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Clinical Trial Results:
A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment with Disease-Modifying Antirheumatic Drugs

Summary
EudraCT number	2012-002324-32
Trial protocol	BE SE DE GB PT AT IT GR
Global end of trial date	26 Aug 2015

Results information
Results version number	v1
This version publication date	26 Mar 2017
First version publication date	26 Mar 2017
Other versions	v2

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

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Trial information

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Sponsor protocol code

14062

ISRCTN number

US NCT number

NCT01711359

WHO universal trial number (UTN)

Other trial identifiers

Trial Alias: I4V-MC-JADZ , Trial Number: 14062

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-CTLilly,

Scientific contact

Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-285-4559,

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

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

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

Analysis stage

Final

Date of interim/final analysis

26 Aug 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Aug 2015

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to determine whether baricitinib therapy alone is noninferior to methotrexate (MTX) therapy alone in the treatment of moderate to severe active rheumatoid arthritis (RA) in those who have had limited or no treatment with MTX and are naive to other conventional or biologic disease-modifying antirheumatic drugs (DMARDs).

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Nov 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 103

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Belgium: 27

Country: Number of subjects enrolled

Brazil: 20

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

Greece: 1

Country: Number of subjects enrolled

India: 47

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

Japan: 104

Country: Number of subjects enrolled

Mexico: 46

Country: Number of subjects enrolled

Portugal: 3

Country: Number of subjects enrolled

Russian Federation: 36

Country: Number of subjects enrolled

South Africa: 20

Country: Number of subjects enrolled

Korea, Republic of: 7

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

United Kingdom: 14

Country: Number of subjects enrolled

United States: 104

Worldwide total number of subjects

584

EEA total number of subjects

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)

501

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

All started participants received at least one dose of study drug.

Screening details

Participants who did not respond (nonresponders) to study drug were eligible for rescue treatment beginning at Week 24. Nonresponders were defined as lack of improvement of at least 20% in both tender joint count and swollen joint count.

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Methotrexate

Arm description

Methotrexate (MTX) administered orally once weekly with dose ranging from 10 to 20 milligram (mg) per week through Week 52. Participants also received baricitinib placebo orally once daily. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly. All started participants received at least one dose of study drug.

Arm type

Active comparator

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

MTX administered orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Participants received baricitinib placebo orally once daily. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.

Investigational medicinal product name

Folic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Folic acid administered orally every day.

Baricitinib

Arm description

Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX placebo orally once weekly through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Baricitinib 4 mg administered orally once daily through Week 52. Participants will receive MTX placebo orally once weekly through Week 52. Starting at Week 24, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.

Investigational medicinal product name

Baricitinib

Investigational medicinal product code

Other name

LY3009104

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Folic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Folic acid administered orally every day.

Baricitinib + MTX

Arm description

Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.

Arm type

Experimental

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Baricitinib 4 milligram (mg) administered orally once daily through Week 52. Participants will receive methotrexate (MTX) orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Starting at Week 24, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.

Investigational medicinal product name

Baricitinib

Investigational medicinal product code

Other name

LY3009104

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Folic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Folic acid administered orally every day.

Number of subjects in period 1	Methotrexate	Baricitinib	Baricitinib + MTX
Started	210	159	215
Rescued	26 ^[1]	7 ^[2]	6 ^[3]
Completed	161	136	173
Not completed	49	23	42
Adverse event, serious fatal	3	-	-
Consent withdrawn by subject	18	7	13
Physician decision	4	3	2
Adverse event, non-fatal	8	10	24
Sponsor Decision	1	-	-
Lost to follow-up	1	1	1
Entry Criteria Not Met	1	-	-
Lack of efficacy	13	2	2

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who were nonresponders based on tender/swollen joint count were entered into the rescue milestone calculation.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who were nonresponders based on tender/swollen joint count were entered into the rescue milestone calculation.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who were nonresponders based on tender/swollen joint count were entered into the rescue milestone calculation.

