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SELECT-COMPARE: A Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Adults With Rheumatoid Arthritis Who Are on a Stable Dose of Methotrexate and Who Have an Inadequate Response to Methotrexate

Sponsor
AbbVie (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02629159
Collaborator
(none)
1,629
Enrollment
370
Locations
3
Arms
142
Anticipated Duration (Months)
4.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to assess efficacy, including inhibition of radiographic progression, and safety with upadacitinib versus placebo and versus an active comparator, adalimumab, in adults with with moderately to severely active rheumatoid arthritis (RA) who are on a stable background of methotrexate (MTX and who have an inadequate response to MTX.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This study consists of a 48-week double-blind treatment period (Period 1) and a long-term extension period (Period 2).

Period 1 is a 48-week randomized, double-blind, parallel-group, placebo-controlled and active comparator-controlled period designed to compare the safety and efficacy of upadacitinib versus placebo, and versus adalimumab. Participants will be randomized in a 2:2:1 ratio to one of three treatment groups:

  • Placebo (up to Week 26)

  • Upadacitinib 15 mg once daily (QD)

  • Adalimumab 40 mg every other week (eow)

Participants randomized to placebo who do not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded upadacitinib treatment. At Week 26, all participants still receiving placebo will be switched to blinded upadacitinib treatment regardless of clinical response.

Participants randomized to adalimumab who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded upadacitinib. Participants still receiving adalimumab at Week 26 who do not achieve low disease activity (LDA) according to Clinical Disease Activity Index (CDAI; LDA is defined as CDAI ≤ 10) will be switched to blinded upadacitinib treatment to Week 48.

Participants randomized to upadacitinib who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline will be switched to blinded adalimumab; participants still receiving upadacitinib at Week 26 who do not achieve LDA (CDAI ≤ 10) will be switched to blinded adalimumab treatment to Week 48.

Participants who complete the Week 48 visit (end of Period 1) will enter the long-term extension phase of the study (Period 2), for up to 5 years. Participants will continue study treatment as assigned at the end of Period 1. Starting at the Week 48 and thereafter, at least 20% improvement in both TJC and SJC compared to Baseline is required to remain on study drug. Anyone who does not fulfill this criterion at 2 consecutive visits (starting at Week 48) will be discontinued.

Study Design

Study Type:
Interventional
Actual Enrollment :
1629 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Are on a Stable Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX (MTX-IR)
Actual Study Start Date :
Dec 1, 2015
Actual Primary Completion Date :
Oct 27, 2017
Anticipated Study Completion Date :
Sep 30, 2027

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo followed by ABT-494

Participants were to receive placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26, all remaining participants were to be switched to 15 mg upadacitinib QD until Week 48 (end of Period 1). Participants who complete Period 1 will continue to receive 15 mg upadacitinib orally QD for up to 5 years in Period 2.

Drug: Placebo for Adalimumab
Administered by subcutaneous injection once every other week

Drug: Placebo for Upadacitinib
Tablets taken orally once a day

Drug: Upadacitinib
Tablets taken orally once a day
Other Names:
  • ABT-494

    		•
    Active Comparator: Adalimumab

    Participants were to receive placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 15 mg upadacitinib orally QD. At Week 26 remaining participants who did not achieve low disease activity (defined as Clinical Disease Activity Index [CDAI] ≤ 10) were to be switched to 15 mg upadacitinib orally QD until Week 48. Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.

    Drug: Adalimumab
    Administered by subcutaneous injection once every other week
    Other Names:
  • Humira

    • Drug: Placebo for Upadacitinib
    Tablets taken orally once a day

    Drug: Upadacitinib
    Tablets taken orally once a day
    Other Names:
  • ABT-494

    		•
    Experimental: Upadacitinib

    Participants were to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were to be switched to 40 mg adalimumab eow. At Week 26 remaining participants who did not achieve low disease activity (defined as CDAI ≤ 10) were to be switched to 40 mg adalimumab eow until Week 48. Participants who complete Period 1 will continue to receive the same treatment assigned at the end of Period 1 (15 mg upadacitinib QD or 40 mg adalimumab eow) for up to 5 years in Period 2.

    Drug: Placebo for Adalimumab
    Administered by subcutaneous injection once every other week

    Drug: Adalimumab
    Administered by subcutaneous injection once every other week
    Other Names:
  • Humira

    • Drug: Upadacitinib
    Tablets taken orally once a day
    Other Names:
  • ABT-494

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 [Baseline and Week 12]

      The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).

    2. Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12 [Week 12]

      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 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 DAS28 score less than 2.6 indicates clinical remission.

    Secondary Outcome Measures

    1. Change From Baseline in DAS28 (CRP) at Week 12 [Baseline and 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.

    2. Change From Baseline in Modified Total Sharp Score (mTSS) at Week 26 [Baseline and Week 26]

      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 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). 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 negative change from Baseline in mTSS indicates improvement in joint damage whereas a change from Baseline greater than 0 indicates progression.

    3. Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 [Baseline and 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.

    4. Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 [Baseline and Week 12]

      Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).

    5. Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 [Baseline and 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.

    6. Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 [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.

    7. Percentage of Participants Achieving Low Disease Activity Based on CDAI at Week 12 [Week 12]

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

    8. Change From Baseline in Duration of Morning Stiffness at Week 12 [Baseline and Week 12]

      Participants were asked to indicate the time it took for them to get as limber as possible after awakening with morning stiffness over the past 7 days. A negative change from Baseline indicates improvement.

    9. Change From Baseline in in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) [Baseline and Week 12]

      The FACIT Fatigue scale is a 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a four point Likert scale. The FACIT Fatigue Scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better the quality of life. A positive change from Baseline indicates improvement.

    10. Change From Baseline in Patient's Assessment of Pain at Week 12 [Baseline and Week 12]

      Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale (VAS) from 0 to 100. A score of 0 indicates "no pain" and a score of 100 indicates "worst possible pain." A negative change from Baseline indicates improvement.

    11. Percentage of Participants With No Radiographic Progression at Week 26 [Baseline and Week 26]

      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 and ranges from 0 (normal) to 448 (worst). 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).

    12. Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 [Baseline and Week 12]

      Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Adult male or female, at least 18 years old.

    • Diagnosis of RA for greater than or equal to 3 months.

    • Subjects must have been on oral or parenteral methotrexate (MTX) therapy greater than or equal to 3 months and on a stable prescription of greater than or equal to 15 to 25 mg/week (or greater than or equal to 10 mg/week in subjects intolerant of MTX at doses greater than or equal to 12.5 mg/week) for at least 4 weeks prior to the first dose of study drug. In addition all subjects should take a dietary supplement of folic acid or folinic acid throughout the study participation.

    • Meets the following minimum disease activity criteria: greater than or equal to 6 swollen joints (based on 66 joint counts) and greater than or equal to 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.

    • At least one of the following at Screening: greater than or equal to 3 bone erosions on x-ray OR greater than or equal to 1 bone erosion and a positive rheumatoid factor OR greater than or equal to 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibodies.

    • Subjects with prior exposure to only one biological disease-modifying anti-rheumatic drugs (bDMARD) (except adalimumab) may be enrolled (up to 20% of total study population) if they have documented evidence of intolerance to the bDMARD or limited exposure (less than 3 months), but required washout periods need to be satisfied.

    • Except for MTX, subject must have discontinued all conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).

    Exclusion Criteria:

    • Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).

    • Subjects who have been exposed to adalimumab or who are considered inadequate responders to bDMARD therapy as determined by the Investigator.

