Rheumatoid Arthritis
Conditions
Keywords
Musculoskeletal disease, Arthritis, Joint disease, Anti-inflammatory agents, Antirheumatic agents, ABT-494, Upadacitinib
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.
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 Rescue therapy is defined for Weeks 12 through 24, Week 26, and Weeks 36 through 40. Starting at Week 12 through Week 24, participants who do not achieve ≥ 20% improvement in both tender joint count (TJC) and swollen joint count (SJC) compared with baseline at two consecutive visits will continue on their blinded therapy and the Investigator should optimize (initiate or increase) background RA medications: non-steroidal anti-inflammatory drug(s) (NSAIDs), corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone equivalent ≤ 0.5 mg/kg/day for 3 consecutive days) and/or low-potency analgesics. Rescue therapy for participants who meet the following criteria at Week 26 are as follows: Participants who do not achieve clinical remission (CR) based on Clinical Disease Activity Index (CDAI) (defined as a CDAI score ≤ 2.8): * but achieve ≥ 20% improvement in both TJC and SJC compared with baseline will continue on blinded study drug and the Investigator should optimize (initiate or increase) background RA medications: NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local injections), low-potency analgesics and conventional synthetic disease-modifying anti-rheumatic drug(s) (csDMARDs) (only 1 of the following: sulfasalazine, hydroxychloroquine or chloroquine) throughout the remainder of Period 1 and until the study is unblinded. * and do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline and originally assigned to methotrexate will be re-randomized in a 1:1 ratio to receive blinded upadacitinib 15 mg QD or upadacitinib 30 mg QD (participants in Japan will be randomized 1:1:1 to receive upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg QD) while continuing methotrexate treatment in a blinded manner until the study is unblinded. Participants originally assigned to upadacitinib will add methotrexate 10 mg/week (7.5 mg for Japan) to upadacitinib in a blinded manner and will remain on upadacitinib plus methotrexate 10 mg/week (7.5 mg for Japan) until the study is unblinded. Starting at Week 36 through Week 40, participants who do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline at two consecutive visits will continue on their blinded therapy and the Investigator should optimize (initiate or increase) background RA medications: NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone equivalent ≤ 0.5 mg/kg/day for 3 consecutive days and up to 2 local injections), low-potency analgesics and csDMARDs (only 1 of the following: sulfasalazine, hydroxychloroquine or chloroquine). 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. When the last participant completes the last visit of Period 1 (Week 48), study drug assignment in both periods may be unblinded, and participants will be dispensed study drug in an open-label fashion until the completion of Period 2. 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.
Interventions
Tablet; Oral
DRUGMethotrexate
Capsule or Tablet; Oral
Capsule or Tablet; Oral
DRUGUpadacitinib
Tablet; Oral
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis | Baseline to Week 24 | The second 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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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. |
| 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: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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 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: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP). |
| 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. |
Countries
Argentina, Australia, Belarus, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Estonia, Germany, Greece, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Kazakhstan, Latvia, Lithuania, Mexico, New Zealand, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, Spain, Switzerland, Taiwan, Tunisia, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were randomized at 236 sites in 43 countries. The study included 2 periods and a Japan sub-study. The global study analysis included participants from Japan, but excluded the upadacitinib 7.5 mg group. The Japan sub-study included all participants from Japan, including the upadacitinib 7.5 mg group.
Pre-assignment details
Participants were randomized in a 1:1:1 ratio to Groups 1, 3, and 4 below, except for participants in Japan who were randomized in a 1:2:1:1 ratio to Groups 1, 2, 3, and 4. Randomization was stratified by geographic region. Efficacy analyses were conducted separately for the Japan sub-study.
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate Participants received up to 20 mg methotrexate orally per week and placebo to upadacitinib once a day for 48 weeks during Period 1. | 314 |
| Upadacitinib 7.5 mg Participants received 7.5 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. | 55 |
| Upadacitinib 15 mg Participants received 15 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. | 317 |
| Upadacitinib 30 mg Participants received 30 mg upadacitinib orally once a day and placebo to methotrexate once a week for 48 weeks in Period 1. | 314 |
| Total | 1,000 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 (Weeks 1 to 48) | Adverse Event | 15 | 3 | 18 | 11 |
| Period 1 (Weeks 1 to 48) | Lack of Efficacy | 12 | 0 | 2 | 4 |
| Period 1 (Weeks 1 to 48) | Lost to Follow-up | 4 | 0 | 6 | 5 |
| Period 1 (Weeks 1 to 48) | Not Dosed | 1 | 0 | 0 | 1 |
| Period 1 (Weeks 1 to 48) | Other | 5 | 1 | 2 | 3 |
| Period 1 (Weeks 1 to 48) | Withdrawal by Subject | 22 | 0 | 12 | 20 |
| Period 2 (Weeks 48 to 260) | Adverse Event | 16 | 4 | 11 | 26 |
| Period 2 (Weeks 48 to 260) | Coronavirus Disease of 2019 (COVID-19) Infection | 0 | 0 | 0 | 3 |
| Period 2 (Weeks 48 to 260) | COVID-19 Logistic Restrictions | 0 | 0 | 2 | 1 |
| Period 2 (Weeks 48 to 260) | Lack of Efficacy | 11 | 0 | 1 | 1 |
| Period 2 (Weeks 48 to 260) | Lost to Follow-up | 17 | 0 | 10 | 6 |
| Period 2 (Weeks 48 to 260) | Other | 14 | 1 | 11 | 17 |
| Period 2 (Weeks 48 to 260) | Withdrawal by Subject | 32 | 5 | 23 | 27 |
Baseline characteristics
| Characteristic | Methotrexate | Upadacitinib 7.5 mg | Upadacitinib 15 mg | Upadacitinib 30 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 12.89 | 59.7 years STANDARD_DEVIATION 13.8 | 51.9 years STANDARD_DEVIATION 12.58 | 54.9 years STANDARD_DEVIATION 12.58 | 53.7 years STANDARD_DEVIATION 12.86 |
| Age, Customized 40 - 65 years | 206 Participants | 25 Participants | 204 Participants | 212 Participants | 647 Participants |
| Age, Customized < 40 years | 50 Participants | 5 Participants | 60 Participants | 34 Participants | 149 Participants |
| Age, Customized ≥ 65 years | 58 Participants | 25 Participants | 53 Participants | 68 Participants | 204 Participants |
| Disease Activity Score 28 Based on CRP (DAS28[CRP]) | 5.9 units on a scale STANDARD_DEVIATION 0.97 | 5.5 units on a scale STANDARD_DEVIATION 0.9 | 5.9 units on a scale STANDARD_DEVIATION 0.97 | 5.8 units on a scale STANDARD_DEVIATION 1.02 | 5.8 units on a scale STANDARD_DEVIATION 0.99 |
| Duration of Rheumatoid Arthritis Diagnosis | 2.6 years STANDARD_DEVIATION 5.14 | 2.3 years STANDARD_DEVIATION 5.77 | 2.9 years STANDARD_DEVIATION 5.38 | 2.8 years STANDARD_DEVIATION 5.63 | 2.7 years STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 102 Participants | 0 Participants | 107 Participants | 107 Participants | 316 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 212 Participants | 55 Participants | 210 Participants | 207 Participants | 684 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Geographic Region Asia - China | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Geographic Region Asia-Japan | 28 Participants | 55 Participants | 27 Participants | 28 Participants | 138 Participants |
| Geographic Region Asia - Other | 3 Participants | 0 Participants | 4 Participants | 2 Participants | 9 Participants |
| Geographic Region Eastern Europe | 85 Participants | 0 Participants | 87 Participants | 87 Participants | 259 Participants |
| Geographic Region North America | 46 Participants | 0 Participants | 48 Participants | 46 Participants | 140 Participants |
| Geographic Region Other | 24 Participants | 0 Participants | 23 Participants | 23 Participants | 70 Participants |
| Geographic Region South/Central America | 90 Participants | 0 Participants | 91 Participants | 91 Participants | 272 Participants |
| Geographic Region Western Europe | 37 Participants | 0 Participants | 36 Participants | 36 Participants | 109 Participants |
| Health Assessment Questionnaire - Disability Index (HAQ-DI) | 1.6 units on a scale STANDARD_DEVIATION 0.67 | 1.3 units on a scale STANDARD_DEVIATION 0.62 | 1.6 units on a scale STANDARD_DEVIATION 0.67 | 1.5 units on a scale STANDARD_DEVIATION 0.66 | 1.6 units on a scale STANDARD_DEVIATION 0.66 |
| High-sensitivity C-reactive Protein (hsCRP) | 21.2 mg/L STANDARD_DEVIATION 22.05 | 18.5 mg/L STANDARD_DEVIATION 17.55 | 23.0 mg/L STANDARD_DEVIATION 27.37 | 19.4 mg/L STANDARD_DEVIATION 22.59 | 21.0 mg/L STANDARD_DEVIATION 23.84 |
| Modified Total Sharp Score (mTSS) | 13.3 units on a scale STANDARD_DEVIATION 30.55 | 15.9 units on a scale STANDARD_DEVIATION 39.1 | 18.1 units on a scale STANDARD_DEVIATION 38.15 | 17.2 units on a scale STANDARD_DEVIATION 38.25 | 16.1 units on a scale STANDARD_DEVIATION 36.02 |
| Patient's Assessment of Pain | 65.7 mm STANDARD_DEVIATION 21.46 | 64.1 mm STANDARD_DEVIATION 21.2 | 68.4 mm STANDARD_DEVIATION 20.6 | 65.3 mm STANDARD_DEVIATION 21.51 | 66.3 mm STANDARD_DEVIATION 21.21 |
