A Cooperative Clinical Study of Abatacept in Multiple Sclerosis

Phase 2

Completed

Conditions: Multiple Sclerosis, Relapsing-Remitting

Interventions: Biological: abatacept
Drug: Placebo

Registration Number: NCT01116427

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The ACCLAIM study is testing whether the medication "abatacept" can be of benefit to patients with relapsing-remitting multiple sclerosis (MS). Although abatacept is an investigational medication for MS, it is not a new drug. Abatacept has been approved by the FDA to treat rheumatoid arthritis.

Detailed Description: MS is a chronic autoimmune disease in which blood cells that are supposed to protect the body from infection mistakenly attack the body's own tissue. In MS, the target of this attack is a protein called myelin that coats nerves throughout the body. Damage to this protective layer can lead to loss of neurologic function.

There are a number of treatments available to MS patients. Interferon beta, Copaxone, and other drugs can delay the worsening of the disease in some patients. For other patients, more aggressive treatment with chemotherapy drugs such as cyclophosphamide or azathioprine are needed. These drugs attempt to slow the disease by limiting the activity of the entire immune system. Because of this, they can often have serious side effects.

This study evaluates the efficacy of abatacept in the treatment of relapsing-remitting MS. In the first phase of the study, all participants will receive 8 intravenous treatments over a period of 24 weeks. Then, if a participant remains eligible, they will enter the second phase of the study and will receive another 8 treatments over the following 24 weeks. Two-thirds (2 out of 3) of participants will receive the study drug abatacept in the first phase, and then an inactive form (placebo) of the drug in the second phase. The remaining one-third (1 in 3) will get the placebo first, then the study drug in the second phase if they remain eligible. Therefore, all participants in the ACCLAIM trial will have the opportunity to receive the study drug abatacept if they remain healthy during the study. Participants will be asked to return for a follow-up visit 12 weeks after all treatments have been completed.

Regular appointments scheduled during the trial will be used to monitor participants' health and progress in the study. These appointments will include: physical and neurological exams, blood tests and motor function assessments. A total of 11 magnetic resonance imaging (MRI) procedures are scheduled during the study. The study medication and procedures related to the study will be provided at no expense to the participant.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 65

Inclusion Criteria

Clinically definite Relapsing-remitting Multiple Sclerosis (RRMS) meeting McDonald's criteria
Expanded Disability Status Scale (EDSS) scores between 0 and 5
Active disease as defined by at least one of the following criteria:
1. One or more documented clinical exacerbations in the past year prior to visit -2
2. One or more gadolinium (Gd)-enhanced MRI lesions in the past year
Willingness to forego available MS therapies
Ability and willingness to provide informed consent and comply with study requirements and procedures

Exclusion Criteria

Normal brain MRI at week -5 scan
Females who are pregnant, intending pregnancy, or lactating, and unwilling to undergo pregnancy testing
Females who are unwilling to use approved methods of contraception for the duration of the study
Any chronic medical disease, other than MS, that compromises organ function
Active infection
Diagnosis of secondary or primary progressive MS
Previous treatment with cyclophosphamide, mitoxantrone, cladribine, or rituximab at any time
Previous treatment with abatacept within the last 52 weeks prior to visit -2
Previous treatment with systemic steroids, interferon, Copaxone, mycophenolate, or other immunosuppressive medications within the last 4 weeks prior to visit -2
Previous treatment with Natalizumab within the last 26 weeks prior to visit -2
Previous vaccination with live vaccine, or previous treatment with fingolimod, within the last 8 weeks prior to visit-2
Diagnosis of malignancy other than basal cell carcinoma or cervical carcinoma in situ
Claustrophobia or other contraindications to Gd-enhanced MRI
Positive for human immunodeficiency virus (HIV) serology
Positive for hepatitis B surface antigen (HBsAg)
Positive for hepatitis C virus (HCV) serology
Purified protein derivative (PPD)-tuberculin skin test result greater than 5 mm induration
Hemoglobin less than 10.5 gm/dL
Platelets less than 100K/µL
Absolute lymphocyte count less than 700 cells/μL
Serum creatinine greater than 1.20 mg/dL
eGFR (estimated glomerular filtration rate) less than 60 mL/min/1.73 m^2
IgG anti-cardiolipin antibody greater than 15 GPL U/mL
Previous participation in another interventional clinical trial within the past 4 weeks prior to visit -2
Allergy or sensitivity to any component of abatacept
The presence of any medical condition that the investigator deems incompatible with participation in the trial

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Abatacept	Placebo	Receives abatacept during first course of treatment, switching to placebo during extension phase.
Placebo, followed by abatacept	Placebo	Receives a placebo for first course of treatment, switching to abatacept in the extension phase.
Abatacept	abatacept	Receives abatacept during first course of treatment, switching to placebo during extension phase.
Placebo, followed by abatacept	abatacept	Receives a placebo for first course of treatment, switching to abatacept in the extension phase.