Period 2 title

Follow Up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Methotrexate - Follow-up

Arm description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Baricitinib - Follow-up

Arm description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Baricitinib + MTX - Follow-up

Arm description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug. Includes participants who were rescued to Baricitinib + MTX.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2 ^[4]	Methotrexate - Follow-up	Baricitinib - Follow-up	Baricitinib + MTX - Follow-up
Started	25	15	28
Completed	25	15	28

Notes
[4] - 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: Includes participants who entered the post-treatment follow-up period

Baseline characteristics

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Reporting group title

Methotrexate

Reporting group description

Reporting group title

Baricitinib

Reporting group description

Reporting group title

Baricitinib + MTX

Reporting group description

Reporting group values	Methotrexate	Baricitinib	Baricitinib + MTX	Total
Number of subjects	210	159	215	584
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.5 ± 13.4	50.9 ± 13	48.5 ± 13.5	-
Gender, Male/Female
Units: participants
Female	148	121	156	425
Male	62	38	59	159
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	11	10	20	41
Asian	60	44	61	165
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	10	5	10	25
White	128	98	123	349
More than one race	1	2	1	4
Unknown or Not Reported	0	0	0	0
Region of Enrollment
Units: Subjects
Argentina	41	29	33	103
Austria	1	1	1	3
Belgium	6	10	11	27
Brazil	8	3	9	20
Canada	5	5	7	17
Germany	5	5	4	14
Greece	0	0	1	1
India	18	12	17	47
Italy	8	2	4	14
Japan	36	29	39	104
Mexico	12	14	20	46
Portugal	1	0	2	3
Russian Federation	11	13	12	36
South Africa	7	4	9	20
Korea, Republic of	4	1	2	7
Sweden	3	0	1	4
United Kingdom	7	3	4	14
United States	37	28	39	104
Duration of Rheumatoid Arthritis
Units: years
median (inter-quartile range (Q1-Q3))	0.2 (0.1 to 0.6)	0.2 (0.1 to 1.1)	0.2 (0.1 to 1)	-
Tender Joint Count of 68 evaluable joints
Units: number of joints
arithmetic mean (standard deviation)	26.5 ± 14.8	26.4 ± 14.1	27.7 ± 14.5	-
Swollen Joint Count of 66 evaluable joints
Units: number of joints
arithmetic mean (standard deviation)	16.4 ± 10.6	16.1 ± 9.2	16.3 ± 9.5	-
High sensitivity C-reactive protein
Units: milligrams per liter (mg/L)
arithmetic mean (standard deviation)	22.34 ± 21.78	23.75 ± 26.24	24.27 ± 29.42	-

End points

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Reporting group title

Methotrexate

Reporting group description

Reporting group title

Baricitinib

Reporting group description

Reporting group title

Baricitinib + MTX

Reporting group description

Reporting group title

Methotrexate - Follow-up

Reporting group description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

Reporting group title

Baricitinib - Follow-up

Reporting group description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

Reporting group title

Baricitinib + MTX - Follow-up

Reporting group description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug. Includes participants who were rescued to Baricitinib + MTX.

Subject analysis set title

Baricitinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

All randomized participants who received at least 1 dose of study drug with evaluable PK data.

Primary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

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End point title

Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

End point description

ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). "ACR20 Responder" is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), participant's assessment of pain, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinue study or drug or are rescued before analysis time point are deemed non-responders. Analysis Population Description: Modified Intent-to-Treat (mITT) population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using nonresponder imputation (NRI).

End point type

Primary

End point timeframe

Week 24

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: Percent of participants
number (not applicable)
Week 24	61.9	76.7	78.1

Statistical Analysis for ACR20

Comparison groups

Baricitinib v Methotrexate

Number of subjects included in analysis

369

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Newcombe-Wilson method

Point estimate

14.8

Confidence interval

level

95%

sides

2-sided

lower limit

5.5

upper limit

24.1

Notes
[1] - Noninferiority is concluded if the lower bound of the 95% CI for the difference in response rate is >-12%

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

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End point title

Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

End point description

HAQ-DI assesses the participant's self-perception on the degree of difficulty [0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area are averaged to calculate the HAQ-DI score, which ranges from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicates an improvement in the participant's condition. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using modified baseline observation carried forward (mBOCF).

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: units on a scale
arithmetic mean (standard deviation)	-0.73 ± 0.71	-1.01 ± 0.74	-0.92 ± 0.74

No statistical analyses for this end point

Secondary: Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)

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End point title

Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)

End point description

Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using the following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mBOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: units on a scale
arithmetic mean (standard deviation)	-2.01 ± 1.51	-2.74 ± 1.39	-2.82 ± 1.58

No statistical analyses for this end point

Secondary: Change from Baseline in the modified Total Sharp Score (mTSS)

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End point title

Change from Baseline in the modified Total Sharp Score (mTSS)

End point description

X-rays of the hands/wrists and feet were scored for structural progression as measured using the mTSS. This methodology quantified the extent of bone erosions and joint space narrowing for 44 and 42 joints, with higher scores representing greater damage. The mTSS at a time point is the sum of the erosion (range from 0 to 280) and JSN (range from 0 to 168) scores, for a maximum score of 448. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessments. Missing values due to discontinuation of study, rescue, or missing data were imputed using linear extrapolation (LE).

