Dose Rationale for Dapagliflozin and Empagliflozin in Paediatric Heart Failure: a Phase II.a Pharmacokinetics, Ease-of-swallow, 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
- 入组人数
- 12
- 试验地点
- 3
- 主要终点
- Pharmacokinetics 1: Dapagliflozin, respectively Empagliflozin half-life
研究概览
简要总结
This study aims at exploring the use of Dapagliflozin and Empagliflozin in children and adolescents 6-18 years old with heart failure. These molecules are effective in reducing hospitalisations and mortality in adults with heart failure and are used in adolescents with type 2 diabetes mellitus, but little is known on children 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 (4-6 weeks) efficacy and efficacy markers.
Participants will be asked to attend 4 study visits over 4-6 weeks, and one end-study visit 2-12 weeks thereafter. Visits 1 and 3 will entail an 8h day-hospital stay, while Visits 2, 4 and the end-study visit will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 4-6 weeks of the study period.
All participants will take both Dapagliflozin and Empagliflozin: 6 will start with Dapagliflozin first (Visits 1-2) and then switch to Empagliflozin (Visits 3-4), while 6 will start with Empagliflozin first (Visits 1-2) and then switch to Dapagliflozin (Visits 3-4). No comparison group is foreseen for this study.
详细描述
Paediatric heart failure is a relevant healthcare issue, with almost 15'000 yearly hospitalizations just in the USA. Sadly, current heart failure therapy in Paediatrics is still unsatisfactory, with high in-hospital (7-26%), and 5-year mortality (30%-50%).
Among the recent improvements in adult heart failure management, impressive is the discovery that Dapagliflozin and Empagliflozin are able 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, cross-over, open-label trial is designed to characterize pharmacokinetics (primary outcome), palatability, safety and explore potential efficacy markers (secondary outcomes) of Dapagliflozin and Empagliflozin in 12 heart failure children, so to inform the design and performance of subsequent, state-of-the-art, high-quality efficacy trials.
Participants will first receive Drug A (either Dapagliflozin, n=6, or Empagliflozin, n=6) during 3-5 weeks, followed by the other molecule (Drug B) for 2 weeks. They will have 4 visits, one end-study visit and 11-15 pharmacokinetic samples (depending on their weight). 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
- Randomized
- 干预模型
- Crossover
- 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 6 to 18 years of age, followed either as in- or outpatients at the Heart failure unit, Great Ormond Street Hospital NHS Foundation Trust, London or at the Paediatric Cardiology Unit, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital, Lausanne, Switzerland 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 local 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.
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.
- •Patients on either Insulin or Metformin will be excluded from participation. This implies the exclusion of patients with Diabetes mellitus (either type 1 or type 2 or other rare forms) necessitating either insulin or metformin.
- •Type 1 Diabetes mellitus or any underlying metabolic disease associated with hypoglycaemias.
- •Body weight <13kg.
- •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).
- •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 (board-certified paediatric cardiologist).
- •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 weeks following Visit 1).
- •Post-menarchal female patients of childbearing potential cannot be included.
- •Known lactose intolerance, galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
- •Known allergies to excipients of either Dapagliflozin or Empagliflozin.
- •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).
研究组 & 干预措施
Group A: Dapagliflozin first, Empagliflozin second
Patients randomized to Group A will start with Dapagliflozin on Visit 1 and take Dapagliflozin once daily up to the day before Visit 3.
On the day of Visit 3, they will switch to Empagliflozin once daily, to be continued up to the day preceding Visit 4.
干预措施: Dapagliflozin tablet (Drug)
Group A: Dapagliflozin first, Empagliflozin second
Patients randomized to Group A will start with Dapagliflozin on Visit 1 and take Dapagliflozin once daily up to the day before Visit 3.
On the day of Visit 3, they will switch to Empagliflozin once daily, to be continued up to the day preceding Visit 4.
干预措施: Empagliflozin Tablets (Drug)
Group B: Empagliflozin first, Dapagliflozin second
Patients randomized to Group B will start with Empagliflozin on Visit 1 and take Empagliflozin once daily up to the day before Visit 3.
On the day of Visit 3, they will switch to Dapagliflozin once daily, to be continued up to the day preceding Visit 4.
干预措施: Dapagliflozin tablet (Drug)
Group B: Empagliflozin first, Dapagliflozin second
Patients randomized to Group B will start with Empagliflozin on Visit 1 and take Empagliflozin once daily up to the day before Visit 3.
On the day of Visit 3, they will switch to Dapagliflozin once daily, to be continued up to the day preceding Visit 4.
干预措施: Empagliflozin Tablets (Drug)
结局指标
主要结局
Pharmacokinetics 1: Dapagliflozin, respectively Empagliflozin half-life
时间窗: Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples \[according to weight\] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples \[according to weight\] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling \& simulation techniques).
Pharmacokinetics 2: Dapagliflozin, respectively Empagliflozin Volume of distribution
时间窗: Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples \[according to weight\] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples \[according to weight\] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling \& simulation techniques).
Pharmacokinetics 3: Dapagliflozin, respectively Empagliflozin AUC
时间窗: Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples \[according to weight\] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples \[according to weight\] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling \& simulation techniques).
次要结局
- Efficacy and efficacy markers (exploratory) 4 - Echocardiography 2: Left-ventricular end-systolic diameter (LVESd)(Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Efficacy and efficacy markers (exploratory) 3 - Echocardiography 1: Left-ventricular end-diastolic diameter (LVEDd)(Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Ease-of-swallow(Visit 1, Visit 3 (Visit 1 = day 1, Visit 3 = week 3 to 5 after study start))
- Safety 1 - eGFR(Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Safety 2 - Occurrence of hypoglycemia(Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Safety 3 - Occurrence of ketoacidosis(Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Efficacy and efficacy markers (exploratory) 1 - Heart failure severity class(Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Efficacy and efficacy markers (exploratory) 5 - Echocardiography 3: Fractional shortening (FS)(Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Efficacy and efficacy markers (exploratory) 2 - NT-proBNP level(Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
- Efficacy and efficacy markers (exploratory) 6 - Echocardiography 4: Left ventricular ejection fraction (LV-EF)(Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start))
研究者
Sebastiano Lava
Principal Investigator, "Chef de clinique"
Centre Hospitalier Universitaire Vaudois