Repurposing Empagliflozin for Duchenne Muscular Dystrophy - Associated Cardiomyopathy: a Pharmacokinetics, Safety and Proof-of-concept Study Among Children 6-18 Years of Age
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Pharmacokinetics - apparent clearance (CL/F)
研究概览
简要总结
This study aims at exploring the use of empagliflozin in children and adolescents 6-18 years old with Duchenne muscular distrophy (DMD) - associated cardiomyopathy. This molecule is effective in reducing hospitalizations and mortality in adults with heart failure and is used in adolescents with type 2 diabetes mellitus, but little is known on children and adolescents with heart failure. Particularly, the best dose to use in this population is currently unknown. This trial aims to:
- define a dose rationale for this indication and age group (pharmacokinetic study),
- assess and monitor safety,
- assess ease-of-swallow,
- explore middle-term (3-6 months) efficacy and efficacy markers.
Participants will be asked to attend 5 study visits over 6 months, and one end-study visit 2-12 weeks thereafter. Visit 1 will entail an 8h day-hospital stay, while Visits 2, 3, 4 and 5, as well as the end-study visit, will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 6 months of the study period.
No comparison group is foreseen for this study.
详细描述
Cardiac disease represents the main life-limiting condition in Duchenne muscular dystrophy (DMD). It is important to recognize and address this early in the disease course. Because of lack of DMD specific drugs, present attitudes for established DMD-related cardiomyopathy ground on current treatment for heart failure. Unfortunately, however, current heart failure therapy in Paediatrics is still unsatisfactory, with high in-hospital (7-26%), and 5-year mortality (30%-50%). Furthermore, mortality rate for DMD cardiomyopathy is worse than similarly aged idiopathic dilated cardiomyopathy (DCM) patients.
Among the recent improvements in adult heart failure management, the sodium glucose transporter type 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin were found to reduce cardiovascular death or worsening heart failure by 25% on top of optimal medical therapy. Indeed, since 2021, they have been recommended as part of standard heart failure therapy.
In the past, paediatric heart failure trials often failed, mainly because of suboptimal dose or inappropriate formulations and endpoints.
This phase II.a, open-label trial is designed to characterize pharmacokinetics (primary outcome), ease-of-swallow, safety and explore potential efficacy markers (secondary outcomes) of empagliflozin in 12 children and adolescents with DMD-related cardiomyopathy, so to inform the design and performance of subsequent, state-of-the-art, high-quality efficacy trials.
Participants will receive empagliflozin during 6 months. They will have 5 visits, one end-study visit and 7 to 8 pharmacokinetic samples. The timing of these samples will be optimized exploiting contemporary modeling and simulation techniques.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children or adolescents 6 to 18 years of age with DMD-associated cardiomyopathy, followed either as in- or outpatients, will be eligible for inclusion.
- •Currently on heart failure medication (any drug or any combination).
- •Patients should potentially benefit from adding a SGLT2i (as judged by the treating physician and the PI or Co-PI).
- •Patients need to be on stable medical treatment, defined as no new heart failure drug started over the preceding 2 weeks and no major drug dose modification (apart minor adaptations, like weight adaptations, rounding or formulation changes) during the 2 weeks prior to enrolment.
- •Adolescents, respectively parents or caregivers of children, capable of giving informed consent.
- •Ability to tolerate a cardiac MRI investigation without the need of general anaesthesia.
排除标准
- •Inability to understand and go through the informed consent procedure.
- •Inability to receive medications per os or through a nasogastric tube.
- •Type 1 or Type 2 Diabetes mellitus or any underlying metabolic disease associated with hypoglycaemias.
- •Body weight <15kg.
- •Current smokers (defined as >1 cigarette/week).
- •Use of any other nicotine-delivering product (e.g. nicotine patches).
- •Any known illicit drug abuse.
- •Active chronic HBV, HCV or HIV.
- •Any major surgery within 4 weeks of first dose administration.
- •Blood transfusion recipient within 4 weeks of dose administration.
- •eGFR <45mL/min/1.73m2 (simplified Schwartz formula or Filler formula).
- •K+ >6.5mmol/L.
- •Blood glucose <4mmol/L.
- •There are no blood pressure exclusion criteria foreseen, but participants need to be haemodynamically stable, as assessed by the local investigator.
- •Sustained or symptomatic arrhythmia insufficiently controlled with drug and/or device therapy.
