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Clinical Trial Results:
Rheumatoid Arthritis: A Phase 2 Study to Investigate the Safety and Efficacy of ABBV-105 Given Alone or in Combination with Upadacitinib (ABBV-599 Combination) with a Background of Conventional Synthetic DMARDs in Subjects with Active Rheumatoid Arthritis with Inadequate Response or Intolerance to Biologic DMARDs

Summary
EudraCT number	2018-000666-10
Trial protocol	GB HU BE ES
Global end of trial date	26 Mar 2020

Results information
Results version number	v2(current)
This version publication date	20 May 2021
First version publication date	20 Mar 2021
Other versions	v1
Version creation reason	Correction of full data set Edited endpoint description and the global end of trial date.

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

M16-063

ISRCTN number

US NCT number

NCT03682705

WHO universal trial number (UTN)

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

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

Public contact

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

Scientific contact

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

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

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

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

Analysis stage

Final

Date of interim/final analysis

26 Mar 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Mar 2020

Was the trial ended prematurely?

Main objective of the trial

This was a 12-week, randomized, double-blind, parallel-group, Phase 2, dose exploratory, multicenter study. to evaluate the safety and efficacy of elsubrutinib (ELS) and ABBV-599 (ELS plus upadacitinib [UPA]) vs placebo on a background of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for the treatment of signs and symptoms of rheumatoid arthritis (RA) in biological disease-modifying anti-rheumatic drugs (bDMARD)-inadequate response (bDMARD-IR) or bDMARD-intolerant participants with moderately to severely active RA and to define optimal dose for further development. Participants who met eligibility criteria were randomized in a 3:2:2:2:2:1 ratio to 1 of 6 treatment groups: ABBV-599 [UPA 15 mg/ ELS 60 mg]); ELS 60 mg/UPA placebo; ELS 20 mg/UPA placebo; ELS 5 mg/UPA placebo; UPA 15 mg/ELS placebo; and ELS placebo/UPA placebo. The study included a 35-day maximum screening period and a 12-week treatment period with 30-day follow-up.

Protection of trial subjects

Subjects or their legally authorized representative must have voluntarily signed and dated an informed consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Oct 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

Puerto Rico: 6

Country: Number of subjects enrolled

United States: 131

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Hungary: 29

Country: Number of subjects enrolled

Poland: 23

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

Czechia: 20

Country: Number of subjects enrolled

United Kingdom: 1

Worldwide total number of subjects

242

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)

162

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Full Analysis Set: all randomized participants who received at least 1 dose of randomized study drug

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Assessor, Subject

Are arms mutually exclusive

Yes

ELS placebo/UPA placebo

Arm description

Placebo capsule for elsubrutinib once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo for elsubrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo capsule for elsubrutinib will be administered orally.

Investigational medicinal product name

Placebo for upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablet for upadacitinib will be administered orally.

UPA 15 mg/ELS 60 mg

Arm description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; 60 mg elsubrutinib capsule once a day by mouth for 12 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Elsubrutinib capsule will be administered orally.

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib tablet will be administered orally.

ELS 60 mg/UPA placebo

Arm description

60 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Elsubrutinib capsule will be administered orally.

Investigational medicinal product name

Placebo for upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablet for upadacitinib will be administered orally.

ELS 20 mg/UPA placebo

Arm description

20 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Elsubrutinib capsule will be administered orally.

Investigational medicinal product name

Placebo for upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablet for upadacitinib will be administered orally.

ELS 5 mg/UPA placebo

Arm description

5 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Elsubrutinib capsule will be administered orally.

Investigational medicinal product name

Placebo for upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablet for upadacitinib will be administered orally.

UPA 15 mg/ELS placebo

Arm description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; placebo capsule for elsubrutinib once a day by mouth for 12 weeks

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

ABT-494

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib tablet will be administered orally.

Investigational medicinal product name

Placebo for elsubrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo capsule for elsubrutinib will be administered orally.

Number of subjects in period 1	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Started	19	62	41	39	41	40
Completed	17	58	38	34	35	38
Not completed	2	4	3	5	6	2
Adverse event, non-fatal	1	1	1	-	1	1
Other, not specified	-	-	-	1	2	-
Lost to follow-up	-	-	-	-	3	-
Withdrawal by subject	1	3	2	4	-	1

Baseline characteristics

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Reporting group title

ELS placebo/UPA placebo

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

UPA 15 mg/ELS 60 mg

Reporting group description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; 60 mg elsubrutinib capsule once a day by mouth for 12 weeks

Reporting group title

ELS 60 mg/UPA placebo

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

ELS 20 mg/UPA placebo

Reporting group description

20 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

ELS 5 mg/UPA placebo

Reporting group description

5 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

UPA 15 mg/ELS placebo

Reporting group description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; placebo capsule for elsubrutinib once a day by mouth for 12 weeks

Reporting group values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo	Total
Number of subjects	19	62	41	39	41	40	242
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	57.6 ( 9.12 )	56.2 ( 12.82 )	59.2 ( 11.11 )	59.7 ( 10.95 )	58.1 ( 11.01 )	57.7 ( 10.60 )	-
Gender categorical
Units: Subjects
Female	17	48	36	35	33	35	204
Male	2	14	5	4	8	5	38

End points

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Reporting group title

ELS placebo/UPA placebo

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

UPA 15 mg/ELS 60 mg

Reporting group description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; 60 mg elsubrutinib capsule once a day by mouth for 12 weeks

Reporting group title

ELS 60 mg/UPA placebo

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

ELS 20 mg/UPA placebo

Reporting group description

20 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

ELS 5 mg/UPA placebo

Reporting group description

5 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

UPA 15 mg/ELS placebo

Reporting group description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; placebo capsule for elsubrutinib once a day by mouth for 12 weeks

Primary: Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

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End point title

Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

End point description

The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Baseline is defined as the last non-missing value prior to the first dose of study drug. A negative change from baseline indicates improvement in disease activity.

