGE

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTRIC ULCER PERFORATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTRITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTROINTESTINAL HAEMORRHAGE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GINGIVAL RECESSION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INCARCERATED INGUINAL HERNIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HIATUS HERNIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LARGE INTESTINE PERFORATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INGUINAL HERNIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

LARGE INTESTINE POLYP

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

0 / 335 (0.00%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

PANCREATIC DISORDER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PANCREATITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

RECTAL HAEMORRHAGE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

SALIVARY GLAND CALCULUS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RECTAL POLYP

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

BILE DUCT STONE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CHOLECYSTITIS ACUTE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CHOLANGITIS

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CHOLELITHIASIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

4 / 314 (1.27%)

0 / 56 (0.00%)

0 / 335 (0.00%)

4 / 332 (1.20%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

GALLBLADDER RUPTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

ANGIOEDEMA

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DIABETIC FOOT

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DRUG ERUPTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SKIN ULCER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

NEPHROLITHIASIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ACUTE KIDNEY INJURY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

2 / 317 (0.63%)

0 / 314 (0.00%)

0 / 56 (0.00%)

2 / 335 (0.60%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

RENAL COLIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RENAL CYST

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RENAL FAILURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

URETEROLITHIASIS

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

ACQUIRED CLAW TOE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BURSITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

INTERVERTEBRAL DISC PROTRUSION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

LUMBAR SPINAL STENOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

2 / 335 (0.60%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

NECK PAIN

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

OSTEOARTHRITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 314 (0.00%)

0 / 55 (0.00%)

3 / 317 (0.95%)

3 / 314 (0.96%)

0 / 56 (0.00%)

4 / 335 (1.19%)

3 / 332 (0.90%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 4

0 / 3

0 / 0

0 / 5

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

OSTEONECROSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 56 (1.79%)

1 / 335 (0.30%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

1 / 1

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

PAIN IN EXTREMITY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PATHOLOGICAL FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ROTATOR CUFF SYNDROME

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SPONDYLOLISTHESIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUBCHONDRAL INSUFFICIENCY FRACTURE

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SYMPATHETIC POSTERIOR CERVICAL SYNDROME

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SYSTEMIC LUPUS ERYTHEMATOSUS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

ACTINOMYCOTIC PULMONARY INFECTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

APPENDICITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BACTERIAL PYELONEPHRITIS

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BRONCHITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BRONCHOPULMONARY ASPERGILLOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19 PNEUMONIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

2 / 317 (0.63%)

2 / 314 (0.64%)

0 / 56 (0.00%)

3 / 335 (0.90%)

2 / 332 (0.60%)

8 / 181 (4.42%)

12 / 218 (5.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

1 / 2

0 / 0

0 / 3

1 / 2

2 / 8

2 / 12

deaths causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

1 / 4

COVID-19

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

1 / 314 (0.32%)

1 / 56 (1.79%)

2 / 335 (0.60%)

1 / 332 (0.30%)

2 / 181 (1.10%)

3 / 218 (1.38%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

1 / 1

0 / 3

0 / 1

1 / 2

2 / 3

deaths causally related to treatment / all

0 / 0

CORONAVIRUS PNEUMONIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CELLULITIS

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

2 / 314 (0.64%)

0 / 55 (0.00%)

2 / 317 (0.63%)

2 / 314 (0.64%)

0 / 56 (0.00%)

2 / 335 (0.60%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

0 / 1

2 / 2

0 / 0

0 / 2

1 / 2

0 / 0

0 / 2

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

DIVERTICULITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

2 / 314 (0.64%)

0 / 56 (0.00%)

1 / 335 (0.30%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

1 / 2

0 / 0

1 / 1

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

EMPYEMA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ENDOCARDITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ERYSIPELAS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ESCHERICHIA INFECTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

FEMALE GENITAL TRACT TUBERCULOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GALLBLADDER ABSCESS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GASTROENTERITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HERPES ZOSTER DISSEMINATED

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

GENITAL HERPES SIMPLEX

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HERPES ZOSTER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

3 / 314 (0.96%)

0 / 56 (0.00%)

1 / 335 (0.30%)

3 / 332 (0.90%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

3 / 3

0 / 0

1 / 1

3 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

HERPES ZOSTER MENINGITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INFECTIVE SPONDYLITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INFLUENZA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

2 / 314 (0.64%)

0 / 56 (0.00%)

1 / 335 (0.30%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

KERATITIS BACTERIAL

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LUNG ABSCESS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

NECROTISING FASCIITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MENINGITIS BACTERIAL

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

OPHTHALMIC HERPES ZOSTER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

1 / 314 (0.32%)

0 / 56 (0.00%)

1 / 335 (0.30%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

0 / 1

1 / 1

deaths causally related to treatment / all

0 / 0

PERITONEAL TUBERCULOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

OSTEOMYELITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PARAINFLUENZAE VIRUS INFECTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PERITONITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

PNEUMONIA

subjects affected / exposed

2 / 314 (0.64%)

0 / 55 (0.00%)

2 / 317 (0.63%)

2 / 314 (0.64%)

3 / 314 (0.96%)

1 / 55 (1.82%)

8 / 317 (2.52%)

5 / 314 (1.59%)

1 / 56 (1.79%)

9 / 335 (2.69%)

5 / 332 (1.51%)

1 / 181 (0.55%)

2 / 218 (0.92%)

occurrences causally related to treatment / all

1 / 2

0 / 0

2 / 2

1 / 2

2 / 3

2 / 2

7 / 8

3 / 5

2 / 2

8 / 9

3 / 5

1 / 1

1 / 2

deaths causally related to treatment / all

0 / 0

PNEUMONIA BACTERIAL

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMONIA CRYPTOCOCCAL

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMONIA ESCHERICHIA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMONIA KLEBSIELLA

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PROSTATITIS ESCHERICHIA COLI

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

PNEUMONIA PNEUMOCOCCAL

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 56 (1.79%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PYELONEPHRITIS ACUTE

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

2 / 55 (3.64%)

0 / 317 (0.00%)

0 / 314 (0.00%)

2 / 56 (3.57%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

PYELONEPHRITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

2 / 314 (0.64%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PYELONEPHRITIS CHRONIC

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RESPIRATORY TRACT INFECTION VIRAL

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SEPSIS

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 55 (1.82%)

2 / 317 (0.63%)

0 / 314 (0.00%)

1 / 56 (1.79%)

2 / 335 (0.60%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

1 / 2

0 / 0

1 / 1

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Q FEVER

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

STAPHYLOCOCCAL INFECTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SEPTIC SHOCK

subjects affected / exposed

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

1 / 55 (1.82%)

