Evaluation of Metoprolol Tartrate as an Adjunct to Standard Care in Preventing Cardiomyopathy in Male Patients with Duchenne Muscular Dystrophy Aged 8-17 Years

The primary objective of this study is to evaluate whether **metoprolol succinate**, when added to standard cardiac care and introduced before the onset of echocardiography-detectable left ventricular dysfunction, can slow the rate of progression of left ventricular ejection fraction drop that leads to cardiomyopathy in males with Duchenne Muscular Dystrophy (DMD) compared to placebo. This is clinically relevant as it aims to prevent the development of cardiomyopathy, a significant complication in DMD patients, thereby potentially improving their cardiac outcomes and quality of life.

The secondary objectives of this study are to assess if metoprolol succinate, in addition to standard care, can:

• Delay the occurrence of cardiomyopathy in children with DMD.
• Delay the occurrence of heart failure in children with DMD.
• Delay the age of onset and/or slow the rate of progression of myocardial fibrosis as assessed by cardiac magnetic resonance (CMR).
• Reduce the prevalence of sinus tachycardia as assessed by Holter ECG.
• Be safe and well tolerated in children with DMD.

The clinical trial involves a study population of **males** aged between 8 and 16 years, diagnosed with **Duchenne muscular dystrophy** (DMD). The trial aims to assess the efficacy of metoprolol succinate in slowing the progression of cardiomyopathy in these patients. Participants are required to have a confirmed diagnosis of DMD, characterized by a clinical picture consistent with typical DMD and supported by genetic or protein analysis indicating dystrophin deficiency. The trial includes individuals who are already on ACE inhibitor treatment for at least 30 days prior to enrollment. The study population is selected based on specific inclusion criteria, including the ability to take oral medication and willingness to adhere to the study regimen. The sponsor has not provided information regarding the total number of participants. The trial does not exclude based on gender, although the primary focus is on male subjects due to the nature of the condition. Participants are expected to comply with all study procedures and be available for the study duration. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided information regarding the total number of participants.

The clinical trial is designed to evaluate the efficacy and safety of **metoprolol** as an add-on treatment to standard care in preventing cardiomyopathy in patients with **Duchenne muscular dystrophy** (DMD) aged 8-17 years. This study is a randomized, double-blind, placebo-controlled trial. The trial is expected to run from April 2021 to March 2026, with the primary objective of assessing whether metoprolol succinate can slow the progression of left ventricular ejection fraction (LVEF) decline, which leads to cardiomyopathy, compared to placebo.

Participants will be involved in the study for a maximum treatment period of 60 days. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor health and treatment effects, and a final end-of-study visit to assess outcomes. The primary endpoint is the change in LVEF by the Teichholtz method, compared to baseline at interim and final analyses. Secondary endpoints include disease-free survival, defined as the time to develop cardiomyopathy or clinically evident heart failure.

Inclusion criteria require participants to be male, aged between 8 and 17 years, with a confirmed diagnosis of DMD and the ability to take oral medication. Participants must also be on ACE inhibitor treatment for at least 30 days prior to the study. Conditions for early termination from the study include non-compliance with study procedures or adverse events that compromise participant safety. The trial aims to provide valuable insights into the potential benefits of metoprolol in managing cardiac complications associated with DMD.

The clinical trial involves the use of **Metoprolol Tartrate** as an experimental medication. The specific formulations used in the study are Betaloc ZOK 100, containing 95 mg of metoprolol tartrate, and Betaloc ZOK 25, containing 23.75 mg of metoprolol tartrate. Both formulations are in the form of **prolonged-release tablets**. The route of administration is **oral**, and the medication is classified as a **beta blocker**. The maximum daily dose is 2 mg/kg, with a total maximum dose of 3600 mg over a treatment period of up to 60 days. The active substance, metoprolol tartrate, is of chemical origin and is manufactured by RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.P.A. The trial aims to evaluate the efficacy of metoprolol as an add-on treatment to standard cardiac care in patients with Duchenne Muscular Dystrophy.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this double-blind, placebo-controlled study. The placebo is designed to match the experimental medication in appearance and administration route to ensure blinding. The placebo does not contain any active pharmaceutical ingredients and is administered orally in the same dosing schedule as the experimental medication. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

Two additional products, labeled as PL1 and PL2, are mentioned in the trial documentation. However, these products do not have specified pharmaceutical forms, active substances, or routes of administration. They are not used as part of the experimental or comparator treatments in this study. Their role in the trial is not detailed, and they are not considered part of the primary or secondary objectives of the study.

The efficacy of the clinical trial will be assessed by evaluating the impact of **metoprolol** as an add-on treatment to standard cardiac care in patients with Duchenne Muscular Dystrophy (DMD). The primary endpoint for efficacy is the change in left ventricular ejection fraction (LVEF) measured by the Teichholtz method using echocardiography. This will be compared to baseline measurements at both Interim Analysis and Final Analysis. Secondary endpoints include Disease Free Survival (DFS), defined as the time to develop cardiomyopathy with LVEF <55% and the prevalence of patients with cardiomyopathy, as well as the time to develop clinically evident Heart Failure (HF).