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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs with Moderately to Severely Active Rheumatoid Arthritis

Summary
EudraCT number	2012-002339-27
Trial protocol	HU BE DE IT PT GB CZ SK ES
Global end of trial date	19 Dec 2014

Results information
Results version number	v1(current)
This version publication date	26 Mar 2017
First version publication date	26 Mar 2017
Other versions

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

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Trial information

Top of page

Sponsor protocol code

14059

ISRCTN number

-

US NCT number

NCT01721057

WHO universal trial number (UTN)

-

Other trial identifiers

Trial Number: 14059, Trial Alias: I4V-MC-JADX

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)

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

19 Dec 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

19 Dec 2014

Was the trial ended prematurely?

No

Main objective of the trial

The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily (QD) is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had inadequate response to or are intolerant to at least 1 conventional disease-modifying antirheumatic drug (cDMARD)(cDMARD-IR [inadequate response] participants) and who have not received a biologic disease-modifying antirheumatic drug (DMARD).

Protection of trial subjects

This study was conducted in accordance with 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

Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study.

Evidence for comparator

-

Actual start date of recruitment

01 Dec 2012

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 64

Country: Number of subjects enrolled

Australia: 15

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

Croatia: 4

Country: Number of subjects enrolled

Czech Republic: 15

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Hungary: 20

Country: Number of subjects enrolled

India: 58

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Japan: 21

Country: Number of subjects enrolled

Korea, Republic of: 17

Country: Number of subjects enrolled

Mexico: 22

Country: Number of subjects enrolled

Poland: 51

Country: Number of subjects enrolled

Portugal: 5

Country: Number of subjects enrolled

Romania: 6

Country: Number of subjects enrolled

Russian Federation: 20

Country: Number of subjects enrolled

Slovakia: 11

Country: Number of subjects enrolled

Spain: 34

Country: Number of subjects enrolled

Taiwan: 82

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

United States: 176

Worldwide total number of subjects

684

EEA total number of subjects

181

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

587

From 65 to 84 years

97

85 years and over

0

Subject disposition

Top of page

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 16. Nonresponders were defined as lack of improvement of at least 20% in both tender joint count and swollen joint count at both Weeks 14 and 16 compared to baseline.

Period 1 title

Treatment Period (Weeks 0 to 24)

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

Placebo

Arm description

Placebo administered orally (PO) once daily (QD)through Week 24. Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD. All started participants received at least one dose of study drug.

Arm type

Placebo

Investigational medicinal product name

Baricitinib Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo administered orally (PO) once daily (QD) through Week 24. Participants continued to take background cDMARD therapy throughout study.

Baricitinib 2 mg

Arm description

Baricitinib 2 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

Arm type

Experimental

Investigational medicinal product name

Baricitinib

Investigational medicinal product code

Other name

LY3009104

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Baricitinib 4 mg PO QD through week 24. Participants continued to take background cDMARD therapy throughout study.

Baricitinib 4 mg

Arm description

Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

Arm type

Experimental

Investigational medicinal product name

Baricitinib

Investigational medicinal product code

Other name

LY3009104

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study.

Number of subjects in period 1	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Started	228	229	227
Rescue Week 16-24	55 ^[1]	21 ^[2]	15 ^[3]
Completed	199	209	203
Not completed	29	20	24
Adverse event, serious fatal	2	-	-
Consent withdrawn by subject	11	5	8
Physician decision	-	1	3
Adverse event, non-fatal	8	10	12
Lost to follow-up	1	-	-
Lack of efficacy	7	4	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants 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?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo-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 2 mg- 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 4 mg- 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 4 mg.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2 ^[4]	Placebo-Follow Up	Baricitinib 2 mg- Follow Up	Baricitinib 4 mg- Follow Up
Started	17	19	22
Completed	17	19	22

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

Top of page

Reporting group title

Placebo

Reporting group description

Placebo administered orally (PO) once daily (QD)through Week 24. Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD. All started participants received at least one dose of study drug.

Reporting group title

Baricitinib 2 mg

Reporting group description

Baricitinib 2 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

Reporting group title

Baricitinib 4 mg

Reporting group description

Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

Reporting group values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg	Total
Number of subjects	228	229	227	684
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	197	196	194	587
From 65-84 years	31	33	33	97
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	51.4 ± 12.5	52.2 ± 12.3	51.8 ± 12.1	-
Gender, Male/Female
Units: participants
Female	189	184	187	560
Male	39	45	40	124
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	12	15	17	44
Not Hispanic or Latino	45	43	43	131
Unknown or Not Reported	171	171	167	509
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	3	2	9	14
Asian	60	61	59	180
Native Hawaiian or Other Pacific Islander	1	0	0	1
Black or African American	10	9	9	28
White	153	156	148	457
More than one race	1	1	1	3
Unknown or Not Reported	0	0	1	1
Region of Enrollment
Units: Subjects
Argentina	25	21	18	64
Australia	8	1	6	15
Belgium	1	4	6	11
Canada	10	10	8	28
Croatia	0	2	2	4
Czech Republic	7	5	3	15
Germany	4	2	3	9
Hungary	7	8	5	20
India	19	19	20	58
Italy	3	3	4	10
Japan	8	6	7	21
Korea, Republic of	6	7	4	17
Mexico	3	8	11	22
Poland	18	13	20	51
Portugal	2	2	1	5
Romania	1	3	2	6
Russian Federation	4	10	6	20
Slovakia	3	5	3	11
Spain	14	10	10	34
Taiwan	26	28	28	82
United Kingdom	1	4	0	5
United States	58	58	60	176
Duration of Rheumatoid Arthritis
n= 228, 225, 225 and 678
Units: years
arithmetic mean (standard deviation)	7.2 ± 7.5	7.6 ± 7.6	7.7 ± 7.9	-
Tender Joint Count of 68 Evaluable Joints
Units: Number of Joints
arithmetic mean (standard deviation)	24.3 ± 15	23.5 ± 14.1	24.3 ± 14	-
Swollen Joint Count of 66 Evaluable Joints
Units: Number of Joints
arithmetic mean (standard deviation)	13.1 ± 7.2	13.6 ± 8.7	13.5 ± 6.9	-
High Sensitivity C-Reactive Protein (hsCRP)
Units: milligram per Liter (mg/L)
arithmetic mean (standard deviation)	17.7 ± 20.4	18.2 ± 21.5	14.2 ± 14.5	-

End points

Top of page

Reporting group title

Placebo

Reporting group description

Placebo administered orally (PO) once daily (QD)through Week 24. Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD. All started participants received at least one dose of study drug.

Reporting group title

Baricitinib 2 mg

Reporting group description

Baricitinib 2 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

Reporting group title

Baricitinib 4 mg

Reporting group description

Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

Reporting group title

Placebo-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 2 mg- 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 4 mg- 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 4 mg.

Subject analysis set title

PK population 2 mg Baricitinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

All randomized participants who received at least 1 dose of 2 mg baricitinib with evaluable PK data.

Subject analysis set title

PK Population 4 mg Baricitinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

All randomized participants who received at least 1 dose of 4 mg baricitinib 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 timepoint are deemed non-responders. Analysis Population Description: All randomized participants who received at least 1 dose of the study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using non-responder imputation (NRI).

End point type

Primary

End point timeframe

Week 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: percentage of participants
number (not applicable)	39.5	65.9	61.7

Statistical Analysis for ACR20

Comparison groups

Baricitinib 4 mg v Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Regression, Logistic

Confidence interval

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

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End point title

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

End point description

The HAQ-DI questionnaire 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 were averaged to calculate the HAQ-DI score, which ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition. Analysis Population Description: All randomized participants who received at least 1 dose of the 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 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: units on a scale
arithmetic mean (standard deviation)	-0.3 ± 0.45	-0.52 ± 0.59	-0.52 ± 0.6