End point type

Primary

End point timeframe

Baseline, Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	18 ^[1]	54 ^[2]	35 ^[3]	29 ^[4]	34 ^[5]	37 ^[6]
Units: units on a scale
least squares mean (confidence interval 90%)	-1.12 (-1.64 to -0.60)	-2.56 (-2.86 to -2.26)	-1.52 (-1.89 to -1.15)	-1.32 (-1.71 to -0.93)	-1.33 (-1.70 to -0.97)	-2.87 (-3.23 to -2.51)

Notes
[1] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[2] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[3] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[4] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[5] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[6] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

UPA 15 mg/ELS 60 mg vs ELS Placebo/UPA Placebo

Statistical analysis description

Mixed-Effect Model Repeated Measure (MMRM) analysis was conducted, testing the superiority of the combination of upadacitinib 15 mg and elsubrutinib 60 mg compared to placebo at Week 12. Data collected after a participant discontinued study drug was considered as missing. The mixed model included the categorical fixed effects of treatment, visit and treatment-by-visit interaction, prior bDMARD use, and baseline DAS28 (CRP) measurement.

Comparison groups

ELS placebo/UPA placebo v UPA 15 mg/ELS 60 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

t-test, 2-sided

Parameter type

LS Mean Difference

Point estimate

-1.44

Confidence interval

level

90%

sides

2-sided

lower limit

-2.03

upper limit

-0.85

Variability estimate

Standard error of the mean

Dispersion value

0.36

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

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End point title

Change from Baseline in Clinical Disease Activity Index (CDAI)

End point description

The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Baseline is defined as the last non-missing value prior to the first dose of study drug. A negative change from baseline indicates improvement in disease activity.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	18 ^[7]	57 ^[8]	38 ^[9]	35 ^[10]	37 ^[11]	37 ^[12]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=17, 56, 38, 35, 35, 37)	-6.08 (-10.48 to -1.67)	-16.00 (-18.53 to -13.47)	-8.95 (-11.99 to -5.91)	-7.36 (-10.44 to -4.27)	-8.38 (-11.48 to -5.28)	-14.03 (-17.04 to -11.02)
Week 4 (n=17, 57, 37, 34, 37, 37)	-11.60 (-16.38 to -6.82)	-20.24 (-22.97 to -17.50)	-11.67 (-15.01 to -8.34)	-10.10 (-13.50 to -6.70)	-12.90 (-16.22 to -9.58)	-20.30 (-23.57 to -17.03)
Week 8 (n= 17, 56, 35, 31, 35, 37)	-12.46 (-17.52 to -7.40)	-24.95 (-27.86 to -22.05)	-15.07 (-18.65 to -11.49)	-17.10 (-20.83 to -13.38)	-14.84 (-18.42 to -11.26)	-23.72 (-27.20 to -20.24)
Week 12 (n= 18, 52, 35, 29, 33, 36))	-14.57 (-19.77 to -9.36)	-27.00 (-30.05 to -23.95)	-17.50 (-21.22 to -13.78)	-16.70 (-20.62 to -12.78)	-16.51 (-20.27 to -12.75)	-28.85 (-32.48 to -25.21)

Notes
[7] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[8] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[9] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[10] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[11] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[12] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

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End point title

Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

End point description

The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Clinical remission (CR) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than 2.6.

End point type

Secondary

End point timeframe

At Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[13]	62 ^[14]	41 ^[15]	39 ^[16]	41 ^[17]	40 ^[18]
Units: percentage of participants
number (confidence interval 90%)	10.5 (3.55 to 27.35)	32.3 (23.41 to 42.59)	19.5 (11.36 to 31.44)	7.7 (3.12 to 17.76)	9.8 (4.46 to 20.04)	42.5 (30.52 to 55.43)

Notes
[13] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[14] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[15] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[16] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[17] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[18] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Change From Baseline in Tender Joint Count 68 (TJC68)

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End point title

Change From Baseline in Tender Joint Count 68 (TJC68)

End point description

Sixty-eight joints were assessed for tenderness by physical examination. Pain or tenderness of each joint was classifiedas present (1) or absent (0), for a total possible score of 0 (0 joints with tenderness) to 68 (worst possible score/68 joints with tenderness). Baseline is defined as the last non-missing value prior to the first dose of study drug. Negative values indicate improvement from baseline.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[19]	61 ^[20]	39 ^[21]	37 ^[22]	40 ^[23]	40 ^[24]
Units: tender joint counts
least squares mean (confidence interval 90%)
Week 2 (n=19, 61, 39, 37, 39, 40)	-2.47 (-6.10 to 1.16)	-8.42 (-10.53 to -6.31)	-3.65 (-6.23 to -1.07)	-3.86 (-6.46 to -1.26)	-4.88 (-7.43 to -2.33)	-8.57 (-11.09 to -6.05)
Week 4 (n=19, 61, 38, 36, 40, 39)	-9.21 (-13.08 to -5.34)	-11.86 (-14.10 to -9.62)	-5.16 (-7.93 to -2.39)	-5.39 (-8.18 to -2.60)	-8.08 (-10.77 to -5.39)	-12.76 (-15.46 to -10.06)
Week 8 (n=18, 59, 36, 33, 38, 38)	-8.82 (-12.85 to -4.79)	-15.44 (-17.75 to -13.12)	-8.43 (-11.31 to -5.55)	-10.83 (-13.78 to -7.88)	-9.08 (-11.88 to -6.27)	-14.76 (-17.56 to -11.97)
Week 12 (n=18, 56, 36, 31, 35, 37)	-8.47 (-12.81 to -4.12)	-16.33 (-18.84 to -13.83)	-9.14 (-12.23 to -6.05)	-9.33 (-12.55 to -6.12)	-12.58 (-15.64 to -9.52)	-17.56 (-20.58 to -14.53)

Notes
[19] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[20] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[21] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[22] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[23] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[24] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response

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End point title

Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 20% response (ACR20) criteria: 1. ≥ 20% improvement in 68-tender joint count 2. ≥ 20% improvement in 66-swollen joint count and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: • Patient's Assessment of Pain (Visual Analog Scale [VAS]) • Patient’s Global Assessment of Disease Activity (PtGA) • Physician’s Global Assessment of Disease Activity (PhGA) • Health Assessment Questionnaire Disability Index (HAQ-DI) • High-sensitivity C-reactive protein (hsCRP)