- •Cardio-surgical procedure within the 2 months prior to Visit 1, or interventional cardiac catheterization within 2 weeks prior to Visit 1, or the patient is planned to undergo cardiac surgery or an interventional cardiac catheterization during the study period (i.e. in the 6 months following Visit 1).
- •Post-menarchal female patients of childbearing potential cannot be included. Participants who begin menstruating during the trial will be discontinued from the IMP. However, their monitoring will continue up to 6 months after their first dose of IMP.
- •Known lactose intolerance, galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
- •Known allergies to active ingredients or excipients of commercially available empagliflozin tablets.
- •Significant medical history of active severe medical disease.
- •Significant liver disease, Child Pugh Class C, or significant laboratory abnormalities at enrolment.
- •Significant gastroenterological or hepatic disease that could significantly impair absorption or metabolism of orally administered drugs.
- •Any medical co-morbidity, which is deemed incompatible (or only with relevant risk) with study participation by the treating clinician and/or the study investigator.
- •Active urinary tract infection (being treated with antibiotics at the moment of Visit 1) or other relevant bacterial infection, as judged by the treating clinician and/or the study investigator.
- •The patient is currently participating in another interventional clinical trial or has participated in such a trial during the <14 days before Visit 1 (or if enrolment in this study is incompatible with the protocol of that preceding trial), or the duration of five half-lives of the IMP, whichever is longer.
研究组 & 干预措施
Empagliflozin
All participants will receive the IMP (open-label trial, primary outcome PK)
干预措施: Empagliflozin Tablets (Drug)
结局指标
主要结局
Pharmacokinetics - apparent clearance (CL/F)
时间窗: Visit 1 to Visit 3 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks after study start)
Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including CL/F).
Pharmacokinetics - apparent (central) volume of distribution (Vd/F)
时间窗: Visit 1 to Visit 3 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks after study start)
Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including Vd/F).
Pharmacokinetics - half-life
时间窗: Visit 1 to Visit 3 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks after study start)
Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including t1/2).
Pharmacokinetics - AUC
时间窗: Visit 1 to Visit 3 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks after study start)
Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including AUC).
Pharmacokinetics - maximal concentration (Cmax)
时间窗: Time Frame: Visit 1 to Visit 3 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks after study start)
Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including Cmax).
次要结局
- Safety 1 - eGFR(Visit 1 to Visit 5 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Safety 2 - Occurrence of hypoglycemia(Visit 1 to Visit 5 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Safety 3 - Occurrence of ketoacidosis(Visit 1 to Visit 5 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Safety 4 - Occurrence of UTI(Visit 1 to Visit 5 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Ease of swallow(Visit 1 (Visit 1 = day 1))
- Efficacy and efficacy markers (exploratory) 1 - Heart failure severity class(Visit 1 to Visit 5 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 2 - NT-proBNP level(Visit 1 to Visit 5 (Visit 1 = day 1, Visit 2 = 1 week, Visit 3 = 5-6 weeks, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 3 - Echocardiography 1: Left-ventricular end-diastolic diameter (LVEDd)(Visits 1, 4 and 5 (Visit 1 = day 1, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 4 - Echocardiography 2: Left-ventricular end-systolic diameter (LVESd)(Visits 1, 4 and 5 (Visit 1 = day 1, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 5 - Echocardiography 3: Fractional shortening (FS)(Visits 1, 4 and 5 (Visit 1 = day 1, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 6 - Echocardiography 4: Left ventricular ejection fraction (LV-EF)(Visits 1, 4 and 5 (Visit 1 = day 1, Visit 4 = 3 months, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 7 - cMRI 1: Left ventricular end-diastolic volume(Visit 1, Visit 5 (Visit 1 = day 1, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 8 - cMRI 2: Left ventricular end-systolic volume(Visit 1, Visit 5 (Visit 1 = day 1, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 9 - cMRI 3: Left ventricular ejection fraction(Visit 1, Visit 5 (Visit 1 = day 1, Visit 5 = 6 months after enrolment)
- Efficacy and efficacy markers (exploratory) 10 - cMRI 4: Presence of late gadolinium enhancement(Visit 1, Visit 5 (Visit 1 = day 1, Visit 5 = 6 months after enrolment))
- Efficacy and efficacy markers (exploratory) 11 - cMRI 5: Extracellular volume (ECV)(Visit 1, Visit 5 (Visit 1 = day 1, Visit 5 = 6 months after enrolment))
研究者
Sebastiano Lava
Chief Investigator
Centre Hospitalier Universitaire Vaudois