Oral Guanabenz for Multiple Sclerosis
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.
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.
-  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