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A Phase 3 Study to Compare Upadacitinib to Abatacept in Subjects With Rheumatoid Arthritis on Stable Dose of Conventional Synthetic Disease- Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response or Intolerance to Biologic DMARDs

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ClinicalTrials.gov Identifier: NCT03086343
Recruitment Status : Active, not recruiting
First Posted : March 22, 2017
Results First Posted : June 4, 2020
Last Update Posted : August 2, 2021
Sponsor:
Information provided by (Responsible Party):
AbbVie

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis (RA)
Interventions Drug: Abatacept
Drug: Placebo for abatacept
Drug: Upadacitinib
Drug: Placebo for upadacitinib
Enrollment 613
Recruitment Details The study had a 24-week, randomized, double-blind, parallel-group, active-controlled period (Period 1) and an ongoing open-label long-term extension study (Period 2). Results from Period 1 are reported.
Pre-assignment Details Full Analysis Set: all randomized participants who received at least one dose of study drug during Period 1; one participant who was a screen failure was randomized in error and did not receive study drug.
Arm/Group Title Abatacept Upadacitinib 15 mg
Hide Arm/Group Description 500 mg (for body weight <60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight >100 kg) intravenous (IV) infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20 One 15 mg tablet taken once per day by mouth for 24 weeks
Period Title: Overall Study
Started 309 303
Completed 277 278
Not Completed 32 25
Reason Not Completed
Adverse Event             7             7
Withdrawal by Subject             10             6
Lost to Follow-up             3             1
Lack of Efficacy             4             6
Other, not specified             8             4
Missing             0             1
Arm/Group Title Abatacept Upadacitinib 15 mg Total
Hide Arm/Group Description 500 mg (for body weight <60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight >100 kg) intravenous (IV) infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20 One 15 mg tablet taken once per day by mouth for 24 weeks Total of all reporting groups
Overall Number of Baseline Participants 309 303 612
Hide Baseline Analysis Population Description
Full Analysis Set: all randomized participants who received at least one dose of study drug during Period 1
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 309 participants 303 participants 612 participants
55.8  (11.91) 55.3  (11.44) 55.6  (11.67)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 309 participants 303 participants 612 participants
Female 253 249 502
Male 56 54 110
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
White Number Analyzed 309 participants 303 participants 612 participants
285 288 573
Black or African American Number Analyzed 309 participants 303 participants 612 participants
14 7 21
American Indian or Alaska Native Number Analyzed 309 participants 303 participants 612 participants
2 1 3
Native Hawaiian or other Pacific Islander Number Analyzed 309 participants 303 participants 612 participants
0 0 0
Asian Number Analyzed 309 participants 303 participants 612 participants
6 5 11
Multiple Number Analyzed 309 participants 303 participants 612 participants
2 2 4
Other Number Analyzed 309 participants 303 participants 612 participants
0 0 0
Geographic Region  
Measure Type: Count of Participants
Unit of measure:  Participants
North America Number Analyzed 309 participants 303 participants 612 participants
73 72 145
South/Central America Number Analyzed 309 participants 303 participants 612 participants
99 98 197
Western Europe Number Analyzed 309 participants 303 participants 612 participants
45 43 88
Eastern Europe Number Analyzed 309 participants 303 participants 612 participants
77 77 154
Asia Number Analyzed 309 participants 303 participants 612 participants
4 4 8
Other Number Analyzed 309 participants 303 participants 612 participants
11 9 20
Duration of Rheumatoid Arthritis Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 309 participants 303 participants 612 participants
11.8  (8.26) 12.4  (9.49) 12.1  (8.89)
Concomitant conventional synthetic disease-modifying antirheumatic drug (csDMARD) at Baseline  
Measure Type: Count of Participants
Unit of measure:  Participants
Methotrexate alone Number Analyzed 309 participants 303 participants 612 participants
215 223 438
Methotrexate and other csDMARD Number Analyzed 309 participants 303 participants 612 participants
38 30 68
csDMARD other than methotrexate Number Analyzed 309 participants 303 participants 612 participants
56 45 101
Missing Number Analyzed 309 participants 303 participants 612 participants
0 5 5
Number of prior biologic disease-modifying anti-rheumatic drugs (bMARD) received  
Measure Type: Count of Participants
Unit of measure:  Participants
1 Number Analyzed 309 participants 303 participants 612 participants
202 206 408
2 Number Analyzed 309 participants 303 participants 612 participants
70 64 134
≥3 Number Analyzed 309 participants 303 participants 612 participants
35 29 64
Missing Number Analyzed 309 participants 303 participants 612 participants
2 4 6
Prior failed biologic disease-modifying anti-rheumatic drug (bDMARD)  
Measure Type: Count of Participants
Unit of measure:  Participants
1 mechanism of action and ≤2 prior bDMARDs Number Analyzed 309 participants 303 participants 612 participants
256 252 508
Other Number Analyzed 309 participants 303 participants 612 participants
51 47 98
Missing Number Analyzed 309 participants 303 participants 612 participants
2 4 6
Tender Joint Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Tender joints
Number Analyzed 309 participants 303 participants 612 participants
25.3  (13.68) 23.9  (13.77) 24.6  (13.73)
[1]
Measure Description: A total of 68 joints were assessed for the presence or absence of tenderness.
Swollen Joint Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Swollen joints
Number Analyzed 309 participants 303 participants 612 participants
14.8  (7.65) 14.2  (7.60) 14.5  (7.63)
[1]
Measure Description: A total of 66 joints were assessed for the presence or absence of swelling.
Disease Activity Score Based on CRP (DAS28 [CRP]) baseline   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 308 participants 303 participants 611 participants
5.9  (0.94) 5.7  (0.90) 5.8  (0.92)
[1]
Measure Description: The DAS28 (CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28 score > 5.1 indicates high disease activity, a DAS28 score ≤ 3.2 indicates low disease activity, and a DAS28 score < 2.6 indicates clinical remission.
[2]
Measure Analysis Population Description: Participants with available data
High-sensitivity C-reactive protein (hsCRP)  
Mean (Standard Deviation)
Unit of measure:  mg/L
Number Analyzed 309 participants 303 participants 612 participants
17.4  (21.12) 16.0  (18.48) 16.7  (19.85)
Clinical Disease Activity Index (CDAI)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 290 participants 298 participants 588 participants
40.7  (12.05) 38.5  (11.37) 39.6  (11.75)
[1]
Measure Description: 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.
[2]
Measure Analysis Population Description: Participants with available data
Health Assessment Questionnaire - Disability Index (HAQ-DI)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 308 participants 303 participants 611 participants
1.7  (0.61) 1.7  (0.61) 1.7  (0.61)
[1]
Measure Description: The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability.
[2]
Measure Analysis Population Description: Participants with available data
Rheumatoid Factor (RF) status  
Measure Type: Count of Participants
Unit of measure:  Participants
Positive Number Analyzed 309 participants 303 participants 612 participants
219 210 429
Negative Number Analyzed 309 participants 303 participants 612 participants
90 93 183
Anti-cyclic citrullinated peptide (anti-CCP) status  
Measure Type: Count of Participants
Unit of measure:  Participants
Positive Number Analyzed 309 participants 303 participants 612 participants
232 221 453
Negative Number Analyzed 309 participants 303 participants 612 participants
76 80 156
Missing Number Analyzed 309 participants 303 participants 612 participants
1 2 3
1.Primary Outcome
Title Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Non-inferiority)
Hide Description The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (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 indicates improvement in disease activity.
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: all randomized participants who received at least one dose of study drug; multiple imputation was used for missing data
Arm/Group Title Abatacept Upadacitinib 15 mg
Hide Arm/Group Description:
500 mg (for body weight <60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight >100 kg) intravenous (IV) infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20
One 15 mg tablet taken once per day by mouth for 24 weeks
Overall Number of Participants Analyzed 309 303
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.00
(-2.14 to -1.85)
-2.52
(-2.66 to -2.37)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Abatacept, Upadacitinib 15 mg
Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked 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.
Type of Statistical Test Non-Inferiority
Comments The non-inferiority of upadacitinib 15 mg versus abatacept was tested using the 95% confidence interval (CI) of treatment difference against a non-inferiority margin of 0.6.
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model included treatment as the fixed factor; corresponding baseline value and the stratification factor of prior bDMARD used as covariates
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.52
Confidence Interval (2-Sided) 95%
-0.69 to -0.35
Estimation Comments Treatment Difference = Upadacitinib 15 mg - Abatacept
2.Secondary Outcome
Title Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)
Hide Description The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (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 indicates improvement in disease activity.
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Abatacept Upadacitinib 15 mg
Hide Arm/Group Description:
500 mg (for body weight <60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight >100 kg) intravenous (IV) infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20
One 15 mg tablet taken once per day by mouth for 24 weeks
Overall Number of Participants Analyzed 309 303
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.00
(-2.14 to -1.85)
-2.52
(-2.66 to -2.37)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Abatacept, Upadacitinib 15 mg
Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments This comparison was a ranked secondary endpoint in the pre-specified multiplicity testing sequence.
Method ANCOVA
Comments The ANCOVA model included treatment as the fixed factor; corresponding baseline value and the stratification factor of prior bDMARD used as covariates
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.52
Confidence Interval (2-Sided) 95%
-0.69 to -0.35
Estimation Comments Treatment Difference = Upadacitinib 15 mg - Abatacept
3.Secondary Outcome
Title Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)
Hide Description The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS 28 score less than 2.6 indicates clinical remission.
Time Frame At Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: all randomized participants who received at least one dose of study drug; participants who prematurely discontinued study drug were considered non-responders after discontinuation
Arm/Group Title Abatacept Upadacitinib 15 mg
Hide Arm/Group Description:
500 mg (for body weight <60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight >100 kg) intravenous (IV) infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20
One 15 mg tablet taken once per day by mouth for 24 weeks
Overall Number of Participants Analyzed 309 303
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
13.3
(9.5 to 17.1)
30.0
(24.9 to 35.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Abatacept, Upadacitinib 15 mg
Comments In order to preserve Type I error, a step-down approach was used to test the primary and ranked 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments This comparison was a ranked secondary endpoint in the pre-specified multiplicity testing sequence.