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 composite score of 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 using visual analog scale (VAS) (participant global VAS). DAS28 was calculated using 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 All randomized participants who received at least 1 dose of the 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 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: units on a scale
arithmetic mean (standard deviation)	-1.05 ± 1.23	-1.83 ± 1.22	-1.91 ± 1.21

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) ≤3.3

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End point title

Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) ≤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 All randomized participants who received at least 1 dose of the 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

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: percentage of participants
number (not applicable)	0.9	9.2	8.8

No statistical analyses for this end point

Secondary: Mean Duration of Morning Joint Stiffness (MJS) in the Prior 7 Days as Collected in Electronic Daily Diaries

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End point title

Mean Duration of Morning Joint Stiffness (MJS) in the Prior 7 Days as Collected in Electronic Daily Diaries

End point description

Participants reported the duration of their morning joint stiffness (MJS) in hours and minutes into daily electronic diaries. If MJS duration was longer than 12 hours (720 minutes), it was truncated to 720 minutes for statistical presentations and analyses. The average value across the 7 days preceding each visit is calculated. A decrease in duration of MJS indicated an improvement in the participant's condition. Analysis Population Description: All randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	221	223	222
Units: minutes
median (confidence interval 95%)	60 (50.7 to 76.7)	44.4 (30 to 60)	34.6 (23.7 to 51.4)

No statistical analyses for this end point

Secondary: Mean Severity of Morning Joint Stiffness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries

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End point title

Mean Severity of Morning Joint Stiffness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries

End point description

Participants rated the severity of their MJS by selecting a number from 0 to 10 that best described their overall level of MJS from the time they woke up, where 0 represents "no joint stiffness" and 10 represents "joint stiffness as bad as you can imagine". Participants reported their severity daily in electronic diaries. The average value across the 7 days preceding each visit is calculated. A decrease in severity rating indicated an improvement in the participant's condition. Analysis Population Description: All randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	221	223	222
Units: units on a scale
arithmetic mean (standard deviation)	4.2 ± 2.3	3.5 ± 2.5	3.4 ± 2.2

No statistical analyses for this end point

Secondary: Mean Worst Tiredness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries

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End point title

Mean Worst Tiredness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries

End point description

Participants rated their tiredness by selecting a number from 0 to 10 that best described their level of worst tiredness during the past 24 hours, where 0 represents "no tiredness" and 10 represents "as bad as you can imagine". Participants reported their worst tiredness in daily electronic diaries. The average value across the 7 days preceding each visit is calculated. A decrease in tiredness severity rating indicated an improvement in the participant's condition. Analysis Population Description: All randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	221	223	222
Units: units on a scale
arithmetic mean (standard deviation)	4.5 ± 2.2	4 ± 2.5	4 ± 2.3

No statistical analyses for this end point

Secondary: Mean Worst Joint Pain Numeric Rating Scale (NRS) in the Prior 7 days as Collected in Electronic Diaries

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End point title

Mean Worst Joint Pain Numeric Rating Scale (NRS) in the Prior 7 days as Collected in Electronic Diaries

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". Participants reported their worst joint pain in daily electronic diaries. The average value across the 7 days preceding each visit is calculated. A decrease in joint pain severity rating indicated an improvement in the participant's condition. Analysis Population Description: All randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	221	223	222
Units: units on a scale
arithmetic mean (standard deviation)	4.7 ± 2.2	3.9 ± 2.5	3.8 ± 2.2

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, 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 timepoint are deemed non-responders. Analysis Population Description: All randomized participants who received at least 1 dose of the 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

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: percentage of participants
number (not applicable)
Week 12	12.7	33.6	33.5
Week 24	21.5	41.5	44.1

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 70% 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, 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 timepoint are deemed non-responders. Analysis Population Description: All randomized participants who received at least 1 dose of the 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

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: percentage of participants
number (not applicable)
Week 12	3.1	17.9	18.1
Week 24	7.9	25.3	24.2

No statistical analyses for this end point

Secondary: Change From Baseline in Measures of Clinical Disease Activity Index (CDAI) Score

