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

• ClinicalTrials.gov Identifier: NCT00767325
• Recruitment Status: Completed
• First Posted: October 7, 2008
• Results First Posted: June 21, 2013
• Last Update Posted: July 2, 2013
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: Abatacept; Drug: Methotrexate	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 104 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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
• Study Start Date: December 2008
• Actual Primary Completion Date: October 2011
• Actual Study Completion Date: October 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Abatacept, 10 mg/kg	Drug: Abatacept; Abatacept, 10 mg/kg, solution given intravenously on Days 1, 15, 29,57, 85, 113, 141, and 169; Other Names: Orencia®; BMS-188667; Drug: 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

Outcome Measures

Primary Outcome Measures :

1. Mean Change From Baseline in Global Power Doppler Ultrasonography (PDUS) Score Assessing the Metacarpophalangeal (MCP) 2-5 Joints of Both Hands (LOCF Analysis) [ Time Frame: Baseline to Days 7, 15, 29, 43, 57, 85, 113, 141, and 169 ]
   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.
2. Earliest Time Point at Which Improvement of Core Component of the Global PDUS in the MCP (2-5) Joints of Both Hands Was Assessed [ Time Frame: Baseline to Days 7, 15, 29, 43, 57, 85, 113, 141, and 169 ]
   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.

Secondary Outcome Measures :

1. Mean Change From Baseline in Global PDUS MCP 2-5 Component Scores Over Time (LOCF Analysis) [ Time Frame: Days 7, 15, 29, and 169 ]
   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.
2. 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 [ Time Frame: Days 1 to 169 ]
   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.
3. 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 [ Time Frame: Days 1 to 169 to 56 days following last infusion ]
   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.
4. Number of Participants With Adverse Events (AEs) of Interest [ Time Frame: Days 1 to 169 to 56 days following last infusion ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Denmark

Local Institution

Glostrup, Denmark, DK-2600

France

Local Institution

Bois Guillaume Cedex, France, 76230

Local Institution

Boulogne, France, 92104

Local Institution

Echirolles, France, 38434

Local Institution

Nice Cedex 03, France, 06202

Germany

Local Institution

Munchen, Germany, 80639

Hungary

Local Institution

Budapest, Hungary, 1036

Italy

Local Institution

Jesi (Ancona), Italy, 60035

Local Institution

Pisa, Italy, 56126

Local Institution

Roma, Italy, 00161

Local Institution

Roma, Italy, 00168

Local Institution

Siena, Italy, 53100

Local Institution

Verona, Italy, 37126

Norway

Local Institution

Oslo, Norway, N0319

Local Institution

Trondheim, Norway, 7006

Spain

Local Institution

Barcelona, Spain, 08006

Local Institution

Madrid, Spain, 28006

Local Institution

Madrid, Spain, 28040

Local Institution

Madrid, Spain, 28911

Local Institution

Madrid, Spain, 28935

United Kingdom

Local Institution

Leeds, North Yorkshire, United Kingdom, LS7 4SA

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

D'Agostino MA, Boers M, Wakefield RJ, Berner Hammer H, Vittecoq O, Filippou G, Balint P, Möller I, Iagnocco A, Naredo E, Østergaard M, Gaillez C, Le Bars M. Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid arthritis starting abatacept: results from the APPRAISE study. RMD Open. 2016 May 5;2(1):e000237. doi: 10.1136/rmdopen-2015-000237. eCollection 2016.

Golinski ML, Vandhuick T, Derambure C, Fréret M, Lecuyer M, Guillou C, Hiron M, Boyer O, Le Loët X, Vittecoq O, Lequerré T. Dysregulation of RasGRP1 in rheumatoid arthritis and modulation of RasGRP3 as a biomarker of TNFα inhibitors. Arthritis Res Ther. 2015 Dec 26;17:382. doi: 10.1186/s13075-015-0894-9.

D'Agostino MA, Wakefield RJ, Berner-Hammer H, Vittecoq O, Filippou G, Balint P, Möller I, Iagnocco A, Naredo E, Østergaard M, Boers M, Gaillez C, Van Holder K, Le Bars M; OMERACT-EULAR-Ultrasound Task Force. Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study. Ann Rheum Dis. 2016 Oct;75(10):1763-9. doi: 10.1136/annrheumdis-2015-207709. Epub 2015 Nov 20.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00767325
• Other Study ID Numbers: IM101-179
• First Posted: October 7, 2008
• Results First Posted: June 21, 2013
• Last Update Posted: July 2, 2013
• Last Verified: June 2013

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Methotrexate; Abatacept; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors