Rheumatoid Arthritis
Conditions
Brief summary
The primary purpose of this study is to identify an appropriate dose of study medication.
Interventions
DRUGClazakizumab
DRUGPlacebo (Matching with Clazakizumab)
Sponsors
CSL Behring
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: * Diagnosis of active Rheumatoid Arthritis (RA) by standard criteria (American Rheumatism association (ARA) \[1987\] or American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) \[2010\]) at least 16 weeks prior to screening * ACR global functional status class of 1 to 3 * Documented evidence of inadequate response tumor necrosis factor (TNF) inhibitors * All subjects must have been receiving treatment with a minimum dose of 15 mg per week of Methotrexate for at least 12 weeks and at a stable dose for 28 days prior to screening. A dose as low as 10 mg Methotrexate is permitted if 15 mg could not be reached, due to toxicity. In Japan, Korea and Taiwan, a minimum dose of 7.5 mg per week is permitted. Additional treatment with Hydroxychloroquine or Chloroquine is permitted, if it is at a dose approved for the treatment of RA and the dose has been stable for at least 28 days prior to screening * Minimum of 6 swollen and 6 tender joints on a 66/68 joint count at screening and at baseline (Day 1) * Elevated High-sensitivity (hs) CRP and/or ESR
Exclusion criteria
* Active serious infection * History of or active tuberculosis (TB) * Elevated liver function tests (LFTs)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Disease Activity Score in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12 | Baseline and Week 12 | DAS28-CRP describes severity of rheumatoid arthritis. The components of the joint count assessment are shoulder, elbow, wrist, metacarpophalangeal joints 1 through 5, proximal interphalangeal joints 1 through 5, and the knee joints on the right and left sides, whereby the number of affected joints, tender and swollen, respectively, are counted. The formula used to calculate the score is: DAS28-CRP=0.56 \\times \\sqrt{TEN28} + 0.28 \\times \\sqrt{SW28} + 0.36 \\times \\ln(CRP+1) + 0.014 \\times SA+0.96 with: TEN28: number of joints with tenderness upon touching SW28: number of swollen joints CRP: C-reactive Protein SA: subjective assessment of disease activity by the patient during the preceding 7 days on a scale between 0 and 100 (0:no activity, 100: highest activity possible). DAS-CRP score range is 0.49 to 9.07 A DAS-CRP value \>5.1 corresponds to a high disease activity A DAS-28 reduction by 0.6 represents a moderate improvement. A reduction \>1.2 represents a major improvement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | Baseline and week 12 | CDAI is a composite index for assessing disease activity. CDAI is based on the simple summation of the count of swollen joint count (SCJ) (0-28) and tender joint count (TJC) (0-28) along with patient global assessment (0-10) Scale and physician global assessment (0-10) for estimating disease activity where 10 means maximal activity. The CDAI has a range from 0 to 76. CDAI \<= 2.8 = Remission CDAI \> 2.8 and \<= 10 = Low Disease Activity CDAI \> 10 and \<= 22 = Moderate Disease Activity CDAI \> 22 = High Disease Activity |
| Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 | Baseline and week 12 | SDAI is a composite index for assessing disease activity. CDAI is based on the simple summation of the count of swollen joint count (0-28) and tender joint count (0-28) along with patient global assessment (0-10) Scale and physician global assessment (0-10) for estimating disease activity where 10 means maximal activity and C-reactive protein (0-10). The SDAI has a range from 0 to 86. 0.0 - 3.3 = Remission 3.4 - 11.0 = Low Activity 11.1 - 26.0 = Moderate Activity 26.1 - 86.0 = High Activity |
| Boolean Remission at Week 12 | At week 12 | Boolean-based definition: At any time point, a patient must satisfy all of the following: TJC ≤1 (0-28) SJC ≤1 (0-28) CRP ≤1 mg/dl Patient Global Assessment ≤1 (on a 0-10 scale) |
| American College of Rheumatology (ACR) 20/50/70 Response Rates | At week 12 | The ACR20/50/70 is a composite measure defined as both improvement of 20%, 50% or 70% in the number of tender and number of swollen joints, and a 20%, 50% or 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[most often Health Assessment Questionnaire (HAQ)\], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). |
| Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6 | At week 12 | DAS28- ESR = Disease Activity Scores 28 based on erythrocyte sedimentation rate. A DAS28-ESR below 2.6 is interpreted as remission. |
| Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6 | At week 12 | DAS28-CRP = Disease Activity Scores 28 based on C Reactive Protein. A DAS28-CRP below 2.6 is interpreted as remission. |
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12 | Baseline and Week 12 | Patients report the amount of difficulty they have in performing 8 categories. Each category is scored on a scale ranging from 0 (performed without any difficulty) to 3 (cannot be done at all). The HAQ-DI is then calculated by summing the scores and dividing by the number of categories answered. Total score is between 0-3.0. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment. The HAQ-DI cannot be calculated if the subject does not have scores for at least 6 categories. A response was defined as a subject with a reduction from baseline in HAQ-DI of at least 0.22. |
Countries
Argentina, Canada, France, Hungary, Italy, Japan, Mexico, South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Methotrexate (MTX) Placebo (5% dextrose) subcutaneous (SC) administration once every 4 weeks for 12 weeks plus background methotrexate (MTX) | 40 |
| Clazakizumab (1 mg) + MTX Clazakizumab (1 mg) SC administration once every 4 weeks for 12 weeks + background Methotrexate | 21 |
| Clazakizumab (5 mg) + MTX Clazakizumab (5 mg) SC administration once every 4 weeks for 12 weeks + background Methotrexate | 42 |
| Clazakizumab (25 mg) + MTX Clazakizumab (25 mg) SC administration once every 4 weeks for 12 weeks + background Methotrexate | 40 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 3 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Subject no Longer Meets Study Criteria | 0 | 1 | 0 | 0 |
| Overall Study | Subject Request to Discontinue Study Treatment | 1 | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo + Methotrexate (MTX) | Clazakizumab (1 mg) + MTX | Total | Clazakizumab (25 mg) + MTX | Clazakizumab (5 mg) + MTX |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 6 Participants | 29 Participants | 8 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 15 Participants | 114 Participants | 32 Participants | 35 Participants |
| Age, Continuous | 54.4 years STANDARD_DEVIATION 11.21 | 55.8 years STANDARD_DEVIATION 11.2 | 53.8 years STANDARD_DEVIATION 12.48 | 52.6 years STANDARD_DEVIATION 13.21 | 53.4 years STANDARD_DEVIATION 13.75 |
| Region of Enrollment Argentina | 4 participants | 4 participants | 18 participants | 6 participants | 4 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 5 participants | 0 participants | 3 participants |
| Region of Enrollment France | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Hungary | 7 participants | 3 participants | 22 participants | 5 participants | 7 participants |
| Region of Enrollment Italy | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment Japan | 4 participants | 3 participants | 16 participants | 4 participants | 5 participants |
| Region of Enrollment Mexico | 8 participants | 1 participants | 29 participants | 12 participants | 8 participants |
| Region of Enrollment South Africa | 4 participants | 2 participants | 12 participants | 4 participants | 2 participants |
| Region of Enrollment United States | 11 participants | 7 participants | 38 participants | 9 participants | 11 participants |
| Sex: Female, Male Female | 35 Participants | 18 Participants | 121 Participants | 35 Participants | 33 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 22 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 40 | 0 / 21 | 0 / 42 | 0 / 40 |
| other Total, other adverse events | 14 / 40 | 5 / 21 | 24 / 42 | 28 / 40 |
| serious Total, serious adverse events | 1 / 40 | 0 / 21 | 0 / 42 | 1 / 40 |
Outcome results
Primary
Change From Baseline in Disease Activity Score in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12
DAS28-CRP describes severity of rheumatoid arthritis. The components of the joint count assessment are shoulder, elbow, wrist, metacarpophalangeal joints 1 through 5, proximal interphalangeal joints 1 through 5, and the knee joints on the right and left sides, whereby the number of affected joints, tender and swollen, respectively, are counted. The formula used to calculate the score is: DAS28-CRP=0.56 \\times \\sqrt{TEN28} + 0.28 \\times \\sqrt{SW28} + 0.36 \\times \\ln(CRP+1) + 0.014 \\times SA+0.96 with: TEN28: number of joints with tenderness upon touching SW28: number of swollen joints CRP: C-reactive Protein SA: subjective assessment of disease activity by the patient during the preceding 7 days on a scale between 0 and 100 (0:no activity, 100: highest activity possible). DAS-CRP score range is 0.49 to 9.07 A DAS-CRP value \>5.1 corresponds to a high disease activity A DAS-28 reduction by 0.6 represents a moderate improvement. A reduction \>1.2 represents a major improvement
Time frame: Baseline and Week 12
Population: Modified Intent-to-Treat (mITT) Analysis Population: All randomized subjects who received at least 1 dose of the study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate (MTX) | Change From Baseline in Disease Activity Score in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12 | -0.75 score on a scale | Standard Error 0.22 |
| Clazakizumab (1 mg) + MTX | Change From Baseline in Disease Activity Score in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12 | -1.10 score on a scale | Standard Error 0.33 |
| Clazakizumab (5 mg) + MTX | Change From Baseline in Disease Activity Score in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12 | -2.10 score on a scale | Standard Error 0.22 |
| Clazakizumab (25 mg) + MTX | Change From Baseline in Disease Activity Score in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12 | -2.43 score on a scale | Standard Error 0.22 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
p-value: 0.38Mixed Models Analysis
Secondary
American College of Rheumatology (ACR) 20/50/70 Response Rates
The ACR20/50/70 is a composite measure defined as both improvement of 20%, 50% or 70% in the number of tender and number of swollen joints, and a 20%, 50% or 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[most often Health Assessment Questionnaire (HAQ)\], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).
Time frame: At week 12
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Methotrexate (MTX) | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC20 responders | 27.5 percentage of responders |
| Placebo + Methotrexate (MTX) | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC70 responders | 2.5 percentage of responders |
| Placebo + Methotrexate (MTX) | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC50 responders | 7.5 percentage of responders |
| Clazakizumab (1 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC20 responders | 14.3 percentage of responders |
| Clazakizumab (1 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC70 responders | 4.8 percentage of responders |
| Clazakizumab (1 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC50 responders | 14.3 percentage of responders |
| Clazakizumab (5 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC50 responders | 21.4 percentage of responders |
| Clazakizumab (5 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC20 responders | 50.0 percentage of responders |
| Clazakizumab (5 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC70 responders | 9.5 percentage of responders |
| Clazakizumab (25 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC20 responders | 47.5 percentage of responders |
| Clazakizumab (25 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC70 responders | 15.0 percentage of responders |
| Clazakizumab (25 mg) + MTX | American College of Rheumatology (ACR) 20/50/70 Response Rates | ARC50 responders | 22.5 percentage of responders |
Secondary
Boolean Remission at Week 12
Boolean-based definition: At any time point, a patient must satisfy all of the following: TJC ≤1 (0-28) SJC ≤1 (0-28) CRP ≤1 mg/dl Patient Global Assessment ≤1 (on a 0-10 scale)
Time frame: At week 12
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate (MTX) | Boolean Remission at Week 12 | 5.0 percentage of participants |
| Clazakizumab (1 mg) + MTX | Boolean Remission at Week 12 | 4.8 percentage of participants |
| Clazakizumab (5 mg) + MTX | Boolean Remission at Week 12 | 2.4 percentage of participants |
| Clazakizumab (25 mg) + MTX | Boolean Remission at Week 12 | 5.0 percentage of participants |
Secondary
Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12
CDAI is a composite index for assessing disease activity. CDAI is based on the simple summation of the count of swollen joint count (SCJ) (0-28) and tender joint count (TJC) (0-28) along with patient global assessment (0-10) Scale and physician global assessment (0-10) for estimating disease activity where 10 means maximal activity. The CDAI has a range from 0 to 76. CDAI \<= 2.8 = Remission CDAI \> 2.8 and \<= 10 = Low Disease Activity CDAI \> 10 and \<= 22 = Moderate Disease Activity CDAI \> 22 = High Disease Activity