    • History of inflammatory joint disease other than RA. History of secondary Sjogren's Syndrome is permitted.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Achieve Clinical Research, LLC /ID# 143136 Birmingham Alabama United States 35216
    2 AZ Arthritis and Rheum Assoc /ID# 143130 Mesa Arizona United States 85202
    3 SunValley Arthritis Center, Lt /ID# 143123 Peoria Arizona United States 85381
    4 Elite Clinical Studies, LLC /ID# 144881 Phoenix Arizona United States 85018
    5 AZ Arthritis and Rheum Researc /ID# 143080 Phoenix Arizona United States 85032-9306
    6 AZ Arthritis and Rheum Researc /ID# 143121 Phoenix Arizona United States 85032-9306
    7 AZ Arthritis & Rheuma Research /ID# 143131 Phoenix Arizona United States 85032
    8 Arizona Research Center, Inc. /ID# 144877 Phoenix Arizona United States 85053-4061
    9 AZ Arthritis & Rheum Research /ID# 156093 Sun City Arizona United States 85351
    10 University of Arizona Cancer Center - North Campus /ID# 143114 Tucson Arizona United States 85719-1478
    11 Osteoporosis Medical Center /ID# 153935 Beverly Hills California United States 90211
    12 T. Joseph Raoof, MD, Inc. /ID# 144884 Encino California United States 91436
    13 Rheumatology Ctr of San Diego /ID# 153747 Escondido California United States 92025
    14 C.V. Mehta MD, Med Corporation /ID# 143116 Hemet California United States 92543
    15 Allergy and Rheum Med Clin /ID# 146083 La Jolla California United States 92037
    16 Kotha and Kotha /ID# 161046 La Mesa California United States 91942
    17 TriWest Research Associates- La Mesa /ID# 143115 La Mesa California United States 91942
    18 Valerius Med Grp & Res Ctr /ID# 143120 Los Alamitos California United States 90720-5402
    19 Discovery MM Services, Inc /ID# 163504 Los Angeles California United States 11373
    20 Desert Medical Advances /ID# 143097 Palm Desert California United States 92260
    21 Sierra Rheumatology /ID# 155672 Roseville California United States 95661
    22 Robin K. Dore MD, Inc /ID# 143090 Tustin California United States 92780
    23 Medvin Clinical Research /ID# 148362 Whittier California United States 90606
    24 Arthritis Assoc & Osteo Ctr /ID# 143122 Colorado Springs Colorado United States 80920
    25 Arthritis and Rheum Clin N. CO /ID# 156094 Fort Collins Colorado United States 80528
    26 AARDS Research, Inc. /ID# 154190 Aventura Florida United States 33180
    27 ZASA Clinical Research /ID# 143134 Boynton Beach Florida United States 33472
    28 Clinical Res of West FL, Inc. /ID# 143112 Clearwater Florida United States 33765
    29 International Medical Research /ID# 143132 Daytona Beach Florida United States 32117
    30 Precision Research Org, LLC /ID# 143092 Miami Lakes Florida United States 33016-1501
    31 Lakes Research, LLC /ID# 145630 Miami Florida United States 33014
    32 FL Med Ctr and Research, Inc. /ID# 143081 Miami Florida United States 33142
    33 Ctr Arthritis & Rheumatic Dise /ID# 143135 Miami Florida United States 33173
    34 Advanced Clin Res of Orlando /ID# 154617 Ocoee Florida United States 34761-4547
    35 Rheum Assoc of Central FL /ID# 145632 Orlando Florida United States 32806
    36 Omega Research Consultants /ID# 145635 Orlando Florida United States 32810
    37 HMD Research LLC /ID# 163292 Orlando Florida United States 32819
    38 Arthritis Research of Florida /ID# 143125 Palm Harbor Florida United States 34684-2672
    39 Arthritis Center, Inc. /ID# 145647 Palm Harbor Florida United States 34684
    40 St. Anthony Comprehsve Res Ins /ID# 143095 Saint Petersburg Florida United States 33705
    41 Clinical Research West FL /ID# 148358 Tampa Florida United States 33603
    42 SW FL Clin Res Ctr, Tampa, FL /ID# 143117 Tampa Florida United States 33609
    43 BayCare Medical Group, Inc. /ID# 143085 Tampa Florida United States 33614-7101
    44 Lovelace Scientific Resources /ID# 143106 Venice Florida United States 34292
    45 Arthritis and Rheumatology /ID# 155668 Atlanta Georgia United States 30342
    46 Arthritis Center of North GA /ID# 155258 Gainesville Georgia United States 30501
    47 North Georgia Rheumatology Grp /ID# 147170 Lawrenceville Georgia United States 30045
    48 Advanced Clinical Research /ID# 153090 Meridian Idaho United States 83642
    49 Great Lakes Clinical Trials /ID# 148357 Chicago Illinois United States 60640
    50 Arthritis Treatment Center /ID# 155260 Frederick Maryland United States 21204
    51 The Center for Rheumatology & /ID# 151356 Wheaton Maryland United States 20902
    52 Clinical Pharmacology Study Gr /ID# 143082 Worcester Massachusetts United States 01605
    53 Advanced Rheumatology, PC /ID# 143118 Lansing Michigan United States 48910
    54 Shores Rheumatology, PC /ID# 162977 Saint Clair Shores Michigan United States 48081
    55 St. Luke's Hospital /ID# 156750 Duluth Minnesota United States 55805
    56 North Mississippi Med Clinics /ID# 145636 Tupelo Mississippi United States 38801
    57 Physician Res. Collaboration /ID# 143087 Lincoln Nebraska United States 68516
    58 Quality Clinical Research Inc. /ID# 156394 Omaha Nebraska United States 68114
    59 Atlantic Coast Research /ID# 148355 Toms River New Jersey United States 08755
    60 Ocean Rheumatology, PA /ID# 143111 Toms River New Jersey United States 08755
    61 Arthritis Rheumatic Back Disorder /ID# 143102 Voorhees New Jersey United States 08043
    62 Albuquerque Clinical Trials, Inc /ID# 143083 Albuquerque New Mexico United States 87102
    63 Arthritis and Osteo Assoc /ID# 143127 Las Cruces New Mexico United States 88011
    64 St. Lawrence Health System /ID# 161619 Potsdam New York United States 13676
    65 Joint & Muscle Research Instit /ID# 143119 Charlotte North Carolina United States 28204
    66 DJL Clinical Research, PLLC /ID# 143101 Charlotte North Carolina United States 28210-8508
    67 EmergeOrtho, P.A. /ID# 143100 Durham North Carolina United States 27704
    68 Cape Fear Arthritis Care /ID# 148361 Leland North Carolina United States 28451
    69 Coastal Carolina Health Care /ID# 148359 New Bern North Carolina United States 28562
    70 Shanahan Rheuma & Immuno /ID# 145643 Raleigh North Carolina United States 27617
    71 Clinical Research Solutions, LLC /ID# 154619 Dayton Ohio United States 45409
    72 Arthritis Assoc of NW Ohio /ID# 143094 Toledo Ohio United States 43606
    73 Healthcare Research Consultant /ID# 143129 Tulsa Oklahoma United States 74135
    74 Altoona Ctr Clinical Res /ID# 143110 Duncansville Pennsylvania United States 16635
    75 Clinical Research Ctr Reading /ID# 143133 Wyomissing Pennsylvania United States 19610
    76 Columbia Arthritis Center /ID# 153730 Columbia South Carolina United States 29204
    77 Innovative Clinical Research /ID# 145637 Greenville South Carolina United States 29601
    78 Articularis Healthcare Group, Inc d/b/a Low Country Rheumatology /ID# 143091 Summerville South Carolina United States 29486-7887
    79 Arthritis Associates, PLLC /ID# 155490 Kingsport Tennessee United States 37660
    80 Rheumatology Consultants, PLLC /ID# 153731 Knoxville Tennessee United States 37909
    81 Dr. Ramesh Gupta /ID# 143099 Memphis Tennessee United States 38119
    82 Austin Regional Clinic /ID# 143084 Austin Texas United States 78731
    83 Diagnostic Group Integrated He /ID# 148356 Beaumont Texas United States 77701
    84 Arthritis Care and Diagnostic /ID# 150677 Dallas Texas United States 75231
    85 Metroplex Clinical Research /ID# 145631 Dallas Texas United States 75231
