Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure from ages 6 months to 18 years. A randomised, double-blind, multicentre, placebo controlled, phase II/III dose-finding study with a PK/PD characterisation and a 1 year efficacy/safety evaluation.
Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure aged from 6 months to less than 18 years
As of 18/01/2012, anticipated end date was modified from 30/09/2012 to 30/09/2013.
Ethics approval was obtained before recruitment of the first participants
Randomised double-blind placebo-controlled Trial
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
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Paediatric dilated cardiomyopathy and symptomatic chronic heart failure
During the titration period:
[6-12] months: ivabradine, oral liquid paediatric formulation, the starting dose 0.02 mg/kg twice daily or placebo, then 4 titrations according to HR matching with placebo, i.e. 0.05 mg/kg, 0.10 mg/kg, 0.15 mg/kg and 0.20 mg/kg twice daily or placebo.
[1-3] and [3-18] years with weight < 40 kg: ivabradine, oral liquid paediatric formulation, at the starting dose 0.05 mg/kg twice daily or placebo, then 4 titrations according to HR matching with placebo, i.e. 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg and 0.30 mg/kg twice daily or placebo.
[3-18] years with weight >= 40 kg: ivabradine adult tablet formulation, at the starting dose 2.5 mg twice daily or placebo, then 4 titrations according to HR matching with placebo, i.e. 5 mg, 7.5 mg, 10 mg and 15 mg twice daily or placebo.
During the maintenance period: ivabradine, oral liquid paediatric formulation (or adult tablet formulation), at the target dose, twice daily or placebo.
During 1 year treatment period: ivabradine, oral liquid paediatric formulation (or adult tablet formulation), at the dose defined during the maintenance period and adapted according to the weight at each visit, twice daily or placebo.
Primary outcome measures
1. Characterization pharmacokinetics (PK) and PK/Pharmacodynamics (PD) at D014 and M000
2. Target HR achievement: HR measurements during titration period (D000, D014, D028, D042, D056, M000)
Secondary outcome measures
1. Echocardiographic parameters over the study
2. Heart failure symptoms severity over the study
3. Cardiovascular biomarker NT- proBNP over the study
4. Safety over the study
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Patients of both gender aged from 6 months to 18 years old
2. Patients with dilated cardiomyopathy (DCM) receiving their usual treatment for chronic heart failure (CHF) at the optimal dose
3. Patients in sinus rhythm
4. Resting heart rate (HR) complying with the following criteria:
4.1. HR >= 105 bpm in the age-subset [6-12] months
4.2. HR >= 95 bpm in the age-subset [1-3] years
4.3. HR >= 75 bpm in the age-subset [3-5] years
4.4. HR >= 70 bpm in the age-subset [5-18] years
5. CHF class II to IV NYHA or Ross classification, stable for at least 1 month prior to selection
6. Left ventricular (LV) dysfunction with left ventricular ejection fraction (LVEF) <= 45% documented by echocardiography LV dysfunction consecutive to idiopathic dilated cardiomyopathy (DCM), post-viral myocarditis DCM or ischaemic DCM
Target number of participants
Participant exclusion criteria
1. Class I NYHA or Ross Classification (asymptomatic patients)
2. Patients actively listed for transplantation at time of entry into the study or anticipated to undergo heart transplantation or corrective heartsurgery during the 1 year following entry into the study
3. History of symptomatic or sustained (≥ 30 sec) ventricular arrhythmiaunless a cardioverter defibrillator was implanted
4. Patients with structural valvular disease or severe functional valvulardisease requiring surgery
5. Significant systemic ventricular outflow obstruction
6. DCM secondary to muscular dystrophies, hemoglobinopathies, HIV,carnitine deficiency, anthracyclines
7. Patients requiring unauthorised concomitant treatment
8. Serum creatinine >2.0 mg/dL or >180 μmol/L (blood sampleperformed at ASSE visit)
9. AST and/or ALT > 3 upper normal limits (blood sample performed at ASSE visit)
10. Unstable cardiovascular condition at selection or inclusion
Recruitment start date
Recruitment end date
Countries of recruitment
Australia, Belgium, Brazil, Bulgaria, Canada, Denmark, Finland, France, Germany, Hungary, India, Italy, Mexico, Poland, Portugal, Romania, Russian Federation, Spain, Sweden, United Kingdom
Trial participating centre
Service de Cardiologie Pédiatrique
Paris Cedex 15
Institut de Recherches Internationales Servier (France)
50 rue Carnot
Institut de Recherches Internationales Servier (France)
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
All phases - Interventional studies ending before 01/10/2018: Summary results will be published on https://clinicaltrials.servier.com/ within 12 months after the end of the study.
All phases - Interventional studies ending after 01/10/2018: Summary results and a lay summary will be published on https://clinicaltrials.servier.com/ within 12 months after the end of the study.
Phase 3 only - The results will be published in scientific literature within 18 months after the end of the study.
IPD sharing statement:
The datasets generated during and/or analysed during the current study will be available upon request from https://clinicaltrials.servier.com/ if a Marketing Authorisation has been granted after 2014.
Intention to publish date
Participant level data
Available on request
Results - basic reporting