A Phase III Study of Abatacept (BMS-188667) in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate

NCT00048568 | Completed Phase 3 Results

• 1 other identifier: IM101-102
• Study Type: interventional
• Target: 1,250
• Locations: 1 country
• Sites: 48

Brief Summary

Short Term: The purpose of this clinical research study is to learn if abatacept (BMS-188667) in combination with methotrexate is better than methotrexate alone in participants that have active rheumatoid arthritis and are not responding to methotrexate. The safety of this treatment will also be studied. Long Term Extension: The purpose of this amendment is to provide participants who have completed the initial 12-month double-blind treatment period the opportunity to receive open label treatment with active drug treatment until abatacept is approved in the local country or until clinical development has been discontinued.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (27)

• Number of American College of Rheumatology 20 (ACR 20) Responders at Day 169

  ACR 20 response requires a patient to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire (HAQ) score. A participant achieved a sustained ACR 20 response if the participant had ACR 20 observed for at least 2 consecutive study visits.

  Day 169

• Number of Participants Achieving Clinically Meaningful Improvement in Health Assessment Questionnaire (HAQ) at Day 365

  The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain dividied by the number of domains answered. HAQ-DI ranges from 0 to a maximum overall score of 3.0. Clinically meaningful HAQ response was defined as an improvement of at least 0.3 units from baseline in HAQ DI.

  Day 365

• Baseline and Mean Change From Baseline (BL) in Radiographic Erosion Score Results at Day 365

  To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions. The erosion score range is 0 (no radiographic damage) to 145 (worst possible radiographic damage). Change from baseline = Post-baseline - Baseline value

  BL (Day 0), Day 365

• Participants With Deaths, Adverse Events (AEs) and SAEs in the Open-Label (OL) Period

  AE was defined as 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 was defined as 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.

  Day 365 to Day 2,185

• Participants With Hematology Values Meeting the Marked Abnormality Criteria in the OL Period

  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 2,185

• Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria in the OL Period

  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 2,185

• Participants With Electrolyte Values Meeting the Marked Abnormality Criteria in the OL Period

  Sodium \< 0.9 \* LLN or \> 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: \< 0.9 \* LLN or \> 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; Chloride: \< 0.9 \* LLN or \> 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 \<0.8 \* LLN or \> 1.2 \* ULN or if BL \< LLN then use \<0.67 \* BL or \> ULN or if BL \> ULN then use \> 1.3 \* BL or \< LLN.

  Day 365 to Day 2,185

• Participants With Glucose, Protein, Metabolites, and Urinalysis Values Meeting the Marked Abnormality Criteria in the OL Period

  Glucose: \< 65 mg/dL or \> 220 mg/dL; Fasting Glucose: \<0.8 \* LLN or \> 1.5 \* ULN or if BL \< LLN then use \< 0.8 \* BL or \> ULN or if BL \> ULN then use 1.1 \* BL or \< LLN; Total protein: \< 0.9 \* LLN or 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; Albumin: \< 0.9 \* LLN or if BL \< LLN then use 0.75 \* BL; Uric acid: \> 1.5 \* ULN or if BL \> ULN then use \> 2.0 \* BL. All urinalysis abnormalities were defined as: if missing BL then use \>= 2 or if value \>=4, or if BL = 0 or 0.5 then use \>= 2, or if BL = 1.0 then use \>= 3, or if BL = 2.0 then use \>=4.

  Day 365 to Day 2,185

• Mean BL Immunoglobulins Over Time in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365, Day 729, and Day 1,093.

  BL (Day 0), Day 365, Day 729, Day 1,093

• Mean Change From BL in Immunoglobulins in the OL Period

  BL (Day 0), Day 365, Day 729, Day 1,093

• Participants With Immunogenicity to Abatacept in the Cumulative DB + OL Period

  Participants with titers to abatacept in the DB and OL periods. Serum samples from abatacept-treated adult participants with active Rheumatoid Arthritis (RA) were screened for the presence of drug-specific antibodies using two validated direct-format enzyme-linked immunosorbent assays (ELISAs) to determine the presence of antibodies to abatacept and or CTLA4-T.