    86 Doctor's Hosp at Renaissance /ID# 154616 Edinburg Texas United States 78539
    87 MedResearch Inc. /ID# 154618 El Paso Texas United States 79935
    88 Accurate Clinical Management /ID# 145644 Houston Texas United States 77004
    89 Accurate Clinical Research /ID# 145645 Houston Texas United States 77034
    90 Rheumatology Clinic of Houston /ID# 150921 Houston Texas United States 77065
    91 Houston Institute for Clin Res /ID# 144879 Houston Texas United States 77074
    92 Pioneer Research Solutions, Inc. /ID# 145640 Houston Texas United States 77098-5294
    93 Arthritis Consultants, P.A. /ID# 144880 Killeen Texas United States 76549
    94 Arthritis & Osteoporosis Assoc /ID# 147364 Lubbock Texas United States 79424
    95 P&I Clinical Research /ID# 161625 Lufkin Texas United States 75904-3132
    96 SW Rheumatology Res. LLC /ID# 143126 Mesquite Texas United States 75150
    97 Discovery MM Services, Inc. /ID# 162578 Missouri City Texas United States 77459-4750
    98 Discovery MM Services, Inc. /ID# 163183 Missouri City Texas United States 77459-4750
    99 Discovery MM Services, Inc. /ID# 163184 Missouri City Texas United States 77459-4750
    100 Sun Research Institute /ID# 159539 San Antonio Texas United States 78215
    101 Accurate Clinical Management /ID# 143089 San Antonio Texas United States 78229
    102 Arthritis & Osteo Ctr of S. TX /ID# 143103 San Antonio Texas United States 78232
    103 DM Clinical Research /ID# 151357 Tomball Texas United States 77375
    104 Arthritis Clinic of N. VA, P.C /ID# 143109 Arlington Virginia United States 22205
    105 Ctr for Arth and Rheum Disease /ID# 143113 Chesapeake Virginia United States 23320
    106 Arthritis Northwest, PLLC /ID# 143088 Spokane Washington United States 99204
    107 The Vancouver Clinic, INC. PS /ID# 143107 Vancouver Washington United States 98664
    108 West Virginia Research Inst /ID# 153088 South Charleston West Virginia United States 25309
    109 Rheumatology and Immunotherapy Center /ID# 145646 Franklin Wisconsin United States 53132
    110 Aprillus Asistencia e Investig /ID# 148406 Capital Federal Buenos Aires Argentina 1046
    111 Mautalen Salud e Investigacion /ID# 142843 Buenos Aires Argentina 1128
    112 Fundacion Sanatorio Guemes /ID# 148405 Buenos Aires Argentina 1180
    113 Consultorio Reumatologic Pampa /ID# 144853 Buenos Aires Argentina 1428
    114 Cemic /Id# 148404 Buenos Aires Argentina 1431
    115 Org Medica de Investigacion /ID# 144855 Buenos Aires Argentina C1015ABO
    116 Inst. Rheumatologic Strusberg /ID# 145601 Cordoba Argentina 5000
    117 Consultora Integral de Salud S /ID# 144856 Cordoba Argentina 5900
    118 Instituto CAICI /ID# 144854 Rosario, Santa FE Argentina 2000
    119 Cordis S.A. /Id# 152622 Salta Argentina 4400
    120 Iari /Id# 151293 San Fernando Argentina 1646
    121 Centro Integral de Reumatologi /ID# 142845 San Miguel de Tucuman Argentina 4000
    122 Centro Medico Privado/Reuma /ID# 142842 San Miguel de Tucuman Argentina 4000
    123 Centro de Enfermedades /ID# 153542 Santa Fe Argentina 2000
    124 Royal Prince Alfred Hospital /ID# 144857 Camperdown New South Wales Australia 2050
    125 Emeritus Research /ID# 142848 Camberwell Victoria Australia 3124
    126 LKH-Univ. Klinikum Graz /ID# 142851 Graz Austria 8036
    127 First City Clinical Hospital /ID# 158011 Minsk Belarus 220013
    128 Cliniques Universitaires Saint Luc /ID# 142858 Woluwe-Saint-Lambert Bruxelles-Capitale Belgium 1200
    129 Rhumaconsult SPRL /ID# 142860 Charleroi Hainaut Belgium 6000
    130 CHU de Liege /ID# 148401 Liège Liege Belgium 4000
    131 UZ Gent /ID# 142859 Gent Oost-Vlaanderen Belgium 9000
    132 CHU Ambroise Pare /ID# 152953 Mons Belgium 7000
    133 University Clinical Centre of the Republic of Srpska /ID# 142862 Banja Luka Republika Srpska Bosnia and Herzegovina 78000
    134 University Clinical Centre of the Republic of Srpska /ID# 142863 Banja Luka Republika Srpska Bosnia and Herzegovina 78000
    135 Clinical Center University of Sarajevo /ID# 142865 Sarajevo Bosnia and Herzegovina 71000
    136 CIP - Centro Internacional de Pesquisa /ID# 142872 Goiânia Goias Brazil 74110-120
    137 Hc Ufmg /Id# 142868 Belo Horizonte Minas Gerais Brazil 30130-100
    138 Ceti - Centro de Estudos Em Terapias Inovadoras Ltda /Id# 142871 Curitiba Parana Brazil 80030-110
    139 Hospital de Clinicas de Porto Alegre /ID# 142870 Porto Alegre Rio Grande Do Sul Brazil 90035-903
    140 LMK Sevicos Medicos S/S /ID# 142869 Porto Alegre Rio Grande Do Sul Brazil 90480-000
    141 CEPIC - Centro Paulista de Investigação Clínica e Serviços Médicos Ltda /ID# 142867 São Paulo Sao Paulo Brazil 04266-010
    142 CCBR Brasil /ID# 150918 Rio de Janeiro Brazil 22271-100
    143 MHAT Trimontsium /ID# 142874 Plovdiv Bulgaria 4000
    144 UMHAT Pulmed OOD /ID# 142877 Plovdiv Bulgaria 4000
    145 MHAT Kaspela /ID# 142873 Plovdiv Bulgaria 4001
    146 Diagnostic Consultative Center /ID# 142875 Sofia Bulgaria 1612
    147 UMHAT Sv. Ivan Rilski /ID# 142876 Sofia Bulgaria 1612
    148 Manitoba Clinic /ID# 161434 Winnipeg Manitoba Canada R3A IM3
    149 Ciads /Id# 142880 Winnipeg Manitoba Canada R3N 0K6
    150 St. Clare's Mercy Hospital /ID# 142879 St. John's Newfoundland and Labrador Canada A1C 5B8
    151 Adachi Medicine Prof. Corp /ID# 154205 Hamilton Ontario Canada L8N 1Y2
    152 CA Ctr for Clin Trials CCCT /ID# 157379 Thornhill Ontario Canada L4J 1W3
    153 Groupe de Recherche en Maladies Osseuses /ID# 142878 Sainte-foy Quebec Canada G1V 3M7
    154 Ctr de Inv Clinica del Sur /ID# 142888 Temuco Araucania Chile 4781156
    155 Reg. Clinical Hosptial Concepcion /ID# 151271 Concepcion Chile 4070038
    156 Corp de Beneficencia Osorno /ID# 147941 Osorno Chile 1710216
    157 Someal /Id# 144704 Providencia-santiago Chile 7510186
    158 Quantum Research LTDA. /ID# 142893 Puerto Varas Chile 5550170
    159 Quantum Research Stgo. /ID# 157933 Santiago Chile 7500588
    160 Soc. de Prestaciones medicas y Paramedicas Goecke /ID# 142890 Santiago Chile 7510047
    161 Clinica DermaCross /ID# 142892 Santiago Chile 7640881
    162 Investigaciones Medicas SSMSO /ID# 151686 Santiago Chile 8207257
    163 Centro Inter Estud Clin CIEC /ID# 144777 Santiago Chile 8420383
    164 Centro Medico de Reumatologia /ID# 148402 Temuco Chile 4790928
    165 Cinvec /Id# 144705 Vina Del Mar Chile 2520997
    166 Centro de Investigacion en Reumatologia y Especialidades Medicas- CIREEM SAS /ID# 142898 Bogota Cundinamarca Colombia 110221
    167 Ctr Int de Reum del Caribe SAS /ID# 142894 Barranquilla Colombia 80002
    168 Fund Inst de Reum F. Chalem /ID# 149847 Bogota DC Colombia
    169 Riesgo de Fractura S.A - CAYRE /ID# 142896 Bogota Colombia 110221
    170 Medicity S.A.S. /ID# 144860 Bucaramanga Colombia 680003
    171 Centro Integral de Reumatologi /ID# 142897 Medellín Colombia 50021
    172 Klinicki bolnicki centar Rijeka /ID# 160232 Rijeka Primorsko-goranska Zupanija Croatia 51000
    173 Klinicki bolnicki centar Split /ID# 152530 Split Croatia 21000
    174 Clinical Hospital Dubrava /ID# 142900 Zagreb Croatia 10000
    175 Medical Center Kuna-Peric /ID# 142901 Zagreb Croatia 10000
    176 Poliklinika Bonifarm /ID# 142899 Zagreb Croatia 10000
    177 L.K.N. Arthrocentrum, s.r.o /ID# 145961 Hlučín Moravskoslezsky Kraj Czechia 748 01
    178 CTCenter MaVe, s.r.o. /ID# 142905 Olomouc Olomoucky Kraj Czechia 779 00
    179 Revmatologicky ustav Praha /ID# 142904 Prague 2 Praha 2 Czechia 128 00
