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

A Randomized, Double-Blind, Placebo-Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study Followed by an Open-Label Safety and Efficacy Evaluation of SRP-4045 in Advanced-Stage Patients With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02530905

Enrollment

Registered

2015-08-21

Start date

2015-10-08

Completion date

2018-10-03

Last updated

2021-05-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne muscular dystrophy, Exon Skipping

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.

Detailed description

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.

Interventions

DRUGSRP-4045

SRP-4045 solution for IV infusion.

DRUGPlacebo

SRP-4045 placebo-matching solution for IV infusion.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

MALE

Age

7 Years to 21 Years

Healthy volunteers

Inclusion criteria

* 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.

Exclusion criteria

* 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. Other inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Baseline up to Week 148	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.
Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs	Baseline up to Week 148	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.
Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs	Baseline up to Week 148	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.
Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs	Baseline up to Week 148	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.
Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)	Baseline up to Week 148	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.

Secondary

Measure	Time frame	Description
Apparent Volume of Distribution at Steady State (Vss) 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	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.
Elimination Half-life (T1/2) 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	T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of casimersen was evaluated.
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	Maximum Concentration (Cmax) of casimersen in plasma was evaluated.
Mean Residence Time Extrapolated to Infinity (MRTinf) 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	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.
Double-Blind Period: Renal Clearance (CLR) of Casimersen	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	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.
Total Clearance (CL) 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	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 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	Time to reach maximum plasma concentration (Tmax) of casimersen was evaluated.
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 the concentration-time curve from time zero to the last quantifiable concentration of casimersen in plasma were evaluated.
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 concentration-time curve from time zero pre-dose to twenty-four hours post-dos of casimersen in plasma were evaluated.
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	Area under the concentration-time curve from time zero extrapolated to the infinity of casimersen in plasma was evaluated.

Countries

United States

Participant flow

Recruitment details

The study was conducted at 3 sites in United States.

Pre-assignment details

Study conducted in 2 parts: Part 1 (Double-Blind Period \[DBP\]) and Part 2 (Open Label Extension Period \[OLEP\]). When Part 1 was completed and cumulative safety data was reviewed by an independent Data Safety Monitoring Board (DSMB), Part 2 was conducted.

Participants by arm

Arm	Count
Double-Blind Period: Placebo Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received placebo-matched to casimersen IV infusions, once weekly over approximately 12 weeks in the double-blind period.	4
Double-Blind Period: Casimersen Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received weekly IV infusions of casimersen at four escalating dose levels, each for at least 2 weeks: 4 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 continued over approximately Week 12 in the double-blind period.	8
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Open Label Extension Period (132 Weeks)	Withdrawal by Subject	0	0	1

Baseline characteristics

Characteristic	Double-Blind Period: Casimersen	Total	Double-Blind Period: Placebo
Age, Continuous	14.4 Years STANDARD_DEVIATION 3.29	13.6 Years STANDARD_DEVIATION 3.09	12.0 Years STANDARD_DEVIATION 2.16
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants	11 Participants	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	6 Participants	10 Participants	4 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	8 Participants	12 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 4	0 / 8	0 / 8	0 / 8	0 / 8	0 / 12
other Total, other adverse events	4 / 4	5 / 8	3 / 8	3 / 8	7 / 8	12 / 12
serious Total, serious adverse events	0 / 4	0 / 8	0 / 8	0 / 8	1 / 8	3 / 12

Outcome results

Primary

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