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A Phase IIIb Study of BMS-188667 in Subjects With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate

Primary Purpose

Active Rheumatoid Arthritis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Abatacept
Placebo
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Active Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Disease activity as defined by a Disease Activity Score 28-C-Reactive Protein (CRP) >3.2 or >6 swollen and ≥6 tender joints and CRP greater than the upper limit of normal
  • At least 1 erosion in hands/wrists or positive anticyclic citrullinated peptides or rheumatoid factor
  • Clinically detectable synovitis of at least 1 wrist/ankle at screening and baseline
  • Participants must have been treated with methotrexate, on a weekly dose of at least 15 mg or a maximum tolerated dose (such as, 10 mg weekly) for at least 3 months before screening. Dose of methotrexate must be stable for at least 28 days prior to the first study dose (Day 1)

Sites / Locations

  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Abatacept + Methotrexate (Double-blind period)

Placebo + Methotrexate (Double-blind period)

Arm Description

Outcomes

Primary Outcome Measures

Double-blind Period: Mean Synovitis Scores at Baseline As Measured by the Rheumatoid Arthritis Clinical Trials 6 (OMERACT 6) Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS)
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. Change in synovitis = Follow-up synovitis score - baseline score.
Double-blind Period: Mean Change From Baseline in OMERACT 6 Wrist Synovitis Score: Planned Analysis Using Non-Parametric ANCOVA
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. Change in synovitis=Follow-up synovitis score-baseline score.
Double-blind Period: Mean Change From Baseline in OMERACT 6 Wrist Synovitis Score: Post Hoc Sensitivity Analysis Using Parametric ANCOVA Analysis
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. Change in synovitis score=Follow-up synovitis score-baseline synovitis score.

