A Cooperative Clinical Study of Abatacept in Multiple Sclerosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Study to Evaluate the Safety and Efficacy of Abatacept in Adults With Relapsing-remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Biological: abatacept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: One or more documented clinical exacerbations in the past year prior to visit -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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abatacept<br>Receives abatacept during first course of treatment, switching to placebo during extension phase. | Biological: abatacept<br>* In core/extension phase: administered IV at weeks 0/28, 2/30, and 4/32, and then every 4 weeks until week 24/52; Dosing: less than 60 kg, 500 mg; 60-100 kg, 750 mg; or greater than 100 kg, 1 gram<br>* Other names: CTLA4-Ig;Drug: Placebo<br>* In core/extension phase: administered IV at weeks 0/28, 2/30, and 4/32, and then every 4 weeks until week 24/52<br>* Other names: placebo abatacept;|
| Placebo Comparator: Placebo, followed by abatacept<br>Receives a placebo for first course of treatment, switching to abatacept in the extension phase. | Biological: abatacept<br>* In core/extension phase: administered IV at weeks 0/28, 2/30, and 4/32, and then every 4 weeks until week 24/52; Dosing: less than 60 kg, 500 mg; 60-100 kg, 750 mg; or greater than 100 kg, 1 gram<br>* Other names: CTLA4-Ig;Drug: Placebo<br>* In core/extension phase: administered IV at weeks 0/28, 2/30, and 4/32, and then every 4 weeks until week 24/52<br>* Other names: placebo abatacept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Number of New Inflammatory MRI Lesions Per Monthly Scans | 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. | Weeks 8-24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Number of New Inflammatory MRI Lesions on Monthly Scans | 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. | Weeks 4-24 | 
| Lesion Volume Accumulation on T2-weighted MRI Scans Over 24 Weeks | 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. | Week -1 to Week 24 | 
| Percent Brain Volume Change | 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. | Week -1 to Week 24 | 
| Mean Number of New Inflammatory Lesions in 8-week Intervals | 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. | Week 8 to Week 24 | 
| Number of Participants Progressing on the EDSS Scale by at Least 1 Point | 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. Baseline EDSS score was the lowest score observed at either visit -2 (Wk -5) or visit -1 (Wk -1). 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). | Week -1 to Week 24 | 
| Annualized Relapse Rate | 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. | Week -1 to Week 24 | 
| Mean Change in the MSFC Over 24 Weeks of Treatment | 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. | Week -1 to Week 24 | 
| Mean Number of New Inflammatory MRI Lesions Per Scan During the Extension Phase | 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. | Weeks 36 and 52 | 
| Lesion Volume Accumulation on T2-Weighted MRI Scans Between 24 Weeks and 52 Weeks | 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. | Week 24 to Week 52 | 
| Percent Brain Volume Change Between 24 Weeks and 52 Weeks | 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. | Week 24 to Week 52 | 
| Number of Participants Progressing on the EDSS Scale by at Least 1 Point | 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). | Week 24 to Week 64 | 
| Annualized Relapse in Extension Phase | 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. | Week 24 to Week 64 | 
| Mean Change in the MSFC in Extension Phase | 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. | Week 24 to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, multiple sclerosis, relapsing-remitting multiple sclerosis, RRMS