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Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis

Summary
EudraCT number	2016-000641-31
Trial protocol	SK NL FI HU CZ SE PL IE PT DE LV LT AT GR BE EE NO ES GB FR HR RO
Global end of trial date	13 Dec 2021

Results information
Results version number	v1(current)
This version publication date	19 Jun 2022
First version publication date	19 Jun 2022
Other versions

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

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Trial information

Top of page

Sponsor protocol code

M14-234

ISRCTN number

US NCT number

NCT02819635

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?

Yes

Analysis stage

Final

Date of interim/final analysis

13 Dec 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Dec 2021

Was the trial ended prematurely?

Main objective of the trial

This study was comprised of three substudies. Substudy 1 (SS1) was a Phase 2b dose-ranging study designed to evaluate the efficacy and safety of different doses of UPA (7.5, 15, 30, and 45 mg) compared to placebo as 8-week induction therapy in subjects with moderately to severely active ulcerative colitis (UC). Substudy 2 (SS2) was a two-part Phase 3 dose-confirming study designed to evaluate the efficacy and safety of oral administration of UPA 45 mg compared to placebo as induction therapy for up to 16 weeks in subjects with moderately to severely active UC. Substudy 3 (SS3) was a Phase 3 maintenance study designed to evaluate the efficacy and safety of UPA 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in subjects with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from SS1, SS2, or Study M14-675 (NCT03653026).

Protection of trial subjects

The investigator or his/her representative explained the nature of the study to the subject and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was to be reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements. For US subjects: at Week 8 or Week 16 (Substudy 1 or 2 or Study M14-675), subjects who will continue into Substudy 3 were to sign and date a study specific Independent Ethics Committee/Institutional Review Board (IEC/IRB) approved Informed Consent Form before Substudy 3 procedures are performed. For adolescent subjects, the investigator or his/her representative explained the nature of the study and optional exploratory research samples to the subject and the subject's parent/legal guardian and answered all questions regarding this study. Adolescent subjects were to be included in all discussions in order to obtain verbal or written assent. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was to be reviewed, signed and dated by the subject's parent/legal guardian, the person who administered the informed consent, and any other signatories according to local requirements. Additionally, in keeping with each institution's IRB/IEC requirements, an informed assent form may also have been obtained by each subject prior to any study-related procedures being performed. If a subject attained legal age during the course of the study, that subject was to be re-consented.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Sep 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: 12

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Austria: 11

Country: Number of subjects enrolled

Belgium: 18

Country: Number of subjects enrolled

Bosnia and Herzegovina: 4

Country: Number of subjects enrolled

Brazil: 12

Country: Number of subjects enrolled

Canada: 114

Country: Number of subjects enrolled

Chile: 2

Country: Number of subjects enrolled

China: 40

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

Croatia: 5

Country: Number of subjects enrolled

Czechia: 14

Country: Number of subjects enrolled

Estonia: 24

Country: Number of subjects enrolled

Finland: 9

Country: Number of subjects enrolled

France: 28

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Greece: 4

Country: Number of subjects enrolled

Hungary: 13

Country: Number of subjects enrolled

Ireland: 8

Country: Number of subjects enrolled

Israel: 11

Country: Number of subjects enrolled

Italy: 63

Country: Number of subjects enrolled

Japan: 198

Country: Number of subjects enrolled

Korea, Republic of: 36

Country: Number of subjects enrolled

Latvia: 17

Country: Number of subjects enrolled

Lithuania: 11

Country: Number of subjects enrolled

Malaysia: 6

Country: Number of subjects enrolled

Mexico: 8

Country: Number of subjects enrolled

Netherlands: 25

Country: Number of subjects enrolled

Norway: 29

Country: Number of subjects enrolled

Poland: 34

Country: Number of subjects enrolled

Portugal: 14

Country: Number of subjects enrolled

Puerto Rico: 2

Country: Number of subjects enrolled

Russian Federation: 50

Country: Number of subjects enrolled

Serbia: 31

Country: Number of subjects enrolled

Singapore: 1

Country: Number of subjects enrolled

Slovakia: 16

Country: Number of subjects enrolled

South Africa: 35

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Switzerland: 34

Country: Number of subjects enrolled

Taiwan: 24

Country: Number of subjects enrolled

Turkey: 8

Country: Number of subjects enrolled

Ukraine: 6

Country: Number of subjects enrolled

United Kingdom: 18

Country: Number of subjects enrolled

United States: 273

Worldwide total number of subjects

1302

EEA total number of subjects

365

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)

1183

From 65 to 84 years

113

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Intent-to-treat (ITT): Substudy 1 (randomized subjects who rcvd at least 1 dose of study drug in Substudy 1); Substudy 2 (randomized subjects who rcvd at least 1 dose of double-blinded study drug in Part 1 and those who rcvd at least 1 dose of upadacitinib 45 mg in Part 2); Substudy 3 (subjects who rcvd at least 1 dose of study drug in Substudy 3)

Period 1 title

Substudy 1 and Substudy 2, Part 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Assessor

Are arms mutually exclusive

Yes

SS1: Placebo

Arm description

During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

SS1: Upadacitinib 7.5 mg

Arm description

During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

SS1: Upadacitinib 15 mg

Arm description

During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

SS1: Upadacitinib 30 mg

Arm description

During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks during the Induction Phase. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

SS1: Upadacitinib 45 mg

Arm description

During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks during the Induction Phase. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

SS2: Placebo/Upadacitinib 45 mg

Arm description

During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

Arm description

During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

SS3: M14-675 Clinical Responders

Arm description

Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth [QD], or 30 mg upadacitinib film-coated tablets QD, or placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that\ study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were re-randomized and treated with placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were re-randomized and treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth [QD], or 30 mg upadacitinib film-coated tablets QD for up to 52 weeks.

Number of subjects in period 1	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg	SS2: Placebo/Upadacitinib 45 mg	SS2: Upadacitinib 45 mg/Upadacitinib 45 mg	SS3: M14-675 Clinical Responders
Started	46	47	49	117	123	155	319	446
Completed	41	45	45	105	113	135	306	446
Not completed	5	2	4	12	10	20	13	0
Adverse event, non-fatal	3	1	3	5	4	9	6	-
COVID-19 Logistical Restrictions	-	-	-	-	-	-	1	-
Other, not specified	2	1	1	7	5	7	3	-
Withdrew consent	-	-	-	-	1	3	2	-
Lost to follow-up	-	-	-	-	-	1	1	-

Period 2 title

Substudy 3

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Assessor

Are arms mutually exclusive

Yes

SS3: Placebo

Arm description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to placebo QD in Substudy 3 for up to 52 weeks. In addition, participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3 for up to 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received placebo QD in Substudy 3 for up to 52 weeks.

SS3: UPA 7.5 mg

Arm description

Participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3 for up to 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for up to 52 weeks.

SS3: UPA 15 mg

Arm description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 15 mg QD in Substudy 3.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for up to 52 weeks.

SS3: UPA 30 mg

Arm description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 30 mg QD in Substudy 3.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for up to 52 weeks.

Number of subjects in period 2 ^[1]	SS3: Placebo	SS3: UPA 7.5 mg	SS3: UPA 15 mg	SS3: UPA 30 mg
Started	386	20	324	316
Completed	140	11	218	248
Not completed	246	9	106	68
Adverse event, non-fatal	32	3	12	18
COVID-19 Logistical Restrictions	-	-	-	1
Other, not specified	202	5	89	39
Withdrew consent	11	1	4	9
Lost to follow-up	1	-	1	1

Notes
[1] - 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: Substudy 3 was a Phase 3 maintenance study designed to evaluate the efficacy and safety of upadacitinib 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in participants with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from Substudy 1, Substudy 2, or Study M14-675.

Period 3 title

Substudy 2, Part 2

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

SS2: Placebo/Upadacitinib 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494, RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 3 ^[2]	SS2: Placebo/Upadacitinib 45 mg	SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
Started	85	59
Completed	74	47
Not completed	11	12
Adverse event, non-fatal	4	-
COVID-19 Logistical Restrictions	-	2
Other, not specified	4	8
Withdrew consent	3	1
Lost to follow-up	-	1

Notes
[2] - 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: Substudy 2 Part 2 was an open-label, 8-week extended treatment period for clinical non-responders from Part 1 of Substudy 2.