  Day 1 to Day 1,821

• Number of Participants Experiencing Clinically Significant Changes in Vital Signs in the OL Period

  Vital signs included body temperature, heart rate, and seated blood pressure. Clinically significant changes were defined as those that were not within the normal range for the participant.

  Day 365 to Day 1,821. All changes in participant vital signs were monitored on each day of study drug administration prior to dosing and 60 minutes after dosing.

• Number of Participants Experiencing AEs of Special Interest in the OL Period

  AEs were defined as 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 have been identified to be those which may be associated with the use of immunomodulatory agents or infusion of therapeutic proteins. Acute infusional AEs were defined as those that occurred within 1 hour after the start of the infusion.

  Day 365 to Day 2,185

• Mean BL Hematocrit in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  Baseline (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in Participant Hematocrit in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean BL Platelet Count in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in Participant Platelet Count in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean BL Hemoglobin, Total Protein, and Albumin in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in Hemoglobin, Total Protein, and Albumin in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean BL White Blood Cells in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in White Blood Cells in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean BL Liver Function Parameters in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in Liver Function Parameters in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean BL Select Laboratory Parameters in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in Select Laboratory Parameters in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean BL Serum Electrolytes in the OL Period

  Mean baseline values are those that are reported for each cohort at each time point on Day 365 to Day 2,185.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

• Mean Change From BL in Serum Electrolytes in the OL Period

  All changes in participant laboratory parameters were monitored on each day of study drug administration.

  BL (Day 0), Day 365, Day 729, Day 1,093, Day 1,457, Day 1,821, Day 1,905, Day 1,989, Day 2,073, Day 2,185

Secondary Outcomes (119)

• Mean Number of Tender Joints and Swollen Joints at DB BL

  BL (Day 0)

• Mean DB BL Participant Physical Pain Assessment, Participant Global Assessment, and Physician Global Assessment

  BL (Day 0)

• BL Rheumatoid Factor (RF) Status for Participants Continuing in the OL Period

  BL (Day 365)

• ACR 20 Responders at Day 365

  Day 365

• ACR 20 Responders in the Double-Blind (DB) Period

  Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 225, Day 281, Day 365

Study Arms (3)

Abatacept + Methotrexate

EXPERIMENTAL

Short Term: Abatacept was dosed by weight with participants weighing \< 60 kg received abatacept 500 mg; participants ≥ 60 kg and ≤ 100 kg received abatacept 750 mg; and participants \> 100 kg received abatacept 1 g. Participants continued treatment with methotrexate (MTX) either orally or parenterally at a minimum dose of 15 mg.

Drug: Abatacept; Drug: Methotrexate

Placebo + Methotrexate

ACTIVE COMPARATOR

Short Term: Participants received a placebo solution intravenously and methotrexate at the dose employed prior to study enrollment and a minimum of 15 mg.

Drug: Methotrexate; Drug: Placebo

Abatacept + Methotrexate Open Label

EXPERIMENTAL

Open Label: Abatacept was dosed intravenously by weight at 10 mg/kg in the OL period under tiered dosing such that participants weighing \< 60 kg received abatacept 500 mg; participants ≥ 60 kg and ≤ 100 kg received abatacept 750 mg; and participants \> 100 kg received abatacept 1 g. MTX was continued at the dose used in the DB period.