    180 Nuselská poliklinika, Revmatologie /ID# 144862 Prague 4 Praha 4 Czechia 140 00
    181 Revmatologická ambulance /ID# 145963 Prague 4 Praha 4 Czechia 140 00
    182 Thomayerova nemocnice /ID# 145962 Prague 4 Praha 4 Czechia 140 00
    183 REVMACLINIC s.r.o. /ID# 142906 Brno Czechia 611 41
    184 Revmatologie Bruntal, s.r.o /ID# 142903 Bruntál Czechia 79201
    185 Revmatologicka a interni ambul /ID# 142907 Kladno Czechia 272 01
    186 Revmatologie MUDr. Klara Sirov /ID# 142908 Ostrava Czechia 702 00
    187 Arthromed, s.r.o. /ID# 144706 Pardubice Czechia 530 02
    188 Aarhus University Hospital /ID# 158838 Aarhus N Midtjylland Denmark 8200
    189 Regionhospital Silkeborg /ID# 142914 Silkeborg Denmark 8600
    190 Center of Clinical and Basic Research /ID# 142922 Tallinn Harjumaa Estonia 10128
    191 MediTrials /ID# 151870 Tartu Tartumaa Estonia 50406
    192 Paernu Hospital /ID# 142921 Pärnu Estonia 80010
    193 East Tallinn Central Hospital /ID# 142923 Tallinn Estonia 10138
    194 North Estonian Medical Centre /ID# 145454 Tallinn Estonia 13419
    195 Hopital Universitaire Purpan /ID# 144707 Toulouse Haute-Garonne France 31059
    196 CHRU Lille - Hôpital Claude Huriez /ID# 151312 Lille CEDEX Hauts-de-France France 59045
    197 Hopital Saint Eloi /ID# 142925 Montpellier CEDEX 5 Herault France 34295
    198 CHU Bordeaux-Hopital Pellegrin /ID# 145618 Bordeaux France 33076
    199 Hopital de la Cote de Nacre /ID# 145616 Caen France 14033
    200 CHU Gabriel Montpied /ID# 145619 Clermont Ferrand France 63000
    201 Hopital de la Conception /ID# 142926 Marseille France 13005
    202 Hopital Pitie Salpetriere /ID# 145605 Paris France 75651
    203 CHU de Rennes - Hospital Sud /ID# 151957 Rennes France 35203
    204 CHU Strasbourg Hautepierre Hos /ID# 144708 Strasbourg France 67200
    205 Rheumazentrum Ruhrgebiet /ID# 145620 Herne Nordrhein-Westfalen Germany 44649
    206 Uniklinik Koln /ID# 145964 Köln Nordrhein-Westfalen Germany 50937
    207 Praxis Walter, Rendsburg /ID# 142932 Rendsburg Schleswig-Holstein Germany 24768
    208 Med Versorgungszentrum AGILOME /ID# 154975 Chemnitz Germany 9126
    209 Rheumaforschungszentrum II /ID# 142930 Hamburg Germany 20095
    210 LMU Klinikum der Universität München /ID# 142931 Munich Germany 80337
    211 General Hospital of Athens Laiko /ID# 142934 Athens Attiki Greece 115 27
    212 University General Hospital Attikon /ID# 142933 Athens Attiki Greece 12462
    213 General Hospital of Athens Ippokratio /ID# 142935 Athens Greece 11527
    214 Queen Mary Hospital /ID# 142938 Hong Kong Hong Kong 999077
    215 Tuen Mun Hospital /ID# 142939 Tuen Mun Hong Kong 999077
    216 CRU Hungary Egeszsegugyi és Szolgaltato Kft. /ID# 142951 Miskolc Borsod-Abauj-Zemplen Hungary 3529
    217 Qualiclinic Kft. /ID# 142953 Budapest III Pest Hungary 1036
    218 Markusovszky Egyetemi Oktatókórház /ID# 145621 Szombathely Vas Hungary 9700
    219 Vital Medical Center Orvosi es /ID# 145950 Veszprém Veszprem Hungary 8200
    220 Budai Irgalmasrendi Korhaz /ID# 142952 Budapest Hungary 1023
    221 Revita Reumatologiai Rendelo /ID# 142950 Budapest Hungary 1027
    222 Synexus Magyarorszag Kft. /ID# 153061 Budapest Hungary 1036
    223 Debreceni Egyetem Kenezy Gyula Egyetemi Korhaz /ID# 142948 Debrecen Hungary 4031
    224 Hevizgyogyfurdo es Szent Andra /ID# 142949 Heviz Hungary 8380
    225 Kiskunhalasi Semmelweis Korhaz /ID# 151944 Kiskunhalas Hungary 6400
    226 Pest Megyei Flor Ferenc Korhaz /ID# 142954 Kistarcsa Hungary 2143
    227 St Vincent's University Hosp /ID# 142957 Dublin Ireland D04 T6F4
    228 Tel Aviv Sourasky Medical Ctr /ID# 144709 Tel Aviv-Yafo Tel-Aviv Israel 6423906
    229 Rambam Health Care Campus /ID# 152050 Haifa Israel 3109601
    230 Bnai Zion Medical Center /ID# 151958 Haifa Israel 3339419
    231 The Lady Davis Carmel MC /ID# 142960 Haifa Israel 3436212
    232 Sheba Medical Center /ID# 145965 Ramat Gan Israel 5262100
    233 Istituto Clinico Humanitas /ID# 147528 Rozzano Milano Italy 20089
    234 AOU Citta della Salute Scienza /ID# 150070 Turin Piemonte Italy 10126
    235 Azienda Ospedaliera Luigi Sacc /ID# 142966 Milan Italy 20157
    236 A.O.U.I. di Verona Policlinico /ID# 142963 Verona Italy 37134
    237 JSC Nat Scientific Med Res Ctr /ID# 142971 Astana Kazakhstan 010009
    238 Karaganda State Medical Univ /ID# 153433 Karaganda Kazakhstan 100008
    239 Semey State Medical University /ID# 152659 Semey Kazakhstan 071403
    240 Regional Clinical Hospital /ID# 147168 Shymkent Kazakhstan 160000
    241 Kyungpook National Univ Hosp /ID# 162073 Daegu Daegu Gwang Yeogsi Korea, Republic of 41944
    242 Chungnam National University Hospital /ID# 142977 Jung-gu Daejeon Gwang Yeogsi Korea, Republic of 35015
    243 Inha University Hospital /ID# 150886 Jung-gu Incheon Gwang Yeogsi Korea, Republic of 22332
    244 Chonnam National University Hospital /ID# 142975 Gwangju Jeonranamdo Korea, Republic of 61469
    245 Hanyang University Seoul Hospi /ID# 142979 Seongdong-gu Seoul Teugbyeolsi Korea, Republic of 04763
    246 Cath Univ Seoul St Mary's Hosp /ID# 142976 Seoul Seoul Teugbyeolsi Korea, Republic of 06591
    247 Daegu Catholic University Med /ID# 142973 Daegu Korea, Republic of 705-718
    248 Seoul National University Hospital /ID# 142978 Seoul Korea, Republic of 03080
    249 Asan Medical Center /ID# 142974 Seoul Korea, Republic of 05505
    250 LTD M+M Centers /ID# 142984 Adazi Latvia 2164
    251 Daugavpils Regional Hospital /ID# 142982 Daugavpils Latvia 5417
    252 D.Saulites-Kandevicas PP /ID# 142985 Liepaja Latvia 3401
    253 Clinic ORTO /ID# 142983 Riga Latvia 1005
    254 Riga East Clinical Univ Hosp /ID# 142981 Riga Latvia 1038
    255 Hosp Lithuanian Univ Health Sc /ID# 142986 Kovno Kaunas Lithuania 50009
    256 Vilnius University Hospital /ID# 142987 Vilnius Lithuania LT-08661
    257 Hospital Raja Perempuan Zainab II /ID# 157862 Kota Bharu Kelantan Malaysia 15586
    258 Hospital Selayang /ID# 156756 Batu Caves Malaysia 68100
    259 Hospital Umum Sarawak /ID# 142990 Kuching Malaysia 93586
    260 Hospital Putrajaya /ID# 142989 Putrajaya Malaysia 62250
    261 Hospital Tuanku Ja afar /ID# 142988 Seremban Malaysia 70300
    262 Clinstile, S.A. de C.V. /ID# 144866 Cuauhtemoc Ciudad De Mexico Mexico 06700
    263 Hosp. Univ. Dr. Jose E. Gonz /ID# 142992 Monterrey Nuevo Leon Mexico 64320
    264 Invest y Biomed de Chihuahua /ID# 142996 Chihuahua Mexico 31000
    265 RM Pharma Specialists, S.A de C.V /ID# 142994 Mexico City Mexico 03100
    266 Hospital de Jesús Nazareno /ID# 142993 Mexico City Mexico 06090
    267 Centro Peninsular de Investiga /ID# 148159 Mérida Mexico 97000
    268 Waikato Hospital /ID# 143002 Hamilton Waikato New Zealand 3204
    269 Porter Rheumatology Ltd /ID# 143001 Nelson New Zealand 7010
    270 Timaru Medical Specialists Ltd /ID# 143000 Timaru New Zealand 7910
    271 WroMedica I. Bielicka, A. Strzalkowska s.c. /ID# 145622 Wrocław Dolnoslaskie Poland 51-685
    272 NZOZ Nasz Lekarz /ID# 143004 Toruń Kujawsko-pomorskie Poland 87-100
    273 REUMED Sp.z o.o. Filia nr 1 /ID# 148189 Lublin Lubelskie Poland 20-607
    274 Malopolskie Centrum Kliniczne /ID# 152782 Cracow Malopolskie Poland 30-149
    275 Pratia MCM Krakow /ID# 143005 Krakow Malopolskie Poland 30-510
    276 McBk Sc /Id# 143003 Grodzisk Mazowiecki Mazowieckie Poland 05-825
    277 Centralny Szpital Kliniczny MSWiA w Warszawie /ID# 151960 Warszawa Mazowieckie Poland 02-507