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[25]	62 ^[26]	41 ^[27]	39 ^[28]	41	40
Units: percentage of participants
number (confidence interval 90%)
Week 2	21.1 (9.82 to 39.50)	45.2 (35.19 to 55.54)	24.4 (15.17 to 36.78)	12.8 (6.38 to 24.08)	14.6 (7.76 to 25.89)	52.5 (39.77 to 64.91)
Week 4	42.1 (25.63 to 60.55)	51.6 (41.33 to 61.76)	29.3 (19.16 to 41.94)	23.1 (13.95 to 35.70)	22.0 (13.24 to 34.13)	55.0 (42.16 to 67.21)
Week 8	36.8 (21.37 to 55.59)	64.5 (54.11 to 73.71)	39.0 (27.55 to 51.86)	30.8 (20.20 to 43.84)	39.0 (27.55 to 51.86)	67.5 (54.55 to 78.23)
Week 12	47.4 (30.07 to 65.33)	64.5 (54.11 to 73.71)	41.5 (29.72 to 54.26)	30.8 (20.20 to 43.84)	34.1 (23.29 to 46.97)	72.5 (59.75 to 82.40)

Notes
[25] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[26] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[27] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[28] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

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End point title

Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

End point description

The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Low Disease Activity (LDA) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than or equal to 3.2.

End point type

Secondary

End point timeframe

At Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[29]	62 ^[30]	41 ^[31]	39 ^[32]	41 ^[33]	40 ^[34]
Units: percentage of participants
least squares mean (confidence interval 90%)	21.1 (9.82 to 39.50)	41.9 (32.18 to 52.37)	22.0 (13.24 to 34.13)	10.3 (4.69 to 20.98)	14.6 (7.76 to 25.89)	55.0 (42.16 to 67.21)

Notes
[29] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[30] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[31] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[32] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[33] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[34] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Change From Baseline in Morning Stiffness Severity

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End point title

Change From Baseline in Morning Stiffness Severity

End point description

Morning stiffness severity was assessed by a numeric rating-scale (NRS). Participants rated the severity of morning stiffness during the past week from 0 to 10 with 0 representing "not severe" and 10 "very severe". Baseline is defined as the last non-missing value prior to the first dose of study drug. Negative values indicate improvement from baseline.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[35]	59 ^[36]	39 ^[37]	35 ^[38]	40 ^[39]	38 ^[40]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=19, 59, 39, 35, 38, 38)	-1.76 (-2.54 to -0.98)	-2.02 (-2.48 to -1.56)	-0.91 (-1.47 to -0.35)	-0.68 (-1.26 to -0.11)	-0.59 (-1.15 to -0.04)	-1.84 (-2.40 to -1.29)
Week 4 (n=19, 59, 37, 34, 40, 38)	-1.76 (-2.63 to -0.90)	-2.71 (-3.22 to -2.21)	-0.82 (-1.45 to -0.20)	-0.83 (-1.47 to -0.19)	-1.08 (-1.67 to -0.48)	-2.51 (-3.13 to -1.90)
Week 8 (n=18, 57, 35, 31, 38, 37)	-1.67 (-2.56 to -0.77)	-3.07 (-3.59 to -2.55)	-1.30 (-1.94 to -0.65)	-0.97 (-1.64 to -0.30)	-1.50 (-2.11 to -0.88)	-3.07 (-3.70 to -2.44)
Week 12 (n=18, 54, 34, 29, 35, 36)	-1.61 (-2.60 to -0.63)	-3.23 (-3.81 to -2.65)	-1.27 (-1.99 to -0.56)	-1.30 (-2.06 to -0.55)	-1.66 (-2.36 to -0.97)	-3.36 (-4.06 to -2.67)

Notes
[35] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[36] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[37] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[38] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[39] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[40] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP])

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End point title

Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP])

End point description

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[41]	59 ^[42]	39 ^[43]	35 ^[44]	40 ^[45]	39 ^[46]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=19, 59, 39, 35, 38, 39)	-0.46 (-0.83 to -0.10)	-1.53 (-1.75 to -1.31)	-0.63 (-0.89 to -0.36)	-0.44 (-0.71 to -0.18)	-0.56 (-0.82 to -0.30)	-1.43 (-1.69 to -1.17)
Week 4 (n=19, 59, 37, 34, 40, 39)	-0.90 (-1.33 to -0.47)	-1.96 (-2.21 to -1.71)	-0.87 (-1.18 to -0.56)	-0.68 (-1.00 to -0.36)	-0.82 (-1.11 to -0.52)	-1.98 (-2.28 to -1.67)
Week 8 (n=18, 57, 35, 30, 38, 38)	-0.78 (-1.27 to -0.29)	-2.40 (-2.68 to -2.11)	-1.21 (-1.56 to -0.86)	-1.24 (-1.61 to -0.87)	-1.11 (-1.45 to -0.77)	-2.34 (-2.68 to -2.00)
Week 12 (n=18, 54, 35, 29, 34, 37)	-1.12 (-1.64 to -0.60)	-2.56 (-2.86 to -2.26)	-1.52 (-1.89 to -1.15)	-1.32 (-1.71 to -0.93)	-1.33 (-1.70 to -0.97)	-2.87 (-3.23 to -2.51)

Notes
[41] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[42] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[43] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[44] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[45] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[46] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

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

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End point title

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

End point description

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

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[47]	59 ^[48]	39 ^[49]	35 ^[50]	40 ^[51]	38 ^[52]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=19, 59, 39, 35, 38, 38)	-0.22 (-0.37 to -0.06)	-0.34 (-0.43 to -0.25)	-0.13 (-0.24 to -0.02)	-0.06 (-0.17 to 0.05)	-0.16 (-0.27 to -0.05)	-0.22 (-0.33 to -0.11)
Week 4 (n=19, 59, 37, 34, 40, 38)	-0.36 (-0.53 to -0.18)	-0.39 (-0.49 to -0.29)	-0.11 (-0.23 to 0.02)	-0.14 (-0.27 to -0.02)	-0.21 (-0.33 to -0.09)	-0.33 (-0.45 to -0.20)
Week 8 (n=18, 57, 35, 31, 38, 37)	-0.24 (-0.44 to -0.05)	-0.47 (-0.59 to -0.36)	-0.29 (-0.43 to -0.15)	-0.15 (-0.30 to -0.00)	-0.15 (-0.29 to -0.02)	-0.47 (-0.61 to -0.33)
Week 12 (n=18, 54, 35, 29, 35, 36)	-0.30 (-0.52 to -0.08)	-0.52 (-0.65 to -0.39)	-0.31 (-0.46 to -0.15)	-0.12 (-0.28 to 0.05)	-0.18 (-0.33 to -0.03)	-0.54 (-0.70 to -0.39)

Notes
[47] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[48] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[49] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[50] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[51] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[52] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

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

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End point title

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

End point description

The EULAR Boolean-based definition of remission is as follows: at any time point, a participant must satisfy all of the following: tender joint count ≤1, swollen joint count ≤1, C-reactive protein ≤1 mg/dl and Patient Global Assessment (PGA) ≤1 (on a 0–10 scale).

