A Phase III Study of BMS-188667 in Subjects With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this clinical research study is to learn if abatacept is safe when co-administered with other approved rheumatoid arthritis medications.

Detailed Description
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This was a multinational, multicenter, randomized, double-blind, 2-arm, parallel-dosing designed study. The treatment period was 12 months. Eligible participants were randomized to 1 of 2 treatment groups: abatacept fixed dose approximating 10 mg/kg (based on participant's body weight; 500 mg for participants weighing < 60kg; 750 mg for participants weighing 60 to 100 kg; and 1 gram for participants weighing > 100 kg, monthly) or placebo intravenous (IV) infusion. All participants continued their background therapy(ies) for rheumatoid arthritis (RA) (non-biologic or biologic disease-modifying drugs [DMARDs], or combination) throughout the double-blind treatment period. Double-blind study medication (abatacept or placebo) was administered on Days 1, 15, 29, and every 28 days thereafter, for a total of 14 doses. All participants who completed the 12-month double-blind study period (Day 1 through Day 365), were eligible to continue into the open-label period. All eligible participants (active or placebo) were re-allocated to receive abatacept at a weight-tiered dose that approximated 10 mg/kg, based on their Day 365 body weight. Participants continued to receive infusions every 28 days.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Double-blind Abatacept
* Drug: Double-blind Placebo
* Drug: Open-label Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet criteria of American Rheumatism Association for the diagnosis of rheumatoid arthritis and the American College of Rheumatology functional classes I, II III or IV Participants must be taking 1 or more DMARDs and/or biologic approved for rheumatoid arthritis (RA) for at least 3 months and be on a stable dose for 28 days prior to Day 1. Exclusion: Other auto-immune disease as a main diagnosis (e.g. Systemic Lupus Erythematosus [SLE], Scleroderma) Active tuberculosis (TB) requiring treatment within last 3 years

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Double-blind abatacept<br>Participants received a fixed dose of abatacept approximating 10 mg/kg (500 mg for participants < 60 kg, 750 mg for participants 60 to 100 kg and 1 g for participants > 100 kg). Abatacept was administered intravenously (IV) on Days 1, 15, 29, and every 28 days thereafter, for a total of 14 doses. Participants also received background therapy(ies) for rheumatoid arthritis (RA) (non-biologic or biologic disease-modifying drugs [DMARDs], or combination) throughout the double-blind treatment period | Drug: Double-blind Abatacept<br>* Concentrate and diluted in a solution, IV, 500 mg (body weight < 60 Kg); 750 mg (body weight 60-100 Kg); 1000 mg (body weight > 100 Kg), Once daily, Day 1, 15, and 29.<br>* Other names: BMS-188667;|
| Placebo Comparator: Double-blind Placebo<br>Participants received Placebo (dextrose 5% water [D5W] for injection U.S.P or normal saline [NS]) for IV infusion administered on Days 1, 15, 29, and every 28 days thereafter, for a total of 14 doses. Participants also received background therapy(ies) for rheumatoid arthritis (RA) (non-biologic or biologic disease-modifying drugs [DMARDs], or combination) throughout the double-blind treatment period. | Drug: Double-blind Placebo<br>* Concentrate and diluted in a solution, IV, 0 mg, Once daily, Day 1, 15, and 29.<br>|
| Active Comparator: Open-label Abatacept<br>Participants received abatacept (weight-tiered 10 mg/kg dose) IV every 28 days during the open-label period. | Drug: Open-label Abatacept<br>* Concentrate and diluted in a solution, IV, 500 mg (body weight < 60 Kg); 750 mg (body weight 60-100 Kg); 1000 mg (body weight > 100 Kg), Once daily, Every 28 days.<br>* Other names: BMS-188667;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double Blind Period (DB); Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, or AEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Related SAE/AE = possibly, probably, or certainly related to study drug | Day 1 to Day 365, and including data up to 56 days post last dose of double-blind medication | 
| DB; Number of Participants With AEs of Special Interest | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, and opportunistic infections; autoimmune disorders; neoplasms; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion). | Day 1 to Day 365, and including data up to 56 days post last dose of double-blind medication | 
| DB; Number of Participants With Hematology Laboratories Meeting Marked Abnormality Criteria | Upper Normal Limit (ULN), Lower Normal Limit (LLN), Baseline (BL). Marked abnormality criteria are: Hemoglobin (HGB): >3 g/dL decrease from BL; Hematocrit: <0.75 * BL; Erythrocytes: <0.75 * BL; Platelets (PLT): <0.67 * LLN/>1.5 * ULN, or if BL < LLN then use <0.5 * BL and <100,000 mm^3; Leukocytes: <0.75 * LLN/ >1.25 * ULN, or if BL<LLN then use <0.8 * BL or >ULN, or if BL>ULN then use >1.2 * BL or <LLN; neutrophils+bands: <1.0 * 10^3 c/uL; eosinophils: >0.750 * 10^3 c/uL; basophils: > 400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750 * 10^3 c/uL/ >7.50 * 10^3 c/uL. | Day 1 to Day 365, and including data up to 56 days post last dose of double-blind medication | 
| DB; Number of Participants With Blood Chemistry Laboratories Meeting Marked Abnormality (MA) Criteria | ULN=upper level of normal; BL=baseline.Marked abnormality criteria: High alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; high aspartate aminotransferase (AST): >3* ULN (80 U/L), or if BL>ULN then use >4* BL; high alanine aminotransferase (ALT): >3* ULN (34-47 U/L), or if BL>ULN then use >4* BL; high G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; high bilirubin: >2* ULN, or if BL>ULN then use >4* BL; high blood urea nitrogen (BUN): >2* BL; high creatinine: >1.5* BL (ULN 14.6 pg/mg. AST ULN=80 U/L; ALT ULN=34-47 U/L;creatinine ULN=14.6 pg/mg. | Day 1 to Day 365, and including data up to 56 days post last dose of double-blind medication | 
| DB; Number of Participants With Clinically Significant Physical Examination or Vital Signs Abnormalities | Physical examinations were performed at the discretion of the investigator and included breast examinations for female participants. Vital sign measurements were performed for participants before and after infusion of study medication at each visit and included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. | Days 1, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337. Vital signs were measured at these visits before and after study medication infusion. | 
| Open Label Period (OL); Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, or AEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Related SAE/AE = possibly, probably, or certainly related to study drug | Day 365 to Day 1,821 | 
| OL; Number of Participants With AEs of Special Interest | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, and opportunistic infections; autoimmune disorders; neoplasms; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion). | Day 365 to Day 1821 | 
| OL; Number of Participants With Hematology Laboratories Meeting Marked Abnormality Criteria | Upper Normal Limit (ULN), Lower Normal Limit (LLN), Baseline (BL). Marked abnormality criteria are: Hemoglobin (HGB): >3 g/dL decrease from BL; Hematocrit: <0.75 * BL; Erythrocytes: <0.75 * BL; Platelets (PLT): <0.67 * LLN/>1.5 * ULN, or if BL < LLN then use <0.5 * BL and <100,000 mm^3; Leukocytes: <0.75 * LLN/ >1.25 * ULN, or if BL<LLN then use <0.8 * BL or >ULN, or if BL>ULN then use >1.2 * BL or <LLN; neutrophils+bands: <1.0 * 10^3 c/uL; eosinophils: >0.750 * 10^3 c/uL; basophils: > 400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750 * 10^3 c/uL/ >7.50 * 10^3 c/uL. | Day 365 to Day 1821, and including data up to 56 days post last dose of double-blind medication | 
| OL; Number of Participants With Liver Function Laboratories Meeting Marked Abnormality Criteria | Marked abnormality criteria: Alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; aspartate aminotransferase (AST): >3* ULN, or if BL>ULN then use >4* BL; alanine aminotransferase (ALT): >3* ULN, or if BL>ULN then use >4* BL; G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; Bilirubin: >2* ULN, or if BL>ULN then use >4* BL; blood urea nitrogen (BUN): >2* BL; creatinine: >1.5* BL | Day 365 to Day 1821, and including data up to 56 days post last dose of double-blind medication | 
| OL; Number of Participants With Electrolyte Laboratories Meeting Marked Abnormality Criteria | Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL<LLN then use <0.95* BL or >ULN, or if BL>ULN then use>1.05* BL or <LLN; potassium (K): <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; (Cl): <0.9* LLN/>1.1* ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; calcium (Ca): <0.8* LLN/>1.2* ULN, or if BL<LLN then use <0.75* BL or >ULN, or if BL>ULN then use>1.25* BL or <LLN; phosphorous (P): <0.75* LLN/ >1.25* ULN, or if BL<LLN then use 0.67* BL or >ULN, or if BL>ULN then use>1.33* BL or <LLN | Day 365 to Day 1821, and including data up to 56 days post last dose of double-blind medication | 
| OL; Number of Participants With Other Chemistry and Urinalysis Laboratories Meeting Marked Abnormality Criteria | MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL<LLN then use 0.8*BL or >ULN,or if BL>ULN then use >2.0*BL or <LLN;total protein: <0.9*LLN/>1.1*ULN,or if BL<LLN then use <0.9*BL or >UNL,or if BL>UNL then use >1.1*BL or <LLN; albumin: <0.9*LLN,or if BL<LLN then use <0.75 BL;uric acid: >1.5*ULN,or if BL>ULN then use >2*BL. Urinalysis (Urine protein,urine Glu,urine blood,leukocyte esterase,Red Blood Cells [RBCs], White Blood Cells [WBCs]):Use ≥2 when BL value missing or when pre-dose=0 or 0.5; use ≥3 when pre-dose=1, use ≥4 when pre-dose=2 or 3 | Day 365 to Day 1821, and including data up to 56 days post last dose of double-blind medication | 
| OL; Number of Participants With Clinically Significant Physical Examination or Vital Signs Abnormalities | Physical examinations were performed at the discretion of the investigator and included breast examinations for female participants. Vital sign measurements were performed for participants before and after infusion of study medication at each visit and included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. | Days 365 to Day 1821 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB; Number of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Responses by Enzyme-Linked Immunosorbant Assay (ELISA) | Serum samples from all treated adult participants with active rheumatoid arthritis (RA) were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody. | Days 1, 29, 57, 85, 113,169, 281, 365 | 
| DB; Number of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Responses by ELISA | Serum samples from all treated adult participants with active rheumatoid arthritis were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody. | Days 1, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337 |