Secondary Outcome Measures

Double-blind Period: Baseline Mean Erosion OMERACT 6 Scores
Bone erosion assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage) according to erosion of the original articular bone (each unit=10% loss of articular bone). The total erosion score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 230. Increasing score=greater severity.
Double-blind Period: Adjusted Mean Change From Baseline in Erosion OMERACT 6 Scores
Bone erosion assessed at 23 anatomic locations: 15 in 1 wrist and 8 in attached hand. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage), indicating erosion (each unit=10% bone loss) of original articular bone. Total erosion score for hands/wrists is sum of the individual scores for each location. Thus the maximum score per hand/wrist is 230. Increasing score=greater severity. Adjusted change from baseline in erosion score=mean score at Day 113-mean erosion score at baseline. Adjustment based on ANCOVA model with treatment=factor and baseline value=covariate.
Double-blind Period: Baseline Mean Osteitis OMERACT 6 Scores
Osteitis assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 to 3, indicating involvement of original articular bone. The total score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 23 (total number of anatomic locations) * 3 (maximum per joint)=69. Minimum score=0, indicating normal. Increasing score=greater severity.
Double-blind Period: Adjusted Mean Change From Baseline in Osteitis OMERACT 6 Scores
Osteitis assessed at 23 anatomic locations: 15 in 1 wrist and 8 in attached. Each site scored in 1.0 increments, indicating involvement of original articular bone (0=none to 3=severe). Total score for hands/wrists is sum of scores for each location. Maximum score per hand/wrist is 23 (total anatomic locations)*3 (maximum score per joint)=69. Minimum score=0(normal). Increasing score=greater severity. Adjusted mean change from baseline in osteitis score=mean score at Day 113-mean score at baseline. Adjustment based on ANCOVA model with treatment=factor and baseline value=covariate.
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
Bone erosion and osteitis were assessed at a total of 23 anatomic locations according to erosion (for bone erosion) or involvement (for osteitis) of the original articular bone. Synovitis assessed as above-normal post-gadolinium enhancement in 3 wrist regions: distal radioulnar joint, radiocarpal joint, and intercarpal and carpometacarpal joints.
Double-blind Period: Baseline Mean RAMRIS Scores
RAMRIS score is the sum of its core components: Synovitis Score, Osteitis Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Osteitis scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score + Osteitis Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Osteitis Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.
Double-blind Period: Adjusted Mean Change From Baseline in RAMRIS Scores
RAMRIS Score=sum of core components: Synovitis (S), Osteitis (O), and Erosion (E) Scores. S scored 0 (none) to 9 (maximum distension of synovial cavity); O scored 0 (none) to 69 (maximum articular bone involvement); E scored 0 (none) to 230 (maximum erosion of articular bone). RAMRIS=S+O+E Scores. RAMRIS minimum score=0 (normal), maximum=308 (severe structural damage). Adjusted change from baseline in RAMRIS=mean RAMRIS at Day 113-mean RAMRIS at baseline. Adjustment based on ANCOVA model: treatment=factor, baseline value=covariate.
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
PINP and osteocalcin are markers of bone formation. Osteocalcin is synthesized by osteoblasts and is associated with osteoblast synthetic activity. Osteoblasts secrete type 1 procollagen, and cleavage of large fragments from the carboxy and amino terminal ends result in formation of mature type 1 collagen and production of PINP fragments.
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
CTX-I and ICTP are biochemical markers of bone resorption or bone degradation
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Urinary CTX-II is a biochemical marker of type II collagen breakdown. In participants with early rheumatoid arthritis, increased levels of CTX-II can be predictive of rapid radiographic progression over periods of 1 to 5 years. These markers of cartilage destruction can predict progression of joint damage, independent of clinical and biologic indices of disease activity and baseline joint damage.
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) is a specific biochemical marker reflecting the degradation of the synovial tissue membrane. It is a glycosylated derivative of the collagen crosslink pyridinoline, and it is present in significant amounts only in the synovial membrane; it is absent from bone and present in minutes amounts in cartilage and other soft tissues. Increased urinary levels of Glc-Gal-PYD have been found in early and long-standing rheumatoid arthritis, high levels being associated with rapid destruction.
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study treatment.
Double-blind Period: Number of Participants With AEs of Special Interest
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including serious, opportunistic, and all other infections; autoimmune disorders; neoplasms; acute infusional AEs (prespecified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (prespecified AEs occurring within 24 hours of start of infusion).
Double-blind Period: Number of Participants With Infections/Infestations of Special Interest
Infections/Infestations of Special Interest are AEs and SAEs considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). AE=any new untoward medical occurrence or worsening of a preexisting medical condition which does not necessarily have a causal relationship with this treatment.
Double-blind Period: Number of Participants With Acute Infusional AEs of Special Interest
Acute infusional AEs are AEs with onset during the first hour after the start of study drug infusion. An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs considered possibly, probably, or certainly related to study treatment were graded according to Common Terminology Criteria for Adverse Events ,Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Peri-infusional AEs are AEs occurring during the first 24 hours after the start of study drug infusion. An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs considered possibly, probably, or certainly related to study treatment were graded according to Common Terminology Criteria for Adverse Events, Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
BL=baseline; LLN=lower limit of normal; ULN=upper limit of normal. Marked abnormality criteria: Hemoglobin: >3 g/dL decrease from BL. Hematocrit: <0.75*BL. Erythrocytes: <0.75*BL. Platelets: <0.67*LLN/>1.5*ULN, or if BL <LLN, use 0.5*BL/<100,000 mm^3. Leukocytes: <0.75*LLN/>1.25*ULN, or if BL<LLN, use <0.8*BL/>ULN, or if BL>ULN, use >1.2*BL/<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.
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
ULN=upper limit of normal; BL=baseline. Marked abnormality criteria: Alkaline phosphatase: >2*ULN, or if BL>ULN, use >3*BL; aspartate aminotransferase: >3*ULN, or if BL>ULN,use >4*BL; alanine aminotransferase: >3*ULN, or if BL>ULN, use >4*BL; G-Glutamyl transferase: >2*ULN, or if BL>ULN, use >3*BL; Bilirubin: >2*ULN, or if BL>ULN, use >4*BL; blood urea nitrogen: >2*BL; creatinine: >1.5*BL.
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Marked abnormality: Sodium: <0.95*LLN/>1.05*ULN,or if BL<LLN, use 0.95*BL or >ULN,or if BL>ULN, use>1.05*BL or <LLN. Potassium: <0.9*LLN/>1.1* ULN,or if BL<LLN, use 0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN. Chloride: <0.9*LLN/>1.1*ULN, or if BL<LLN, use 0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN. Calcium: <0.8*LLN/>1.2*ULN, or if BL<LLN, use 0.75*BL or >ULN, or if BL>ULN, use>1.25*BL or <LLN. Phosphorous: <0.75*LLN/>1.25*ULN, or if BL<LLN, use 0.67*BL or >ULN, or if BL>ULN, use>1.33*BL or <LLN.
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
LLN=lower limit of normal; ULN=upper limit of normal; BL-baseline. Marked abnormality c: serum glucose:<65 mg/dL/>220 mg/dL; fasting serum glucose: <0.8* LLN/>1.5* ULN, or if BL<LLN, use 0.8*BL or >ULN, or if BL>ULN, use >2.0*BL or <LLN; total protein: <0.9*LLN/>1.1* ULN; albumin: <0.9*LLN,or if BL<LLN, use <0.75 BL; uric acid: >1.5* ULN, or if BL>ULN, use >2*BL. Urinalysis (Urine protein, urine Glu, urine blood, leukocyte esterase, red blood cells, white blood cells):Use ≥2 when BL value missing or value ≥4,or when predose=0 or 0.5. Use ≥3 when predose=1. Use ≥4 when predose=2 or 3
Double-blind Period:Number of Participants With Significantly Abnormal Changes in Vital Signs
Vital signs, which included blood pressure, heart rate, respiration, and temperature, were monitored predose and 1 hour after start of infusion. Changes in vital signs were determined to be significantly abnormal at the discretion of the investigator but were generally those that either exceeded, or failed to reach, normal parameters. Normal vital sign parameter ranges varied by site.
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
On-Rx=on treatment; post-Rx=post treatment. ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction Category=reactivity against constant regions and/or hinge region of human IgG1.

Full Information

First Posted
January 8, 2007
Last Updated
January 13, 2012
Sponsor
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT00420199
Brief Title
A Phase IIIb Study of BMS-188667 in Subjects With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate
Official Title
A Phase IIIB Multicenter, Randomized, Double-Blind, Placebo-controlled Study to Assess Short-term Changes in Synovitis and Structural Damage Outcomes in Subjects With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate, Treated With Abatacept Versus Placebo on a Background Therapy With Methotrexate
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Completed
Study Start Date
May 2007 (undefined)
Primary Completion Date
August 2009 (Actual)
Study Completion Date
May 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The only trial in participants who are methotrexate-inadequate responders and have active Rheumatoid Arthritis, in which gadolinium-enhanced Magnetic Resonance Imaging; Bone Mineral Density; and biochemical markers of bone, cartilage, and synovial tissue metabolism are used to evaluate early effects (4 months) of Abatacept on inflammation/structural damage. Study will provide valuable mechanism-of-action information on how Abatacept exerts its effects (including on bone) through new techniques.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Active Rheumatoid Arthritis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Abatacept + Methotrexate (Double-blind period)
Arm Type
Active Comparator
Arm Title
Placebo + Methotrexate (Double-blind period)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Abatacept
Other Intervention Name(s)
(BMS-188667), Orencia
Intervention Description
Vials (250 mg/vial), intravenous (IV), 10 mg/kg, monthly infusion , 12 months of treatment
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Intravenous (IV) bags, IV, 0 mg, monthly infusion, 12 months of treatment
Primary Outcome Measure Information:
Title
Double-blind Period: Mean Synovitis Scores at Baseline As Measured by the Rheumatoid Arthritis Clinical Trials 6 (OMERACT 6) Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS)
Description
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. Change in synovitis = Follow-up synovitis score - baseline score.
Time Frame
At baseline
Title
Double-blind Period: Mean Change From Baseline in OMERACT 6 Wrist Synovitis Score: Planned Analysis Using Non-Parametric ANCOVA
Description
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. Change in synovitis=Follow-up synovitis score-baseline score.
Time Frame
Baseline to Day 113
Title
Double-blind Period: Mean Change From Baseline in OMERACT 6 Wrist Synovitis Score: Post Hoc Sensitivity Analysis Using Parametric ANCOVA Analysis
Description
Wrist synovitis was assessed by postgadolinium MRI enhancement according to OMERACT 6 RAMRIS in 3 wrist regions: distal radioulnar, radiocarpal, and intercarpal and carpometacarpal joints. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. Change in synovitis score=Follow-up synovitis score-baseline synovitis score.
Time Frame
Baseline to Day 113
Secondary Outcome Measure Information:
Title
Double-blind Period: Baseline Mean Erosion OMERACT 6 Scores
Description
Bone erosion assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage) according to erosion of the original articular bone (each unit=10% loss of articular bone). The total erosion score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 230. Increasing score=greater severity.
Time Frame
At baseline
Title
Double-blind Period: Adjusted Mean Change From Baseline in Erosion OMERACT 6 Scores
Description
Bone erosion assessed at 23 anatomic locations: 15 in 1 wrist and 8 in attached hand. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage), indicating erosion (each unit=10% bone loss) of original articular bone. Total erosion score for hands/wrists is sum of the individual scores for each location. Thus the maximum score per hand/wrist is 230. Increasing score=greater severity. Adjusted change from baseline in erosion score=mean score at Day 113-mean erosion score at baseline. Adjustment based on ANCOVA model with treatment=factor and baseline value=covariate.
Time Frame
Baseline to Day 113
Title
Double-blind Period: Baseline Mean Osteitis OMERACT 6 Scores
Description
Osteitis assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 to 3, indicating involvement of original articular bone. The total score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 23 (total number of anatomic locations) * 3 (maximum per joint)=69. Minimum score=0, indicating normal. Increasing score=greater severity.
Time Frame
At baseline
Title
Double-blind Period: Adjusted Mean Change From Baseline in Osteitis OMERACT 6 Scores
Description
Osteitis assessed at 23 anatomic locations: 15 in 1 wrist and 8 in attached. Each site scored in 1.0 increments, indicating involvement of original articular bone (0=none to 3=severe). Total score for hands/wrists is sum of scores for each location. Maximum score per hand/wrist is 23 (total anatomic locations)*3 (maximum score per joint)=69. Minimum score=0(normal). Increasing score=greater severity. Adjusted mean change from baseline in osteitis score=mean score at Day 113-mean score at baseline. Adjustment based on ANCOVA model with treatment=factor and baseline value=covariate.
Time Frame
Baseline to Day 113
Title
Double-blind Period: Number of Participants With Newly Involved Joints in Bone Erosion, Edema/Osteitis, and Synovitis
Description
Bone erosion and osteitis were assessed at a total of 23 anatomic locations according to erosion (for bone erosion) or involvement (for osteitis) of the original articular bone. Synovitis assessed as above-normal post-gadolinium enhancement in 3 wrist regions: distal radioulnar joint, radiocarpal joint, and intercarpal and carpometacarpal joints.
Time Frame
Baseline to Day 113
Title
Double-blind Period: Baseline Mean RAMRIS Scores
Description
RAMRIS score is the sum of its core components: Synovitis Score, Osteitis Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Osteitis scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score + Osteitis Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Osteitis Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.
Time Frame
Baseline
Title
Double-blind Period: Adjusted Mean Change From Baseline in RAMRIS Scores
Description
RAMRIS Score=sum of core components: Synovitis (S), Osteitis (O), and Erosion (E) Scores. S scored 0 (none) to 9 (maximum distension of synovial cavity); O scored 0 (none) to 69 (maximum articular bone involvement); E scored 0 (none) to 230 (maximum erosion of articular bone). RAMRIS=S+O+E Scores. RAMRIS minimum score=0 (normal), maximum=308 (severe structural damage). Adjusted change from baseline in RAMRIS=mean RAMRIS at Day 113-mean RAMRIS at baseline. Adjustment based on ANCOVA model: treatment=factor, baseline value=covariate.
Time Frame
Baseline to Day 113
Title
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Formation: Osteocalcin and Serum Intact N-terminal Propeptide of Type I Procollagen (PINP)
Description
PINP and osteocalcin are markers of bone formation. Osteocalcin is synthesized by osteoblasts and is associated with osteoblast synthetic activity. Osteoblasts secrete type 1 procollagen, and cleavage of large fragments from the carboxy and amino terminal ends result in formation of mature type 1 collagen and production of PINP fragments.
Time Frame
Baseline to Days 15, 29, 57, 85, and 113
Title
Double-blind Period: Median Percent Change From Baseline in Systemic Markers of Bone Destruction (Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen [CTX-I] and Serum Pyridinoline Cross-linked Telopeptide Domain of Type I Collagen [ICTP])
Description
CTX-I and ICTP are biochemical markers of bone resorption or bone degradation
Time Frame
Baseline to Days 15, 29, 57, 85, and 113
Title
Double-blind Period: Median Percent Change From Baseline in a Systemic Marker of Cartilage Degradation (Creatinine-corrected Urinary Carboxyterminal Crosslinking Telopeptide of Type II Collagen [UCTX2C])
Description
Urinary CTX-II is a biochemical marker of type II collagen breakdown. In participants with early rheumatoid arthritis, increased levels of CTX-II can be predictive of rapid radiographic progression over periods of 1 to 5 years. These markers of cartilage destruction can predict progression of joint damage, independent of clinical and biologic indices of disease activity and baseline joint damage.
Time Frame
Baseline to Days 15, 29, 57, 85, and 113
Title
Double-blind Period: Median Percent Change From Baseline in Systemic Marker of Synovial Tissue Metabolism (Creatinine-corrected Urinary Glucosyl-Galactosyl-Pyridinoline [UGGPC])
Description
Glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) is a specific biochemical marker reflecting the degradation of the synovial tissue membrane. It is a glycosylated derivative of the collagen crosslink pyridinoline, and it is present in significant amounts only in the synovial membrane; it is absent from bone and present in minutes amounts in cartilage and other soft tissues. Increased urinary levels of Glc-Gal-PYD have been found in early and long-standing rheumatoid arthritis, high levels being associated with rapid destruction.
Time Frame
Baseline to Days 15, 29, 57, 85, and 113
Title
Double-blind Period: Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation
Description
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study treatment.
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With AEs of Special Interest
Description
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including serious, opportunistic, and all other infections; autoimmune disorders; neoplasms; acute infusional AEs (prespecified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (prespecified AEs occurring within 24 hours of start of infusion).
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Infections/Infestations of Special Interest
Description
Infections/Infestations of Special Interest are AEs and SAEs considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). AE=any new untoward medical occurrence or worsening of a preexisting medical condition which does not necessarily have a causal relationship with this treatment.
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Acute Infusional AEs of Special Interest
Description
Acute infusional AEs are AEs with onset during the first hour after the start of study drug infusion. An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs considered possibly, probably, or certainly related to study treatment were graded according to Common Terminology Criteria for Adverse Events ,Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Peri-infusional AEs of Special Interest
Description
Peri-infusional AEs are AEs occurring during the first 24 hours after the start of study drug infusion. An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. AEs considered possibly, probably, or certainly related to study treatment were graded according to Common Terminology Criteria for Adverse Events, Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality
Description
BL=baseline; LLN=lower limit of normal; ULN=upper limit of normal. Marked abnormality criteria: Hemoglobin: >3 g/dL decrease from BL. Hematocrit: <0.75*BL. Erythrocytes: <0.75*BL. Platelets: <0.67*LLN/>1.5*ULN, or if BL <LLN, use 0.5*BL/<100,000 mm^3. Leukocytes: <0.75*LLN/>1.25*ULN, or if BL<LLN, use <0.8*BL/>ULN, or if BL>ULN, use >1.2*BL/<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.
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Laboratory Test Results for Liver and Kidney Function Meeting Criteria for Marked Abnormality
Description
ULN=upper limit of normal; BL=baseline. Marked abnormality criteria: Alkaline phosphatase: >2*ULN, or if BL>ULN, use >3*BL; aspartate aminotransferase: >3*ULN, or if BL>ULN,use >4*BL; alanine aminotransferase: >3*ULN, or if BL>ULN, use >4*BL; G-Glutamyl transferase: >2*ULN, or if BL>ULN, use >3*BL; Bilirubin: >2*ULN, or if BL>ULN, use >4*BL; blood urea nitrogen: >2*BL; creatinine: >1.5*BL.
Time Frame
From Day 1 to Day 113, and including up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Laboratory Test Results for Electrolytes Meeting the Criteria for Marked Abnormality
Description
LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Marked abnormality: Sodium: <0.95*LLN/>1.05*ULN,or if BL<LLN, use 0.95*BL or >ULN,or if BL>ULN, use>1.05*BL or <LLN. Potassium: <0.9*LLN/>1.1* ULN,or if BL<LLN, use 0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN. Chloride: <0.9*LLN/>1.1*ULN, or if BL<LLN, use 0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN. Calcium: <0.8*LLN/>1.2*ULN, or if BL<LLN, use 0.75*BL or >ULN, or if BL>ULN, use>1.25*BL or <LLN. Phosphorous: <0.75*LLN/>1.25*ULN, or if BL<LLN, use 0.67*BL or >ULN, or if BL>ULN, use>1.33*BL or <LLN.
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period: Number of Participants With Laboratory Test Results in Other Chemistries and Urinalysis Meeting the Criteria for Marked Abnormality
Description
LLN=lower limit of normal; ULN=upper limit of normal; BL-baseline. Marked abnormality c: serum glucose:<65 mg/dL/>220 mg/dL; fasting serum glucose: <0.8* LLN/>1.5* ULN, or if BL<LLN, use 0.8*BL or >ULN, or if BL>ULN, use >2.0*BL or <LLN; total protein: <0.9*LLN/>1.1* ULN; albumin: <0.9*LLN,or if BL<LLN, use <0.75 BL; uric acid: >1.5* ULN, or if BL>ULN, use >2*BL. Urinalysis (Urine protein, urine Glu, urine blood, leukocyte esterase, red blood cells, white blood cells):Use ≥2 when BL value missing or value ≥4,or when predose=0 or 0.5. Use ≥3 when predose=1. Use ≥4 when predose=2 or 3
Time Frame
From Day 1 to Day 113, and up to 56 days post last dose of double-blind period, or start of first dose of open-label period
Title
Double-blind Period:Number of Participants With Significantly Abnormal Changes in Vital Signs
Description
Vital signs, which included blood pressure, heart rate, respiration, and temperature, were monitored predose and 1 hour after start of infusion. Changes in vital signs were determined to be significantly abnormal at the discretion of the investigator but were generally those that either exceeded, or failed to reach, normal parameters. Normal vital sign parameter ranges varied by site.
Time Frame
Days 1, 15, 29, 57, 85, and 113
Title
Double-blind Period: Number of Participants With Positive Antibodies to Abatacept by Electrochemiluminescence (ECL) Assay
Description
On-Rx=on treatment; post-Rx=post treatment. ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction Category=reactivity against constant regions and/or hinge region of human IgG1.
Time Frame
Day 1 to Day 113

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Disease activity as defined by a Disease Activity Score 28-C-Reactive Protein (CRP) >3.2 or >6 swollen and ≥6 tender joints and CRP greater than the upper limit of normal At least 1 erosion in hands/wrists or positive anticyclic citrullinated peptides or rheumatoid factor Clinically detectable synovitis of at least 1 wrist/ankle at screening and baseline Participants must have been treated with methotrexate, on a weekly dose of at least 15 mg or a maximum tolerated dose (such as, 10 mg weekly) for at least 3 months before screening. Dose of methotrexate must be stable for at least 28 days prior to the first study dose (Day 1)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Local Institution
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
Local Institution
City
Yvoir
ZIP/Postal Code
5530
Country
Belgium
Facility Name
Local Institution
City
Berlin
ZIP/Postal Code
14059
Country
Germany
Facility Name
Local Institution
City
Berlin
ZIP/Postal Code
BE-10117
Country
Germany
Facility Name
Local Institution
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Local Institution
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Local Institution
City
Barcelona
ZIP/Postal Code
08907
Country
Spain
Facility Name
Local Institution
City
Stockholm
ZIP/Postal Code
171 76
Country
Sweden
Facility Name
Local Institution
City
London
State/Province
Greater London
ZIP/Postal Code
SE19RT
Country
United Kingdom
Facility Name
Local Institution
City
Leeds
State/Province
North Yorkshire
ZIP/Postal Code
LS7 4SA
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
22915624
Citation
Conaghan PG, Durez P, Alten RE, Burmester GR, Tak PP, Klareskog L, Catrina AI, DiCarlo J, Gaillez C, Le Bars M, Zhou X, Peterfy C. Impact of intravenous abatacept on synovitis, osteitis and structural damage in patients with rheumatoid arthritis and an inadequate response to methotrexate: the ASSET randomised controlled trial. Ann Rheum Dis. 2013 Aug;72(8):1287-94. doi: 10.1136/annrheumdis-2012-201611. Epub 2012 Aug 21.
Results Reference
derived

Learn more about this trial

A Phase IIIb Study of BMS-188667 in Subjects With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate

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