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End point title

Change From Baseline in Measures of 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: All randomized participants who received at least 1 dose of the 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

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	218	224	219
Units: units on a scale
arithmetic mean (standard deviation)	-14.29 ± 16.04	-20.99 ± 14.48	-23.18 ± 13.47

No statistical analyses for this end point

Secondary: Change from Baseline in Measures of Simplified Disease Activity Index (SDAI) Score

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End point title

Change from Baseline in Measures of Simplified Disease Activity Index (SDAI) Score

End point description

The 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), 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 SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. Analysis Population Description: All randomized participants who received at least 1 dose of the 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

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	218	224	219
Units: units on a scale
arithmetic mean (standard deviation)	-14.55 ± 16.37	-21.87 ± 14.99	-23.78 ± 13.94

No statistical analyses for this end point

Secondary: Change from Baseline in DAS28-Erythrocyte Sedimentation Rate (DAS28-ESR)

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End point title

Change from Baseline in DAS28-Erythrocyte Sedimentation Rate (DAS28-ESR)

End point description

DAS28 consisted of composite score of 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 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: All randomized participants who received at least 1 dose of the study drug. 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 12

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	220	226	221
Units: units on a scale
arithmetic mean (standard deviation)	-1.16 ± 1.27	-1.89 ± 1.23	-1.97 ± 1.16

No statistical analyses for this end point

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

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End point title

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

End point description

The ACR/EULAR definition 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: All randomized participants who received at least 1 dose of the 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

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: percentage of participants
number (not applicable)	0.4	7	6.6

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 brief 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: All randomized participants who received at least 1 dose of the 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 12; Baseline Week 24

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	216	227	216
Units: units on a scale
arithmetic mean (standard deviation)
Week 12	7.6 ± 10.3	8.7 ± 11.1	8.8 ± 10.6
Week 24	7.8 ± 11	9.2 ± 10.7	9.7 ± 10.8

No statistical analyses for this end point

Secondary: Change from Baseline in Mental Component Score (MCS), 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), 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, as well as 2 component scores (mental [MCS] and physical [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: All randomized participants who received at least 1 dose of the 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 12; Baseline, Week 24

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	218	229	219
Units: units on a scale
arithmetic mean (standard deviation)
Week 12, MCS	3.3 ± 10.6	3.6 ± 10.5	3.3 ± 11
Week 24, MCS	2.7 ± 11.5	3 ± 10.4	3.3 ± 11.3
Week 12, PCS	4.1 ± 7.3	7.7 ± 8.5	7 ± 8.3
Week 24, PCS	4.9 ± 8	8.5 ± 9	8.6 ± 9

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

European Quality of Life-5 Dimensions-5 Level (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: All randomized participants who received at least 1 dose of the 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 12; Baseline Week 24

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	216	227	216
Units: units on a scale
arithmetic mean (standard deviation)
Index Score (US Algorithm) Week 12	0.054 ± 0.155	0.117 ± 0.151	0.109 ± 0.165
Index Score (US Algorithm) Week 24	0.051 ± 0.149	0.113 ± 0.172	0.129 ± 0.173
Index Score (UK Algorithm) Week 12	0.074 ± 0.23	0.167 ± 0.221	0.159 ± 0.237
Index Score (UK Algorithm) Week 24	0.075 ± 0.218	0.162 ± 0.254	0.185 ± 0.25

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: All randomized participants who received at least 1 dose of the 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 12; Baseline Week 24

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	216	227	216
Units: mm
arithmetic mean (standard deviation)
Self-Perceived Health, Week 12	5.7 ± 23.8	13.4 ± 21.8	11.5 ± 25.2
Self-Perceived Health, Week 24	8.4 ± 25.1	13.1 ± 25.8	10.4 ± 28.9

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: All randomized participants who received at least 1 dose of the study drug. Change from baseline includes participants with a baseline value and an observed value at the time point being summarized.

