The Efficacy and Safety of Metoprolol as add-on Treatment to Standard of Care in Preventing Cardiomyopathy in Patients With Duchenne Muscular Dystrophy Aged 8-16 Years. A Randomized, Double-blind, Placebo-controlled Study
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Change in left ventricular ejection fraction (LVEF %) by Teichholtz method (echocardiography), compared to baseline at Interim Analysis and Final Analysis.
研究概览
简要总结
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.
详细描述
Patients will be evaluated for inclusion during a Screening period of up to one year (possible to extend for another year if warranted). Written informed consent from the patient and/or parent/legal guardian and assent, if applicable, to participate in the study must be obtained prior to beginning any study-related procedures. Once eligibility is confirmed, patients will undergo Screening Assessments.
Two groups will receive either metoprolol succinate (Treatment 1 - Intervention) at a dose depending on the weight category as described below or matching placebo (Treatment 2 - Control) to maintain the study blinding, one per day for up to 60 months. All patients (both arms) will receive ACEi (e.g. perindopril, enarenal, lisinopril) or, if indicated, ARB (e.g. losartan) as a standard of care at an appropriate therapeutic dose (see below) through all the study duration. A total of approximately 150 subjects will be randomized into the study.
Subjects will be assessed for safety and tolerability, clinical efficacy, at scheduled visits throughout the study. Adverse events, including SAEs, and concomitant medications will be recorded throughout the study in eCRF record.
Access credentials for ePROP will be dispensed to the participant or his legal guardian when appropriate at the Enrolment Visit to record vital signs (HR and NIBP) and peak-flow-meter readings, AEs, changes to concomitant medications taken during the study, and any missed or incomplete doses of study medication.
Site study staff will contact the parent(s)/ legal guardian(s) by telephone at quarterly to ensure that the tablet dispensing is proceeding according to protocol and to address any questions the parent(s)/guardian(s) may have.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 8 Years 至 17 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Control Group
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.
干预措施: Placebo (Drug)
Treatment Group
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.
干预措施: Metoprolol Succinate (Drug)
结局指标
主要结局
Change in left ventricular ejection fraction (LVEF %) by Teichholtz method (echocardiography), compared to baseline at Interim Analysis and Final Analysis.
时间窗: 24 months
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.
次要结局
- Prevalence of patients with myocardial fibrosis assessed by LGE Cardiac magnetic resonance (CMR)(24 months)
- DFS (the time to develop clinically evident heart failure)(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)