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	191	152	198
Units: units on a scale
arithmetic mean (standard deviation)	0.64 ± 1.81	0.43 ± 1.18	0.32 ± 1.14

No statistical analyses for this end point

Secondary: Percentage of Participants Who Achieved a Simplified Disease Activity Index (SDAI) Score ≤3.3

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End point title

Percentage of Participants Who Achieved a Simplified Disease Activity Index (SDAI) Score ≤3.3

End point description

SDAI is a tool for measurement of disease activity in RA that integrates TJC28, SJC28, acute phase response using C-reactive protein (milligrams per liter), Participant's Global Assessment of Disease Activity using VAS centimeters (cm), and Physician's Global Assessment of Disease Activity using VAS (cm). The SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. An index-based definition of remission occurs with an SDAI score ≤3.3. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.

End point type

Secondary

End point timeframe

Week 24

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: percentage of participants
number (not applicable)	10.5	22	22.8

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response

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End point title

Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response

End point description

ACR50 Responder Index is composite of clinical, laboratory, and functional measures in RA. "ACR50 Responder" is a participant who has at least 50% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), HAQ-DI, participant's assessment of pain, and hsCRP. Participants with missing responses and participants who discontinue study or drug or are rescued before analysis time point are deemed non-responders. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: Percent of participants
number (not applicable)
Week 12	32.9	54.7	60
Week 24	43.3	59.7	63.3
Week 52	37.6	57.2	61.9

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response

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End point title

Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response

End point description

ACR70 Responder Index is composite of clinical, laboratory, and functional measures in RA. "ACR70 Responder" is a participant who has at least 50% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), HAQ-DI, participant's assessment of pain, and hsCRP. Participants with missing responses and participants who discontinue study or drug or are rescued before analysis time point are deemed non-responders. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: Percent of participants
number (not applicable)
Week 12	15.7	30.8	33.5
Week 24	21.4	42.1	39.5
Week 52	25.2	42.1	46

No statistical analyses for this end point

Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Score

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End point title

Change from Baseline in Clinical Disease Activity Index (CDAI) Score

End point description

The CDAI is a tool for measurement of disease activity in RA that does not require a laboratory component and was scored by the investigative site. It integrates TJC28, SJC28, Patient's Global Assessment of Disease Activity using visual analog scale (cm), and Physician's Global Assessment of Disease Activity using visual analog scale (cm). The CDAI is calculated by summing the values of the 4 components. Lower scores indicated less disease activity. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using modified last observation carried forward (mLOCF).

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	200	157	208
Units: units on a scale
arithmetic mean (standard deviation)
Week 24	-22.12 ± 16.12	-28.2 ± 13.96	-29.86 ± 14.05
Week 52	-21.95 ± 18.07	-28.94 ± 14.58	-30.72 ± 14.87

No statistical analyses for this end point

Secondary: Change From Baseline in Disease Activity Score 28–Erythrocyte Sedimentation Rate (DAS28-ESR)

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End point title

Change From Baseline in Disease Activity Score 28–Erythrocyte Sedimentation Rate (DAS28-ESR)

End point description

DAS28 consisted of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), erythrocyte sedimentation rate (ESR) (millimeters per hour), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using the following formula: DAS28-ESR=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.70*natural log(ESR)+0.014*Patient's Global VAS. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	203	159	209
Units: units on a scale
arithmetic mean (standard deviation)
Week 24	-2.2 ± 1.53	-2.76 ± 1.45	-3.06 ± 1.46
Week 52	-2.32 ± 1.77	-2.84 ± 1.57	-3.22 ± 1.48

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission

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End point title

Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission

End point description

The ACR/EULAR definitions of RA remission include a "Boolean-based definition". The Boolean-based definition of remission occurs when all 4 of the following criteria are met at the same visit: TJC28 ≤1, SJC28 ≤1, acute phase response using C-reactive protein (milligrams per deciliter) ≤1, Patient's Global Assessment of Disease Activity using VAS (cm) ≤1. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: percentage of participants
number (not applicable)
Week 12	5.7	13.8	14.4
Week 24	8.6	18.9	16.3
Week 52	11.4	17	20.9

