Oral Ifetroban in Subjects With Duchenne Muscular Dystrophy (DMD)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy Cardiomyopathy; Cardiomyopathy, Dilated	Drug: Ifetroban; Drug: Placebo	Phase 2

Detailed Description:

This is a phase 2 randomized, double-blind, placebo-controlled, multiple dose study with an optional open-label extension to determine the safety, pharmacokinetics 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	48 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Randomized, placebo-controlled, double-blind, dose-ranging
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:	Each individual bottle is labelled with a unique numeric code that identifies the contents to the unblinded sponsor representative.
Primary Purpose:	Treatment
Official Title:	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
Estimated Study Start Date :	February 2019
Estimated Primary Completion Date :	December 2021
Estimated Study Completion Date :	December 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Oral Ifetroban - Low Dose; Weight based, once daily oral ifetroban	Drug: Ifetroban; Weight based, once daily oral ifetroban
Experimental: Oral Ifetroban - High Dose; Weight based, once daily oral ifetroban	Drug: Ifetroban; Weight based, once daily oral ifetroban
Placebo Comparator: Placebos; Matching Placebo	Drug: Placebo; Matching oral placebo

Outcome Measures

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Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (safety & tolerability) [ Time Frame: Baseline through 12 months ]
   Percentage of subjects with one or more treatment emergent adverse event

Secondary Outcome Measures :

1. Pharmacokinetics [ Time Frame: Day 0 and Day 7 ]
   Peak plasma concentration of ifetroban and its acyl glucuronide metabolite after administration
2. Change from baseline in left ventricular ejection fraction [ Time Frame: Baseline through 12 months ]
   There should be no change in left ventricular ejection fraction. Patients with DMD have a decline.
3. Change from baseline in pulmonary function [ Time Frame: Baseline through 12 months ]
   Change from baseline in forced expiratory volume in 1 second
4. Change from baseline in quality-of-life [ Time Frame: Baseline through 12 months ]
   The 23 items PedQL measure 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.

Eligibility Criteria

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Ages Eligible for Study:	7 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

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.
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 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

Contacts and Locations

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Contacts

Contact: Ines M Macias-Perez, PhD	6159795778	imaciasperez@cumberlandpharma.com
Contact: Byron Kaelin, RN	6156274121	bkaelin@cumberlandpharma.com

Sponsors and Collaborators

Cumberland Pharmaceuticals

Vanderbilt University Medical Center

Investigators

Principal Investigator:	Larry Markham, MD	Vanderbilt University School of Medicine

More Information

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Responsible Party:	Cumberland Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT03340675 History of Changes
Other Study ID Numbers:	CPI-IFE-007
First Posted:	November 13, 2017
Last Update Posted:	October 17, 2018
Last Verified:	October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Cardiomyopathies; Muscular Dystrophies; Muscular Dystrophy, Duchenne; Cardiomyopathy, Dilated; Heart Diseases; Cardiovascular Diseases; Muscular Disorders, Atrophic; Muscular Diseases	Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Cardiomegaly; Ifetroban; Platelet Aggregation Inhibitors