Oral Ifetroban in Subjects With Duchenne Muscular Dystrophy

Study Overview
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Brief Summary
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Duchenne muscular dystrophy (DMD) is a devastating X-linked disease which leads to loss of ambulation between ages 7 and 13, respiratory failure and cardiomyopathy (CM) at any age, and inevitably premature death of affected young men in their late twenties. DMD is the most common fatal genetic disorder diagnosed in childhood. It affects approximately 1 in every 3,500 live male births across all races and cultures, and results in 20,000 new cases each year worldwide.Significant advances in respiratory care have unmasked CM as the leading cause of death. As there are yet no specific cardiac treatments to extend life, the current study aims to address this unmet medical need using a new therapeutic strategy for patients with DMD. Funding Source - FDA OOPD

Detailed Description
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This is a phase 2 randomized, double-blind, placebo-controlled, multiple dose study with an optional open-label extension to determine the safety, pharmacokinetics (PK) and efficacy of two doses of oral ifetroban in subjects with DMD. DMD patients who meet the inclusion criteria and none of the exclusion criteria will receive oral ifetroban or placebo once daily for 12 months. Subjects will be enrolled onto one of three treatment groups, low-dose ifetroban, high-dose ifetroban or placebo. Each dose level will be evaluated by eight subjects with early stage (LVEF > 45%) DMD-associated cardiomyopathy and eight subjects with more advanced stage (LVEF 35-45%) cardiac disease as there may be differences in the treatment effect based on cardiac involvement. Each subject treated will be evaluated for first-dose and steady-state exposure PK. All subjects who receive treatment will be assessed for safety. All subjects with at least one efficacy assessment post-baseline will be evaluated for efficacy. Blood and urine will be collected for standard and novel cardiac biomarkers. Target enrollment met for early-stage subjects (LVEF > 45%) and cohort is closed; enrollment remains open for the late-stage cohort (LVEF 35-45%).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study With an Open-Label Extension to Determine the Safety, Pharmacokinetics and Efficacy of Oral Ifetroban in Subjects With Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy Cardiomyopathy, Cardiomyopathy, Dilated

Intervention / Treatment
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* Drug: Ifetroban
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Males 7 years of age and older with the diagnosis of DMD, defined as phenotype consistent with DMD and either positive genotype, first degree relative with positive genotype, or confirmatory muscle biopsy. Stable dose of oral corticosteroids for at least 8 weeks or has not received corticosteroids for at least 30 days. Stable cardiac function defined as change in left ventricular ejection fraction (LVEF) of < 15% and no heart failure admission over the last 12 months; LVEF 35% or greater by cine cardiac magnetic resonance imaging (MRI) or echocardiography; myocardial damage in one or more left ventricular segments evident by late gadolinium enhancement allowed; concurrent angiotensin-converting enzyme inhibitors (ACEI), beta-blocker (BB) or angiotensin receptor blocker (ARB) therapy allowed (selection of which dictated by clinical care) if started three months or greater from first dose of IMP without change in dose. Aldosterone receptor antagonists (eg. Spironolactone or eplerenone) allowed if started 12 months or greater from first dose of Investigational Medicinal Product (IMP). No changes throughout the study allowed, except in the event of a decline in left ventricular ejection fraction (LVEF) >5% following the baseline CMR as measured by a subsequent CMR at the same center. Should this occur, changes in cardiac medications are allowed on the study. Subjects aged 18 years and older, informed consent obtained directly. For subjects ages 7-17 years old (yo), both assent from the subject and permission from a parent or guardian. Exclusion criteria: Clinically significant illness other than DMD Clinically significant laboratory abnormality not associated with DMD Major surgery within six weeks prior to the first dose of study drug, or planned surgery during this study which would interfere with the ability to perform study procedures Require antiarrhythmic therapy and/or initiation of diuretic therapy for management of acute heart failure in the last 6 months A LVEF of < 35% by Cardiac Magnetic Resonance Imaging (CMR) and/or fractional shortening of < 15% based on echocardiography (ECHO) during screening A known bleeding disorder or has received anticoagulant treatment within 2 weeks of study entry Allergy to gadolinium contrast or known renal insufficiency defined as abnormal cystatin C or creatinine above the upper limit of normal for age. The male serum reference ranges as follows: Age 7-9 years - 0.2-0.6 mg/dL Age 10-11 years - 0.3-0.7 mg/dL Age 12-13 years - 0.4-0.8 mg/dL Age 14-15 years - 0.5-0.9 mg/dL Age 16 years or older - 0.8-1.3 mg/dL Non-MR compatible implants (e.g. neurostimulator, automatic implantable cardioverter-defibrillator [AICD]) Subjects who participated in a therapeutic clinical trial within 30 days or five half-lives (whichever is longer) of study entry Any other condition that could interfere with the subject's participation

Ages Eligible for Study
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Minimum Age: 7 Years

Sexes Eligible for Study
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Male

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: Randomized, placebo-controlled, double-blind, dose-ranging
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Ifetroban - Low Dose<br>Weight based, once daily oral ifetroban | Drug: Ifetroban<br>* Weight based, once daily oral ifetroban<br>|
| Experimental: Oral Ifetroban - High Dose<br>Weight based, once daily oral ifetroban | Drug: Ifetroban<br>* Weight based, once daily oral ifetroban<br>|
| Placebo Comparator: Placebos<br>Matching Placebo | Drug: Placebo<br>* Matching oral placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (safety & tolerability) | Percentage of subjects with one or more treatment emergent adverse event | Baseline through 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics Area under the curve | Measurements of Area under the curve concentration of ifetroban and its acyl glucuronide metabolite | Day 0 and Day 7 | 
| Pharmacokinetics maximum serum concentration (Cmax) | Measurements of maximum serum concentration (Cmax) of ifetroban and its acyl glucuronide metabolite | Day 0 and Day 7 | 
| Pharmacokinetics time to reach Cmax (Tmax) concentration | Measurement of time to reach Cmax (Tmax) concentration of ifetroban and its acyl glucuronide metabolite | Day 0 and Day 7 | 
| Pharmacokinetics plasma terminal half-life concentration | Measurement of plasma terminal half-life concentration of ifetroban and its acyl glucuronide metabolite | Day 0 and Day 7 | 
| Change from baseline in left ventricular ejection fraction | There should be no change in left ventricular ejection fraction. Patients with DMD have a decline. | Baseline through 12 months | 
| Change from baseline in pulmonary function | Change from baseline in forced expiratory volume in 1 second | Baseline through 12 months | 
| Change from baseline in quality-of-life | The 23 items Pediatric Quality of Life Inventory (PedQL) questionnaire measures these core dimensions of health as delineated by the World Health Organization, as well as role (school) functioning. Items measured include 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social Functioning (5 items), and 4) School Functioning (5 items). Each item is measured on a 5 point Likert scale with 0 indicating never and 4 indicating almost always.The Likert scores are reversed scored and linearly transform to a 0-100 scale with 0=100, 1-75, 2=50, 5=25, and 4=0. A higher score indicates better health-related quality of life. | Baseline through 12 months |