    278 Centrum Medyczne AMED Warszawa Targowek /ID# 157621 Warszawa Mazowieckie Poland 03-291
    279 Osteo-Medic spolka cywilna /ID# 143006 Białystok Podlaskie Poland 15-351
    280 Synexus Polska Sp. z o.o. Oddz. Poznan /ID# 163293 Gdynia Pomorskie Poland 81-384
    281 Synexus Polska Sp. z o.o. Oddz. Poznan /ID# 163294 Gdynia Pomorskie Poland 81-384
    282 Synexus Polska Sp. z o.o. Oddz. Poznan /ID# 163295 Gdynia Pomorskie Poland 81-384
    283 Silmedic Sp z o.o /ID# 152914 Katowice Slaskie Poland 40-282
    284 ClinicMed Badurski i wspolnicy SJ /ID# 163300 Bialystok Poland 15-879
    285 Solumed Sp. zoo Cent Medyczne /ID# 152783 Poznan Poland 60-425
    286 Rheuma Medicus /ID# 143007 Warsaw Poland 02-118
    287 Instituto Portugues De Reumatologia /ID# 148316 Lisbon Lisboa Portugal 1050-034
    288 Centro Hospitalar De Vila Nova /ID# 143010 Vila Nova De Gaia Porto Portugal 4434-502
    289 CCA Braga - Hospital de Braga /ID# 148317 Braga Portugal 4710-243
    290 Hospital CUF Descobertas /ID# 160539 Lisbon Portugal 1998-018
    291 Centro Hospitalar de Sao Joao, EPE /ID# 152871 Porto Portugal 4200-319
    292 Unidade Local De Saude Do Alto Minho /ID# 143009 Viana Do Castelo Portugal 4901-858
    293 Ponce School of Medicine /ID# 151961 Ponce Puerto Rico 00716
    294 GCM Medical Group /ID# 143011 San Juan Puerto Rico 00909
    295 Spitalul Clinic Dr. I. Cantacuzino /ID# 143012 Bucharest Bucuresti Romania 020475
    296 Spitalul Clinic Dr. I. Cantacuzino /ID# 143017 Bucharest Bucuresti Romania 020475
    297 Spitalul Clinic Sf. Maria /ID# 144868 Bucuresti Romania 011172
    298 Spitalul Clinic Sf. Maria /ID# 144869 Bucuresti Romania 011172
    299 Spitalul Clinic Sf. Maria /ID# 145966 Bucuresti Romania 011172
    300 Spitalul Clinic de Recuperare /ID# 144867 Iasi Romania 700656
    301 Ecomed SRL /ID# 144870 Oradea Romania 410028
    302 Family Outpatient clinic#4,LLC /ID# 148319 Korolev Moskva Russian Federation 141060
    303 Clinical Hospital No.1 n.a. N.I.Pirogov /ID# 143138 Moscow Moskva Russian Federation 119049
    304 Perm Clinical Center of FMBA /ID# 145627 Perm Permskiy Kray Russian Federation 614109
    305 LLC Novaya Klinika /ID# 143019 Pyatigorsk Stavropol Skiy Kray Russian Federation 357500
    306 Kazan State Medical University /ID# 144871 Kazan Tatarstan, Respublika Russian Federation 420012
    307 Tver Regional Clinical Hosp. /ID# 143026 Tver Tverskaya Oblast Russian Federation 170036
    308 Сity Clinical Hospital #4 /ID# 143023 Ivanovo Russian Federation 153005
    309 Russian National Research Medi /ID# 143028 Moscow Russian Federation 117997
    310 City Clinical Hospital Botkina /ID# 145628 Moscow Russian Federation 125284
    311 Moscow State Univ Med and Dent /ID# 145623 Moscow Russian Federation 127473
    312 City Clinical Hospital #5 /ID# 148318 Nizhnij Novgorod Russian Federation 603005
    313 Orenburg State Medical Academy /ID# 143018 Orenburg Russian Federation 460000
    314 Ryazan State Medical Universit /ID# 143031 Ryazan Russian Federation 390026
    315 II Dzhan Research Center /ID# 143027 St. Petersburg Russian Federation 192242
    316 NW State Med Univ NA Mechnikov /ID# 143022 St. Petersburg Russian Federation 193015
    317 Republican clinical hospital n /ID# 145626 UFA Russian Federation 450005
    318 Ulyanovsk Regional Clin Hosp /ID# 143030 Ulyanovsk Russian Federation 432018
    319 Institute for Rheumatology /ID# 143032 Belgrade Beograd Serbia 11000
    320 Institute for Rheumatology /ID# 143035 Belgrade Beograd Serbia 11000
    321 Institute for Rheumatology /ID# 143036 Belgrade Beograd Serbia 11000
    322 Institute for Rheumatology /ID# 143037 Belgrade Beograd Serbia 11000
    323 Special Hospital for Rheuma /ID# 143034 Novi Sad Vojvodina Serbia 21101
    324 Clinical Center of Vojvodina /ID# 143033 Novi Sad Vojvodina Serbia 21137
    325 MEDMAN s.r.o. /ID# 143045 Martin Slovakia 036 01
    326 Reumatologická ambulancia Reum.hapi s.r.o. /ID# 147169 Nové Mesto Nad Váhom Slovakia 915 01
    327 REUMACENTRUM s.r.o. /ID# 143041 Partizanske Slovakia 958 01
    328 Slovak research center Team Member, Thermium s.r.o. /ID# 147614 Pieštany Slovakia 921 01
    329 Reumex, s.r.o. /ID# 143043 Rimavska Sobota Slovakia 97 101
    330 Reumatologicka ambulancia /ID# 144873 Sabinov Slovakia 083 01
    331 TIMMED spol. s r.o. /ID# 144872 Stará Lubovna Slovakia 06401
    332 Reumatologicka ambulancia, LER /ID# 143044 Topolcany Slovakia 955 01
    333 ALBAMED s.r.o. /ID# 143042 Zvolen Slovakia 960 01
    334 Greenacres Hospital /ID# 144710 Port Elizabeth Eastern Cape South Africa 6045
    335 Wits Clinical Research Site /ID# 148320 Johannesburg Gauteng South Africa 2193
    336 University of Pretoria /ID# 148353 Pretoria Gauteng South Africa 0001
    337 Jakaranda Hosp, Emmed Research /ID# 143046 Pretoria Gauteng South Africa 0132
    338 Jakaranda Hosp, Emmed Research /ID# 145968 Pretoria Gauteng South Africa 0132
    339 St. Augustine's Hospital /ID# 143047 Durban Kwazulu-Natal South Africa 4001
    340 Synexus Helderberg Clinical Tr /ID# 148322 Cape Town Western Cape South Africa 7130
    341 Arthritis Clinical Research Tr /ID# 144874 Cape Town Western Cape South Africa 7405
    342 Tiervlei Trial Centre /ID# 153085 Cape Town Western Cape South Africa 7530
    343 Winelands Medical Research Ctr /ID# 143048 Stellenbosch Western Cape South Africa 7600
    344 H. Un. Marques de Valdecilla /ID# 143050 Santander Cantabria Spain 39008
    345 Comple Hosp Univ de A Coruna /ID# 143051 A Coruna Spain 15006
    346 Hospital Universitario Reina S /ID# 153566 Cordoba Spain 14004
    347 Clinica Gaias /ID# 143052 Santiago de Compostela Spain 15702
    348 Complejo Hosp Santiago /ID# 153727 Santiago de Compostela Spain 15706
    349 China Medical University Hosp /ID# 143058 Taichung City Taichung Taiwan 40447
    350 National Taiwan Univ Hosp /ID# 143056 Taipei City Taipei Taiwan 10002
    351 Kaohsiung Medical University /ID# 143059 Kaohsiung Taiwan 80708
    352 Kaohsiung Chang Gung Memorial Hospital /ID# 143055 Kaohsiung Taiwan 833
    353 Far Eastern Memorial Hospital /ID# 143061 New Taipei City Taiwan 22060
    354 Chung Shan Medical University /ID# 143060 Taichung City Taiwan 40201
    355 Taipei Veterans General Hosp /ID# 157940 Taipei City Taiwan 11217
    356 Linkou Chang Gung Memorial Ho /ID# 143057 Taoyuan City Taiwan 33305
    357 Istanbul Universitesi Cerrahpa /ID# 156088 Cerrahpasa Turkey 34098
    358 Istanbul Fizik Tedavi Rehabilitasyon Egitim ve Arastırma Hastanesi /ID# 143063 Istanbul Turkey 34147
    359 Izmir Katip Celebi Ataturk Training & Research Hospital /ID# 143062 Izmir Turkey 35360
    360 LLC Revmocentr /ID# 143067 Kiev Kyiv Ukraine 04070
    361 Lviv Regional Clinical Hospita /ID# 154450 Lviv Lvivska Oblast Ukraine 79013
    362 Vinnytsia Regional Clinical Hospital n.a. M.I.Pyrogov /ID# 143071 Vinnytsia Vinnytska Oblast Ukraine 21018
    363 Regional Clinical Hospital /ID# 152025 Ivano-frankivsk Ukraine 76018
    364 NSC-Strazhesko Ist Cardiology /ID# 152030 Kiev Ukraine 03680
    365 Lviv Municipal City Clinical /ID# 143068 Lviv Ukraine 79007
    366 Odessa National Medical Univ /ID# 143072 Odesa Ukraine 65026
    367 Zaporizhzhia Regional Clinical /ID# 143069 Zaporizhia Ukraine 69600
    368 The Royal Free Hospital /ID# 143074 London London, City Of United Kingdom NW3 2QG
    369 Queen Alexandra Hospital /ID# 143077 Portsmouth United Kingdom PO6 3LY
    370 Warrington + Halton Hosp NHS /ID# 143075 Warrington United Kingdom WA5 1LZ

