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A Study to Compare Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have Not Previously Taken Methotrexate (SELECT-EARLY)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02706873
Recruitment Status : Active, not recruiting
First Posted : March 11, 2016
Results First Posted : October 4, 2019
Last Update Posted : March 11, 2020
Sponsor:
Information provided by (Responsible Party):
AbbVie

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Drug: Upadacitinib Placebo
Drug: Methotrexate
Drug: Methotrexate Placebo
Drug: Upadacitinib
Enrollment 1002
Recruitment Details Participants were randomized at 136 sites in 43 countries. The study included 2 periods and a Japan sub-study. The global study analysis included participants from Japan, but excluded the upadacitinib 7.5 mg group. The Japan sub-study included all participants from Japan, including the upadacitinib 7.5 mg group.
Pre-assignment Details

Participants were randomized in a 1:1:1 ratio to Groups 1, 3, and 4 below, except for participants in Japan who were randomized in a 1:2:1:1 ratio to Groups 1, 2, 3, and 4. Randomization was stratified by geographic region.

Results are reported up to Week 24 of Period 1. Efficacy analyses were conducted separately for the Japan sub-study.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1. Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Period Title: Overall Study
Started 315 55 317 315
Received Study Drug 314 55 317 314
Global Analysis Population [1] 314 [2] 0 317 [3] 314 [2]
Japan Sub-study [4] 28 55 27 28
Completed [5] 268 51 290 282
Not Completed 47 4 27 33
Reason Not Completed
Adverse Event             13             3             13             12
Withdrawal by Subject             15             0             8             11
Lost to Follow-up             3             0             4             2
Lack of Efficacy             10             0             0             3
Other             5             1             2             3
Not Dosed             1             0             0             1
Ongoing             0             0             0             1
[1]
Participants enrolled in the methotrexate, upadacitinib 15 mg and 30 mg treatment groups
[2]
Includes 28 participants in the Japan sub-study
[3]
Includes 27 participants in the Japan sub-study
[4]
Participants in the methotrexate, upadacitinib 7.5, 15, and 30 mg treatment groups enrolled in Japan
[5]
Completed Week 24 study drug
Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg Total
Hide Arm/Group Description Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1. Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Total of all reporting groups
Overall Number of Baseline Participants 314 55 317 314 1000
Hide Baseline Analysis Population Description
The full analysis set included all randomized participants who received at least 1 dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
53.3  (12.89) 59.7  (13.8) 51.9  (12.58) 54.9  (12.58) 53.7  (12.86)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
< 40 years
50
  15.9%
5
   9.1%
60
  18.9%
34
  10.8%
149
  14.9%
40 - 65 years
206
  65.6%
25
  45.5%
204
  64.4%
212
  67.5%
647
  64.7%
≥ 65 years
58
  18.5%
25
  45.5%
53
  16.7%
68
  21.7%
204
  20.4%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
Female
240
  76.4%
36
  65.5%
241
  76.0%
240
  76.4%
757
  75.7%
Male
74
  23.6%
19
  34.5%
76
  24.0%
74
  23.6%
243
  24.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
Hispanic or Latino
102
  32.5%
0
   0.0%
107
  33.8%
107
  34.1%
316
  31.6%
Not Hispanic or Latino
212
  67.5%
55
 100.0%
210
  66.2%
207
  65.9%
684
  68.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
White
256
  81.5%
0
   0.0%
256
  80.8%
254
  80.9%
766
  76.6%
Black or African American
12
   3.8%
0
   0.0%
8
   2.5%
13
   4.1%
33
   3.3%
American Indian/Alaska Native
2
   0.6%
0
   0.0%
8
   2.5%
7
   2.2%
17
   1.7%
Native Hawaiian or other Pacific Islander
2
   0.6%
0
   0.0%
3
   0.9%
1
   0.3%
6
   0.6%
Asian
37
  11.8%
55
 100.0%
35
  11.0%
34
  10.8%
161
  16.1%
Multiple
5
   1.6%
0
   0.0%
7
   2.2%
5
   1.6%
17
   1.7%
Geographic Region  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
North America
46
  14.6%
0
   0.0%
48
  15.1%
46
  14.6%
140
  14.0%
South/Central America
90
  28.7%
0
   0.0%
91
  28.7%
91
  29.0%
272
  27.2%
Western Europe
37
  11.8%
0
   0.0%
36
  11.4%
36
  11.5%
109
  10.9%
Eastern Europe
85
  27.1%
0
   0.0%
87
  27.4%
87
  27.7%
259
  25.9%
Asia-Japan
28
   8.9%
55
 100.0%
27
   8.5%
28
   8.9%
138
  13.8%
Asia - China
1
   0.3%
0
   0.0%
1
   0.3%
1
   0.3%
3
   0.3%
Asia - Other
3
   1.0%
0
   0.0%
4
   1.3%
2
   0.6%
9
   0.9%
Other
24
   7.6%
0
   0.0%
23
   7.3%
23
   7.3%
70
   7.0%
Duration of Rheumatoid Arthritis Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
2.6  (5.14) 2.3  (5.77) 2.9  (5.38) 2.8  (5.63) 2.7  (5.40)
Tender Joint Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Tender joints
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
26.4  (16.15) 18.0  (11.75) 25.4  (14.42) 25.2  (14.99) 25.3  (15.12)
[1]
Measure Description: A total of 68 joints were assessed for the presence or absence of tenderness.
Swollen Joint Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Swollen joints
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
16.9  (10.58) 14.7  (8.24) 16.9  (10.35) 15.7  (9.71) 16.4  (10.13)
[1]
Measure Description: A total of 66 joints were assessed for the presence or absence of swelling.
Patient's Assessment of Pain   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 314 participants 55 participants 317 participants 311 participants 997 participants
65.7  (21.46) 64.1  (21.20) 68.4  (20.60) 65.3  (21.51) 66.3  (21.21)
[1]
Measure Description: Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale (VAS) from 0 to 100 mm. A score of 0 mm indicates "no pain" and a score of 100 mm indicates "worst possible pain."
[2]
Measure Analysis Population Description: Participants with available data
Patient's Global Assessment of Disease Activity   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 314 participants 55 participants 317 participants 311 participants 997 participants
65.8  (21.45) 64.1  (21.36) 66.6  (22.01) 64.9  (21.63) 65.7  (21.66)
[1]
Measure Description: The participant was asked to rate their current RA disease activity over the past 24 hours on a 100 mm VAS, where 0 mm indicates very low disease activity and 100 mm indicates very high disease activity.
[2]
Measure Analysis Population Description: Participants with available data
Physician's Global Assessment of Disease Activity   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 299 participants 54 participants 301 participants 304 participants 958 participants
68.7  (16.45) 63.3  (19.34) 67.1  (17.00) 65.3  (16.60) 66.8  (16.89)
[1]
Measure Description: The physician rated the participant's current global RA disease activity (independently from the participant's assessment) on a VAS scale from 0 to 100 mm, where 0 mm indicates very low disease activity and 100 mm indicates very high disease activity.
[2]
Measure Analysis Population Description: Participants with available data
Health Assessment Questionnaire - Disability Index (HAQ-DI)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 314 participants 55 participants 317 participants 311 participants 997 participants
1.6  (0.67) 1.3  (0.62) 1.6  (0.67) 1.5  (0.66) 1.6  (0.66)
[1]
Measure 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.
[2]
Measure Analysis Population Description: Participants with available data
High-sensitivity C-reactive Protein (hsCRP)  
Mean (Standard Deviation)
Unit of measure:  mg/L
Number Analyzed 314 participants 55 participants 317 participants 314 participants 1000 participants
21.2  (22.05) 18.5  (17.55) 23.0  (27.37) 19.4  (22.59) 21.0  (23.84)
Disease Activity Score 28 Based on CRP (DAS28[CRP])   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 314 participants 55 participants 317 participants 311 participants 997 participants
5.9  (0.97) 5.5  (0.90) 5.9  (0.97) 5.8  (1.02) 5.8  (0.99)
[1]
Measure Description:

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

A DAS28 score > 5.1 indicates high disease activity, a DAS28 score ≤ 3.2 indicates low disease activity, and a DAS28 score < 2.6 indicates clinical remission.