0 / 317 (0.00%)

1 / 314 (0.32%)

1 / 56 (1.79%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

0 / 1

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

SINOBRONCHITIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

TOOTH ABSCESS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUBCUTANEOUS ABSCESS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

UPPER RESPIRATORY TRACT INFECTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

URINARY TRACT INFECTION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

1 / 314 (0.32%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

1 / 181 (0.55%)

1 / 218 (0.46%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

1 / 1

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

ABNORMAL WEIGHT GAIN

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

2 / 317 (0.63%)

2 / 314 (0.64%)

0 / 56 (0.00%)

2 / 335 (0.60%)

2 / 332 (0.60%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

CENTRAL OBESITY

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

1 / 332 (0.30%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DEHYDRATION

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DIABETIC KETOACIDOSIS

subjects affected / exposed

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 55 (0.00%)

1 / 317 (0.32%)

0 / 314 (0.00%)

0 / 56 (0.00%)

1 / 335 (0.30%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 2

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

HYPOKALAEMIA

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

OBESITY

subjects affected / exposed

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

1 / 314 (0.32%)

0 / 55 (0.00%)

0 / 317 (0.00%)

0 / 314 (0.00%)

0 / 56 (0.00%)

0 / 335 (0.00%)

0 / 332 (0.00%)

0 / 181 (0.00%)

