SELECT-EARLY: A Study to Compare Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have Not Previously Taken Methotrexate
Sponsor
AbbVie (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02706873
Collaborator
(none)
1,002
290
4
79.9
3.5
0
Study Details
Study Description
Brief Summary
The objectives of Period 1 were the following:
-
To compare the safety and efficacy of upadacitinib 7.5 mg once daily (QD) monotherapy (for participants in Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy versus weekly methotrexate monotherapy for the treatment of signs and symptoms of RA in methotrexate-naïve adults with moderately to severely active RA;
-
To compare the efficacy of upadacitinib 15 mg QD monotherapy and upadacitinib 30 mg QD monotherapy versus weekly methotrexate monotherapy for prevention of structural progression in methotrexate-naïve adults with moderately to severely active RA.
The objective of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 7.5 mg QD (for participants in Japan only), 15 mg QD, and 30 mg QD in adults with RA who have completed Period 1.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This study includes 2 periods (a 48-week double-blind treatment period and a long-term extension period) and a Japan substudy. In Period 1 participants will be randomized in a 1:1:1 ratio to treatment Groups 2, 3, and 4 below, except for participants from Japan, who will be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3, and 4:
-
Group 1: Upadacitinib 7.5 mg once daily (QD) monotherapy (participants in Japan only)
-
Group 2: Upadacitinib 15 mg QD monotherapy
-
Group 3: Upadacitinib 30 mg QD monotherapy
-
Group 4: Methotrexate monotherapy
Participants who complete the Week 48 visit (end of Period 1) will enter the long-term extension, Period 2 (212 weeks) and continue study treatment per assignment at the end of Period 1 in a blinded fashion. Starting with Protocol Amendment 6, participants receiving upadacitinib 15 mg and 30 mg QD will receive open-label upadacitinib 15 mg QD, and participants receiving methotrexate will receive open-label methotrexate.
A global analysis will be conducted for the comparisons of the primary and secondary efficacy endpoints between the upadacitinib 15 mg QD and 30 mg QD treatment groups versus the methotrexate treatment group for all participants (excluding the Japan specific upadacitinib 7.5 mg treatment group). Analyses will be conducted separately for United States (US)/Food and Drug Administration (FDA), European Union (EU)/European Medicines Agency (EMA), and Japan/Pharmaceuticals and Medical Devices Agency (PMDA) regulatory purposes, each according to a pre-specified sequence of primary and ranked secondary endpoints.
A separate Japan sub-study analysis will be conducted for the comparisons of the efficacy endpoints between the upadacitinib 7.5 mg QD, 15 mg QD, and 30 mg QD treatment groups versus the methotrexate treatment group for participants enrolled in Japan only.
Study Design
Study Type:
Interventional
Actual Enrollment
:
1002 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Participants were to be randomized in a 1:1:1 ratio to treatment Groups 2, 3, and 4 below, except for participants from Japan, who were to be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3, and 4:
Group 1: Upadacitinib 7.5 mg QD monotherapy (Japan only)
Group 2: Upadacitinib 15 mg QD monotherapy (43 countries, including Japan)
Group 3: Upadacitinib 30 mg QD monotherapy (43 countries, including Japan)
Group 4: MTX monotherapy (43 countries, including Japan)Participants were to be randomized in a 1:1:1 ratio to treatment Groups 2, 3, and 4 below, except for participants from Japan, who were to be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3, and 4:Group 1: Upadacitinib 7.5 mg QD monotherapy (Japan only)
Group 2: Upadacitinib 15 mg QD monotherapy (43 countries, including Japan)
Group 3: Upadacitinib 30 mg QD monotherapy (43 countries, including Japan)
Group 4: MTX monotherapy (43 countries, including Japan)
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) Once Daily Monotherapy to Methotrexate (MTX) Monotherapy in MTX-Naïve Subjects With Moderately to Severely Active Rheumatoid Arthritis
Actual Study Start Date
:
Feb 23, 2016
Actual Primary Completion Date
:
Mar 15, 2018
Anticipated Study Completion Date
:
Oct 22, 2022
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Methotrexate Period 1: Participants will receive placebo to upadacitinib once daily and methotrexate once weekly for 48 weeks. Period 2: Participants will continue on placebo to upadacitinib once daily and methotrexate once weekly until the study is unblinded, after which participants will receive open-label methotrexate up to Week 260. |
Drug: Placebo to Upadacitinib
Tablet; Oral
Drug: Methotrexate
Capsule or Tablet; Oral
|
| Experimental: Upadacitinib 7.5 mg (Japan-only) Period 1: Participants will receive upadacitinib 7.5 mg once daily and placebo to methotrexate once weekly for 48 weeks. Period 2: Participants will continue on upadacitinib 7.5 mg once daily and placebo to methotrexate once weekly until the study is unblinded, after which participants will receive open-label upadacitinib 7.5 mg up to Week 260. |
Drug: Placebo to Methotrexate
Capsule or Tablet; Oral
Drug: Upadacitinib
Tablet; Oral
Other Names:
|
| Experimental: Upadacitinib 15 mg Period 1: Participants will receive upadacitinib 15 mg once daily and placebo to methotrexate once weekly for 48 weeks. Period 2: Participants will continue on upadacitinib 15 mg once daily and placebo to methotrexate once weekly until the study is unblinded, after which participants will receive open-label upadacitinib 15 mg up to Week 260. |
Drug: Placebo to Methotrexate
Capsule or Tablet; Oral
Drug: Upadacitinib
Tablet; Oral
Other Names:
|
| Experimental: Upadacitinib 30 mg Period 1: Participants will receive upadacitinib 30 mg once daily and placebo to methotrexate once weekly for 48 weeks. Period 2: Participants will continue on upadacitinib 30 mg once daily and placebo to methotrexate once weekly until the study is unblinded, after which participants will receive open-label upadacitinib 30 mg once daily. After implementation of Protocol Amendment 6 participants will receive upadacitinib 15 mg once daily up to Week 260. |
Drug: Placebo to Methotrexate
Capsule or Tablet; Oral
Drug: Upadacitinib
Tablet; Oral
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis [Baseline and Week 12]
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: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis [Week 24]
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.
- Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis [Baseline and Week 12]
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: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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).
- Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis [Baseline to Week 24]
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.
Secondary Outcome Measures
- Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis [Baseline to Week 12]
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.
- Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis [Baseline to week 12]
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.
- Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis [Week 12]
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.
- Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis [Baseline to week 12]
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.
- Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis [Baseline to 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 negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
- Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis [Baseline to Week 24]
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.
- Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis [Baseline and Week 24]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis [Week 24]
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.
- Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis [Baseline to Week 24]
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.
- Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis [Week 24]
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).
- Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis [Baseline and Week 12]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis [Baseline and Week 24]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis [Baseline and Week 24]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study [Baseline and Week 12]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study [Baseline and Week 12]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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).
- Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study [Baseline and Week 12]
Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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).
- Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study [Baseline to Week 12]
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.
- Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study [Baseline to week 12]
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.
- Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study [Baseline to Week 12]
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.
- Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study [Week 12]
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.
- Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study [Week 24]
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.
- Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study [Baseline to 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.
- Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study [Week 24]
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).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Duration of symptoms consistent with RA for ≥ 6 weeks who also fulfill the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA.
-
Naïve to Methotrexate (MTX) or, if already on MTX, have received no more than 3 weekly MTX doses with requirement to complete a 4-week MTX washout before the first dose of study drug.
-
Participants with prior exposure to conventional synthetic disease-modifying anti-rheumatic drugs(csDMARDs) other than MTX may be enrolled if completed the washout period.
-
Participant meets both of the following minimum disease activity criteria:
-≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.
-
high sensitivity C reactive protein (hsCRP) ≥ 5 mg/L (central lab, upper limit of normal [ULN] 2.87 mg/L at Screening Visit.