End point type

Secondary

End point timeframe

Baseline, Week 12; Baseline, Week 24

End point values	Placebo	Baricitinib 2 mg	Baricitinib 4 mg
Number of subjects analysed	228	229	227
Units: percentage of impairment
arithmetic mean (standard deviation)
Absenteeism Week 12 (n= 73,72,69)	2.6 ± 23.5	-6.3 ± 26.5	2.5 ± 24.7
Absenteeism Week 24 (n= 44,62,56)	-2.1 ± 13.9	-3.8 ± 28.2	4 ± 27.2
Presenteeism Week 12 (n= 71, 69, 66)	-8 ± 26	-17 ± 25	-15 ± 27
Presenteeism Week 24 (n= 44,61,53)	-17 ± 26	-20 ± 23	-17 ± 21
Work Productivity Loss Week 12 (n= 71,69,66)	-4.2 ± 27.7	-17.6 ± 30.4	-9.9 ± 23.7
Work Productivity Loss Week 24 (n= 44,61,53)	-15.9 ± 26.1	-19.6 ± 25	-14.3 ± 23
Activity Impairment Week 12(n=206, 222, 213)	-13 ± 25	-19 ± 27	-19 ± 25
Activity Impairment Week 24 (n= 141,187,187)	-18 ± 27	-23 ± 28	-21 ± 27

No statistical analyses for this end point

Secondary: Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of LY3009104

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End point title

Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of LY3009104

End point description

End point type

Secondary

End point timeframe

Week 0: 30 and 90 minutes postdose; Week 8: 1 hour postdose; Week 12, Week 20 and Week 24:predose

End point values	PK population 2 mg Baricitinib	PK Population 4 mg Baricitinib
Number of subjects analysed	246	245
Units: nanogram per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)	70.2 ± 26.2	138 ± 25.7

No statistical analyses for this end point

Secondary: Population PK: Maximum Concentration at Steady State of Dosing (AUC,ss) of LY3009104

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End point title

Population PK: Maximum Concentration at Steady State of Dosing (AUC,ss) of LY3009104

End point description

End point type

Secondary

End point timeframe

Week 0: 30 and 90 minutes postdose; Week 8: 1 hour postdose; Week 12, Week 20 and Week 24; predose

End point values	PK population 2 mg Baricitinib	PK Population 4 mg Baricitinib
Number of subjects analysed	246	245
Units: nanograms per mL per hour (ng/mL*h)
geometric mean (geometric coefficient of variation)	637 ± 44.5	1210 ± 47

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Entire Study

Adverse event reporting additional description

I4V-MC-JADX

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

PLACEBO

Reporting group description

-

Reporting group title

Baricitinib 2 mg

Reporting group description

-

Reporting group title

Baricitinib 4 mg

Reporting group description

-

Reporting group title

Rescue

Reporting group description

-

Reporting group title

Placebo- Follow Up

Reporting group description

-

Reporting group title

Baricitinib 2 mg – Follow Up

Reporting group description

-

Reporting group title

Baricitinib 4 mg – Follow Up

Reporting group description

-

Serious adverse events	PLACEBO	Baricitinib 2 mg	Baricitinib 4 mg	Rescue	Placebo- Follow Up	Baricitinib 2 mg – Follow Up	Baricitinib 4 mg – Follow Up
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 228 (5.70%)	6 / 229 (2.62%)	12 / 227 (5.29%)	1 / 91 (1.10%)	1 / 17 (5.88%)	0 / 19 (0.00%)	1 / 22 (4.55%)
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
Injury, poisoning and procedural complications
animal bite
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
fall
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
patella fracture
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
tibia fracture
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
upper limb fracture
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Cardiac disorders
angina pectoris
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
atrial fibrillation
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
myocardial infarction
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
ventricular tachycardia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Nervous system disorders
migraine
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
subarachnoid haemorrhage
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Gastrointestinal disorders
diverticulum intestinal
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
dyspepsia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
gastrointestinal haemorrhage
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Respiratory, thoracic and mediastinal disorders
acute respiratory distress syndrome
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
acute respiratory failure
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
allergic bronchitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
interstitial lung disease
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
pleural effusion
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
pulmonary embolism
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
cholecystitis acute
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Skin and subcutaneous tissue disorders
psoriasis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
rash pruritic
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
subcutaneous emphysema
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Psychiatric disorders
depression
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
post-traumatic stress disorder
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
suicidal ideation
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Renal and urinary disorders
renal failure
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
back pain
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
muscular weakness
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
myalgia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
myositis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
polymyositis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
rheumatoid arthritis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
spinal pain
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
synovial cyst
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
Infections and infestations
appendicitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
bacterial infection
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
bronchitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
cellulitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	1 / 91 (1.10%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
disseminated tuberculosis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
gastroenteritis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	1 / 229 (0.44%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
lower respiratory tract infection
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
pelvic abscess
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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 17.1
subjects affected / exposed	2 / 228 (0.88%)	1 / 229 (0.44%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 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
sepsis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
urinary tract infection
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	1 / 91 (1.10%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
viral infection
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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
wound infection staphylococcal
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (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

