Clinical trial NCT02500381: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD)
Official title: A Double-Blind, Placebo-Controlled, Multi-Center Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Exon Skipping
DMD
Exon 53
Exon 45
Ambulatory
Pediatric
Duchenne
Lead sponsor: Sarepta Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-07-16
Enrollment: 228
Sex: MALE
Minimum age (years): 6
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective of this study is to evaluate the efficacy of SRP-4045 (casimersen) and SRP-4053 (golodirsen) compared to placebo in participants with DMD with out-of-frame deletion mutations amenable to skipping exon 45 and exon 53, respectively.

Detailed description: This is a double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of SRP-4045 and SRP-4053. Eligible participants with out-of-frame deletion mutations amenable to exon 45 or 53 skipping will be randomized to receive once weekly intravenous (IV) infusions of 30 milligrams/kilograms (mg/kg) SRP-4045 or 30 mg/kg SRP-4053 respectively (combined-active group) or placebo for up to 96 weeks (the placebo-controlled period of the trial). This will be followed by an open-label extension period in which all participants will receive open-label active treatment for 48 weeks (up to Week 144 of study).

The study will enroll approximately 222 participants. Twice as many participants will be randomized to receive active treatment as will receive placebo (2:1 randomization).

Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests, such as the 6-minute walk test (6MWT). All participants will undergo a muscle biopsy at baseline and a second muscle biopsy either at Week 48 or Week 96.

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

Blood samples will be taken periodically throughout the study to assess the pharmacokinetics of both drugs.

Eligibility criteria: Inclusion Criteria:

* Genotypically confirmed DMD, with genetic deletion amenable to exon 45 or exon 53 skipping
* Stable dose of oral corticosteroids for at least 24 weeks prior to Week 1, and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight).
* Intact right and left biceps brachii muscles or 2 alternative upper arm muscle groups
* Mean 6MWT ≥300 meters and ≤450 meters
* Stable pulmonary function: forced vital capacity (FVC) ≥50% predicted

Exclusion Criteria:

* Treatment with gene therapy at any time
* Previous treatment with SMT C1100 within 1 week prior to Week 1 and previous treatment with PRO045 (BMN 045), PRO053 (BMN 053), or PRO051 (BMN 051) within 24 weeks prior to Week 1
* Current or previous treatment with any other experimental treatment within 12 weeks prior to Week 1
* Major surgery within 3 months prior to Week 1
* Presence of other clinically significant illness
* Other inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Change From Baseline in the 4-Step Ascend Velocity at Week 96
timeFrame: Baseline, Week 96
Secondary outcomes:
measure: Change from Baseline in the Total Distance Walked During 6MWT at Week 96
timeFrame: Baseline, Week 96
measure: Change from Baseline in Rise from Floor Velocity at Week 96
timeFrame: Baseline, Week 96
measure: Change From Baseline in the 4-Step Ascend Velocity at Week 144
timeFrame: Baseline, Week 144
measure: Change From Baseline in Total Distance Walked During the 10-meter walk/run (10-MWR) Velocity
timeFrame: Baseline, Week 96
measure: Change From Baseline in the North Star Ambulatory Assessment (NSAA) Total Score at Week 96
timeFrame: Baseline, Week 96
measure: Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Weeks 48 or 96
timeFrame: Baseline, Week 48 or Week 96
measure: Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Weeks 48 or 96
timeFrame: Baseline, Week 48 or Week 96
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Neuromuscular Research Center
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine, UCLA
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego/ UCSD
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine/Medical Center
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Gulf Breeze
country: United States
facility: NW Florida Clinical Research Group, LLC
state: Florida
city: Atlanta
country: United States
facility: Center for Integrative Rare Disease Research (CIRDR)
state: Georgia
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Children's Hospital
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas, Medical Center
state: Kansas
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Las Vegas
country: United States
facility: Las Vegas Clinic
state: Nevada
city: Rochester
country: United States
facility: University of Rochester Clinical Research Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center (CCHMC)
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Shriners Hospital for Children
state: Oregon
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Norfolk
country: United States
facility: Children's Hospital of the King's Daughters
state: Virginia
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: DOM Centro de Reumatologia
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
state: Sofia-Grad
city: Calgary
country: Canada
facility: Alberta Childrens Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's and Women's Health Centre of British Columbia
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Brno
country: Czechia
facility: University Hospital Brno
city: Praha
country: Czechia
facility: Fakultni nemocnice v Motole
city: København Ø
country: Denmark
facility: Rigshospitalet Copenhagen University Hospital
city: Toulouse
country: France
facility: Hôpital Des Enfants
state: Haute-Garonne
city: Nantes
country: France
facility: Reference Centre for Neuromuscular Diseases
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: University Hospital Freiburg
city: Maroussi
country: Greece
facility: IASO Children's Hospital
city: Thessaloniki
country: Greece
facility: Ippokratio General Hospital of Thessaloniki
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Genomikai Medicina és Ritka Betegsegek Intezete
city: Ahmedabad
country: India
facility: Royal Instituite of Child Neurosciences
state: Gujarat
city: Pune
country: India
facility: Deenanth Mangeshkar Hospital
state: Maharashtra
city: Dublin
country: Ireland
facility: The Children's University Hospital
city: Petah Tikvah
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Ferrara
country: Italy
facility: Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant' Anna
city: Genoa
country: Italy
facility: Istituto Giannina Gaslini
city: Messina
country: Italy
facility: Az Ospedaliera Universitaria Policlinico G Martino
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Rome
country: Italy
facility: Policlinico Universitario A Gemelli
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
city: Culiacán
country: Mexico
facility: Neurociencias Estudios Clínicos S.C
city: Durango
country: Mexico
facility: Instituto de Investigaciones Clínicas para la Salud A.C
city: Warsaw
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny
state: Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Moscow
country: Russian Federation
facility: Federal state budget educational institution of higher education "Russian national research medical university n.a. N.I. Pirogov" of Ministry of healthcare of Russian Federation
city: Yekaterinburg
country: Russian Federation
facility: State Autonomous Healthcare Institution of Sverdlovsk Region Children's Clinical Hospital No. 9 City of Ekaterinburg
city: Belgrade
country: Serbia
facility: Clinic for Neurology and Psychiatry for Children and Youth
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Göteborg
country: Sweden
facility: Drottning Silvias Barn Och Ungdomssjukhus
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children (Glasgow)
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Liverpool
country: United Kingdom
facility: Alder Hey Childrens Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital (GOSH)
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
affiliation: Sarepta Therapeutics, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Wagner KR, Kuntz NL, Koenig E, East L, Upadhyay S, Han B, Shieh PB. Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve. 2021 Sep;64(3):285-292. doi: 10.1002/mus.27347. Epub 2021 Jun 29.