-
Greater than or equal to 1 bone erosion on x-ray (by local reading) OR in the absence of documented bone erosion, both positive rheumatoid factor (RF) and positive anti-cyclic citrullinated peptide (anti CCP) autoantibodies are required at Screening.
-
Stable dose of non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, oral corticosteroids (equivalent to prednisone ≤ 10 mg/day), or inhaled corticosteroids for stable medical conditions are allowed but must have been at a stable dose ≥ 1 week prior to the first dose of study drug.
Exclusion Criteria:
-
Intolerant to Methotrexate (MTX).
-
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).
-
Prior exposure to any biologic disease-modifying anti-rheumatic drugs (bDMARDs).
-
History of any arthritis with onset prior to age 17 years or current diagnosis, inflammatory joint disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, fibromyalgia [currently with active symptoms]. Current diagnosis of secondary Sjogren's Syndrome is permitted.
-
Has been treated with intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa, or intra-tendon sheath corticosteroids in the preceding 8 weeks prior to the first dose of study drug.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | TriWest Research Associates- La Mesa /ID# 143738 | La Mesa | California | United States | 91942 |
| 2 | Desert Medical Advances /ID# 143730 | Palm Desert | California | United States | 92260 |
| 3 | International Medical Research - Daytona /ID# 143748 | Daytona Beach | Florida | United States | 32117 |
| 4 | FL Med Ctr and Research, Inc. /ID# 143724 | Miami | Florida | United States | 33142 |
| 5 | Millennium Research /ID# 143736 | Ormond Beach | Florida | United States | 32174 |
| 6 | Arthritis Research of Florida /ID# 143743 | Palm Harbor | Florida | United States | 34684-2672 |
| 7 | Sarasota Arthritis Center /ID# 145978 | Sarasota | Florida | United States | 34239 |
| 8 | FL Med Clinic, PA /ID# 143744 | Zephyrhills | Florida | United States | 33542 |
| 9 | Deerbrook Medical Associates /ID# 143728 | Vernon Hills | Illinois | United States | 60061 |
| 10 | Four Rivers Clinical Research /ID# 143741 | Paducah | Kentucky | United States | 42003 |
| 11 | Ocean Rheumatology, PA /ID# 143737 | Toms River | New Jersey | United States | 08755 |
| 12 | Arthritis Rheumatic Back Disorder /ID# 143733 | Voorhees | New Jersey | United States | 08043 |
| 13 | Trinity Health Med Arts Clinic /ID# 143727 | Minot | North Dakota | United States | 58701 |
| 14 | STAT Research, Inc. /ID# 143750 | Vandalia | Ohio | United States | 45377-9464 |
| 15 | Healthcare Research Consultant /ID# 143747 | Tulsa | Oklahoma | United States | 74135 |
| 16 | Advanced Rheumatology & Arthri /ID# 147947 | Wexford | Pennsylvania | United States | 15090 |
| 17 | Articularis Healthcare Group, Inc d/b/a Low Country Rheumatology /ID# 145653 | Summerville | South Carolina | United States | 29486-7887 |
| 18 | West Tennessee Research Inst /ID# 143723 | Jackson | Tennessee | United States | 38305 |
| 19 | Dr. Ramesh Gupta /ID# 143732 | Memphis | Tennessee | United States | 38119 |
| 20 | Diagnostic Group Integrated He /ID# 152921 | Beaumont | Texas | United States | 77701 |
| 21 | Adriana Pop-Moody MD Clinic PA /ID# 147626 | Corpus Christi | Texas | United States | 78404 |
| 22 | Doctor's Hosp at Renaissance /ID# 156407 | Edinburg | Texas | United States | 78539 |
| 23 | MedResearch Inc. /ID# 156409 | El Paso | Texas | United States | 79935 |
| 24 | Rheumatic Disease Clin Res Ctr /ID# 151103 | Houston | Texas | United States | 77004 |
| 25 | Accurate Clinical Research /ID# 143749 | Houston | Texas | United States | 77089 |
| 26 | SW Rheumatology Res. LLC /ID# 143745 | Mesquite | Texas | United States | 75150 |
| 27 | Sun Research Institute /ID# 159546 | San Antonio | Texas | United States | 78215 |
| 28 | Accurate Clinical Management /ID# 159543 | San Antonio | Texas | United States | 78229 |
| 29 | NextGen Clinical Trials LLP /ID# 150930 | San Antonio | Texas | United States | 78229 |
| 30 | Arthritis Clinic of Central TX /ID# 159541 | San Marcos | Texas | United States | 78666 |
| 31 | Arthritis & Osteoporosis Clinic /ID# 159542 | Waco | Texas | United States | 76710 |
| 32 | Arthritis Clinic of N. VA, P.C /ID# 143734 | Arlington | Virginia | United States | 22205 |
| 33 | Aprillus Asistencia e Investig /ID# 149179 | Capital Federal | Buenos Aires | Argentina | 1046 |
| 34 | Iari /Id# 148595 | San isidro | Buenos Aires | Argentina | 1646 |
| 35 | Instituto CAICI /ID# 143141 | Rosario | Santa FE | Argentina | 2000 |
| 36 | Org Medica de Investigacion /ID# 143142 | Buenos Aires | Argentina | C1015ABO | |
| 37 | Consultora Integral de Salud S /ID# 143144 | Cordoba | Argentina | 5900 | |
| 38 | Centro Integral de Reumatologi /ID# 143143 | San Miguel de Tucuman | Argentina | 4000 | |
| 39 | Centro Medico Privado/Reuma /ID# 143140 | San Miguel de Tucuman | Argentina | 4000 | |
| 40 | Royal Prince Alfred Hospital /ID# 143149 | Camperdown | New South Wales | Australia | 2050 |
| 41 | Rheumatology Research Unit /ID# 143147 | Maroochydore | Queensland | Australia | 4558 |
| 42 | The Queen Elizabeth Hospital /ID# 143148 | Woodville | South Australia | Australia | 5011 |
| 43 | Southern Clinical Research Pty /ID# 143150 | Hobart | Tasmania | Australia | 7000 |
| 44 | Emeritus Research /ID# 143146 | Camberwell | Victoria | Australia | 3124 |
| 45 | First City Clinical Hospital /ID# 159020 | Minsk | Belarus | 220013 | |
| 46 | City Clinical Hospital #9 /ID# 145650 | Minsk | Belarus | 220116 | |
| 47 | Rhumaconsult SPRL /ID# 143158 | Charleroi | Hainaut | Belgium | 6000 |
| 48 | Algemeen Stedelijk Ziekenhuis /ID# 153504 | Aalst | Oost-Vlaanderen | Belgium | 9300 |
| 49 | UZ Gent /ID# 143157 | Gent | Oost-Vlaanderen | Belgium | 9000 |
| 50 | ReumaClinic Genk /ID# 143159 | Genk | Belgium | 3600 | |
| 51 | CHU Ambroise Pare /ID# 152955 | Mons | Belgium | 7000 | |
| 52 | University Clinical Centre of the Republic of Srpska /ID# 143161 | Banja Luka | Republika Srpska | Bosnia and Herzegovina | 78000 |
| 53 | University Clinical Centre of the Republic of Srpska /ID# 143162 | Banja Luka | Republika Srpska | Bosnia and Herzegovina | 78000 |
| 54 | Clinical Center University of Sarajevo /ID# 143164 | Sarajevo | Bosnia and Herzegovina | 71000 | |
| 55 | CIP - Centro Internacional de Pesquisa /ID# 143171 | Goiânia | Goias | Brazil | 74110-120 |
| 56 | Ceti - Centro de Estudos Em Terapias Inovadoras Ltda /Id# 143169 | Curitiba | Parana | Brazil | 80030-110 |