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

Non-serious adverse events	PLACEBO	Baricitinib 2 mg	Baricitinib 4 mg	Rescue	Placebo- Follow Up	Baricitinib 2 mg – Follow Up	Baricitinib 4 mg – Follow Up
Total subjects affected by non serious adverse events
subjects affected / exposed	105 / 228 (46.05%)	108 / 229 (47.16%)	127 / 227 (55.95%)	21 / 91 (23.08%)	2 / 17 (11.76%)	0 / 19 (0.00%)	4 / 22 (18.18%)
Vascular disorders
hypertension
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	10 / 229 (4.37%)	6 / 227 (2.64%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	10	6	0	0	0	0
General disorders and administration site conditions
fatigue
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	5 / 228 (2.19%)	2 / 229 (0.87%)	5 / 227 (2.20%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	5	3	5	0	0	0	0
oedema peripheral
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	6 / 228 (2.63%)	3 / 229 (1.31%)	3 / 227 (1.32%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	6	3	3	0	0	0	0
pyrexia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	1 / 229 (0.44%)	5 / 227 (2.20%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	1	7	0	1	0	0
Reproductive system and breast disorders
erectile dysfunction
alternative dictionary used: MedDRA 17.1
subjects affected / exposed ^[1]	0 / 39 (0.00%)	0 / 45 (0.00%)	1 / 40 (2.50%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
vulvovaginal pruritus
alternative dictionary used: MedDRA 17.1
subjects affected / exposed ^[2]	0 / 189 (0.00%)	0 / 184 (0.00%)	0 / 187 (0.00%)	0 / 78 (0.00%)	1 / 11 (9.09%)	0 / 15 (0.00%)	0 / 19 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
cough
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	3 / 228 (1.32%)	9 / 229 (3.93%)	9 / 227 (3.96%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 22 (4.55%)
occurrences all number	4	11	10	0	0	0	1
dyspnoea
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	0	0	0	0	1
oropharyngeal pain
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	4 / 229 (1.75%)	9 / 227 (3.96%)	3 / 91 (3.30%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	4	9	3	0	0	0
Psychiatric disorders
depression
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	7 / 228 (3.07%)	0 / 229 (0.00%)	1 / 227 (0.44%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	7	0	1	0	0	0	0
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	5 / 229 (2.18%)	5 / 227 (2.20%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	6	6	0	0	0	0
aspartate aminotransferase increased
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	3 / 229 (1.31%)	6 / 227 (2.64%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	3	7	0	0	0	0
blood creatine phosphokinase increased
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	8 / 229 (3.49%)	15 / 227 (6.61%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	8	17	0	1	0	0
Cardiac disorders
sinus bradycardia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	0	0	0	0	1
Nervous system disorders
dizziness
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	4 / 228 (1.75%)	3 / 229 (1.31%)	7 / 227 (3.08%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	3	9	0	0	0	0
headache
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	8 / 228 (3.51%)	15 / 229 (6.55%)	9 / 227 (3.96%)	3 / 91 (3.30%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	10	17	10	3	0	0	0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	6 / 228 (2.63%)	6 / 229 (2.62%)	4 / 227 (1.76%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	6	6	4	0	0	0	0
Gastrointestinal disorders
abdominal pain
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	5 / 229 (2.18%)	3 / 227 (1.32%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	5	3	0	0	0	0
abdominal pain upper
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	5 / 229 (2.18%)	4 / 227 (1.76%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	5	4	0	0	0	0
constipation
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	3 / 228 (1.32%)	7 / 229 (3.06%)	5 / 227 (2.20%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	7	5	0	0	0	0
diarrhoea