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[53]	62 ^[54]	41 ^[55]	39 ^[56]	41 ^[57]	40 ^[58]
Units: percentage of participants
number (confidence interval 90%)
Week 2	0 (0.00 to 12.46)	1.6 (0.36 to 6.91)	0 (0.00 to 6.19)	0 (0.00 to 6.49)	0 (0.00 to 6.19)	0 (0.00 to 6.34)
Week 4	0 (0.00 to 12.46)	6.5 (2.93 to 13.62)	2.4 (0.55 to 10.22)	0 (0.00 to 6.49)	0 (0.00 to 6.19)	2.5 (0.56 to 10.46)
Week 8	0 (0.00 to 12.46)	6.5 (2.93 to 13.62)	2.4 (0.55 to 10.22)	5.1 (1.71 to 14.37)	0 (0.00 to 6.19)	12.5 (6.22 to 23.53)
Week 12	0 (0.00 to 12.46)	11.3 (6.24 to 19.58)	9.8 (4.46 to 20.04)	2.6 (0.57 to 10.71)	2.4 (0.55 to 10.22)	10.0 (4.57 to 20.50)

Notes
[53] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[54] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[55] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[56] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[57] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[58] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Minimal Clinically Important Difference (MCID) in Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

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End point title

Percentage of Participants Achieving Minimal Clinically Important Difference (MCID) in Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

End point description

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. The minimal clinically important difference (MCID) in HAQ-DI is defined as change from Baseline ≤ -0.22 for rheumatoid arthritis.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[59]	62 ^[60]	41 ^[61]	39 ^[62]	41 ^[63]	40 ^[64]
Units: percentage of participants
number (confidence interval 90%)
Week 2	52.6 (34.67 to 69.93)	51.6 (41.33 to 61.76)	36.6 (25.40 to 49.43)	30.8 (20.20 to 43.84)	36.6 (25.40 to 49.43)	52.5 (39.77 to 64.91)
Week 4	68.4 (49.55 to 82.70)	54.8 (44.46 to 64.81)	34.1 (23.29 to 46.97)	41.0 (29.07 to 54.15)	53.7 (41.02 to 65.84)	45.0 (32.79 to 57.84)
Week 8	52.6 (34.67 to 69.93)	58.1 (47.63 to 67.82)	51.2 (38.71 to 63.58)	51.3 (38.47 to 63.93)	36.6 (25.40 to 49.43)	65.0 (52.01 to 76.09)
Week 12	47.4 (30.07 to 65.33)	58.1 (47.63 to 67.82)	53.7 (41.02 to 65.84)	43.6 (31.37 to 56.64)	43.9 (31.93 to 56.63)	55.0 (42.16 to 67.21)

Notes
[59] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[60] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[61] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[62] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[63] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[64] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI)

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End point title

Change From Baseline in Simplified Disease Activity Index (SDAI)

End point description

The SDAI is a validated measure of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, global disease activity assessed by the participant on a visual analogue scale from 0 to 10 (cm), global disease activity assessed by an investigator on a visual analogue scale from 0 to 10 (cm), and serum levels of C-reactive protein (CRP; mg/dL) were included in the SDAI score. Scores on the SDAI range from 0 to 86.with higher scores indicating higher disease activity. Baseline is defined as the last non-missing value prior to the first dose of study drug. A negative change from baseline indicates improvement in disease activity.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	18 ^[65]	57 ^[66]	38 ^[67]	35 ^[68]	37 ^[69]	37 ^[70]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=17, 56, 38, 35, 35, 37)	-6.17 (-10.67 to -1.67)	-17.01 (-19.60 to -14.43)	-8.79 (-11.89 to -5.68)	-7.42 (-10.57 to -4.26)	-8.54 (-11.71 to -5.38)	-15.30 (-18.37 to -12.22)
Week 4 (n=17, 57, 37, 34, 37, 37)	-11.80 (-16.67 to -6.93)	-21.24 (-24.02 to -18.45)	-11.46 (-14.85 to -8.06)	-10.15 (-13.61 to -6.68)	-12.87 (-16.25 to -9.49)	-21.59 (-24.92 to -18.26)
Week 8 (n=17, 56, 35, 30, 35, 37)	-12.15 (-17.35 to -6.95)	-25.96 (-28.95 to -22.98)	-15.26 (-18.94 to -11.57)	-17.32 (-21.17 to -13.46)	-15.21 (-18.89 to -11.53)	-25.07 (-28.65 to -21.49)
Week 12 (n=18, 52, 35, 29, 32, 36)	-14.44 (-19.84 to -9.04)	-28.06 (-31.22 to -24.89)	-18.01 (-21.86 to -14.15)	-17.12 (-21.20 to -13.05)	-16.73 (-20.65 to -12.81)	-29.65 (-33.42 to -25.88)

Notes
[65] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[66] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[67] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[68] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[69] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[70] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

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

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End point title

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

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 50% response (ACR50) criteria: 1. ≥ 50% improvement in 68-tender joint count 2. ≥ 50% improvement in 66-swollen joint count and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: • Patient's Assessment of Pain (Visual Analog Scale [VAS]) • Patient’s Global Assessment of Disease Activity (PtGA) • Physician’s Global Assessment of Disease Activity (PhGA) • Health Assessment Questionnaire Disability Index (HAQ-DI) • High-sensitivity C-reactive protein (hsCRP)

