Safety and Tolerability of ISX (Isoxsuprine HCL) in MS Relapses

Study Overview
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Brief Summary
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This is a proof of concept, randomized, double-blind, placebo-controlled, 2-arm, parallel group study of Isoxsuprine in MS subjects experiencing a typical relapse. Evidence from preclinical stroke models and experimental allergic encephalomyelitis suggest that isoxsuprine hydrochloride may have neuroprotective activity and reduce disability in animal models. Given its potential neuroprotective effects in CNS injury models, the investigators propose to test it as a safe, tolerable add on treatment for acute relapses in patients with relapsing forms of MS.

Detailed Description
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This is a proof of concept, randomized, double-blind, placebo-controlled, 2-arm, parallel group study of Isoxsuprine in MS subjects experiencing a typical relapse. All subjects will have a documented diagnosis of relapsing MS or a clinically isolated syndrome by international criteria. The relapse will be of sufficient severity that their physician recommends treatment with a high dose corticosteroid pulse. All subjects will have a physical examination and history with questions on drug sensitivities. Subjects experiencing the onset of objective neurological deficits consistent with relapse within 7 days of randomization are eligible for screening for this study. Those currently on MS disease modifying therapy will have received a stable regimen of the medications for at least 30 days prior to screening and will continue the same doses and regimens for the duration of their study participation. Consented subjects will be assessed for relapse criteria and those who meet study eligibility criteria and agree to be treated with a standard 3 to 5 day pulse of high dose corticosteroids, will be randomized with equal probability to 1 of 2 treatment groups: placebo capsule or active Isoxsuprine (ISX). The Screening Visit will take place within 7 days of relapse onset and within 48 hours of initiating high dose steroids. Subjects may start corticosteroids anytime during this 7 day window. During the screening period, subjects will be assessed with the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and cognitive testing prior to treatment with ISX or placebo (1:1 ratio). Safety Assessments during screening will include a physical exam, electrocardiogram, vital signs, weight and a urine pregnancy test for females of child bearing potential. At 7 (± 1) days following the completion of the 5-day ISX dosing, subjects will be re-assessed with the EDSS. Subjects will be evaluated for treatment response using the EDSS and other standard measures. Study drug will be administered as one (1) 10 mg capsule, 3 times daily for 5 days in conjunction with concomitant dosing with high dose corticosteroids. This can be any accepted regimen, including daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon, with food, as typically provided by UNM MS Specialty Clinic.

Official Title
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Double-blind, Placebo-controlled, Randomized Study of the Safety and Tolerability of Isoxsuprine HCL Combined With High Dose Steroid Treatment of Multiple Sclerosis (MS) Relapse

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Isoxsuprine Hydrochloride
* Drug: Placebo
* Drug: Corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Subjects must be adequately informed and understand the nature and risks of the study and must be able to provide a signature and date on the ICF; 2. Male or female subjects between 18 and 50 years of age, inclusive; 3. Confirmed diagnosis of Multiple Sclerosis or Clinically Isolated Syndrome (CIS) suggestive of MS, according to the 2010 Revised McDonald criteria. 4. On a stable regimen of medications taken specifically to treat MS for at least 30 days prior to screening, and willing to continue the same doses and regimens for the duration of study participation; 5. New neurological disability consistent with MS relapse no longer than 7 days prior to screening; 6. Screen visit and randomization must occur within 48 hours of subject initiating steroid treatment. 7. Maximum EDSS score during screening of 6.5; 8. Sufficient ambulatory ability (ambulatory aids acceptable if used consistently) to complete two trials of the Timed 25 Foot Walk (T25FW) at the screening visit with the two trials completed within 5 minutes of each other in accordance with the specific instructions provided by the National MS Society Functional Composite Manual. 9. Subject must be willing to take a high dose steroid (600mg oral prednisone two times a day (bid). 10. Subjects must have a mean systolic blood pressure ≤ 160 and greater than 100 mm Hg and a mean diastolic blood pressure of ≤ 100 and greater than 50 mm Hg determined by the average of 3 seated readings taken at least 5 minutes apart at the Screening Visit. 11. Subjects must be able to communicate effectively with study personnel. For this reason only English speaking subjects will be eligible for the study. 12. Subjects must be able and willing to follow all protocol requirements and study restrictions. 13. Subjects must be able and willing to return for all study visits. Exclusion Criteria: 1. Subject is from a vulnerable population, as defined by the US CFR Title 45, Part 46, Section 46.111(b) and other local and national regulations, including but not limited to, employees (temporary, part-time, full time, etc) or a family member of the research staff conducting the study, or of the sponsor, or of the IRB. 2. Subject has only sensory, bowel/bladder, and/or cognitive symptoms of MS associated with the most recent relapse. 3. Subject has cognitive or behavioral impairment that in the opinion of the investigator would impair the ability of the subject to comply with study procedures. 4. Subject has any known contraindication(s) to the use of corticosteroids or isoxsuprine hydrochloride (ISX), including, but not limited to: any current uncontrolled hypertension, primary adrenocortical insufficiency Any current psychoses, infectious disease, or Cushing's syndrome. Any current congestive heart failure (defined as New York Heart Association (Functional Class III to IV). Peptic ulcer (within 24 weeks prior to the Screening Visit). Recent major surgery (within 24 weeks prior to the Screening Visit). Use of tizanidine any time in the past 30 days. 5. Subject has a clinically significant infection requiring intravenous administration of antibiotics and hospitalization prior to the Screening Visit. 6. Subject has poorly controlled type 1 or type 2 diabetes mellitus (prior diagnosis of gestational diabetes mellitus is not exclusionary 7. Received systemic steroids for a problem unrelated to the MS relapse within 30 days prior to screening. 8. History of other neurological disease that, 'in the opinion of the Investigator, would affect motor function or cognition; 9. For patients with a history of Major Depressive Disorder, at risk for worsening depression due to steroids or the presence of active depressive symptoms sufficient, in the opinion of the investigator, to affect the subject's ability to complete study assessments, or which would not be in the subject's best Interest to participate in the study; 10. Presence of cognitive impairment sufficient, in the opinion of the investigator, to affect the subject's ability to complete study assessments, or which would not be In the subject's best interest to participate in the study 11. History of sensory impairments (e.g., hearing, vision) that, In the opinion of the investigator, would impair the subject's ability to complete study assessments; 12. History of current alcohol or substance abuse or dependence; 13. History of myocardial infarction, or NYHA Functional Classification of Heart Failure Class 3 or 4 within 2 years prior to screening, or history of coronary artery disease and/or active angina pectoris; 14. Any clinically significant ECG abnormalities;; 15. Inability to swallow oral capsules, or a history of gastrointestinal malabsorption that would preclude the use of oral medication; 16. If female, is pregnant or lactating; 17. History of hypersensitivity or allergic reaction to any of the study drugs. 18. History of heavy use of tobacco/smoking

