Efficacy and Safety Evaluation of Givinostat in Non-Ambulant Duchenne Muscular Dystrophy: A Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

The primary objective of this study is to demonstrate the **efficacy** of givinostat in reducing muscle decline in non-ambulant patients with Duchenne Muscular Dystrophy (DMD). This is clinically relevant as DMD is a progressive neuromuscular disorder characterized by muscle degeneration and weakness, and reducing muscle decline can significantly impact the quality of life and disease progression in affected individuals.

Secondary objectives include:

• To evaluate the **safety** and tolerability of givinostat in non-ambulant DMD patients, which is crucial for ensuring that the treatment does not pose undue risk to patients.
• To further investigate the **efficacy** of givinostat in this patient population, providing additional insights into its potential benefits and therapeutic value.

The clinical trial involves a total of **48 participants** diagnosed with **Duchenne muscular dystrophy (DMD)**. The study population consists exclusively of male children and adolescents aged 9 to less than 18 years at the time of screening. Participants are required to be non-ambulant, defined as being wheelchair-bound and unable to perform the 10-meter walk/run test or unable to complete it in 30 seconds or less without support. The trial population was selected based on specific inclusion criteria, including a genetic diagnosis of DMD and stable use of corticosteroids for at least six months prior to the study. Participants must also be willing to use adequate contraception during the trial and for three months after the last dose of the study drug. The trial does not include female subjects, and the population is considered vulnerable due to the age and health condition of the participants. The sponsor has not provided information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of **givinostat** in non-ambulant patients with **Duchenne muscular dystrophy (DMD)**. The trial will involve a total duration of 18 months, with the estimated recruitment start date set for December 30, 2023, and an estimated end date of December 30, 2027. The primary objective is to demonstrate the efficacy of givinostat in reducing muscle decline in the target patient population. The study will include a series of visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, genetic diagnosis, and current medication stability. Participants will be required to be children and adolescent males aged 9 to less than 18 years, with a confirmed genetic diagnosis of DMD and non-ambulant status.

Following the screening, eligible participants will be randomized to receive either the active treatment, givinostat, or a placebo, both administered as an oral suspension. The trial will include regular follow-up visits to monitor the participants' health and response to the treatment. These visits will assess primary and secondary endpoints, including changes in the Performance of the Upper Limb (PUL) total score, respiratory function, and the incidence of treatment-emergent adverse events (TEAEs). The end-of-study visit will conclude the trial, evaluating the cumulative effects of the treatment over the 18-month period.

Participant involvement is expected to last for the entire duration of the trial, approximately 18 months, unless conditions arise that necessitate early termination. Such conditions may include significant adverse reactions, non-compliance with the study protocol, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are aware of the potential risks and benefits associated with the study. The study aims to provide valuable insights into the potential of givinostat as a treatment for DMD, contributing to the broader understanding of therapeutic options for this rare disease.

The clinical trial involves the administration of **Givinostat**, an experimental medication, in the form of an **oral suspension**. The active substance, Givinostat, is a **histone deacetylase (HDAC) inhibitor** and is chemically derived. The pharmaceutical form is specifically designed for oral use, with a maximum daily dose of 93.4 mg and a total maximum dose of 47073 mg over the treatment period. The treatment duration is set for a maximum of 18 months. The medication is not formulated for pediatric use. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

The study also includes a **placebo** comparator, which is designed to match the Givinostat oral suspension in appearance and administration route. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the efficacy and safety of Givinostat in non-ambulant patients with Duchenne Muscular Dystrophy. Compliance with the placebo administration is similarly monitored to maintain the integrity of the study results.

The efficacy of **givinostat** in the treatment of non-ambulant patients with Duchenne Muscular Dystrophy (DMD) will be assessed through a randomized, double-blind, placebo-controlled, multicenter study. The primary endpoint for evaluating efficacy is the change in the Performance of the Upper Limb (PUL) total score at 18 months of treatment with givinostat compared to the placebo group. Secondary endpoints include changes from baseline in Peak Expiratory Flow percent predicted (PEF%p) and Forced Vital Capacity percent predicted (FVC%p) at 18 months, as well as the cumulative loss of PUL items over the same period.

Additional secondary endpoints involve the type, incidence, and severity of treatment-emergent adverse events (TEAEs), the proportion of patients experiencing TEAEs from baseline to the end of the study or follow-up, and changes in vital signs, laboratory tests, ECG, and ECHO. The study will also measure the time to assisted ventilation, the rate and severity of respiratory infections, the duration and use of antibiotics, the time to onset of diarrhea, and height and weight Z-scores. These parameters will be collected and analyzed to determine the efficacy of givinostat in reducing muscle decline in the target patient population.