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[71]	62 ^[72]	41 ^[73]	39 ^[74]	41 ^[75]	40 ^[76]
Units: percentage of participants
number (confidence interval 90%)
Week 2	0 (0.00 to 12.46)	16.1 (9.89 to 25.20)	4.9 (1.63 to 13.71)	0 (0.00 to 6.49)	0 (0.00 to 6.19)	12.5 (6.22 to 23.53)
Week 4	10.5 (3.55 to 27.35)	19.4 (12.46 to 28.82)	17.1 (9.53 to 28.69)	2.6 (0.57 to 10.71)	4.9 (1.63 to 13.71)	30.0 (19.66 to 42.87)
Week 8	5.3 (1.18 to 20.50)	41.9 (32.18 to 52.37)	19.5 (11.36 to 31.44)	12.8 (6.38 to 24.08)	7.3 (2.96 to 16.96)	40.0 (28.29 to 52.98)
Week 12	21.1 (9.82 to 39.50)	45.2 (35.19 to 55.54)	29.3 (19.16 to 41.94)	12.8 (6.38 to 24.08)	17.1 (9.53 to 28.69)	47.5 (35.09 to 60.23)

Notes
[71] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[72] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[73] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[74] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[75] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[76] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

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

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End point title

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

End point description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 70% response (ACR70) criteria: 1. ≥ 70% improvement in 68-tender joint count 2. ≥ 70% improvement in 66-swollen joint count and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: • Patient's Assessment of Pain (Visual Analog Scale [VAS]) • Patient’s Global Assessment of Disease Activity (PtGA) • Physician’s Global Assessment of Disease Activity (PhGA) • Health Assessment Questionnaire Disability Index (HAQ-DI) • High-sensitivity C-reactive protein (hsCRP)

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[77]	62 ^[78]	41 ^[79]	39 ^[80]	41 ^[81]	40 ^[82]
Units: percentage of participants
number (confidence interval 90%)
Week 2	0 (0.00 to 12.46)	8.1 (3.98 to 15.66)	2.4 (0.55 to 10.22)	0 (0.00 to 6.49)	0 (0.00 to 6.19)	0 (0.00 to 6.34)
Week 4	0 (0.00 to 12.46)	9.7 (5.09 to 17.64)	4.9 (1.63 to 13.71)	2.6 (0.57 to 10.71)	0 (0.00 to 6.19)	15.0 (7.96 to 26.47)
Week 8	0 (0.00 to 12.46)	17.7 (11.16 to 27.02)	4.9 (1.63 to 13.71)	2.6 (0.57 to 10.71)	0 (0.00 to 6.19)	25.0 (15.57 to 37.60)
Week 12	15.8 (6.49 to 33.62)	25.8 (17.81 to 35.82)	14.6 (7.76 to 25.89)	5.1 (1.71 to 14.37)	9.8 (4.46 to 20.04)	27.5 (17.60 to 40.25)

Notes
[77] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[78] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[79] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[80] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[81] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[82] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP)

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End point title

Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP)

End point description

C-reactive protein is a blood test marker for inflammation in the body, and levels rise in response to inflammation. Baseline is defined as the last non-missing value prior to the first dose of study drug. A negative change from baseline in indicates improvement.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[83]	61 ^[84]	39 ^[85]	37 ^[86]	40 ^[87]	40 ^[88]
Units: mg/L
least squares mean (confidence interval 90%)
Week 2 (n=19, 61, 39, 37, 39, 40)	-0.51 (-4.82 to 3.81)	-9.29 (-11.79 to -6.80)	2.26 (-0.81 to 5.33)	-0.34 (-3.43 to 2.74)	-0.72 (-3.74 to 2.30)	-12.27 (-15.26 to -9.27)
Week 4 (n=19, 61, 38, 36, 40, 39)	1.54 (-3.72 to 6.79)	-10.08 (-13.08 to -7.08)	2.71 (-1.05 to 6.46)	-0.78 (-4.58 to 3.02)	0.72 (-2.91 to 4.35)	-12.59 (-16.27 to -8.92)
Week 8 (n=18, 59, 36, 32, 38, 38)	3.23 (-1.56 to 8.03)	-9.97 (-12.70 to -7.24)	-1.39 (-4.83 to 2.05)	-2.58 (-6.15 to 1.00)	-2.93 (-6.26 to 0.39)	-13.13 (-16.46 to -9.81)
Week 12 (n=18, 56, 36, 31, 34, 37)	1.45 (-5.10 to 8.00)	-10.95 (-14.73 to -7.18)	-4.58 (-9.26 to 0.09)	-5.78 (-10.77 to -0.78)	-0.81 (-5.58 to 3.97)	-7.44 (-12.03 to -2.86)

Notes
[83] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[84] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[85] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[86] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[87] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[88] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

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

The DAS28-ESR is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 100 mm) are included in the DAS28 -ESR score. Scores on the DAS28-ESR range from 0 to 10; higher scores indicate more disease activity. Baseline is defined as the last non-missing value prior to the first dose of study drug.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[89]	59 ^[90]	39 ^[91]	34 ^[92]	40 ^[93]	39 ^[94]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=19, 59, 39, 34, 38, 39)	-0.46 (-0.82 to -0.09)	-1.48 (-1.69 to -1.26)	-0.52 (-0.79 to -0.26)	-0.46 (-0.74 to -0.19)	-0.57 (-0.83 to -0.32)	-1.32 (-1.58 to -1.06)
Week 4 (n=19, 58, 37, 34, 40, 39)	-0.86 (-1.30 to -0.43)	-1.93 (-2.19 to -1.68)	-0.79 (-1.11 to -0.48)	-0.59 (-0.91 to -0.26)	-0.92 (-1.23 to -0.62)	-1.90 (-2.20 to -1.59)
Week 8 (n=18, 57, 35, 30, 37, 38)	-0.80 (-1.29 to -0.31)	-2.41 (-2.69 to -2.12)	-1.07 (-1.42 to -0.71)	-1.15 (-1.52 to -0.78)	-1.20 (-1.54 to -0.86)	-2.31 (-2.65 to -1.97)
Week 12 (n=18, 54, 35, 29, 35, 37)	-1.18 (-1.71 to -0.64)	-2.53 (-2.84 to -2.22)	-1.41 (-1.80 to -1.03)	-1.24 (-1.65 to -0.83)	-1.44 (-1.82 to -1.06)	-2.88 (-3.25 to -2.50)

Notes
[89] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[90] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[91] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[92] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[93] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[94] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria

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End point title

Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria

End point description

The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Low Disease Activity (LDA) based on CDAI is defined as achieving a CDAI of less than or equal to 10.