[2]
Measure Analysis Population Description: Participants with available data
Modified Total Sharp Score (mTSS)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 309 participants 55 participants 309 participants 309 participants 982 participants
13.3  (30.55) 15.9  (39.10) 18.1  (38.15) 17.2  (38.25) 16.1  (36.02)
[1]
Measure Description: The mTSS measures the level of joint damage from radiographs of the hands and feet, calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score and ranges from 0 (normal) to 448 (worst).
[2]
Measure Analysis Population Description: Participants with available data
1.Primary Outcome
Title Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis
Hide Description

The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 50% response (ACR50) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria:

  1. ≥ 50% improvement in 68-tender joint count;
  2. ≥ 50% improvement in 66-swollen joint count; and
  3. ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
28.3
(23.4 to 33.3)
52.1
(46.6 to 57.5)
56.4
(50.9 to 61.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 23.7
Confidence Interval (2-Sided) 95%
16.3 to 31.1
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 28.0
Confidence Interval (2-Sided) 95%
20.6 to 35.4
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
2.Primary Outcome
Title Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis
Hide Description

The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission, based on a Disease Activity Score 28 (DAS28)-CRP score of < 2.6 at Week 24.

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity.

A DAS28 score less than 2.6 indicates clinical remission.

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom DAS28 data were missing at Week 24 were considered non-responders.

The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
18.5
(14.2 to 22.8)
48.3
(42.8 to 53.8)
50.0
(44.5 to 55.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 29.8
Confidence Interval (2-Sided) 95%
22.8 to 36.8
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 31.5
Confidence Interval (2-Sided) 95%
24.5 to 38.5
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
3.Primary Outcome
Title Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis
Hide Description

The primary endpoint for Japan/Pharmaceuticals and Medical Devices Agency (PMDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria:

  1. ≥ 20% improvement in 68-tender joint count;
  2. ≥ 20% improvement in 66-swollen joint count; and
  3. ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
54.1
(48.6 to 59.7)
75.7
(71.0 to 80.4)
77.1
(72.4 to 81.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 21.6
Confidence Interval (2-Sided) 95%
14.3 to 28.8
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 22.9
Confidence Interval (2-Sided) 95%
15.7 to 30.1
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
4.Primary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis
Hide Description

The 2nd primary endpoint for Japan/PMDA regulatory purposes was change from baseline in mTSS at Week 24.

The mTSS measures the level of joint damage from radiographs of the hands and feet, assessed by 2 independent, blinded readers. mTSS is calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score.

Joint erosion was assessed in 16 joints in each hand/wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst).

JSN was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst).

The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst). A change from Baseline greater than 0 indicates progression.

Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 264 279 270
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.67
(0.43 to 0.90)
0.14
(-0.09 to 0.37)
0.07
(-0.16 to 0.31)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value 0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method ANCOVA
Comments Analysis of covariance (ANCOVA) model with treatment, geographic region as fixed factors and baseline value as the covariate.
Method of Estimation Estimation Parameter Least Squares (LS) Mean Difference
Estimated Value -0.53
Confidence Interval (2-Sided) 95%
-0.85 to -0.20
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments For the global analysis, comparisons of the primary and key secondary efficacy endpoints were made between the upadacitinib 15 mg and 30 mg groups versus the methotrexate group.
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two upadacitinib doses (15 mg and 30 mg) was controlled using a graphical multiple testing procedure defined separately for US/FDA, European Union/European Medicines Agency and Japan/Pharmaceuticals and Medical Devices Agency regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.59
Confidence Interval (2-Sided) 95%
-0.91 to -0.27
Estimation Comments Difference = Upadacitinib - Methotrexate
5.Secondary Outcome
Title Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis
Hide Description The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
Time Frame Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 312 317 310
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
-1.85
(-2.00 to -1.69)
-2.73
(-2.87 to -2.58)
-2.85
(-3.00 to -2.70)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.88
Confidence Interval (2-Sided) 95%
-1.09 to -0.67
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.01
Confidence Interval (2-Sided) 95%
-1.21 to -0.80
Estimation Comments Difference = Upadacitinib - Methotrexate
6.Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis
Hide Description

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

A negative change from Baseline in the overall score indicates improvement.

Time Frame Baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 313 317 310
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
-0.49
(-0.55 to -0.42)
-0.83
(-0.90 to -0.76)
-0.86
(-0.93 to -0.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.34
Confidence Interval (2-Sided) 95%
-0.44 to -0.25
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.37
Confidence Interval (2-Sided) 95%
-0.47 to -0.28
Estimation Comments Difference = Upadacitinib - Methotrexate
7.Secondary Outcome
Title Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis
Hide Description

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

A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity.

Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
28.3
(23.4 to 33.3)
53.3
(47.8 to 58.8)
54.8
(49.3 to 60.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 25.0
Confidence Interval (2-Sided) 95%
17.6 to 32.4
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Chi-squared, Corrected
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 26.4
Confidence Interval (2-Sided) 95%
19.0 to 33.9
Estimation Comments [Not Specified]
Other Statistical Analysis Response Rate Difference = Upadacitinib - Methotrexate
8.Secondary Outcome
Title Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis
Hide Description

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).

The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.

Time Frame Baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 311 315 311
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
5.74
(4.84 to 6.64)
9.99
(9.11 to 10.88)
10.08
(9.19 to 10.98)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 4.25
Confidence Interval (2-Sided) 95%
3.00 to 5.50
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for US/FDA and Japan/PMDA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 4.34
Confidence Interval (2-Sided) 95%
3.09 to 5.59
Estimation Comments Difference = Upadacitinib - Methotrexate
9.Secondary Outcome
Title Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis
Hide Description The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 312 317 310
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
-2.15
(-2.31 to -1.99)
-3.07
(-3.21 to -2.92)
-3.34
(-3.49 to -3.19)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.92
Confidence Interval (2-Sided) 95%
-1.12 to -0.71
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.19
Confidence Interval (2-Sided) 95%
-1.40 to -0.99
Estimation Comments Difference = Upadacitinib - Methotrexate
10.Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis
Hide Description

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

A negative change from Baseline in the overall score indicates improvement.

Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 313 317 310
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
-0.60
(-0.67 to -0.52)
-0.87
(-0.94 to -0.80)
-0.91
(-0.98 to -0.84)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.27
Confidence Interval (2-Sided) 95%
-0.37 to -0.17
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.31
Confidence Interval (2-Sided) 95%
-0.41 to -0.21
Estimation Comments Difference = Upadacitinib - Methotrexate
11.Secondary Outcome
Title Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria:

  1. ≥ 50% improvement in 68-tender joint count;
  2. ≥ 50% improvement in 66-swollen joint count; and
  3. ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
33.4
(28.2 to 38.7)
60.3
(54.9 to 65.6)
65.6
(60.4 to 70.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 26.8
Confidence Interval (2-Sided) 95%
19.3 to 34.3
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 32.2
Confidence Interval (2-Sided) 95%
24.8 to 39.6
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
12.Secondary Outcome
Title Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis
Hide Description

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

A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity.

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom DAS28 data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
32.2
(27.0 to 37.3)
59.9
(54.5 to 65.3)
65.0
(59.7 to 70.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 27.8
Confidence Interval (2-Sided) 95%
20.3 to 35.2
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 32.8
Confidence Interval (2-Sided) 95%
25.4 to 40.2
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
13.Secondary Outcome
Title Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis
Hide Description

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).

The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.

Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 313 315 312
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
6.97
(6.03 to 7.91)
10.70
(9.76 to 11.63)
11.39
(10.42 to 12.36)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.72
Confidence Interval (2-Sided) 95%
2.42 to 5.03
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method ANCOVA
Comments ANCOVA model with treatment and geographic region as fixed factors and Baseline value as the covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 4.42
Confidence Interval (2-Sided) 95%
3.12 to 5.72
Estimation Comments Difference = Upadacitinib - Methotrexate
14.Secondary Outcome
Title Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis
Hide Description

No radiographic progression is defined as a change from Baseline in mTSS ≤ 0. The mTSS measures the level of joint damage from radiographs of the hands and feet, which were assessed by 2 independent, blinded readers. mTSS is calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score. Joint erosion severity was assessed in 16 joints in each hand and wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst).

Joint space narrowing (JSN) was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst).

The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst).