    Sponsors and Collaborators

    • AbbVie

    Investigators

    • Study Director: AbbVie Inc., AbbVie

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    AbbVie
    ClinicalTrials.gov Identifier:
    NCT02629159
    Other Study ID Numbers:
    • M14-465
    • 2015-003333-95
    First Posted:
    Dec 14, 2015
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by AbbVie
    Musculoskeletal disease
    Arthritis
    Joint disease
    Anti-inflammatory agents
    Antirheumatic agents
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Adalimumab
    Upadacitinib

    Study Results

    Participant Flow

    Recruitment Details Participants with moderately to severely active rheumatoid arthritis (RA) on a stable dose of methotrexate with an inadequate response were randomized at 286 study sites in 41 countries. This study is currently ongoing; results are reported as of the data cut-off date of 02 February 2018, when all participants were to have completed Week 26.
    Pre-assignment Detail Participants were randomized in a 2:1:2 ratio to receive placebo, adalimumab, or upadacitinib. Randomization was stratified by prior exposure to biologic disease-modifying anti-rheumatic drug(s) (bDMARD) (yes/no) and geographic region. Rescue therapy was offered to participants who met protocol-specified criteria at Weeks 14, 18, 22, or 26.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants randomized to receive placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. At Week 26, all remaining participants were switched to 15 mg upadacitinib QD. Participants randomized to receive placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. At Week 26 remaining participants who did not achieve low disease activity (defined as Clinical Disease Activity Index [CDAI] ≤ 10) were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow. At Week 26 remaining participants who did not achieve low disease activity (defined as CDAI ≤ 10) were switched to 40 mg adalimumab eow.
    Period Title: Overall Study
    STARTED 651 327 651
    Received Assigned Study Drug 651 327 650
    Completed Week 14 on Study Drug 620 300 620
    Rescued at Week 14 231 56 78
    Rescued at Week 18 48 14 29
    Rescued at Week 22 26 7 18
    COMPLETED 595 288 600
    NOT COMPLETED 56 39 51

    Baseline Characteristics

    Arm/Group Title Placebo Adalimumab Upadacitinib Total
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow. Total of all reporting groups
    Overall Participants 651 327 651 1629
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    53.6
    (12.24)
    53.7
    (11.70)
    54.2
    (12.08)
    53.9
    (12.07)
    Age, Customized (Count of Participants)
    < 40 years
    91
    14%
    39
    11.9%
    81
    12.4%
    211
    13%
    40 to 64 years
    437
    67.1%
    232
    70.9%
    439
    67.4%
    1108
    68%
    ≥ 65 years
    123
    18.9%
    56
    17.1%
    131
    20.1%
    310
    19%
    Sex: Female, Male (Count of Participants)
    Female
    512
    78.6%
    259
    79.2%
    521
    80%
    1292
    79.3%
    Male
    139
    21.4%
    68
    20.8%
    130
    20%
    337
    20.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    206
    31.6%
    106
    32.4%
    215
    33%
    527
    32.4%
    Not Hispanic or Latino
    445
    68.4%
    221
    67.6%
    436
    67%
    1102
    67.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    561
    86.2%
    292
    89.3%
    576
    88.5%
    1429
    87.7%
    Black or African American
    38
    5.8%
    17
    5.2%
    33
    5.1%
    88
    5.4%
    American Indian/Alaska Native
    2
    0.3%
    1
    0.3%
    1
    0.2%
    4
    0.2%
    Native Hawaiian or other Pacific Islander
    1
    0.2%
    0
    0%
    0
    0%
    1
    0.1%
    Asian
    39
    6%
    15
    4.6%
    31
    4.8%
    85
    5.2%
    Multiple
    10
    1.5%
    2
    0.6%
    10
    1.5%
    22
    1.4%
    Geographic Region (Count of Participants)
    North America
    121
    18.6%
    60
    18.3%
    122
    18.7%
    303
    18.6%
    South/Central America
    173
    26.6%
    86
    26.3%
    173
    26.6%
    432
    26.5%
    Western Europe
    35
    5.4%
    19
    5.8%
    35
    5.4%
    89
    5.5%
    Eastern Europe
    262
    40.2%
    132
    40.4%
    262
    40.2%
    656
    40.3%
    Asia
    21
    3.2%
    10
    3.1%
    21
    3.2%
    52
    3.2%
    Other
    39
    6%
    20
    6.1%
    38
    5.8%
    97
    6%
    Duration of Rheumatoid Arthritis Diagnosis (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    8.3
    (8.00)
    8.3
    (8.41)
    8.1
    (7.73)
    8.2
    (7.97)
    Tender Joint Count (tender joints) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [tender joints]
    26.0
    (14.30)
    26.4
    (15.16)
    26.4
    (15.15)
    26.2
    (14.81)
    Swollen Joint Count (swollen joints) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [swollen joints]
    16.2
    (8.97)
    16.3
    (9.19)
    16.6
    (10.31)
    16.4
    (9.57)
    Patient's Assessment of Pain (mm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mm]
    65.0
    (20.67)
    66.2
    (20.51)
    65.7
    (21.02)
    65.5
    (20.77)
    Patient's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mm]
    63.8
    (21.49)
    65.8
    (21.08)
    64.3
    (21.83)
    64.4
    (21.55)
    Physician's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mm]
    66.0
    (18.17)
    65.1
    (17.60)
    65.6
    (17.06)
    65.7
    (17.62)
    Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    1.6
    (0.61)
    1.6
    (0.59)
    1.6
    (0.64)
    1.6
    (0.62)
    High-sensitivity C-reactive Protein (hsCRP) (mg/L) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/L]
    18.0
    (21.52)
    19.8
    (21.51)
    17.9
    (22.49)
    18.3
    (21.91)
    Disease Activity Score 28 Based on CRP (DAS28[CRP]) (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    5.8
    (0.94)
    5.9
    (0.96)
    5.8
    (0.97)
    5.8
    (0.96)

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
    Description The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 651 327 651
    Number (95% Confidence Interval) [percentage of participants]
    36.4
    5.6%
    63.0
    19.3%
    70.5
    10.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was the primary analysis for US/FDA regulatory purposes, and a ranked key secondary endpoint for EU/EMA regulatory purposes.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 34.1
    Confidence Interval (2-Sided) 95%
    29.0 to 39.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.018
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 7.5
    Confidence Interval (2-Sided) 95%
    1.2 to 13.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab
    2. Primary Outcome
    Title Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12
    Description The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission, based on a Disease Activity Score 28 (DAS28)-CRP score of < 2.6 at Week 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 DAS28 score less than 2.6 indicates clinical remission.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 651 327 651
    Number (95% Confidence Interval) [percentage of participants]
    6.1
    0.9%
    18.0
    5.5%
    28.7
    4.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was the primary analysis for EU/EMA regulatory purposes, and a ranked key secondary endpoint for US/FDA regulatory purposes.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 22.6
    Confidence Interval (2-Sided) 95%
    18.6 to 26.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 10.7
    Confidence Interval (2-Sided) 95%
    5.3 to 16.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab
    3. Secondary Outcome
    Title Change From Baseline in DAS28 (CRP) at Week 12
    Description The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 643 319 634
    Least Squares Mean (95% Confidence Interval) [units on a scale]
    -1.15
    -2.01
    -2.48
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method ANCOVA
    Comments Analysis of covariance (ANCOVA) model with treatment, prior biological DMARD use, and Baseline value as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.33
    Confidence Interval (2-Sided) 95%
    -1.469 to -1.194
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method ANCOVA
    Comments ANCOVA model with treatment, prior biological DMARD use and Baseline value as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.47
    Confidence Interval (2-Sided) 95%
    -0.638 to -0.295
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    4. Secondary Outcome
    Title Change From Baseline in Modified Total Sharp Score (mTSS) at Week 26
    Description The mTSS measures the level of joint damage from radiographs of the hands and feet, assessed by 2 independent, blinded readers. mTSS is calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score. Joint erosion 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). 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 negative change from Baseline in mTSS indicates improvement in joint damage whereas a change from Baseline greater than 0 indicates progression.
    Time Frame Baseline and Week 26

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 26 or who were rescued prior to Week 26.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 599 296 593
    Least Squares Mean (95% Confidence Interval) [units on a scale]
    0.92
    0.10
    0.24
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method ANCOVA
    Comments ANCOVA model with treatment, prior biological DMARD use and Baseline value as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.67
    Confidence Interval (2-Sided) 95%
    -0.97 to -0.37
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.448
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method ANCOVA
    Comments ANCOVA model with treatment, prior biological DMARD use and Baseline value as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.14
    Confidence Interval (2-Sided) 95%
    -0.23 to 0.51
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    5. Secondary Outcome
    Title Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12
    Description The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from Baseline in the overall score indicates improvement.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data at baseline; multiple imputation was used for missing data.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 648 324 644
    Least Squares Mean (95% Confidence Interval) [units on a scale]
    -0.28
    -0.49
    -0.60
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method ANCOVA
    Comments ANCOVA model with treatment, prior biological DMARD use and Baseline value as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.31
    Confidence Interval (2-Sided) 95%
    -0.372 to -0.253
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value 0.004
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA only.
    Method ANCOVA
    Comments ANCOVA model with treatment, prior biological DMARD use and Baseline value as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.11
    Confidence Interval (2-Sided) 95%
    -0.184 to -0.036
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    6. Secondary Outcome
    Title Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12
    Description Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 651 327 651
    Number (95% Confidence Interval) [percentage of participants]
    14.9
    2.3%
    29.1
    8.9%
    45.2
    6.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Non-Inferiority
    Comments A non-inferiority test of upadacitinib versus adalimumab was evaluated using the lower bound of the 95% confidence interval (CI) of the treatment difference against a non-inferiority margin of 10%. This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA only.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 16.1
    Confidence Interval (2-Sided) 95%
    9.9 to 22.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA only.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 30.3
    Confidence Interval (2-Sided) 95%
    25.6 to 35.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    7. Secondary Outcome
    Title Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12
    Description The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 616 309 616
    Least Squares Mean (95% Confidence Interval) [units on a scale]
    3.56
    6.27
    7.89
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 4.33
    Confidence Interval (2-Sided) 95%
    3.52 to 5.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 1.62
    Confidence Interval (2-Sided) 95%
    0.62 to 2.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    8. Secondary Outcome
    Title Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12
    Description The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 651 327 651
    Number (95% Confidence Interval) [percentage of participants]
    13.8
    2.1%
    28.7
    8.8%
    45.0
    6.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 31.2
    Confidence Interval (2-Sided) 95%
    26.5 to 35.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Non-Inferiority
    Comments A non-inferiority test of upadacitinib versus adalimumab was evaluated using the lower bound of the 95% confidence interval (CI) of the treatment difference against a non-inferiority margin of 10%. This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for EU/EMA only.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 16.3
    Confidence Interval (2-Sided) 95%
    10.0 to 22.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    9. Secondary Outcome
    Title Percentage of Participants Achieving Low Disease Activity Based on CDAI at Week 12
    Description Low disease activity based on the clinical disease activity index (CDAI) is defined as a CDAI score ≤ 10. CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom CDAI data were missing at Week 12 were considered non-responders
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 651 327 651
    Number (95% Confidence Interval) [percentage of participants]
    16.3
    2.5%
    30.0
    9.2%
    40.4
    6.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use.
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 24.1
    Confidence Interval (2-Sided) 95%
    19.4 to 28.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 10.4
    Confidence Interval (2-Sided) 95%
    4.2 to 16.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab
    10. Secondary Outcome
    Title Change From Baseline in Duration of Morning Stiffness at Week 12
    Description Participants were asked to indicate the time it took for them to get as limber as possible after awakening with morning stiffness over the past 7 days. A negative change from Baseline indicates improvement.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 619 306 618
    Least Squares Mean (95% Confidence Interval) [minutes]
    -48.59
    -82.71
    -92.63
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -44.04
    Confidence Interval (2-Sided) 95%
    -55.39 to -32.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.164
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -9.92
    Confidence Interval (2-Sided) 95%
    -23.89 to 4.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    11. Secondary Outcome
    Title Change From Baseline in in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)
    Description The FACIT Fatigue scale is a 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a four point Likert scale. The FACIT Fatigue Scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better the quality of life. A positive change from Baseline indicates improvement.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 613 307 612
    Least Squares Mean (95% Confidence Interval) [units on a scale]
    4.81
    7.44
    8.95
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA and EU/EMA.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 4.15
    Confidence Interval (2-Sided) 95%
    3.13 to 5.16
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.017
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 1.51
    Confidence Interval (2-Sided) 95%
    0.27 to 2.76
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    12. Secondary Outcome
    Title Change From Baseline in Patient's Assessment of Pain at Week 12
    Description Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale (VAS) from 0 to 100. A score of 0 indicates "no pain" and a score of 100 indicates "worst possible pain." A negative change from Baseline indicates improvement.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 616 307 614
    Least Squares Mean (95% Confidence Interval) [mm]
    -15.46
    -25.31
    -31.76
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for US/FDA only.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -6.45
    Confidence Interval (2-Sided) 95%
    -9.63 to -3.27
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Adalimumab
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Mixed Effect Model Repeat Measurement
    Comments MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -16.30
    Confidence Interval (2-Sided) 95%
    -18.89 to -13.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments Treatment Difference = Upadacitinib - Placebo
    13. Secondary Outcome
    Title Percentage of Participants With No Radiographic Progression at Week 26
    Description No radiographic progression is defined as a change from Baseline in mTSS ≤ 0. The mTSS measures the level of joint damage from radiographs of the hands and feet, which were assessed by 2 independent, blinded readers. mTSS is calculated as the sum of the total joint erosion score and total joint space narrowing (JSN) score and ranges from 0 (normal) to 448 (worst). 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).
    Time Frame Baseline and Week 26

    Outcome Measure Data

    Analysis Population Description
    Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 26 or who were rescued prior to Week 26.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 599 296 593
    Number (95% Confidence Interval) [percentage of participants]
    76.0
    11.7%
    86.8
    26.5%
    83.5
    12.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked key secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was a ranked key secondary endpoint in the pre-specified multiplicity testing sequence for EU/EMA only.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 7.5
    Confidence Interval (2-Sided) 95%
    3.0 to 12.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.187
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use.
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value -3.4
    Confidence Interval (2-Sided) 95%
    -8.2 to 1.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab
    14. Secondary Outcome
    Title Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12
    Description Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.
    Arm/Group Title Placebo Adalimumab Upadacitinib
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in tender joint count (TJC) and swollen joint count (SJC) at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow.
    Measure Participants 651 327 651
    Number (95% Confidence Interval) [percentage of participants]
    4.9
    0.8%
    13.5
    4.1%
    24.9
    3.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 20.0
    Confidence Interval (2-Sided) 95%
    16.3 to 23.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Adalimumab, Upadacitinib
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments This comparison was not part of the pre-specified multiplicity testing sequence.
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use
    Method of Estimation Estimation Parameter Response Rate Difference
    Estimated Value 11.4
    Confidence Interval (2-Sided) 95%
    6.5 to 16.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Response Rate Difference = Upadacitinib - Adalimumab