Primary Outcome Measures

Name	Time	Method
Mean Number of New Inflammatory MRI Lesions Per Monthly Scans	Weeks 8-24	The mean number of new inflammatory MRI lesions obtained on scans every 4 weeks from Week 8 to Week 24, adjusted for differences between subjects before treatment by subtracting the number of new inflammatory lesions observed from the week -1 MRI scan . An inflammatory lesion is defined as a gadolinium (Gd)-enhancing lesion that shows hyperintensity on postcontrast but no hyperintensity on noncontrast T1 images. A new inflammatory lesion is one that was not present on the previously scheduled MRI scan. If the previously scheduled MRI scan was missing, the scan was compared to the last available MRI.

Secondary Outcome Measures

Name	Time	Method
Percent Brain Volume Change	Week -1 to Week 24	Percent Brain Volume Change is a measure of brain atrophy. Brain volume was calculated from a MRI scan at Week -1 and a MRI scan at Week 24 then the percent change from Week -1 to Week 24 was calculated. A negative change score means volume decreased. A decrease in volume indicates progression of multiple sclerosis severity.
Mean Number of New Inflammatory Lesions in 8-week Intervals	Week 8 to Week 24	The mean number of new inflammatory MRI lesions obtained on scans every 8 weeks from Week 8 to Week 24. An inflammatory lesion is defined as a gadolinium (Gd)-enhancing lesion that shows hyperintensity on postcontrast but no hyperintensity on noncontrast T1 images. A new inflammatory lesion is one that was not present on the previously scheduled MRI scan. If the previously scheduled MRI scan was missing, the scan was compared to the last available MRI.
Lesion Volume Accumulation on T2-weighted MRI Scans Over 24 Weeks	Week -1 to Week 24	Difference in total volume of all T2 lesions detected at Week 24 MRI scan compared to Week -1 MRI scan. A T2 lesion is defined as an abnormal, hyperintense white-matter area visible on T2 weighted images. A higher score indicates more severe multiple sclerosis.
Absolute Number of New Inflammatory MRI Lesions on Monthly Scans	Weeks 4-24	The absolute number of new inflammatory MRI lesions obtained on scans every 4 weeks from Week 8 to Week 24. An inflammatory lesion is defined as a gadolinium (Gd)-enhancing lesion that shows hyperintensity on postcontrast but no hyperintensity on noncontrast T1 images. A new inflammatory lesion is one that was not present on the previously scheduled MRI scan. If the previously scheduled MRI scan was missing, the scan was compared to the last available MRI.
Number of Participants Progressing on the EDSS Scale by at Least 1 Point	Week 24 to Week 64	The Expanded Disability Status Scale (EDSS) is an assessment for severity of multiple sclerosis. The EDSS an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to multiple sclerosis) in half-point increments. Extension baseline EDSS score was the most recent non-missing value on or before Week 28. Only participants who scored between a 0 and a 5 at baseline were analyzed for this outcome measure. EDSS progression is defined as an increase of at least 1 point on the EDSS compared to baseline if the baseline was greater than 1.0, or 1.5 points on EDSS if baseline was less than or equal to 1.0, which persisted for a minimum of 12 weeks or was found on three consecutive EDSS assessments starting at Visit 3 (Wk 8).
Annualized Relapse Rate	Week -1 to Week 24	The rate of multiple sclerosis relapse by year. Annualized relapse rate is calculated by dividing the total number of relapse events in the core phase in each treatment group by the total number of days participants participated in the study during the core phase. This number is then multiplied by 365.25 to get an annualized rate.
Mean Change in the MSFC Over 24 Weeks of Treatment	Week -1 to Week 24	The Multiple Sclerosis Functional Composite (MSFC) is a three-part, standardized, quantitative assessment instrument to measure severity of multiple sclerosis. The MSFC combines three component measures to create a composite measure. The three component measures of the MSFC include the 1) Time 25-foot Walk (a measure of lower extremity function), 2) 9-hole Peg Test (a measure of upper extremity function), and 3) Paced Auditory Serial Addition Test (a measure of cognitive function). Mean change in MSFC scores from baseline to Week 24 were assessed. Scores from all three components are combined then are converted into a Z-score for analyses, with a range from -1 to 1. A positive score indicates improvement in the severity of multiple sclerosis symptoms while negative scores indicate decline in multiple sclerosis symptoms.
Mean Number of New Inflammatory MRI Lesions Per Scan During the Extension Phase	Weeks 36 and 52	The mean number of new inflammatory MRI lesions obtained on scans at Weeks 36 and 52, adjusted for differences between subjects before treatment by subtracting the number of new inflammatory lesions observed from the week 24 MRI scan. An inflammatory lesion is defined as a gadolinium (Gd)-enhancing lesion that shows hyperintensity on postcontrast but no hyperintensity on noncontrast T1 images. A new inflammatory lesion is one that was not present on the previously scheduled MRI scan. If the previously scheduled MRI scan was missing, the scan was compared to the last available MRI.
Lesion Volume Accumulation on T2-Weighted MRI Scans Between 24 Weeks and 52 Weeks	Week 24 to Week 52	Difference in total volume of all T2 lesions detected at Week 52 MRI scan compared to Week 24 MRI scan. A T2 lesion is defined as an abnormal, hyperintense white-matter area visible on T2 weighted images. A higher score indicates more severe multiple sclerosis.
Percent Brain Volume Change Between 24 Weeks and 52 Weeks	Week 24 to Week 52	Percent Brain Volume Change is a measure of brain atrophy. Brain volume was calculated from a MRI scan at Week 24 and a MRI scan at Week 25 then the percent change from Week 24 to Week 52 was calculated. A negative change score means volume decreased. A decrease in volume indicates progression of multiple sclerosis severity.
Annualized Relapse in Extension Phase	Week 24 to Week 64	The rate of multiple sclerosis relapse by year. Annualized relapse rate is calculated by dividing the total number of relapse events in the extension and follow-up phases in each treatment group by the total number of days participants participated in the study during the extension and follow-up phases. This number is then multiplied by 365.25 to get an annualized rate.
Mean Change in the MSFC in Extension Phase	Week 24 to Week 52	The Multiple Sclerosis Functional Composite (MSFC) is a three-part, standardized, quantitative assessment instrument to measure severity of multiple sclerosis. The MSFC combines three component measures to create a composite measure. The three component measures of the MSFC include the 1) Time 25-foot Walk (a measure of lower extremity function), 2) 9-hole Peg Test (a measure of upper extremity function), and 3) Paced Auditory Serial Addition Test (a measure of cognitive function). Mean change in MSFC scores from Week 24 to Week 52 were assessed. Scores from all three components are combined then are converted into a Z-score for analyses, with a range from -1 to 1. A positive score indicates improvement in the severity of multiple sclerosis symptoms while negative scores indicate decline in multiple sclerosis symptoms.