Baseline characteristics

Top of page

Reporting group title

SS1: Placebo

Reporting group description

During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 7.5 mg

Reporting group description

During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 15 mg

Reporting group description

During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 30 mg

Reporting group description

Reporting group title

SS1: Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Placebo/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS3: M14-675 Clinical Responders

Reporting group description

Reporting group values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg	SS2: Placebo/Upadacitinib 45 mg	SS2: Upadacitinib 45 mg/Upadacitinib 45 mg	SS3: M14-675 Clinical Responders	Total
Number of subjects	46	47	49	117	123	155	319	446	1302
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	42.3 ± 13.29	41.7 ± 14.58	46.0 ± 13.58	42.9 ± 14.44	41.6 ± 14.19	44.3 ± 14.64	43.6 ± 14.04	42.1 ± 14.42	-
Gender categorical
Units: Subjects
Female	17	24	19	47	44	58	121	170	500
Male	29	23	30	70	79	97	198	276	802
Race/Ethnicity
Units: Subjects
White	37	36	38	88	90	101	206	302	898
Black or African American	0	3	1	3	2	4	12	15	40
Asian	8	7	10	23	28	46	95	124	341
American Indian or Alaska Native	0	0	0	1	0	2	0	1	4
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	1	1	2
Multiple	1	1	0	2	3	2	5	3	17
Previous Biologic Use
Units: Subjects
Yes	35	36	38	87	92	0	0	0	288
No	11	11	11	30	31	0	0	0	94
Not recorded	0	0	0	0	0	155	319	446	920
Biologicinadequate Responder (BioIR) Status
Biologic-inadequate responders (Bio-IR) are defined as participants who had inadequate response, loss of response, or intolerance to biologic therapy. Non-biologic-inadequate responders (non-bio-IR) are defined as participants who had inadequate response, loss of response, or intolerance to conventional therapy but had not failed biologic therapy.
Units: Subjects
Bio-IR	0	0	0	0	0	79	168	221	468
Non-Bio-IR	0	0	0	0	0	76	151	225	452
Not recorded	46	47	49	117	123	0	0	0	382
Baseline Corticosteroid Use
Units: Subjects
Yes	26	24	27	51	53	62	124	173	540
No	20	23	22	66	70	93	195	273	762
Average Stool Frequency Subscore
Measure Description: Participants recorded stool frequency using an electronic subject diary on a daily basis. The stool frequency subscore (SFS) ranges from 0 to 3 according to the following scale: Score 0: Normal number of stools Score 1: 1 to 2 stools more than normal Score 2: 3 to 4 stools more than normal Score 3: 5 or more stools more than normal Participants with available data; Group 5 (n=122), Group 7 (n=318), Group 8 (n=445)
Units: units on a scale
arithmetic mean (standard deviation)	2.56 ± 0.667	2.62 ± 0.600	2.68 ± 0.565	2.61 ± 0.613	2.58 ± 0.648	2.52 ± 0.668	2.60 ± 0.624	2.55 ± 0.623	-
Average Rectal Bleeding Subscore
Participants recorded rectal bleeding in an electronic subject diary on a daily basis. The rectal bleeding subscore ranges from 0 to 3 according to the following scale: Score 0: No blood seen Score 1: Streaks of blood with stool less than half the time Score 2: Obvious blood with stool most of the time Score 3: Blood alone passed Participants with available data; Group 5 (n=122), Group 7 (n=318), Group 8 (n=445)
Units: units on a scale
arithmetic mean (standard deviation)	1.66 ± 1.034	1.61 ± 1.027	1.55 ± 0.915	1.51 ± 0.975	1.49 ± 0.960	1.76 ± 0.994	1.71 ± 1.046	1.77 ± 0.990	-
Average Endoscopy Subscore
Findings on endoscopy were scored according to the following: Score 0: Normal or inactive disease Score 1: Mild disease (erythema, decreased vascular pattern) Score 2: Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions) Score 3: Severe disease (spontaneous bleeding, ulceration)
Units: units on a scale
arithmetic mean (standard deviation)	2.8 ± 0.43	2.8 ± 0.40	2.8 ± 0.39	2.7 ± 0.47	2.7 ± 0.48	2.7 ± 0.47	2.7 ± 0.46	2.7 ± 0.47	-

End points

Top of page

Reporting group title

SS1: Placebo

Reporting group description

During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 7.5 mg

Reporting group description

During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 15 mg

Reporting group description

During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 30 mg

Reporting group description

Reporting group title

SS1: Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Placebo/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS3: M14-675 Clinical Responders

Reporting group description

Reporting group title

SS3: Placebo

Reporting group description

Reporting group title

SS3: UPA 7.5 mg

Reporting group description

Reporting group title

SS3: UPA 15 mg

Reporting group description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 15 mg QD in Substudy 3.

Reporting group title

SS3: UPA 30 mg

Reporting group description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 30 mg QD in Substudy 3.

Reporting group title

SS2: Placebo/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

Reporting group description

Subject analysis set title

SS2: Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Subject analysis set title

SS2: Upadacitinib 45 mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Subject analysis set title

SS3: Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at Week 8, while receiving upadacitinib 15, 30, or 45 mg QD and were randomized to placebo QD in Substudy 3 for up to 52 weeks. In addition, participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3 for up to 52 weeks.

Subject analysis set title

SS3: UPA 15 mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at Week 8 while receiving upadacitinib 15, 30, or 45 mg QD and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks

Subject analysis set title

SS3: UPA 30 mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

Top of page

End point title

Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 ^[1]

End point description

End point type

Primary

End point timeframe

At Week 8

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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[2]	47 ^[3]	49 ^[4]	52 ^[5]	56 ^[6]
Units: percentage of participants
number (not applicable)	0	8.5	14.3	13.5	21.4

Notes
[2] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[3] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[4] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[5] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[6] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.049 ^[8]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

8.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

16.8

Notes
[7] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[8] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.01 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

13.5

Confidence interval

level

95%

sides

2-sided

lower limit

3.3

upper limit

23.8

Notes
[9] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[10] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.007 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

13.8

Confidence interval

level

95%

sides

2-sided

lower limit

3.8

upper limit

23.9

Notes
[11] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[12] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 45 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.001 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

21.1

Confidence interval

level

95%

sides

2-sided

lower limit

8.6

upper limit

33.6

Notes
[13] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[14] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Primary: Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

Top of page

End point title

Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 2, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In Substudy 2, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2. Participants were analyzed according to the treatment groups to which they were randomized.

End point type

Primary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[15]	319 ^[16]
Units: percentage of participants
number (not applicable)	4.8	26.1

Notes
[15] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[16] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Upadacitinib 45 mg v SS2: Placebo

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.001 ^[18]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

21.6

Confidence interval

level

95%

sides

2-sided

lower limit

15.8

upper limit

27.4

Notes
[17] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[18] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Primary: Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2.

End point type

Primary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[19]	148 ^[20]	154 ^[21]
Units: percentage of participants
number (confidence interval 95%)	12.1 (6.9 to 17.4)	42.3 (34.3 to 50.3)	51.7 (43.6 to 59.8)

Notes
[19] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[20] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[21] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

< 0.001 ^[23]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

30.7

Confidence interval

level

95%

sides

2-sided

lower limit

21.7

upper limit

39.8

Notes
[22] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[23] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Baseline of Induction Study; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

< 0.001 ^[25]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

29.7

upper limit

48.2

Notes
[24] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[25] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Baseline of Induction Study; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8

Top of page

End point title

Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 ^[26]

End point description

Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).

End point type

Secondary

End point timeframe

At Week 8

Notes
[26] - 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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[27]	47 ^[28]	49 ^[29]	52 ^[30]	56 ^[31]
Units: percentage of participants
number (not applicable)	2.2	14.9	30.6	26.9	35.7

Notes
[27] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[28] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[29] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[30] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[31] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.03 ^[33]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

13.1

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

Notes
[32] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[33] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

< 0.001 ^[35]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

27.6

Confidence interval

level

95%

sides

2-sided

lower limit

13.1

upper limit

42.1

Notes
[34] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[35] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

< 0.001 ^[37]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

26.6

Confidence interval

level

95%

sides

2-sided

lower limit

12.3

upper limit

40.8

Notes
[36] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[37] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Upadacitinib 45 mg v SS1: Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

< 0.001 ^[39]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

35.4

Confidence interval

level

95%

sides

2-sided

lower limit

19.2

upper limit

51.7

Notes
[38] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[39] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8

Top of page

End point title

Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 ^[40]

End point description

The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1.

End point type

Secondary

End point timeframe

At Week 8

Notes
[40] - 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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[41]	47 ^[42]	49 ^[43]	52 ^[44]	56
Units: percentage of participants
number (not applicable)	0	10.6	10.2	11.5	19.6

Notes
[41] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[42] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[43] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[44] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

= 0.021 ^[46]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

20.4

Notes
[45] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[46] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.024 ^[48]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

Notes
[47] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[48] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.015 ^[50]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

12.2

Confidence interval

level

95%

sides

2-sided

lower limit

2.3

upper limit

Notes
[49] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[50] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 45 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

P-value

= 0.001 ^[52]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

20.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

32.1

Notes
[51] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[52] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

Top of page

End point title

Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 ^[53]

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).