End point type

Secondary

End point timeframe

Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[95]	62 ^[96]	41 ^[97]	39 ^[98]	41 ^[99]	40 ^[100]
Units: percentage of participants
number (confidence interval 90%)
Week 2	10.5 (3.55 to 27.35)	16.1 (9.89 to 25.20)	9.8 (4.46 to 20.04)	0 (0.00 to 6.49)	2.4 (0.55 to 10.22)	12.5 (6.22 to 23.53)
Week 4	10.5 (3.55 to 27.35)	29.0 (20.59 to 39.23)	12.2 (6.06 to 23.01)	7.7 (3.12 to 17.76)	12.2 (6.06 to 23.01)	22.5 (13.59 to 34.90)
Week 8	5.3 (1.18 to 20.50)	46.8 (36.71 to 57.11)	17.1 (9.53 to 28.69)	20.5 (11.96 to 32.89)	24.4 (15.17 to 36.78)	35.0 (23.91 to 47.99)
Week 12	26.3 (13.44 to 45.09)	37.1 (27.74 to 47.53)	34.1 (23.29 to 46.97)	17.9 (10.03 to 30.02)	17.1 (9.53 to 28.69)	57.5 (44.57 to 69.48)

Notes
[95] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[96] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[97] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[98] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[99] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[100] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Complete Remission (CR) Based on Clinical Disease Activity Index (CDAI) Criteria

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End point title

Percentage of Participants Achieving Complete Remission (CR) Based on Clinical Disease Activity Index (CDAI) Criteria

End point description

The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Complete Remission (CR) based on CDAI is defined as achieving a CDAI of less than or equal to 2.8.

End point type

Secondary

End point timeframe

Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[101]	62 ^[102]	41 ^[103]	39 ^[104]	41 ^[105]	40 ^[106]
Units: percentage of participants
number (confidence interval 90%)
Week 2	0 (0.00 to 12.46)	3.2 (1.07 to 9.29)	0 (0.00 to 6.19)	0 (0.00 to 6.49)	0 (0.00 to 6.19)	0 (0.00 to 6.34)
Week 4	0 (0.00 to 12.46)	6.5 (2.93 to 13.62)	2.4 (0.55 to 10.22)	2.6 (0.57 to 10.71)	0 (0.00 to 6.19)	2.5 (0.56 to 10.46)
Week 8	0 (0.00 to 12.46)	12.9 (7.43 to 21.48)	7.3 (2.96 to 16.96)	2.6 (0.57 to 10.71)	2.4 (0.55 to 10.22)	12.5 (6.22 to 23.53)
Week 12	5.3 (1.18 to 20.50)	14.5 (8.65 to 23.35)	7.3 (2.96 to 16.96)	5.1 (1.71 to 14.37)	0 (0.00 to 6.19)	15.0 (7.96 to 26.47)

Notes
[101] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[102] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[103] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[104] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[105] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data
[106] - FAS:randomized subjects rcvd ≥1 dose randomized study drug, nonresponder imputation for missing data

No statistical analyses for this end point

Secondary: Change From Baseline in Swollen Joint Count 66 (SJC66)

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End point title

Change From Baseline in Swollen Joint Count 66 (SJC66)

End point description

Sixty-six joints were assessed for swelling by physical examination. Swelling of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with swelling) to 66 (worst possible score/66 joints with swelling). Baseline is defined as the last non-missing value prior to the first dose of study drug. Negative values indicate improvement from baseline.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[107]	61 ^[108]	39 ^[109]	37 ^[110]	40 ^[111]	40 ^[112]
Units: swollen joint counts
least squares mean (confidence interval 90%)
Week 2 (n=19, 61, 39, 37, 39, 40)	-3.12 (-5.20 to -1.05)	-6.06 (-7.26 to -4.86)	-3.61 (-5.08 to -2.14)	-3.30 (-4.78 to -1.82)	-4.13 (-5.60 to -2.67)	-6.02 (-7.46 to -4.58)
Week 4 (n=19, 61, 38, 36, 40, 39)	-4.70 (-6.92 to -2.49)	-7.96 (-9.24 to -6.68)	-5.11 (-6.69 to -3.53)	-4.67 (-6.27 to -3.07)	-6.05 (-7.60 to -4.51)	-8.81 (-10.35 to -7.26)
Week 8 (n=18, 59, 36, 33, 38, 38)	-4.32 (-6.57 to -2.06)	-10.28 (-11.57 to -8.99)	-6.15 (-7.77 to -4.54)	-8.08 (-9.74 to -6.42)	-7.58 (-9.15 to -6.00)	-10.11 (-11.68 to -8.55)
Week 12 (n=18, 56, 36, 31, 35, 37)	-5.58 (-8.05 to -3.11)	-10.86 (-12.29 to -9.44)	-6.68 (-8.44 to -4.92)	-7.85 (-9.70 to -6.01)	-8.59 (-10.35 to -6.83)	-11.14 (-12.86 to -9.42)

Notes
[107] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[108] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[109] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[110] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[111] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[112] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Change From Baseline in Participant's Assessment of Pain (Visual Analog Scale [VAS])

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End point title

Change From Baseline in Participant's Assessment of Pain (Visual Analog Scale [VAS])

End point description

Participants rated their pain on a visual analogue scale (VAS) of 0 to 100 (mm), with 0 representing no pain and 100 representing the worst possible pain. Baseline is defined as the last non-missing value prior to the first dose of study drug. Negative values indicate improvement from baseline.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[113]	59 ^[114]	39 ^[115]	35 ^[116]	40 ^[117]	39 ^[118]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=19, 59, 39, 35, 38, 39)	-14.97 (-22.80 to -7.14)	-24.02 (-28.63 to -19.41)	-10.22 (-15.81 to -4.63)	-8.78 (-14.49 to -3.07)	-7.61 (-13.12 to -2.11)	-15.99 (-21.49 to -10.48)
Week 4 (n=19, 59, 37, 34, 40, 39)	-20.87 (-29.60 to -12.14)	-28.17 (-33.28 to -23.07)	-12.95 (-19.27 to -6.63)	-8.41 (-14.85 to -1.97)	-9.91 (-15.93 to -3.88)	-25.58 (-31.69 to -19.48)
Week 8 (n=18, 57, 35, 31, 38, 38)	-16.21 (-25.97 to -6.45)	-31.86 (-37.50 to -26.22)	-20.92 (-27.96 to -13.88)	-11.12 (-18.46 to -3.79)	-13.90 (-20.64 to -7.16)	-30.70 (-37.47 to -23.92)
Week 12 (n=18, 54, 35, 29, 35, 37)	-23.37 (-33.74 to -13.01)	-32.27 (-38.32 to -26.23)	-19.52 (-26.97 to -12.06)	-10.46 (-18.38 to -2.55)	-17.84 (-25.13 to -10.55)	-38.34 (-45.57 to -31.12)

