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

Duchenne Muscular Dystrophy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02310906
• Other study ID #: 4053-101
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 13, 2015
• Est. completion date: March 25, 2019

Study information

• Verified date: October 2020
• Source: Sarepta Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 39
• Est. completion date: March 25, 2019
• Est. primary completion date: March 25, 2019
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 6 Years to 15 Years

Eligibility

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.

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Placebo
SRP-4053 placebo-matching solution for IV infusion.
• SRP-4053
SRP-4053 (golodirsen) solution for IV infusion.

Locations

Country	Name	City	State
France	Institute de Myologie	Paris
Italy	Policlinico Universitario A Gemelli	Rome
United Kingdom	Great Ormond Street Hospital for Children NHS Foundation Trust	London
United Kingdom	Newcastle University Hospital	Newcastle
United States	Boston Children's Hospital	Boston	Massachusetts

Sponsors (9)

Lead Sponsor	Collaborator
Sarepta Therapeutics, Inc.	Catholic University of the Sacred Heart, Consultants for Research in Imaging and Spectroscopy, Great Ormond Street Hospital for Children NHS Foundation Trust, Institut de Myologie, France, Royal Holloway University, SYSNAV, University College, London, University of Newcastle Upon-Tyne

Countries where clinical trial is conducted

United States,  France,  Italy,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation	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. A Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs that were reported or worsened on or after the start of study drug dosing through 12 weeks. TEAEs included both Serious TEAEs and non-serious TEAEs.	Baseline up to Week 12
Primary	Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs	Laboratory parameters included hematology, serum chemistry (SC), urinalysis and coagulation. Number of participants with at least one 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 12
Primary	Part 1: 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 12
Primary	Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations	Physical examinations were performed by the Investigator, or qualified study staff. A full physical examination included a review of general appearance, head, eyes, ears, nose and throat, heart, lungs, abdomen, extremities, skin, lymph nodes, musculoskeletal, and neurological systems. Number of participants with potentially clinically significant abnormalities in physical examinations were reported. Potentially clinically significant abnormalities in physical examinations were based on Investigator's discretion.	Baseline up to Week 12
Primary	Part 1: 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 presented here. The Investigator determined whether abnormal assessment results were potentially clinically significant or not.	Baseline up to Week 12
Primary	Part 1: 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. Cardiac function events included cardiomegaly, tachycardia, and dyspnoea. 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 12
Primary	Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group	6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 144 in total golodirsen group was reported.	Baseline and Week 144
Primary	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)	6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 144 in untreated group (non-exon 53 amenable participants) was calculated.	Baseline and Week 144
Primary	Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group	Change from baseline in dystrophin protein levels (in muscle biopsy samples) was determined by Western blot in total golodirsen group.	Baseline, Week 48
Secondary	Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen	Maximum Concentration (Cmax) of golodirsen in plasma was evaluated.	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)
Secondary	Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen	Time to reach maximum plasma concentration (Tmax) of golodirsen was evaluated.	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)
Secondary	Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma	Area under the concentration-time curve from time zero extrapolated to the infinity was evaluated.	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)
Secondary	Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution at steady state of golodirsen was evaluated.	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)
Secondary	Part 1: Elimination Half-life (T1/2) of Golodirsen	T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of golodirsen was evaluated.	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)
Secondary	Part 1: Total Clearance (CL) of Golodirsen	Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	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)
Secondary	Part 1: Mean Residence Time (MRT) of Golodirsen	MRT= AUMCinf/AUCinf, where AUMCinf is the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. Mean residence time of golodirsen was evaluated.	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)
Secondary	Part 1: Renal Clearance (CLR) of Golodirsen	Renal clearance was calculated using the partial AUC0-24 from the non-compartmental analysis in plasma and AE0-24. AUC0-24 was defined as area under the plasma concentration-time curve, from time 0 to 24 hours after completion of dosing. AE0-24 was defined as total cumulative amount excreted from 0 to 24 hours. Summarized data of all urine collection intervals are reported.	0 to 1440 min after initiation of dosing on Day 1
Secondary	Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group	FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and the most important measurement of lung function. This test required participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which was used to dilate participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) * 100%.	Baseline, Week 144
Secondary	Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Non-exon 53 Amenable Participants)	FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and is the most important measurement of lung function. This test requires participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which was used to dilate participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) * 100%.	Baseline, Week 144
Secondary	Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group	Change from baseline in dystrophin Intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry in total golodirsen group.	Baseline, Week 48
Secondary	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	Percent change from baseline in Exon 53 skipping (in muscle biopsy samples) was determined by reverse transcription polymerase chain reaction in total golodirsen group.	Baseline, Week 48
Secondary	Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group	Percent change from baseline in dystrophin positive fibers (in muscle biopsy samples) were determined by Immunohistochemistry at Week 48 in total golodirsen group.	Baseline, Week 48