| 57 | Hospital de Clinicas de Porto Alegre /ID# 143168 | Porto Alegre | Rio Grande Do Sul | Brazil | 90035-903 |
| 58 | LMK Sevicos Medicos S/S /ID# 143167 | Porto Alegre | Rio Grande Do Sul | Brazil | 90480-000 |
| 59 | CEPIC - Centro Paulista de Investigação Clínica e Serviços Médicos Ltda /ID# 143166 | São Paulo | Sao Paulo | Brazil | 04266-010 |
| 60 | CCBR Brasil /ID# 150925 | Rio de Janeiro | Brazil | 22271-100 | |
| 61 | MHAT Trimontsium /ID# 143173 | Plovdiv | Bulgaria | 4000 | |
| 62 | UMHAT Pulmed OOD /ID# 143176 | Plovdiv | Bulgaria | 4000 | |
| 63 | MHAT Kaspela /ID# 143172 | Plovdiv | Bulgaria | 4001 | |
| 64 | Diagnostic Consultative Center /ID# 143174 | Sofia | Bulgaria | 1612 | |
| 65 | UMHAT Sv. Ivan Rilski /ID# 143175 | Sofia | Bulgaria | 1612 | |
| 66 | Rheumatology Research Assoc /ID# 143206 | Edmonton | Alberta | Canada | T5M 0H4 |
| 67 | Manitoba Clinic /ID# 143203 | Winnipeg | Manitoba | Canada | R3A IM3 |
| 68 | Ciads /Id# 143205 | Winnipeg | Manitoba | Canada | R3N 0K6 |
| 69 | CA Ctr for Clin Trials CCCT /ID# 159080 | Thornhill | Ontario | Canada | L4J 1W3 |
| 70 | Ctr. de Rheum de l'est du QC /ID# 151317 | Rimouski | Quebec | Canada | G5L 8W1 |
| 71 | Ctr de Inv Clinica del Sur /ID# 143208 | Temuco | Araucania | Chile | 4781156 |
| 72 | Someal /Id# 143207 | Providencia | Santiago | Chile | 7510186 |
| 73 | Quantum Research LTDA. /ID# 143210 | Puerto Varas | Chile | 5550170 | |
| 74 | Quantum Research Stgo. /ID# 145651 | Santiago | Chile | 7500588 | |
| 75 | Soc. de Prestaciones medicas y Paramedicas Goecke /ID# 143209 | Santiago | Chile | 7510047 | |
| 76 | Investigaciones Medicas SSMSO /ID# 151685 | Santiago | Chile | 8207257 | |
| 77 | Centro de Estudios Clinicos Qu /ID# 152913 | Vina Del Mar | Chile | ||
| 78 | 1st Aff Hosp of Bengbu Med Col /ID# 162974 | Bengbu | Anhui | China | 233099 |
| 79 | The 1st Aff Hosp Xiamen Univ /ID# 162076 | Xiamen | Fujian | China | 361003 |
| 80 | 1st Aff Hosp of Shantou Univ /ID# 162968 | Shantou | Guangdong | China | 515041 |
| 81 | Centro de Investigacion en Reumatologia y Especialidades Medicas- CIREEM SAS /ID# 143214 | Bogota | Cundinamarca | Colombia | 110221 |
| 82 | Ctr Int de Reum del Caribe SAS /ID# 143211 | Barranquilla | Colombia | 80002 | |
| 83 | Riesgo de Fractura S.A - CAYRE /ID# 143212 | Bogota | Colombia | 110221 | |
| 84 | Simedics IPS SAS /ID# 152572 | Bogota | Colombia | 110221 | |
| 85 | Fund Inst de Reum F. Chalem /ID# 159544 | Bogotá | Colombia | ||
| 86 | Medicity S.A.S. /ID# 143213 | Bucaramanga | Colombia | 680003 | |
| 87 | Klinicki bolnicki centar Split /ID# 143216 | Split | Croatia | 21000 | |
| 88 | Clinical Hospital Dubrava /ID# 143217 | Zagreb | Croatia | 10000 | |
| 89 | Medical Center Kuna-Peric /ID# 143218 | Zagreb | Croatia | 10000 | |
| 90 | Poliklinika Bonifarm /ID# 143215 | Zagreb | Croatia | 10000 | |
| 91 | L.K.N. Arthrocentrum, s.r.o /ID# 143224 | Hlučín | Moravskoslezsky Kraj | Czechia | 748 01 |
| 92 | CTCenter MaVe, s.r.o. /ID# 143226 | Olomouc | Olomoucky Kraj | Czechia | 779 00 |
| 93 | Nuselská poliklinika, Revmatologie /ID# 143232 | Prague 4 | Praha 4 | Czechia | 140 00 |
| 94 | Nuselská poliklinika, Revmatologie /ID# 143233 | Prague 4 | Praha 4 | Czechia | 140 00 |
| 95 | Thomayerova nemocnice /ID# 143228 | Prague | Praha 4 | Czechia | 140 59 |
| 96 | PV MEDICAL Services s.r.o. /ID# 143234 | Zlín 1 | Zlin | Czechia | 760 01 |
| 97 | RHEUMA s.r.o. /ID# 143230 | Breclav | Czechia | 690 02 | |
| 98 | Revmatologie, s.r.o. /ID# 143223 | Brno | Czechia | 638 00 | |
| 99 | Revmatologie Bruntal, s.r.o /ID# 143220 | Bruntál | Czechia | 79201 | |
| 100 | Nemocnice Slany /ID# 143221 | Slany | Czechia | 274 01 | |
| 101 | Medical Plus, s.r.o. /ID# 143219 | Uherské Hradište | Czechia | 686 01 | |
| 102 | Center of Clinical and Basic Research /ID# 143239 | Tallinn | Harjumaa | Estonia | 10128 |
| 103 | Paernu Hospital /ID# 143238 | Pärnu | Estonia | 80010 | |
| 104 | East Tallinn Central Hospital /ID# 143240 | Tallinn | Estonia | 10138 | |
| 105 | North Estonian Medical Centre /ID# 145456 | Tallinn | Estonia | 13419 | |
| 106 | Rheumazentrum Ruhrgebiet /ID# 145652 | Herne | Nordrhein-Westfalen | Germany | 44649 |
| 107 | Uniklinik Koln /ID# 143248 | Köln | Nordrhein-Westfalen | Germany | 50937 |
| 108 | Praxis Walter, Rendsburg /ID# 143250 | Rendsburg | Schleswig-Holstein | Germany | 24768 |
| 109 | Rheumaforschungszentrum II /ID# 143247 | Hamburg | Germany | 20095 | |
| 110 | Schoen Klinikum Hamburg Eilbek /ID# 143251 | Hamburg | Germany | 22081 | |
| 111 | LMU Klinikum der Universität München /ID# 143249 | Munich | Germany | 80337 | |
| 112 | University General Hospital Attikon /ID# 143252 | Athens | Attiki | Greece | 12462 |
| 113 | Clinicas Hospital Herrera Ller /ID# 153715 | Ciudad de Guatemala | Guatemala | 01010 | |
| 114 | Creer /Id# 153713 | Ciudad de Guatemala | Guatemala | 10010 | |
| 115 | Clin Especializada Med Interna /ID# 153716 | Ciudad de Guatemala | Guatemala | 1011 | |
| 116 | Clinica Medica Reumatologia /ID# 153714 | Ciudad de Guatemala | Guatemala | 1021 | |
| 117 | Clinica Medica Reumatologia /ID# 153931 | Ciudad de Guatemala | Guatemala | 1021 | |
| 118 | Queen Mary Hospital /ID# 143255 | Hong Kong | Hong Kong | 999077 | |
| 119 | Tuen Mun Hospital /ID# 143256 | Tuen Mun | Hong Kong | 999077 | |
| 120 | CRU Hungary Egeszsegugyi és Szolgaltato Kft. /ID# 143258 | Miskolc | Borsod-Abauj-Zemplen | Hungary | 3529 |
| 121 | Qualiclinic Kft. /ID# 143259 | Budapest | Pest | Hungary | 1036 |
| 122 | Markusovszky Egyetemi Oktatókórház /ID# 143261 | Szombathely | Vas | Hungary | 9700 |
| 123 | Hevizgyogyfurdo es Szent Andra /ID# 143257 | Heviz | Hungary | 8380 | |
| 124 | Pest Megyei Flor Ferenc Korhaz /ID# 143260 | Kistarcsa | Hungary | 2143 | |
| 125 | Fejer Megyei Szent Gyorgy Korh /ID# 144724 | Szekesfehervar | Hungary | 8000 | |
| 126 | St Vincent's University Hosp /ID# 143262 | Dublin | Ireland | D04 T6F4 | |
| 127 | Barzilai Medical Center /ID# 144725 | Ashkelon | Israel | 78278 | |
| 128 | Rambam Health Care Campus /ID# 143263 | Haifa | Israel | 3109601 | |
| 129 | Sheba Medical Center /ID# 145975 | Ramat Gan | Israel | 5262100 | |
| 130 | Istituto Clinico Humanitas /ID# 147531 | Rozzano | Milano | Italy | 20089 |
| 131 | Azienda Ospedaliera Luigi Sacc /ID# 143270 | Milan | Italy | 20157 | |
| 132 | Fondazione IRCCS Policlinico /ID# 143265 | Pavia | Italy | 27100 | |
| 133 | A.O.U.I. di Verona Policlinico /ID# 143266 | Verona | Italy | 37134 | |
| 134 | Nagoya University Hospital /ID# 148031 | Nagoya-shi | Aichi | Japan | 466-8560 |
| 135 | NHO Toyohashi Medical Center /ID# 161033 | Toyohashi-shi | Aichi | Japan | 440-8510 |