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 264 279 270
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
77.7
(72.6 to 82.7)
87.5
(83.6 to 91.3)
89.3
(85.6 to 93.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value 0.002
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 9.8
Confidence Interval (2-Sided) 95%
3.5 to 16.2
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. This endpoint was a ranked key secondary endpoint for EU/EMA regulatory purposes.
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 11.6
Confidence Interval (2-Sided) 95%
5.4 to 17.8
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
15.Secondary Outcome
Title Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria:

  1. ≥ 70% improvement in 68-tender joint count;
  2. ≥ 70% improvement in 66-swollen joint count; and
  3. ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
14.0
(10.2 to 17.9)
32.5
(27.3 to 37.6)
36.9
(31.6 to 42.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 18.5
Confidence Interval (2-Sided) 95%
12.1 to 24.9
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 22.9
Confidence Interval (2-Sided) 95%
16.4 to 29.5
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
16.Secondary Outcome
Title Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria:

  1. ≥ 20% improvement in 68-tender joint count;
  2. ≥ 20% improvement in 66-swollen joint count; and
  3. ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
58.6
(53.2 to 64.0)
78.9
(74.4 to 83.4)
78.0
(73.4 to 82.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 20.3
Confidence Interval (2-Sided) 95%
13.2 to 27.3
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 19.4
Confidence Interval (2-Sided) 95%
12.3 to 26.5
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
17.Secondary Outcome
Title Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria:

  1. ≥ 70% improvement in 68-tender joint count;
  2. ≥ 70% improvement in 66-swollen joint count; and
  3. ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 314 317 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
18.5
(14.2 to 22.8)
44.5
(39.0 to 49.9)
49.7
(44.2 to 55.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 26.0
Confidence Interval (2-Sided) 95%
19.1 to 33.0
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The nominal p-value is reported
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel test adjusting for geographic region (North America, South/central America, Western Europe, Eastern Europe, Asia/other).
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 31.2
Confidence Interval (2-Sided) 95%
24.2 to 38.2
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
18.Secondary Outcome
Title Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria:

  1. ≥ 20% improvement in 68-tender joint count;
  2. ≥ 20% improvement in 66-swollen joint count; and
  3. ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
57.1
(38.8 to 75.5)
85.5
(76.1 to 94.8)
85.2
(71.8 to 98.6)
78.6
(63.4 to 93.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments For the Japan sub-study, no multiplicity adjustments were applied and only nominal p-values were provided for all efficacy analyses.
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 28.3
Confidence Interval (2-Sided) 95%
7.7 to 48.9
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 28.0
Confidence Interval (2-Sided) 95%
5.3 to 50.7
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.086
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 21.4
Confidence Interval (2-Sided) 95%
-2.4 to 45.2
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
19.Secondary Outcome
Title Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria:

  1. ≥ 50% improvement in 68-tender joint count;
  2. ≥ 50% improvement in 66-swollen joint count; and
  3. ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
21.4
(6.2 to 36.6)
60.0
(47.1 to 72.9)
66.7
(48.9 to 84.4)
71.4
(54.7 to 88.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 38.6
Confidence Interval (2-Sided) 95%
18.6 to 58.5
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 45.2
Confidence Interval (2-Sided) 95%
21.8 to 68.6
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 50.0
Confidence Interval (2-Sided) 95%
27.4 to 72.6
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
20.Secondary Outcome
Title Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study
Hide Description

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria:

  1. ≥ 70% improvement in 68-tender joint count;
  2. ≥ 70% improvement in 66-swollen joint count; and
  3. ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Physician global assessment of disease activity
    • Patient global assessment of disease activity
    • Patient assessment of pain
    • Health Assessment Questionnaire - Disability Index (HAQ-DI)
    • High-sensitivity C-reactive protein (hsCRP).
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
0.0
(0.0 to 0.0)
34.5
(22.0 to 47.1)
51.9
(33.0 to 70.7)
64.3
(46.5 to 82.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 34.5
Confidence Interval (2-Sided) 95%
22.0 to 47.1
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 51.9
Confidence Interval (2-Sided) 95%
33.0 to 70.7
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 64.3
Confidence Interval (2-Sided) 95%
46.5 to 82.0
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
21.Secondary Outcome
Title Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study
Hide Description The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
Time Frame Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
-1.42
(-1.82 to -1.03)
-2.86
(-3.14 to -2.58)
-3.28
(-3.68 to -2.89)
-3.34
(-3.74 to -2.95)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.43
Confidence Interval (2-Sided) 95%
-1.92 to -0.95
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.86
Confidence Interval (2-Sided) 95%
-2.42 to -1.30
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.92
Confidence Interval (2-Sided) 95%
-2.48 to -1.36
Estimation Comments Difference = Upadacitinib - Methotrexate
22.Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study
Hide Description

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

A negative change from Baseline in the overall score indicates improvement.

