Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis (perfuseMS)

• ClinicalTrials.gov Identifier: NCT02466074
• Recruitment Status: Terminated
• First Posted: June 9, 2015
• Last Update Posted: May 27, 2022
• Sponsor: The University of Texas Health Science Center, Houston
• Information provided by (Responsible Party): John A. Lincoln, The University of Texas Health Science Center, Houston

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: Acetazolamide; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Two phase design: phase 1, patients randomized to ACZ or placebo and followed for 24 weeks; phase 2, patients that received placebo in phase 1 switch to ACZ (delayed-start group) and patients that received ACZ in phase 1 continue on ACZ (ACZ-ACZ group)
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis
• Actual Study Start Date: August 17, 2016
• Actual Primary Completion Date: February 7, 2022
• Actual Study Completion Date: February 7, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Acetazolamide; Acetazolamide in oral daily divided dose administered for 6 consecutive months	Drug: Acetazolamide; see arm description; Other Name: Diamox
Placebo Comparator: Placebo; Placebo in oral daily divided dose administered for 6 consecutive months	Drug: Placebo; Placebo arm

Outcome Measures

Primary Outcome Measures :

1. Change in global cerebral blood flow with intervention [ Time Frame: 24 weeks and at 48 weeks ]
   The primary outcome is to determine the change in global cerebral blood flow (CBF) after 24 weeks relative to pre-treatment baseline. CBF is determined using two independent but well correlated magnetic resonance imaging (MRI) methods, pseudo-continuous arterial spin labeling and dynamic susceptibility contrast imaging.

Secondary Outcome Measures :

1. Change in tissue integrity in areas with and without increased cerebral blood flow with intervention [ Time Frame: 24 weeks and at 48 weeks ]
   The key secondary outcome is to determine change in tissue integrity from baseline to 24 weeks after acetazolamide (ACZ) therapy as determined using diffusion tensor imaging (DTI-MRI) measures of mean diffusivity and fractional anisotropy. These changes will be compared between regions with and without increased cerebral blood flow (>15% difference from baseline).
2. Composite changes in disability measures after acetazolamide (ACZ) compared to baseline [ Time Frame: 1 year ]
   We will investigate composite changes in disability measures after acetazolamide (ACZ) compared to baseline. We define composite for an individual as at least one of: a) any decrease in Expanded Disability Status Score (EDSS), b) 20% reduction in time to complete 9-Hole Peg Test (9HPT) for either the dominant or non-dominant hand, c) 20% decrease in Timed 25-Foot Walk (T25FW) or d) a >= 4-point or 10% improvement in accuracy for Symbol Digit Modalities Test (SDMT).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Diagnosis of relapsing forms of multiple sclerosis using revised McDonald criteria
2. 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.
3. Expanded Disability Status Scale (EDSS) score of 0-6.0 inclusive
4. Understood and signed written informed consent, obtained prior to the study subject undergoing any study related procedure, including screening tests.

Exclusion Criteria:

1. Known hypersensitivity to sulfonamides or derivatives
2. Known history of renal or hepatic disease, cerebrovascular disease including stroke, transient ischemic attack, myocardial infarction, angina or congestive heart failure.
3. 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).
4. Evidence to suggest suprarenal gland failure.
5. Evidence of hyperchloremic acidosis.
6. Initiation of new immunosuppressant treatment after the subject becomes protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial.
7. Prior treatment with mitoxantrone, natalizumab, methotrexate, cladribine cyclophosphamide or other change in disease modifying therapy (DMT) within 6 months of initiation of study.
8. Subjects with any history of cytopenia.
9. History of pulmonary obstruction or emphysema.
10. Active hepatitis B or hepatitis C infection or evidence of cirrhosis.
11. Human immunodeficiency virus (HIV) positivity.
12. Uncontrolled diabetes mellitus defined as HbA1c>8% and/or requiring intensive management.
13. Uncontrolled viral, fungal, or bacterial infection (excluding asymptomatic bacteriuria).
14. Any condition that, in the opinion of the investigators, would jeopardize the ability of the subject to tolerate treatment with ACZ.
15. Prior history of malignancy.

16. Positive pregnancy test or inability or unwillingness to use effective means of birth control. Effective birth control defines as:

    • Refraining from all acts of vaginal intercourse (abstinence)
    • Consistent use of birth control pills
    • Tubal sterilization or male partner who has undergone vasectomy
    • Placement of an intrauterine device (IUD)
    • Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam
17. Presence of metallic objects implanted in the body that would preclude the ability of the subject to safely have MRI exams.
18. Psychiatric illness, mental deficiency, or cognitive dysfunction making compliance with treatment of informed consent impossible.

Contacts and Locations

Locations

United States, Texas

UTHealth

Houston, Texas, United States, 77030

Sponsors and Collaborators

The University of Texas Health Science Center, Houston

Investigators

• Principal Investigator: John Lincoln, MD, PhD; UTHealth

More Information

• Responsible Party: John A. Lincoln, Assistant Professor, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT02466074
• Other Study ID Numbers: HSC-MS-14-0450
• First Posted: June 9, 2015
• Last Update Posted: May 27, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by John A. Lincoln, The University of Texas Health Science Center, Houston:

Acetazolamide; Lesions; Neurodegeneration; Repair

Additional relevant MeSH terms:

Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Acetazolamide; Anticonvulsants; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Diuretics; Natriuretic Agents; Physiological Effects of Drugs