Clinical trial NCT03992430: A Study to Compare Safety and Efficacy of High Doses of Eteplirsen in Participants With Duchenne Muscular Dystrophy (DMD) (MIS51ON)
Official title: A Randomized, Double-Blind, Dose Finding and Comparison Study of the Safety and Efficacy of High Doses of Eteplirsen, Preceded by an Open-label Dose Escalation, in Patients With Duchenne Muscular Dystrophy With Deletion Mutations Amenable to Exon 51 Skipping
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Muscular Dystrophy, Duchenne
Keywords: Duchenne muscular dystrophy
Exon Skipping
Exon 51
North Star Ambulatory Assessment
Ambulatory
DMD
Pediatric
Duchenne
EXONDYS
MIS51ON
Lead sponsor: Sarepta Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2019-06-20
Enrollment: 160
Sex: MALE
Minimum age (years): 4
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Part 1 (dose escalation) will evaluate the safety and tolerability of 2 doses (100 milligrams/kilogram \[mg/kg\] and 200 mg/kg) of eteplirsen in approximately 10 participants with DMD; Part 2 (dose finding and dose comparison) will evaluate the efficacy and safety of the high doses (100 mg/kg and 200 mg/kg) of eteplirsen compared with that of the 30 mg/kg dose of eteplirsen, in approximately 144 participants with genetically confirmed deletion mutations amenable to treatment by skipping exon 51.


Eligibility criteria: Inclusion Criteria:

* Be a male with an established clinical diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping.
* Ambulatory participant, able to perform TTRISE in 10 seconds or less at the time of screening visit.
* Able to walk independently without assistive devices.
* Have intact right and left biceps muscles or an alternative upper arm muscle group.
* Have been on a stable dose or dose equivalent of oral corticosteroids for at least 12 weeks prior to randomization and the dose is expected to remain constant (except for modifications to accommodate changes in weight and stress-related needs as per the recently published guidelines throughout the study.
* For ages 7 years and older, has stable pulmonary function (forced vital capacity ≥50 percent (%) of predicted and no requirement for nocturnal ventilation). For ages 4 to 6 years, does not require support from ventilator or non-invasive ventilation at time of screening.

Exclusion Criteria:

* Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to randomization.
* Current or previous treatment with any other experimental pharmacologic treatment for DMD or any prior exposure to antisense oligonucleotide, gene therapy or gene editing; except the following: Ezutromid in the last 12 weeks prior to first dose; Drisapersen in the last 36 weeks prior to first dose; Suvodirsen in the last 12 weeks prior to first dose; Vamorolone in the last 12 weeks prior to first dose; Eteplirsen (previous or current use); and Tamoxifen in the last 4 weeks prior to first dose.
* Major surgery within 3 months prior to randomization.
* Presence of any other significant neuromuscular or genetic disease other than DMD.
* Presence of any known impairment of renal function and/or other clinically significant illness.
* Has evidence of cardiomyopathy, as defined by left ventricular ejection fraction less than \<50% on the screening echocardiogram or Fridericia's correction formula (QTcF) ≥450 millisecond based on the screening electrocardiograms (ECGs).

Other inclusion/exclusion criteria apply.