No statistical analyses for this end point

Secondary: Change From Baseline in Joint Space Narrowing and Bone Erosion Scores

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End point title

Change From Baseline in Joint Space Narrowing and Bone Erosion Scores

End point description

X-rays of the hands/wrists and feet were assessed for joint space narrowing (JSN) and bone erosions. Assessment of JSN for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, is scored from 0 to 4, with 0 indicating no (normal) JSN and 4 indicating complete loss of joint space, bony ankylosis or luxation. JSN scores ranged from 0-168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints of the feet. Each joint is scored according to the surface area involved from 0 to 5 for hand joints and 0 to 10 for the foot joints, with 0 indicating no erosion and the highest score (5 for the hand and 10 for the foot) indicating extensive loss of bone from more than one half of the articulating bone. Erosion scores ranged from 0 (no erosion) to 280 (high erosion). Analysis Population Description: mITT population.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	191	152	198
Units: units on a scale
arithmetic mean (standard deviation)
JSN Week 24	0.15 ± 0.94	0.08 ± 0.44	0.05 ± 0.44
JSN Week 52	0.23 ± 1	0.26 ± 1.14	0.08 ± 0.88
Bone Erosion Week 24	0.49 ± 1.14	0.35 ± 0.92	0.27 ± 0.95
Bone Erosion Week 52	0.8 ± 1.8	0.55 ± 1.48	0.33 ± 1.21

No statistical analyses for this end point

Secondary: Change From Baseline in Duration of Morning Joint Stiffness

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End point title

Change From Baseline in Duration of Morning Joint Stiffness

End point description

Participants reported the duration of their morning joint stiffness (MJS) in hours and minutes. The participants were asked about their duration of morning joint stiffness on the day prior to the study visit to capture actual symptoms, since the participant may have had an atypical morning routine on the day of the study visit. If morning joint stiffness duration was longer than 12 hours (720 minutes), it was truncated to 720 minutes for statistical presentations and analyses. A decrease in duration of morning joint stiffness indicated an improvement in the participant's condition. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	204	159	209
Units: Minutes
median (confidence interval 95%)	-40 (-55 to -30)	-55 (-60 to -40)	-60 (-80 to -50)

No statistical analyses for this end point

Secondary: Change from Baseline in Worst Tiredness Numeric Rating Scale (NRS)

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End point title

Change from Baseline in Worst Tiredness Numeric Rating Scale (NRS)

End point description

Participants rated their tiredness by selecting a number from 0 to 10 that best described their worst tiredness during the last 24 hours, where 0 represents "no tiredness" and 10 represents "as bad as you can imagine". Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	204	159	209
Units: units on a scale
arithmetic mean (standard deviation)
Week 24	-2.2 ± 2.7	-3 ± 3.1	-3 ± 2.8
Week 52	-2.3 ± 2.8	-2.9 ± 3.1	-3 ± 2.9

No statistical analyses for this end point

Secondary: Change From Baseline in Worst Joint Pain Numeric Rating Scale (NRS)

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End point title

Change From Baseline in Worst Joint Pain Numeric Rating Scale (NRS)

End point description

Participants rated their joint pain by selecting a number from 0 to 10 that best described their worst joint pain during the last 24 hours, where 0 represents "no pain" and 10 represents "pain as bad as you can imagine". Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value.Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	204	159	209
Units: units on a scale
arithmetic mean (standard deviation)
Week 24	-2.8 ± 2.5	-3.9 ± 2.7	-3.9 ± 2.6
Week 52	-3 ± 2.8	-3.9 ± 2.9	-4.1 ± 2.7

No statistical analyses for this end point

Secondary: Change from Baseline in Mental Component Score (MCS) and Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)

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End point title

Change from Baseline in Mental Component Score (MCS) and Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)

End point description

The SF-36 is a health-related survey that assesses participant's quality of life and consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (MCS and PCS). MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale with higher scores indicating better health status or functioning. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	202	159	207
Units: units on a scale
arithmetic mean (standard deviation)
MCS Week 24	3.4 ± 10.8	5.9 ± 11.7	4.6 ± 11.6
MCS Week 52	2.4 ± 10.9	5.8 ± 11.9	5 ± 11.5
PCS Week 24	9.4 ± 9.2	12.5 ± 9.1	13.2 ± 9.6
PCS Week 52	9.4 ± 10.1	11.6 ± 9.6	13.3 ± 9.8

No statistical analyses for this end point

Secondary: Change From Baseline in European Quality of Life–5 Dimensions–5 Level (EQ-5D-5L) scores

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End point title

Change From Baseline in European Quality of Life–5 Dimensions–5 Level (EQ-5D-5L) scores

