A Rheumatoid Arthritis Study to Assess Early Response to Abatacept+MTX as Defined by Improvement of Synovitis Measures by Power Doppler Ultrasonography

Rheumatoid Arthritis Clinical Trial

Official title:

Multi-Center, Open Label Study to Assess Early Response to Abatacept With Background Methotrexate Using Power Doppler Ultrasonography in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00767325
• Other study ID #: IM101-179
• Status: Completed
• Phase: Phase 3
• First received: October 6, 2008
• Last updated: June 24, 2013
• Start date: December 2008
• Est. completion date: October 2011

Study information

• Verified date: June 2013
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of HealthSpain: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyItaly: Ministry of HealthNorway: Norwegian Medicines AgencyDenmark: Ethics CommitteeGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of Pharmacy
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to assess early signs of response to abatacept+methotrexate in metacarpophalangeal joints in both hands using power Doppler ultrasonography in patients with active rheumatoid arthritis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: October 2011
• Est. primary completion date: October 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Key inclusion riteria:

• Disease activity defined by a disease activity score 28-C-reactive protein >3.2, or meeting the following criteria: a tender joint count =6; a swollen joint count =6; C-reactive protein measurement greater than the upper limit of normal

• Diagnosis of rheumatoid arthritis for longer than 6 months from time of initial diagnosis

• Total synovitis power Doppler ultrasonography (PDUS) score >1 for at least 2 metacarpophalangeal (MCP) joints (MCP2-5) and a total synovitis PDUS score =1 for at least 1 other MCP joint (MCP2-5)

• Concomitant treatment with methotrexate at a dose =15 mg for at least 3 months before Day 1 and a stable dose for the last 28 days before Day 1

• No treatment with any background nonbiologic disease-modifying antirheumatic drug (DMARD) other than methotrexate for at least 28 days before treatment (Day 1)

• Stable dose of corticosteroids equivalent of 10 mg prednisone /day during the 28 days prior to Day 1

• Naive to treatment with biologic DMARDs

Key exclusion criteria:

• Women of childbearing potential who are unwilling or unable to use birth control

• Women who are pregnant or breastfeeding

• Meeting all diagnostic criteria for any other rheumatic disease

• Previous MCP arthroplasty, with such a procedure scheduled, or anticipating the need for such a procedure during the study. Participants who had undergone or were scheduled to undergo joint arthroplasties other than of the MCP joints were permitted to enroll in the study provided all other eligibility criteria were met.

• Active vasculitis of a major organ system with the exception of rheumatoid nodule

• Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, whether or not related to rheumatoid arthritis

• History of cancer in the last 5 years, other than nonmelanoma skin cell cancer cured by local resection or carcinoma in situ. Existing nonmelanoma skin cell cancers should have been removed, the lesion site healed, and residual cancer ruled out prior to administration of study medication

• Clinically significant abuse of alcohol or drugs

• Evidence of active or latent bacterial or viral infections at the time of potential enrollment

• Herpes zoster or cytomegalovirus infection that resolved less than 2 months before the informed consent document was signed

• For participants at risk for tuberculosis (TB):

• A history of active (TB) within the last 3 years, even if treated

• Latent TB that was not successfully treated =4 weeks

• Current clinical, radiographic, or laboratory evidence of active TB.

• Participants who have received live vaccines within 3 months of the anticipated first dose of study medication

• Participants with positive test results for hepatitis B surface antigen or hepatitis C antibody, with hepatitis C virus detected with polymerase chain reaction or recombinant immunoblot assay.

• Participants with hemoglobin level <8.5 g/dL or white blood cell count< 3000/mm^3 or platelet count <100,000/mm^3 or serum creatinin level >2*the upper limit of normal (ULN) or serum alanine transaminase level or aspartate aminotransferase level >2*ULN

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Abatacept
Abatacept, 10 mg/kg, solution given intravenously on Days 1, 15, 29,57, 85, 113, 141, and 169
• Methotrexate
Methotrexate administered in a dose of 15 mg/week or higher for at least 3 months and at a stable dose for at least 28 days prior to baseline

Locations

Country	Name	City	State
Denmark	Local Institution	Glostrup
France	Local Institution	Bois Guillaume Cedex
France	Local Institution	Boulogne
France	Local Institution	Echirolles
France	Local Institution	Nice Cedex 03
Germany	Local Institution	Munchen
Hungary	Local Institution	Budapest
Italy	Local Institution	Jesi (Ancona)
Italy	Local Institution	Pisa
Italy	Local Institution	Roma
Italy	Local Institution	Roma
Italy	Local Institution	Siena
Italy	Local Institution	Verona
Norway	Local Institution	Oslo
Norway	Local Institution	Trondheim
Spain	Local Institution	Barcelona
Spain	Local Institution	Madrid
Spain	Local Institution	Madrid
Spain	Local Institution	Madrid
Spain	Local Institution	Madrid
United Kingdom	Local Institution	Leeds	North Yorkshire

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

Denmark,  France,  Germany,  Hungary,  Italy,  Norway,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline in Global Power Doppler Ultrasonography (PDUS) Score Assessing the Metacarpophalangeal (MCP) 2-5 Joints of Both Hands (LOCF Analysis)	LOCF=last observation carried forward. PDUS assessed the degree of synovial inflammation of the MCP joints (2nd to 5th) of both hands and was performed at approximately the same time of day for each participant. Total PDUS scores are independent of the presence and grade of joint effusion and are evaluated as follows: Grade 0 or normal=normal joint (no synovial hypertrophy, no Doppler signal); Grade 1 or minimal=minimal synovitis (minimal synovial hypertrophy, with =Grade 1 Doppler signal); Grade 2 or moderate=moderate synovitis (moderate synovial hypertrophy with =Grade 2 Doppler signal or minimal synovial hypertrophy and Grade 2 Doppler signal; Grade 3 or severe=severe synovitis (severe synovial hypertrophy with =Grade 3 Doppler signal or minimal or moderate synovial hypertrophy and Grade 3 Doppler signal). Each joint is rated 1 to 3, for a total possible score ranging from 8 to 24 (8*1, 8*3) for 2 hands. Higher grade/score=more severe disease. Change=score Day x - baseline score.	Baseline to Days 7, 15, 29, 43, 57, 85, 113, 141, and 169	No
Primary	Earliest Time Point at Which Improvement of Core Component of the Global PDUS in the MCP (2-5) Joints of Both Hands Was Assessed	MCP=metacarpophalangeal; PDUS=power Doppler ultrasonography. Time point at which early signs of Global PDUS improvement were observed=earliest time point for which 0 was not included in the 95% confidence interval for the mean changes from baseline in Global PDUS (MCP 2-5) score at that and all later time points. Total PDUS scores are independent of the presence and grade of joint effusion: Grade (Gr) 0 or normal=normal joint (no synovial hypertrophy [SH], no Doppler signal); Gr 1 or minimal=minimal synovitis (minimal SH, with =Gr 1 Doppler signal); Gr 2 or moderate=moderate synovitis (moderate SH, with =Gr 2 Doppler signal or minimal SH and grade 2 Doppler signal); Gr 3 or severe=severe synovitis (severe SH with =Gr 3 Doppler signal or minimal or moderate SH and Gr 3 Doppler signal). Each joint is rated 1 to 3, for a total possible score ranging from 8 to 24 (8*1, 8*3) for the 2 hands. Higher Gr/score=more severe disease.	Baseline to Days 7, 15, 29, 43, 57, 85, 113, 141, and 169	No
Secondary	Mean Change From Baseline in Global PDUS MCP 2-5 Component Scores Over Time (LOCF Analysis)	PDUS=power Doppler ultrasonography; MCP=metacarpophalangeal; LOCF=last observation carried forward. PDUS was used to assess the degree of synovial inflammation of the MCP joints (2nd to 5th) of both hands and was performed at approximately the same time of day for each participant. PDUS scores are independent of the presence and grade of joint effusion and are evaluated as follows: Grade 0 or normal=normal joint (no synovial hypertrophy, no Doppler signal); Grade 1 or minimal=minimal synovitis (minimal synovial hypertrophy, with =Grade 1 Doppler signal); Grade 2 or moderate=moderate synovitis (moderate synovial hypertrophy with =Grade 2 Doppler signal or minimal synovial hypertrophy and grade 2 Doppler signal); Grade 3 or severe=severe synovitis (severe synovial hypertrophy with = Grade 3 Doppler signal or minimal or 1-3, for a total possible score ranging from 8 to 24 (8*1, 8*3) for the 2 hands. Higher grade/score=more severe disease. Change=score Day X-baseline score.	Days 7, 15, 29, and 169	No
Secondary	Number of Early (Days 7 to 113) Global PDUS MCP 2-5 Scores or Global PDUS Component MCP 2-5 Scores Associated With an Acceptable Predictability of Clinical Response at Day 169, As Assessed by DAS28-CRP	MCP=metacarpophalangeal; PDUS=power Doppler ultrasonography; DAS=Disease Activity Score;CRP=C-reactive protein. Receiver Operator Characteristics (ROC) analysis assessed predicatability. ROC curve analyses performed; area under the curve of =0.7 was considered acceptable for prediction. Clinical response defined as: Clinically Meaningful Improvement=drop from baseline of =1.2 in DAS28-CRP; Remission=DAS28-CRP score <2.6; Low Disease Activity==3.2. PDUS scores: Grade (Gr) 0 or normal=normal joint (no synovial hypertrophy [SH], no Doppler signal); Gr 1 or minimal=minimal synovitis (minimal SH, with =Gr 1 Doppler signal); Gr 2 or moderate=moderate synovitis (moderate SH with =Gr 2 Doppler signal or minimal SH and Gr 2 Doppler signal); Gr 3 or severe=severe synovitis (severe SH with =Gr 3 Doppler signal or minimal or moderate SH and Gr 3 Doppler signal). Each joint rated 1-3, for a total possible score ranging from 8-24 (8*1, 8*3)for the 2 hands. Higher gr/score=more severe disease.	Days 1 to 169	No
Secondary	Number of Participants With Death as Outcome, Serious Adverse Events(SAEs), Treatment-related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), Treatment-related AEs, Discontinuations Due to AEs	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug.	Days 1 to 169 to 56 days following last infusion	Yes
Secondary	Number of Participants With Adverse Events (AEs) of Interest	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Infusion reaction: acute=1 hour or less after start of dosing; periinfusional=24 hours or less after start of dosing.	Days 1 to 169 to 56 days following last infusion	Yes

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