End point type

Secondary

End point timeframe

At Week 8

Notes
[53] - 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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[54]	47 ^[55]	49 ^[56]	52 ^[57]	56 ^[58]
Units: percentage of participants
number (not applicable)	13.0	29.8	49.0	46.2	55.4

Notes
[54] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[55] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[56] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[57] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[58] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

P-value

= 0.038 ^[60]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

16.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

32.5

Notes
[59] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[60] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[61]

P-value

< 0.001 ^[62]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

35.2

Confidence interval

level

95%

sides

2-sided

lower limit

17.5

upper limit

52.8

Notes
[61] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[62] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[63]

P-value

< 0.001 ^[64]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

33.6

Confidence interval

level

95%

sides

2-sided

lower limit

16.3

upper limit

50.8

Notes
[63] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[64] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 45 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[65]

P-value

< 0.001 ^[66]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

45.1

Confidence interval

level

95%

sides

2-sided

lower limit

26.2

upper limit

63.9

Notes
[65] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[66] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

Top of page

End point title

Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 ^[67]

End point description

The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.

End point type

Secondary

End point timeframe

At Week 2

Notes
[67] - 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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[68]	47 ^[69]	49 ^[70]	52 ^[71]	56 ^[72]
Units: percentage of participants
number (not applicable)	17.4	23.4	34.7	36.5	55.4

Notes
[68] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[69] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[70] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[71] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[72] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[73]

P-value

= 0.495 ^[74]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

5.9

Confidence interval

level

95%

sides

2-sided

lower limit

-11.1

upper limit

22.9

Notes
[73] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[74] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[75]

P-value

= 0.074 ^[76]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

15.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

33.4

Notes
[75] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[76] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[77]

P-value

= 0.033 ^[78]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

19.2

Confidence interval

level

95%

sides

2-sided

lower limit

1.6

upper limit

36.9

Notes
[77] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[78] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 45 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[79]

P-value

< 0.001 ^[80]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

40.1

Confidence interval

level

95%

sides

2-sided

lower limit

20.5

upper limit

59.7

Notes
[79] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[80] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Secondary: Substudy 1: Change in Full Mayo Score From Baseline to Week 8

Top of page

End point title

Substudy 1: Change in Full Mayo Score From Baseline to Week 8 ^[81]

End point description

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 8

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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	41 ^[82]	43 ^[83]	44 ^[84]	44 ^[85]	48 ^[86]
Units: units on a scale
arithmetic mean (standard deviation)	-0.741 ± 2.3302	-2.870 ± 2.9685	-3.589 ± 2.4984	-4.211 ± 3.0886	-4.606 ± 2.8976

Notes
[82] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
[83] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
[84] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
[85] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
[86] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[87]

P-value

< 0.001 ^[88]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-2.142

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2323

upper limit

-1.052

Notes
[87] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[88] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[89]

P-value

< 0.001 ^[90]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-2.938

Confidence interval

level

95%

sides

2-sided

lower limit

-4.0284

upper limit

-1.8478

Notes
[89] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[90] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[91]

P-value

< 0.001 ^[92]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.736

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8247

upper limit

-2.647

Notes
[91] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[92] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Upadacitinib 45 mg v SS1: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[93]

P-value

< 0.001 ^[94]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-4.061

Confidence interval

level

95%

sides

2-sided

lower limit

-5.1252

upper limit

-2.9974

Notes
[93] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[94] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.

Secondary: Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8

Top of page

End point title

Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 ^[95]

End point description

Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).

End point type

Secondary

End point timeframe

At Week 8

Notes
[95] - 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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[96]	47 ^[97]	49 ^[98]	52 ^[99]	56 ^[100]
Units: percentage of participants
number (not applicable)	0	6.4	4.1	9.6	17.9

Notes
[96] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[97] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[98] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[99] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[100] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[101]

P-value

= 0.075 ^[102]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

13.9

Notes
[101] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[102] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[103]

P-value

= 0.199 ^[104]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

9.6

Notes
[103] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[104] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[105]

P-value

= 0.015 ^[106]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

11.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

Notes
[105] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[106] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 45 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[107]

P-value

= 0.004 ^[108]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

17.8

Confidence interval

level

95%

sides

2-sided

lower limit

5.8

upper limit

29.9

Notes
[107] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[108] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Secondary: Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

Top of page

End point title

Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 ^[109]

End point description

The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score.

End point type

Secondary

End point timeframe

At Week 8

Notes
[109] - 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: This endpoint included Substudy 1, Part 1 participants.

End point values	SS1: Placebo	SS1: Upadacitinib 7.5 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 45 mg
Number of subjects analysed	46 ^[110]	47 ^[111]	49 ^[112]	52 ^[113]	56 ^[114]
Units: percentage of participants
number (not applicable)	6.5	31.9	51.0	44.2	48.2

Notes
[110] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[111] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[112] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[113] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
[114] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values

Substudy 1: Upadacitinib 7.5 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 7.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[115]

P-value

= 0.003 ^[116]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

25.6

Confidence interval

level

95%

sides

2-sided

lower limit

8.9

upper limit

42.3

Notes
[115] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[116] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 15 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 15 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[117]

P-value

< 0.001 ^[118]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

43.6

Confidence interval

level

95%

sides

2-sided

lower limit

25.4

upper limit

61.8

Notes
[117] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[118] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 30 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 30 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[119]

P-value

< 0.001 ^[120]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

39.4

Confidence interval

level

95%

sides

2-sided

lower limit

21.3

upper limit

57.5

Notes
[119] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[120] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Substudy 1: Upadacitinib 45 mg vs Placebo

Comparison groups

SS1: Placebo v SS1: Upadacitinib 45 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[121]

P-value

< 0.001 ^[122]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

43.1

Confidence interval

level

95%

sides

2-sided

lower limit

24.4

upper limit

61.9

Notes
[121] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[122] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

Secondary: Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8

Top of page

End point title

Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8

End point description

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[123]	319 ^[124]
Units: percentage of participants
number (confidence interval 95%)	7.4 (3.2 to 11.5)	36.3 (31.0 to 41.7)

Notes
[123] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[124] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[125]

P-value

< 0.001 ^[126]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

29.3

Confidence interval

level

95%

sides

2-sided

lower limit

22.6

upper limit

35.9

Notes
[125] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[126] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8

Top of page

End point title

Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8

End point description

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[127]	319 ^[128]
Units: percentage of participants
number (confidence interval 95%)	1.3 (0.0 to 3.1)	13.7 (9.9 to 17.6)

Notes
[127] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[128] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Upadacitinib 45 mg v SS2: Placebo

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[129]

P-value

< 0.001 ^[130]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

12.7

Confidence interval

level

95%

sides

2-sided

lower limit

8.4

upper limit

Notes
[129] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[130] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

Top of page

End point title

Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[131]	319 ^[132]
Units: percentage of participants
number (confidence interval 95%)	27.3 (20.2 to 34.3)	72.6 (67.7 to 77.5)

Notes
[131] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[132] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[133]

P-value

< 0.001 ^[134]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

46.3

Confidence interval

level

95%

sides

2-sided

lower limit

38.4

upper limit

54.2

Notes
[133] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[134] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

Top of page

End point title

Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

End point description

The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease from Baseline ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.

End point type

Secondary

End point timeframe

At Week 2

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[135]	319 ^[136]
Units: percentage of participants
number (confidence interval 95%)	27.3 (20.2 to 34.3)	60.1 (54.7 to 65.5)

Notes
[135] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[136] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[137]

P-value

< 0.001 ^[138]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

33.3

Confidence interval

level

95%

sides

2-sided

lower limit

24.8

upper limit

41.8

Notes
[137] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[138] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8

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End point title

Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8

End point description

Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[139]	319 ^[140]
Units: percentage of participants
number (confidence interval 95%)	6.6 (2.6 to 10.5)	30.1 (25.0 to 35.1)

Notes
[139] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[140] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[141]

P-value

< 0.001 ^[142]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

23.7

Confidence interval

level

95%

sides

2-sided

lower limit

17.5

upper limit

Notes
[141] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[142] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8

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End point title

Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8

End point description

Bowel urgency was assessed by participants in a subject diary completed once a day.

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[143]	319 ^[144]
Units: percentage of participants
number (confidence interval 95%)	21.4 (14.9 to 27.9)	48.4 (42.9 to 53.9)

Notes
[143] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[144] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[145]

P-value

< 0.001 ^[146]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

27.4

Confidence interval

level

95%

sides

2-sided

lower limit

19.2

upper limit

35.6

Notes
[145] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[146] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8

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End point title

Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8

End point description

Abdominal pain was assessed by participants in a subject diary completed once a day.

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[147]	319 ^[148]
Units: percentage of participants
number (confidence interval 95%)	23.4 (16.7 to 30.1)	46.6 (41.1 to 52.1)

Notes
[147] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[148] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[149]

P-value

< 0.001 ^[150]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

23.6

Confidence interval

level

95%

sides

2-sided

lower limit

15.1

upper limit

32.1

Notes
[149] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[150] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

Top of page

End point title

Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

End point description

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[151]	319 ^[152]
Units: percentage of participants
number (confidence interval 95%)	22.5 (15.9 to 29.1)	55.0 (49.5 to 60.5)

Notes
[151] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[152] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[153]

P-value

< 0.001 ^[154]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

32.2

Confidence interval

level

95%

sides

2-sided

lower limit

23.8

upper limit

40.7

Notes
[153] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[154] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

Secondary: Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8

Top of page

End point title

Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8

End point description

The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. It consists of 32 questions evaluating bowel and systemic symptoms, as well as emotional and social functions. Each question is answered on a scale from 1 (worst) to 7 (best). The total score ranges from 32 to 224 with higher scores indicating better health-related quality of life. A positive change from Baseline indicates improvement.

