Dose-Titration and Open-label Extension Study of SRP-4045 in Advanced Stage Duchenne Muscular Dystrophy (DMD) Patients

NCT02530905 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 4045-101
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 3

Brief Summary

This is a first-in-human dose-titration and open-label extension study to assess safety, tolerability, and pharmacokinetics of SRP-4045 in advanced-stage Duchenne muscular dystrophy (DMD) patients with deletions amenable to exon 45 skipping.

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne muscular dystrophy; Exon Skipping

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs)

  Adverse event (AE) was any untoward medical occurrence in a clinical trial participant, which does not necessarily have a causal relationship with the investigational drug. AEs also included abnormal physical examination findings (Physical examination were conducted per protocol and any clinically significant abnormal findings were recorded in medical history if pre-existing or addressed as an AE if new or worsening). TEAEs was defined as AEs that started, worsened, or became serious on or after the start of first infusion through 148 weeks. Number of participants with TEAEs were reported.

  Baseline up to Week 148

• Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs

  Laboratory parameters included serum chemistry (hepatic chemistry and renal chemistry), hematology, coagulation, and urinalysis. Number of participants with potentially clinically significant abnormal finding were reported as TEAEs. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Potentially clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care.

  Baseline up to Week 148

• Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs

  Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Number of participants with at least one potentially clinically significant abnormal vital signs findings were reported as TEAEs. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Potential clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care.

  Baseline up to Week 148

• Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs

  Twelve-lead ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the participant was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel. Number of participants with potentially clinically significant abnormalities in ECG reported as TEAEs were presented here. The Investigator determined whether abnormal assessment results were potentially clinically significant or not.

  Baseline up to Week 148

• Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)

  Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study.The ECHO was reviewed and interpreted by medically qualified personnel. Number of participants with potentially clinically significant abnormalities in ECHO were reported.

  Baseline up to Week 148

Secondary Outcomes (10)

• Maximum Plasma Concentration (Cmax) of Casimersen

  Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP

• Time to Reach Maximum Plasma Concentration (Tmax) of Casimersen

  Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP

• Area Under Concentration-time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Casimersen in Plasma

  Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP

• Area Under Concentration-Time Curve From Time Zero Pre-dose to Twenty-Four Hours Post-dose (AUC0-24) of Casimersen in Plasma

  Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP

• Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Casimersen in Plasma

  Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP

Study Arms (3)

Placebo (double-blind dose titration)

PLACEBO COMPARATOR

Participants with genotypically confirmed Duchenne muscular dystrophy (DMD) characterized by deletions amenable to exon 45 skipping will receive placebo-matching to casimersen intravenous (IV) infusions, once weekly over approximately 12 weeks in the double-blind period.

Drug: Placebo

SRP-4045 (double-blind dose titration)

EXPERIMENTAL

Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping will receive weekly IV infusions of casimersen at four escalating dose levels, each for at least 2 weeks: 4 milligrams per kilograms (mg/kg) during Week 1 to Week 2, followed by 10 mg/kg during Week 3 to Week 4, followed by 20 mg/kg during Week 5 to Week 6, followed by 30 mg/kg beginning at Week 7 and continue over approximately Week 12 in the double-blind period.

Drug: SRP-4045

SRP-4045 (open label extension period)

EXPERIMENTAL

All participants who completed double blind period will be enrolled to receive casimersen 30 mg/kg once weekly, for up to Week 144 in the open label extension period.

Drug: SRP-4045

Interventions

SRP-4045 DRUG

SRP-4045 solution for IV infusion.

SRP-4045 (double-blind dose titration); SRP-4045 (open label extension period)

Placebo DRUG

SRP-4045 placebo-matching solution for IV infusion.

Placebo (double-blind dose titration)

Eligibility Criteria

• Age: 7 Years - 21 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Genotypically confirmed DMD (amenable to exon 45 skipping).
• Stable cardiac and pulmonary function.
• Limited or no ambulation.
• On a stable dose of oral corticosteroids for at least 24 weeks OR has not received corticosteroids for at least 24 weeks.

You may not qualify if:

• Current or previous treatment with the experimental agents SMT C1100 (BMN-195) or PRO045.
• Other experimental treatment in the past 12 weeks.
• If on cardiac medication, must be on a stable dose for the past 12 weeks.
• Major surgery within the past 3 months.

Sponsors & Collaborators

• Sarepta Therapeutics, Inc.: lead

Study Sites (3)

David Geffen School of Medicine at UCLA

Los Angeles, California, 90095, United States

Location

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

Chicago, Illinois, 60611, United States

Location

Kennedy Krieger Institute

Baltimore, Maryland, 21205, United States

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

casimersen

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Medical Director
• Organization: Sarepta Therapeutics, Inc.

clinicaltrials@sarepta.com

1-800-690-2003

Study Officials

• Medical Director

  Sarepta Therapeutics, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2015
• First Posted: August 21, 2015
• Study Start: October 8, 2015
• Primary Completion: October 3, 2018
• Study Completion: October 3, 2018
• Last Updated: May 17, 2021
• Results First Posted: May 17, 2021

Record last verified: 2021-04

Locations

US (3)