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.
This is a randomized, placebo-controlled dose-titration study to assess safety, tolerability, and pharmacokinetics of 4 dose levels of SRP-4045 in genotypically confirmed advanced-stage DMD patients with deletions amenable to exon 45 skipping. After completion of the dose-titration portion of the study and SRP-4045 is determined to be safe, all patients will be evaluated on open-label SRP-4045 for the duration of the study. Safety, including adverse event monitoring, routine laboratory assessments, and cardiac testing will be monitored through the duration of the dose-titration and open-label portions of the study. Clinical efficacy will be assessed at regularly scheduled study visits via quality of life questionnaires and tests of pulmonary and upper extremity function through the duration of the dose-titration and open-label portions of the trial.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
12
David Geffen School of Medicine at UCLA
Los Angeles, California, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Kennedy Krieger Institute
Baltimore, Maryland, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to Week 148
Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs
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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.
Time frame: 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.
Time frame: Baseline up to Week 148
Maximum Plasma Concentration (Cmax) of Casimersen
Maximum Concentration (Cmax) of casimersen in plasma was evaluated.
Time frame: 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
Time to reach maximum plasma concentration (Tmax) of casimersen was evaluated.
Time frame: 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
Area under the concentration-time curve from time zero to the last quantifiable concentration of casimersen in plasma were evaluated.
Time frame: 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
Area under concentration-time curve from time zero pre-dose to twenty-four hours post-dos of casimersen in plasma were evaluated.
Time frame: 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
Area under the concentration-time curve from time zero extrapolated to the infinity of casimersen in plasma was evaluated.
Time frame: 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
Apparent Volume of Distribution at Steady State (Vss) of Casimersen
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 casimersen was evaluated.
Time frame: 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
Elimination Half-life (T1/2) of Casimersen
T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of casimersen was evaluated.
Time frame: 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
Total Clearance (CL) of Casimersen
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL of casimersen was evaluated.
Time frame: 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
Mean Residence Time Extrapolated to Infinity (MRTinf) of Casimersen
MRTinf = AUMCinf/AUCinf - T/2, where T was the infusion duration, and AUMCinf was the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. MRTinf of casimersen was evaluated.
Time frame: 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
Double-Blind Period: Renal Clearance (CLR) of Casimersen
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.
Time frame: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours post-dose at Weeks 1 (for 4 mg/kg ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 and 12 (for 30 mg/kg arm) in double-blind period