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

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

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Double-blind Abatacept; Drug: Double-blind Placebo; Drug: Open-label Abatacept

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1795
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Decatur, Alabama, United States
      • Local Institution
  • Arizona
    • Paradise, Arizona, United States
      • Local Institution
    • Phoenix, Arizona, United States
      • Local Institution
    • Tucson, Arizona, United States
      • Local Institution
  • California
    • San Francisco, California, United States
      • Local Institution
  • Colorado
    • Loveland, Colorado, United States
      • Local Institution
  • Connecticut
    • Hamden, Connecticut, United States
      • Local Institution
  • Florida
    • Lake Worth, Florida, United States
      • Local Institution
    • Largo, Florida, United States
      • Local Institution
  • Georgia
    • Blairsville, Georgia, United States
      • Local Institution
  • Illinois
    • Chicago, Illinois, United States
      • Local Institution
  • Indiana
    • Evansville, Indiana, United States
      • Local Institution
    • Indianapolis, Indiana, United States
      • Local Institution
  • Kansas
    • Wichita, Kansas, United States
      • Local Institution
  • Kentucky
    • Louisville, Kentucky, United States
      • Local Institution
  • Louisiana
    • New Orleans, Louisiana, United States
      • Local Institution
  • Maryland
    • Baltimore, Maryland, United States
      • Local Institution
    • Cumberland, Maryland, United States
      • Local Institution
    • Westminster, Maryland, United States
      • Local Institution
  • Massachusetts
    • Boston, Massachusetts, United States
      • Local Institution
  • Michigan
    • Grand Rapids, Michigan, United States
      • Local Institution
    • Royal Oak, Michigan, United States
      • Local Institution
  • New Jersey
    • Toms River, New Jersey, United States
      • Local Institution
  • New Mexico
    • Los Alamos, New Mexico, United States
      • Local Institution
  • New York
    • New York, New York, United States
      • Local Institution
  • North Carolina
    • Durham, North Carolina, United States
      • Local Institution
    • Hickory, North Carolina, United States
      • Local Institution
  • Ohio
    • Canton, Ohio, United States
      • Local Institution
    • Cleveland, Ohio, United States
      • Local Institution
    • Columbus, Ohio, United States
      • Local Institution
    • Elyria, Ohio, United States
      • Local Institution
    • Youngstown, Ohio, United States
      • Local Institution
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Local Institution
  • Pennsylvania
    • Wyomissing, Pennsylvania, United States
      • Local Institution
  • South Carolina
    • Columbia, South Carolina, United States
      • Local Institution
  • South Dakota
    • Sioux Falls, South Dakota, United States
      • Local Institution
  • Tennessee
    • Ducktown, Tennessee, United States
      • Local Institution
    • Nashville, Tennessee, United States
      • Local Institution
  • Virginia
    • Richmond, Virginia, United States
      • Local Institution
  • Washington
    • Edmonds, Washington, United States
      • Local Institution
    • Olympia, Washington, United States
      • Local Institution
    • Tacoma, Washington, United States
      • Local Institution
  • Wisconsin
    • Menomonee Falls, Wisconsin, United States
      • Local Institution
    • Milwaukee, Wisconsin, United States
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Double-blind abatacept; 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; 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.; Other Names: Orencia; BMS-188667
Placebo Comparator: Double-blind Placebo; 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; Concentrate and diluted in a solution, IV, 0 mg, Once daily, Day 1, 15, and 29.
Active Comparator: Open-label Abatacept; Participants received abatacept (weight-tiered 10 mg/kg dose) IV every 28 days during the open-label period.	Drug: Open-label Abatacept; 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.; Other Names: Orencia; BMS-188667

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Alten R, Burkhardt H, Feist E, Kruger K, Rech J, Rubbert-Roth A, Voll RE, Elbez Y, Rauch C. Abatacept used in combination with non-methotrexate disease-modifying antirheumatic drugs: a descriptive analysis of data from interventional trials and the real-world setting. Arthritis Res Ther. 2018 Jan 2;20(1):1. doi: 10.1186/s13075-017-1488-5.

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: November 11, 2002
• First Submitted That Met QC Criteria: November 12, 2002
• First Posted (Estimate): November 13, 2002

Study Record Updates

• Last Update Posted (Estimate): November 24, 2011
• Last Update Submitted That Met QC Criteria: November 15, 2011
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: IM101-031