| 136 | Teikyo University Chiba Medical Center /ID# 159618 | Ichihara | Chiba | Japan | 299-0111 |
| 137 | NHO Kyushu Medical Center /ID# 148263 | Fukuoka-shi | Fukuoka | Japan | 810-8563 |
| 138 | NHO Kyushu Medical Center /ID# 148264 | Fukuoka-shi | Fukuoka | Japan | 810-8563 |
| 139 | National Hospital Organization Asahikawa Medical Center /ID# 148021 | Asahikawa | Hokkaido | Japan | 070-8644 |
| 140 | Katayama Orthopedic Rheumatology Clinic /ID# 148029 | Asahikawa | Hokkaido | Japan | 078-8243 |
| 141 | Kobe University Hospital /ID# 153461 | Kobe | Hyogo | Japan | 650-0017 |
| 142 | National Hospital Organization Sagamihara National Hospital /ID# 148019 | Sagamihara-shi | Kanagawa | Japan | 252-0315 |
| 143 | NHO Osaka Minami Med Ctr /ID# 148042 | Osaka | Kawachinagano-shi | Japan | 586-8521 |
| 144 | Bay Side Misato Medical Center /ID# 148256 | Kochi-shi | Kochi | Japan | 781-0112 |
| 145 | Center for Arthritis and Clinical Rheumatology Matsubara Clinic /ID# 148254 | Kumamoto-shi | Kumamoto | Japan | 862-0920 |
| 146 | Kumamoto Orthopaedic Hospital /ID# 148054 | Kumamoto-shi | Kumamoto | Japan | 862-0976 |
| 147 | Kumamoto Shinto General Hospital /ID# 148266 | Kumamoto-shi | Kumamoto | Japan | 8628655 |
| 148 | Sasebo Chuo Hospital /ID# 148261 | Sasebo-city | Nagasaki | Japan | 857-1195 |
| 149 | Nagaoka Red Cross Hospital /ID# 148018 | Nagaoka-shi | Niigata | Japan | 940-2108 |
| 150 | Japanese Red Cross Okayama Hospital /ID# 159619 | Okayama-shi | Okayama | Japan | 7008607 |
| 151 | Kansai Medical University Hospital /ID# 159622 | Hirakata-shi | Osaka | Japan | 573-1191 |
| 152 | Osaka Medical College Hospital /ID# 159624 | Takatsuki -shi | Osaka | Japan | 569-8686 |
| 153 | Saitama Medical Center, Saitama Medical University /ID# 148015 | Kawagoe-shi | Saitama | Japan | 350-8550 |
| 154 | Jichi Medical University Hospital /ID# 159620 | Shimotsuke-shi | Tochigi | Japan | 329-0498 |
| 155 | Juntendo University Hospital /ID# 148050 | Bunkyo-ku | Tokyo | Japan | 113-8431 |
| 156 | St.Luke's International Hospital /ID# 148041 | Chuo-ku | Tokyo | Japan | 104-8560 |
| 157 | Toho University Ohashi Medical Center /ID# 148027 | Meguro-ku | Tokyo | Japan | 1538515 |
| 158 | Keio University Hospital /ID# 148057 | Shinjuku-ku | Tokyo | Japan | 160-8582 |
| 159 | Tokito Clinic Rheumatology and Orthopaedics Surgery /ID# 148052 | Shimonoseki-shi | Yamaguchi | Japan | 752-0976 |
| 160 | National Hospital Organization Beppu Medical Center /ID# 161058 | Beppu | Japan | 874 - 001 | |
| 161 | NHO Chiba-East-Hospital /ID# 148035 | Chiba | Japan | 260-8712 | |
| 162 | Sugimoto Rheumatology and Internal Medicine Clinic /ID# 148047 | Fukui | Japan | 910-0068 | |
| 163 | Shono Rheumatism Clinic /ID# 148046 | Fukuoka | Japan | 814-0002 | |
| 164 | Matsubara Mayflower Hospital /ID# 148033 | Kato | Japan | 673-1462 | |
| 165 | St. Mary's Hospital /ID# 148038 | Kurume | Japan | 830-8543 | |
| 166 | Kagawa University Hospital /ID# 148016 | Kyoto | Japan | 615-8256 | |
| 167 | Yu Family Clinic /ID# 148048 | Miyagi | Japan | 981-0112 | |
| 168 | Daido Hospital /ID# 160868 | Nagoya | Japan | 457-8511 | |
| 169 | Kondo Clinic for Ortho & Rheum /ID# 148032 | Nagoya | Japan | 464-0071 | |
| 170 | Shirahama Hamayu Hospital /ID# 148253 | Nishimura | Japan | 649-2211 | |
| 171 | Oribe Clinic of Rheumatology and Internal Medicine /ID# 156035 | Oita | Japan | 870-0823 | |
| 172 | Osaka City General Hospital /ID# 159617 | Osaka | Japan | 534-0021 | |
| 173 | Sanuki Municipal Hospital /ID# 158842 | Sanuki | Japan | 769-2321 | |
| 174 | Sagawa Akira Rheumatology Clin /ID# 148043 | Sapporo | Japan | 060-0001 | |
| 175 | Sapporo City General Hospital /ID# 148037 | Sapporo | Japan | 060-8604 | |
| 176 | Hokkaido University Hospital /ID# 148262 | Sapporo | Japan | 060-8648 | |
| 177 | Hokkaido Medical Center for Rheumatic Diseases /ID# 148259 | Sapporo | Japan | 063-0811 | |
| 178 | Azuma Rheumatology Clinic /ID# 161050 | Sayama | Japan | 350-1305 | |
| 179 | Hikarigaoka Spellman Hospital /ID# 148020 | Sendai | Japan | 983-0833 | |
| 180 | Takaoka Rheumatic Orthopedic Clinic /ID# 148022 | Takaoka | Japan | 933-0874 | |
| 181 | National Hospital Organization Tokyo Medical Center /ID# 148040 | Tokyo | Japan | 152-8902 | |
| 182 | National Hospital Organization Shimoshizu National Hospital /ID# 148258 | Yotsukaido | Japan | 284-0003 | |
| 183 | JSC Nat Scientific Med Res Ctr /ID# 143272 | Astana | Kazakhstan | 010009 | |
| 184 | Karaganda State Medical Univ /ID# 153431 | Karaganda | Kazakhstan | 100008 | |
| 185 | Semey State Medical University /ID# 152661 | Semey | Kazakhstan | 071403 | |
| 186 | Regional Clinical Hospital /ID# 147173 | Shymkent | Kazakhstan | 160000 | |
| 187 | LTD M+M Centers /ID# 143279 | Adazi | Latvia | 2164 | |
| 188 | Hosp Lithuanian Univ Health Sc /ID# 143582 | Kaunas | Kovno | Lithuania | 50009 |
| 189 | Klaipeda University Hospital /ID# 143583 | Klaipeda | Lithuania | 92288 | |
| 190 | Vilnius University Hospital /ID# 143584 | Vilnius | Lithuania | LT-08661 | |
| 191 | Clinstile, S.A. de C.V. /ID# 143591 | Cuauhtemoc | Ciudad De Mexico | Mexico | 06700 |
| 192 | CINTRE, Centro de Investigación y Tratamiento Reumatológico SC /ID# 153562 | Mexico City | Ciudad De Mexico | Mexico | 11850 |
| 193 | Invest y Biomed de Chihuahua /ID# 143595 | Chihuahua | Mexico | 31000 | |
| 194 | RM Pharma Specialists, S.A de C.V /ID# 143593 | Mexico City | Mexico | 03100 | |
| 195 | Unidad de Investigacion de las Enfermedades Reumatologicas SA de CV /ID# 143592 | Mexico City | Mexico | 06090 | |
| 196 | Centro Especializado en Diabetes, Obesidad y Prevención de Enfermedades Cardiova /ID# 143589 | Mexico City | Mexico | 11650 | |
| 197 | Centro Reumatologico de Queret /ID# 149493 | Queretaro | Mexico | 76178 | |
| 198 | Waikato Hospital /ID# 143602 | Hamilton | Waikato | New Zealand | 3204 |
| 199 | Middlemore Clinical Trials /ID# 143600 | Auckland | New Zealand | 2025 | |
| 200 | Porter Rheumatology Ltd /ID# 143601 | Nelson | New Zealand | 7010 | |
| 201 | Timaru Medical Specialists Ltd /ID# 143599 | Timaru | New Zealand | 7910 | |
| 202 | WroMedica I. Bielicka, A. Strzalkowska s.c. /ID# 143606 | Wrocław | Dolnoslaskie | Poland | 51-685 |
| 203 | Centrum Medyczne AMED /ID# 143604 | Warsaw | Mazowieckie | Poland | 01-518 |
| 204 | Centrum Medyczne Pratia Warszawa /ID# 143608 | Warsaw | Mazowieckie | Poland | 01-869 |
| 205 | Centrum Medyczne Pratia Gdynia /ID# 143607 | Gdynia | Pomorskie | Poland | 81-338 |
| 206 | Silmedic Sp z o.o /ID# 143605 | Katowice | Slaskie | Poland | 40-282 |
