Duchenne Muscular Dystrophy
Conditions
Brief summary
The main objective of this study is to evaluate the efficacy of Viltolarsen compared to placebo in Duchenne muscular dystrophy (DMD) patients amenable to exon 53 skipping.
Detailed description
This is a Phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of Viltolarsen in ambulant boys with Duchenne muscular dystrophy. Eligible patients with out-of-frame deletion mutations amenable to exon 53 skipping will be randomized to receive once weekly intravenous (IV) infusions of 80 mg/kg Viltolarsen or placebo for up to 48 weeks. The study will enroll approximately 74 patients amenable to exon 53 skipping. Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests such as Time to Stand Test (TTSTAND), Time to Run/Walk 10 Meters Test (TTRW), Six-minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), Time to Climb 4 Steps Test (TTCLIMB) and Hand-held dynamometer (elbow extension, elbow flexion, knee extension and knee flexion on the dominant side only). Safety will be assessed through the collection of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations throughout the study. Blood samples will be taken periodically throughout the study to assess the pharmacokinetics of study drug.
Interventions
DRUGViltolarsen
IV infusion
DRUGPlacebo
IV infusion
Sponsors
Nippon Shinyaku Co., Ltd.
NS Pharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
4 Years to 7 Years
Healthy volunteers
No
Inclusion criteria
* Male ≥ 4 years and \< 8 years of age * Confirmed DMD mutation(s) in the dystrophin gene that is amenable to skipping of exon 53 to restore the dystrophin mRNA reading frame * Able to walk independently without assistive devices * TTSTAND \< 10 seconds * Stable dose of glucocorticoid (GC) for at least 3 months prior to study entry and is expected to remain on stable dose of GC treatment for the duration of the study * Other inclusion criteria may apply
Exclusion criteria
* Current or history of chronic systemic fungal or viral infections * Acute illness within 4 weeks prior to the first dose of study drug * Evidence of symptomatic cardiomyopathy (Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary) * Allergy or hypersensitivity to the study drug or to any of its constituents * Severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the investigator * Previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the investigator; * Surgery within the 3 months prior to the first dose of study drug or surgery is planned for anytime during the duration of the study * Participant has positive test results for hepatitis B antigen, hepatitis C antibody or human immunodeficiency virus (HIV) * Currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to the first dose of study drug or within 5 times the half-life of a medication, whichever is longer * Previously enrolled in an interventional study of viltolarsen * Currently taking any other exon skipping agent or has taken any other exon skipping agent within 3 months prior to the first dose of study drug * Having taken any gene therapy * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Time to Stand (TTSTAND) Velocity | baseline, Week 13, 25, 37, 49 | The change from baseline for velocity converted from TTSTAND was compared between the viltolarsen-treated patients and the placebo-treated patients. TTSTAND was assessed as the time it takes the participant to go from lying flat on the floor to standing. The time measured for TTSTAND was converted to a velocity expressed as rise per second. |
Countries
Australia, Canada, Chile, China, Greece, Hong Kong, Italy, Mexico, Netherlands, New Zealand, Norway, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in the study from April 14, 2020 to October 19, 2023 at 30 sites in 17 countries, predominantly in Europe, Asia, North America, and South America
Pre-assignment details
Eighty-three patients were screened. Six patients were screen failed due to failure to satisfy inclusion/exclusion criteria. Analysis Populations for all randomized patients was 77 patients.
Participants by arm
| Arm | Count |
|---|---|
| Viltolarsen Patients amenable to exon 53 skipping will receive viltolarsen intravenous (IV) infusions, weekly, at 80 mg/kg for up to 48 weeks.
Viltolarsen: IV infusion | 38 |
| Placebo Patients amenable to exon 53 skipping will receive placebo intravenous (IV) infusions, weekly, for up to 48 weeks.
Placebo: IV infusion | 39 |
| Total | 77 |
Baseline characteristics
| Characteristic | Viltolarsen | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 5.5 years STANDARD_DEVIATION 1.2 | 5.7 years STANDARD_DEVIATION 1.16 | 5.6 years STANDARD_DEVIATION 1.18 |
| Body Mass Index (BMI) | 17.053 kg/m^2 STANDARD_DEVIATION 1.9427 | 16.439 kg/m^2 STANDARD_DEVIATION 2.1105 | 16.742 kg/m^2 STANDARD_DEVIATION 2.0396 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 33 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Height | 110.9 cm STANDARD_DEVIATION 9.78 | 111.8 cm STANDARD_DEVIATION 7.78 | 111.4 cm STANDARD_DEVIATION 8.78 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 11 Participants | 21 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 | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 27 Participants | 26 Participants | 53 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 38 Participants | 39 Participants | 77 Participants |
| Weight | 21.12 kg STANDARD_DEVIATION 4.354 | 20.70 kg STANDARD_DEVIATION 4.277 | 20.91 kg STANDARD_DEVIATION 4.292 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 39 |
| other Total, other adverse events | 33 / 38 | 37 / 39 |
| serious Total, serious adverse events | 2 / 38 | 3 / 39 |
Outcome results
Primary
Change From Baseline in Time to Stand (TTSTAND) Velocity
The change from baseline for velocity converted from TTSTAND was compared between the viltolarsen-treated patients and the placebo-treated patients. TTSTAND was assessed as the time it takes the participant to go from lying flat on the floor to standing. The time measured for TTSTAND was converted to a velocity expressed as rise per second.
Time frame: baseline, Week 13, 25, 37, 49
Population: The modified ITT (mITT) Population was set as the analysis population. The mITT Population was defined as all randomized patients who received at least 1 dose of IP and had a baseline assessment and at least 1 post baseline efficacy assessment. The change from baseline for velocity converted from TTSTAND was compared between the viltolarsen-treated patients and the placebo-treated patients using a mixed-effect model for repeated measures (MMRM) analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Viltolarsen | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 13 | 0.026 rise/s | Standard Error 0.0103 |
| Viltolarsen | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 25 | 0.027 rise/s | Standard Error 0.01 |
| Viltolarsen | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 37 | 0.027 rise/s | Standard Error 0.0107 |
| Viltolarsen | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 49 | 0.009 rise/s | Standard Error 0.0096 |
| Placebo | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 49 | 0.013 rise/s | Standard Error 0.0096 |
| Placebo | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 13 | 0.013 rise/s | Standard Error 0.0104 |
| Placebo | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 37 | 0.027 rise/s | Standard Error 0.0108 |
| Placebo | Change From Baseline in Time to Stand (TTSTAND) Velocity | Week 25 | 0.014 rise/s | Standard Error 0.01 |