Oral Guanabenz for Multiple Sclerosis

December 11, 2019 updated by: National Institute of Neurological Disorders and Stroke (NINDS)

Phase I Study of Oral Guanabenz for Multiple Sclerosis

Background:

- People with multiple sclerosis (MS) get lesions in their brain and spinal cord. These cause neurological symptoms and sometimes disability. Researchers want to see if a blood pressure drug called guanabenz can repair lesions and help people with MS.

Objective:

- To see if guanabenz is safe and well tolerated in people with MS.

Eligibility:

- People 18 55 years old with MS who have taken glatiramer acetate for the past year.

Design:

  • Participants will be screened in a separate protocol. For 2 months, they will be examined and have magnetic resonance imaging (MRI) scans. This will decide if they are in the Stable or Active MS study group.
  • The study will last 5 months. There will be up to 11 visits, 5 overnight.
  • Visit 1: overnight stay at the clinic:
  • Medical history and physical exam.
  • Health questionnaire
  • Bladder ultrasound scan
  • Brain MRI
  • Electrocardiogram (EKG) to measure heart electrical activity
  • Blood will be drawn through an intravenous (IV) line.
  • Participants may have tests of strength, muscle tone, and movement.
  • They will get their first dose of the study drug, a tablet taken once a day.
  • Participants will take the study drug at home and keep a medicine diary.
  • The dose will slowly increase. Each time, participants will stay overnight at the clinic. They will have a physical exam, EKG, MRI, and IV blood draw.
  • Visit 6: Participants will have a physical exam, MRI, and blood drawn. They will get a schedule to slowly lower their drug dose and stop taking guanabenz.
  • Participants will have 2 final visits. They will have a physical exam, EKG, MRI, and IV blood draw.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVE:

This Phase 1 clinical study will aim to determine whether therapeutically adequate dosages of guanabenz are safe and well tolerated in patients with multiple sclerosis (MS). It will further provide pharmacokinetic data important for determination of optimal dosing schedule for possible future Phase 2 study.

STUDY POPULATION:

Six patients, ages between 18-55 inclusive, and diagnosis of definite multiple sclerosis by 2010 Revised McDonald Diagnostic Criteria (Polman et al, 2010) will be enrolled. All patients will have been on treatment with glatiramer acetate, a Food and Drug Administration (FDA) approved disease-modifying therapy, for a minimum of year. Four of the patients will be clinically stable with no clinical relapse in the preceding year and no evidence of active inflammation by MRI during the 2-month screening period; 2 patients will be selected based on evidence of on-going, active inflammation seen by MRI during the screening period.

DESIGN:

In this open-label, single site, dose escalation study, the maximum tolerated dose (MTD) of guanabenz in MS patients will be determined. Patients will be screened for participation under the existing MS natural history study 89-N-0045. Sequential patient enrollment will be spaced at least 6 weeks apart. Five study drug doses will be explored: 4mg, 8mg, 16mg, 32mg and 64mg. Dose escalation will ensue if the preceding dose is tolerated, defined both by patient-reported outcomes and objective clinical and imaging assessments. Patients will be maintained on lower doses (4mg-16mg) for 14 days and on higher doses (32 and 64mg) for 28 days.

OUTCOMES:

The primary outcome is MTD, defined as the maximum dose that produces dose-limiting toxicity (DLT) in at most 2 out of the 6 participants. Secondary outcomes include patient-reported outcomes, objective clinical and imaging assessments at 32mg and 64mg, and pharmacokinetics.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 55 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:
  • MS as defined by the 2010 Revised McDonald MS Diagnostic Criteria (19)
  • Age 18-55, inclusive, at the time of the first screening baseline visit
  • EDSS 1.0 to 6, inclusive, at the time of the first screening baseline visit
  • Able to provide informed consent
  • Willing and able to participate in all aspects of trial design and follow-up
  • Undergoing treatment with glatiramer acetate for a period of at least 1 year prior to enrollment in the study
  • For female patients, agreeing to commit to the use of a reliable/accepted method of birth control (i.e. hormonal contraception, including

birth control pills, injected hormones, and vaginal ring; intrauterine device; barrier methods with spermicide, including diaphragm and condom; or surgical sterilization, including hysterectomy, tubal ligation, and vasectomy) for the duration of the study

ADDITIONAL INCLUSION CRITERION FOR ACTIVE MS COHORT

-Development of new T2 hyperintense or contrast enhancing lesions by MRI during the screening phase, but 3 such lesions on any single scan

EXCLUSION CRITERIA:

  • Alternative diagnoses that better explain neurological disability and MRI findings
  • Clinically significant medical condition that, in the best judgment of the investigators, may expose the patient to undue risk of harm or prevent the patient from completing the study (examples include, but are not limited to, cerebrovascular disease, substance abuse, ischemic cardiomyopathy, clotting disorder, brittle diabetes, neurodegenerative disorder)
  • Undergoing treatment with medications that may interact with guanabenz, including anti-hypertensive agents and/or agents leading to increase in catecholamines (such as tricyclic antidepressants and monoamine oxidase inhibitors)
  • Medical contraindication to MRI
  • Determination, in the best judgment of the investigators, of the need to treat a prospective participant with steroids for management of MS during the screening period
  • Pregnant or breastfeeding woman
  • Abnormal screening/baseline blood tests exceeding any of the limits defined below:

A) Serum alanine transaminase or aspartate transaminase levels greater than 3 times the upper limit of normal values

B) Total white blood cell count < 3000/mm3

C) Platelet count < 85000/mm3

D) Serum creatinine level > 2.0 mg/dl and eGFR (estimated glomerular filtration rate) < 60

ADDITIONAL EXCLUSION CRITERIA FOR STABLE MS COHORT

  • Evidence of 1 or more clearly documented MS relapses within the last 1 year
  • Development of more than 2 lesions per year relative to an MRI performed at least one year before the first screening MRI (the prior MRI can be an outside MRI)
  • Development of new T2 hyperintense or contrast-enhancing lesions by MRI during the screening phase

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treatment arm
Drug: Guanabenz

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Maximum tolerated dose (MTD)
Time Frame: 3.5 months
3.5 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Pharmacokinetics of guanabenz in MS patients
Time Frame: 3.5 months
3.5 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 21, 2015

Primary Completion (ACTUAL)

October 30, 2017

Study Completion (ACTUAL)

October 30, 2017

Study Registration Dates

First Submitted

April 21, 2015

First Submitted That Met QC Criteria

April 21, 2015

First Posted (ESTIMATE)

April 22, 2015

Study Record Updates

Last Update Posted (ACTUAL)

December 12, 2019

Last Update Submitted That Met QC Criteria

December 11, 2019

Last Verified

October 30, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 150117
  • 15-N-0117

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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