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Effects of Abatacept in Patients With Early Rheumatoid Arthritis (AVERT-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02504268
Recruitment Status : Active, not recruiting
First Posted : July 21, 2015
Results First Posted : April 8, 2019
Last Update Posted : September 6, 2019
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

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
Interventions Drug: Abatacept
Drug: Methotrexate
Other: Abatacept Placebo
Other: Methotrexate Placebo
Enrollment 1067
Recruitment Details  
Pre-assignment Details 1067 participants were enrolled, 753 were randomized. Of the 753 randomized, 1 participant was randomized but not treated. Full cohort 1 analysis population which is the primary endpoint analysis population includes 752 participants
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Period Title: Overall Study
Started 451 301
Completed [1] 388 233
Not Completed 63 68
Reason Not Completed
Adverse Event             18             8
Withdrawal of Consent             11             10
Pregnancy             2             0
Lost to Follow-up             3             6
Death             1             1
Subject Request to Discontinue             11             3
No Longer Meets Study Criteria             2             3
Lack of Efficacy             11             35
Poor/Non-Compliance             3             2
Not Disclosed             1             0
[1]
Completed = Completed Induction Period
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate Total
Hide Arm/Group Description Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week Total of all reporting groups
Overall Number of Baseline Participants 451 301 752
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 451 participants 301 participants 752 participants
48.9  (12.74) 48.8  (13.99) 48.8  (13.25)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 451 participants 301 participants 752 participants
Female
349
  77.4%
243
  80.7%
592
  78.7%
Male
102
  22.6%
58
  19.3%
160
  21.3%
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
WHITE Number Analyzed 451 participants 301 participants 752 participants
315 209 524
BLACK/AFRICAN AMERICAN Number Analyzed 451 participants 301 participants 752 participants
20 16 36
AMERICAN INDIAN/ALASKA NATIVE Number Analyzed 451 participants 301 participants 752 participants
0 3 3
ASIAN Number Analyzed 451 participants 301 participants 752 participants
77 52 129
RACE - OTHER/ NOT REPORTED Number Analyzed 451 participants 301 participants 752 participants
39 21 60
HISPANIC OR LATINO Number Analyzed 451 participants 301 participants 752 participants
8 5 13
NOT HISPANIC OR LATINO Number Analyzed 451 participants 301 participants 752 participants
43 37 80
ETHNICITY - NOT REPORTED Number Analyzed 451 participants 301 participants 752 participants
400 259 659
[1]
Measure Analysis Population Description: Ethnicity data was collected for US Subjects only.
MODIFIED SHARP/VAN DER HEIJDE TOTAL SCORE (mTSS)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 442 participants 292 participants 734 participants
9.82  (16.342) 12.99  (19.769) 11.08  (17.839)
[1]
Measure Description: The Modified Total Sharp Score (mTSS) is calculated as the bilateral sum of erosion and Joint Space Narrowing (JSN) scores across all joints of the hands and feet.The score range for mTSS is 0-448. Higher scores indicate more joint damage.
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
Tender Joints - 28   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Joint Count
Number Analyzed 448 participants 298 participants 746 participants
13.2  (6.76) 13.7  (6.77) 13.4  (6.76)
[1]
Measure Description: number of painful joints from 28 joints
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
Swollen Joints - 28   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Joint Count
Number Analyzed 448 participants 298 participants 746 participants
10.0  (5.71) 10.7  (5.85) 10.3  (5.77)
[1]
Measure Description: number of swollen joints from 28 joints
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
Subject global assessment of disease activity   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 450 participants 301 participants 751 participants
65.7  (22.7) 62.7  (24.05) 64.5  (23.28)
[1]
Measure Description: Subject’s global assessment of disease activity by using a Visual Analog Scale (VAS). The scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
Physician global assessment of disease activity   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 446 participants 296 participants 742 participants
65.1  (18.48) 66.1  (19.75) 65.5  (18.99)
[1]
Measure Description: physician's global assessment of disease activity using a Visual Analog Scale (VAS). The scale ranges from 0 to 100 mm, [0=no arthritis activity to 100 =extremely active arthritis]
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
C-Reactive Protein (CRP)   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 450 participants 301 participants 751 participants
1.998  (2.7062) 1.904  (2.1956) 1.960  (2.5129)
[1]
Measure Analysis Population Description: Cohort 1 Analysis Population
DAS28-CRP   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 446 participants 298 participants 744 participants
5.56  (1.062) 5.61  (1.032) 5.58  (1.049)
[1]
Measure Description: The Disease Activity Score (DAS28-CRP) =0.56×sqrt(tender joints [count:1-28])+0.28×sqrt(swollen joints [count:1-28])+0.36×Ln(CRP level+1)+0.014×(patient’s disease assessment on 0-100 mm scale [100=most severe])+0.96. Range: 0.96 to no upper limit. Higher score=more severe disease.
