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.

Tracking Information

• First Submitted Date: July 14, 2015
• First Posted Date: July 16, 2015
• Last Update Posted Date: February 21, 2023
• Actual Study Start Date: September 28, 2016
• Estimated Primary Completion Date: October 3, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 12, 2021): Change From Baseline in the Total Distance Walked During 6MWT at Week 96 [ Time Frame: Baseline, Week 96 ]
• Original Primary Outcome Measures (submitted: July 14, 2015): Change in 6 Minute Walk Test (6MWT) from Baseline [ Time Frame: Baseline to Week 48 ]

Current Secondary Outcome Measures (submitted: August 12, 2021)

• 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 ]
• Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Weeks 48 or 96 [ Time Frame: Baseline, Week 48 or Week 96 ]
• Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Weeks 48 or 96 [ Time Frame: Baseline, Week 48 or Week 96 ]
• 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).
• Time to Loss of Ambulation (LOA) [ Time Frame: Baseline, Week 96, and Week 144 ]
• 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.
• Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 96 and Week 144 [ Time Frame: Baseline, Week 96 and Week 144 ]

Original Secondary Outcome Measures (submitted: July 14, 2015)

• Percentage of dystrophin-positive fibers [ Time Frame: Baseline to Week 24 and 48 ]
• Change in maximum inspiratory pressure (MIP) % predicted, maximum expiratory pressure (MEP) % predicted from Baseline [ Time Frame: Baseline to Week 48 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

• Condition: Duchenne Muscular Dystrophy

Intervention

• 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

Study Arms

• 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).
  Intervention: Drug: SRP-4045
• 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).
  Intervention: Drug: SRP-4053
• 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).
  Interventions:

  • Drug: SRP-4045
  • Drug: SRP-4053
  • Drug: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 17, 2023): 229
• Original Estimated Enrollment (submitted: July 14, 2015): 99
• Estimated Study Completion Date: October 3, 2025
• Estimated Primary Completion Date: October 3, 2025 (Final data collection date for primary outcome measure)

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 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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 6 Years to 13 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Korea, Republic of, Mexico, Poland, Russian Federation, Serbia, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02500381
• Other Study ID Numbers: 4045-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Sarepta Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Sarepta Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Sarepta Therapeutics, Inc.
• Verification Date: February 2023