0 / 218 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Weeks 1-24: Methotrexate Monotherapy	Weeks 1-24: Upadacitinib 7.5 mg Monotherapy	Weeks 1-24: Upadacitinib 15 mg Monotherapy	Weeks 1-24: Upadacitinib 30 mg Monotherapy	Weeks 1-260: Methotrexate Monotherapy	Weeks 1-260: Upadacitinib 7.5 mg Monotherapy	Weeks 1-260: Upadacitinib 15 mg Monotherapy	Weeks 1-260/Switch: Upadacitinib 30 mg Monotherapy	Weeks 1-260: Any Upadacitinib 7.5 mg	Weeks 1-260: Any Upadacitinib 15 mg	Weeks 1-260/Switch: Any Upadacitinib 30 mg	After Switch: Upadacitinib 15 mg Monotherapy	After Switch: Any Upadacitinib 15 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	159 / 314 (50.64%)	38 / 55 (69.09%)	169 / 317 (53.31%)	174 / 314 (55.41%)	234 / 314 (74.52%)	52 / 55 (94.55%)	242 / 317 (76.34%)	256 / 314 (81.53%)	55 / 56 (98.21%)	272 / 335 (81.19%)	277 / 332 (83.43%)	100 / 181 (55.25%)	126 / 218 (57.80%)
Vascular disorders
HYPERTENSION
subjects affected / exposed	8 / 314 (2.55%)	3 / 55 (5.45%)	12 / 317 (3.79%)	14 / 314 (4.46%)	31 / 314 (9.87%)	8 / 55 (14.55%)	36 / 317 (11.36%)	44 / 314 (14.01%)	9 / 56 (16.07%)	43 / 335 (12.84%)	47 / 332 (14.16%)	8 / 181 (4.42%)	10 / 218 (4.59%)
occurrences all number	9	3	12	14	34	9	40	46	10	48	51	8	10
General disorders and administration site conditions
FATIGUE
subjects affected / exposed	1 / 314 (0.32%)	0 / 55 (0.00%)	7 / 317 (2.21%)	2 / 314 (0.64%)	3 / 314 (0.96%)	1 / 55 (1.82%)	16 / 317 (5.05%)	3 / 314 (0.96%)	1 / 56 (1.79%)	16 / 335 (4.78%)	3 / 332 (0.90%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	1	0	8	2	3	1	20	3	1	21	3	1	1
INFLUENZA LIKE ILLNESS
subjects affected / exposed	8 / 314 (2.55%)	0 / 55 (0.00%)	7 / 317 (2.21%)	2 / 314 (0.64%)	15 / 314 (4.78%)	1 / 55 (1.82%)	17 / 317 (5.36%)	14 / 314 (4.46%)	1 / 56 (1.79%)	21 / 335 (6.27%)	18 / 332 (5.42%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	8	0	8	3	20	1	19	15	1	24	21	1	1
PYREXIA
subjects affected / exposed	1 / 314 (0.32%)	0 / 55 (0.00%)	1 / 317 (0.32%)	5 / 314 (1.59%)	6 / 314 (1.91%)	5 / 55 (9.09%)	9 / 317 (2.84%)	9 / 314 (2.87%)	7 / 56 (12.50%)	11 / 335 (3.28%)	9 / 332 (2.71%)	2 / 181 (1.10%)	3 / 218 (1.38%)
occurrences all number	1	0	1	5	6	5	10	9	8	12	9	2	3
Respiratory, thoracic and mediastinal disorders
ASTHMA
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	4 / 314 (1.27%)	3 / 55 (5.45%)	1 / 317 (0.32%)	1 / 314 (0.32%)	3 / 56 (5.36%)	3 / 335 (0.90%)	1 / 332 (0.30%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	0	0	0	4	4	1	1	4	3	1	0	0
COUGH
subjects affected / exposed	5 / 314 (1.59%)	0 / 55 (0.00%)	10 / 317 (3.15%)	10 / 314 (3.18%)	15 / 314 (4.78%)	2 / 55 (3.64%)	24 / 317 (7.57%)	19 / 314 (6.05%)	2 / 56 (3.57%)	29 / 335 (8.66%)	22 / 332 (6.63%)	3 / 181 (1.66%)	3 / 218 (1.38%)
occurrences all number	5	0	12	11	15	2	28	23	2	35	26	3	3
RHINITIS ALLERGIC
subjects affected / exposed	1 / 314 (0.32%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	3 / 314 (0.96%)	3 / 55 (5.45%)	2 / 317 (0.63%)	3 / 314 (0.96%)	3 / 56 (5.36%)	4 / 335 (1.19%)	3 / 332 (0.90%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	1	0	0	0	4	3	2	3	3	4	3	1	1
Psychiatric disorders
INSOMNIA
subjects affected / exposed	4 / 314 (1.27%)	0 / 55 (0.00%)	3 / 317 (0.95%)	3 / 314 (0.96%)	9 / 314 (2.87%)	1 / 55 (1.82%)	16 / 317 (5.05%)	5 / 314 (1.59%)	2 / 56 (3.57%)	17 / 335 (5.07%)	5 / 332 (1.51%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	4	0	3	4	9	1	18	6	2	19	7	1	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	12 / 314 (3.82%)	2 / 55 (3.64%)	16 / 317 (5.05%)	8 / 314 (2.55%)	28 / 314 (8.92%)	3 / 55 (5.45%)	27 / 317 (8.52%)	28 / 314 (8.92%)	4 / 56 (7.14%)	32 / 335 (9.55%)	32 / 332 (9.64%)	3 / 181 (1.66%)	4 / 218 (1.83%)
occurrences all number	12	2	21	9	34	3	49	48	4	58	52	4	5
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	8 / 314 (2.55%)	0 / 55 (0.00%)	10 / 317 (3.15%)	7 / 314 (2.23%)	23 / 314 (7.32%)	1 / 55 (1.82%)	21 / 317 (6.62%)	24 / 314 (7.64%)	2 / 56 (3.57%)	24 / 335 (7.16%)	27 / 332 (8.13%)	2 / 181 (1.10%)	3 / 218 (1.38%)
occurrences all number	8	0	14	8	27	1	31	33	2	35	36	2	3
BLOOD CREATINE PHOSPHOKINASE INCREASED
subjects affected / exposed	2 / 314 (0.64%)	2 / 55 (3.64%)	9 / 317 (2.84%)	34 / 314 (10.83%)	10 / 314 (3.18%)	3 / 55 (5.45%)	37 / 317 (11.67%)	51 / 314 (16.24%)	5 / 56 (8.93%)	46 / 335 (13.73%)	54 / 332 (16.27%)	10 / 181 (5.52%)	12 / 218 (5.50%)
occurrences all number	3	2	10	39	12	4	68	106	6	79	110	14	17
BLOOD CREATININE INCREASED
subjects affected / exposed	2 / 314 (0.64%)	1 / 55 (1.82%)	1 / 317 (0.32%)	2 / 314 (0.64%)	6 / 314 (1.91%)	3 / 55 (5.45%)	6 / 317 (1.89%)	8 / 314 (2.55%)	3 / 56 (5.36%)	9 / 335 (2.69%)	9 / 332 (2.71%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	2	1	1	4	8	3	10	13	3	14	15	0	0
LIVER FUNCTION TEST INCREASED
subjects affected / exposed	2 / 314 (0.64%)	1 / 55 (1.82%)	0 / 317 (0.00%)	0 / 314 (0.00%)	3 / 314 (0.96%)	3 / 55 (5.45%)	0 / 317 (0.00%)	1 / 314 (0.32%)	3 / 56 (5.36%)	0 / 335 (0.00%)	1 / 332 (0.30%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	2	1	0	0	3	5	0	2	5	0	2	0	0
LYMPHOCYTE COUNT DECREASED
subjects affected / exposed	2 / 314 (0.64%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	2 / 314 (0.64%)	3 / 55 (5.45%)	2 / 317 (0.63%)	3 / 314 (0.96%)	3 / 56 (5.36%)	2 / 335 (0.60%)	3 / 332 (0.90%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	2	0	0	0	2	5	2	3	5	2	3	1	1
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	3 / 317 (0.95%)	2 / 314 (0.64%)	0 / 314 (0.00%)	3 / 55 (5.45%)	5 / 317 (1.58%)	3 / 314 (0.96%)	3 / 56 (5.36%)	5 / 335 (1.49%)	4 / 332 (1.20%)	2 / 181 (1.10%)	3 / 218 (1.38%)
occurrences all number	0	1	3	2	0	3	8	4	3	8	5	2	3
WEIGHT INCREASED
