Clinical trial NCT02310906: Phase I/II Study of SRP-4053 in DMD Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Exon Skipping
DMD
Exon 53
Ambulatory
Pediatric
Lead sponsor: Sarepta Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Institut de Myologie, France
name: Consultants for Research in Imaging and Spectroscopy
name: Great Ormond Street Hospital for Children NHS Foundation Trust
name: Catholic University of the Sacred Heart
name: Royal Holloway University
name: SYSNAV
name: University College, London
name: University of Newcastle Upon-Tyne
First posted: 2014-12-08
Enrollment: 39
Sex: MALE
Minimum age (years): 6
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation
timeFrame: Baseline up to Week 12
measure: Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs
timeFrame: Baseline up to Week 12
measure: Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs
timeFrame: Baseline up to Week 12
measure: Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations
timeFrame: Baseline up to Week 12
measure: Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs
timeFrame: Baseline up to Week 12
measure: Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)
timeFrame: Baseline up to Week 12
measure: Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group
timeFrame: Baseline and Week 144
measure: Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Non-exon 53 Amenable Participants)
timeFrame: Baseline and Week 144
measure: Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Elimination Half-life (T1/2) of Golodirsen
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Total Clearance (CL) of Golodirsen
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Mean Residence Time (MRT) of Golodirsen
timeFrame: Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)
measure: Part 1: Renal Clearance (CLR) of Golodirsen
timeFrame: 0 to 1440 min after initiation of dosing on Day 1
measure: Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group
timeFrame: Baseline, Week 144
measure: Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Non-exon 53 Amenable Participants)
timeFrame: Baseline, Week 144
measure: Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group
timeFrame: Baseline, Week 48
measure: Part 2a: Percent Change From Baseline in Exon 53 Skipping Determined by Reverse Transcription Polymerase Chain Reaction (PCR) at Week 48 in Total Golodirsen Group
timeFrame: Baseline, Week 48
measure: Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group
timeFrame: Baseline, Week 48
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Paris
country: France
facility: Institute de Myologie
city: Rome
country: Italy
facility: Policlinico Universitario A Gemelli
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Newcastle University Hospital
Study officials:
affiliation: Sarepta Therapeutics, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Servais L, Mercuri E, Straub V, Guglieri M, Seferian AM, Scoto M, Leone D, Koenig E, Khan N, Dugar A, Wang X, Han B, Wang D, Muntoni F; SKIP-NMD Study Group. Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial. Nucleic Acid Ther. 2022 Feb;32(1):29-39. doi: 10.1089/nat.2021.0043. Epub 2021 Nov 17.