Method Cochran-Mantel-Haenszel
Comments The stratification factor of prior failed bDMARD was used.
Method of Estimation Estimation Parameter Mean Difference
Estimated Value 16.8
Confidence Interval (2-Sided) 95%
10.4 to 23.2
Estimation Comments Treatment Difference = Upadacitinib 15 mg - Abatacept
Time Frame Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) in Period 1 were collected from the first dose of study drug until 70 days after the last dose of study drug, up to 34 weeks.
Adverse Event Reporting Description TEAEs and SAEs are defined as any adverse event (AE) with an onset date that is on or after the first dose of study drug in Period 1 until 70 days after the last dose of study drug and were collected whether elicited or spontaneously reported by the participant.
 
Arm/Group Title Abatacept Upadacitinib 15 mg
Hide Arm/Group Description 500 mg (for body weight <60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight >100 kg) intravenous (IV) infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20 One 15 mg tablet taken once per day by mouth for 24 weeks
All-Cause Mortality
Abatacept Upadacitinib 15 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   1/309 (0.32%)      2/303 (0.66%)    
Hide Serious Adverse Events
Abatacept Upadacitinib 15 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/309 (1.62%)      10/303 (3.30%)    
Cardiac disorders     
ATRIOVENTRICULAR BLOCK COMPLETE  1  0/309 (0.00%)  0 1/303 (0.33%)  1
CARDIO-RESPIRATORY ARREST  1  0/309 (0.00%)  0 1/303 (0.33%)  2
Gastrointestinal disorders     
HAEMORRHOIDS  1  0/309 (0.00%)  0 1/303 (0.33%)  1
Infections and infestations     
ARTHRITIS BACTERIAL  1  0/309 (0.00%)  0 1/303 (0.33%)  1
PNEUMONIA  1  1/309 (0.32%)  1 1/303 (0.33%)  1
PYELONEPHRITIS  1  0/309 (0.00%)  0 1/303 (0.33%)  1
SEPSIS  1  1/309 (0.32%)  1 0/303 (0.00%)  0
Injury, poisoning and procedural complications     
PELVIC FRACTURE  1  0/309 (0.00%)  0 1/303 (0.33%)  1
SPINAL COMPRESSION FRACTURE  1  1/309 (0.32%)  1 0/303 (0.00%)  0
Metabolism and nutrition disorders     
DEHYDRATION  1  0/309 (0.00%)  0 1/303 (0.33%)  1
Musculoskeletal and connective tissue disorders     
OSTEOARTHRITIS  1  1/309 (0.32%)  1 0/303 (0.00%)  0
Nervous system disorders     
MOTOR NEURONE DISEASE  1  0/309 (0.00%)  0 1/303 (0.33%)  1
SYNCOPE  1  1/309 (0.32%)  1 0/303 (0.00%)  0
Pregnancy, puerperium and perinatal conditions     
ABORTION SPONTANEOUS  1  0/309 (0.00%)  0 1/303 (0.33%)  1
Respiratory, thoracic and mediastinal disorders     
EPISTAXIS  1  0/309 (0.00%)  0 1/303 (0.33%)  1
PLEURAL EFFUSION  1  0/309 (0.00%)  0 1/303 (0.33%)  1
PULMONARY EMBOLISM  1  0/309 (0.00%)  0 1/303 (0.33%)  1
UPPER-AIRWAY COUGH SYNDROME  1  1/309 (0.32%)  1 0/303 (0.00%)  0
Vascular disorders     
HYPERTENSION  1  0/309 (0.00%)  0 1/303 (0.33%)  1
1
Term from vocabulary, MedDRA 22.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Abatacept Upadacitinib 15 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   54/309 (17.48%)      74/303 (24.42%)    
Infections and infestations     
NASOPHARYNGITIS  1  14/309 (4.53%)  15 22/303 (7.26%)  22
UPPER RESPIRATORY TRACT INFECTION  1  15/309 (4.85%)  18 26/303 (8.58%)  31
URINARY TRACT INFECTION  1  20/309 (6.47%)  26 20/303 (6.60%)  27
Vascular disorders     
HYPERTENSION  1  10/309 (3.24%)  10 16/303 (5.28%)  16
1
Term from vocabulary, MedDRA 22.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Global Medical Services
Organization: AbbVie
Phone: 800-633-9110
EMail: abbvieclinicaltrials@abbvie.com
Layout table for additonal information
Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT03086343    
Other Study ID Numbers: M15-925
2016-000933-37 ( EudraCT Number )
First Submitted: March 20, 2017
First Posted: March 22, 2017
Results First Submitted: May 8, 2020
Results First Posted: June 4, 2020
Last Update Posted: August 2, 2021