subjects affected / exposed	2 / 314 (0.64%)	0 / 55 (0.00%)	8 / 317 (2.52%)	2 / 314 (0.64%)	6 / 314 (1.91%)	3 / 55 (5.45%)	15 / 317 (4.73%)	7 / 314 (2.23%)	3 / 56 (5.36%)	17 / 335 (5.07%)	7 / 332 (2.11%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	2	0	8	2	7	3	17	8	3	19	8	1	1
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	0 / 317 (0.00%)	1 / 314 (0.32%)	0 / 314 (0.00%)	3 / 55 (5.45%)	2 / 317 (0.63%)	5 / 314 (1.59%)	3 / 56 (5.36%)	2 / 335 (0.60%)	7 / 332 (2.11%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	0	1	0	1	0	5	2	7	5	2	9	1	1
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	2 / 314 (0.64%)	1 / 55 (1.82%)	2 / 317 (0.63%)	2 / 314 (0.64%)	8 / 314 (2.55%)	8 / 55 (14.55%)	10 / 317 (3.15%)	5 / 314 (1.59%)	10 / 56 (17.86%)	11 / 335 (3.28%)	5 / 332 (1.51%)	3 / 181 (1.66%)	5 / 218 (2.29%)
occurrences all number	2	1	2	2	8	10	10	6	12	11	6	4	6
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	1 / 314 (0.32%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	1 / 314 (0.32%)	2 / 55 (3.64%)	3 / 317 (0.95%)	0 / 314 (0.00%)	3 / 56 (5.36%)	3 / 335 (0.90%)	0 / 332 (0.00%)	0 / 181 (0.00%)	1 / 218 (0.46%)
occurrences all number	1	0	0	0	1	2	3	0	4	3	0	0	1
Nervous system disorders
DIZZINESS
subjects affected / exposed	4 / 314 (1.27%)	0 / 55 (0.00%)	5 / 317 (1.58%)	2 / 314 (0.64%)	8 / 314 (2.55%)	4 / 55 (7.27%)	8 / 317 (2.52%)	8 / 314 (2.55%)	4 / 56 (7.14%)	9 / 335 (2.69%)	8 / 332 (2.41%)	1 / 181 (0.55%)	2 / 218 (0.92%)
occurrences all number	4	0	5	2	9	4	11	8	4	13	8	1	2
HEADACHE
subjects affected / exposed	6 / 314 (1.91%)	2 / 55 (3.64%)	7 / 317 (2.21%)	14 / 314 (4.46%)	17 / 314 (5.41%)	4 / 55 (7.27%)	12 / 317 (3.79%)	21 / 314 (6.69%)	4 / 56 (7.14%)	18 / 335 (5.37%)	28 / 332 (8.43%)	2 / 181 (1.10%)	4 / 218 (1.83%)
occurrences all number	6	2	7	16	19	4	13	26	4	20	33	2	4
POST HERPETIC NEURALGIA
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	0 / 314 (0.00%)	4 / 55 (7.27%)	2 / 317 (0.63%)	2 / 314 (0.64%)	5 / 56 (8.93%)	4 / 335 (1.19%)	2 / 332 (0.60%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	0	0	0	0	4	2	2	5	4	2	0	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	5 / 314 (1.59%)	3 / 55 (5.45%)	6 / 317 (1.89%)	9 / 314 (2.87%)	17 / 314 (5.41%)	4 / 55 (7.27%)	20 / 317 (6.31%)	16 / 314 (5.10%)	5 / 56 (8.93%)	22 / 335 (6.57%)	18 / 332 (5.42%)	4 / 181 (2.21%)	7 / 218 (3.21%)
occurrences all number	5	3	8	10	19	4	31	21	5	34	24	4	8
LEUKOPENIA
subjects affected / exposed	4 / 314 (1.27%)	1 / 55 (1.82%)	6 / 317 (1.89%)	4 / 314 (1.27%)	13 / 314 (4.14%)	2 / 55 (3.64%)	9 / 317 (2.84%)	15 / 314 (4.78%)	2 / 56 (3.57%)	11 / 335 (3.28%)	18 / 332 (5.42%)	10 / 181 (5.52%)	10 / 218 (4.59%)
occurrences all number	5	1	6	4	23	2	19	25	2	24	39	14	14
NEUTROPENIA
subjects affected / exposed	2 / 314 (0.64%)	1 / 55 (1.82%)	7 / 317 (2.21%)	9 / 314 (2.87%)	11 / 314 (3.50%)	1 / 55 (1.82%)	13 / 317 (4.10%)	25 / 314 (7.96%)	1 / 56 (1.79%)	15 / 335 (4.48%)	27 / 332 (8.13%)	8 / 181 (4.42%)	9 / 218 (4.13%)
occurrences all number	3	1	7	11	15	1	26	37	1	32	56	9	11
Eye disorders
CATARACT
subjects affected / exposed	2 / 314 (0.64%)	0 / 55 (0.00%)	1 / 317 (0.32%)	0 / 314 (0.00%)	4 / 314 (1.27%)	3 / 55 (5.45%)	3 / 317 (0.95%)	2 / 314 (0.64%)	3 / 56 (5.36%)	5 / 335 (1.49%)	3 / 332 (0.90%)	2 / 181 (1.10%)	2 / 218 (0.92%)
occurrences all number	2	0	1	0	4	4	3	3	4	5	4	3	3
DRY EYE
subjects affected / exposed	3 / 314 (0.96%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	4 / 314 (1.27%)	3 / 55 (5.45%)	1 / 317 (0.32%)	3 / 314 (0.96%)	3 / 56 (5.36%)	3 / 335 (0.90%)	3 / 332 (0.90%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	3	0	0	0	4	3	1	3	3	3	3	1	1
Gastrointestinal disorders
CHRONIC GASTRITIS
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	0 / 317 (0.00%)	1 / 314 (0.32%)	1 / 314 (0.32%)	4 / 55 (7.27%)	2 / 317 (0.63%)	3 / 314 (0.96%)	5 / 56 (8.93%)	2 / 335 (0.60%)	3 / 332 (0.90%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	0	1	0	1	1	4	2	3	5	2	3	1	1
CONSTIPATION
subjects affected / exposed	2 / 314 (0.64%)	3 / 55 (5.45%)	0 / 317 (0.00%)	13 / 314 (4.14%)	6 / 314 (1.91%)	4 / 55 (7.27%)	12 / 317 (3.79%)	18 / 314 (5.73%)	6 / 56 (10.71%)	13 / 335 (3.88%)	20 / 332 (6.02%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	2	3	0	13	6	4	13	21	6	14	23	1	1
DENTAL CARIES
subjects affected / exposed	1 / 314 (0.32%)	2 / 55 (3.64%)	1 / 317 (0.32%)	1 / 314 (0.32%)	4 / 314 (1.27%)	4 / 55 (7.27%)	5 / 317 (1.58%)	3 / 314 (0.96%)	4 / 56 (7.14%)	5 / 335 (1.49%)	4 / 332 (1.20%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	1	2	1	1	4	5	5	3	5	5	4	1	1
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	2 / 314 (0.64%)	0 / 55 (0.00%)	4 / 317 (1.26%)	3 / 314 (0.96%)	9 / 314 (2.87%)	4 / 55 (7.27%)	7 / 317 (2.21%)	9 / 314 (2.87%)	5 / 56 (8.93%)	8 / 335 (2.39%)	10 / 332 (3.01%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	2	0	4	3	9	5	7	9	6	8	10	0	0
DYSPEPSIA
subjects affected / exposed	12 / 314 (3.82%)	0 / 55 (0.00%)	8 / 317 (2.52%)	4 / 314 (1.27%)	20 / 314 (6.37%)	1 / 55 (1.82%)	12 / 317 (3.79%)	6 / 314 (1.91%)	1 / 56 (1.79%)	13 / 335 (3.88%)	6 / 332 (1.81%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	13	0	8	4	29	1	12	6	1	14	6	1	1
DIARRHOEA
subjects affected / exposed	10 / 314 (3.18%)	0 / 55 (0.00%)	11 / 317 (3.47%)	6 / 314 (1.91%)	16 / 314 (5.10%)	3 / 55 (5.45%)	25 / 317 (7.89%)	19 / 314 (6.05%)	3 / 56 (5.36%)	27 / 335 (8.06%)	21 / 332 (6.33%)	3 / 181 (1.66%)	3 / 218 (1.38%)
occurrences all number	10	0	12	6	16	3	33	26	3	36	28	3	3
HAEMORRHOIDS
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	0 / 317 (0.00%)	1 / 314 (0.32%)	1 / 314 (0.32%)	3 / 55 (5.45%)	4 / 317 (1.26%)	4 / 314 (1.27%)	3 / 56 (5.36%)	4 / 335 (1.19%)	4 / 332 (1.20%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	1	0	1	1	3	4	4	3	4	4	0	0
