Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease
试验速览
- 阶段
- 2 期
- 入组人数
- 50
- 试验地点
- 6
- 主要终点
- Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
研究概览
简要总结
Paediatric clinical trial in 50 children, from newborn to less than 6 years of age, suffering from heart failure due to congenital heart disease, to obtain paediatric pharmacokinetic and pharmacodynamic data of enalapril and its active metabolite enalaprilat while treated for 8 weeks with enalapril in form of Orodispersible Minitablets (ODMTs), to describe the dose exposure in this patient population.
详细描述
This clinical trial is one of three clinical trials of the European Commission (FP7)-funded "LENA" (Labeling of Enalapril from Neonates to Adolescents) project: 50 children with heart failure due to congenital heart disease (LENA-Work Package (WP)09 Trial), and 50 children with heart failure due to dilated cardiomyopathy (LENA-WP08 Trial) get treated with an optimal dose of enalapril ODMTs for up to 8 weeks after thorough, individualised titration and get invited to join the 10 months Safety Follow-up Study (LENA-WP10 Trial).
In this WP09 Trial children from age of newborn to less than 6 years, naive to enalapril treatment or switched from an Angiotensin-Converting-Enzyme (ACE)-Inhibitor pre-treatment, receive an Initial Dose to investigate the reaction over 8 hours before a decision on the first dose level is made. Always up to 7 days later a next higher dose is given at the hospital, the patient is supervised for 4 and then always 2 hours before a decision on the prescribed dose for the next dosing period is made. In this study a target dose similar to the adult target dose (20 mg enalapril in a 70 year old adult result in 0.282 mg/kg/day enalapril) is defined. Enalapril ODMTs of 0.25 mg and 1 mg strength are available to allow for an individual dose titration scheme.
Weight-dependently, pharmacokinetic (PK) and pharmacodynamic (PD) data are collected once in a full PK/PD day over 12, respectively 6 hours, and single PK/PD samples at each Dose Titration Visit and each bi-weekly Study Control Visit until the Last Visit after 8 weeks of treatment. Blood pressure and renal monitoring is performed at each visit before deciding on the dose level for the next treatment period.
Pharmacogenomics and metabolomics exploratory studies are added as a sub-study to better understand the underlying disease, its progression as well as the impact of the ACE-inhibition on cardiac outcome and renal function.
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
- 1 Day 至 5 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients fulfilling the following Inclusion Criteria can be enrolled:
- •Age from birth to less than 6 years.
- •Male and female patients.
- •Weight greater than 2.5 kg.
- •Diagnosis of heart failure due to congenital heart disease requiring after-load reduction by drug therapy.
- •Subjects may be naïve to ACE-Inhibitors.
- •Subjects already on ACE-Inhibitors willing to switch to enalapril Orodispersible Minitablets.
- •Patient and/or parent(s)/legal representative provided written informed consent and assent from the patient according to national legislation and as far as achievable from the child.
排除标准
- •Patients fulfilling any of the following Exclusion Criteria cannot be enrolled into this trial:
- •Neonates if born < 37 weeks of gestation.
- •Severe heart failure and/or end stage heart failure precluding introduction or continuation of ACE-Inhibitor.
- •Too low blood pressure, e.g. ˂P5
- •Uncorrected primary obstructive valvular disease, or significant systemic ventricular outflow obstruction, dilated restrictive or hypertrophic cardiomyopathy.
- •Uncorrected severe peripheral stenosis of large arteries including severe coarctation of the aorta.
- •Severe renal impairment with serum creatinine >2x Upper Limit of Normal (ULN) (according to the hospital's test methodology)
- •History of angioedema.
- •Hypersensitivity to ACE-Inhibitors.
- •Concommitant medication:
- •Dual ACE-Inhibitor therapy
- •Renin inhibitors
- •Angiotensin II antagonists
- •Non-Steroidal Anti-Inflammatory Drugs (including ibuprofen) except for aspirin and paracetamol
- •Already enrolled in an interventional trial with an investigational drug, unless no interference with the current study can be shown.
研究组 & 干预措施
Drug administration
Enalapril Orodispersible Minitablet (ODMT), 0.25 mg or 1 mg, administered 1x/day or 2x/day for up to 8 weeks
干预措施: Enalapril Orodispersible Minitablet (Drug)
结局指标
主要结局
Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
时间窗: 0 hours to 12 hours
Area under the Curve (AUC) of enalapril and enalaprilat are measured at first dose or at any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation
Time to Maximum Concentration (Tmax) of enalapril and its active metabolite
时间窗: 0 hours to 12 hours
Time to Maximum Concentration (Tmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation
Maximum Concentration (Cmax) of enalapril and its active metabolite
时间窗: 0 hours to 12 hours
Maximum Concentration (Cmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation
次要结局
- Plasma Renin Activity(Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56))
- Blood urea nitrogen (BUN)(Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56))
- Number of patients experiencing rehospitalisation due to heart failure(During 8 weeks of treatment)
- Shortening Fraction(Assessment time points: at Screening Visit and at Last Visit (day 56))
- Renin(Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56))
- Angiotensin 1(Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56))
- Aldosterone(Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56))
- Brain natriuretic peptides (BNPs).(At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56))
- Blood pressure(Pre-dose at each Visit, over 8 hours at Initial Dose Visit, over 4 hours at First Titration Visit (day 3 to 7), for 2 hours after all following Titration Visits, pre-dose at all Study Control Visits (day 14, 28, 42), at last Visit (day 56))
- Micro-albuminuria(Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56))
- Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure(0 hours to 12 hours)
- Acceptability of the ODMTs(Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56))
- Palatability of the ODMTs(Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56))
- Serum potassium(Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56))
- AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure(0 hours to 12 hours)
- Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure(0 hours to 12 hours)
- Creatinine(Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56))
- Death due to worsening of the underlying disease(During 8 weeks of treatment)