End point description

EQ-5D-5L is a standardized measure of health status of the participant. One component consists of a descriptive system of the respondent's health comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using the United Kingdom (UK) algorithm, with scores ranging from -0.594 to 1, and the United States (US) algorithm, with scores ranging from -0.109 to 1. A higher score indicates better health state. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post-baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	202	159	207
Units: units on a scale
arithmetic mean (standard deviation)
Index Score (US Algorithm) Week 24	0.142 ± 0.189	0.197 ± 0.164	0.194 ± 0.18
Index Score (US Algorithm) Week 52	0.138 ± 0.203	0.186 ± 0.177	0.185 ± 0.186
Index Score (UK Algorithm) Week 24	0.205 ± 0.274	0.285 ± 0.241	0.282 ± 0.255
Index Score (UK Algorithm) Week 52	0.197 ± 0.294	0.271 ± 0.258	0.268 ± 0.266

No statistical analyses for this end point

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Scores

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Scores

End point description

The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale is a 13-item, symptom-specific questionnaire that specifically assesses the participant's self-reported severity of fatigue and its impact upon daily activities and functioning. The FACIT-F uses a numeric rating scale of 0 ("Not at all") to 4 ("Very much") for each item to assess fatigue and its impact in the past 7 days. Total scores range from 0 to 52, with higher scores indicating less fatigue. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	204	159	209
Units: units on a scale
arithmetic mean (standard deviation)
Week 24	9.3 ± 11.2	13 ± 10.8	12.3 ± 11.5
Week 52	9.1 ± 10.9	11.3 ± 10.8	12.6 ± 11.8

No statistical analyses for this end point

Secondary: Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores

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End point title

Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores

End point description

The Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) questionnaire was developed to measure the effect of general health and symptom severity on work productivity and regular activities in the 7 days prior to the visit. It contains 6 items covering overall work productivity (health), overall work productivity (symptom), impairment of regular activities (health), and impairment of regular activities (symptom). Scores are calculated as impairment percentages. The WPAI-RA yields four types of scores: Absenteeism (work time missed), Presenteeism (impairment at work), Work productivity loss (overall work impairment), and Activity impairment. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and an observed value at the time point being summarized.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: Percentage of Impairment
arithmetic mean (standard deviation)
Absenteeism Week 24 (n=76, 56, 90)	-3.6 ± 35.5	-8.7 ± 30.4	-7.6 ± 26.5
Absenteeism Week 52 (n=52, 51, 71)	-3 ± 29.2	-8.4 ± 29.7	-7.3 ± 21.8
Presenteeism Week 24 (n=70, 51, 86)	-19 ± 25	-26 ± 27	-32 ± 26
Presenteeism Week 52 (n=51, 47, 75)	-26 ± 26	-27 ± 24	-33 ± 25
Work Productivity Loss Week 24 (n=70, 71, 86)	-17.8 ± 30.2	-25.6 ± 29.1	-30.9 ± 29.6
Work Productivity Loss Week 52 (n=51, 47, 75)	-24.1 ± 30.5	-27.6 ± 27.3	-33.8 ± 27.5
Activity Impairment Week 24 (n=184, 145, 192)	-25 ± 26	-36 ± 28	-31 ± 28
Activity Impairment Week 52 (n=141, 131, 172)	-28 ± 27	-34 ± 27	-37 ± 27

No statistical analyses for this end point

Secondary: Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib

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End point title

Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib

End point description

Analysis population description: all randomized participants who received at least 1 dose of study drug with evaluable PK data.

End point type

Secondary

End point timeframe

Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 24; Week 32; Pre-dose

End point values	Baricitinib
Number of subjects analysed	355
Units: nanomole/Liter (nmol/L)
geometric mean (geometric coefficient of variation)	135 ± 23.1

No statistical analyses for this end point

Secondary: Population PK: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib

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End point title

Population PK: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib

End point description

Analysis population description: all randomized participants who received at least 1 dose of study drug with evaluable PK data.

End point type

Secondary

End point timeframe

Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 24; Week 32; Pre-dose

End point values	Baricitinib
Number of subjects analysed	355
Units: nanomole/Liter (nmol/L)
geometric mean (geometric coefficient of variation)	1280 ± 47.2

No statistical analyses for this end point

Secondary: Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)

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End point title

Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)

End point description

A second component of the EQ-5D-5L is a self-perceived health score which is assessed using a VAS that ranges from 0 to 100 millimeter (mm), where 0 indicates the worst health you can imagine and 100 indicates the best health you can imagine. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.

