Safety Study of Eteplirsen to Treat Advanced Stage Duchenne Muscular Dystrophy

• Sponsor: Sarepta Therapeutics
• Information provided by (Responsible Party): Sarepta Therapeutics

Study Description

Brief Summary:

The primary objective of this study is to explore safety and tolerability of eteplirsen in participants with advanced stage Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.

Condition or disease	Intervention/treatment	Phase
Muscular Dystrophy, Duchenne	Drug: Eteplirsen	Phase 2

Detailed Description:

This is an open-label, multi-center study to explore the safety and tolerability of eteplirsen injection in participants with advanced stage DMD with confirmed genetic mutations amenable to treatment by exon 51 skipping.

Participants will be evaluated for inclusion during a Screening/Baseline period of up to 4 weeks. Eligible participants will receive once weekly intravenous (IV) infusions of 30 mg/kg eteplirsen for 96 weeks, followed by a safety extension (not to exceed 48 weeks).

Safety will be regularly assessed throughout the study via the collection of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	24 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open-Label, Multi-Center Study to Evaluate the Safety and Tolerability of Eteplirsen in Patients With Advanced Stage Duchenne Muscular Dystrophy
Actual Study Start Date :	November 2014
Actual Primary Completion Date :	April 21, 2017
Actual Study Completion Date :	March 23, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Eteplirsen 30 mg/kg; Participants will receive eteplirsen 30 mg/kg/week intravenous (IV) infusions, weekly, for up to 96 weeks.	Drug: Eteplirsen; Eteplirsen solution for IV infusion; Other Names: AVI-4658; EXONDYS 51®

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From first dose of drug up to 100 weeks ]
   An adverse event (AE) was any untoward medical occurrence in a participant that did not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events that developed or worsened during the on-treatment period (defined as time from first dose of study drug and up to 28 days after last dose of study drug (up to 100 weeks) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

Secondary Outcome Measures :

1. Number of Participants With Potentially Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline up to 100 weeks ]

   Laboratory parameters included hematology, clinical chemistry, urinalysis and coagulation. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal findings.

   Incr=increase; LLN=lower limit of normal; ULN=upper limit of normal; GGT=gamma glutamyl transferase

2. Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs [ Time Frame: Baseline up to 100 weeks ]
   Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal vital sign findings.
3. Number of Participants With at Least One Potentially Clinically Significant Abnormalities in Physical Examinations [ Time Frame: Baseline up to 100 weeks ]
   Physical examinations, full and brief, were performed by the Investigator, a physician Sub-Investigator, or a Nurse Practitioner (if licensed in the state or province to perform physical examinations). Full physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; skin; lymph nodes; and musculoskeletal and neurological systems. Brief physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; and skin.
4. Number of Participants With Abnormalities in Electrocardiograms (ECGs) [ Time Frame: Baseline up to 100 weeks ]

   Twelve-lead ECGs and Holter ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the patient was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel using a central vendor according to prespecified criteria. The Investigator reviewed the results of the centrally read ECG report and determined if the findings were clinically significant. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal ECG findings.

   msec=milliseconds; QTcF=QT interval corrected with Fridericia's method

5. Number of Participants With Abnormalities in Echocardiograms (ECHO) [ Time Frame: Baseline up to 100 weeks ]

   Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study. The ECHO was reviewed and interpreted by medically qualified personnel using a central vendor according to prespecified criteria. Ejection fraction was noted. The Investigator reviewed the results of the ECHO report and determined if the findings were clinically significant.

   LEVF=left ventricular ejection fraction

Eligibility Criteria

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Ages Eligible for Study:	7 Years to 21 Years (Child, Adult)
Sexes Eligible for Study:	Male
Gender Based Eligibility:	Yes
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Male 7 - 21 years of age
• Diagnosis of DMD with a mutation that is amenable to exon 51 skipping, confirmed by a genetic report
• Stable dose of oral corticosteroids for at least 24 weeks or has not received corticosteroids for at least 24 weeks
• Non-ambulatory, or incapable of walking ≥300 meters on the 6-Minute Walk Test (6MWT).
• Score of ≤4 on the Brooke Score for Arms and Shoulders.
• Stable cardiac and pulmonary function
• Use of contraceptives for sexually active males throughout the study
• Willing to provide consent and comply with the study

Exclusion Criteria:

• Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks that may have an effect on muscle strength or function (e.g., growth hormone, anabolic steroids).
• Previous treatment with SMT C1100/BMN 195 at any time.
• Previous treatment with drisapersen (PRO051) within the last 6 months.
• Participation in any other DMD interventional clinical study within 12 weeks
• Major change in physiotherapy regimen within the past 3 months
• Major surgery within 3 months
• Presence of other clinically significant illness
• Use of an aminoglycoside antibiotic within 12 weeks or the need for this antibiotic or statin during study
• Forced vital capacity % predicted [FVC % predicted] <40%, or requiring daytime ventilation.
• Require antiarrhythmic and/or antidiuretic therapy for heart failure.
• Have a left ventricular ejection fraction (LVEF) of <40%.
• Prior or ongoing medical condition that could adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results.

Contacts and Locations

Locations

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United States, California
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States, 90095
University of California, Davis Medical Center
Sacramento, California, United States, 95817
United States, Iowa
University of Iowa Children's Hospital
Iowa City, Iowa, United States, 52242
United States, Maryland
Kennedy Krieger Institute
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Missouri
St. Louis Children's Hospital
Saint Louis, Missouri, United States, 63110
United States, New York
University of Rochester Medical Center
Rochester, New York, United States, 14642
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105

Sponsors and Collaborators

Sarepta Therapeutics

Investigators

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Study Director:	Medical Director	Sarepta Therapeutics, Inc.

  Study Documents (Full-Text)

Documents provided by Sarepta Therapeutics:

Study Protocol  [PDF] July 5, 2016

Statistical Analysis Plan  [PDF] April 20, 2017

More Information

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Responsible Party:	Sarepta Therapeutics
ClinicalTrials.gov Identifier:	NCT02286947 History of Changes
Other Study ID Numbers:	4658-204
First Posted:	November 10, 2014
Results First Posted:	February 20, 2019
Last Update Posted:	February 20, 2019
Last Verified:	January 2019

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

Keywords provided by Sarepta Therapeutics:

DMD; exon 51; dystrophin	dystrophy; eteplirsen; Duchenne

Additional relevant MeSH terms:

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Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases	Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked