The Efficacy and Safety of Metoprolol as add-on Treatment to Standard of Care in Preventing Cardiomyopathy in Patients With DMD

NCT05066633 | Recruiting Phase 3 DMC

• 2 other identifiers: NBK 154/1/20202020-004901-29
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

The study includes 150 patients with DMD diagnosis confirmed by genetic testing, 8-16 years old (≥8 and \<17) at the study entry with a follow-up of up to 5 years. Random enrollment of a patient to one of two groups (intervention or control) takes place after pre-screening and screening stage starts the first phase of the trial. To be eligible for participation in the study, patients must receive standard of care cardiac therapy, which is an Angiotensin-converting-enzyme inhibitor (ACEi) for at least one-month prior to enrollment. A major part of the trial is equal for all patients - who will be receiving indistinguishable investigational medicinal products (IMPs), the drug metoprolol succinate or placebo. As a part of the clinical trial, diagnostic examinations evaluating progression of the disease, will be performed periodically. In addition, all patients will be monitored at home. Heart rate, blood pressure and patients' personal well-being will be controlled using telemedicine technologies. Additional visits in the research center will be provided if any adverse events occur. This model will be continued for 30 months from the enrollment of a first patient. After this period the first drug efficiency analysis will be performed. After that, the intervention may be continued or in case of negative impact of the intervention on patients' health and well-being, terminated with further patients monitoring.

Conditions

Muscular Dystrophy, Duchenne

Outcome Measures

Primary Outcomes (1)

• Change in left ventricular ejection fraction (LVEF %) by Teichholtz method (echocardiography), compared to baseline at Interim Analysis and Final Analysis.

  To evaluate whether metoprolol succinate in addition to standard of care treatment compared to placebo in children with DMD delays the progression of LV function loss.

  24 months

Secondary Outcomes (4)

• DFS (the time to develop clinically evident heart failure)

  24 months

• Prevalence of patients with myocardial fibrosis assessed by LGE Cardiac magnetic resonance (CMR)

  24 months

• Prevalence of patients with sinus tachycardia based on resting HR (ECG) or defined as mean daily heart rate above 95th percentile for age and sex

  24 months

• The rate of AE and SAE

  24 months

Study Arms (2)

Control Group

PLACEBO COMPARATOR

Matching placebo will be supplied by the sponsor in child-proof bottles containing dividable tablets with the following dosage of 25mg of IMP and 100mg of IMP. The drug will be administered orally at singular daily doses ranging from 0.75 to 4.5 mg/kg over a Double-Blind Treatment Period (DBTP) of up to 60 months or less dependently on the time of enrolment. The Treatment Period will begin with up to 12-weeks long Up-titration Phase, during which the dose will be gradually escalated. If patient presents with signs and symptoms of intolerance the dose may be temporarily or permanently downgraded at the discretion of the clinician. The up titration ends with reaching maximal tolerated dose level or at a dose corresponding to 4.5 mg/kg.

Drug: Placebo

Treatment Group

EXPERIMENTAL

Metoprolol succinate will be supplied by the sponsor in child-proof bottles containing dividable tablets with the following dosage of 25mg of IMP and 100mg of IMP. The drug will be administered orally at singular daily doses ranging from 0.75 to 4.5 mg/kg over a Double-Blind Treatment Period (DBTP) of up to 60 months or less dependently on the time of enrolment. The Treatment Period will begin with up to 12-weeks long Up-titration Phase, during which the dose will be gradually escalated. If patient presents with signs and symptoms of intolerance the dose may be temporarily or permanently downgraded at the discretion of the clinician. The up titration ends with reaching maximal tolerated dose level or at a dose corresponding to 4.5 mg/kg.

Drug: Metoprolol Succinate

Interventions

Metoprolol Succinate DRUG

Metoprolol Succinate will be in the form of tablets and will be administered orally once daily. The dose will depend on the patient's weight category. Subject should take their treatment at a consistent time each day to promote compliance. IMP will be up titrated. Every two weeks the patients will be given the higher dose of metoprolol succinate or placebo accordingly to scheme.

Treatment Group

Placebo DRUG

Placebo will be in the form of identical tablets and will be administered orally once daily.

Control Group

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Subject's parent(s) or legal guardian(s) has (have) provided written informed consent, where applicable, prior to any study-related procedures; participants will be asked to give written or verbal assent according to requirements (\>16 years old)
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Ability to take oral medication and be willing to adhere to the study intervention regimen
• Subject has confirmed diagnosis of DMD, as defined as clinical picture consistent with typical DMD and: i) Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, or ii) Identifiable mutation within the DMD gene (deletion/duplication of one or more exons), where reading frame can be predicted as 'out-of-frame' or, iii) Complete dystrophin gene sequencing showing an alteration (point mutation, duplication, other) that is expected to preclude production of the dystrophin protein (i.e., nonsense mutation, deletion/duplication leading to a downstream stop codon)
• Taking ACEi treatment at minimum required doses for at least 30 days

You may not qualify if:

• Current or previous permanent use of any beta-blocker medication
• Treatment with another investigational drug or other intervention within 3 months prior to screening
• Clinically significant bradycardia at rest or by Holter ECG, based on age and sex adjusted normal values, atrioventricular block higher than first degree at rest, or second degree Wenckebach at night, pauses longer than 2.5 seconds
• Presence of pacemaker or ICD
• Clinical signs or symptoms of heart failure
• Left ventricular Ejection Fraction (LVEF) \<57% (assessed by Teichholtz echocardiography)
• Inability to obtain adequate quality echocardiography images (necessary to monitor for primary endpoint and safety)
• Known allergic reactions to components of the IMPs

Sponsors & Collaborators

• Medical University of Gdansk: lead

Study Sites (1)

University Clinical Centre in Gdańsk, Clinic of Paediatric Cardiology and Congenital Heart Defects

Gdansk, Pomeranian Voivodeship, 80-211, Poland

RECRUITING

Related Links

• Official website

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

Metoprolol

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Central Study Contacts

Joanna Kwiatkowska, MD, PhD

CONTACT

58349 2899; joanna.kwiatkowska@gumed.edu.pl

Jarosław Meyer-Szary, MD, PhD

CONTACT

583492870; jaroslaw.meyer-szary@gumed.edu.pl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 23, 2021
• First Posted: October 4, 2021
• Study Start: August 18, 2021
• Primary Completion: June 30, 2023
• Study Completion (Estimated): June 30, 2026
• Last Updated: October 4, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1)