BMS-188667 in Children and Adolescents With Juvenile Rheumatoid Arthritis

Study Overview
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Brief Summary
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The primary purpose of the clinical research study is to assess the safety of treating children and juvenile subjects with BMS-188667 (Abatacept). In addition, the study will assess the effectiveness of BMS-188667 in reducing disease activity of Juvenile Rheumatoid Arthritis (JRA) or Juvenile Idiopathic Arthritis (JIA) as measured by the time to occurrence of disease flare.

Official Title
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A Phase III, Multi-Center, Multi-National, Randomized Withdrawal Study to Evaluate the Safety and Efficacy of BMS-188667 in Children and Adolescents With Active Polyarticular Juvenile Rheumatoid Arthritis (JRA)

Conditions
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Juvenile Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Abatacept
* Drug: Placebo
* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Juvenile Rheumatoid Arthritis or Juvenile Idiopathic Arthritis; Current active arthritis; Failed treatment with at least one disease modifying anti-rheumatic drug (DMARD); Subjects must discontinue use of any DMARD other than methotrexate prior to the first dose of study medication Exclusion Criteria: Presence of infection or history of frequent acute or chronic infections; Joint replacement surgery required during the study or history of surgery on more than 5 joints; Live vaccines within 3 months of the first dose of study medication; Unresolved serious bacterial infection or chronic bacterial infection; Subjects who currently have intermittent fever due to JRA/JIA, rheumatoid rash, hepato-splenomegaly, pleuritis, pericarditis, or macrophage activation syndrome.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Abatacept<br>Double Blind Period | Drug: Abatacept<br>* IV infusions, IV, 10mg/kg body weight, every 4 weeks, 6 months (unless a disease flare discontinued the patient earlier).<br>* Other names: Orencia;|
| Placebo Comparator: Placebo<br>Double Blind Period | Drug: Placebo<br>* IV infusions, IV, N/A, every 4 weeks, 6 months.<br>|
| Experimental: Abatacept - Open Label<br> | Drug: Abatacept<br>* Solution, intravenous, Approximately 10 mg/kg fixed dose, based on subject's body weight; 500 mg for subjects weighing < 60kg; 750 mg for subjects weighing 60 to 100 kg; and 1 gram for subjects weighing > 100 kg, monthly<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Occurrence of Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease Flare During Double-Blind Phase (Period B) | Time to flare is defined as the elapsed number of days between the first dose date in Period B and the study day that disease flare is confirmed. All of the following criteria must be met to be defined as a flare: > 30% worsening in at least 3 of the 6 JRA/JIA core response variables > 30% improvement in not more than 1 of the 6 JRA/JIA core set variables ≥ 2 cm of worsening must be present if the Physician or Parent Global Assessment is used to define flare worsening in ≥ 2 joints must be present if the number of active joints or joints with limitation of motion is used to define flare based on changes in the surrogate marker, erythrocyte sedimentation rate (ESR) | Period B (Day 113 to Day 282) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease With a Flare During Double-Blind Phase (Period B) | All of the following criteria must be met to be defined as a flare: > 30% worsening in at least 3 of the 6 JRA/JIA core response variables > 30% improvement in not more than 1 of the 6 JRA/JIA core set variables ≥ 2 cm of worsening must be present if the Physician or Parent Global Assessment is used to define flare worsening in ≥ 2 joints must be present if the number of active joints or joints with limitation of motion is used to define flare based on changes in the surrogate marker, erythrocyte sedimentation rate (ESR) | Period B (Day 113 to Day 282) | 
| Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Lead-In Phase (Period A) | AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v14.1). | Period A (Day 1 to Day 113) | 
| Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Double-Blind Phase (Period B) | AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v14.1). | Period B (Day 113 to Day 282) | 
| Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Phase (Period C) | AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 85 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v14.1). | Period C (Day 282 to end of study) | 
| Median Percent Change From Baseline in JRA/JIA Core Set Variables During Double-Blind Phase (Period B) | Percent change from baseline was calculated from the difference between post-baseline and baseline divided by baseline multiplied by 100 and reported as the range between 25th and 75th percentile, not full range; American College of Rheumatology (ACR) Pediatric 30 JRA/JIA core set variables include active joints, limited range of motion, physician global assessment of disease severity, parent global assessment of overall well-being, change in physical function as measured by the Childhood Health Assessment Questionnaire (CHAQ), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Disease activity was assessed by the physician and parent on a 0-100 mm visual analog scale (VAS). Low values represent low severity of disease and good well-being whereas high values represent highly severe disease and very poor well-being. | Period B (Day 113 to Day 282) | 
| Median Percent Change From Baseline in JRA/JIA Core Set Variables During Open-Label Phase (Period C) | Percent change from baseline was calculated from the difference between post-baseline and baseline divided by baseline multiplied by 100 and reported as the range between 25th and 75th percentile, not full range; American College of Rheumatology (ACR) Pediatric 30 JRA/JIA core set variables include active joints, limited range of motion, physician's global assessment of disease severity, parent global assessment of overall well-being, change in physical function as measured by the Childhood Health Assessment Questionnaire (CHAQ), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Disease activity was assessed by the physician and parent on a 0-100 mm visual analog scale (VAS). Low values represent low severity of disease and good well-being whereas high values represent highly severe disease and very poor well-being. | Period C (Day 282 to end of study) | 
| Events of Special Interest During Open-Label Lead-In Phase (Period A), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies | The sponsor prospectively identified categories of AEs that may be associated with the use of immunomodulatory drugs including infections, peri-infusional AEs, autoimmune disorders, malignancies. Peri-infusional AEs are defined as those AEs of special interest occurring during the first 24 hours after the start of study drug infusion. Malignancies definitions were based on events in the MedDRA Maintenance and Support Services Organization (MSSO) malignancies Structured MedDRA Query (SMQ).Autoimmune disorders are in alignment with the pre-specified MedDRA codes of autoimmune disorders events of interest. | Period A (Day 1 to Day 113) | 
| Events of Special Interest During Double-Blind Phase (Period B), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies | The sponsor prospectively identified categories of AEs that may be associated with the use of immunomodulatory drugs including infections, peri-infusional AEs, autoimmune disorders, malignancies. Peri-infusional AEs are defined as those AEs of special interest occurring during the first 24 hours after the start of study drug infusion. Malignancies definitions were based on events in the MedDRA Maintenance and Support Services Organization (MSSO) malignancies Structured MedDRA Query (SMQ).Autoimmune disorders are in alignment with the pre-specified MedDRA codes of autoimmune disorders events of interest. | Period B (Day 113 to Day 282) | 
| Events of Special Interest During Open-Label Phase (Period C), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies | The sponsor prospectively identified categories of AEs that may be associated with the use of immunomodulatory drugs including infections, peri-infusional AEs, autoimmune disorders, malignancies. Peri-infusional AEs are defined as those AEs of special interest occurring during the first 24 hours after the start of study drug infusion. Malignancies definitions were based on events in the MedDRA Maintenance and Support Services Organization (MSSO) malignancies Structured MedDRA Query (SMQ).Autoimmune disorders are in alignment with the pre-specified MedDRA codes of autoimmune disorders events of interest. | Period C (Day 282 up to 56 days after the last dose of study medication) | 
| Percentage of Participants Achieving American College of Rheumatology (ACR) Pediatric 30 (ACRP30), ACR Pediatric 50, ACR Pediatric 70, ACR Pediatric 90, and Inactive Disease Status Erythrocyte Sedimentation Rate (ESR) Response Rate | The ACRP30 response criteria were defined as a ≥ 30% improvement over baseline in ESR. ACRP 50, 70, and 90 responses were defined similarly with 50%, 70%, and 90% improvements required, respectively. | Day 113, Day 282, and Day 2047 | 
| Number of Treated Participants With Marked Laboratory Abnormalities During Open-Label Lead-In Phase (Period A) | Marked abnormalities were pre-defined as changes in lab tests that occurred after drug infusion and were reported relative to the normal range for each analyte. Hemoglobin, 11.6-14.8 grams per deciliter (g/dL);Hematocrit, 36.0-50.0 percent;Erythrocytes, 3.80-5.10x10*6 cells per microliter (c/uL);Platelets, 140-44 cells per liter (c/L);Leukocytes, 4.00-12.50 c/uL;Absolute Neutrophils + Bands, if <1.00x10^3 c/uL;Absolute Lymphocytes, if <0.72x10^3 or >7.50x10^3 c/uL;Absolute Eosinophils, if >0.750X10^3 c/uL;Alanine Aminotransferase, 0-40 units per liter (U/L);G-Glutamyl Transferase, 0-60 U/L;Bilirubin, 0.1-1.2 milligrams per deciliter (mg/dL);Blood Urea Nitrogen, 5.9-26.0 mg/dL;Creatinine, 0.50-1.50 mg/dL;Serum Potassium, 3.5-5.5 milliequivalents per liter (mEq/L);Serum Glucose, 65-99 mg/dL;Fasting Serum Glucose, 65-99 mg/dL;Total Protein, 6.0-8.5 g/dL;Albumin, 3.5-5.5 g/dL;Urine Protein, >=4;Urine Glucose, >=4;Urine Blood, >=4;Urine Red Blood Cells >=4;Urine White Blood Cells, >=4. | Period A (Day 1 to Day 113) | 
| Number of Treated Participants With Marked Laboratory Abnormalities During Double-Blind Phase (Period B) | Marked abnormalities were pre-defined as changes in lab tests that occurred after drug infusion and were reported relative to the normal range for each analyte. Hemoglobin, 11.6-14.8 grams per deciliter (g/dL);Hematocrit, 36.0-50.0 percent;Erythrocytes, 3.80-5.10x10*6 cells per microliter (c/uL);Platelets, 140-44 cells per liter (c/L);Leukocytes, 4.00-12.50 c/uL;Absolute Neutrophils + Bands, if <1.00x10^3 c/uL;Absolute Lymphocytes, if <0.72x10^3 or >7.50x10^3 c/uL;Absolute Eosinophils, if >0.750X10^3 c/uL;Aspartate Aminotransferase, 0-40 units per liter (U/L); Alanine Aminotransferase, 0-40 U/L;Blood Urea Nitrogen, 5.9-26.0 mg/dL;Serum Sodium, 135-148 milliequivalents per liter (mEq/L);Serum Potassium, 3.5-5.5 mEq/L;Serum Glucose, 65-99 mg/dL;Fasting Serum Glucose, 65-99 mg/dL;Urine Protein, >=4;Urine Blood, >=4;Urine Red Blood Cells >=4;Urine White Blood Cells, >=4. | Period B (Day 113 to Day 282) | 
| Number of Treated Participants With Marked Laboratory Abnormalities During Open-Label Phase (Period C) | Marked abnormalities were pre-defined as changes in lab tests after drug infusion and relative to normal range. Hemoglobin,11.6-14.8grams per deciliter(g/dL);Hematocrit,36.0-50.0 percent;Erythrocytes,3.80-5.10x10*6 cells per microliter(c/uL);Platelets,140-44 cells per liter(c/L);Leukocytes,4.00-12.50c/uL;Absolute(Abs)Neutrophils+Bands,<1.00x10^3 c/uL;Abs Lymphocytes,<0.72x10^3 or>7.50x10^3 c/uL;Abs Eosinophils,>0.750X10^3 c/uL;Alkaline Phosphatase,0-40 units per liter(U/L);Aspartate Aminotransferase,0-40 U/L;Alanine Aminotransferase,0-40U/L;G-Glutamyl Transferase,0-60 U/L;Bilirubin, 0.1-1.2 milligrams per deciliter(mg/dL);Blood Urea Nitrogen,5.9-26.0 mg/dL;Creatinine, 0.50-1.50mg/dL;Inorganic Phosphorus,2.8-6.2 U/L;Serum Potassium,3.5-5.5 milliequivalents per liter(mEq/L);Serum Glucose,65-99 mg/dL;Fasting Serum Glucose,65-99 mg/dL;Total Protein, 6.0-8.5 g/dL;Albumin,3.5-5.5 g/dL;Urine Protein,>=4;Urine Glucose,>=4;Urine Blood,>=4;Urine Red Blood Cells>=4;Urine White Blood Cells,>=4. | Period C (Day 282 to end of study) | 
| Number of Participants With Anti-Abatacept or Anti-CTLA4 Positive Responses Over Time During Open-Label Phase (Period C) | During Period C, blood samples for immunogenicity assessments were obtained just prior to the start of the IV infusion of abatacept at 3-month intervals during the first 2 years of Period C, at 6-month intervals thereafter, and again 28, 56, and 85 days after the last infusion. Direct-format, enzyme-linked immunosorbent assays (ELISAs) were used to evaluate the cytotoxic T-lymphocyte antigen 4 (CTLA4) and the anti-CTLA4-T antibody. | Period C (Day 282 to 85 days after the last dose of study medication) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Juvenile Idiopathic Arthritis