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

Primary Purpose

Multiple Sclerosis

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Acetazolamide

Placebo

About this trial

This is an interventional treatment trial for Multiple Sclerosis focused on measuring Acetazolamide, Lesions, Neurodegeneration, Repair

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

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.
Human immunodeficiency virus (HIV) positivity.
Uncontrolled diabetes mellitus defined as HbA1c>8% and/or requiring intensive management.
Uncontrolled viral, fungal, or bacterial infection (excluding asymptomatic bacteriuria).
Any condition that, in the opinion of the investigators, would jeopardize the ability of the subject to tolerate treatment with ACZ.
Prior history of malignancy.
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
Presence of metallic objects implanted in the body that would preclude the ability of the subject to safely have MRI exams.
Psychiatric illness, mental deficiency, or cognitive dysfunction making compliance with treatment of informed consent impossible.

Sites / Locations

UTHealth

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Acetazolamide

Placebo

Arm Description

Acetazolamide in oral daily divided dose administered for 6 consecutive months

Placebo in oral daily divided dose administered for 6 consecutive months

Outcomes

Primary Outcome Measures

Percent Change in Global Cerebral Blood Flow

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 Outcome Measures

Percent Change in Tissue Integrity in White Matter (Mean Diffusivity)

The data reported indicate the extent of change in white matter integrity as determined using the diffusion tensor imaging-magnetic resonance imaging (DTI-MRI) measure of mean diffusivity. A positive percent change value indicates an increase in mean diffusivity between baseline and 24 weeks, and a higher mean diffusivity value indicates a breakdown in white matter integrity, so the greater the percent change, the greater the breakdown of white matter integrity and the worse the outcome.

Percent Change in Tissue Integrity in White Matter (Fractional Anisotropy)

The data reported indicate the extent of change in white matter integrity as determined using the diffusion tensor imaging-magnetic resonance imaging (DTI-MRI) measure of fractional anisotropy. A negative percent change value indicates a decrease in fractional anisotropy between baseline and 24 weeks, and a lower fractional anisotropy value indicates a breakdown in white matter integrity, so the lower (and more negative) the percent change, the greater the breakdown of white matter integrity and the worse the outcome.

Full Information

NCT ID

NCT02466074

First Posted

June 3, 2015

Last Updated

March 31, 2023

Sponsor

The University of Texas Health Science Center, Houston

1. Study Identification

Unique Protocol Identification Number

NCT02466074

Brief Title

Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis

Acronym

perfuseMS

Official Title

Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Terminated

Why Stopped

Inadequate recruitment; termination of funding

Study Start Date

August 17, 2016 (Actual)

Primary Completion Date

February 7, 2022 (Actual)

Study Completion Date

February 7, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The University of Texas Health Science Center, Houston

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Sclerosis

Keywords

Acetazolamide, Lesions, Neurodegeneration, Repair

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Acetazolamide

Arm Type

Experimental

Arm Description

Acetazolamide in oral daily divided dose administered for 6 consecutive months

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo in oral daily divided dose administered for 6 consecutive months

Intervention Type

Drug

Intervention Name(s)

Acetazolamide

Other Intervention Name(s)

Diamox

Intervention Description

see arm description

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo arm

Primary Outcome Measure Information:

Title

Percent Change in Global Cerebral Blood Flow

Description

Time Frame

baseline, 24 weeks

Secondary Outcome Measure Information:

Title

Percent Change in Tissue Integrity in White Matter (Mean Diffusivity)

Description

Time Frame

baseline, 24 weeks

Title

Percent Change in Tissue Integrity in White Matter (Fractional Anisotropy)

Description

Time Frame

baseline, 24 weeks

Other Pre-specified Outcome Measures:

Title

Composite Changes in Disability Measures

Description

Composite disability for an individual is defined as at least one of the following: 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).

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

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. Human immunodeficiency virus (HIV) positivity. Uncontrolled diabetes mellitus defined as HbA1c>8% and/or requiring intensive management. Uncontrolled viral, fungal, or bacterial infection (excluding asymptomatic bacteriuria). Any condition that, in the opinion of the investigators, would jeopardize the ability of the subject to tolerate treatment with ACZ. Prior history of malignancy. 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 Presence of metallic objects implanted in the body that would preclude the ability of the subject to safely have MRI exams. Psychiatric illness, mental deficiency, or cognitive dysfunction making compliance with treatment of informed consent impossible.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John Lincoln, MD, PhD

Organizational Affiliation

UTHealth

Official's Role

Principal Investigator

Facility Information:

Facility Name

UTHealth

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Augmenting Cerebral Blood Flow to Treat Established Multiple Sclerosis

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