STOMATITIS
subjects affected / exposed	2 / 314 (0.64%)	4 / 55 (7.27%)	1 / 317 (0.32%)	3 / 314 (0.96%)	4 / 314 (1.27%)	8 / 55 (14.55%)	4 / 317 (1.26%)	3 / 314 (0.96%)	8 / 56 (14.29%)	4 / 335 (1.19%)	3 / 332 (0.90%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	2	5	2	3	5	10	6	3	10	6	4	0	0
NAUSEA
subjects affected / exposed	17 / 314 (5.41%)	1 / 55 (1.82%)	18 / 317 (5.68%)	12 / 314 (3.82%)	29 / 314 (9.24%)	4 / 55 (7.27%)	25 / 317 (7.89%)	17 / 314 (5.41%)	4 / 56 (7.14%)	25 / 335 (7.46%)	19 / 332 (5.72%)	1 / 181 (0.55%)	3 / 218 (1.38%)
occurrences all number	29	2	20	13	47	5	28	19	5	30	22	1	7
Hepatobiliary disorders
HEPATIC STEATOSIS
subjects affected / exposed	1 / 314 (0.32%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	5 / 314 (1.59%)	3 / 55 (5.45%)	6 / 317 (1.89%)	6 / 314 (1.91%)	3 / 56 (5.36%)	8 / 335 (2.39%)	7 / 332 (2.11%)	5 / 181 (2.76%)	5 / 218 (2.29%)
occurrences all number	1	0	0	0	5	3	6	6	3	8	7	6	6
Skin and subcutaneous tissue disorders
DRY SKIN
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	1 / 317 (0.32%)	1 / 314 (0.32%)	0 / 314 (0.00%)	3 / 55 (5.45%)	1 / 317 (0.32%)	1 / 314 (0.32%)	3 / 56 (5.36%)	1 / 335 (0.30%)	1 / 332 (0.30%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	1	1	1	0	3	1	1	3	1	1	0	0
ECZEMA
subjects affected / exposed	1 / 314 (0.32%)	2 / 55 (3.64%)	1 / 317 (0.32%)	2 / 314 (0.64%)	3 / 314 (0.96%)	5 / 55 (9.09%)	6 / 317 (1.89%)	6 / 314 (1.91%)	5 / 56 (8.93%)	8 / 335 (2.39%)	6 / 332 (1.81%)	3 / 181 (1.66%)	3 / 218 (1.38%)
occurrences all number	1	2	1	2	4	5	7	7	5	9	7	3	3
DERMATITIS
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	1 / 317 (0.32%)	0 / 314 (0.00%)	2 / 314 (0.64%)	3 / 55 (5.45%)	4 / 317 (1.26%)	1 / 314 (0.32%)	3 / 56 (5.36%)	4 / 335 (1.19%)	2 / 332 (0.60%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	0	1	0	2	3	4	1	3	4	2	0	0
RASH
subjects affected / exposed	5 / 314 (1.59%)	1 / 55 (1.82%)	5 / 317 (1.58%)	4 / 314 (1.27%)	9 / 314 (2.87%)	5 / 55 (9.09%)	8 / 317 (2.52%)	11 / 314 (3.50%)	5 / 56 (8.93%)	9 / 335 (2.69%)	13 / 332 (3.92%)	2 / 181 (1.10%)	2 / 218 (0.92%)
occurrences all number	5	1	6	4	12	5	9	13	5	10	17	2	2
PRURITUS
subjects affected / exposed	3 / 314 (0.96%)	0 / 55 (0.00%)	3 / 317 (0.95%)	2 / 314 (0.64%)	5 / 314 (1.59%)	3 / 55 (5.45%)	6 / 317 (1.89%)	5 / 314 (1.59%)	3 / 56 (5.36%)	6 / 335 (1.79%)	5 / 332 (1.51%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	3	0	3	3	6	4	7	6	4	7	6	1	1
Renal and urinary disorders
POLLAKIURIA
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	0 / 314 (0.00%)	2 / 55 (3.64%)	1 / 317 (0.32%)	0 / 314 (0.00%)	3 / 56 (5.36%)	1 / 335 (0.30%)	0 / 332 (0.00%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0	3	1	0	0	0
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	3 / 314 (0.96%)	1 / 55 (1.82%)	4 / 317 (1.26%)	4 / 314 (1.27%)	10 / 314 (3.18%)	6 / 55 (10.91%)	20 / 317 (6.31%)	20 / 314 (6.37%)	6 / 56 (10.71%)	25 / 335 (7.46%)	23 / 332 (6.93%)	6 / 181 (3.31%)	7 / 218 (3.21%)
occurrences all number	3	1	4	4	12	7	20	27	7	27	30	6	7
ARTHRALGIA
subjects affected / exposed	3 / 314 (0.96%)	0 / 55 (0.00%)	6 / 317 (1.89%)	6 / 314 (1.91%)	13 / 314 (4.14%)	3 / 55 (5.45%)	20 / 317 (6.31%)	16 / 314 (5.10%)	3 / 56 (5.36%)	26 / 335 (7.76%)	17 / 332 (5.12%)	3 / 181 (1.66%)	6 / 218 (2.75%)
occurrences all number	3	0	6	6	14	3	31	19	3	40	22	3	7
INTERVERTEBRAL DISC PROTRUSION
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	1 / 317 (0.32%)	1 / 314 (0.32%)	0 / 314 (0.00%)	2 / 55 (3.64%)	5 / 317 (1.58%)	1 / 314 (0.32%)	3 / 56 (5.36%)	6 / 335 (1.79%)	1 / 332 (0.30%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	0	0	1	1	0	2	7	1	3	8	1	1	1
MYALGIA
subjects affected / exposed	3 / 314 (0.96%)	1 / 55 (1.82%)	3 / 317 (0.95%)	2 / 314 (0.64%)	5 / 314 (1.59%)	4 / 55 (7.27%)	6 / 317 (1.89%)	3 / 314 (0.96%)	4 / 56 (7.14%)	7 / 335 (2.09%)	5 / 332 (1.51%)	0 / 181 (0.00%)	1 / 218 (0.46%)
occurrences all number	3	1	3	2	5	5	6	3	5	7	5	0	1
RHEUMATOID ARTHRITIS
subjects affected / exposed	19 / 314 (6.05%)	0 / 55 (0.00%)	6 / 317 (1.89%)	1 / 314 (0.32%)	44 / 314 (14.01%)	4 / 55 (7.27%)	29 / 317 (9.15%)	11 / 314 (3.50%)	5 / 56 (8.93%)	39 / 335 (11.64%)	12 / 332 (3.61%)	17 / 181 (9.39%)	25 / 218 (11.47%)
occurrences all number	20	0	7	1	65	4	37	12	5	57	14	19	31
PERIARTHRITIS
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	1 / 314 (0.32%)	3 / 55 (5.45%)	1 / 317 (0.32%)	1 / 314 (0.32%)	3 / 56 (5.36%)	2 / 335 (0.60%)	1 / 332 (0.30%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	0	0	0	1	3	1	1	3	2	1	0	0
OSTEOPOROSIS
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	1 / 317 (0.32%)	1 / 314 (0.32%)	6 / 314 (1.91%)	3 / 55 (5.45%)	4 / 317 (1.26%)	8 / 314 (2.55%)	3 / 56 (5.36%)	6 / 335 (1.79%)	8 / 332 (2.41%)	1 / 181 (0.55%)	3 / 218 (1.38%)
occurrences all number	0	1	1	1	6	3	4	8	3	6	8	1	3
Infections and infestations
CONJUNCTIVITIS
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	2 / 314 (0.64%)	6 / 314 (1.91%)	3 / 55 (5.45%)	7 / 317 (2.21%)	4 / 314 (1.27%)	4 / 56 (7.14%)	9 / 335 (2.69%)	4 / 332 (1.20%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	0	0	0	2	6	3	7	4	4	9	4	1	1
COVID-19
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	18 / 314 (5.73%)	4 / 55 (7.27%)	28 / 317 (8.83%)	3 / 314 (0.96%)	4 / 56 (7.14%)	37 / 335 (11.04%)	4 / 332 (1.20%)	19 / 181 (10.50%)	22 / 218 (10.09%)
occurrences all number	0	0	0	0	20	4	28	3	4	38	4	20	23
BRONCHITIS
subjects affected / exposed	6 / 314 (1.91%)	0 / 55 (0.00%)	7 / 317 (2.21%)	5 / 314 (1.59%)	24 / 314 (7.64%)	7 / 55 (12.73%)	22 / 317 (6.94%)	27 / 314 (8.60%)	9 / 56 (16.07%)	33 / 335 (9.85%)	29 / 332 (8.73%)	5 / 181 (2.76%)	7 / 218 (3.21%)
