Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis
Overview
- Phase
- Phase 2
- Intervention
- Acetazolamide
- Conditions
- Multiple Sclerosis
- Sponsor
- The University of Texas Health Science Center, Houston
- Enrollment
- 5
- Locations
- 1
- Primary Endpoint
- Percent Change in Global Cerebral Blood Flow
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
This study will evaluate how improved cerebral blood flow affects the way in which newly formed MS lesions evolve and whether tissue repair is improved. Patients with multiple sclerosis (MS) will be treated with acetazolamide in daily divided doses and obtain MRI to determine how much and in which regions of the brain cerebral perfusion improves as well as the extent to which tissue integrity is improved in these areas.
Detailed Description
Cerebral perfusion is altered in many disease states, including MS. Altered perfusion has been seen in patients with all multiple sclerosis (MS) phenotypes and is well established as occurring early in relapsing-remitting disease. Previous research in our laboratory has shown that reduced cerebral perfusion in MS patients is a precursor to the formation of chronic lesions. In addition, studies have suggested that "virtual hypoxia", resultant from the combination of diminished cerebral perfusion and increased energy demand, contributes to tissue damage that strongly correlates with clinical disability in persons with MS. Our preliminary studies have already shown short-term increases in global and regional cerebral perfusion in MS patients after therapy with acetazolamide (ACZ). The central hypothesis is that if cerebral perfusion is important in tissue injury, then MS lesions within hypoperfused areas are more likely to develop permanent tissue damage, and medications that improve cerebral perfusion might beneficially alter the evolution of MS plaques, enhance remyelination and repair and diminish clinical disability progression. Sixty MS patients will be enrolled in this single-center exploratory RCT. Half of the patients will be randomly assigned to get ACZ treatment in phase 1 consisting of 24 weeks on ACZ, followed by another 24 weeks on ACZ during phase 2. The other half of the patients will be assigned to placebo for 24 weeks in phase 1 and then switched to ACZ and followed for 24 weeks in phase 2. This study will utilize various imaging techniques to determine the degree to which cerebral blood flow is improved in MS subjects after administration of ACZ.
Investigators
John A. Lincoln
Assistant Professor
The University of Texas Health Science Center, Houston
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of relapsing forms of multiple sclerosis using revised McDonald criteria
- •Stable on any FDA-approved disease-modifying therapy. The term "stable" implies that the subject has not had change in therapy for any reason for the 6 months prior to study entry.
- •Expanded Disability Status Scale (EDSS) score of 0-6.0 inclusive
- •Understood and signed written informed consent, obtained prior to the study subject undergoing any study related procedure, including screening tests.
Exclusion Criteria
- •Known hypersensitivity to sulfonamides or derivatives
- •Known history of renal or hepatic disease, cerebrovascular disease including stroke, transient ischemic attack, myocardial infarction, angina or congestive heart failure.
- •Evidence to suggest hyponatremia or hypokalemia, marked kidney dysfunction defined as creatinine greater than 2.0 mg/dL or liver disease dysfunction defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three-fold upper limit of normal (ULN).
- •Evidence to suggest suprarenal gland failure.
- •Evidence of hyperchloremic acidosis.
- •Initiation of new immunosuppressant treatment after the subject becomes protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial.
- •Prior treatment with mitoxantrone, natalizumab, methotrexate, cladribine cyclophosphamide or other change in disease modifying therapy (DMT) within 6 months of initiation of study.
- •Subjects with any history of cytopenia.
- •History of pulmonary obstruction or emphysema.
- •Active hepatitis B or hepatitis C infection or evidence of cirrhosis.
Arms & Interventions
Acetazolamide
Acetazolamide in oral daily divided dose administered for 6 consecutive months
Intervention: Acetazolamide
Placebo
Placebo in oral daily divided dose administered for 6 consecutive months
Intervention: Placebo
Outcomes
Primary Outcomes
Percent Change in Global Cerebral Blood Flow
Time Frame: baseline, 24 weeks
Percent change in global cerebral blood flow (CBF) after 24 weeks relative to pre-treatment baseline. Global CBF is determined using magnetic resonance imaging (MRI) methods. The data reported indicate the extent of change in global CBF--the higher the percent change, the greater the increase in global CBF and the better the outcome.
Secondary Outcomes
- Percent Change in Tissue Integrity in White Matter (Mean Diffusivity)(baseline, 24 weeks)
- Percent Change in Tissue Integrity in White Matter (Fractional Anisotropy)(baseline, 24 weeks)