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	10 / 228 (4.39%)	10 / 229 (4.37%)	4 / 227 (1.76%)	2 / 91 (2.20%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	11	11	5	2	1	0	0
dyspepsia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	1 / 229 (0.44%)	5 / 227 (2.20%)	2 / 91 (2.20%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	1	5	2	0	0	0
gastritis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	0	0	0	0	1
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	5 / 228 (2.19%)	2 / 229 (0.87%)	1 / 227 (0.44%)	2 / 91 (2.20%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	5	2	1	2	0	0	0
lip disorder
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	0	0	0	0	1
mouth ulceration
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	5 / 229 (2.18%)	3 / 227 (1.32%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	6	3	0	0	0	0
nausea
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	8 / 228 (3.51%)	7 / 229 (3.06%)	5 / 227 (2.20%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	9	7	5	0	0	0	0
vomiting
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	4 / 228 (1.75%)	7 / 229 (3.06%)	4 / 227 (1.76%)	2 / 91 (2.20%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	5	7	4	2	0	0	0
Skin and subcutaneous tissue disorders
acne
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	2 / 91 (2.20%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0	0	0
alopecia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	4 / 228 (1.75%)	1 / 229 (0.44%)	6 / 227 (2.64%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	1	6	0	0	0	0
dermatitis bullous
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	3 / 228 (1.32%)	6 / 229 (2.62%)	6 / 227 (2.64%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	8	6	0	0	0	0
back pain
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	10 / 228 (4.39%)	9 / 229 (3.93%)	5 / 227 (2.20%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	10	9	5	0	0	0	0
Infections and infestations
bronchitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	11 / 228 (4.82%)	6 / 229 (2.62%)	7 / 227 (3.08%)	2 / 91 (2.20%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	12	7	8	2	0	0	0
gastroenteritis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	1 / 228 (0.44%)	4 / 229 (1.75%)	9 / 227 (3.96%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	4	9	0	0	0	0
nasopharyngitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	18 / 228 (7.89%)	10 / 229 (4.37%)	18 / 227 (7.93%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	19	10	22	0	0	0	0
pharyngitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	3 / 228 (1.32%)	6 / 229 (2.62%)	8 / 227 (3.52%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	6	8	0	0	0	0
rash pustular
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	0 / 228 (0.00%)	0 / 229 (0.00%)	0 / 227 (0.00%)	0 / 91 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	0	1	0	0
sinusitis
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	6 / 228 (2.63%)	3 / 229 (1.31%)	4 / 227 (1.76%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	6	3	4	0	0	0	0
upper respiratory tract infection
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	18 / 228 (7.89%)	14 / 229 (6.11%)	24 / 227 (10.57%)	2 / 91 (2.20%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	19	16	26	2	0	0	0
urinary tract infection
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	4 / 228 (1.75%)	12 / 229 (5.24%)	9 / 227 (3.96%)	3 / 91 (3.30%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	5	13	9	3	0	0	0
Metabolism and nutrition disorders
hypercholesterolaemia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	5 / 229 (2.18%)	9 / 227 (3.96%)	4 / 91 (4.40%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	5	9	4	0	0	0
hyperlipidaemia
alternative dictionary used: MedDRA 17.1
subjects affected / exposed	2 / 228 (0.88%)	2 / 229 (0.87%)	6 / 227 (2.64%)	0 / 91 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	2	6	0	0	0	0

Notes
[1] - 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.
[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.

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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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