Notes
[113] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[114] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[115] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[116] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[117] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[118] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Change From Baseline in Patient's Global Assessment of Disease Activity (PGA)

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End point title

Change From Baseline in Patient's Global Assessment of Disease Activity (PGA)

End point description

Participants rated their disease activity for the past 24 hours using a Patient’s Global Assessment of Disease Activity Global visual analogue scale (VAS). The range is 0 to 100 mm, with 0 representing no disease activity and 100 representing severe disease activity. Negative values indicate improvement from baseline.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	19 ^[119]	59 ^[120]	39 ^[121]	35 ^[122]	40 ^[123]	39 ^[124]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=19, 59, 39, 35, 38, 39)	-11.87 (-20.12 to -3.63)	-23.44 (-28.31 to -18.57)	-11.16 (-17.07 to -5.25)	-6.47 (-12.51 to -0.44)	-5.95 (-11.76 to -0.14)	-14.76 (-20.56 to -8.95)
Week 4 (n=19, 59, 37, 34, 40, 39)	-20.93 (-29.91 to -11.94)	-25.97 (-31.24 to -20.70)	-12.79 (-19.32 to -6.26)	-7.15 (-13.79 to -0.50)	-8.73 (-14.94 to -2.51)	-23.02 (-29.31 to -16.73)
Week 8 (n=18, 57, 35, 31, 38, 38)	-15.14 (-25.37 to -4.91)	-28.05 (-33.97 to -22.13)	-17.25 (-24.65 to -9.84)	-6.27 (-14.00 to 1.45)	-14.25 (-21.34 to -7.17)	-26.79 (-33.90 to -19.69)
Week 12 (n=18, 54, 35, 29, 35, 37)	-19.55 (-30.15 to -8.95)	-30.52 (-36.72 to -24.32)	-19.47 (-27.13 to -11.81)	-8.45 (-16.58 to -0.33)	-16.40 (-23.89 to -8.92)	-33.53 (-40.94 to -26.13)

Notes
[119] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[120] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[121] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[122] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[123] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[124] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Secondary: Change From Baseline in Physician's Global Assessment of Disease Activity (PhGA)

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End point title

Change From Baseline in Physician's Global Assessment of Disease Activity (PhGA)

End point description

The physician assessed a participant’s disease activity at the time of the visit using a Physician's Global Assessment of Disease visual analogue scale (VAS). The range is 0 to 100 mm, with 0 representing no disease activity and 100 representing severe disease activity. Negative values indicate improvement from baseline.

End point type

Secondary

End point timeframe

Baseline, Week 2, Week 4, Week 8, and Week 12

End point values	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Number of subjects analysed	18 ^[125]	58 ^[126]	38 ^[127]	35 ^[128]	37 ^[129]	38 ^[130]
Units: units on a scale
least squares mean (confidence interval 90%)
Week 2 (n=17, 57, 38, 35, 36, 38)	-16.31 (-24.67 to -7.96)	-22.35 (-27.10 to -17.60)	-19.01 (-24.74 to -13.27)	-16.12 (-21.97 to -10.26)	-11.64 (-17.44 to -5.84)	-24.71 (-30.37 to -19.05)
Week 4 (n=17, 58, 37, 34, 37, 37)	-25.20 (-33.52 to -16.89)	-33.54 (-38.26 to -28.82)	-25.33 (-31.11 to -19.55)	-19.59 (-25.49 to -13.69)	-18.31 (-24.05 to -12.56)	-34.17 (-39.86 to -28.49)
Week 8 (n=17, 57, 35, 31, 35, 37)	-24.47 (-32.71 to -16.22)	-40.00 (-44.71 to -35.29)	-30.06 (-35.91 to -24.22)	-33.93 (-39.99 to -27.87)	-25.21 (-31.03 to -19.40)	-41.02 (-46.69 to -35.36)
Week 12 (n=18, 53, 35, 29, 33, 36)	-23.19 (-31.69 to -14.69)	-46.98 (-52.00 to -41.96)	-30.15 (-36.28 to -24.03)	-31.68 (-38.19 to -25.18)	-24.55 (-30.75 to -18.36)	-50.89 (-56.87 to -44.91)

Notes
[125] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[126] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[127] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[128] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[129] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values
[130] - FAS: randomized, rcvd ≥ 1 dose randomized study drug, non-missing baseline, ≥ 1 post-baseline values

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) collected from 1st dose of study drug until 30 d after last dose, up to 16 wks. SAEs and protocol-related nonserious AEs were collected from the time the subject signed consent.

Adverse event reporting additional description

TEAEs and SAEs are defined as any AE or SAE with onset or worsening reported by a participant from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug. TEAEs were collected whether elicited or spontaneously reported by the participant.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

ELS placebo/UPA placebo

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

UPA 15 mg/ELS 60 mg

Reporting group description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; 60 mg elsubrutinib capsule once a day by mouth for 12 weeks

Reporting group title

ELS 60 mg/UPA placebo

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

ELS 20 mg/UPA placebo

Reporting group description

20 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

ELS 5 mg/UPA placebo

Reporting group description

5 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks

Reporting group title

UPA 15 mg/ELS placebo

Reporting group description

15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; placebo capsule for elsubrutinib once a day by mouth for 12 weeks