occurrences all number	6	0	8	6	27	9	26	38	11	37	40	9	11
GASTROENTERITIS
subjects affected / exposed	7 / 314 (2.23%)	2 / 55 (3.64%)	5 / 317 (1.58%)	5 / 314 (1.59%)	12 / 314 (3.82%)	8 / 55 (14.55%)	11 / 317 (3.47%)	10 / 314 (3.18%)	9 / 56 (16.07%)	13 / 335 (3.88%)	10 / 332 (3.01%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	7	2	5	5	12	9	14	11	10	17	11	1	1
CYSTITIS
subjects affected / exposed	2 / 314 (0.64%)	1 / 55 (1.82%)	2 / 317 (0.63%)	2 / 314 (0.64%)	4 / 314 (1.27%)	5 / 55 (9.09%)	8 / 317 (2.52%)	9 / 314 (2.87%)	6 / 56 (10.71%)	8 / 335 (2.39%)	11 / 332 (3.31%)	5 / 181 (2.76%)	5 / 218 (2.29%)
occurrences all number	2	1	2	2	4	6	10	9	9	10	11	5	5
HERPES ZOSTER
subjects affected / exposed	1 / 314 (0.32%)	2 / 55 (3.64%)	7 / 317 (2.21%)	7 / 314 (2.23%)	7 / 314 (2.23%)	12 / 55 (21.82%)	32 / 317 (10.09%)	24 / 314 (7.64%)	13 / 56 (23.21%)	34 / 335 (10.15%)	27 / 332 (8.13%)	7 / 181 (3.87%)	8 / 218 (3.67%)
occurrences all number	1	2	8	7	7	12	38	26	13	42	29	8	9
INFLUENZA
subjects affected / exposed	1 / 314 (0.32%)	2 / 55 (3.64%)	1 / 317 (0.32%)	3 / 314 (0.96%)	7 / 314 (2.23%)	8 / 55 (14.55%)	5 / 317 (1.58%)	9 / 314 (2.87%)	10 / 56 (17.86%)	9 / 335 (2.69%)	11 / 332 (3.31%)	2 / 181 (1.10%)	2 / 218 (0.92%)
occurrences all number	1	2	1	3	7	8	5	10	10	9	12	2	2
NASOPHARYNGITIS
subjects affected / exposed	13 / 314 (4.14%)	5 / 55 (9.09%)	18 / 317 (5.68%)	17 / 314 (5.41%)	43 / 314 (13.69%)	22 / 55 (40.00%)	48 / 317 (15.14%)	51 / 314 (16.24%)	25 / 56 (44.64%)	57 / 335 (17.01%)	58 / 332 (17.47%)	8 / 181 (4.42%)	10 / 218 (4.59%)
occurrences all number	15	10	22	18	70	49	87	72	59	99	79	10	12
LATENT TUBERCULOSIS
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	14 / 314 (4.46%)	0 / 55 (0.00%)	11 / 317 (3.47%)	15 / 314 (4.78%)	0 / 56 (0.00%)	14 / 335 (4.18%)	18 / 332 (5.42%)	2 / 181 (1.10%)	3 / 218 (1.38%)
occurrences all number	0	0	0	0	14	0	11	15	0	14	18	2	3
ORAL CANDIDIASIS
subjects affected / exposed	0 / 314 (0.00%)	2 / 55 (3.64%)	0 / 317 (0.00%)	0 / 314 (0.00%)	0 / 314 (0.00%)	4 / 55 (7.27%)	5 / 317 (1.58%)	1 / 314 (0.32%)	4 / 56 (7.14%)	5 / 335 (1.49%)	2 / 332 (0.60%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	0	2	0	0	0	5	9	1	5	9	2	0	0
PERIODONTITIS
subjects affected / exposed	1 / 314 (0.32%)	1 / 55 (1.82%)	1 / 317 (0.32%)	2 / 314 (0.64%)	4 / 314 (1.27%)	4 / 55 (7.27%)	4 / 317 (1.26%)	3 / 314 (0.96%)	5 / 56 (8.93%)	4 / 335 (1.19%)	3 / 332 (0.90%)	0 / 181 (0.00%)	0 / 218 (0.00%)
occurrences all number	1	1	1	2	7	4	6	3	5	6	3	0	0
ORAL HERPES
subjects affected / exposed	2 / 314 (0.64%)	3 / 55 (5.45%)	4 / 317 (1.26%)	4 / 314 (1.27%)	8 / 314 (2.55%)	7 / 55 (12.73%)	16 / 317 (5.05%)	11 / 314 (3.50%)	8 / 56 (14.29%)	17 / 335 (5.07%)	13 / 332 (3.92%)	1 / 181 (0.55%)	1 / 218 (0.46%)
occurrences all number	2	3	4	4	10	9	21	13	10	22	16	1	1
SINUSITIS
subjects affected / exposed	6 / 314 (1.91%)	1 / 55 (1.82%)	5 / 317 (1.58%)	4 / 314 (1.27%)	11 / 314 (3.50%)	3 / 55 (5.45%)	14 / 317 (4.42%)	6 / 314 (1.91%)	3 / 56 (5.36%)	16 / 335 (4.78%)	8 / 332 (2.41%)	2 / 181 (1.10%)	3 / 218 (1.38%)
occurrences all number	6	1	7	4	19	3	27	7	3	29	10	2	3
TINEA PEDIS
subjects affected / exposed	0 / 314 (0.00%)	0 / 55 (0.00%)	0 / 317 (0.00%)	0 / 314 (0.00%)	2 / 314 (0.64%)	3 / 55 (5.45%)	4 / 317 (1.26%)	3 / 314 (0.96%)	3 / 56 (5.36%)	6 / 335 (1.79%)	3 / 332 (0.90%)	2 / 181 (1.10%)	2 / 218 (0.92%)
occurrences all number	0	0	0	0	3	3	4	4	3	6	4	2	2
PHARYNGITIS
subjects affected / exposed	6 / 314 (1.91%)	5 / 55 (9.09%)	4 / 317 (1.26%)	8 / 314 (2.55%)	16 / 314 (5.10%)	12 / 55 (21.82%)	12 / 317 (3.79%)	17 / 314 (5.41%)	13 / 56 (23.21%)	14 / 335 (4.18%)	18 / 332 (5.42%)	3 / 181 (1.66%)	4 / 218 (1.83%)
occurrences all number	6	7	4	9	20	22	14	22	24	18	23	3	4
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	14 / 314 (4.46%)	3 / 55 (5.45%)	20 / 317 (6.31%)	23 / 314 (7.32%)	31 / 314 (9.87%)	9 / 55 (16.36%)	49 / 317 (15.46%)	43 / 314 (13.69%)	9 / 56 (16.07%)	59 / 335 (17.61%)	51 / 332 (15.36%)	5 / 181 (2.76%)	7 / 218 (3.21%)
occurrences all number	17	3	23	28	45	14	88	72	14	102	87	7	9
URINARY TRACT INFECTION
subjects affected / exposed	20 / 314 (6.37%)	1 / 55 (1.82%)	17 / 317 (5.36%)	18 / 314 (5.73%)	41 / 314 (13.06%)	1 / 55 (1.82%)	43 / 317 (13.56%)	38 / 314 (12.10%)	1 / 56 (1.79%)	51 / 335 (15.22%)	45 / 332 (13.55%)	13 / 181 (7.18%)	19 / 218 (8.72%)
occurrences all number	24	1	19	21	59	3	93	64	3	107	76	14	21
Metabolism and nutrition disorders
DYSLIPIDAEMIA
subjects affected / exposed	0 / 314 (0.00%)	3 / 55 (5.45%)	3 / 317 (0.95%)	6 / 314 (1.91%)	3 / 314 (0.96%)	5 / 55 (9.09%)	15 / 317 (4.73%)	15 / 314 (4.78%)	5 / 56 (8.93%)	17 / 335 (5.07%)	15 / 332 (4.52%)	2 / 181 (1.10%)	2 / 218 (0.92%)
occurrences all number	0	3	3	6	4	5	17	17	5	22	18	2	2
HYPERCHOLESTEROLAEMIA
subjects affected / exposed	0 / 314 (0.00%)	1 / 55 (1.82%)	7 / 317 (2.21%)	8 / 314 (2.55%)	2 / 314 (0.64%)	2 / 55 (3.64%)	17 / 317 (5.36%)	14 / 314 (4.46%)	2 / 56 (3.57%)	19 / 335 (5.67%)	16 / 332 (4.82%)	3 / 181 (1.66%)	3 / 218 (1.38%)
occurrences all number	0	1	7	9	2	2	23	19	2	27	21	3	3
HYPERLIPIDAEMIA
subjects affected / exposed	1 / 314 (0.32%)	1 / 55 (1.82%)	4 / 317 (1.26%)	3 / 314 (0.96%)	2 / 314 (0.64%)	4 / 55 (7.27%)	7 / 317 (2.21%)	6 / 314 (1.91%)	4 / 56 (7.14%)	8 / 335 (2.39%)	8 / 332 (2.41%)	1 / 181 (0.55%)	2 / 218 (0.92%)
occurrences all number	1	1	4	3	2	4	8	6	4	9	9	1	2
HYPERTRIGLYCERIDAEMIA
subjects affected / exposed	8 / 314 (2.55%)	0 / 55 (0.00%)	11 / 317 (3.47%)	8 / 314 (2.55%)	10 / 314 (3.18%)	0 / 55 (0.00%)	21 / 317 (6.62%)	19 / 314 (6.05%)	0 / 56 (0.00%)	22 / 335 (6.57%)	21 / 332 (6.33%)	4 / 181 (2.21%)	5 / 218 (2.29%)
occurrences all number	8	0	12	10	12	0	31	31	0	33	33	4	5

