Study of Eteplirsen in Young Participants With Duchenne Muscular Dystrophy (DMD) Amenable to Exon 51 Skipping

• ClinicalTrials.gov Identifier: NCT03218995
• Recruitment Status: Completed
• First Posted: July 17, 2017
• Results First Posted: December 9, 2021
• Last Update Posted: December 9, 2021
• Sponsor: Sarepta Therapeutics, Inc.
• Information provided by (Responsible Party): Sarepta Therapeutics, Inc.

Study Description

Brief Summary:

This is a multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, and PK of once-weekly IV infusions of eteplirsen in approximately 12 male participants, ages 6 months to 48 months (inclusive), who have genotypically confirmed DMD with a deletion mutation amenable to exon 51 skipping.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Safety, Tolerability, and Pharmacokinetics Study of Eteplirsen in Young Patients With Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping
• Actual Study Start Date: August 16, 2017
• Actual Primary Completion Date: March 10, 2021
• Actual Study Completion Date: March 10, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Eteplirsen; Eteplirsen will be administered once every 7 days by intravenous (IV) infusion starting on Day 1 for up to 96 weeks. The starting dose will be 2 milligrams/kilogram (mg/kg) eteplirsen, with escalation to 4, 10, 20, and 30 mg/kg for 10 weeks, and then participants will continue to receive eteplirsen at 30 mg/kg for the duration of the study.	Drug: Eteplirsen; Infusion for intravenous use.; Other Names: AVI-4658; EXONDYS 51®

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and TEAEs Leading to Discontinuation From Study Drug [ Time Frame: Baseline up to Week 100 ]
   TEAEs were defined as adverse events (AEs) with an onset following administration of the first dose of study drug. An AE was any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with the study drug. Abnormalities presented at Baseline were considered AEs if they reoccurred after resolution or worsen during the AE collection period. An SAE was defined as any AE that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes as fatal, life-threatening, required hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or an important medical event. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in the 'Adverse Events' Section.
2. Number of Participants With at Least 1 Potentially Clinically Significant Clinical Safety Laboratory Abnormality [ Time Frame: Baseline up to Week 100 ]

   Clinical laboratory parameters that were evaluated included

   • Any Grade ≥2 (moderate) or serious event without an alternative etiology that the Investigator deemed was related to study drug
   • Two consecutive drug-related serum creatinine levels ≥2*upper limit of normal (ULN) without an alternative etiology
   • Creatine kinase (CK) levels >50,000 units/liter (U/L)
   • A confirmed, unexplained, increase in gamma glutamyl transferase (GGT) >3*ULN and either an increase in bilirubin >2*ULN or nascent prothrombin time >2*ULN concurrently, without an alternative etiology
3. Number of Participants With at Least 1 Markedly Abnormal Vital Sign [ Time Frame: Baseline up to Week 100 ]
   The vital sign parameters that were evaluated included blood pressure, heart rate, respiration, and temperature. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in the 'Adverse Events' Section.
4. Abnormal Changes From Baseline or Worsening of Physical Examination Findings [ Time Frame: Baseline up to Week 100 ]
   Data not collected during the study for this Outcome Measure. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in the 'Adverse Events' Section.
5. Number of Participants With at Least 1 Markedly Abnormal Electrocardiogram (ECG) and Echocardiogram (ECHO) [ Time Frame: Weeks 8, 12, 24, 36, 48, 60, 72, 84, 96 ]
   The ECG was manually reviewed and interpreted by medically qualified personnel using a central vendor according to pre-specified criteria. The Investigator determined if the findings in the centrally read ECG report were clinically significant. Clinical significance was defined as any variation in ECG findings that had medical relevance resulting in an alteration in medical care. The ECHO was reviewed and interpreted by medically qualified personnel using a central vendor according to pre-specified criteria. The Investigator determined if the findings in the ECHO report were clinically significant. Clinical significance was defined as any variation in ECHO findings that had medical relevance resulting in an alteration in medical care. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in the 'Adverse Events' Section.

Secondary Outcome Measures :

1. Maximum Plasma Concentration (Cmax) of Eteplirsen [ Time Frame: Pre-infusion, immediately prior to end of infusion, and approximately 1-3 hours and 6-8 hours after completion of infusion during Weeks 2 (2 mg/kg dose level), 6 (10 mg/kg dose level), 8 (20 mg/kg dose level), and 10 and 24 (30 mg/kg dose level) ]
2. Time to Reach Maximum Plasma Concentration (Tmax) of Eteplirsen [ Time Frame: Pre-infusion, immediately prior to end of infusion, and approximately 1-3 hours and 6-8 hours after completion of infusion during Weeks 2 (2 mg/kg dose level), 6 (10 mg/kg dose level), 8 (20 mg/kg dose level), and 10 and 24 (30 mg/kg dose level) ]
3. Area Under Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Eteplirsen in Plasma [ Time Frame: Pre-infusion, immediately prior to end of infusion, and approximately 1-3 hours and 6-8 hours after completion of infusion during Weeks 2 (2 mg/kg dose level), 6 (10 mg/kg dose level), 8 (20 mg/kg dose level), and 10 and 24 (30 mg/kg dose level) ]
4. Amount of Drug Eliminated in Urine [ Time Frame: Pre-infusion, immediately prior to end of infusion, and approximately 1-3 hours and 6-8 hours after completion of infusion during Weeks 2 (2 mg/kg dose level), 6 (10 mg/kg dose level), 8 (20 mg/kg dose level), and 10 and 24 (30 mg/kg dose level) ]
   Amount of unchanged drug excreted in urine from time 0 to 4 hours after completion of dosing is reported.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 48 Months (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male between 6 months to 48 months of age (inclusive)
• Diagnosis of DMD with a deletion mutation amenable to exon 51 skipping
• Parent(s) or legal guardian(s) who is willing to provide written informed consent

Exclusion Criteria:

• Received treatment that might have an effect on muscle strength or function within 12 weeks prior to dosing
• Received previous or current treatment with any experimental treatment
• Clinically significant illness other than DMD
• Clinically significant laboratory abnormality
• Any other condition that could interfere with the participation in the study.

Contacts and Locations

Locations

Belgium

Universitair ziekenhuis Gent

Gent, Belgium, 9000

France

Armand-Trousseau Hospital

Paris, France, 75012

Italy

Site Fondazione Policlinico Universitario Agostino Gemelli

Roma, Italy

United Kingdom

UCL Great Ormond Street Institute of Child Health

London, United Kingdom, WC1N 1EH

Sponsors and Collaborators

Sarepta Therapeutics, Inc.

Investigators

• Study Chair: Medical Director; Sarepta Therapeutics, Inc.

  Study Documents (Full-Text)

Documents provided by Sarepta Therapeutics, Inc.:

Study Protocol  [PDF] February 7, 2020

Statistical Analysis Plan  [PDF] April 14, 2021

More Information

• Responsible Party: Sarepta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03218995
• Other Study ID Numbers: 4658-102
• First Posted: July 17, 2017
• Results First Posted: December 9, 2021
• Last Update Posted: December 9, 2021
• Last Verified: November 2021

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
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Sarepta Therapeutics, Inc.:

DMD; Duchenne; Eteplirsen; dystrophy; dystrophin; exon 51

Additional relevant MeSH terms:

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