    Adverse Events

    Time Frame From first dose of study drug up to Week 26, or up to 30 days after last dose for those receiving placebo or upadacitinib who discontinued prior to Week 26, or up to 70 days after last dose for those receiving adalimumab who discontinued prior to Week 26.
    Adverse Event Reporting Description One participant randomized to upadacitinib received placebo to adalimumab but did not receive upadacitinib and is counted in the placebo group for analyses of safety. One participant who switched from placebo to upadacitinib at Week 18 did not receive any upadacitinib and is therefore not counted in the placebo / upadacitinib treatment group.
    Arm/Group Title Placebo Adalimumab Upadacitinib Placebo / Upadacitinib Adalimumab / Upadacitinib Upadacitinib / Adalimumab
    Arm/Group Description Participants received placebo to upadacitinib orally once daily (QD) and placebo to adalimumab by subcutaneous injection once every two weeks (eow) for up to 26 weeks. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Includes events up to the time of rescue (at Weeks 14, 18, 22) or up to Week 26 for those who were not rescued. Participants received placebo to upadacitinib orally QD and 40 mg adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 15 mg upadacitinib orally QD. Includes events up to the time of rescue (at Weeks 14, 18, 22) or up to Week 26 for those who were not rescued. Participants randomized to receive 15 mg upadacitinib orally QD and placebo to adalimumab by subcutaneous injection eow for up to 48 weeks in Period 1. Participants who did not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to Baseline were switched to 40 mg adalimumab eow. Includes events up to the time of rescue (at Weeks 14, 18, 22) or up to Week 26 for those who were not rescued. Participants who originally received placebo were switched at Weeks 14, 18, or 22 to receive 15 mg upadacitinib orally QD. Includes all events that occurred after the switch to rescue treatment up to Week 26. Participants who originally received adalimumab were switched at Weeks 14, 18, or 22 to receive 15 mg upadacitinib orally QD. Includes all events that occurred after the switch to rescue treatment up to Week 26. Participants who originally received 15 mg upadacitinib QD were switched at Weeks 14, 18, or 22 to receive 40 mg adalimumab eow. Includes all events that occurred after the switch to rescue treatment up to Week 26.
    All Cause Mortality
    Placebo Adalimumab Upadacitinib Placebo / Upadacitinib Adalimumab / Upadacitinib Upadacitinib / Adalimumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/652 (0.3%) 2/327 (0.6%) 0/650 (0%) 0/304 (0%) 0/77 (0%) 0/125 (0%)
    Serious Adverse Events
    Placebo Adalimumab Upadacitinib Placebo / Upadacitinib Adalimumab / Upadacitinib Upadacitinib / Adalimumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 19/652 (2.9%) 14/327 (4.3%) 24/650 (3.7%) 7/304 (2.3%) 0/77 (0%) 2/125 (1.6%)
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION 0/652 (0%) 0 0/327 (0%) 0 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    ATRIAL FLUTTER 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    CARDIAC FAILURE 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    CARDIOGENIC SHOCK 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    LEFT VENTRICULAR FAILURE 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    MYOCARDIAL INFARCTION 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    RIGHT VENTRICULAR DILATATION 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Eye disorders
    CATARACT 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Gastrointestinal disorders
    DIARRHOEA 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 2 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    FOOD POISONING 0/652 (0%) 0 0/327 (0%) 0 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    GASTRIC POLYPS 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    General disorders
    PYREXIA 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    SUDDEN DEATH 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Hepatobiliary disorders
    CHOLELITHIASIS 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    HEPATITIS TOXIC 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Infections and infestations
    APPENDICITIS 0/652 (0%) 0 0/327 (0%) 0 2/650 (0.3%) 2 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    BRONCHIOLITIS 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    BRONCHITIS BACTERIAL 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    CELLULITIS 0/652 (0%) 0 2/327 (0.6%) 2 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    FALLOPIAN TUBE ABSCESS 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    GASTROENTERITIS 3/652 (0.5%) 3 0/327 (0%) 0 2/650 (0.3%) 2 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    INFECTED BITE 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    INFECTIOUS COLITIS 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    INFLUENZA 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    KIDNEY INFECTION 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    LOWER RESPIRATORY TRACT INFECTION 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    LUNG INFECTION 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    PERITONITIS 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA 2/652 (0.3%) 2 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    PNEUMONIA 0/652 (0%) 0 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 1/125 (0.8%) 1
    PYELONEPHRITIS ACUTE 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    SEPSIS 1/652 (0.2%) 1 1/327 (0.3%) 1 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    SOFT TISSUE INFECTION 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    UROSEPSIS 0/652 (0%) 0 1/327 (0.3%) 1 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    VIRAL INFECTION 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Injury, poisoning and procedural complications
    AIRWAY COMPLICATION OF ANAESTHESIA 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    CRANIOCEREBRAL INJURY 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    FALL 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    FIBULA FRACTURE 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    HEAD INJURY 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    HIP FRACTURE 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    SPINAL COMPRESSION FRACTURE 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    TIBIA FRACTURE 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    TOXICITY TO VARIOUS AGENTS 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    UPPER LIMB FRACTURE 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Musculoskeletal and connective tissue disorders
    ARTHRITIS 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    LUMBAR SPINAL STENOSIS 1/652 (0.2%) 1 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    NECK PAIN 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    OSTEOARTHRITIS 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    RHEUMATOID ARTHRITIS 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    VERTEBRAL LESION 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    CERVIX CARCINOMA 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Nervous system disorders
    DEMYELINATION 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    DIZZINESS 0/652 (0%) 0 0/327 (0%) 0 0/650 (0%) 0 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    NEUROTOXICITY 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    PARAPLEGIA 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    SEIZURE 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 1/304 (0.3%) 1 0/77 (0%) 0 0/125 (0%) 0
    SPINAL CORD HAEMORRHAGE 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    SYNCOPE 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    ABORTION SPONTANEOUS 0/652 (0%) 0 0/327 (0%) 0 2/650 (0.3%) 2 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Psychiatric disorders
    CONFUSIONAL STATE 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Renal and urinary disorders
    BLADDER PROLAPSE 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    RENAL FAILURE 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Reproductive system and breast disorders
    ENDOMETRIAL HYPERPLASIA 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    MENORRHAGIA 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    OVARIAN CYST RUPTURED 1/652 (0.2%) 1 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    VAGINAL HAEMORRHAGE 0/652 (0%) 0 0/327 (0%) 0 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 1/125 (0.8%) 1
    Respiratory, thoracic and mediastinal disorders
    ASTHMA 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    BRONCHOSPASM 0/652 (0%) 0 0/327 (0%) 0 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    IDIOPATHIC PULMONARY FIBROSIS 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    PULMONARY EMBOLISM 1/652 (0.2%) 1 3/327 (0.9%) 3 1/650 (0.2%) 1 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    PULMONARY FIBROSIS 0/652 (0%) 0 1/327 (0.3%) 1 0/650 (0%) 0 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    Other (Not Including Serious) Adverse Events
    Placebo Adalimumab Upadacitinib Placebo / Upadacitinib Adalimumab / Upadacitinib Upadacitinib / Adalimumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 43/652 (6.6%) 16/327 (4.9%) 72/650 (11.1%) 9/304 (3%) 6/77 (7.8%) 4/125 (3.2%)
    Infections and infestations
    NASOPHARYNGITIS 19/652 (2.9%) 20 9/327 (2.8%) 10 36/650 (5.5%) 42 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    UPPER RESPIRATORY TRACT INFECTION 24/652 (3.7%) 24 7/327 (2.1%) 8 37/650 (5.7%) 43 0/304 (0%) 0 0/77 (0%) 0 0/125 (0%) 0
    URINARY TRACT INFECTION 0/652 (0%) 0 0/327 (0%) 0 0/650 (0%) 0 9/304 (3%) 9 6/77 (7.8%) 6 4/125 (3.2%) 4

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.

    Results Point of Contact

    Name/Title Global Medical Services
    Organization AbbVie
    Phone 800-633-9110
    Email abbvieclinicaltrials@abbvie.com
    Responsible Party:
    AbbVie
    ClinicalTrials.gov Identifier:
    NCT02629159
    Other Study ID Numbers:
    • M14-465
    • 2015-003333-95
    First Posted:
    Dec 14, 2015
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022