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
SDAI   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 443 participants 294 participants 737 participants
38.24  (14.084) 39.36  (13.770) 38.69  (13.961)
[1]
Measure Description: Simple Disease Activity Index is the numerical sum of five outcome parameters: tender joint count and swollen joint count based on a 28-joint assessment, patient global assessment and physician global assessment assessed on a visual analogue scale scale (range 0 to 10 cm), and C-reactive protein measured in mg/dL. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI >26 = high disease activity.
[2]
Measure Analysis Population Description: Cohort 1 Analysis Population
1.Primary Outcome
Title Percentage of Subjects in Simple Disease Activity Index (SDAI) Remission at Week 24
Hide Description

Simple Disease Activity Index (SDAI) is calculated using the following formula: TJC + SJC + PGA + MDGA + CRP (TJC = number of painful joints from 28 joints, SJC = number of swollen joints from 28 joints, PGA = patient global assessment on a visual analog scale 0-10 cm, MDGA = physician global assessment on a visual analog scale 0-10 cm, and CRP = c-reactive protein in mg/dL) SDAI Remission is defined as SDAI <= 3.3.

Using a logistic regression model that includes treatment arm, randomization stratification factor, and baseline SDAI as continuous variable and point estimate of adjusted ORs, corresponding 95% CI and p-value was provided. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI >26 = high disease activity.

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis population included the first 50 Japanese and 325 rest of world (ROW) randomized and treated subjects in cohort 1 in the Induction Period. Intention to treat analysis. Non-Responder imputation.
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description:
Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Overall Number of Participants Analyzed 225 150
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Subjects
21.3
(16.0 to 26.7)
16.0
(10.1 to 21.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Abatacept + Methotrexate, Placebo + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2359
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Subjects in Disease Activity Score (DAS)28 - C-reactive Protein (CRP) Remission at Week 24
Hide Description DAS28-CRP = Disease Activity Score 28 based on C-reactive protein DAS28-CRP Remission is defined as DAS28-CRP <= 2.6 Using a logistic regression model that includes treatment arm, stratification variable and baseline measure as continuous variable and point estimate of adjusted ORs, corresponding 95% CI and p-value was provided.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis population included the first 50 Japanese and 325 rest of world (ROW) randomized and treated subjects in cohort 1 in the Induction Period. Intention to treat analysis. Non-Responder imputation.
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description:
Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Overall Number of Participants Analyzed 225 150
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Subjects
38.7
(32.3 to 45.0)
25.3
(18.4 to 32.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Abatacept + Methotrexate, Placebo + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0112
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Subjects in SDAI Remission at Week 52
Hide Description Simple Disease Activity Index (SDAI) is calculated using the following formula: TJC + SJC + PGA + MDGA + CRP (TJC = number of painful joints from 28 joints, SJC = number of swollen joints from 28 joints, PGA = patient global assessment on a visual analog scale 0-10 cm, MDGA = physician global assessment on a visual analog scale 0-10 cm, and CRP = c-reactive protein in mg/dL) SDAI Remission is defined as SDAI <= 3.3. Using a logistic regression model that includes treatment arm, randomization stratification factor, and baseline SDAI as continuous variable and point estimate of adjusted ORs, corresponding 95% CI and p-value was provided. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI >26 = high disease activity.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis population included the first 50 Japanese and 325 rest of world (ROW) randomized and treated subjects in cohort 1 in the Induction Period. Intention to treat analysis. Non-Responder imputation.
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description:
Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Overall Number of Participants Analyzed 225 150
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Subjects
29.8
(23.8 to 35.8)
15.3
(9.6 to 21.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Abatacept + Methotrexate, Placebo + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0021
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
4.Secondary Outcome
Title Mean Change From Baseline in Radiographic Progression of Joint Damage as Measured by Modified Sharp/Van Der Heijide Total Sharp Scores (TSS) at Week 52
Hide Description The Modified Total Sharp Score (mTSS) is calculated as the bilateral sum of erosion and Joint Space Narrowing (JSN) scores across all joints of the hands and feet.The score range for mTSS is 0-448. Higher scores indicate more joint damage. The mean change from baseline in TSS using modified Sharp/van der Heijide scores was assessed using a rank-based nonparametric ANCOVA model.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 analysis population included all randomized and treated subjects in the Induction Period. Intention to treat analysis. Linear extrapolation imputation.
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description:
Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Overall Number of Participants Analyzed 401 249
Mean (Standard Deviation)
Unit of Measure: Total Sharp Score
0.53  (2.279) 2.52  (6.205)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Abatacept + Methotrexate, Placebo + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method rank-based ANCOVA
Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Subjects in Boolean Remission at Week 52
Hide Description Boolean Remission is defined as Tender joint count less than 1, Swollen joint count less than 1, CRP less than 1 mg/dL, patient global assessment less than 1 (on 0 to 10 VAS scale). Logistic regression was used for this endpoint.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 analysis population included all randomized and treated subjects in the Induction Period. Intention to treat analysis. Non-Responder imputation.
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description:
Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
Overall Number of Participants Analyzed 451 301
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Subjects
21.5
(17.7 to 25.3)
11.6
(8.0 to 15.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination Therapy: Abatacept + Methotrexate, Placebo + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Time Frame From first dose to Week 52 (assessed from Sept 2015 to March 2018, approximately 30 months)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Hide Arm/Group Description Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week
All-Cause Mortality
Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Affected / at Risk (%) Affected / at Risk (%)
Total   1/451 (0.22%)   1/301 (0.33%) 
Show Serious Adverse Events Hide Serious Adverse Events
Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Affected / at Risk (%) Affected / at Risk (%)
Total   30/451 (6.65%)   8/301 (2.66%) 
Cardiac disorders     
Angina unstable  1  1/451 (0.22%)  0/301 (0.00%) 
Atrial fibrillation  1  1/451 (0.22%)  0/301 (0.00%) 
Cardiac arrest  1  1/451 (0.22%)  0/301 (0.00%) 
Cardiac failure congestive  1  0/451 (0.00%)  1/301 (0.33%) 
Eye disorders     
Cataract  1  1/451 (0.22%)  0/301 (0.00%) 
Gastrointestinal disorders     
Gastritis erosive  1  1/451 (0.22%)  0/301 (0.00%) 
Gastrooesophageal reflux disease  1  1/451 (0.22%)  0/301 (0.00%) 
Pancreatitis  1  1/451 (0.22%)  0/301 (0.00%) 
General disorders     
Chest pain  1  1/451 (0.22%)  0/301 (0.00%) 
Hepatobiliary disorders     
Cholecystitis acute  1  1/451 (0.22%)  0/301 (0.00%) 
Immune system disorders     
Anaphylactic reaction  1  1/451 (0.22%)  0/301 (0.00%) 
Infections and infestations     
Appendicitis  1  1/451 (0.22%)  0/301 (0.00%) 
Diverticulitis  1  0/451 (0.00%)  1/301 (0.33%) 
Gastroenteritis  1  1/451 (0.22%)  0/301 (0.00%) 
Pneumonia  1  2/451 (0.44%)  2/301 (0.66%) 
Pyelonephritis  1  0/451 (0.00%)  1/301 (0.33%) 
Urinary tract infection  1  2/451 (0.44%)  1/301 (0.33%) 
Injury, poisoning and procedural complications     
Laceration  1  1/451 (0.22%)  1/301 (0.33%) 
Overdose  1  2/451 (0.44%)  0/301 (0.00%) 
Subarachnoid haemorrhage  1  1/451 (0.22%)  0/301 (0.00%) 
Subdural haematoma  1  1/451 (0.22%)  0/301 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  1/451 (0.22%)  0/301 (0.00%) 
Intervertebral disc protrusion  1  2/451 (0.44%)  0/301 (0.00%) 
Osteoarthritis  1  1/451 (0.22%)  1/301 (0.33%) 
Rheumatoid arthritis  1  0/451 (0.00%)  1/301 (0.33%) 
Spinal pain  1  1/451 (0.22%)  0/301 (0.00%) 
Spondylolisthesis  1  1/451 (0.22%)  0/301 (0.00%) 
Synovial cyst  1  1/451 (0.22%)  0/301 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Carcinoid tumour of the gastrointestinal tract  1  1/451 (0.22%)  0/301 (0.00%) 
Pancreatic carcinoma  1  1/451 (0.22%)  0/301 (0.00%) 
Nervous system disorders     
Cerebrovascular accident  1  1/451 (0.22%)  0/301 (0.00%) 
Seizure  1  1/451 (0.22%)  0/301 (0.00%) 
Vascular disorders     
Hypotension  1  1/451 (0.22%)  0/301 (0.00%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Combination Therapy: Abatacept + Methotrexate Placebo + Methotrexate
Affected / at Risk (%) Affected / at Risk (%)
Total   192/451 (42.57%)   124/301 (41.20%) 
Blood and lymphatic system disorders     
Anaemia  1  10/451 (2.22%)  18/301 (5.98%) 
Gastrointestinal disorders     
Nausea  1  42/451 (9.31%)  24/301 (7.97%) 
Stomatitis  1  27/451 (5.99%)  8/301 (2.66%) 
Infections and infestations     
Nasopharyngitis  1  64/451 (14.19%)  43/301 (14.29%) 
Pharyngitis  1  22/451 (4.88%)  17/301 (5.65%) 
Upper respiratory tract infection  1  24/451 (5.32%)  16/301 (5.32%) 
Investigations     
Alanine aminotransferase increased  1  23/451 (5.10%)  15/301 (4.98%) 
Nervous system disorders     
Headache  1  31/451 (6.87%)  20/301 (6.64%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  15/451 (3.33%)  16/301 (5.32%) 
1
Term from vocabulary, MedDRA 20.1
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.
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
Phone: Please Email:
EMail: Clinical.Trials@bms.com
Layout table for additonal information
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT02504268     History of Changes
Other Study ID Numbers: IM101-550
2015-001275-50 ( EudraCT Number )
First Submitted: July 20, 2015
First Posted: July 21, 2015
Results First Submitted: January 16, 2019
Results First Posted: April 8, 2019
Last Update Posted: September 6, 2019