| 207 | NZOZ Centrum Reumatologiczne /ID# 143603 | Elblag | Warminsko-mazurskie | Poland | 82-300 |
| 208 | Medyczne Centrum Hetmanska /ID# 144726 | Poznań | Wielkopolskie | Poland | 60-218 |
| 209 | Instituto Portugues De Reumatologia /ID# 148313 | Lisbon | Lisboa | Portugal | 1050-034 |
| 210 | Centro Hospitalar Lisboa Ocidental, EPE /ID# 151009 | Lisbon | Lisboa | Portugal | 1349-019 |
| 211 | Centro Hospitalar De Vila Nova /ID# 143615 | Vila Nova De Gaia | Porto | Portugal | 4434-502 |
| 212 | Centro Hospitalar Lisboa Norte, EPE /ID# 143613 | Lisboa | Portugal | 1649-035 | |
| 213 | Centro Hospitalar Baixo Vouga /ID# 153726 | Porto | Portugal | 4050-111 | |
| 214 | Centro Hospitalar de Sao Joao, EPE /ID# 153575 | Porto | Portugal | 4200-319 | |
| 215 | Unidade Local De Saude Do Alto Minho /ID# 143611 | Viana Do Castelo | Portugal | 4901-858 | |
| 216 | Centro Hosp de Tondela-Viseu /ID# 143612 | Viseu | Portugal | 3504-509 | |
| 217 | Ponce School of Medicine /ID# 145657 | Ponce | Puerto Rico | 00716 | |
| 218 | GCM Medical Group /ID# 143618 | San Juan | Puerto Rico | 00909 | |
| 219 | School of Medicine University of Puerto Rico-Medical Sciences Campus /ID# 143619 | San Juan | Puerto Rico | 00935 | |
| 220 | Spitalul Clinic Dr. I. Cantacuzino /ID# 143622 | Bucharest | Bucuresti | Romania | 020475 |
| 221 | Spitalul Clinic Sf. Maria /ID# 143623 | Bucuresti | Romania | 011172 | |
| 222 | Spitalul Clinic Sf. Maria /ID# 143625 | Bucuresti | Romania | 011172 | |
| 223 | Spitalul Clinic Sf. Maria /ID# 143627 | Bucuresti | Romania | 011172 | |
| 224 | Spitalul Clinic de Recuperare /ID# 143620 | Iasi | Romania | 700656 | |
| 225 | Ecomed SRL /ID# 143629 | Oradea | Romania | 410028 | |
| 226 | Family Outpatient clinic#4,LLC /ID# 151010 | Korolev | Moskva | Russian Federation | 141060 |
| 227 | Clinical Hospital No.1 n.a. N.I.Pirogov /ID# 143641 | Moscow | Moskva | Russian Federation | 119049 |
| 228 | LLC Medical Center /ID# 143647 | Novosibirsk | Novosibirskaya Oblast | Russian Federation | 630099 |
| 229 | LLC Novaya Klinika /ID# 143631 | Pyatigorsk | Stavropol Skiy Kray | Russian Federation | 357500 |
| 230 | Kazan State Medical University /ID# 143645 | Kazan | Tatarstan, Respublika | Russian Federation | 420012 |
| 231 | Tver Regional Clinical Hosp. /ID# 143639 | Tver | Tverskaya Oblast | Russian Federation | 170036 |
| 232 | Russian National Research Medi /ID# 143642 | Moscow | Russian Federation | 117997 | |
| 233 | Orenburg Regional Clinical Hos /ID# 143630 | Orenburg | Russian Federation | 460018 | |
| 234 | Republican Clin Hos n.a. Baran /ID# 143634 | Petrozavodsk | Russian Federation | 185019 | |
| 235 | Ryazan State Medical Universit /ID# 143646 | Ryazan | Russian Federation | 390026 | |
| 236 | Samara Regional Clinical Hosp /ID# 150928 | Samara | Russian Federation | 443095 | |
| 237 | Reg Clin Hosp n.a. Kuvatova G. /ID# 143632 | UFA | Russian Federation | 450005 | |
| 238 | Ulyanovsk Regional Clin Hosp /ID# 143644 | Ulyanovsk | Russian Federation | 432018 | |
| 239 | Voronezh State Medical Univers /ID# 150926 | Voronezh | Russian Federation | 394036 | |
| 240 | Clinical Center Serbia /ID# 143649 | Belgrade | Beograd | Serbia | 11000 |
| 241 | Clinical Center Serbia /ID# 143650 | Belgrade | Beograd | Serbia | 11000 |
| 242 | Special Hospital for Rheuma /ID# 143648 | Novi Sad | Vojvodina | Serbia | 21000 |
| 243 | MEDMAN s.r.o. /ID# 143661 | Martin | Slovakia | 036 01 | |
| 244 | Reumatologická ambulancia Reum.hapi s.r.o. /ID# 143657 | Nové Mesto Nad Váhom | Slovakia | 915 01 | |
| 245 | REUMACENTRUM s.r.o. /ID# 143653 | Partizanske | Slovakia | 958 01 | |
| 246 | Slovak research center Team Member, Thermium s.r.o. /ID# 143663 | Pieštany | Slovakia | 921 01 | |
| 247 | Slovak Research Center /ID# 143659 | Puchov | Slovakia | 02001 | |
| 248 | TIMMED spol. s r.o. /ID# 143664 | Stará Lubovna | Slovakia | 06401 | |
| 249 | Reumatologicka ambulancia, LER /ID# 143660 | Topolcany | Slovakia | 955 01 | |
| 250 | MEDEOS s.r.o. /ID# 143656 | Trencin | Slovakia | 91101 | |
| 251 | REUMA-GLOBAL, s.r.o. /ID# 143655 | Trnava | Slovakia | 91701 | |
| 252 | ALBAMED s.r.o. /ID# 143654 | Zvolen | Slovakia | 960 01 | |
| 253 | Reuma -MUDr. Maria Palasthyova /ID# 143662 | Žiar nad Hronom | Slovakia | 965 01 | |
| 254 | Univ Medical Ctr Ljubljana /ID# 143667 | Ljubljana | Slovenia | 1000 | |
| 255 | Jakaranda Hosp, Emmed Research /ID# 143668 | Pretoria | Gauteng | South Africa | 0132 |
| 256 | Jakaranda Hosp, Emmed Research /ID# 145976 | Pretoria | Gauteng | South Africa | 0132 |
| 257 | Arthritis Clinical Research Tr /ID# 143670 | Cape Town | Western Cape | South Africa | 7405 |
| 258 | Winelands Medical Research Ctr /ID# 143669 | Stellenbosch | Western Cape | South Africa | 7600 |
| 259 | H. Un. Marques de Valdecilla /ID# 143671 | Santander | Cantabria | Spain | 39008 |
| 260 | Comple Hosp Univ de A Coruna /ID# 143672 | A Coruna | Spain | 15006 | |
| 261 | Hospital Univ Vall d'Hebron /ID# 143675 | Barcelona | Spain | 08035 | |
| 262 | Hospital Clin Univ San Carlos /ID# 143674 | Madrid | Spain | 28040 | |
| 263 | Clinica Gaias /ID# 143673 | Santiago de Compostela | Spain | 15702 | |
| 264 | Hosp Nuestra Senora Esperanza /ID# 143677 | Santiago de Compostela | Spain | 15705 | |
| 265 | HFR Fribourg - Hopital Canton /ID# 143700 | Fribourg | Switzerland | 1708 | |
| 266 | China Medical University Hosp /ID# 143703 | Taichung City | Taichung | Taiwan | 40447 |
| 267 | National Taiwan Univ Hosp /ID# 143702 | Taipei City | Taipei | Taiwan | 10002 |
| 268 | Dalin Tzu Chi General Hospital /ID# 153535 | Dalin | Taiwan | 622 | |
| 269 | Hopital Mongi Slim /ID# 152870 | La Marsa | Tunisia | 2046 | |
| 270 | Institut Mohamed Kassab /ID# 152869 | Manouba | Tunisia | 2010 | |
| 271 | Hopital Farhat Hached /ID# 152868 | Sousse | Tunisia | 4000 | |
| 272 | Charles Nicolle Univ Hosp /ID# 152866 | Tunis | Tunisia | 1006 | |
| 273 | Hospital La Rabta /ID# 152867 | Tunis | Tunisia | 1007 | |
| 274 | Uludag Universitesi Ataturk Rehabilitasyon ve Uygulama Merkezi /ID# 143705 | Osmangazi | Bursa | Turkey | 16080 |
| 275 | Izmir Tepecik Training and Research Hospital /ID# 157863 | Konak | Izmir | Turkey | 35180 |
| 276 | Izmir Katip Celebi Ataturk Training & Research Hospital /ID# 143704 | Izmir | Turkey | 35360 | |
| 277 | Lviv Regional Clinical Hospita /ID# 154449 | Lviv | Lvivska Oblast | Ukraine | 79013 |
| 278 | Vinnytsia Regional Clinical Hospital n.a. M.I.Pyrogov /ID# 143714 | Vinnytsia | Vinnytska Oblast | Ukraine | 21018 |
| 279 | Regional Clinical Hospital /ID# 152029 | Ivano-frankivsk | Ukraine | 76018 | |