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	125 ^[155]	292 ^[156]
Units: units on a scale
least squares mean (confidence interval 95%)	21.7 (16.03 to 27.28)	55.3 (51.54 to 59.15)

Notes
[155] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc
[156] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

417

Analysis specification

Pre-specified

Analysis type

superiority ^[157]

P-value

< 0.001 ^[158]

Method

Mixed-effect model repeated measurement

Parameter type

LS Mean Difference

Point estimate

33.7

Confidence interval

level

95%

sides

2-sided

lower limit

27.02

upper limit

40.36

Variability estimate

Standard error of the mean

Dispersion value

3.39

Notes
[157] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[158] - MMRM with Baseline, treatment, visit, treatment-by-visit interaction, and strata (Baseline Adapted Mayo score, corticosteroid use, and bio-IR status).

Secondary: Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8

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End point title

Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8

End point description

Mucosal healing is defined as an endoscopic score of 0 and Geboes score < 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.

End point type

Secondary

End point timeframe

At Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	154 ^[159]	319 ^[160]
Units: percentage of participants
number (confidence interval 95%)	1.3 (0.0 to 3.1)	10.7 (7.3 to 14.1)

Notes
[159] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
[160] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

473

Analysis specification

Pre-specified

Analysis type

superiority ^[161]

P-value

< 0.001 ^[162]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

9.7

Confidence interval

level

95%

sides

2-sided

lower limit

5.7

upper limit

13.7

Notes
[161] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[162] - Stratified by Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), and bio-IR status (bio-IR or non-bio-IR)

Secondary: Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8

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End point title

Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8

End point description

The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement.

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 8

End point values	SS2: Placebo	SS2: Upadacitinib 45 mg
Number of subjects analysed	125 ^[163]	291 ^[164]
Units: units on a scale
least squares mean (confidence interval 95%)	2.8 (1.23 to 4.44)	9.5 (8.44 to 10.61)

Notes
[163] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc
[164] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc

Substudy 2: Upadacitinib 45 mg vs Placebo

Comparison groups

SS2: Placebo v SS2: Upadacitinib 45 mg

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority ^[165]

P-value

< 0.001 ^[166]

Method

Mixed-effect model repeated measurement

Parameter type

LS Mean Difference

Point estimate

6.7

Confidence interval

level

95%

sides

2-sided

lower limit

4.79

upper limit

8.59

Variability estimate

Standard error of the mean

Dispersion value

0.97

Notes
[165] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
[166] - MMRM with Baseline, treatment, visit, treatment-by-visit interaction, and strata (Baseline Adapted Mayo score, corticosteroid use, and bio-IR status)

Secondary: Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[167]	148 ^[168]	154 ^[169]
Units: percentage of participants
number (confidence interval 95%)	14.5 (8.7 to 20.3)	48.7 (40.5 to 56.8)	61.6 (53.6 to 69.6)

Notes
[167] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[168] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[169] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[170]

P-value

< 0.001 ^[171]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

34.4

Confidence interval

level

95%

sides

2-sided

lower limit

25.1

upper limit

43.7

Notes
[170] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[171] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[172]

P-value

< 0.001 ^[173]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

46.3

Confidence interval

level

95%

sides

2-sided

lower limit

36.7

upper limit

55.8

Notes
[172] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[173] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

Top of page

End point title

Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2.

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	54 ^[174]	47 ^[175]	58 ^[176]
Units: percentage of participants
number (confidence interval 95%)	22.2 (11.1 to 33.3)	59.2 (45.1 to 73.4)	69.7 (57.7 to 81.8)

Notes
[174] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[175] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[176] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[177]

P-value

< 0.001 ^[178]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

37.4

Confidence interval

level

95%

sides

2-sided

lower limit

20.3

upper limit

54.6

Notes
[177] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[178] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

superiority ^[179]

P-value

< 0.001 ^[180]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

30.7

upper limit

63.3

Notes
[179] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[180] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

Top of page

End point title

Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2.

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	54 ^[181]	47 ^[182]	58 ^[183]
Units: percentage of participants
number (confidence interval 95%)	22.2 (11.1 to 33.3)	57.1 (42.9 to 71.3)	68.0 (55.8 to 80.2)

Notes
[181] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[182] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[183] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[184]

P-value

< 0.001 ^[185]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

35.4

Confidence interval

level

95%

sides

2-sided

lower limit

18.2

upper limit

52.7

Notes
[184] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[185] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

superiority ^[186]

P-value

< 0.001 ^[187]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

45.1

Confidence interval

level

95%

sides

2-sided

lower limit

28.7

upper limit

61.6

Notes
[186] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[187] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment

Top of page

End point title

Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	73 ^[188]	63 ^[189]	79 ^[190]
Units: percentage of participants
number (confidence interval 95%)	19.2 (9.9 to 28.4)	61.6 (49.6 to 73.7)	69.5 (59.1 to 80.0)

Notes
[188] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[189] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[190] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority ^[191]

P-value

< 0.001 ^[192]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

27.8

upper limit

56.2

Notes
[191] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[192] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority ^[193]

P-value

< 0.001 ^[194]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

48.6

Confidence interval

level

95%

sides

2-sided

lower limit

35.5

upper limit

61.7

Notes
[193] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[194] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[195]	148	154 ^[196]
Units: percentage of participants
number (confidence interval 95%)	5.6 (1.8 to 9.3)	24.2 (17.3 to 31.2)	25.9 (18.8 to 33.0)

Notes
[195] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[196] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[197]

P-value

< 0.001 ^[198]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

18.7

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

26.4

Notes
[197] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[198] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[199]

P-value

< 0.001 ^[200]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

19.4

Confidence interval

level

95%

sides

2-sided

lower limit

11.7

upper limit

27.2

Notes
[199] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[200] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment

Top of page

End point title

Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment

End point description

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	134 ^[201]	135 ^[202]	144 ^[203]
Units: percentage of participants
number (confidence interval 95%)	18.8 (12.1 to 25.5)	63.0 (54.8 to 71.1)	76.6 (69.6 to 83.6)

Notes
[201] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[202] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[203] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority ^[204]

P-value

< 0.001 ^[205]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

44.6

Confidence interval

level

95%

sides

2-sided

lower limit

34.5

upper limit

54.7

Notes
[204] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[205] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority ^[206]

P-value

< 0.001 ^[207]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

56.6

Confidence interval

level

95%

sides

2-sided

lower limit

47.2

upper limit

Notes
[206] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[207] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[208]	148 ^[209]	154 ^[210]
Units: percentage of participants
number (confidence interval 95%)	11.9 (6.7 to 17.2)	35.0 (27.1 to 42.8)	49.8 (41.5 to 58.0)

Notes
[208] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[209] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[210] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[211]

P-value

< 0.001 ^[212]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

23.8

Confidence interval

level

95%

sides

2-sided

lower limit

14.8

upper limit

32.8

Notes
[211] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[212] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[213]

P-value

< 0.001 ^[214]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

37.3

Confidence interval

level

95%

sides

2-sided

lower limit

27.8

upper limit

46.8

Notes
[213] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[214] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52

Top of page

End point title

Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52

End point description

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[215]	148 ^[216]	154 ^[217]
Units: units on a scale
least squares mean (confidence interval 95%)	17.9 (10.79 to 25.00)	49.2 (42.59 to 55.89)	58.9 (52.14 to 65.59)

Notes
[215] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
[216] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
[217] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[218]

P-value

< 0.001 ^[219]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

31.3

Confidence interval

level

95%

sides

2-sided

lower limit

21.98

upper limit

40.7

Variability estimate

Standard error of the mean

Dispersion value

4.77

Notes
[218] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[219] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[220]

P-value

< 0.001 ^[221]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

31.39

upper limit

50.55

Variability estimate

Standard error of the mean

Dispersion value

4.88

Notes
[220] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[221] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)

Secondary: Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52

End point description

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[222]	148 ^[223]	154 ^[224]
Units: percentage of participants
number (confidence interval 95%)	4.7 (1.3 to 8.2)	17.6 (11.4 to 23.8)	19.0 (12.6 to 25.4)

Notes
[222] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[223] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[224] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[225]

P-value

< 0.001 ^[226]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[225] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[226] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[227]

P-value

< 0.001 ^[228]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

13.6

Confidence interval

level

95%

sides

2-sided

lower limit

6.6

upper limit

20.6

Notes
[227] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[228] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52

End point description

Bowel urgency was assessed by participants in a subject diary completed once a day.

