Oral Ifetroban in Subjects With Duchenne Muscular Dystrophy (DMD)

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

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

Study Overview

• Status: Completed
• Conditions: Cardiomyopathy, Dilated; Duchenne Muscular Dystrophy Cardiomyopathy
• Intervention / Treatment: Drug: Ifetroban; Drug: Placebo

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 (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
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90095
      • Mattel Children's Hospital
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30341
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Saint. Louis Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carrell Jr. Children's Hospital at Vanderbilt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	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	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	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	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	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	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	Baseline visit and Month 12 visit
Change From Baseline in FEV1	Change from baseline at month 12 in Forced Expiratory Volume in 1 second	Baseline through month 12
Change From Baseline in Percent Predicted FEV1	Change from baseline at month 12 in percent predicted Forced Expiratory Volume in 1 second	Baseline through month 12
Change From Baseline in FVC	Change from baseline at month 12 in Forced Vital Capacity	Baseline through month 12
Change From Baseline in Percent Predicted FVC	Change from baseline at month 12 in percent predicted Forced Vital Capacity	Baseline through month 12
Change From Baseline in Maximal Expiratory Pressure	Change from baseline at month 12 in maximal expiratory pressure	Baseline through month 12
Change From Baseline in Maximal Inspiratory Pressure	Change from baseline at month 12 in maximal inspiratory pressure	Baseline through month 12
Change From Baseline in Peak Expiratory Flow Rate	Change from baseline at month 12 in peak expiratory flow rate	Baseline through month 12
Change From Baseline in Percent Predicted Peak Expiratory Flow Rate	Change from baseline at month 12 in percent predicted peak expiratory flow rate	Baseline through month 12
Change From Baseline in Quality-of-life	The Pediatric Quality of Life Inventory (PedQL) questionnaire measures core dimensions of health as delineated by the World Health Organization. The core module includes 23 items comprising 14 dimensions. The Gastrointestinal module includes 74 items comprising 14 dimensions. The Neuromuscular module includes 25 items comprising 3 dimensions. Each item in the modules is measured on a 5-point Likert scale of 0-4 with 0 indicating 'never' and 4 indicating 'almost always'. The Likert scores for each subscale 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. Subscale scores are averaged to generate the total score reported with a range of 0-100. Results are presented as change from baseline at 12 months. The questionnaire was completed by the participant and the parent/guardian of the participant.	Baseline through 12 months

Collaborators and Investigators

• Sponsor: Cumberland Pharmaceuticals
• Collaborators: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Larry Markham, MD, Riley Children's Hospital

Publications and helpful links

General Publications

• Mitchell R, Frederick NE, Holzman ER, Agobe F, Allaway HCM, Bagher P. Ifetroban reduces coronary artery dysfunction in a mouse model of Duchenne muscular dystrophy. Am J Physiol Heart Circ Physiol. 2021 Jul 1;321(1):H52-H58. doi: 10.1152/ajpheart.00180.2021. Epub 2021 May 28.

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Actual): March 6, 2024
• Study Completion (Actual): January 23, 2026

Study Registration Dates

• First Submitted: November 3, 2017
• First Submitted That Met QC Criteria: November 8, 2017
• First Posted (Actual): November 13, 2017

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Laminopathies; Cardiovascular Diseases; Heart Diseases; Genetic Diseases, Inborn; Cardiomyopathies; Cardiomegaly; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cardiomyopathy, Dilated; Platelet Aggregation Inhibitors; ifetroban
• Other Study ID Numbers: CPI-IFE-007; FD-R-6371 (Other Grant/Funding Number: FDA Orphan Products Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No