Randomised, Double-blind, Placebo-controlled, Multicentre Study to Evaluate the Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy
Overview
- Phase
- Phase 3
- Intervention
- Placebo
- Conditions
- Duchenne Muscular Dystrophy
- Sponsor
- Italfarmaco
- Enrollment
- 138
- Locations
- 20
- Primary Endpoint
- Change of Performance of Upper Limb 2.0 (PUL) total score at 18 months of treatment of givinostat compared to placebo group.
- Status
- Recruiting
- Last Updated
- 11 months ago
Overview
Brief Summary
This is a randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant male paediatric (aged 9 to <18 years) patients with DMD. 138 patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months.
- Planned screening duration: approximately 4 weeks (±14 days)
- Planned treatment duration: 18 months (approximately 72 weeks)
- Planned follow-up duration: 4 weeks (±7 days) (for patients not participating in the long-term safety study)
- Total duration of study participation: up to 83 weeks (ie, 20-21 months)
Detailed Description
Duchenne muscular dystrophy is a rare, progressive, debilitating and life-threatening condition for which there is a critical need for novel therapies that are effective and well-tolerated in all DMD patients. Steroids are generally recognised as the standard of care in the general DMD population; however, they are not suitable for all patients. Givinostat, a HDAC inhibitor, was developed for the treatment of DMD based on: (i) the role that increased HDAC activity is thought to exert in contributing to DMD pathogenesis; and (ii) givinostat's ability to counter the pathophysiological and degenerative mechanisms causing muscle insufficiency in boys with DMD. This study will evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant patients to further corroborate data from the completed phase 3 pivotal study of givinostat in ambulant patients with DMD (ie, Study DSC/14/2357/48, NCT02851797). Primary Objective of the study is to demonstrate the efficacy of givinostat in reducing muscle decline in non-ambulant DMD patients, as measured by Performance of the Upper Limb (PUL) 2.0. Secondary Objectives of the study are to evaluate the safety and tolerability of givinostat in non-ambulant DMD patients, and to further explore the efficacy of givinostat in non-ambulant DMD patients. A total of 138 patients are planned for enrolment. Patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months. The study will be comprised of: * A screening period, during which eligibility will be confirmed within 4 weeks (±14 days) * A baseline visit, during which randomisation will be performed * A double-blind treatment period, during which patients will receive either givinostat or placebo for 18 months (approximately 72 weeks) * An end of study visit, occurring at Week 72 (±7 days) at the end of the treatment period. At the end of study visit, all the patients (regardless of treatment arm) will be offered enrolment in the long-term safety study DSC/14/2357/51 (NCT03373968) during which they will receive givinostat. * A follow-up visit, for those patients not consenting to participation in the long-term safety study, that will occur 4 weeks after the end of study visit (ie, Week 76 ±7 days).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must satisfy all the following criteria:
- •Children and adolescent males aged ≥ 9 to \<18 years at screening (patients ≥ 18 years of age at screening will not be enrolled into the study)
- •Are able to give informed assent and/or consent in writing signed by the patient and/or parent/legal guardian (according to local regulations)
- •A genetic diagnosis of DMD
- •Non-ambulant, defined as being wheelchair bound and:
- •Unable to perform the 10-meter walk/run test (10MWT), or
- •Unable to complete the 10MWT in 30 seconds or less, without any support or devices
- •Performance of the Upper Limb test (PUL version 2.0) entry item scores 3 to 6
- •If on medication for DMD-associated cardiomyopathy (eg, ACE inhibitor, β-blocker, diuretics), stable for ≥1 month immediately prior to start of study treatment, if any
- •Stable corticosteroids, defined as:
Exclusion Criteria
- •Patients will be excluded from the study if they satisfy any of the following criteria:
- •Exposure to another investigational drug within 3 months prior to start of study treatment.
- •Have exposure to any dystrophin restoration product (eg, Ataluren, Exon skipping) within 6 months prior to the start of study treatment
- •Having received any gene therapy (eg, AAV Micro-dystrophin delivery) prior to start of study treatment
- •Use of any pharmacologic treatment or supplement (other than corticosteroids), that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (eg, growth hormone); vitamin D, calcium and any other supplements will be allowed
- •Use of testosterone, unless used as a replacement therapy for the treatment of delayed puberty. The testosterone dose and regimen should be stable within 6 months prior to the start of study treatment, and circulating testosterone levels should be within the normal ranges for the patient's age
- •Elbow-flexion contractures \>30° in the dominant arm
- •Inability to perform consistent PUL 2.0 measurement within ±2 points without shoulder domain or within ±3 points with shoulder domain during paired testing at screening
- •Forced Vital Capacity % of predicted \<40%
- •Requirement for daytime ventilator assistance (Note: Night ventilator assistance and use of bi-level positive airway pressure therapy is allowed)
Arms & Interventions
Placebo
Patients will receive concomitant corticosteroid treatment as part of the standard of care.
Intervention: Placebo
Givinostat
Patients will receive concomitant corticosteroid treatment as part of the standard of care.
Intervention: Givinostat
Outcomes
Primary Outcomes
Change of Performance of Upper Limb 2.0 (PUL) total score at 18 months of treatment of givinostat compared to placebo group.
Time Frame: Baseline and 18 months
The PUL examines 3 major "dimensions" of upper extremity function: shoulder, middle, and distal functions. It includes 22 scored items; a score of 42 (12 for shoulder; 17 for mid-level, and 13 for distal) indicates the highest level of independent function and 0 the lowest.
Secondary Outcomes
- Change from baseline of Peak Expiratory Flow percent predicted (PEF%p) at 18 months of treatment of givinostat compared to placebo group(Baseline and 18 months)
- Change from baseline of Forced Vital Capacity percent predicted (FVC%p) at 18 months of treatment of givinostat compared to placebo group(Baseline and 18 months)
- Cumulative loss of PUL total score over 18 months of treatment of givinostat compared to placebo group.(Baseline to 18 months)
- Type, incidence, and severity of treatment-emergent adverse events(Baseline to 18 months)
- Proportion of patients experiencing treatment-emergent adverse events(Baseline to 18 months)
- Change from baseline vital signs and clinical laboratory tests(Baseline and 18 months)
- Change from baseline electrocardiogram and echocardiogram(Baseline and 18 months)
- Time to assisted ventilation and rate of respiratory infection including duration, severity of respiratory infection and use of antibiotics, of givinostat compared to placebo group.(Baseline to 18 months)