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[229]	148 ^[230]	154 ^[231]
Units: percentage of participants
number (confidence interval 95%)	17.4 (11.4 to 23.5)	56.1 (48.1 to 64.1)	63.6 (56.0 to 71.2)

Notes
[229] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[230] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[231] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[232]

P-value

< 0.001 ^[233]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

38.7

Confidence interval

level

95%

sides

2-sided

lower limit

28.9

upper limit

48.5

Notes
[232] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[233] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[234]

P-value

< 0.001 ^[235]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

45.1

Confidence interval

level

95%

sides

2-sided

lower limit

35.5

upper limit

54.8

Notes
[234] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[235] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52

Top of page

End point title

Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52

End point description

Abdominal pain was assessed by participants in a subject diary completed once a day.

End point type

Secondary

End point timeframe

At Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[236]	148 ^[237]	154 ^[238]
Units: percentage of participants
number (confidence interval 95%)	20.8 (14.2 to 27.3)	45.9 (37.9 to 54.0)	55.3 (47.4 to 63.2)

Notes
[236] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[237] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
[238] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[239]

P-value

< 0.001 ^[240]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

24.3

Confidence interval

level

95%

sides

2-sided

lower limit

14.2

upper limit

34.5

Notes
[239] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[240] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[241]

P-value

< 0.001 ^[242]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted risk difference (%)

Point estimate

33.7

Confidence interval

level

95%

sides

2-sided

lower limit

23.6

upper limit

43.9

Notes
[241] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[242] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

Secondary: Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52

Top of page

End point title

Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52

End point description

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 52

End point values	SS3: Placebo	SS3: UPA 15 mg	SS3: UPA 30 mg
Number of subjects analysed	149 ^[243]	148 ^[244]	154 ^[245]
Units: units on a scale
least squares mean (confidence interval 95%)	3.7 (1.88 to 5.43)	8.7 (7.01 to 10.49)	9.5 (7.80 to 11.22)

Notes
[243] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
[244] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
[245] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI

Substudy 3: Upadacitinib 15 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 15 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[246]

P-value

< 0.001 ^[247]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

5.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.67

upper limit

7.52

Notes
[246] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[247] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)

Substudy 3: Upadacitinib 30 mg vs Placebo

Comparison groups

SS3: Placebo v SS3: UPA 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority ^[248]

P-value

< 0.001 ^[249]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

5.9

Confidence interval

level

95%

sides

2-sided

lower limit

3.44

upper limit

8.27

Notes
[248] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
[249] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)

Adverse events

Top of page

Timeframe for reporting adverse events

All-cause mortality from enrollment to study end: median follow-up was ≤ 57, 61, and 364 days (SS 1, 2, and 3). TEAEs/SAEs collected from 1st dose of study drug until 30 days after last dose; mean duration was ≤ 57, 56, and 364 days for SS 1, 2, and 3.

Adverse event reporting additional description

For safety analyses, participants were assigned to a treatment group based on the treatment actually received, regardless of the treatment randomized. The "as treated" group was determined by the most frequent dose regimen received in the analysis period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

SS1: Upadacitinib 7.5 mg

Reporting group description

During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Placebo

Reporting group description

During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 30 mg

Reporting group description

Reporting group title

SS1: Upadacitinib 15 mg

Reporting group description

During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS1: Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Placebo

Reporting group description

During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS3: Upadacitinib 15 mg

Reporting group description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 15 mg QD in Substudy 3.

Reporting group title

SS3: Placebo

Reporting group description

Reporting group title

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS2: Upadacitinib 45 mg

Reporting group description

During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

Reporting group title

SS2: Placebo/Upadacitinib 45 mg

Reporting group description

Reporting group title

SS3: Upadacitinib 30 mg

Reporting group description

Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 30 mg QD in Substudy 3.

Reporting group title

SS3: Upadacitinib 7.5 mg

Reporting group description

SS1: Upadacitinib 7.5 mg

SS1: Placebo

SS1: Upadacitinib 30 mg

SS1: Upadacitinib 15 mg

SS1: Upadacitinib 45 mg

SS2: Placebo

SS3: Upadacitinib 15 mg

SS3: Placebo

SS2: Upadacitinib 45 mg/Upadacitinib 45 mg

SS2: Upadacitinib 45 mg

SS2: Placebo/Upadacitinib 45 mg

SS3: Upadacitinib 30 mg

SS3: Upadacitinib 7.5 mg

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 47 (0.00%)

5 / 46 (10.87%)

5 / 117 (4.27%)

2 / 49 (4.08%)

6 / 123 (4.88%)

9 / 155 (5.81%)

24 / 323 (7.43%)

32 / 385 (8.31%)

2 / 59 (3.39%)

8 / 319 (2.51%)

2 / 85 (2.35%)

25 / 316 (7.91%)

0 / 20 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

ADENOCARCINOMA OF COLON

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BASAL CELL CARCINOMA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

INVASIVE BREAST CARCINOMA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SEBORRHOEIC KERATOSIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SMALL CELL CARCINOMA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

DEEP VEIN THROMBOSIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HYPOTENSION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

1 / 59 (1.69%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Surgical and medical procedures

ABORTION INDUCED

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

2 / 323 (0.62%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

DEVICE INTOLERANCE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PYREXIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

1 / 319 (0.31%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (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

Reproductive system and breast disorders

CERVICAL DYSPLASIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

2 / 316 (0.63%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

ACUTE RESPIRATORY FAILURE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (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

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INTERSTITIAL LUNG DISEASE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

NONINFECTIVE BRONCHITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PULMONARY EMBOLISM

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

2 / 323 (0.62%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

ANXIETY

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (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

DEPRESSION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (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

MENTAL DISORDER

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUICIDAL IDEATION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

ASPARTATE AMINOTRANSFERASE INCREASED

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

HIP FRACTURE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PULMONARY CONTUSION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SKIN LACERATION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

THORACIC VERTEBRAL FRACTURE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

ACUTE MYOCARDIAL INFARCTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (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

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

CARPAL TUNNEL SYNDROME

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CEREBROVASCULAR ACCIDENT

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SUBARACHNOID HAEMORRHAGE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

ANAEMIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

2 / 85 (2.35%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

IRON DEFICIENCY ANAEMIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

CATARACT

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

ABDOMINAL PAIN

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ANAL FISTULA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COLITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

1 / 155 (0.65%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COLITIS ULCERATIVE

subjects affected / exposed

0 / 47 (0.00%)

2 / 46 (4.35%)

4 / 117 (3.42%)

1 / 49 (2.04%)

3 / 123 (2.44%)

5 / 155 (3.23%)

1 / 323 (0.31%)

9 / 385 (2.34%)

1 / 59 (1.69%)

2 / 319 (0.63%)

1 / 85 (1.18%)

3 / 316 (0.95%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 5

0 / 1

1 / 3

3 / 6

0 / 1

4 / 9

0 / 1

0 / 2

0 / 1

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

COLON DYSPLASIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

DIAPHRAGMATIC HERNIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

1 / 155 (0.65%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ILEUS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

1 / 117 (0.85%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INTESTINAL OBSTRUCTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PANCREATITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

HEPATITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LIVER DISORDER

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

ERYTHEMA NODOSUM

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PANNICULITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SKIN ULCER

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

CYSTITIS HAEMORRHAGIC

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

1 / 117 (0.85%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

URINARY RETENTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

ARTHRITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CHONDROMALACIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (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

ABDOMINAL ABSCESS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ACUTE ENDOCARDITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

ANAL ABSCESS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

APPENDICITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

2 / 319 (0.63%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

ARTHRITIS BACTERIAL

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BREAST ABSCESS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BRONCHITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

BURSITIS INFECTIVE

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CELLULITIS

subjects affected / exposed

0 / 47 (0.00%)

1 / 46 (2.17%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

1 / 155 (0.65%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

CLOSTRIDIUM DIFFICILE INFECTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19 PNEUMONIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

2 / 323 (0.62%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

2 / 316 (0.63%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

GASTROENTERITIS NOROVIRUS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

1 / 319 (0.31%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HERPES ZOSTER

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (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 MENINGITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INFECTIOUS MONONUCLEOSIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

INFLUENZA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

LARGE INTESTINE INFECTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MASTITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

MUSCLE ABSCESS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

1 / 155 (0.65%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMOCYSTIS JIROVECII PNEUMONIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMONIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

3 / 385 (0.78%)

0 / 59 (0.00%)

1 / 319 (0.31%)

0 / 85 (0.00%)

1 / 316 (0.32%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMONIA CRYPTOCOCCAL

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

2 / 316 (0.63%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

PNEUMONIA PNEUMOCOCCAL

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

1 / 323 (0.31%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

POST PROCEDURAL INFECTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

RESPIRATORY SYNCYTIAL VIRUS INFECTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SEPSIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SINUSITIS

subjects affected / exposed

0 / 47 (0.00%)

1 / 46 (2.17%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

TONSILLITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

1 / 385 (0.26%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

UROSEPSIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

1 / 49 (2.04%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

VIRAL INFECTION

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

1 / 319 (0.31%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

VIRAL PHARYNGITIS

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

1 / 123 (0.81%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

HYPOALBUMINAEMIA

subjects affected / exposed

0 / 47 (0.00%)

0 / 46 (0.00%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

1 / 155 (0.65%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

HYPOPHOSPHATAEMIA

subjects affected / exposed

0 / 47 (0.00%)

1 / 46 (2.17%)

0 / 117 (0.00%)

0 / 49 (0.00%)

0 / 123 (0.00%)

0 / 155 (0.00%)

0 / 323 (0.00%)

0 / 385 (0.00%)

0 / 59 (0.00%)

0 / 319 (0.00%)

0 / 85 (0.00%)

0 / 316 (0.00%)

0 / 20 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	SS1: Upadacitinib 7.5 mg	SS1: Placebo	SS1: Upadacitinib 30 mg	SS1: Upadacitinib 15 mg	SS1: Upadacitinib 45 mg	SS2: Placebo	SS3: Upadacitinib 15 mg	SS3: Placebo	SS2: Upadacitinib 45 mg/Upadacitinib 45 mg	SS2: Upadacitinib 45 mg	SS2: Placebo/Upadacitinib 45 mg	SS3: Upadacitinib 30 mg	SS3: Upadacitinib 7.5 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 47 (38.30%)	27 / 46 (58.70%)	58 / 117 (49.57%)	22 / 49 (44.90%)	50 / 123 (40.65%)	62 / 155 (40.00%)	181 / 323 (56.04%)	216 / 385 (56.10%)	17 / 59 (28.81%)	121 / 319 (37.93%)	36 / 85 (42.35%)	166 / 316 (52.53%)	18 / 20 (90.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MALIGNANT MELANOMA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
MELANOCYTIC NAEVUS
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	0	1
SKIN PAPILLOMA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	2 / 319 (0.63%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	2	1
General disorders and administration site conditions
INFLUENZA LIKE ILLNESS
subjects affected / exposed	1 / 47 (2.13%)	1 / 46 (2.17%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	2 / 385 (0.52%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	1	1	1	0	0	0	0	2	0	0	0	2	1
PSEUDOPOLYP
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	1
PYREXIA
subjects affected / exposed	1 / 47 (2.13%)	1 / 46 (2.17%)	5 / 117 (4.27%)	0 / 49 (0.00%)	1 / 123 (0.81%)	2 / 155 (1.29%)	10 / 323 (3.10%)	11 / 385 (2.86%)	0 / 59 (0.00%)	8 / 319 (2.51%)	6 / 85 (7.06%)	18 / 316 (5.70%)	1 / 20 (5.00%)
occurrences all number	1	1	5	0	1	3	10	13	0	8	7	19	1
Respiratory, thoracic and mediastinal disorders
ASTHMA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	2
COUGH
subjects affected / exposed	1 / 47 (2.13%)	1 / 46 (2.17%)	3 / 117 (2.56%)	1 / 49 (2.04%)	4 / 123 (3.25%)	2 / 155 (1.29%)	6 / 323 (1.86%)	6 / 385 (1.56%)	1 / 59 (1.69%)	5 / 319 (1.57%)	2 / 85 (2.35%)	4 / 316 (1.27%)	2 / 20 (10.00%)
occurrences all number	1	1	3	1	4	2	6	6	1	5	2	5	2
NASAL CONGESTION
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	3 / 385 (0.78%)	0 / 59 (0.00%)	0 / 319 (0.00%)	1 / 85 (1.18%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	0	1	3	0	0	1	2	1
OROPHARYNGEAL PAIN
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	4 / 117 (3.42%)	2 / 49 (4.08%)	0 / 123 (0.00%)	1 / 155 (0.65%)	5 / 323 (1.55%)	6 / 385 (1.56%)	0 / 59 (0.00%)	6 / 319 (1.88%)	1 / 85 (1.18%)	8 / 316 (2.53%)	1 / 20 (5.00%)
occurrences all number	1	0	4	2	0	1	5	6	0	6	1	8	1
PULMONARY MASS
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	2 / 155 (1.29%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	1 / 319 (0.31%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	1	0	0	2
Psychiatric disorders
DEPRESSED MOOD
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
IRRITABILITY
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	2 / 385 (0.52%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	0	0	0	1
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	4 / 117 (3.42%)	3 / 49 (6.12%)	8 / 123 (6.50%)	3 / 155 (1.94%)	20 / 323 (6.19%)	7 / 385 (1.82%)	4 / 59 (6.78%)	16 / 319 (5.02%)	5 / 85 (5.88%)	21 / 316 (6.65%)	0 / 20 (0.00%)
occurrences all number	0	0	4	3	8	3	21	7	4	18	5	25	0
HAEMOGLOBIN DECREASED
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	0 / 117 (0.00%)	1 / 49 (2.04%)	2 / 123 (1.63%)	3 / 155 (1.94%)	2 / 323 (0.62%)	1 / 385 (0.26%)	1 / 59 (1.69%)	0 / 319 (0.00%)	0 / 85 (0.00%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	1	0	0	1	2	4	2	1	1	0	0	3	1
LYMPHOCYTE COUNT DECREASED
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	1 / 117 (0.85%)	1 / 49 (2.04%)	2 / 123 (1.63%)	0 / 155 (0.00%)	6 / 323 (1.86%)	3 / 385 (0.78%)	1 / 59 (1.69%)	3 / 319 (0.94%)	0 / 85 (0.00%)	5 / 316 (1.58%)	1 / 20 (5.00%)
occurrences all number	0	0	1	1	2	0	7	3	1	3	0	6	1
LYMPHOCYTE COUNT INCREASED
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	1 / 385 (0.26%)	0 / 59 (0.00%)	3 / 319 (0.94%)	0 / 85 (0.00%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	3	0	2	1
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE
subjects affected / exposed	0 / 47 (0.00%)	3 / 46 (6.52%)	5 / 117 (4.27%)	2 / 49 (4.08%)	3 / 123 (2.44%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	3	5	2	3	0	0	0	0	0	0	0	0
FALL
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Nervous system disorders
HEADACHE
subjects affected / exposed	4 / 47 (8.51%)	5 / 46 (10.87%)	9 / 117 (7.69%)	4 / 49 (8.16%)	8 / 123 (6.50%)	4 / 155 (2.58%)	10 / 323 (3.10%)	16 / 385 (4.16%)	2 / 59 (3.39%)	13 / 319 (4.08%)	4 / 85 (4.71%)	14 / 316 (4.43%)	0 / 20 (0.00%)
occurrences all number	4	5	9	4	9	4	10	16	3	16	4	16	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	0 / 47 (0.00%)	3 / 46 (6.52%)	4 / 117 (3.42%)	3 / 49 (6.12%)	1 / 123 (0.81%)	9 / 155 (5.81%)	11 / 323 (3.41%)	20 / 385 (5.19%)	1 / 59 (1.69%)	8 / 319 (2.51%)	5 / 85 (5.88%)	7 / 316 (2.22%)	1 / 20 (5.00%)
occurrences all number	0	3	4	3	1	9	12	24	1	8	5	7	2
LYMPHOPENIA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	1 / 123 (0.81%)	1 / 155 (0.65%)	3 / 323 (0.93%)	3 / 385 (0.78%)	0 / 59 (0.00%)	6 / 319 (1.88%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	1	1	4	4	0	7	0	1	1
Ear and labyrinth disorders
CERUMEN IMPACTION
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Eye disorders
CATARACT
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	2 / 385 (0.52%)	0 / 59 (0.00%)	1 / 319 (0.31%)	1 / 85 (1.18%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	1	1	2	2
VISUAL IMPAIRMENT
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Gastrointestinal disorders
ABDOMINAL DISTENSION
subjects affected / exposed	3 / 47 (6.38%)	0 / 46 (0.00%)	0 / 117 (0.00%)	1 / 49 (2.04%)	1 / 123 (0.81%)	0 / 155 (0.00%)	2 / 323 (0.62%)	2 / 385 (0.52%)	0 / 59 (0.00%)	3 / 319 (0.94%)	1 / 85 (1.18%)	5 / 316 (1.58%)	1 / 20 (5.00%)
occurrences all number	3	0	0	1	1	0	2	2	0	4	1	5	1
ABDOMINAL PAIN
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	1 / 117 (0.85%)	1 / 49 (2.04%)	3 / 123 (2.44%)	1 / 155 (0.65%)	8 / 323 (2.48%)	8 / 385 (2.08%)	2 / 59 (3.39%)	4 / 319 (1.25%)	1 / 85 (1.18%)	5 / 316 (1.58%)	1 / 20 (5.00%)
occurrences all number	0	1	1	1	3	1	9	8	2	5	1	5	2
ABDOMINAL TENDERNESS
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	1 / 117 (0.85%)	0 / 49 (0.00%)	3 / 123 (2.44%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	1	1	0	3	0	0	0	0	0	0	2	1
APHTHOUS ULCER
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	3 / 385 (0.78%)	0 / 59 (0.00%)	2 / 319 (0.63%)	0 / 85 (0.00%)	4 / 316 (1.27%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	4	0	2	0	4	1
COLITIS ULCERATIVE
subjects affected / exposed	1 / 47 (2.13%)	4 / 46 (8.70%)	4 / 117 (3.42%)	2 / 49 (4.08%)	3 / 123 (2.44%)	16 / 155 (10.32%)	40 / 323 (12.38%)	101 / 385 (26.23%)	1 / 59 (1.69%)	1 / 319 (0.31%)	2 / 85 (2.35%)	24 / 316 (7.59%)	3 / 20 (15.00%)
occurrences all number	1	4	4	2	3	16	47	110	1	1	2	25	3
CONSTIPATION
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	1 / 117 (0.85%)	0 / 49 (0.00%)	1 / 123 (0.81%)	0 / 155 (0.00%)	4 / 323 (1.24%)	2 / 385 (0.52%)	0 / 59 (0.00%)	6 / 319 (1.88%)	2 / 85 (2.35%)	7 / 316 (2.22%)	2 / 20 (10.00%)
occurrences all number	0	1	1	0	1	0	5	2	0	6	2	7	2
DIARRHOEA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	2 / 123 (1.63%)	0 / 155 (0.00%)	2 / 323 (0.62%)	4 / 385 (1.04%)	0 / 59 (0.00%)	1 / 319 (0.31%)	0 / 85 (0.00%)	2 / 316 (0.63%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	2	0	2	4	0	1	0	2	2