Drug: Abatacept; Drug: Methotrexate

Interventions

Abatacept DRUG

Intravenous (IV) Solution, - Weight Titered (500 mg \< 60 kg); (750 mg 60-100 kg), )1 gram \> 100 kg), Day 1, Day 15, Day 29; every 28 days thereafter, 1 year

Also known as: BMS-188667

Abatacept + Methotrexate; Abatacept + Methotrexate Open Label

Methotrexate DRUG

Tablets, Oral, \>= 15 mg, weekly, 1 year

Also known as: MTX

Abatacept + Methotrexate; Abatacept + Methotrexate Open Label; Placebo + Methotrexate

Placebo DRUG

IV solution, Intravenous, D5W, Day 1, Day 15, Day 29; every 28 days thereafter, 1 year

Placebo + Methotrexate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

* Rheumatoid Arthritis (RA) for greater than 1 year from the time of initial diagnosis of RA. * Participants must have been taking methotrexate for at least 3 months with at least a weekly dose of 15 mg.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Bristol-Myers Squibb: lead

Study Sites (48)

Local Institution

Birmingham, Alabama, United States

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Huntsville, Alabama, United States

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Mobile, Alabama, United States

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Phoenix, Arizona, United States

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Scottsdale, Arizona, United States

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Corona, California, United States

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Irvine, California, United States

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La Jolla, California, United States

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Long Beach, California, United States

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Rancho Mirage, California, United States

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Aurora, Colorado, United States

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Colorado Springs, Colorado, United States

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Denver, Colorado, United States

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Hamden, Connecticut, United States

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Washington D.C., District of Columbia, United States

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Fort Lauderdale, Florida, United States

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Gainsville, Florida, United States

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Palm Harbor, Florida, United States

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Sarasota, Florida, United States

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St. Petersburg, Florida, United States

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Chicago, Illinois, United States

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Rockford, Illinois, United States

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Wichita, Kansas, United States

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Coeur d'Alene, Maryland, United States

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Cumberland, Maryland, United States

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Springfield, Massachusetts, United States

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Duluth, Minnesota, United States

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Lincoln, Nebraska, United States

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New Brunswick, New Jersey, United States

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Albuquerque, New Mexico, United States

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Albany, New York, United States

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Binghamton, New York, United States

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Mineola, New York, United States

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New York, New York, United States

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Syracuse, New York, United States

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The Bronx, New York, United States

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Wilmington, North Carolina, United States

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Cincinnati, Ohio, United States

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Oklahoma City, Oklahoma, United States

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Duncansville, Pennsylvania, United States

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Norristown, Pennsylvania, United States

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Sellersville, Pennsylvania, United States

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Willow Grove, Pennsylvania, United States

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North Charleston, South Carolina, United States

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Austin, Texas, United States

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San Antonio, Texas, United States

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Arlington, Virginia, United States

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Milwaukee, Wisconsin, United States

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Related Publications (3)

• Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Li T, Ge Z, Becker JC, Westhovens R. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006 Jun 20;144(12):865-76. doi: 10.7326/0003-4819-144-12-200606200-00003.

  PMID: 16785475 RESULT

• Kremer JM, Peterfy C, Russell AS, Emery P, Abud-Mendoza C, Sibilia J, Becker JC, Westhovens R, Genant HK. Longterm safety, efficacy, and inhibition of structural damage progression over 5 years of treatment with abatacept in patients with rheumatoid arthritis in the abatacept in inadequate responders to methotrexate trial. J Rheumatol. 2014 Jun;41(6):1077-87. doi: 10.3899/jrheum.130263. Epub 2014 May 1.

  PMID: 24786925 DERIVED

• Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Li T, Teng J, Becker JC, Westhovens R. Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum. 2008 Apr;58(4):953-63. doi: 10.1002/art.23397.

  PMID: 18383390 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Abatacept; Methotrexate

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: BMS Study Director
• Organization: Bristol Myers-Squibb

clinical.trials@bms.com

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2002
• First Posted: November 13, 2002
• Study Start: December 1, 2002
• Primary Completion: October 1, 2009
• Study Completion: October 1, 2009
• Last Updated: December 5, 2011
• Results First Posted: December 5, 2011

Record last verified: 2011-10

Locations

US (48)