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

Active Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00420199
• Other study ID #: IM101-119
• Secondary ID: Eudract: 2006-00
• Status: Completed
• Phase: Phase 3
• First received: January 8, 2007
• Last updated: January 13, 2012
• Start date: May 2007
• Est. completion date: May 2010

Study information

• Verified date: January 2012
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: Sweden: Lakemedelsverket Medical Products Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: May 2010
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Active Rheumatoid Arthritis
• Arthritis
• Arthritis, Rheumatoid

Intervention

Drug:
• Abatacept
Vials (250 mg/vial), intravenous (IV), 10 mg/kg, monthly infusion , 12 months of treatment
• Placebo
Intravenous (IV) bags, IV, 0 mg, monthly infusion, 12 months of treatment

Locations

Country	Name	City	State
Belgium	Local Institution	Bruxelles
Belgium	Local Institution	Yvoir
Germany	Local Institution	Berlin
Germany	Local Institution	Berlin
Netherlands	Local Institution	Amsterdam
Spain	Local Institution	Barcelona
Spain	Local Institution	Barcelona
Sweden	Local Institution	Stockholm
United Kingdom	Local Institution	Leeds	North Yorkshire
United Kingdom	Local Institution	London	Greater London

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

Belgium,  Germany,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	At baseline	No
Primary	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.	Baseline to Day 113	No
Primary	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.	Baseline to Day 113	No
Secondary	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.	At baseline	No
Secondary	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.	Baseline to Day 113	No
Secondary	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.	At baseline	No
Secondary	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.	Baseline to Day 113	No
Secondary	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.	Baseline to Day 113	No
Secondary	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.	Baseline	No
Secondary	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.	Baseline to Day 113	No
Secondary	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.	Baseline to Days 15, 29, 57, 85, and 113	No
Secondary	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	Baseline to Days 15, 29, 57, 85, and 113	No
Secondary	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.	Baseline to Days 15, 29, 57, 85, and 113	No
Secondary	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.	Baseline to Days 15, 29, 57, 85, and 113	No
Secondary	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.	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	Yes
Secondary	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).	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	Yes
Secondary	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.	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	Yes
Secondary	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).	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	Yes
Secondary	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).	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	Yes
Secondary	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	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	Yes
Secondary	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.	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	Yes
Secondary	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	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	Yes
Secondary	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	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	Yes
Secondary	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.	Days 1, 15, 29, 57, 85, and 113	Yes
Secondary	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.	Day 1 to Day 113	No

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
•   Investigator Inquiry form