NAUSEA
subjects affected / exposed	1 / 47 (2.13%)	2 / 46 (4.35%)	8 / 117 (6.84%)	1 / 49 (2.04%)	0 / 123 (0.00%)	3 / 155 (1.94%)	6 / 323 (1.86%)	6 / 385 (1.56%)	0 / 59 (0.00%)	4 / 319 (1.25%)	1 / 85 (1.18%)	7 / 316 (2.22%)	1 / 20 (5.00%)
occurrences all number	1	2	8	1	0	3	6	7	0	5	1	7	1
PERIANAL ERYTHEMA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
VOMITING
subjects affected / exposed	1 / 47 (2.13%)	1 / 46 (2.17%)	1 / 117 (0.85%)	1 / 49 (2.04%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	1 / 385 (0.26%)	0 / 59 (0.00%)	2 / 319 (0.63%)	1 / 85 (1.18%)	3 / 316 (0.95%)	1 / 20 (5.00%)
occurrences all number	1	1	1	1	0	0	1	1	0	2	1	3	1
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	6 / 117 (5.13%)	1 / 49 (2.04%)	6 / 123 (4.88%)	1 / 155 (0.65%)	7 / 323 (2.17%)	8 / 385 (2.08%)	1 / 59 (1.69%)	15 / 319 (4.70%)	2 / 85 (2.35%)	11 / 316 (3.48%)	0 / 20 (0.00%)
occurrences all number	1	0	6	1	6	1	8	8	1	15	2	14	0
DERMATITIS ACNEIFORM
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	2 / 117 (1.71%)	0 / 49 (0.00%)	0 / 123 (0.00%)	1 / 155 (0.65%)	1 / 323 (0.31%)	0 / 385 (0.00%)	0 / 59 (0.00%)	4 / 319 (1.25%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	2	0	0	1	1	0	0	4	0	0	1
PRURITUS
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	4 / 155 (2.58%)	2 / 323 (0.62%)	9 / 385 (2.34%)	0 / 59 (0.00%)	1 / 319 (0.31%)	0 / 85 (0.00%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	1	1	0	0	4	2	12	0	1	0	2	1
RASH
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	5 / 117 (4.27%)	0 / 49 (0.00%)	1 / 123 (0.81%)	1 / 155 (0.65%)	9 / 323 (2.79%)	14 / 385 (3.64%)	1 / 59 (1.69%)	8 / 319 (2.51%)	0 / 85 (0.00%)	14 / 316 (4.43%)	2 / 20 (10.00%)
occurrences all number	1	0	5	0	1	1	9	14	1	8	0	15	2
ROSACEA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	4 / 323 (1.24%)	1 / 385 (0.26%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	0	4	1	0	0	0	1	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	2 / 47 (4.26%)	1 / 46 (2.17%)	2 / 117 (1.71%)	0 / 49 (0.00%)	3 / 123 (2.44%)	7 / 155 (4.52%)	19 / 323 (5.88%)	28 / 385 (7.27%)	0 / 59 (0.00%)	5 / 319 (1.57%)	0 / 85 (0.00%)	8 / 316 (2.53%)	4 / 20 (20.00%)
occurrences all number	2	1	2	0	3	7	19	28	0	5	0	9	5
BACK PAIN
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	2 / 117 (1.71%)	0 / 49 (0.00%)	1 / 123 (0.81%)	1 / 155 (0.65%)	11 / 323 (3.41%)	15 / 385 (3.90%)	0 / 59 (0.00%)	3 / 319 (0.94%)	1 / 85 (1.18%)	4 / 316 (1.27%)	1 / 20 (5.00%)
occurrences all number	0	1	2	0	1	1	11	15	0	3	1	4	1
BURSITIS
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	1 / 49 (2.04%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	1
MUSCLE SPASMS
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	2 / 117 (1.71%)	1 / 49 (2.04%)	2 / 123 (1.63%)	1 / 155 (0.65%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	1 / 319 (0.31%)	2 / 85 (2.35%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	1	2	1	2	1	0	0	0	1	2	0	1
MUSCULOSKELETAL PAIN
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	2 / 323 (0.62%)	3 / 385 (0.78%)	0 / 59 (0.00%)	1 / 319 (0.31%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	1	1	0	0	0	2	3	0	1	0	1	1
OSTEOPENIA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	1 / 155 (0.65%)	1 / 323 (0.31%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0	2	1
PAIN IN EXTREMITY
subjects affected / exposed	0 / 47 (0.00%)	3 / 46 (6.52%)	0 / 117 (0.00%)	0 / 49 (0.00%)	2 / 123 (1.63%)	1 / 155 (0.65%)	1 / 323 (0.31%)	4 / 385 (1.04%)	0 / 59 (0.00%)	1 / 319 (0.31%)	2 / 85 (2.35%)	6 / 316 (1.90%)	0 / 20 (0.00%)
occurrences all number	0	3	0	0	2	1	1	4	0	1	2	6	0
Infections and infestations
BRONCHITIS
subjects affected / exposed	0 / 47 (0.00%)	2 / 46 (4.35%)	2 / 117 (1.71%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	4 / 323 (1.24%)	4 / 385 (1.04%)	0 / 59 (0.00%)	0 / 319 (0.00%)	2 / 85 (2.35%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	0	2	2	0	0	0	4	4	0	0	2	2	1
CYSTITIS
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	3 / 323 (0.93%)	1 / 385 (0.26%)	0 / 59 (0.00%)	1 / 319 (0.31%)	1 / 85 (1.18%)	2 / 316 (0.63%)	1 / 20 (5.00%)
occurrences all number	1	0	1	0	0	0	3	1	0	1	1	3	1
EAR INFECTION
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	2 / 155 (1.29%)	3 / 323 (0.93%)	0 / 385 (0.00%)	1 / 59 (1.69%)	0 / 319 (0.00%)	0 / 85 (0.00%)	3 / 316 (0.95%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	2	3	0	1	0	0	3	1
HERPES ZOSTER
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	10 / 323 (3.10%)	0 / 385 (0.00%)	3 / 59 (5.08%)	1 / 319 (0.31%)	5 / 85 (5.88%)	15 / 316 (4.75%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	10	0	3	1	5	16	0
INFLUENZA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	2 / 117 (1.71%)	0 / 49 (0.00%)	3 / 123 (2.44%)	1 / 155 (0.65%)	10 / 323 (3.10%)	4 / 385 (1.04%)	0 / 59 (0.00%)	3 / 319 (0.94%)	1 / 85 (1.18%)	8 / 316 (2.53%)	1 / 20 (5.00%)
occurrences all number	0	0	2	0	3	1	10	4	0	3	1	10	2
NASOPHARYNGITIS
subjects affected / exposed	1 / 47 (2.13%)	3 / 46 (6.52%)	3 / 117 (2.56%)	3 / 49 (6.12%)	4 / 123 (3.25%)	6 / 155 (3.87%)	31 / 323 (9.60%)	27 / 385 (7.01%)	1 / 59 (1.69%)	15 / 319 (4.70%)	4 / 85 (4.71%)	30 / 316 (9.49%)	0 / 20 (0.00%)
occurrences all number	1	3	3	3	4	6	40	28	1	16	4	43	0
ORAL HERPES
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	2 / 117 (1.71%)	0 / 49 (0.00%)	1 / 123 (0.81%)	0 / 155 (0.00%)	6 / 323 (1.86%)	7 / 385 (1.82%)	0 / 59 (0.00%)	4 / 319 (1.25%)	2 / 85 (2.35%)	9 / 316 (2.85%)	1 / 20 (5.00%)
occurrences all number	0	1	2	0	1	0	8	8	0	4	2	11	1
PULPITIS DENTAL
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	1 / 323 (0.31%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	1
RESPIRATORY TRACT INFECTION VIRAL
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	1 / 155 (0.65%)	4 / 323 (1.24%)	1 / 385 (0.26%)	0 / 59 (0.00%)	1 / 319 (0.31%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1	4	1	0	1	0	0	1
SKIN CANDIDA
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	3 / 117 (2.56%)	4 / 49 (8.16%)	6 / 123 (4.88%)	6 / 155 (3.87%)	19 / 323 (5.88%)	11 / 385 (2.86%)	0 / 59 (0.00%)	8 / 319 (2.51%)	0 / 85 (0.00%)	15 / 316 (4.75%)	2 / 20 (10.00%)
occurrences all number	1	0	3	4	7	6	20	12	0	9	0	18	2
URINARY TRACT INFECTION
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	3 / 117 (2.56%)	0 / 49 (0.00%)	1 / 123 (0.81%)	3 / 155 (1.94%)	10 / 323 (3.10%)	9 / 385 (2.34%)	0 / 59 (0.00%)	3 / 319 (0.94%)	2 / 85 (2.35%)	4 / 316 (1.27%)	2 / 20 (10.00%)
occurrences all number	1	0	3	0	1	3	13	10	0	3	3	6	2
VAGINAL INFECTION
subjects affected / exposed	0 / 47 (0.00%)	0 / 46 (0.00%)	0 / 117 (0.00%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	0 / 323 (0.00%)	0 / 385 (0.00%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	0 / 47 (0.00%)	2 / 46 (4.35%)	0 / 117 (0.00%)	1 / 49 (2.04%)	0 / 123 (0.00%)	1 / 155 (0.65%)	1 / 323 (0.31%)	2 / 385 (0.52%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	2	0	1	0	1	1	2	0	0	0	0	1
HYPOKALAEMIA
subjects affected / exposed	1 / 47 (2.13%)	0 / 46 (0.00%)	1 / 117 (0.85%)	0 / 49 (0.00%)	0 / 123 (0.00%)	0 / 155 (0.00%)	3 / 323 (0.93%)	5 / 385 (1.30%)	0 / 59 (0.00%)	1 / 319 (0.31%)	0 / 85 (0.00%)	0 / 316 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	1	0	0	0	3	5	0	1	0	0	1
IRON DEFICIENCY
subjects affected / exposed	0 / 47 (0.00%)	1 / 46 (2.17%)	0 / 117 (0.00%)	0 / 49 (0.00%)	1 / 123 (0.81%)	2 / 155 (1.29%)	0 / 323 (0.00%)	2 / 385 (0.52%)	0 / 59 (0.00%)	0 / 319 (0.00%)	0 / 85 (0.00%)	1 / 316 (0.32%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	1	2	0	2	0	0	0	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