End point type

Secondary

End point timeframe

Baseline, Week 24; Baseline Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	202	159	207
Units: millimeter(s)
arithmetic mean (standard deviation)
Self-Perceived Health (Week 24)	14.5 ± 28.3	24.1 ± 26	21.4 ± 31.4
Self-Perceived Health (Week 52)	13.6 ± 30.1	24.5 ± 28.7	24.5 ± 30.6

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

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End point title

Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

End point description

ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). "ACR20 Responder" is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain due to arthritis, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinue study or drug or are rescued before analysis time point are deemed non-responders. Analysis Population Description: Modified Intent-to-Treat (mITT) population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using nonresponder imputation (NRI).

End point type

Secondary

End point timeframe

Week 52

End point values	Methotrexate	Baricitinib	Baricitinib + MTX
Number of subjects analysed	210	159	215
Units: Percent of participants
number (not applicable)	55.7	73	72.6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All enrolled participants including those receiving rescue therapy, with events occurring after rescue accounted separately. Rescue therapy occurred at Week 24 or later, if determined to be nonresponders.

Adverse event reporting additional description

I4V-MC-JADZ

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Baricitinib

Reporting group description

Reporting group title

Baricitinib + MTX

Reporting group description

Reporting group title

Methotrexate

Reporting group description

Reporting group title

Rescue

Reporting group description

Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX orally once weekly with dose ranging from 10 to 20 mg per week through Week 52.

Reporting group title

Baricitinib - Follow-up

Reporting group description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

Reporting group title

Methotrexate - Follow-up

Reporting group description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

Reporting group title

Baricitinib + MTX - Follow-up

Reporting group description

No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug. Includes participants who were rescued to Baricitinib + MTX.

