A Cooperative Clinical Study of Abatacept in Multiple Sclerosis (ACCLAIM)

This study has been completed.
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01116427
First received: May 3, 2010
Last updated: April 7, 2016
Last verified: April 2016
  Purpose
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.

Condition Intervention Phase
Multiple Sclerosis, Relapsing-Remitting
Biological: abatacept
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Mean Number of New Inflammatory MRI Lesions Per Monthly Scans [ Time Frame: Weeks 8-24 ] [ Designated as safety issue: No ]
    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:
  • Absolute Number of New Inflammatory MRI Lesions on Monthly Scans [ Time Frame: Weeks 4-24 ] [ Designated as safety issue: No ]
    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.

  • Lesion Volume Accumulation on T2-weighted MRI Scans Over 24 Weeks [ Time Frame: Week -1 to Week 24 ] [ Designated as safety issue: No ]
    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.

  • Percent Brain Volume Change [ Time Frame: Week -1 to Week 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 8 to Week 24 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Progressing on the EDSS Scale by at Least 1 Point [ Time Frame: Week -1 to Week 24 ] [ Designated as safety issue: No ]
    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).

  • Annualized Relapse Rate [ Time Frame: Week -1 to Week 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week -1 to Week 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Weeks 36 and 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 24 to Week 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 24 to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Progressing on the EDSS Scale by at Least 1 Point [ Time Frame: Week 24 to Week 64 ] [ Designated as safety issue: No ]
    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 in Extension Phase [ Time Frame: Week 24 to Week 64 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 24 to Week 52 ] [ Designated as safety issue: No ]
    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.


Enrollment: 65
Study Start Date: September 2010
Study Completion Date: February 2015
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Abatacept
Receives abatacept during first course of treatment, switching to placebo during extension phase.
Biological: abatacept
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
Other Names:
  • Orencia®
  • CTLA4-Ig
Drug: Placebo
In core/extension phase: administered IV at weeks 0/28, 2/30, and 4/32, and then every 4 weeks until week 24/52
Other Name: placebo abatacept
Placebo Comparator: Placebo, followed by abatacept
Receives a placebo for first course of treatment, switching to abatacept in the extension phase.
Biological: abatacept
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
Other Names:
  • Orencia®
  • CTLA4-Ig
Drug: Placebo
In core/extension phase: administered IV at weeks 0/28, 2/30, and 4/32, and then every 4 weeks until week 24/52
Other Name: placebo abatacept

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01116427

  Show 21 Study Locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Investigators
Principal Investigator: Samia Khoury, MD Brigham and Women's Hospital
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01116427     History of Changes
Other Study ID Numbers: DAIT ITN035AI 
Study First Received: May 3, 2010
Results First Received: December 15, 2015
Last Updated: April 7, 2016
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Federal Government
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: The plan is to share data in: 1.)ImmPort, a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts that also provides data analysis tools that are available to researchers who register online and subsequently receive DAIT approval; and 2.)TrialShare, a clinical trials research portal developed by the Immune Tolerance Network that makes data from the consortium's clinical trials publicly available without charge.

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
MS
multiple sclerosis
relapsing-remitting multiple sclerosis
RRMS

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on July 21, 2016