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a proof of concept, randomized, double-blind, placebo-controlled, 2-arm, parallel group study of Isoxsuprine in MS subjects experiencing a typical relapse
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Corticosteroid & Isoxsuprine HCL<br>Corticosteroid pulse of either daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon for 3 to 5 consecutive days and Isoxsuprine Hydrochloride one 10 mg Capsule 3 times daily for 5 consecutive days | Drug: Isoxsuprine Hydrochloride<br>* Compounded Isoxsuprine hydrochloride capsules<br>* Other names: Duvadilan;Drug: Corticosteroid<br>* This can be any accepted regimen, including daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon<br>* Other names: Prednisone;|
| Placebo Comparator: Corticosteroid & Placebo<br>Corticosteroid pulse of either daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon for 3 to 5 consecutive day and placebo one Capsule 3 times daily for 5 consecutive days | Drug: Placebo<br>* Identical microcrystalline cellulose placebo manufactured to mimic Isoxsuprine Hydrochloride 10 MG capsules<br>Drug: Corticosteroid<br>* This can be any accepted regimen, including daily iv methylprednisolone 1000 mg/day or 600mg oral prednisone two times a day at approximately 8AM and noon<br>* Other names: Prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events in Subjects receiving Steroids and ISX or Placebo (Blood Pressure) | Changes in systolic and diastolic blood pressure. | Baseline to Week 12 | 
| Incidence of Treatment Emergent Adverse Events in Subjects receiving Steroids and ISX or Placebo (Respiratory Rate and Pulse) | Changes in respiratory rate and pulse (per minute) at assessment intervals. | Baseline to Week 12 | 
| Incidence of Treatment Emergent Adverse Events in Subjects receiving Steroids and ISX or Placebo (Temperature) | Changes in temperature (degrees Celsius) | Baseline to Week 12 | 
| Incidence of Treatment Emergent Adverse Events in Subjects receiving Steroids and ISX or Placebo (ECG changes) | Electrocardiogram (ECG) parameters of heart rate, QT, QTcF, QTcB, PR, and QRS intervals) | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exploratory Treatment Efficacy Measures (Expanded Disability Status Scale) | Evaluate the potential efficacy of Isoxuprine as add-on treatment for improving neurological disability on Expanded Disability Status Scale (EDSS). The EDSS is based on a standard neurological examination to determine 7 Functional Systems Scores (FSS) (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral function). Each FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6. The EDSS is a composite ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. It is calculated from standard tables based on the individual FSS scores. | Baseline to Week 12 | 
| Exploratory Treatment Efficacy Measures (Multiple Sclerosis Functional Composite) | The MSFC requires the 1) Timed 25-Foot walk; 2) 9-Hole PegTest (9-HPT); and 3) Paced Auditory Serial Addition Test (PASAT-3 version). The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each patient at each time point (higher scores represent more disability). The MSFC score is a continuous variable that can be used as a numerical variable in analyses. Each of the 3 MSFC tests can also be analyzed and compared as individual measures. | Baseline to Week 12 |