29 Sep 2016

Global Amendment 1 ● Corrected the definition of clinical response per Adapted Mayo score ● Further clarified the timeframe of providing written informed consent as it relates to screening procedures ● Excluded subjects who received traditional Chinese medicines within 28 days prior to Baseline and during the study ● Added birth control requirements for US and Colombian women of childbearing potential and updated effective birth control methods ● Updated text regarding 30 day follow up pregnancy testing ● Updated requirements and acceptable procedures for chest x-ray and computed tomography (CT) scan ● Added the Ulcerative Colitis Symptoms Questionnaire (UC-SQ) ● Clarified that local testing for C-reactive protein was not allowed ● Removed proportion of subjects with stool frequency subscore (SFS) ≤ 1 and proportion of subjects with RBS of 0 as multiplicity-controlled secondary endpoints and included them as non-multiplicity-controlled secondary endpoints ● Added the justification of the assumption of 60% average induction response rates for upadacitinib doses in the sample size determination

10 Oct 2017

Global Amendment 2 ● Updated the percentage of subjects with a history of inadequate response or intolerance to biologic therapies expected to enroll in Substudy 1 from 50% to 75% ● Made several administrative changes

03 Jul 2018

Global Amendment 3 ● Updated the protocol to reflect the selected Phase 3 Substudy 2 induction dose of upadacitinib 45 mg and updated the study design for both induction and maintenance studies ● Added the Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity (PGIS), added Cohort 3 in Substudy 3 for subjects treated with upadacitinib 45 mg for 16 weeks who achieved clinical response at the end of the Extended Treatment Period at Week 16 (Study M14-234 Substudy 2 Part 2 and Study M14-675 Part 2) ● Added the Extended Treatment Period in Substudy 2 to offer upadacitinib induction treatment to placebo clinical non-responders from 8-week induction therapy and evaluate the delayed clinical response in upadacitinib clinical non-responders from 8-week induction therapy ● Updated the sample size based on Phase 2b results ● Clarified that serious and disease-related events that are at least possibly related to study drug should also be reported in an expedited manner ● Reduced the number of pharmacokinetic samples ● Increased the duration of the maintenance period from 44 to 52 weeks ● Updated sample size calculations to reflect study design changes ● Added concomitant medication and rescue therapy wording ● Updated vaccine wording, removed requirement for male contraception ● Updated pregnancy test wording ● Updated the primary and secondary endpoints based on Food and Drug Administration guidance ● Modified the stratification factors ● Set maximum enrollment at 50% for non-bio-IR subjects, 30% for Bio-IR subjects who failed 3 or more biologics, and 20% non-bio-IR subjects who had exposure to biologics

24 Apr 2019

Global Amendment 4 Aligned Study M14-234 and Study M14-675 protocols by: ● Updating the study objective to include the secondary objectives ● Updating the benefit risk language, modifying Exclusion Criterion #14 to allow for undetectable biologic levels to be measured via a commercially available assay as an alternative to the washout period, based on regulatory feedback ● Adding the country-specific requirements in the inclusion/exclusion criteria (included 16- and 17-year-old subjects, where locally permitted) ● Adding, amending, and clarifying the study procedures ● Adding justification for the use of placebo and further elaborating on the details of the DMC

29 Apr 2020

Global Amendment 5 ● Updated wording about re-testing of exclusionary laboratory values during the screening period ● Clarified intervals for testing biologic drug levels ● Updated the criteria of clinical response for entering extended treatment period for subjects with missing Week 8 endoscopy when endoscopies cannot be performed due to the COVID-19 pandemic ● Moved non-multiplicity-controlled secondary efficacy variables to additional efficacy variables ● Added criteria for failure of ustekinumab treatment, added wording to define borderline serum pregnancy test results, clarified that live vaccines should not be administered for at least 30 days prior to or after study drug administration ● Excluded subjects with a history of gastrointestinal (GI) perforation (perforation due to mechanical injury should not exclude a subject from participation) ● Prohibited cytapheresis treatment for 60 days prior to screening ● Excluded subjects with prior history of thrombotic events including deep vein thrombosis (DVT) and pulmonary embolism (PE) or known inherited conditions that predispose to hypercoagulability ● Added wording about gastric banding/segmentation to make clear that it is not an exclusion ● Added wording to the washout requirements for all biologic therapies ● Removed wording about women classified as non-childbearing potential ● Updated ECG review requirements ● Updated the type of QuantiFERON TB test used ● Updated toxicity management for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), thrombosis events, and herpes zoster ● Revised the Statistical and Analytical Plans in Protocol Section 8.1

31 Jul 2020

Global Amendment 6 ● Updated information on the re-evaluation of the benefit and risk to subjects participating in the study ● Updated wording to allow for changes in visits and procedures affected by the COVID-19 pandemic and associated changes in global/local regulations ● Updated the wording on enrollment to note that enrollment is closed for Substudy 2

10 May 2021

Global Amendment 7 ● Removed UC-related hospitalizations and UC-related surgeries from the multiplicity-controlled secondary endpoints ● Clarified the primary ITT and Substudy 3 ITT populations ● Added non-responder imputation (NRI) while incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) and mixed-effect model repeated measurement (MMRM) methods to ensure clarity of statistical analysis; clarified rescue handling approaches used ● Added a subgroup analysis of the primary endpoint: Baseline aminosalicylate use (yes, no) ● Clarified the analysis for continuous laboratory and vital sign parameters

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 Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

Primary: Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

Primary: Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

Primary: Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

Primary: Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52

Primary: Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52

Secondary: Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8

Secondary: Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

Secondary: Substudy 1: Change in Full Mayo Score From Baseline to Week 8

Secondary: Substudy 1: Change in Full Mayo Score From Baseline to Week 8

Secondary: Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8

Secondary: Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8

Secondary: Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

Secondary: Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

Secondary: Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8

Secondary: Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8

Secondary: Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8

Secondary: Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8

Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

Secondary: Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8

Secondary: Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8

Secondary: Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8

Secondary: Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8

Secondary: Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8

Secondary: Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8

Secondary: Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52

Secondary: Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52

Secondary: Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

Secondary: Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

Secondary: Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

Secondary: Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

Secondary: Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment

Secondary: Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment

Secondary: Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52

Secondary: Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52

Secondary: Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment

Secondary: Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment

Secondary: Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52

Secondary: Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52

Secondary: Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52

Secondary: Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52

Secondary: Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52

Secondary: Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52

Secondary: Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52

Secondary: Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52

Secondary: Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52

Secondary: Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52

Secondary: Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52

Secondary: Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis