Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis

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.

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.