Study of Eteplirsen in DMD Patients (PROMOVI)

An Open-Label, Multi-Center, Study With a Concurrent Untreated Control Arm to Evaluate the Efficacy and Safety of Eteplirsen in Duchenne Muscular Dystrophy

The main objective of this study is to provide evidence of efficacy of eteplirsen (AVI-4658) in Duchenne muscular dystrophy (DMD) patients that are amenable to skipping exon 51. Additional objectives include evaluation of safety, biomarkers and the long-term effects of eteplirsen up to 96 weeks, followed by a safety extension (not to exceed 48 weeks).

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy (DMD)
• Intervention / Treatment: Drug: eteplirsen

Detailed Description

This is an open-label, multi-center study to evaluate the efficacy and safety of eteplirsen in patients with genotypically confirmed Duchenne muscular dystrophy (DMD) with genetic deletions amenable to exon 51 skipping (treated group), with a concurrent control arm of DMD patients not amenable to exon 51 skipping (untreated group). Following primary efficacy endpoints, dosing will continue to week 144 to evaluate the long term effects of eteplirsen.

Patients in the treated group 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). Patients in the untreated group will not receive treatment.

Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests such as the six minute walk test. Patients in the treated group will undergo a muscle biopsy at Baseline and a second muscle biopsy over the course of the study. Patients in the untreated group will not undergo muscle biopsy.

Safety, including adverse event monitoring and routine laboratory assessments, will be continuously monitored for all patients.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85028
      • Neuromuscular Research Center
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center
    • San Diego, California, United States, 92130
      • Rady Children's Hospital, U.C. San Diego
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine/Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • Florida
    • Gainesville, Florida, United States, 32610
      • The University of Florida, Powell Gene Therapy Center
    • Gulf Breeze, Florida, United States, 32561
      • NW FL Clinical Research Group, LLC
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Rare Disease Research Center
    • Atlanta, Georgia, United States, 30324
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Clinical Research Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Levine Childrens Hospital, Carolinas Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center (CCHMC)
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Shriners Hospital for Children
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male 7-16 years old
• Diagnosed with DMD, genotypically confirmed
• Stable dose of corticosteroids for at least 24 weeks
• Have intact right and left alternative upper muscle groups
• Mean 6MWT greater than 300m (primary analysis on 300 to 450 meters)
• Stable pulmonary and cardiac function: predicted FVC equal to or greater than 50% and LVEF of greater than 50%

Exclusion Criteria:

• Previous treatment with drisapersen or any other RNA antisense agent or any gene therapy within the last 6 months
• Participation in any other DMD interventional clinical study within 12 weeks
• Major surgery within 3 months
• Presence of other clinically significant illness
• Major change in the physical therapy regime within 3 months

Other inclusion/exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treated Group; Approximately 80 patients with genotypically confirmed Duchenne muscular dystrophy (DMD) with genetic deletions amenable to treatment by exon 51 skipping will receive 30 mg/kg of eteplirsen weekly for 96 weeks, followed by a safety extension (not to exceed 48 weeks).	Drug: eteplirsen; Eteplirsen 30 mg/kg will be administered as an IV infusion once a week for 96 weeks, followed by a safety extension (not to exceed 48 weeks).; Other Names: AVI-4658; EXONDYS 51®
No Intervention: Untreated Group; Approximately 30 DMD patients not amenable to exon 51 skipping will not receive eteplirsen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the 6 Minute Walk Test (6MWT) Distance at Week 96	6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 96 was reported.	Baseline, Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 96	Change from baseline in dystrophin protein levels (in muscle biopsy samples) were determined by Western blot. For each time point, 2 blocks of tissues were analyzed by Western blot, each with 2 replicates of gels to determine the dystrophin level as compared to a healthy individual (Percent Normal). The block average value from 2 replicate gels was computed. The overall average was calculated as the mean of the block average values. The overall average values were used for all analyses. In case only 1 gel was available for a block, then that value was used as the block average value.	Baseline, Week 96
Number of Participants Having Ability to Rise Independently From the Floor Determined Based on North Star Ambulatory Assessment (NSAA) at Week 96	NSAA is a clinician-administered scale that rates participant performance on 17-items and included assessments of abilities such as 10-meter walk/run, rising from a sit to stand, standing on 1 leg, climbing a box step, descending a box step, rising from lying to sitting, rising from the floor, lifting the head, standing on heels, and jumping. For all activities, participants were graded as follows: 0 = unable to achieve goal independently; 1 = modified method but achieves goal independent of physical assistance from another and 2 = normal, no obvious modification of activity. Number of participants having ability to rise independently from the floor indicated by a NSAA Rise from floor sub score greater than 0 (unable to achieve goal independently) was reported.	Week 96
Number of Participants Who Lost Ambulation (LOA) by Week 96	Number of participants who lost ambulation (LOA) by Week 96 was reported. Participant were considered non-ambulatory if each of the 3 conditions below were met: NSAA walk subscore was "0" (unable to achieve goal independently) on 2 consecutive days within a visit or NSAA was not done due to reason related to non-ambulation; 6MWT was not done with any reason related to permanent non-ambulation; and no later data showing this participant was still ambulatory. This was not required if non ambulatory status occurred at the time of early withdrawal or at the end of Week 96 assessment. NSAA is a 17-item scale to assess the participant's abilities; total score range from 0 (if all the activities are failed) to 34 (if all the activities are achieved) with higher scores indicating better performance on the assessment/ fully-independent function.	Up to Week 96
Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Weeks 96	FVC is the total amount of air exhaled during the forced expiratory volume test that is measured during spirometry; and is the most important measurement of lung function. This test requires participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which is used to dilate participant's bronchial (breathing) tubes. Percent of predicted FVC = (observed value) / (predicted value) * 100%.	Baseline, Week 96
Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Scores at Week 96	NSAA is a clinician-administered scale that rates participant performance on 17-items and included assessments of abilities such as 10-meter walk/run, rising from a sit to stand, standing on 1 leg, climbing a box step, descending a box step, rising from lying to sitting, rising from the floor, lifting the head, standing on heels, and jumping. Participant were graded as follows: 0 = unable to achieve goal independently; 1 = modified method but achieves goal independent of physical assistance from another and 2 = normal, no obvious modification of activity. NSAA total score was derived by summing the scores for all the individual items and range from 0 (if all the activities are failed) to 34 (if all the activities are achieved) with higher scores indicating better performance on the assessment/ fully-independent function.	Baseline, Week 96
Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 96	Change from baseline in dystrophin intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry.	Baseline, Week 96

Collaborators and Investigators

• Sponsor: Sarepta Therapeutics, Inc.
• Investigators: Study Director: Medical Director, Sarepta Therapeutics, Inc.

Publications and helpful links

General Publications

• Brogna C, Coratti G, Pane M, Ricotti V, Messina S, D'Amico A, Bruno C, Vita G, Berardinelli A, Mazzone E, Magri F, Ricci F, Mongini T, Battini R, Bello L, Pegoraro E, Baranello G, Previtali SC, Politano L, Comi GP, Sansone VA, Donati A, Bertini E, Muntoni F, Goemans N, Mercuri E; on behalf on the International DMD group. Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53. PLoS One. 2019 Jun 25;14(6):e0218683. doi: 10.1371/journal.pone.0218683. eCollection 2019. Erratum In: PLoS One. 2019 Jul 31;14(7):e0220714.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2014
• Primary Completion (Actual): June 14, 2019
• Study Completion (Actual): June 14, 2019

Study Registration Dates

• First Submitted: September 25, 2014
• First Submitted That Met QC Criteria: September 29, 2014
• First Posted (Estimate): October 2, 2014

Study Record Updates

• Last Update Posted (Actual): January 25, 2021
• Last Update Submitted That Met QC Criteria: December 31, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: DMD, Duchenne, Eteplirsen, dystrophy, dystrophin, exon 51
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: 4658-301

Plan for Individual participant data (IPD)

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