Duchenne Muscular Dystrophy (DMD)
Conditions
Brief summary
The primary purpose of this study is to evaluate the safety, tolerability, and dystrophin protein levels in muscle tissue following multiple intravenous (IV) doses of DYNE-251 in participants with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. The study consists of 3 periods: a multiple-ascending dose (MAD) / placebo-controlled period (24 weeks), an open-label period (24 weeks) and a long-term extension (LTE) period (288 weeks).
Interventions
DRUGDYNE-251
Administered by IV infusion
DRUGPlacebo
Administered by IV infusion
Sponsors
Dyne Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
4 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Age 4 to 16 years inclusive, at the time of informed consent/assent. * Male with a confirmed diagnosis of DMD and with a mutation in the dystrophin gene characterized by exon deletion amenable to exon 51 skipping. * Upper extremity muscle group that is amenable to muscle biopsy. * Brooke Upper Extremity Scale score of 1 or 2. * Ambulatory or non-ambulatory. A non-ambulatory participant must have been non-ambulatory for \<2 years before enrollment. * Receiving a stable dosage of glucocorticoids for at least 12 weeks prior to the start of study drug administration, with the expectation of maintaining a stable dose during the Placebo-Controlled and Open-Label Periods of the study (unless dose adjustment is required by weight change). * Left ventricular ejection fraction of ≥50% by echocardiogram or ≥55% by cardiac magnetic resonance imaging (MRI).
Exclusion criteria
* Uncontrolled clinical symptoms and signs of congestive heart failure (CHF). * Any change in prophylaxis/treatment for CHF within 3 months prior to the start of study treatment. * History of major surgical procedure within 12 weeks prior to the start of study drug administration or an expectation of a major surgical procedure during the study. * Requirement of daytime ventilator assistance. * Percent predicted FVC \<40 % (applies only for participants who are age ≥7 years). * Receipt of eteplirsen, or alternative exon-skipping/dystrophin-modifying therapy, within 12 weeks of randomization. * Receipt of non-exon skipping investigational drug within 4 months before the start of study drug administration. * Receipt of gene therapy at any time. Other inclusion and
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Through study completion, up to Week 337 |
| Change From Baseline in Dystrophin Protein Levels in Muscle Tissue at Week 25 | Baseline, Week 25 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Muscle Tissue Exon 51 Skipping Levels at Week 25 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25 | Baseline, Week 25 | — |
| Change From Baseline in Muscle Tissue Percent Dystrophin-Positive Fiber (PDPF) at Week 25 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25 | Baseline, Week 25 | — |
| Change From Baseline in Blood Creatine Kinase (CK) Levels up to Week 337 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25 | Baseline, up to Week 337 | — |
| Change From Baseline in Dystrophin Protein Level in Muscle Tissue as Determined by Western Blot at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49 | Baseline, Week 49 | — |
| Change From Baseline in Muscle Tissue Exon 51 Skipping Levels at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49 | Baseline, Week 49 | — |
| Change From Baseline in Muscle Tissue PDPF at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49 | Baseline, Week 49 | — |
| Change From Baseline in Blood CK Levels up to Week 337 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49 | Baseline, up to Week 337 | — |
| Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 337 | Baseline, up to Week 337 | The NSAA is a 17-item functional scale used to measure functional motor abilities in ambulant participants with DMD and monitor progression of the disease and treatment effects in each of the items. The items are graded on a 3-point scale: 0=unable to achieve independently, 1=modified method but achieves goal with no physical assistance, and 2=normal, no obvious modification of activity. Total score range is 0 to 34. |
| Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 337 | Baseline, up to Week 337 | — |
| Change From Baseline in 10-Meter Run/Walk (10MRW) Time in Ambulatory Participants up to Week 337 | Baseline, up to Week 337 | — |
| Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 337 | Baseline, up to Week 337 | The PUL scale is a validated tool specifically designed for assessing upper limb function in ambulant and non-ambulant individuals with DMD. It includes an entry item to define the broad starting functional level and 22 items subdivided into 3 areas indicative of upper limb strength as, shoulder level, midlevel, and distal level. The global score is a combination of the 3 areas and ranges from 0 to 42. Lower scores indicate higher disability. |
| Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 337 | Baseline, up to Week 337 | — |
| Change From Baseline in Stride Velocity 95th Centile (SV95C) in Ambulatory Participants up to Week 337 | Baseline, up to Week 337 | — |
| Maximum Observed Plasma Drug Concentration of DYNE-251 (Cmax) | Through study completion, up to Week 337 | — |
| Time to Maximum Observed Plasma Drug Concentration of DYNE-251 (tmax) | Through study completion, up to Week 337 | — |
| Area Under the Plasma Drug Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration of DYNE-251 in Plasma (AUC0-tlast) | Through study completion, up to Week 337 | — |
| Area Under the Plasma Drug Concentration Versus Time Curve From Time 0 (Dosing) Extrapolated to Time Infinity of DYNE-251 (AUC∞) | Through study completion, up to Week 337 | — |
| Apparent Terminal Phase Elimination Rate Constant of DYNE-251 in Plasma (λz) | Through study completion, up to Week 337 | — |
| Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½) | Through study completion, up to Week 337 | — |
| Total Body Clearance (CL) of DYNE-251 | Through study completion, up to Week 337 | — |
| Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz) | Through study completion, up to Week 337 | — |
| Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss) | Through study completion, up to Week 337 | — |
| Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue | Through study completion, up to Week 337 | — |
| Incidence of Antidrug Antibodies (ADAs) | Through study completion, up to Week 337 | — |
Countries
Australia, Belgium, Canada, Ireland, Italy, South Korea, Spain, United Kingdom, United States
Outcome results
None listed