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

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

Tracking Information
First Submitted Date  ICMJE February 18, 2016
First Posted Date  ICMJE March 11, 2016
Results First Submitted Date  ICMJE September 13, 2019
Results First Posted Date  ICMJE October 4, 2019
Last Update Posted Date March 11, 2020
Actual Study Start Date  ICMJE February 23, 2016
Actual Primary Completion Date March 15, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2019)
  • Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 - Global Analysis [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
  • Proportion of participants achieving American College Rheumatology (ACR) 50 response [ Time Frame: At week 24 ]
    ACR criteria measure improvements in tender and swollen joint counts, patient assessments of pain, global disease activity and physical function, physician global assessment of disease activity and acute phase reactant.
  • Clinical remission (CR) (DAS28 [CRP] < 2.6) [ Time Frame: At Week 24 ]
    CR based on DAS28 (CRP) response rate is defined as DAS28 (CRP) less than 2.6
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 13, 2019)
  • Change From Baseline in DAS28 (CRP) at Week 12 - Global Analysis [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
  • Percentage of Participants With an ACR20 Response at Week 12 - Japan Sub-study [ Time Frame: 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).
  • Percentage of Participants With an ACR50 Response at Week 12 - Japan Sub-study [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
  • Change in modified Total Sharp Score (mTSS) [ Time Frame: From day 1 to week 24 ]
    For mTSS, x-rays of hand/wrist, feet joints and joint spaces are scored for erosions, which will be summed to determine the total score, which ranges from 0 (no damage) to 448.
  • Change in Disease Activity Score (DAS)28 C-Reactive Protein (CRP) [ Time Frame: From day 1 to week 24 ]
    The DAS28 is a validated index of rheumatoid arthritis disease activity. Scores on the DAS28 range from 0 to 10.
  • ACR70 response rate [ Time Frame: At week 24 ]
    ACR criteria measure improvements in tender and swollen joint counts, patient assessments of pain, global disease activity and physical function, physician global assessment of disease activity and acute phase reactant.
  • Change in Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: From day 1 to week 24 ]
    HAQ-DI is a participant questionnaire with questions regarding the participant's illness and how it affect their daily life activities.
  • ACR20 response rate [ Time Frame: At week 24 ]
    ACR criteria measure improvements in tender and swollen joint counts, patient assessments of pain, global disease activity and physical function, physician global assessment of disease activity and acute phase reactant.
  • Change in Short Form-36 (SF-36) Physical Component Score (PCS) [ Time Frame: From day 1 to week 24 ]
    SF-36 is a 36 item participant questionnaire with questions regarding participant health and daily activities.
  • Proportion of subjects achieving Low Disease Activity (LDA) [ Time Frame: Week 24 ]
    Low Disease Activity (LDA)is defined as Disease Activity Score (DAS)28 (CRP) <= 3.2
  • Proportion of subjects with no radiographic progression [ Time Frame: Up to week 48 ]
    It is defined as change in mTSS <= 0
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Compare Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have Not Previously Taken Methotrexate
Official Title  ICMJE 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
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

Participants who complete the Week 48 visit (end of Period 1) will enter the long-term extension, Period 2 (192 weeks) and continue study treatment per assignment at the end of Period 1 in a blinded fashion.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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)

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • Drug: Upadacitinib Placebo
    Tablet; Oral
  • Drug: Methotrexate
    Capsule or Tablet; Oral
  • Drug: Methotrexate Placebo
    Capsule or Tablet; Oral
  • Drug: Upadacitinib
    Tablet; Oral
    Other Names:
    • ABT-494
    • Rinvoq
Study Arms  ICMJE
  • Active Comparator: Placebo Upadacitinib and Methotrexate

    Period 1: Participants will receive Upadacitinib placebo once daily and methotrexate once weekly for 48 weeks.

    Period 2: Participants will continue on Upadacitinib placebo once daily and methotrexate once weekly followed by methotrexate alone once weekly.

    Interventions:
    • Drug: Upadacitinib Placebo
    • Drug: Methotrexate
  • Experimental: Upadacitinib 7.5 mg and Placebo Methotrexate (Japan-only)

    Period 1: Participants will receive Upadacitinib 7.5 mg once daily and methotrexate placebo once weekly for 48 weeks.

    Period 2: Participants will continue on Upadacitinib 7.5 mg once daily and methotrexate placebo once weekly followed by Upadacitinib 7.5 mg once daily without methotrexate placebo once the treatment assignment is unblinded to sites and participants.

    Interventions:
    • Drug: Methotrexate Placebo
    • Drug: Upadacitinib
  • Experimental: Upadacitinib 15 mg and Placebo Methotrexate

    Period 1: Participants will receive Upadacitinib 15 mg once daily and methotrexate placebo once weekly for 48 weeks.

    Period 2: Participants will continue on Upadacitinib 15 mg once daily and methotrexate placebo once weekly followed by Upadacitinib 15 mg once daily without methotrexate placebo once the treatment assignment is unblinded to sites and participants.

    Interventions:
    • Drug: Methotrexate Placebo
    • Drug: Upadacitinib
  • Experimental: Upadacitinib 30 mg and Placebo Methotrexate

    Period 1: Participants will receive Upadacitinib 30 mg once daily and methotrexate placebo once weekly for 48 weeks.

    Period 2: Participants will continue on Upadacitinib 30 mg once daily and methotrexate placebo once weekly until participants begin to receive Upadacitinib 15 mg once daily without methotrexate placebo once the treatment assignment is unblinded to sites and participants.

    Interventions:
    • Drug: Methotrexate Placebo
    • Drug: Upadacitinib
Publications * Nader A, Mohamed MF, Winzenborg I, Doelger E, Noertersheuser P, Pangan AL, Othman AA. Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis. Clin Pharmacol Ther. 2020 Apr;107(4):994-1003. doi: 10.1002/cpt.1671. Epub 2019 Nov 30.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 18, 2018)
1002
Original Estimated Enrollment  ICMJE
 (submitted: March 8, 2016)
975
Estimated Study Completion Date  ICMJE October 22, 2022
Actual Primary Completion Date March 15, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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,   Russian Federation,   Serbia,   Slovakia,   Slovenia,   South Africa,   Spain,   Switzerland,   Taiwan,   Tunisia,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Finland,   Malaysia,   Netherlands
 
Administrative Information
NCT Number  ICMJE NCT02706873
Other Study ID Numbers  ICMJE M13-545
2015-003334-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP