Rheumatoid Arthritis
Conditions
Brief summary
The purpose of this study is to determine if abatacept is effective in the treatment of early rheumatoid arthritis.
Detailed description
Subcutaneous (SC)
Interventions
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Rheumatoid arthritis (RA) diagnosis less than 6 months * CRP \> 3 mg/L or Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/h * At least 3 swollen and 3 tender joints * Anti-citrullinated protein antibodies (ACPA) positive
Exclusion criteria
* At risk for tuberculosis * Have acute infection * Have chronic or recurrent bacterial or serious latent viral infection * History of malignancies in the last 5 years except squamous skin, basal skin or cervical carcinoma * Previous treatment with any conventional or biologic Disease-modifying anti rheumatic drugs (DMARD)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Simple Disease Activity Index (SDAI) Remission at Week 24 | Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Disease Activity Score (DAS)28 - C-reactive Protein (CRP) Remission at Week 24 | Week 24 | 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. |
| Percentage of Participants in SDAI Remission at Week 52 | Week 52 | 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. |
| 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 | Week 52 | 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. |
| Percentage of Participants in Boolean Remission at Week 52 | Week 52 | 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. |
Countries
Argentina, Australia, Austria, Brazil, Canada, Chile, Colombia, Czechia, Finland, France, Germany, Hungary, Israel, Italy, Japan, Mexico, Monaco, Netherlands, Peru, Poland, Qatar, Romania, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
994 treated in the induction period (IP). 184 from IP randomized and treated in De-Escalation (DeE), 685 treated in the Open Label (OL) and 120 treated in the Open Label Extension (OLE) period. Participants in IP could move to the OL period after IP completion or through early IP escape. Participants from DeE could transfer to OL through early escape or to OLE after completing DeE.
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week | 451 |
| Placebo + Methotrexate (Cohort 1, IP) Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week | 301 |
| Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP) Active abatacept SC (125 mg) weekly + methotrexate weekly | 242 |
| Total | 994 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 18 | 8 | 14 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 11 | 35 | 9 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 6 | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | No Longer Meets Study Criteria | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Not Disclosed | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Poor/Non-Compliance | 3 | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Subject Request to Discontinue | 11 | 3 | 6 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal of Consent | 11 | 10 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) | Placebo + Methotrexate (Cohort 1, IP) | Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP) | Total |
|---|---|---|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 12.74 | 48.8 years STANDARD_DEVIATION 13.99 | 50.0 years STANDARD_DEVIATION 12.91 | 49.1 years STANDARD_DEVIATION 13.17 |
| C-Reactive Protein (CRP) | 1.998 mg/dL STANDARD_DEVIATION 2.7062 | 1.904 mg/dL STANDARD_DEVIATION 2.1956 | — | 1.960 mg/dL STANDARD_DEVIATION 2.5129 |
| DAS28-CRP | 5.56 Scores on a scale STANDARD_DEVIATION 1.062 | 5.61 Scores on a scale STANDARD_DEVIATION 1.032 | — | 5.58 Scores on a scale STANDARD_DEVIATION 1.049 |
| MODIFIED SHARP/VAN DER HEIJDE TOTAL SCORE (mTSS) | 9.82 Scores on a scale STANDARD_DEVIATION 16.342 | 12.99 Scores on a scale STANDARD_DEVIATION 19.769 | — | 11.08 Scores on a scale STANDARD_DEVIATION 17.839 |
| Physician global assessment of disease activity | 65.1 mm STANDARD_DEVIATION 18.48 | 66.1 mm STANDARD_DEVIATION 19.75 | — | 65.5 mm STANDARD_DEVIATION 18.99 |
| Race/Ethnicity, Customized AMERICAN INDIAN/ALASKA NATIVE | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized ASIAN | 77 Participants | 52 Participants | 11 Participants | 140 Participants |
| Race/Ethnicity, Customized BLACK/AFRICAN AMERICAN | 20 Participants | 16 Participants | 7 Participants | 43 Participants |
| Race/Ethnicity, Customized ETHNICITY - NOT REPORTED | 400 Participants | 259 Participants | 201 Participants | 860 Participants |
| Race/Ethnicity, Customized HISPANIC OR LATINO | 8 Participants | 5 Participants | 9 Participants | 22 Participants |
| Race/Ethnicity, Customized NOT HISPANIC OR LATINO | 43 Participants | 37 Participants | 32 Participants | 112 Participants |
| Race/Ethnicity, Customized RACE - OTHER/ NOT REPORTED | 39 Participants | 21 Participants | 49 Participants | 109 Participants |
| Race/Ethnicity, Customized WHITE | 315 Participants | 209 Participants | 174 Participants | 698 Participants |
| SDAI | 38.24 Scores on a scale STANDARD_DEVIATION 14.084 | 39.36 Scores on a scale STANDARD_DEVIATION 13.77 | — | 38.69 Scores on a scale STANDARD_DEVIATION 13.961 |
| Sex: Female, Male Female | 349 Participants | 243 Participants | 189 Participants | 781 Participants |
| Sex: Female, Male Male | 102 Participants | 58 Participants | 53 Participants | 213 Participants |
| Subject global assessment of disease activity | 65.7 mm STANDARD_DEVIATION 22.7 | 62.7 mm STANDARD_DEVIATION 24.05 | — | 64.5 mm STANDARD_DEVIATION 23.28 |
| Swollen Joints - 28 | 10.0 Joint Count STANDARD_DEVIATION 5.71 | 10.7 Joint Count STANDARD_DEVIATION 5.85 | — | 10.3 Joint Count STANDARD_DEVIATION 5.77 |
| Tender Joints - 28 | 13.2 Joint Count STANDARD_DEVIATION 6.76 | 13.7 Joint Count STANDARD_DEVIATION 6.77 | — | 13.4 Joint Count STANDARD_DEVIATION 6.76 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 451 | 1 / 301 | 0 / 242 | 0 / 50 | 1 / 50 | 0 / 47 | 0 / 37 | 1 / 685 | 0 / 120 |
| other Total, other adverse events | 237 / 451 | 152 / 301 | 123 / 242 | 12 / 50 | 22 / 50 | 10 / 47 | 16 / 37 | 230 / 685 | 15 / 120 |
| serious Total, serious adverse events | 32 / 451 | 9 / 301 | 23 / 242 | 3 / 50 | 3 / 50 | 0 / 47 | 0 / 37 | 40 / 685 | 0 / 120 |
Outcome results
Primary
Percentage of Participants in Simple Disease Activity Index (SDAI) Remission at Week 24
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) | Percentage of Participants in Simple Disease Activity Index (SDAI) Remission at Week 24 | 21.3 Percentage of participants |
| Placebo + Methotrexate (Cohort 1, IP) | Percentage of Participants in Simple Disease Activity Index (SDAI) Remission at Week 24 | 16.0 Percentage of participants |
p-value: 0.2359Regression, Logistic
Secondary
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
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
Population: Cohort 1 analysis population included all randomized and treated subjects in the Induction Period. Intention to treat analysis. Linear extrapolation imputation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) | 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 | 0.53 Total Sharp Score | Standard Deviation 2.279 |
| Placebo + Methotrexate (Cohort 1, IP) | 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 | 2.52 Total Sharp Score | Standard Deviation 6.205 |
p-value: <0.0001rank-based ANCOVA
Secondary
Percentage of Participants in Boolean Remission at Week 52
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
Population: Cohort 1 analysis population included all randomized and treated subjects in the Induction Period. Intention to treat analysis. Non-Responder imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) | Percentage of Participants in Boolean Remission at Week 52 | 21.5 Percentage of participants |
| Placebo + Methotrexate (Cohort 1, IP) | Percentage of Participants in Boolean Remission at Week 52 | 11.6 Percentage of participants |
p-value: 0.0006Regression, Logistic
Secondary
Percentage of Participants in Disease Activity Score (DAS)28 - C-reactive Protein (CRP) Remission at Week 24
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) | Percentage of Participants in Disease Activity Score (DAS)28 - C-reactive Protein (CRP) Remission at Week 24 | 38.7 Percentage of Participants |
| Placebo + Methotrexate (Cohort 1, IP) | Percentage of Participants in Disease Activity Score (DAS)28 - C-reactive Protein (CRP) Remission at Week 24 | 25.3 Percentage of Participants |
p-value: 0.0112Regression, Logistic
Secondary
Percentage of Participants in SDAI Remission at Week 52
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) | Percentage of Participants in SDAI Remission at Week 52 | 29.8 Percentage of participants |
| Placebo + Methotrexate (Cohort 1, IP) | Percentage of Participants in SDAI Remission at Week 52 | 15.3 Percentage of participants |
p-value: 0.0021Regression, Logistic