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Oral Guanabenz for Multiple Sclerosis

Primary Purpose

Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Guanabenz

About this trial

This is an interventional treatment trial for Multiple Sclerosis, Relapsing-Remitting focused on measuring Neuroprotection, Multiple Sclerosis, Clinical Trial, Safety and Tolerability

Eligibility Criteria

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

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

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD)

Secondary Outcome Measures

Pharmacokinetics of guanabenz in MS patients

Full Information

NCT ID

NCT02423083

First Posted

April 21, 2015

Last Updated

December 11, 2019

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

1. Study Identification

Unique Protocol Identification Number

NCT02423083

Brief Title

Oral Guanabenz for Multiple Sclerosis

Official Title

Phase I Study of Oral Guanabenz for Multiple Sclerosis

Study Type

Interventional

2. Study Status

Record Verification Date

October 30, 2017

Overall Recruitment Status

Terminated

Study Start Date

April 21, 2015 (undefined)

Primary Completion Date

October 30, 2017 (Actual)

Study Completion Date

October 30, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

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

Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis

Keywords

Neuroprotection, Multiple Sclerosis, Clinical Trial, Safety and Tolerability

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment arm

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Guanabenz

Primary Outcome Measure Information:

Title

Maximum tolerated dose (MTD)

Time Frame

3.5 months

Secondary Outcome Measure Information:

Title

Pharmacokinetics of guanabenz in MS patients

Time Frame

3.5 months

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: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Irene CM Cortese, M.D.

Organizational Affiliation

National Institute of Neurological Disorders and Stroke (NINDS)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

19287390

Citation

Lin W, Popko B. Endoplasmic reticulum stress in disorders of myelinating cells. Nat Neurosci. 2009 Apr;12(4):379-85. doi: 10.1038/nn.2273. Epub 2009 Mar 15.

Results Reference

background

PubMed Identifier

18818381

Citation

Lin W, Kunkler PE, Harding HP, Ron D, Kraig RP, Popko B. Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-gamma. Am J Pathol. 2008 Nov;173(5):1508-17. doi: 10.2353/ajpath.2008.080449. Epub 2008 Sep 25.

Results Reference

background

PubMed Identifier

23554479

Citation

Lin W, Lin Y, Li J, Fenstermaker AG, Way SW, Clayton B, Jamison S, Harding HP, Ron D, Popko B. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci. 2013 Apr 3;33(14):5980-91. doi: 10.1523/JNEUROSCI.1636-12.2013.

Results Reference

background

PubMed Identifier

27055915

Citation

Clayton BLL, Popko B. Endoplasmic reticulum stress and the unfolded protein response in disorders of myelinating glia. Brain Res. 2016 Oct 1;1648(Pt B):594-602. doi: 10.1016/j.brainres.2016.03.046. Epub 2016 Apr 4.

Results Reference

derived

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Oral Guanabenz for Multiple Sclerosis

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