| 280 | NSC-Strazhesko Ist Cardiology /ID# 152026 | Kiev | Ukraine | 03680 | |
| 281 | LLC Revmocentr /ID# 143710 | Kyiv | Ukraine | 04070 | |
| 282 | MNCE "Lviv City Clinical Hospital #4" /ID# 143711 | Lviv | Ukraine | 79007 | |
| 283 | Odessa National Medical Univ /ID# 143715 | Odesa | Ukraine | 65026 | |
| 284 | Zaporizhzhia Regional Clinical /ID# 143712 | Zaporizhia | Ukraine | 69600 | |
| 285 | Leicester Royal Infirmary /ID# 143718 | Leicester | England | United Kingdom | LE1 5WW |
| 286 | Whipps Cross Univ Hospital /ID# 143721 | London | London, City Of | United Kingdom | E11 1NR |
| 287 | Western General Hospital /ID# 144431 | Edinburgh | United Kingdom | EH4 2XU | |
| 288 | Chapel Allerton Hospital /ID# 143717 | Leeds | United Kingdom | LS7 4SA | |
| 289 | Queen Alexandra Hospital /ID# 143722 | Portsmouth | United Kingdom | PO6 3LY | |
| 290 | Southampton General Hospital /ID# 143716 | Southampton | United Kingdom | SO16 6YD |
Sponsors and Collaborators
- AbbVie
Investigators
- Study Director: AbbVie Inc., AbbVie
Study Documents (Full-Text)
More Information
Additional Information:
Publications
Responsible Party:
AbbVie
ClinicalTrials.gov Identifier:
NCT02706873
Other Study ID Numbers:
- M13-545
- 2015-003334-27
First Posted:
Mar 11, 2016
Last Update Posted:
Jul 18, 2022
Last Verified:
Jul 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by AbbVie
Additional relevant MeSH terms:
Study Results
Participant Flow
| 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 Detail | 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 |
|---|---|---|---|---|
| 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 | 314 | 0 | 317 | 314 |
| Japan Sub-study | 28 | 55 | 27 | 28 |
| COMPLETED | 268 | 51 | 290 | 282 |
| NOT COMPLETED | 47 | 4 | 27 | 33 |
Baseline Characteristics
| Arm/Group Title | Methotrexate | Upadacitinib 7.5 mg | Upadacitinib 15 mg | Upadacitinib 30 mg | Total |
|---|---|---|---|---|---|
| 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 Participants | 314 | 55 | 317 | 314 | 1000 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
53.3
(12.89)
|
59.7
(13.8)
|
51.9
(12.58)
|
54.9
(12.58)
|
53.7
(12.86)
|
| Age, Customized (Count of 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 (Count of Participants) | |||||
| Female |
240
76.4%
|
36
65.5%
|
241
76%
|
240
76.4%
|
757
75.7%
|
| Male |
74
23.6%
|
19
34.5%
|
76
24%
|
74
23.6%
|
243
24.3%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||
| Hispanic or Latino |
102
32.5%
|
0
0%
|
107
33.8%
|
107
34.1%
|
316
31.6%
|
| Not Hispanic or Latino |
212
67.5%
|
55
100%
|
210
66.2%
|
207
65.9%
|
684
68.4%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||
| White |
256
81.5%
|
0
0%
|
256
80.8%
|
254
80.9%
|
766
76.6%
|
| Black or African American |
12
3.8%
|
0
0%
|
8
2.5%
|
13
4.1%
|
33
3.3%
|
| American Indian/Alaska Native |
2
0.6%
|
0
0%
|
8
2.5%
|
7
2.2%
|
17
1.7%
|
| Native Hawaiian or other Pacific Islander |
2
0.6%
|
0
0%
|
3
0.9%
|
1
0.3%
|
6
0.6%
|
| Asian |
37
11.8%
|
55
100%
|
35
11%
|
34
10.8%
|
161
16.1%
|
| Multiple |
5
1.6%
|
0
0%
|
7
2.2%
|
5
1.6%
|
17
1.7%
|
| Geographic Region (Count of Participants) | |||||
| North America |
46
14.6%
|
0
0%
|
48
15.1%
|
46
14.6%
|
140
14%
|
| South/Central America |
90
28.7%
|
0
0%
|
91
28.7%
|
91
29%
|
272
27.2%
|
| Western Europe |
37
11.8%
|
0
0%
|
36
11.4%
|
36
11.5%
|
109
10.9%
|
| Eastern Europe |
85
27.1%
|
0
0%
|
87
27.4%
|
87
27.7%
|
259
25.9%
|
| Asia-Japan |
28
8.9%
|
55
100%
|
27
8.5%
|
28
8.9%
|
138
13.8%
|
| Asia - China |
1
0.3%
|
0
0%
|
1
0.3%
|
1
0.3%
|
3
0.3%
|
| Asia - Other |
3
1%
|
0
0%
|
4
1.3%
|
2
0.6%
|
9
0.9%
|
| Other |
24
7.6%
|
0
0%
|
23
7.3%
|
23
7.3%
|
70
7%
|
| Duration of Rheumatoid Arthritis Diagnosis (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
2.6
(5.14)
|
2.3
(5.77)
|
2.9
(5.38)
|
2.8
(5.63)
|
2.7
(5.40)
|
| Tender Joint Count (tender joints) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [tender joints] |
26.4
(16.15)
|
18.0
(11.75)
|
25.4
(14.42)
|
25.2
(14.99)
|
25.3
(15.12)
|
| Swollen Joint Count (swollen joints) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [swollen joints] |
16.9
(10.58)
|
14.7
(8.24)
|
16.9
(10.35)
|
15.7
(9.71)
|
16.4
(10.13)
|
| Patient's Assessment of Pain (mm) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [mm] |
65.7
(21.46)
|
64.1
(21.20)
|
68.4
(20.60)
|
65.3
(21.51)
|
66.3
(21.21)
|
| Patient's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [mm] |
65.8
(21.45)
|
64.1
(21.36)
|
66.6
(22.01)
|
64.9
(21.63)
|
65.7
(21.66)
|
| Physician's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [mm] |
68.7
(16.45)
|
63.3
(19.34)
|
67.1
(17.00)
|
65.3
(16.60)
|
66.8
(16.89)
|
| Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [units on a scale] |
1.6
(0.67)
|
1.3
(0.62)
|
1.6
(0.67)
|
1.5
(0.66)
|
1.6
(0.66)
|
| High-sensitivity C-reactive Protein (hsCRP) (mg/L) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [mg/L] |
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]) (units on a scale) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [units on a scale] |
5.9
(0.97)
|
5.5
(0.90)
|
5.9
(0.97)
|
5.8
(1.02)
|
5.8
(0.99)
|
| Modified Total Sharp Score (mTSS) (units on a scale) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [units on a scale] |
13.3
(30.55)
|
15.9
(39.10)
|
18.1
(38.15)
|
17.2
(38.25)
|
16.1
(36.02)
|
Outcome Measures
| Title | Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis |
|---|---|
| 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: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
28.3
9%
|
52.1
94.7%
|
56.4
17.8%
|
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
18.5
5.9%
|
48.3
87.8%
|
50.0
15.8%
|
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
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 | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis |
|---|---|
| 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: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
54.1
17.2%
|
75.7
137.6%
|
77.1
24.3%
|
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 264 | 279 | 270 |
| Least Squares Mean (95% Confidence Interval) [units on a scale] |
0.67
|
0.14
|
0.07
|
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 312 | 317 | 310 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
-1.85
|
-2.73
|
-2.85
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 313 | 317 | 310 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
-0.49
|
-0.83
|
-0.86
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
28.3
9%
|
53.3
96.9%
|
54.8
17.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 311 | 315 | 311 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
5.74
|
9.99
|
10.08
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 312 | 317 | 310 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
-2.15
|
-3.07
|
-3.34
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 313 | 317 | 310 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
-0.60
|
-0.87
|
-0.91
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
33.4
10.6%
|
60.3
109.6%
|
65.6
20.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
32.2
10.3%
|
59.9
108.9%
|
65.0
20.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 313 | 315 | 312 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
6.97
|
10.70
|
11.39
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 264 | 279 | 270 |
| Number (95% Confidence Interval) [percentage of participants] |
77.7
24.7%
|
87.5
159.1%
|
89.3
28.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
14.0
4.5%
|
32.5
59.1%
|
36.9
11.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
58.6
18.7%
|
78.9
143.5%
|
78.0
24.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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. |
| Measure Participants | 314 | 317 | 314 |
| Number (95% Confidence Interval) [percentage of participants] |
18.5
5.9%
|
44.5
80.9%
|
49.7
15.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Number (95% Confidence Interval) [percentage of participants] |
57.1
18.2%
|
85.5
155.5%
|
85.2
26.9%
|
78.6
25%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| 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 | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 28.3 | |
| Confidence Interval |
(2-Sided) 95% 7.7 to 48.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.022 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 28.0 | |
| Confidence Interval |
(2-Sided) 95% 5.3 to 50.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.086 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 21.4 | |
| Confidence Interval |
(2-Sided) 95% -2.4 to 45.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Number (95% Confidence Interval) [percentage of participants] |
21.4
6.8%
|
60.0
109.1%
|
66.7
21%
|
71.4
22.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 38.6 | |
| Confidence Interval |
(2-Sided) 95% 18.6 to 58.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 45.2 | |
| Confidence Interval |
(2-Sided) 95% 21.8 to 68.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 50.0 | |
| Confidence Interval |
(2-Sided) 95% 27.4 to 72.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study |
|---|---|
| Description | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Number (95% Confidence Interval) [percentage of participants] |
0.0
0%
|
34.5
62.7%
|
51.9
16.4%
|
64.3
20.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 34.5 | |
| Confidence Interval |
(2-Sided) 95% 22.0 to 47.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 51.9 | |
| Confidence Interval |
(2-Sided) 95% 33.0 to 70.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 64.3 | |
| Confidence Interval |
(2-Sided) 95% 46.5 to 82.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
-1.42
|
-2.86
|
-3.28
|
-3.34
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
-0.20
|
-0.75
|
-0.95
|
-0.95
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Least Squares Mean (95% Confidence Interval) [scores on a scale] |
2.87
|
8.84
|
10.79
|
9.63
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Number (95% Confidence Interval) [percentage of participants] |
17.9
5.7%
|
69.1
125.6%
|
77.8
24.5%
|
78.6
25%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 51.2 | |
| Confidence Interval |
(2-Sided) 95% 32.5 to 70.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 59.9 | |
| Confidence Interval |
(2-Sided) 95% 38.8 to 81.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 60.7 | |
| Confidence Interval |
(2-Sided) 95% 39.9 to 81.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 28 | 55 | 27 | 28 |
| Number (95% Confidence Interval) [percentage of participants] |
17.9
5.7%
|
67.3
122.4%
|
70.4
22.2%
|
82.1
26.1%
|
| Title | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 26 | 51 | 26 | 24 |
| Least Squares Mean (95% Confidence Interval) [units on a scale] |
2.64
|
0.95
|
0.24
|
0.19
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.063 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.022 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.022 |
| Comments | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference = Upadacitinib - Methotrexate | |
| Title | Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|
| 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. |
| Measure Participants | 26 | 51 | 26 | 24 |
| Number (95% Confidence Interval) [percentage of participants] |
46.2
14.7%
|
82.4
149.8%
|
80.8
25.5%
|
79.2
25.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 15 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.001 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 36.2 | |
| Confidence Interval |
(2-Sided) 95% 14.4 to 58.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.010 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 34.6 | |
| Confidence Interval |
(2-Sided) 95% 10.2 to 59.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Methotrexate, Upadacitinib 30 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.016 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Response Rate Difference |
| Estimated Value | 33.0 | |
| Confidence Interval |
(2-Sided) 95% 7.9 to 58.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Response Rate Difference = Upadacitinib - Methotrexate | |
Adverse Events
| Time Frame | 24 weeks | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | Methotrexate | Upadacitinib 7.5 mg | Upadacitinib 15 mg | Upadacitinib 30 mg | ||||
| 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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/314 (0.3%) | 0/55 (0%) | 2/317 (0.6%) | 3/314 (1%) | ||||
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 (4.1%) | 5/55 (9.1%) | 15/317 (4.7%) | 20/314 (6.4%) | ||||
| Cardiac disorders | ||||||||
| ACUTE MYOCARDIAL INFARCTION | 2/314 (0.6%) | 2 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| ATRIAL FIBRILLATION | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| MYOCARDIAL INFARCTION | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| POSTINFARCTION ANGINA | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| CARDIAC TAMPONADE | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| PERICARDITIS | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| Gastrointestinal disorders | ||||||||