| Patient's Global Assessment of Disease Activity | 65.8 mm STANDARD_DEVIATION 21.45 | 64.1 mm STANDARD_DEVIATION 21.36 | 66.6 mm STANDARD_DEVIATION 22.01 | 64.9 mm STANDARD_DEVIATION 21.63 | 65.7 mm STANDARD_DEVIATION 21.66 |
| Physician's Global Assessment of Disease Activity | 68.7 mm STANDARD_DEVIATION 16.45 | 63.3 mm STANDARD_DEVIATION 19.34 | 67.1 mm STANDARD_DEVIATION 17 | 65.3 mm STANDARD_DEVIATION 16.6 | 66.8 mm STANDARD_DEVIATION 16.89 |
| Race/Ethnicity, Customized American Indian/Alaska Native | 2 Participants | 0 Participants | 8 Participants | 7 Participants | 17 Participants |
| Race/Ethnicity, Customized Asian | 37 Participants | 55 Participants | 35 Participants | 34 Participants | 161 Participants |
| Race/Ethnicity, Customized Black or African American | 12 Participants | 0 Participants | 8 Participants | 13 Participants | 33 Participants |
| Race/Ethnicity, Customized Multiple | 5 Participants | 0 Participants | 7 Participants | 5 Participants | 17 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 2 Participants | 0 Participants | 3 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 256 Participants | 0 Participants | 256 Participants | 254 Participants | 766 Participants |
| Sex: Female, Male Female | 240 Participants | 36 Participants | 241 Participants | 240 Participants | 757 Participants |
| Sex: Female, Male Male | 74 Participants | 19 Participants | 76 Participants | 74 Participants | 243 Participants |
| Swollen Joint Count | 16.9 swollen joints STANDARD_DEVIATION 10.58 | 14.7 swollen joints STANDARD_DEVIATION 8.24 | 16.9 swollen joints STANDARD_DEVIATION 10.35 | 15.7 swollen joints STANDARD_DEVIATION 9.71 | 16.4 swollen joints STANDARD_DEVIATION 10.13 |
| Tender Joint Count | 26.4 tender joints STANDARD_DEVIATION 16.15 | 18.0 tender joints STANDARD_DEVIATION 11.75 | 25.4 tender joints STANDARD_DEVIATION 14.42 | 25.2 tender joints STANDARD_DEVIATION 14.99 | 25.3 tender joints STANDARD_DEVIATION 15.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 314 | 0 / 55 | 2 / 317 | 3 / 314 | 8 / 314 | 1 / 55 | 6 / 317 | 9 / 314 | 1 / 56 | 6 / 335 | 10 / 332 | 5 / 181 | 7 / 218 |
| other Total, other adverse events | 159 / 314 | 38 / 55 | 169 / 317 | 174 / 314 | 234 / 314 | 52 / 55 | 242 / 317 | 256 / 314 | 55 / 56 | 272 / 335 | 277 / 332 | 100 / 181 | 126 / 218 |
| serious Total, serious adverse events | 13 / 314 | 5 / 55 | 16 / 317 | 20 / 314 | 49 / 314 | 13 / 55 | 68 / 317 | 71 / 314 | 15 / 56 | 88 / 335 | 79 / 332 | 28 / 181 | 35 / 218 |
Outcome results
Primary
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis
The second 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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis | 0.67 units on a scale |
| Upadacitinib 15 mg | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis | 0.14 units on a scale |
| Upadacitinib 30 mg | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Global Analysis | 0.07 units on a scale |
Comparison: 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.p-value: 0.00195% CI: [-0.85, -0.2]ANCOVA
Comparison: 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.p-value: <0.00195% CI: [-0.91, -0.27]ANCOVA
Primary
Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis | 18.5 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis | 48.3 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Global Analysis | 50.0 percentage of participants |
Comparison: 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.p-value: <0.00195% CI: [22.8, 36.8]Cochran-Mantel-Haenszel
Comparison: 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.p-value: <0.00195% CI: [24.5, 38.5]Cochran-Mantel-Haenszel
Primary
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis
The primary endpoint for Japan/Pharmaceuticals and Medical Devices Agency (PMDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis | 54.1 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis | 75.7 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 - Global Analysis | 77.1 percentage of participants |
Comparison: 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.p-value: <0.00195% CI: [14.3, 28.8]Cochran-Mantel-Haenszel
Comparison: 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.p-value: <0.00195% CI: [15.7, 30.1]Cochran-Mantel-Haenszel
Primary
Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis
The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 50% response (ACR50) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis | 28.3 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis | 52.1 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis | 56.4 percentage of participants |
Comparison: 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.p-value: <0.00195% CI: [16.3, 31.1]Cochran-Mantel-Haenszel
Comparison: 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.p-value: <0.00195% CI: [20.6, 35.4]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis | -1.85 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis | -2.73 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis | -2.85 scores on a scale |
p-value: <0.00195% CI: [-1.09, -0.67]ANCOVA
p-value: <0.00195% CI: [-1.21, -0.8]ANCOVA
Secondary
Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study | -1.42 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study | -2.86 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study | -3.28 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in DAS28 (CRP) at Week 12 - Japan Sub-study | -3.34 scores on a scale |
p-value: <0.00195% CI: [-1.92, -0.95]ANOVA
p-value: <0.00195% CI: [-2.42, -1.3]ANOVA
p-value: <0.00195% CI: [-2.48, -1.36]ANOVA
Secondary
Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis | -2.15 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis | -3.07 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in DAS28 (CRP) at Week 24 - Global Analysis | -3.34 scores on a scale |
p-value: <0.00195% CI: [-1.12, -0.71]ANCOVA
p-value: <0.00195% CI: [-1.4, -0.99]ANCOVA
Secondary
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis | -0.49 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis | -0.83 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Global Analysis | -0.86 scores on a scale |
p-value: <0.00195% CI: [-0.44, -0.25]ANCOVA
p-value: <0.00195% CI: [-0.47, -0.28]ANCOVA
Secondary
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study | -0.20 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study | -0.75 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study | -0.95 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 - Japan Sub-study | -0.95 scores on a scale |
p-value: <0.00195% CI: [-0.75, -0.34]ANOVA
p-value: <0.00195% CI: [-0.99, -0.51]ANOVA
p-value: <0.00195% CI: [-0.99, -0.51]ANOVA
Secondary
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis | -0.60 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis | -0.87 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 - Global Analysis | -0.91 scores on a scale |
p-value: <0.00195% CI: [-0.37, -0.17]ANCOVA
p-value: <0.00195% CI: [-0.41, -0.21]ANCOVA
Secondary
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study
The mTSS measures the level of joint damage from radiographs of the hands and feet. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study | 2.64 units on a scale |
| Upadacitinib 15 mg | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study | 0.95 units on a scale |
| Upadacitinib 30 mg | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study | 0.24 units on a scale |
| Upadacitinib 30 mg | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24 - Japan Sub-study | 0.19 units on a scale |
p-value: 0.06395% CI: [-3.47, 0.09]ANOVA
p-value: 0.02295% CI: [-4.45, -0.35]ANOVA
p-value: 0.02295% CI: [-4.54, -0.35]ANOVA
Secondary
Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis | 5.74 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis | 9.99 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Global Analysis | 10.08 scores on a scale |
p-value: <0.00195% CI: [3, 5.5]ANCOVA
p-value: <0.00195% CI: [3.09, 5.59]ANCOVA
Secondary
Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study | 2.87 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study | 8.84 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study | 10.79 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 - Japan Sub-study | 9.63 scores on a scale |
p-value: <0.00195% CI: [3.15, 8.8]ANOVA
p-value: <0.00195% CI: [4.66, 11.19]ANOVA
p-value: <0.00195% CI: [3.33, 10.2]ANOVA
Secondary
Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methotrexate | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis | 6.97 scores on a scale |
| Upadacitinib 15 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis | 10.70 scores on a scale |
| Upadacitinib 30 mg | Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 24 - Global Analysis | 11.39 scores on a scale |
p-value: <0.00195% CI: [2.42, 5.03]ANCOVA
p-value: <0.00195% CI: [3.12, 5.72]ANCOVA
Secondary
Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study | 17.9 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study | 67.3 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study | 70.4 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 24 - Japan Sub-study | 82.1 percentage of participants |
p-value: <0.00195% CI: [30.6, 68.3]Chi-squared
p-value: <0.00195% CI: [30.2, 74.8]Chi-squared
p-value: <0.00195% CI: [44.2, 84.3]Chi-squared
Secondary
Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis | 28.3 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis | 53.3 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Global Analysis | 54.8 percentage of participants |
p-value: <0.00195% CI: [17.6, 32.4]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [19, 33.9]Chi-squared, Corrected
Secondary
Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study | 17.9 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study | 69.1 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study | 77.8 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 - Japan Sub-study | 78.6 percentage of participants |
p-value: <0.00195% CI: [32.5, 70]Chi-squared
p-value: <0.00195% CI: [38.8, 81.1]Chi-squared
p-value: <0.00195% CI: [39.9, 81.5]Chi-squared
Secondary
Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis | 32.2 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis | 59.9 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 24 - Global Analysis | 65.0 percentage of participants |
p-value: <0.00195% CI: [20.3, 35.2]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [25.4, 40.2]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study | 57.1 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study | 85.5 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study | 85.2 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study | 78.6 percentage of participants |
p-value: 0.00495% CI: [7.7, 48.9]Chi-squared
p-value: 0.02295% CI: [5.3, 50.7]Chi-squared
p-value: 0.08695% CI: [-2.4, 45.2]Chi-squared
Secondary
Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 24
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis | 58.6 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis | 78.9 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR20 Response at Week 24 - Global Analysis | 78.0 percentage of participants |
p-value: <0.00195% CI: [13.2, 27.3]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [12.3, 26.5]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study | 21.4 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study | 60.0 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study | 66.7 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study | 71.4 percentage of participants |
p-value: <0.00195% CI: [18.6, 58.5]Chi-squared
p-value: <0.00195% CI: [21.8, 68.6]Chi-squared
p-value: <0.00195% CI: [27.4, 72.6]Chi-squared
Secondary
Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 24
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis | 33.4 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis | 60.3 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR50 Response at Week 24 - Global Analysis | 65.6 percentage of participants |
p-value: <0.00195% CI: [19.3, 34.3]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [24.8, 39.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study | 0.0 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study | 34.5 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study | 51.9 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR70 Response at Week 12 - Japan Sub-study | 64.3 percentage of participants |
p-value: <0.00195% CI: [22, 47.1]Chi-squared
p-value: <0.00195% CI: [33, 70.7]Chi-squared
p-value: <0.00195% CI: [46.5, 82]Chi-squared
Secondary
Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 24
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis | 18.5 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis | 44.5 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an ACR70 Response at Week 24 - Global Analysis | 49.7 percentage of participants |
p-value: <0.00195% CI: [19.1, 33]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [24.2, 38.2]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis
Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis | 14.0 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis | 32.5 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 - Global Analysis | 36.9 percentage of participants |
p-value: <0.00195% CI: [12.1, 24.9]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [16.4, 29.5]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis
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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis | 77.7 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis | 87.5 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With No Radiographic Progression at Week 24 - Global Analysis | 89.3 percentage of participants |
p-value: 0.00295% CI: [3.5, 16.2]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [5.4, 17.8]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study
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. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers. 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study | 46.2 percentage of participants |
| Upadacitinib 15 mg | Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study | 82.4 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study | 80.8 percentage of participants |
| Upadacitinib 30 mg | Percentage of Participants With No Radiographic Progression at Week 24 - Japan Sub-study | 79.2 percentage of participants |
p-value: 0.00195% CI: [14.4, 58]Chi-squared
p-value: 0.0195% CI: [10.2, 59]Chi-squared
p-value: 0.01695% CI: [7.9, 58.1]Chi-squared