Time Frame Baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
-0.20
(-0.37 to -0.04)
-0.75
(-0.86 to -0.63)
-0.95
(-1.12 to -0.78)
-0.95
(-1.12 to -0.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.54
Confidence Interval (2-Sided) 95%
-0.75 to -0.34
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.75
Confidence Interval (2-Sided) 95%
-0.99 to -0.51
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.75
Confidence Interval (2-Sided) 95%
-0.99 to -0.51
Estimation Comments Difference = Upadacitinib - Methotrexate
23.Secondary Outcome
Title Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study
Hide Description

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).

The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.

Time Frame Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Least Squares Mean (95% Confidence Interval)
Unit of Measure: scores on a scale
2.87
(0.56 to 5.18)
8.84
(7.18 to 10.50)
10.79
(8.48 to 13.09)
9.63
(7.13 to 12.13)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 5.97
Confidence Interval (2-Sided) 95%
3.15 to 8.80
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 7.92
Confidence Interval (2-Sided) 95%
4.66 to 11.19
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 6.76
Confidence Interval (2-Sided) 95%
3.33 to 10.20
Estimation Comments Difference = Upadacitinib - Methotrexate
24.Secondary Outcome
Title Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study
Hide Description

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

A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity.

Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
17.9
(3.7 to 32.0)
69.1
(56.9 to 81.3)
77.8
(62.1 to 93.5)
78.6
(63.4 to 93.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 51.2
Confidence Interval (2-Sided) 95%
32.5 to 70.0
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 59.9
Confidence Interval (2-Sided) 95%
38.8 to 81.1
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 60.7
Confidence Interval (2-Sided) 95%
39.9 to 81.5
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
25.Secondary Outcome
Title Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study
Hide Description

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

A DAS28 score less than 2.6 indicates clinical remission.

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 28 55 27 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
17.9
(3.7 to 32.0)
67.3
(54.9 to 79.7)
70.4
(53.1 to 87.6)
82.1
(68.0 to 96.3)
26.Secondary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study
Hide Description

The mTSS measures the level of joint damage from radiographs of the hands and feet, assessed by 2 independent, blinded readers. mTSS is calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score.

Joint erosion was assessed in 16 joints in each hand/wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst).

JSN was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst).

The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst). A change from Baseline greater than 0 indicates progression.

Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 26 51 26 24
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
2.64
(1.19 to 4.09)
0.95
(-0.09 to 1.98)
0.24
(-1.21 to 1.69)
0.19
(-1.31 to 1.70)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.063
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.69
Confidence Interval (2-Sided) 95%
-3.47 to 0.09
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -2.40
Confidence Interval (2-Sided) 95%
-4.45 to -0.35
Estimation Comments Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.022
Comments [Not Specified]
Method ANOVA
Comments ANOVA model with Baseline value as covariate.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -2.45
Confidence Interval (2-Sided) 95%
-4.54 to -0.35
Estimation Comments Difference = Upadacitinib - Methotrexate
27.Secondary Outcome
Title Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study
Hide Description

No radiographic progression is defined as a change from Baseline in mTSS ≤ 0. The mTSS measures the level of joint damage from radiographs of the hands and feet, which were assessed by 2 independent, blinded readers. mTSS is calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score. Joint erosion severity was assessed in 16 joints in each hand and wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst).

Joint space narrowing (JSN) was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst).

The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst).