Trial Locations

Locations (21): Newport Beach Clinical Research Associates, Inc.
🇺🇸
Newport Beach, California, United States
Louisiana State University
🇺🇸
Shreveport, Louisiana, United States
St. Josephs Hospital and Medical Center - Barrow Neurology
🇺🇸
Phonix, Arizona, United States
Jordan Research and Education Institute (REDI): Alta Bates Summit Medical Center
🇺🇸
Berkeley, California, United States
University of Southern California - Keck School of Medicine
🇺🇸
Los Angeles, California, United States
Norton Neuroscience Institute - Norton Neurology Services MS Center
🇺🇸
Louisville, Kentucky, United States
University of Maryland
🇺🇸
Baltimore, Maryland, United States
University of Miami
🇺🇸
Miami, Florida, United States
University of California, Davis
🇺🇸
Sacramento, California, United States
South Suburban Neurology
🇺🇸
Flossmoor, Illinois, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Neurology Specialists, Inc.
🇺🇸
Dayton, Ohio, United States
Judith Jaffe Multiple Sclerosis Center: Weill Cornell Medical College
🇺🇸
New York, New York, United States
Providence St. Vincent Medical Center
🇺🇸
Portland, Oregon, United States
Advanced Neurosciences Institute
🇺🇸
Franklin, Tennessee, United States
The Neurology Foundation, Inc.
🇺🇸
Providence, Rhode Island, United States
Benaroya Research Institute at Virginia Mason
🇺🇸
Seattle, Washington, United States
Ottawa Hospital Research Institute
🇨🇦
Ottawa, Ontario, Canada
University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Brigham & Women's Hospital
🇺🇸
Boston, Massachusetts, United States