Serious adverse events	Baricitinib	Baricitinib + MTX	Methotrexate	Rescue	Baricitinib - Follow-up	Methotrexate - Follow-up	Baricitinib + MTX - Follow-up
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 159 (7.55%)	17 / 215 (7.91%)	20 / 210 (9.52%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
cervix carcinoma
alternative dictionary used: MedDRA 18.0
subjects affected / exposed ^[1]	1 / 121 (0.83%)	0 / 156 (0.00%)	0 / 148 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
gallbladder adenosquamous carcinoma
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
malignant melanoma
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
drowning
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
fatigue
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
non-cardiac chest pain
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
oedema peripheral
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pyrexia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
genital prolapse
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
asthma
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
chronic obstructive pulmonary disease
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pneumothorax spontaneous
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pulmonary embolism
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
pulmonary fibrosis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
lymphocyte count decreased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
fall
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	2 / 210 (0.95%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
femur fracture
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
overdose
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
spinal compression fracture
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	2 / 210 (0.95%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
tibia fracture
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
toxicity to various agents
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
wrist fracture
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
atrial fibrillation
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
coronary artery disease
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
myocardial infarction
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
myocardial ischaemia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
cerebral haemorrhage
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
headache
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
migraine
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
syncope
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
cataract
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
chronic gastritis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
duodenal ulcer
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
enterocolitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
gastric ulcer haemorrhage
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
umbilical hernia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
cholecystitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
acute kidney injury
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
rheumatoid arthritis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
acute hepatitis b
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
bronchitis haemophilus
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
campylobacter gastroenteritis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
cellulitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
diverticulitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
escherichia sepsis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
herpes zoster
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	2 / 210 (0.95%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
infectious colitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
lung infection
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
meningitis bacterial
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pneumocystis jirovecii pneumonia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pneumonia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	1 / 215 (0.47%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pyelonephritis acute
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	1 / 215 (0.47%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
sepsis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
urinary tract infection
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Baricitinib	Baricitinib + MTX	Methotrexate	Rescue	Baricitinib - Follow-up	Methotrexate - Follow-up	Baricitinib + MTX - Follow-up
Total subjects affected by non serious adverse events
subjects affected / exposed	81 / 159 (50.94%)	129 / 215 (60.00%)	115 / 210 (54.76%)	21 / 39 (53.85%)	2 / 15 (13.33%)	2 / 25 (8.00%)	0 / 28 (0.00%)
Vascular disorders
hypertension
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	2 / 159 (1.26%)	13 / 215 (6.05%)	7 / 210 (3.33%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	13	7	1	0	0	0
Pregnancy, puerperium and perinatal conditions
pregnancy
alternative dictionary used: MedDRA 18.0
subjects affected / exposed ^[2]	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
General disorders and administration site conditions
fatigue
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	8 / 215 (3.72%)	5 / 210 (2.38%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	8	5	0	0	0	0
oedema peripheral
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	1 / 25 (4.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
pyrexia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	5 / 215 (2.33%)	4 / 210 (1.90%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	6	5	0	0	0	0
Respiratory, thoracic and mediastinal disorders
catarrh
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
cough
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	5 / 159 (3.14%)	6 / 215 (2.79%)	13 / 210 (6.19%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	7	6	14	1	0	0	0
sinus congestion
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Psychiatric disorders
depression
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	6 / 159 (3.77%)	2 / 215 (0.93%)	4 / 210 (1.90%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	6	2	4	0	0	0	0
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	13 / 215 (6.05%)	5 / 210 (2.38%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	15	5	1	0	0	0
aspartate aminotransferase increased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	7 / 215 (3.26%)	3 / 210 (1.43%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	8	3	1	0	0	0
blood creatine phosphokinase increased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	4 / 159 (2.52%)	10 / 215 (4.65%)	2 / 210 (0.95%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	5	11	2	1	0	0	0
blood creatinine increased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
liver function test abnormal
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
lymphocyte count increased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
weight increased
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	4 / 159 (2.52%)	1 / 215 (0.47%)	3 / 210 (1.43%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	1	3	0	0	0	0
Injury, poisoning and procedural complications
ankle fracture
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
arthropod bite
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
joint injury
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
thermal burn
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	2 / 39 (5.13%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	2	0	0	0
wrist fracture
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Cardiac disorders
cardiomegaly
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
left ventricular hypertrophy
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nervous system disorders
dizziness
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	3 / 215 (1.40%)	5 / 210 (2.38%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	4	6	0	0	0	0
headache
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	5 / 159 (3.14%)	6 / 215 (2.79%)	3 / 210 (1.43%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	6	7	3	0	0	0	0
sciatica
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	4 / 159 (2.52%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	0	0	0	0	0	0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	2 / 159 (1.26%)	6 / 215 (2.79%)	2 / 210 (0.95%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	6	2	0	0	0	0
thrombocytosis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	4 / 159 (2.52%)	3 / 215 (1.40%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	3	0	0	0	0	0
Ear and labyrinth disorders
ear pruritus
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Eye disorders
scleritis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
scleromalacia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Gastrointestinal disorders
abdominal discomfort
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
abdominal pain upper
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	1 / 215 (0.47%)	6 / 210 (2.86%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	1	6	0	0	0	0
constipation
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	2 / 159 (1.26%)	7 / 215 (3.26%)	3 / 210 (1.43%)	0 / 39 (0.00%)	1 / 15 (6.67%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	8	3	0	1	0	0
diarrhoea
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	5 / 215 (2.33%)	12 / 210 (5.71%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	6	15	0	0	0	0
dyspepsia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	8 / 215 (3.72%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	9	1	0	0	0	0
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	5 / 215 (2.33%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	5	1	0	0	0	0
large intestine polyp
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
nausea
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	7 / 159 (4.40%)	20 / 215 (9.30%)	13 / 210 (6.19%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	7	26	16	0	0	0	0
stomatitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
vomiting
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	5 / 159 (3.14%)	5 / 215 (2.33%)	6 / 210 (2.86%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	5	8	6	0	0	0	0
Hepatobiliary disorders
hepatic function abnormal
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	8 / 215 (3.72%)	5 / 210 (2.38%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	9	5	0	0	0	0
Skin and subcutaneous tissue disorders
alopecia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	6 / 215 (2.79%)	5 / 210 (2.38%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	6	5	0	0	0	0
dermatitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
eczema asteatotic
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	1 / 15 (6.67%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	0	0
miliaria
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	1 / 15 (6.67%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	0	0
petechiae
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
pruritus
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
purpura
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
seborrhoeic dermatitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	1 / 15 (6.67%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Renal and urinary disorders
polyuria
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Endocrine disorders
hypothyroidism
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	0 / 39 (0.00%)	0 / 15 (0.00%)	1 / 25 (4.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
back pain
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	9 / 215 (4.19%)	5 / 210 (2.38%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	10	5	1	0	0	0
muscle spasms
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	2 / 159 (1.26%)	7 / 215 (3.26%)	1 / 210 (0.48%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	7	2	0	0	0	0
rheumatoid arthritis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	1 / 215 (0.47%)	7 / 210 (3.33%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	1	7	0	0	0	0
Infections and infestations
bronchitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	5 / 159 (3.14%)	9 / 215 (4.19%)	4 / 210 (1.90%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	5	10	4	0	0	0	0
gastroenteritis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	10 / 159 (6.29%)	6 / 215 (2.79%)	4 / 210 (1.90%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	10	6	4	0	0	0	0
hepatitis e
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
herpes zoster
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	5 / 215 (2.33%)	0 / 210 (0.00%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	5	0	1	0	0	0
influenza
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	7 / 159 (4.40%)	11 / 215 (5.12%)	4 / 210 (1.90%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	7	11	4	0	0	0	0
nasopharyngitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	16 / 159 (10.06%)	21 / 215 (9.77%)	17 / 210 (8.10%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	21	32	20	1	0	0	0
pharyngitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	2 / 159 (1.26%)	7 / 215 (3.26%)	4 / 210 (1.90%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	9	6	1	0	0	0
rhinitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	2 / 215 (0.93%)	7 / 210 (3.33%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	3	7	0	0	0	0
sinusitis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	1 / 159 (0.63%)	7 / 215 (3.26%)	5 / 210 (2.38%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	8	5	0	0	0	0
upper respiratory tract infection
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	12 / 159 (7.55%)	16 / 215 (7.44%)	15 / 210 (7.14%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	14	19	15	1	0	0	0
urinary tract infection
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	6 / 159 (3.77%)	14 / 215 (6.51%)	7 / 210 (3.33%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	7	16	7	0	0	0	0
vaginal infection
alternative dictionary used: MedDRA 18.0
subjects affected / exposed ^[3]	0 / 159 (0.00%)	0 / 215 (0.00%)	0 / 210 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0
vulvovaginal candidiasis
alternative dictionary used: MedDRA 18.0
subjects affected / exposed ^[4]	0 / 121 (0.00%)	6 / 156 (3.85%)	1 / 148 (0.68%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	8	1	0	0	0	0
Metabolism and nutrition disorders
dyslipidaemia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	2 / 159 (1.26%)	8 / 215 (3.72%)	2 / 210 (0.95%)	0 / 39 (0.00%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	8	2	0	0	0	0
hypercholesterolaemia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	4 / 159 (2.52%)	4 / 215 (1.86%)	3 / 210 (1.43%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	4	3	1	0	0	0
hyperlipidaemia
alternative dictionary used: MedDRA 18.0
subjects affected / exposed	3 / 159 (1.89%)	6 / 215 (2.79%)	1 / 210 (0.48%)	1 / 39 (2.56%)	0 / 15 (0.00%)	0 / 25 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	6	1	1	0	0	0

