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BMS-188667 in Children and Adolescents With Juvenile Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00095173
First received: November 1, 2004
Last updated: November 22, 2016
Last verified: November 2016
  Purpose
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.

Condition Intervention Phase
Juvenile Rheumatoid Arthritis
Drug: Abatacept
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double Blind (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Time to Occurrence of Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease Flare During Double-Blind Phase (Period B) [ Time Frame: Period B (Day 113 to Day 282) ]

    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)


Secondary Outcome Measures:
  • Number of Participants With a Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease With a Flare During Double-Blind Phase (Period B) [ Time Frame: Period B (Day 113 to Day 282) ]

    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)

  • 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) [ Time Frame: Period A (Day 1 to Day 113) ]

    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).


  • 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) [ Time Frame: Period B (Day 113 to Day 282) ]

    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).


  • 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) [ Time Frame: Period C (Day 282 to end of study) ]
    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).

  • Median Percent Change From Baseline in JRA/JIA Core Set Variables During Double-Blind Phase (Period B) [ Time Frame: Period B (Day 113 to Day 282) ]
    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.

  • Median Percent Change From Baseline in JRA/JIA Core Set Variables During Open-Label Phase (Period C) [ Time Frame: Period C (Day 282 to end of study) ]
    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.

  • Events of Special Interest During Open-Label Lead-In Phase (Period A), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies [ Time Frame: Period A (Day 1 to Day 113) ]
    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.

  • Events of Special Interest During Double-Blind Phase (Period B), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies [ Time Frame: Period B (Day 113 to Day 282) ]
    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.

  • Events of Special Interest During Open-Label Phase (Period C), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies [ Time Frame: Period C (Day 282 up to 56 days after the last dose of study medication) ]
    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.

  • 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 [ Time Frame: Day 113, Day 282, and Day 2047 ]
    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.

  • Number of Treated Participants With Marked Laboratory Abnormalities During Open-Label Lead-In Phase (Period A) [ Time Frame: Period A (Day 1 to Day 113) ]
    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.

  • Number of Treated Participants With Marked Laboratory Abnormalities During Double-Blind Phase (Period B) [ Time Frame: Period B (Day 113 to Day 282) ]
    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.

  • Number of Treated Participants With Marked Laboratory Abnormalities During Open-Label Phase (Period C) [ Time Frame: Period C (Day 282 to end of study) ]
    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.

  • Number of Participants With Anti-Abatacept or Anti-CTLA4 Positive Responses Over Time During Open-Label Phase (Period C) [ Time Frame: Period C (Day 282 to 85 days after the last dose of study medication) ]
    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.


Enrollment: 214
Study Start Date: December 2003
Study Completion Date: November 2011
Primary Completion Date: June 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Abatacept
Double Blind Period
Drug: Abatacept
IV infusions, IV, 10mg/kg body weight, every 4 weeks, 6 months (unless a disease flare discontinued the patient earlier).
Other Name: Orencia
Placebo Comparator: Placebo
Double Blind Period
Drug: Placebo
IV infusions, IV, N/A, every 4 weeks, 6 months.
Experimental: Abatacept - Open Label Drug: Abatacept
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
Other Name: Orencia

  Eligibility

Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00095173

  Show 36 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00095173     History of Changes
Other Study ID Numbers: IM101-033
Study First Received: November 1, 2004
Results First Received: September 22, 2016
Last Updated: November 22, 2016

Keywords provided by Bristol-Myers Squibb:
Juvenile Idiopathic Arthritis

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Arthritis, Juvenile
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on May 22, 2017