Time frame: Baseline and week 12
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate (MTX) | Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | -9.9 score on a scale | Standard Error 2.656 |
| Clazakizumab (1 mg) + MTX | Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | -12.8 score on a scale | Standard Error 3.961 |
| Clazakizumab (5 mg) + MTX | Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | -17.4 score on a scale | Standard Error 2.545 |
| Clazakizumab (25 mg) + MTX | Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | -21.6 score on a scale | Standard Error 2.539 |
Secondary
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12
Patients report the amount of difficulty they have in performing 8 categories. Each category is scored on a scale ranging from 0 (performed without any difficulty) to 3 (cannot be done at all). The HAQ-DI is then calculated by summing the scores and dividing by the number of categories answered. Total score is between 0-3.0. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment. The HAQ-DI cannot be calculated if the subject does not have scores for at least 6 categories. A response was defined as a subject with a reduction from baseline in HAQ-DI of at least 0.22.
Time frame: Baseline and Week 12
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate (MTX) | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12 | -0.25 score on a scale | Standard Error 0.0906 |
| Clazakizumab (1 mg) + MTX | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12 | -0.09 score on a scale | Standard Error 0.1307 |
| Clazakizumab (5 mg) + MTX | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12 | -0.31 score on a scale | Standard Error 0.0889 |
| Clazakizumab (25 mg) + MTX | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12 | -0.46 score on a scale | Standard Error 0.0905 |
Secondary
Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12
SDAI is a composite index for assessing disease activity. CDAI is based on the simple summation of the count of swollen joint count (0-28) and tender joint count (0-28) along with patient global assessment (0-10) Scale and physician global assessment (0-10) for estimating disease activity where 10 means maximal activity and C-reactive protein (0-10). The SDAI has a range from 0 to 86. 0.0 - 3.3 = Remission 3.4 - 11.0 = Low Activity 11.1 - 26.0 = Moderate Activity 26.1 - 86.0 = High Activity
Time frame: Baseline and week 12
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate (MTX) | Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 | -9.68 score on a scale | Standard Error 2.6846 |
| Clazakizumab (1 mg) + MTX | Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 | -13.08 score on a scale | Standard Error 4.0011 |
| Clazakizumab (5 mg) + MTX | Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 | -20.15 score on a scale | Standard Error 2.5928 |
| Clazakizumab (25 mg) + MTX | Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 | -24.02 score on a scale | Standard Error 2.5677 |
Secondary
Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6
DAS28-CRP = Disease Activity Scores 28 based on C Reactive Protein. A DAS28-CRP below 2.6 is interpreted as remission.
Time frame: At week 12
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate (MTX) | Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6 | 5.0 percentage of participants |
| Clazakizumab (1 mg) + MTX | Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6 | 9.5 percentage of participants |
| Clazakizumab (5 mg) + MTX | Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6 | 14.3 percentage of participants |
| Clazakizumab (25 mg) + MTX | Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6 | 15.0 percentage of participants |
Secondary
Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6
DAS28- ESR = Disease Activity Scores 28 based on erythrocyte sedimentation rate. A DAS28-ESR below 2.6 is interpreted as remission.
Time frame: At week 12
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate (MTX) | Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6 | 2.5 percentage of participants |
| Clazakizumab (1 mg) + MTX | Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6 | 4.8 percentage of participants |
| Clazakizumab (5 mg) + MTX | Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6 | 7.1 percentage of participants |
| Clazakizumab (25 mg) + MTX | Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6 | 15.0 percentage of participants |