Notes
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

More information

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Were there any global substantial amendments to the protocol? No

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 Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment with Disease-Modifying Antirheumatic Drugs

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

Primary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

Secondary: Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)

Secondary: Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)

Secondary: Change from Baseline in the modified Total Sharp Score (mTSS)

Secondary: Change from Baseline in the modified Total Sharp Score (mTSS)

Secondary: Percentage of Participants Who Achieved a Simplified Disease Activity Index (SDAI) Score ≤3.3

Secondary: Percentage of Participants Who Achieved a Simplified Disease Activity Index (SDAI) Score ≤3.3

Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response

Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response

Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response

Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response

Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Score

Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Score

Secondary: Change From Baseline in Disease Activity Score 28–Erythrocyte Sedimentation Rate (DAS28-ESR)

Secondary: Change From Baseline in Disease Activity Score 28–Erythrocyte Sedimentation Rate (DAS28-ESR)

Secondary: Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission

Secondary: Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission

Secondary: Change From Baseline in Joint Space Narrowing and Bone Erosion Scores

Secondary: Change From Baseline in Joint Space Narrowing and Bone Erosion Scores

Secondary: Change From Baseline in Duration of Morning Joint Stiffness

Secondary: Change From Baseline in Duration of Morning Joint Stiffness

Secondary: Change from Baseline in Worst Tiredness Numeric Rating Scale (NRS)

Secondary: Change from Baseline in Worst Tiredness Numeric Rating Scale (NRS)

Secondary: Change From Baseline in Worst Joint Pain Numeric Rating Scale (NRS)

Secondary: Change From Baseline in Worst Joint Pain Numeric Rating Scale (NRS)

Secondary: Change from Baseline in Mental Component Score (MCS) and Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)

Secondary: Change from Baseline in Mental Component Score (MCS) and Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)

Secondary: Change From Baseline in European Quality of Life–5 Dimensions–5 Level (EQ-5D-5L) scores

Secondary: Change From Baseline in European Quality of Life–5 Dimensions–5 Level (EQ-5D-5L) scores

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Scores

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Scores

Secondary: Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores

Secondary: Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores

Secondary: Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib

Secondary: Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib

Secondary: Population PK: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib

Secondary: Population PK: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib

Secondary: Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)

Secondary: Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)

Secondary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

Secondary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment with Disease-Modifying Antirheumatic Drugs