Study of Eteplirsen in DMD Patients

Duchenne Muscular Dystrophy (DMD) Clinical Trial

— PROMOVI  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02255552
• Other study ID #: 4658-301
• Status: Completed
• Phase: Phase 3
• Start date: November 17, 2014
• Est. completion date: June 14, 2019

Study information

• Verified date: December 2020
• Source: Sarepta Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 109
• Est. completion date: June 14, 2019
• Est. primary completion date: June 14, 2019
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 7 Years to 16 Years

Eligibility

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.

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy (DMD)
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

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).

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Rare Disease Research Center	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Kennedy Krieger Institute	Baltimore	Maryland
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Levine Childrens Hospital, Carolinas Medical Center	Charlotte	North Carolina
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center (CCHMC)	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	The University of Florida, Powell Gene Therapy Center	Gainesville	Florida
United States	NW FL Clinical Research Group, LLC	Gulf Breeze	Florida
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Children's Hospital	Houston	Texas
United States	University of Iowa Children's Hospital	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Nemours Children's Hospital	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Neuromuscular Research Center	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Shriners Hospital for Children	Portland	Oregon
United States	University of Rochester Clinical Research Center	Rochester	New York
United States	University of California, Davis Medical Center	Sacramento	California
United States	St. Louis Children's Hospital	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Rady Children's Hospital, U.C. San Diego	San Diego	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Stanford University School of Medicine/Medical Center	Stanford	California
United States	Children's National Health System	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Sarepta Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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