Primary outcomes:
measure: Part 1: Incidence of Adverse Events (AEs)
timeFrame: Up to Week 148
measure: Part 2: Change From Baseline at Week 144 in the NSAA Total Score (for Final Analysis)
timeFrame: Baseline, Week 144
measure: Part 2: Change from Baseline at Week 72 or Week 96 in NSAA Total Score (for Conditional Efficacy Interim Analysis)
timeFrame: Baseline, Week 72 or Week 96
Secondary outcomes:
measure: Part 2: Change From Baseline in Time to Rise From the Floor, Time to Complete 10-Meter Walk/Run, and the Timed Stair Ascend Test
timeFrame: Baseline, Week 144
measure: Part 2: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT)
timeFrame: Baseline, Week 144
measure: Part 2: Change from Baseline at Week 144 in Forced Vital Capacity Percent Predicted (FVC%p)
timeFrame: Baseline, Week 144
measure: Part 2: Time to Loss of Ambulation (LOA)
timeFrame: Baseline up to Week 144
measure: Part 2: Change From Baseline in Skeletal Muscle Dystrophin Expression
timeFrame: Baseline, Postdose (at Week 24, Week 48, or Week 144)
measure: Part 2: Incidence of Adverse Events (AEs)
timeFrame: Baseline up to Week 148
measure: Part 2: Pharmacokinetic (PK) Plasma Concentration of Eteplirsen
timeFrame: 0 (predose) to 2 hours postdose up to Week 144
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Rare Disease Research, LLC
state: Georgia
city: Bogotá
country: Colombia
facility: Hospital Universitario San Ignacio
city: Medellin
country: Colombia
facility: Instituto Neurologico de Colombia (INDEC)
city: Medellin
country: Colombia
facility: Hospital Pablo Tobón Uribe
city: Brno
country: Czechia
facility: Brno Klinika detske neurologie
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Copenhagen
country: Denmark
facility: Rigshospitalet Copenhagen University Hospital
city: Bron
country: France
facility: Hopital Femme Mere Enfant
city: Paris
country: France
facility: Hopital Armand Trousseau
city: Strasbourg
country: France
facility: CHRU de Strasbourg
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin CVK
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Marousi
country: Greece
facility: IASO Children's Hospital
state: Attiki
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Genomikai Medicina és Ritka Betegsegek Intezete
city: Ahmedabad
country: India
facility: Royal Institute of Child Neurosciences
city: Bengaluru
country: India
facility: Aster RV Hospital
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences
city: Madurai
country: India
facility: Jaicare Hospital (A Unit of Sarvee Integra Pvt Ltd.)
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
city: Pune
country: India
facility: Deenanath Mangeshkar Hospital & Research Centre
city: Vellore
country: India
facility: Christian Medical College
city: Dublin 1
country: Ireland
facility: Children's Health Ireland (CHI) at Temple Street
city: Genova
country: Italy
facility: IRCCS Instituto Gianna Gaslini
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli- IRCCS
city: Amman
country: Jordan
facility: The Specialty Hospital (TSH)/Advanced Clinical Center
city: Amman
country: Jordan
facility: Istiklal Hosptial (IST)
city: Irbid
country: Jordan
facility: Irbid Specialty Hospital
city: Irbid
country: Jordan
facility: Pharmaceutical Research Center/Jordan University of Science and Technology
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
city: Culiacán
country: Mexico
facility: Neurociencias Estudios Clínicos S.C.
state: Sinaloa
city: Durango
country: Mexico
facility: Instituto de Investigaciones Clinicas para la Salud A.C
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Auckland
country: New Zealand
facility: New Zealand Clinical Research - Auckland
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF Rikshospitalet
city: Stavanger
country: Norway
facility: Children's Department and Department for Children's Habilitation at Stavanger University Hospital
city: Gdansk
country: Poland
facility: Klinika Neurologii Rozwojowej
state: Pomorskie
city: Bucharest
country: Romania
facility: National Clinical Hospital for Children Neurorehabilitation "Dr. Nicolae Robănescu"
city: Belgrade
country: Serbia
facility: Clinic for Neurology and Psychiatry for Children and Youth
city: Belgrade
country: Serbia
facility: University Children's Hospital
city: Belgrade
country: Serbia
facility: Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic"
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Antalya
country: Turkey
facility: Akdeniz Universitesi Tip Fakultesi
city: Mersin
country: Turkey
facility: Mersin University Medical Faculty
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
state: West Yorkshire
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: UCL Institute of Child Health Great Ormond Street
Study officials:
affiliation: Sarepta Therapeutics, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: