Oral Ifetroban in Subjects With Duchenne Muscular Dystrophy

Cumberland Pharmaceuticals46 enrolled

Overview

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

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 into 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%); study closed to enrollment prior to meeting target enrollment in the late-stage cohort (LVEF 35-45%). All subjects who complete the 12-month study are eligible to enter an optional open label extension period consisting of treatment with high-dose ifetroban only. Subjects in the open label extension will be evaluated for safety and cardiac efficacy every 12 months.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

Eligibility

Sex: MALEMin age: 7 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. 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. 2. Stable dose of oral corticosteroids for at least 8 weeks or has not received corticosteroids for at least 30 days. 3. 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. a. Late-stage cohort: Subjects are eligible for the late-stage cohort if the subject has: i. LVEF 35%-45% by cine cardiac magnetic resonance imaging (MRI) or echocardiography or ii. historically documented LVEF 35%-45% by cine cardiac magnetic resonance imaging (MRI) or echocardiography and if their baseline MRI is less than 50%. 4. 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: 1. Clinically significant illness other than DMD 2. Clinically significant laboratory abnormality not associated with DMD 3. 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 4. Require antiarrhythmic therapy and/or initiation of diuretic therapy for management of acute heart failure in the last 6 months 5. A LVEF of \< 35% by Cardiac Magnetic Resonance Imaging (CMR) and/or fractional shortening of \< 15% based on echocardiography (ECHO) during screening 6. A known bleeding disorder or has received anticoagulant treatment within 2 weeks of study entry 7. 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 8. Non-MR compatible implants (e.g. neurostimulator, automatic implantable cardioverter-defibrillator \[AICD\]) 9. Subjects who participated in a therapeutic clinical trial within 30 days or five half-lives (whichever is longer) of study entry 10. Any other condition that could interfere with the subject's participation

Locations (10)

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Mattel Children's Hospital

Los Angeles, California, United States

Children's National Hospital

Washington D.C., District of Columbia, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Lurie Children's Hospital

Chicago, Illinois, United States

Riley Children's Hospital

Indianapolis, Indiana, United States

Kennedy Krieger Institute

Baltimore, Maryland, United States

Saint. Louis Children's Hospital

St Louis, Missouri, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Monroe Carrell Jr. Children's Hospital at Vanderbilt

Nashville, Tennessee, United States

Outcomes

Primary Outcomes

Incidence of Treatment-Emergent Adverse Events

Percentage of subjects with one or more treatment emergent adverse event

Time frame: Baseline through 12 months

Secondary Outcomes

Pharmacokinetics Area Under the Curve

Plasma ifetroban and its acyl glucuronide metabolite were measured pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7. Area under the curve until the last measurement was calculated for the plasma concentration versus time curves for ifetroban and its acyl glucuronide metabolite after administration of assigned oral ifetroban dose

Time frame: Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post-dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7

Pharmacokinetics Maximum Serum Concentration (Cmax)

Plasma ifetroban and its acyl glucuronide metabolite were measured pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7 to determine the maximum plasma concentration of ifetroban and its acyl glucuronide metabolite after administration of assigned oral ifetroban dose

Time frame: Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7

Pharmacokinetics Time to Reach Cmax (Tmax) Concentration

Plasma ifetroban and its acyl glucuronide metabolite were measured pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7 to determine the time to maximum plasma concentration of ifetroban and its acyl glucuronide metabolite following administration of assigned oral ifetroban dose

Time frame: Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7

Pharmacokinetics Plasma Terminal Half-life Concentration

Plasma ifetroban were measured pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7. The terminal elimination half-life was calculated from the plasma concentration versus time curves for ifetroban following administration of assigned oral ifetroban dose

Time frame: Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7

Change From Baseline in Left Ventricular Ejection Fraction

Change from baseline at month 12 in left ventricular ejection fraction

Time frame: Baseline visit and Month 12 visit

Change From Baseline in FEV1

Change from baseline at month 12 in Forced Expiratory Volume in 1 second