Serious adverse events	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	2 / 39 (5.13%)	3 / 41 (7.32%)	0 / 40 (0.00%)
number of deaths (all causes)	0	0	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	1	0
Investigations
PROSTATIC SPECIFIC ANTIGEN INCREASED
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
CLAVICLE FRACTURE
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RIB FRACTURE
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ROAD TRAFFIC ACCIDENT
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
CARDIAC ARREST
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
CORONARY ARTERY DISEASE
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
LUMBAR RADICULOPATHY
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
PYELONEPHRITIS
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	ELS placebo/UPA placebo	UPA 15 mg/ELS 60 mg	ELS 60 mg/UPA placebo	ELS 20 mg/UPA placebo	ELS 5 mg/UPA placebo	UPA 15 mg/ELS placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 19 (52.63%)	7 / 62 (11.29%)	17 / 41 (41.46%)	10 / 39 (25.64%)	8 / 41 (19.51%)	9 / 40 (22.50%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	2
BLOOD GLUCOSE INCREASED
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ENDOMETRIAL ADENOCARCINOMA
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0
Injury, poisoning and procedural complications
ANIMAL BITE
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0
General disorders and administration site conditions
PERIPHERAL SWELLING
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	1 / 41 (2.44%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	1	0	0	0
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	3 / 41 (7.32%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	3	0	0	0
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	0 / 19 (0.00%)	1 / 62 (1.61%)	2 / 41 (4.88%)	0 / 39 (0.00%)	0 / 41 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	1	2	0	0	2
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	0 / 41 (0.00%)	2 / 39 (5.13%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	2	0	0
ERYTHEMA
subjects affected / exposed	1 / 19 (5.26%)	1 / 62 (1.61%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	1	0	0	0	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	1 / 19 (5.26%)	1 / 62 (1.61%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	1	0	0	0	0
ARTHRITIS
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	1 / 41 (2.44%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	1	0	0	0
BONE DEFORMITY
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0
PAIN IN EXTREMITY
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0
RHEUMATOID ARTHRITIS
subjects affected / exposed	2 / 19 (10.53%)	0 / 62 (0.00%)	3 / 41 (7.32%)	3 / 39 (7.69%)	3 / 41 (7.32%)	0 / 40 (0.00%)
occurrences all number	2	0	3	3	3	0
Infections and infestations
BRONCHITIS
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	1 / 41 (2.44%)	0 / 39 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences all number	1	0	1	0	1	0
SINUSITIS
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	1 / 41 (2.44%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	1	0	0	0
TOOTH INFECTION
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	0	0	1	0	1
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 19 (5.26%)	4 / 62 (6.45%)	2 / 41 (4.88%)	3 / 39 (7.69%)	2 / 41 (4.88%)	2 / 40 (5.00%)
occurrences all number	1	4	2	3	2	2
URINARY TRACT INFECTION
subjects affected / exposed	0 / 19 (0.00%)	0 / 62 (0.00%)	4 / 41 (9.76%)	2 / 39 (5.13%)	2 / 41 (4.88%)	3 / 40 (7.50%)
occurrences all number	0	0	5	2	2	4
Metabolism and nutrition disorders
VITAMIN D DEFICIENCY
subjects affected / exposed	1 / 19 (5.26%)	0 / 62 (0.00%)	0 / 41 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

11 Jul 2018

Version 2.0 • Modified categorization of PhGA assessment (from patient-reported outcome to exam) • Clarified PK sample collection and creatine phosphokinase (CPK) laboratory test requirements • Updated biomarker collection requirements • Added respiratory rate to vital signs collected and abnormal labs to the list of potential reasons for study drug discontinuation

05 Oct 2018

Version 3.0 • Added a 12-lead ECG to Weeks 2, 4, and 8 • Added information on subject at-home weekly temperature monitoring for assessment of serious infections

11 Mar 2019

Version 4.0 • Reduced the washout period from ≥ 10 weeks to ≥ 4 weeks for adalimumab, infliximab, certolizumab, golimumab, tocilizumab, and abatacept • Prior exposure to JAK inhibitors changed from not allowed to not greater than 2 weeks with the addition of a washout period ≥ 30 days required prior to first dose of study drug • Added clarification that nonsteroidal anti-inflammatory drugs, acetaminophen/paracetamol, oral corticosteroids (equivalent to prednisone ≤ 10 mg/day), or inhaled corticosteroids, if not taken at Baseline, should not be initiated. • Added TBNK cell testing may be completed at Screening (rather than Baseline) if indicated • Added footnote regarding pre-dose collection for biomarker samples at Baseline to the Activity Schedule • Added information on dispensing the subject dosing diary and at-home temperature monitoring log at Baseline and a reminder to review the at-home temperature monitoring log during weekly at-home temperature monitoring • Added T or T SPOT®.TB test language from the Canada-specific amendment • Added an unblinded administrative interim assessment of efficacy when 80% of subjects have completed the Week 12 visit (to be performed in addition to the previously planned unblinded safety assessments)

15 Oct 2019

Version 5.0 • Updated Sponsor/Emergency Medical Contact info

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

Primary: Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

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

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

Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

Secondary: Change From Baseline in Tender Joint Count 68 (TJC68)

Secondary: Change From Baseline in Tender Joint Count 68 (TJC68)

Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response

Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12

Secondary: Change From Baseline in Morning Stiffness Severity

Secondary: Change From Baseline in Morning Stiffness Severity

Secondary: Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP])

Secondary: Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP])

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

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

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

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

Secondary: Percentage of Participants Achieving Minimal Clinically Important Difference (MCID) in Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

Secondary: Percentage of Participants Achieving Minimal Clinically Important Difference (MCID) in Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI)

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI)

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

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

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

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

Secondary: Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP)

Secondary: Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP)

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 Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria

Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria

Secondary: Percentage of Participants Achieving Complete Remission (CR) Based on Clinical Disease Activity Index (CDAI) Criteria

Secondary: Percentage of Participants Achieving Complete Remission (CR) Based on Clinical Disease Activity Index (CDAI) Criteria

Secondary: Change From Baseline in Swollen Joint Count 66 (SJC66)

Secondary: Change From Baseline in Swollen Joint Count 66 (SJC66)

Secondary: Change From Baseline in Participant's Assessment of Pain (Visual Analog Scale [VAS])

Secondary: Change From Baseline in Participant's Assessment of Pain (Visual Analog Scale [VAS])

Secondary: Change From Baseline in Patient's Global Assessment of Disease Activity (PGA)

Secondary: Change From Baseline in Patient's Global Assessment of Disease Activity (PGA)

Secondary: Change From Baseline in Physician's Global Assessment of Disease Activity (PhGA)

Secondary: Change From Baseline in Physician's Global Assessment of Disease Activity (PhGA)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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