Phase I/II Study of SRP-4053 in DMD Patients

• ClinicalTrials.gov Identifier: NCT02310906
• Recruitment Status: Completed
• First Posted: December 8, 2014
• Last Update Posted: June 12, 2019
• Sponsor: Sarepta Therapeutics, Inc.
• Collaborators: Institut de Myologie, France; Consultants for Research in Imaging and Spectroscopy; Great Ormond Street Hospital for Children NHS Foundation Trust; Catholic University of the Sacred Heart; Royal Holloway University; SYSNAV; University College, London; University of Newcastle Upon-Tyne
• Information provided by (Responsible Party): Sarepta Therapeutics, Inc.

Study Description

Brief Summary:

This is a first-in-human, multiple-dose 2-part study to assess the safety, tolerability, efficacy, and pharmacokinetics of SRP-4053 in Duchenne muscular dystrophy (DMD) patients with deletions amenable to exon 53 skipping.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: Placebo; Drug: SRP-4053	Phase 1; Phase 2

Detailed Description:

Part 1: Randomized, placebo-controlled dose-titration to assess safety, tolerability and pharmacokinetics of 4 dose levels of SRP-4053 in genotypically-confirmed DMD patients with deletions amenable to exon 53 skipping.

Part 2: Open-label evaluation of SRP-4053 in patients from Part 1, along with newly enrolled DMD patients with deletions amenable to exon 53 skipping and an untreated group of DMD patients with deletions not amenable to exon 53 skipping.

Safety, including adverse event monitoring and routine laboratory assessments, will be followed on an ongoing basis for all patients.

Clinical efficacy, including functional tests such as the six-minute walk test (6MWT), will be assessed at regularly scheduled study visits. Patients in the treated groups will undergo one baseline and one follow-up muscle biopsy. Patients in the untreated group will not undergo biopsies and will follow an abbreviated schedule of study assessments.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Masking Description: Part 1 is double-blind and randomized; Part 2 is open-label.
• Primary Purpose: Treatment
• Official Title: A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping
• Actual Study Start Date: January 13, 2015
• Actual Primary Completion Date: March 25, 2019
• Actual Study Completion Date: March 25, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: SRP-4053; Patients will receive SRP-4053 intravenous (IV) infusions, weekly, at escalating dose levels as follows: Weeks 1-2, 4 mg/kg/week; Weeks 3-4, 10 mg/kg/week; Weeks 5-6, 20 mg/kg/week; Weeks 7-12, 30 mg/kg/week. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator.	Drug: SRP-4053; SRP-4053 solution for IV infusion
Placebo Comparator: Part 1: Placebo; Patients will receive SRP-4053 placebo-matching IV infusions, weekly, for 12 weeks. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator.	Drug: Placebo; SRP-4053 placebo-matching solution for IV infusion
Experimental: Part 2: SRP-4053; All eligible patients from Part 1, as well as new patients, will receive SRP-4053 30 mg/kg/week IV infusions, weekly, for up to 168 weeks.	Drug: SRP-4053; SRP-4053 solution for IV infusion
No Intervention: Part 2: Untreated Group; Patients with DMD who have a genotypically confirmed deletion of exon(s) not amenable to treatment by exon 53 skipping, but who otherwise meet the same eligibility criteria as treated patients newly recruited to Part 2, will undergo the same study assessments as treated Patients (except for pharmacokinetic [PK] sampling and muscle biopsies), but at a reduced schedule through Week 144.

Outcome Measures

Primary Outcome Measures :

1. Part 1: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: approximately 12 weeks ]
2. Part 2: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 [ Time Frame: Baseline and Week 144 ]
3. Part 2: Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 [ Time Frame: Baseline to Week 48 ]

Secondary Outcome Measures :

1. Part 1: Maximum Plasma Concentration (Cmax) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
2. Part 1: Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
3. Part 1: Area Under the Plasma Concentration-time Curve (AUC) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
4. Part 1: Apparent Volume of Distribution at Steady State (Vss) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
5. Part 1: Elimination Half-life (t½) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
6. Part 1: Total Clearance (CL) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
7. Part 1: Mean Residence Time (MRT) [ Time Frame: Pre-dose, 5 to 10 minutes and 1 to 24 hours post-dose at Weeks 1, 3, 5 and 7 ]
8. Part 1: Urinary Clearance (CLR) [ Time Frame: Day 1, 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 after initiation of dosing ]
9. Part 2: Change from Baseline in Forced Vital Capacity Percent Predicted (FVC%p) through Week144 [ Time Frame: Baseline through Week 144 ]
   The FVC is the maximal volume of air that can be exhaled from full inhalation by exhaling as forcefully and rapidly as possible. Patients will be assessed with delayed in the loss of respiratory function.
10. Part 2: Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 [ Time Frame: Baseline and Week 48 ]
11. Part 2: Exon 53 Skipping Determined by Measurement and Sequence Verification of Exon 53 Skipped Messenger Ribonucleic Acid (RNA) [ Time Frame: Baseline and Week 48 ]

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 15 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosed with DMD, genotypically confirmed.
• Intact right and left biceps muscles or an alternative upper arm muscle group.
• Stable pulmonary and cardiac function.
• Minimum performance on 6MWT, North Star Ambulatory Assessment, and rise (Gowers) test as specified in the study protocol.
• On a stable dose of corticosteroids for at least 6 months.

Exclusion Criteria:

• Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053.
• Current or previous treatment with any other experimental treatments within 12 weeks prior to study entry.
• Major surgery within the last 3 months.
• Presence of other clinically significant illness.
• Major change in physical therapy regime within the last 3 months.

Other inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02116

France

Institute de Myologie

Paris, France, 75013

Italy

Policlinico Universitario A Gemelli

Rome, Italy, 00168

United Kingdom

Great Ormond Street Hospital for Children NHS Foundation Trust

London, United Kingdom, WC1N 3JH

Newcastle University Hospital

Newcastle, United Kingdom

Sponsors and Collaborators

Sarepta Therapeutics, Inc.

Institut de Myologie, France

Consultants for Research in Imaging and Spectroscopy

Great Ormond Street Hospital for Children NHS Foundation Trust

Catholic University of the Sacred Heart

Royal Holloway University

SYSNAV

University College, London

University of Newcastle Upon-Tyne

Investigators

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

More Information

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

Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, Charleston JS, Sardone V, Domingos J, Dickson G, Straub V, Guglieri M, Mercuri E, Servais L, Muntoni F; SKIP-NMD Study Group. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020 May 26;94(21):e2270-e2282. doi: 10.1212/WNL.0000000000009233. Epub 2020 Mar 5.

• Responsible Party: Sarepta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02310906
• Other Study ID Numbers: 4053-101
• First Posted: December 8, 2014
• Last Update Posted: June 12, 2019
• Last Verified: June 2019

• 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; Ambulatory; Pediatric

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