Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (ESSENCE)

• ClinicalTrials.gov Identifier: NCT02500381
• Recruitment Status: Active, not recruiting
• First Posted: July 16, 2015
• Last Update Posted: February 21, 2023
• Sponsor: Sarepta Therapeutics, Inc.
• Information provided by (Responsible Party): Sarepta Therapeutics, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: SRP-4045; Drug: SRP-4053; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 229 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Part 1 is double-blind and randomized; Part 2 is open-label.
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 28, 2016
• Estimated Primary Completion Date: October 3, 2025
• Estimated Study Completion Date: October 3, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: SRP-4045; Participants amenable to exon 45 skipping will receive SRP-4045 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4045; SRP-4045 solution for IV infusion; Other Names: Casimersen; AMONDYS 45
Experimental: SRP-4053; Participants amenable to exon 53 skipping will receive SRP-4053 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4053; SRP-4053 solution for IV infusion; Other Names: Golodirsen; VYONDYS 53
Placebo Comparator: Placebo followed by SRP-4045 or SRP-4053; Participants amenable to exon 45 or 53 skipping will receive SRP-4045 or SRP-4053 placebo-matching IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 or SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4045; SRP-4045 solution for IV infusion; Other Names: Casimersen; AMONDYS 45; Drug: SRP-4053; SRP-4053 solution for IV infusion; Other Names: Golodirsen; VYONDYS 53; Drug: Placebo; SRP-4045 or SRP-4053 placebo-matching solution for IV infusion

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in the Total Distance Walked During 6MWT at Week 96 [ Time Frame: Baseline, Week 96 ]

Secondary Outcome Measures :

1. Change from Baseline in the Total Distance Walked During 6MWT at Week 144 (Week 48 of the Open-Label Extension Period) [ Time Frame: Baseline, Week 144 ]
2. Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Weeks 48 or 96 [ Time Frame: Baseline, Week 48 or Week 96 ]
3. Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Weeks 48 or 96 [ Time Frame: Baseline, Week 48 or Week 96 ]
4. Participant's Ability to Rise Independently From the Floor, as indicated by a North Star Ambulatory Assessment (NSAA) Subscore [ Time Frame: Week 96, Week 144 ]
   The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, the participant's ability to rise independently from the floor (without external support) will be reported as an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver).
5. Time to Loss of Ambulation (LOA) [ Time Frame: Baseline, Week 96, and Week 144 ]
6. Change From Baseline in the NSAA Total Score at Week 96 and Week 144 [ Time Frame: Baseline, Week 96 and Week 144 ]
   The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, participants will be asked to perform 17 different functional activities, including a 10 meter walk/run, rising from a sit to standing, 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. Participants will be graded as follows: 2 = achieves goal without any assistance; 1 = modified method but achieves goal independent of physical assistance from another person; and 0 = unable to achieve goal independently. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function.
7. Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 96 and Week 144 [ Time Frame: Baseline, Week 96 and Week 144 ]

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 13 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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 or 2 alternative upper 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.

Contacts and Locations

Locations

United States, Arizona

Neuromuscular Research Center

Phoenix, Arizona, United States, 85028

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

David Geffen School of Medicine, UCLA

Los Angeles, California, United States, 90095

Rady Children's Hospital San Diego/ UCSD

San Diego, California, United States, 92123

Stanford University School of Medicine/Medical Center

Stanford, California, United States, 94305

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

NW Florida Clinical Research Group, LLC

Gulf Breeze, Florida, United States, 32561

United States, Georgia

Center for Integrative Rare Disease Research (CIRDR)

Atlanta, Georgia, United States, 30318

United States, Illinois

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States, 60611

United States, Iowa

University of Iowa Children's Hospital

Iowa City, Iowa, United States, 52242

United States, Kansas

University of Kansas, Medical Center

Kansas City, Kansas, United States, 66160

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Missouri

St. Louis Children's Hospital

Saint Louis, Missouri, United States, 63110

United States, Nevada

Las Vegas Clinic

Las Vegas, Nevada, United States, 89145

United States, New York

University of Rochester Clinical Research Center

Rochester, New York, United States, 14642

United States, Ohio

Cincinnati Children's Hospital Medical Center (CCHMC)

Cincinnati, Ohio, United States, 45229

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Oregon

Shriners Hospital for Children

Portland, Oregon, United States, 97239

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Texas

Children's Medical Center Dallas

Dallas, Texas, United States, 75235

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

United States, Virginia

Children's Hospital of the King's Daughters

Norfolk, Virginia, United States, 23507

United States, Wisconsin

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Argentina

DOM Centro de Reumatologia

Ciudad Autonoma de Buenos Aires, Argentina, 1111

Australia, Victoria

Royal Children's Hospital Melbourne

Parkville, Victoria, Australia, 3052

Australia

Queensland Children's Hospital

South Brisbane, Australia, 4101

Children's Hospital at Westmead

Westmead, Australia, 2145

Belgium

Universitair Ziekenhuis Gent

Ghent, Belgium, 9000

Universitair Ziekenhuis Leuven

Leuven, Belgium, 3000

CHR de la Citadelle

Liège, Belgium, 4000

Bulgaria

University Multiprofile Hospital for Active Treatment Aleksandrovska EAD

Sofia, Sofia-Grad, Bulgaria, 1431

Canada, Alberta

Alberta Childrens Hospital

Calgary, Alberta, Canada, T3B 6A8

Canada, British Columbia

Children's and Women's Health Centre of British Columbia

Vancouver, British Columbia, Canada, V6H 3V4

Canada, Ontario

London Health Sciences Centre

London, Ontario, Canada, N6A 5W9

Children's Hospital of Eastern Ontario

Ottawa, Ontario, Canada, K1H 8L1

Czechia

University Hospital Brno

Brno, Czechia, 61300

Fakultni nemocnice v Motole

Praha, Czechia, 15008

Denmark

Rigshospitalet Copenhagen University Hospital

København Ø, Denmark, 2100

France

Hôpital Des Enfants

Toulouse, Haute-Garonne, France, 31059

Reference Centre for Neuromuscular Diseases

Nantes, France, 44093

Hôpital Armand Trousseau

Paris, France, 75012

Germany

Charité - Universitätsmedizin Berlin

Berlin, Germany, 13353

Universitätsklinikum Essen

Essen, Germany, 45122

University Hospital Freiburg

Freiburg, Germany, 79106

Greece

IASO Children's Hospital

Maroussi, Greece, 15123

Ippokratio General Hospital of Thessaloniki

Thessaloniki, Greece, 54642

Hungary

Semmelweis Egyetem Genomikai Medicina és Ritka Betegsegek Intezete

Budapest, Hungary, 1083

India

Royal Instituite of Child Neurosciences

Ahmedabad, Gujarat, India, 380054

Deenanth Mangeshkar Hospital

Pune, Maharashtra, India, 411004

Ireland

The Children's University Hospital

Dublin, Ireland, D1

Israel

Schneider Children's Medical Center of Israel

Petah Tikvah, Israel, 49102

Italy

Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant' Anna

Ferrara, Italy, 44124

Istituto Giannina Gaslini

Genoa, Italy, 16147

Az Ospedaliera Universitaria Policlinico G Martino

Messina, Italy, 98125

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milano, Italy, 20133

Policlinico Universitario A Gemelli

Rome, Italy, 00168

Korea, Republic of

Seoul National University Hospital

Seoul, Korea, Republic of, 03080

Pusan National University Yangsan Hospital

Yangsan, Korea, Republic of, 50612

Mexico

Neurociencias Estudios Clínicos S.C

Culiacán, Mexico, 80020

Instituto de Investigaciones Clínicas para la Salud A.C

Durango, Mexico, 34000

Poland

Samodzielny Publiczny Centralny Szpital Kliniczny

Warsaw, Mazowieckie, Poland, 02-097

Uniwersyteckie Centrum Kliniczne

Gdansk, Poland, 80-952

Russian Federation

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

Moscow, Russian Federation, 125412

State Autonomous Healthcare Institution of Sverdlovsk Region Children's Clinical Hospital No. 9 City of Ekaterinburg

Yekaterinburg, Russian Federation

Serbia

Clinic for Neurology and Psychiatry for Children and Youth

Belgrade, Serbia, 11000

Spain

Hospital de La Santa Creu i Sant Pau

Barcelona, Spain, 08041

Hospital Sant Joan de Deu

Barcelona, Spain, 08950

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, Spain

Sweden

Drottning Silvias Barn Och Ungdomssjukhus

Göteborg, Sweden, SE-41685

United Kingdom

Royal Hospital for Children (Glasgow)

Glasgow, United Kingdom, G51 4TF

Leeds Teaching Hospitals NHS Trust

Leeds, United Kingdom, LS1 3EX

Alder Hey Childrens Hospital

Liverpool, United Kingdom, L12 2AP

Great Ormond Street Hospital (GOSH)

London, United Kingdom, WC1N 1EH

Royal Victoria Infirmary

Newcastle upon Tyne, United Kingdom, NE1 4LP

John Radcliffe Hospital

Oxford, United Kingdom, OX3 9DU

Sponsors and Collaborators

Sarepta Therapeutics, Inc.

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sarepta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02500381
• Other Study ID Numbers: 4045-301
• First Posted: July 16, 2015
• Last Update Posted: February 21, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sarepta Therapeutics, Inc.:

Duchenne muscular dystrophy; Exon Skipping; DMD; Exon 53; Exon 45; Ambulatory; Pediatric; Duchenne

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