More information

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Were there any global substantial amendments to the protocol? Yes

15 Jan 2016

○Added Period 2 study objectives. ○Added 7.5 mg treatment group for subjects in Japan and increased the number of subjects to be enrolled accordingly. ○Added frequency of methotrexate (MTX) administration. ○Updated study duration and study design to include a 48-week randomized, double-blind treatment period (Period 1), and to add a long-term extension (Period 2). ○Clarify the double-blind details and how the blind will be maintained and the Week 24 interim analysis. ○Added language regarding study drug dose reduction and background RA medication(s). ○Added the following exclusion criteria: females who are considering becoming pregnant or males considering fathering a child or donating sperm during the study or for up to 180 days after last dose of study drug; subjects with a history of gastrointestinal (GI) perforation or a history of associated GI diseases, with conditions that could interfere with drug absorption, who have been the recipient of an organ transplant, who had significant electrocardiogram (ECG) abnormalities and with a positive result of beta-D-glucan (Japan only). ○Updated permitted RA therapies. ○Updated durations of prohibited therapies. ○Added criteria for rescue therapy at Week 26. ○Clarified informed consent details. ○Clarified tuberculosis (TB) testing. ○Added requirement in Japan that a positive result for hepatitis B surface (HBs) antibody (Ab)/anti-HBs requires hepatitis B virus (HBV) DNA polymerase chain reaction testing and added testing for varicella zoster virus. ○Updated PK sampling visits. ○Added efficacy assessments for Period 2; Primary, secondary, and other variables updated to reflect current rationale and planned analyses. ○Updated discontinuation procedures. ○Updated rules regarding study drug interruption; clarified that administration of both daily and weekly study drug must be stopped if study drug is interrupted or withdrawn. ○Updated the AST or ALT specific toxicity management guidelines.

29 Feb 2016

○ Updated text to provide clarification for discontinuation criteria. ○ Updated Inclusion Criterion 2 text to avoid ambiguity regarding RA classification criteria. Updated Inclusion Criterion 9 text to clarify pregnancy testing and women of childbearing potential. ○ Updated text to clarify RA optimization therapies. ○ Added criteria for adjusting or adding background medication at Week 26 if subjects do not achieve LDA as defined by CDAI or do not achieve > 20% improvement from baseline in both TJC and SJC. ○ Updated text to clarify Independent Joint Assessor. Updated text to clarify tuberculosis (TB) assessment and testing. Added text that all subjects to have electrocardiogram (ECG) performed at screening and every 48 weeks.

31 May 2016

○ Added criteria for rescue therapy between Weeks 12 and 24 and between Weeks 36 and 40 if subjects do not achieve ≥ 20% improvement from baseline in both TJC and SJC. ○ Updated text to clarify exceptions for rescue therapy. ○ Added text to follow MTX local label for concomitant treatment contraindications.

18 Aug 2016

○ Updated Inclusion Criterion 2 text to select subject population based on duration of symptoms consistent with RA. ○ Updated text to clarify when to administer live vaccines and to provide examples of inactivated vaccines. ○ Added text to describe the addition of MTX for Week 26 rescue therapy. ○ Added requirement to perform pregnancy testing if follicle-stimulating hormone results are consistent with premenopausal status. Updated text to account for local contraception requirements. ○ Added text to clarify different primary efficacy variable for different regulatory purposes. ○ Updated time points for key secondary variables to allow for rescue therapy at Week 12. ○ Added text for local country requirements for Colombia.

26 Dec 2017

○Included approved International Nonproprietary Name. ○Clarified Period 1 blinding and additional unblinded analyses. ○Clarified that study drug dose changes are not permitted in unblinded Period 2. ○Clarified 30-day follow-up visit and premature discontinuation requirements. ○Added text on oral traditional Chinese medicines. ○Clarified use of grapefruit; updated list of commonly used strong cytochrome 3A inhibitors and inducers. ○Clarified that live vaccines may not be administered up to 30 days after last dose of study drug. ○Added injectable hormonal contraception; clarified contraception requirements for females if childbearing potential status changes. ○Clarified TB testing and prophylaxis requirements; Added rifapentine as excluded medication. ○Allowed a pulmonologist to perform chest x-ray assessments. ○Clarified QT interval calculation. ○Updated x-ray time points for subjects who prematurely discontinue study drug but continue in the study. ○Clarified that serum samples may be used to assay study drugs. ○Updated efficacy variables for different regulatory purposes and to align with the Statistical Analysis Plan. ○Reduced malignancy and lymphoproliferative disorders to malignancy (all types). Removed hemoglobin effects. Included embolic and thrombotic events as AEs of special interest. ○Updated text for assessing the relationship of AEs to use of study drug and Suspected Unexpected Serious Adverse Reaction reporting text per sponsor guidelines. ○Clarified discontinuation criteria for ECG abnormalities. ○Clarified that all abnormal lab tests considered clinically significant should be followed to resolution. ○Clarified toxicity management for ALT, AST, international normalized ratio (INR) and for serum creatinine levels within normal reference range. ○Added text for management of subjects with laboratory values that may indicate active hepatitis. ○Clarified procedures for elevated creatine phosphokinase without clinical signs and symtoms.

16 Dec 2019

○ Changed length of study from 240 weeks to 260 weeks. ○ Changed dosing for subjects from blinded upadacitinib 15 mg and 30 mg QD to upadacitinib 15 mg QD open-label throughout protocol. ○ Specified throughout protocol that subjects receiving MTX will continue receiving MTX open-label. ○ Clarified that restart of study drug after an interruption of > 30 consecutive days is at the discretion of the Investigator. ○ Removed the limit for only two corticosteroid injections. ○ Clarified concurrent use of JAK inhibitors is prohibited during the study. Added excluded biologic therapies to be consistent with current available biologic therapies in RA. Added allowance of systemic use of known strong CYP3A inhibitors or strong CYP3A inducers for subjects not receiving upadacitinib. Added allowance of high potency opiates for analgesic care related to AEs or serious AEs (SAEs) as there is no expected effect on major efficacy outcomes now that the study is in long-term extension. Added guidance for use of live vaccines administration during Period 2 to align with guidelines on live vaccine administration in the setting of immunosuppressive. ○ Removed male contraception requirements for subject receiving upadacitinib, as based on the calculated safety margins for human fetal exposure with seminal fluid transfer, risks to a fetus from a male taking the study drug are not anticipated. ○ Clarified that all cardiac, embolic and thrombotic events will be adjudicated. ○ Added an additional safety precaution for subjects, given the recent concerns raised for the JAK inhibitor class regarding risk of VTE.

01 Jul 2020

○ Added allowance for administration of live vaccines during Period 2.

03 Dec 2020

○Clarified that the state of emergency and pandemic-related restrictions may allow mitigation strategies to ensure subject safety and continuity of care as an alternative to discontinuation and AbbVie TA MD role in reviewing cases. Modified study visits and procedures impacted by COVID-19 as follows ●Revised benefit-risk section. ●Verbal consent may be obtained in addition to study informed consent per local regulations. ●Added provisions for virtual or alternative location for study visits; added home healthcare visits and remote monitoring as options. ●Clarified study activities that can be performed by phone/video conference or at local clinic/hospital/laboratory or through the optional home healthcare service, including pregnancy and laboratory testing, and allowed study drug dispensation in such cases. ●Specified that Questionnaires and PhGA cannot be completed virtually and will be completed at the next earliest feasible visit. ●Specified tests that can be performed at the next earliest feasible visit, unless required to ensure safety of continuing study drug, including x-rays, ECG, physical exam, TJC, SJC. ●Added provision allowing Direct-to Patient shipment of study drug and study ancillaries. ●Added guidance for investigators on management of subjects with COVID-19 infection. ●Added supplemental COVID-19 case report forms for missed or virtual visits, study drug interruptions or discontinuations, or AEs and instructions to collect safety data related to COVID-19. ●Added provision for modifications due to protocol deviations that may be due to pandemic to guide investigators to notify IRB/EC when deviations occur. ○Updated Synopsis to be consistent with Amendment 7. ○Updated list of commonly used strong cytochrome 3A inducers. ○Clarified that subjects should discontinue study drug immediately if they develop a GI perforation except for appendicitis or mechanical injury. ○Clarified and updated the list of the AEs of special interest.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) Once Daily Monotherapy to Methotrexate (MTX) Monotherapy in MTX-Naïve Subjects with Moderately to Severely Active Rheumatoid Arthritis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis

Primary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis

Primary: Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis

Primary: Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis

Primary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis

Primary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis

Primary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis

Primary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis

Secondary: Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis

Secondary: Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis

Secondary: Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis

Secondary: Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis

Secondary: Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis

Secondary: Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis

Secondary: Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis

Secondary: Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis

Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 24 - Global Analysis

Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 24 - Global Analysis

Secondary: Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis

Secondary: Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis

Secondary: Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis

Secondary: Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis

Secondary: Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study

Secondary: Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study

Secondary: Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study

Secondary: Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study

Secondary: Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study

Secondary: Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study

Secondary: Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study

Secondary: Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study

Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study

Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study

Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study

Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study

Secondary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study

Secondary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study

Secondary: Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study

Secondary: Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) Once Daily Monotherapy to Methotrexate (MTX) Monotherapy in MTX-Naïve Subjects with Moderately to Severely Active Rheumatoid Arthritis