| ABDOMINAL PAIN | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| ASCITES | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| FOOD POISONING | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| GASTRIC ULCER | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| INGUINAL HERNIA | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| LARGE INTESTINE PERFORATION | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| LARGE INTESTINE POLYP | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| GASTRIC ULCER HAEMORRHAGE | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| General disorders | ||||||||
| SUDDEN DEATH | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| Hepatobiliary disorders | ||||||||
| CHOLANGIOLITIS | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| HEPATIC VEIN THROMBOSIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| Infections and infestations | ||||||||
| BACTERIAL PYELONEPHRITIS | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| CELLULITIS | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 1/314 (0.3%) | 1 |
| DIVERTICULITIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 1/314 (0.3%) | 1 |
| LUNG INFECTION | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| PERITONITIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| PNEUMONIA | 2/314 (0.6%) | 2 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 3/314 (1%) | 3 |
| PNEUMONIA CRYPTOCOCCAL | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| SEPSIS | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| URINARY TRACT INFECTION | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| PNEUMONIA PNEUMOCOCCAL | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| PYELONEPHRITIS ACUTE | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| SEPTIC SHOCK | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||
| HIP FRACTURE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| JOINT DISLOCATION | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| POST PROCEDURAL FISTULA | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| RADIUS FRACTURE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| ROAD TRAFFIC ACCIDENT | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| TENDON RUPTURE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 2 | 0/314 (0%) | 0 |
| WRIST FRACTURE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| CONTUSION | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||
| ABNORMAL WEIGHT GAIN | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| DIABETIC KETOACIDOSIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| HYPOKALAEMIA | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| OBESITY | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||
| OSTEOARTHRITIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 2/314 (0.6%) | 2 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| METASTATIC MALIGNANT MELANOMA | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| OVARIAN CANCER | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| SQUAMOUS CELL CARCINOMA | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| UTERINE CARCINOMA IN SITU | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| Nervous system disorders | ||||||||
| HYPOXIC-ISCHAEMIC ENCEPHALOPATHY | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| TRANSIENT ISCHAEMIC ATTACK | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| Renal and urinary disorders | ||||||||
| RENAL FAILURE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| URETEROLITHIASIS | 0/314 (0%) | 0 | 1/55 (1.8%) | 1 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||
| OVARIAN CYST | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| OVARIAN CYST RUPTURED | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| PROSTATITIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| ASTHMA | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| PLEURISY | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| PULMONARY EMBOLISM | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 0/314 (0%) | 0 |
| PULMONARY FIBROSIS | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| RESPIRATORY FAILURE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||||
| ANGIOEDEMA | 1/314 (0.3%) | 1 | 0/55 (0%) | 0 | 1/317 (0.3%) | 1 | 0/314 (0%) | 0 |
| Vascular disorders | ||||||||
| PERIPHERAL ARTERIAL OCCLUSIVE DISEASE | 0/314 (0%) | 0 | 0/55 (0%) | 0 | 0/317 (0%) | 0 | 1/314 (0.3%) | 1 |
Other (Not Including 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 | 78/314 (24.8%) | 29/55 (52.7%) | 92/317 (29%) | 120/314 (38.2%) | ||||
| Blood and lymphatic system disorders | ||||||||
| ANAEMIA | 5/314 (1.6%) | 5 | 3/55 (5.5%) | 3 | 6/317 (1.9%) | 9 | 9/314 (2.9%) | 10 |
| Gastrointestinal disorders | ||||||||
| NAUSEA | 15/314 (4.8%) | 27 | 1/55 (1.8%) | 2 | 17/317 (5.4%) | 19 | 13/314 (4.1%) | 14 |
| CONSTIPATION | 2/314 (0.6%) | 2 | 3/55 (5.5%) | 3 | 0/317 (0%) | 0 | 13/314 (4.1%) | 13 |
| STOMATITIS | 2/314 (0.6%) | 2 | 4/55 (7.3%) | 5 | 1/317 (0.3%) | 2 | 3/314 (1%) | 3 |
| Infections and infestations | ||||||||
| NASOPHARYNGITIS | 13/314 (4.1%) | 15 | 5/55 (9.1%) | 10 | 18/317 (5.7%) | 22 | 17/314 (5.4%) | 18 |
| UPPER RESPIRATORY TRACT INFECTION | 13/314 (4.1%) | 16 | 3/55 (5.5%) | 3 | 20/317 (6.3%) | 23 | 22/314 (7%) | 27 |
| URINARY TRACT INFECTION | 20/314 (6.4%) | 24 | 1/55 (1.8%) | 1 | 17/317 (5.4%) | 18 | 17/314 (5.4%) | 20 |
| ORAL HERPES | 2/314 (0.6%) | 2 | 3/55 (5.5%) | 3 | 4/317 (1.3%) | 4 | 4/314 (1.3%) | 4 |
| PHARYNGITIS | 6/314 (1.9%) | 6 | 5/55 (9.1%) | 7 | 4/317 (1.3%) | 4 | 8/314 (2.5%) | 9 |
| Investigations | ||||||||
| BLOOD CREATINE PHOSPHOKINASE INCREASED | 3/314 (1%) | 4 | 2/55 (3.6%) | 2 | 9/317 (2.8%) | 10 | 35/314 (11.1%) | 40 |
| Metabolism and nutrition disorders | ||||||||
| DYSLIPIDAEMIA | 0/314 (0%) | 0 | 3/55 (5.5%) | 3 | 3/317 (0.9%) | 3 | 6/314 (1.9%) | 6 |
| Vascular disorders | ||||||||
| HYPERTENSION | 8/314 (2.5%) | 9 | 3/55 (5.5%) | 3 | 12/317 (3.8%) | 12 | 13/314 (4.1%) | 13 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
Results Point of Contact
| Name/Title | Global Medical Services |
|---|---|
| Organization | AbbVie |
| Phone | 800-633-9110 |
| abbvieclinicaltrials@abbvie.com |
Responsible Party:
AbbVie
ClinicalTrials.gov Identifier:
NCT02706873
Other Study ID Numbers:
- M13-545
- 2015-003334-27
First Posted:
Mar 11, 2016
Last Update Posted:
Jul 18, 2022
Last Verified:
Jul 1, 2022