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description

Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description:
Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1.
Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
Overall Number of Participants Analyzed 26 51 26 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
46.2
(27.0 to 65.3)
82.4
(71.9 to 92.8)
80.8
(65.6 to 95.9)
79.2
(62.9 to 95.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 7.5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 36.2
Confidence Interval (2-Sided) 95%
14.4 to 58.0
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 15 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 34.6
Confidence Interval (2-Sided) 95%
10.2 to 59.0
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Methotrexate, Upadacitinib 30 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.016
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Response Rate Difference
Estimated Value 33.0
Confidence Interval (2-Sided) 95%
7.9 to 58.1
Estimation Comments Response Rate Difference = Upadacitinib - Methotrexate
Time Frame 24 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Hide Arm/Group Description Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1. Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1.
All-Cause Mortality
Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/314 (0.32%)      0/55 (0.00%)      2/317 (0.63%)      3/314 (0.96%)    
Hide Serious Adverse Events
Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/314 (4.14%)      5/55 (9.09%)      15/317 (4.73%)      20/314 (6.37%)    
Cardiac disorders         
ACUTE MYOCARDIAL INFARCTION  1  2/314 (0.64%)  2 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
ATRIAL FIBRILLATION  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
MYOCARDIAL INFARCTION  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
POSTINFARCTION ANGINA  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
CARDIAC TAMPONADE  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
PERICARDITIS  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
Gastrointestinal disorders         
ABDOMINAL PAIN  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
ASCITES  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
FOOD POISONING  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
GASTRIC ULCER  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
INGUINAL HERNIA  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
LARGE INTESTINE PERFORATION  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
LARGE INTESTINE POLYP  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
GASTRIC ULCER HAEMORRHAGE  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
General disorders         
SUDDEN DEATH  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
Hepatobiliary disorders         
CHOLANGIOLITIS  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
HEPATIC VEIN THROMBOSIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
Infections and infestations         
BACTERIAL PYELONEPHRITIS  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
CELLULITIS  1  1/314 (0.32%)  1 0/55 (0.00%)  0 1/317 (0.32%)  1 1/314 (0.32%)  1
DIVERTICULITIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 1/314 (0.32%)  1
LUNG INFECTION  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
PERITONITIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
PNEUMONIA  1  2/314 (0.64%)  2 0/55 (0.00%)  0 1/317 (0.32%)  1 3/314 (0.96%)  3
PNEUMONIA CRYPTOCOCCAL  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
SEPSIS  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 1/314 (0.32%)  1
URINARY TRACT INFECTION  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
PNEUMONIA PNEUMOCOCCAL  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
PYELONEPHRITIS ACUTE  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
SEPTIC SHOCK  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
Injury, poisoning and procedural complications         
HIP FRACTURE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
JOINT DISLOCATION  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
POST PROCEDURAL FISTULA  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
RADIUS FRACTURE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
ROAD TRAFFIC ACCIDENT  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
TENDON RUPTURE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  2 0/314 (0.00%)  0
WRIST FRACTURE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
CONTUSION  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
Metabolism and nutrition disorders         
ABNORMAL WEIGHT GAIN  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
DIABETIC KETOACIDOSIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
HYPOKALAEMIA  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
OBESITY  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
Musculoskeletal and connective tissue disorders         
OSTEOARTHRITIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 2/314 (0.64%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
METASTATIC MALIGNANT MELANOMA  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
OVARIAN CANCER  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
SQUAMOUS CELL CARCINOMA  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
UTERINE CARCINOMA IN SITU  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
Nervous system disorders         
HYPOXIC-ISCHAEMIC ENCEPHALOPATHY  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
TRANSIENT ISCHAEMIC ATTACK  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
Renal and urinary disorders         
RENAL FAILURE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
URETEROLITHIASIS  1  0/314 (0.00%)  0 1/55 (1.82%)  1 0/317 (0.00%)  0 0/314 (0.00%)  0
Reproductive system and breast disorders         
OVARIAN CYST  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
OVARIAN CYST RUPTURED  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
PROSTATITIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
Respiratory, thoracic and mediastinal disorders         
ASTHMA  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
PLEURISY  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
PULMONARY EMBOLISM  1  1/314 (0.32%)  1 0/55 (0.00%)  0 0/317 (0.00%)  0 0/314 (0.00%)  0
PULMONARY FIBROSIS  1  0/314 (0.00%)  0 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
RESPIRATORY FAILURE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
Skin and subcutaneous tissue disorders         
ANGIOEDEMA  1  1/314 (0.32%)  1 0/55 (0.00%)  0 1/317 (0.32%)  1 0/314 (0.00%)  0
Vascular disorders         
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE  1  0/314 (0.00%)  0 0/55 (0.00%)  0 0/317 (0.00%)  0 1/314 (0.32%)  1
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Methotrexate Upadacitinib 7.5 mg Upadacitinib 15 mg Upadacitinib 30 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   78/314 (24.84%)      29/55 (52.73%)      92/317 (29.02%)      120/314 (38.22%)    
Blood and lymphatic system disorders