20 children with non-cyanotic congenital heart defects especially atrial septal defects (ASD) and ventricular septal defects (VSD) in admitted to the paediatric cardiology wards will be included. These children undergo a cardiac surgery prior to the study participation.
Conditions
Interventions
Product Name: Edoxaban-Konzentrag zut Herstellung einer Lösung zum Einnehmen
Pharmaceutical Form: Concentrate for oral solution
INN or Proposed INN: EDOXABAN TOSYLATE
CAS Number: 480449-71-6
Concentra
Sponsors
Ruprecht-Karls University Heidelberg Medical Faculty, University Hospital represented in law by its commercial director
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age 6 month up to 6 years. • Body weight at least 7 kg. • Admitted as inpatient to the paediatric cardiac ward after congenital cardiac surgery • Cardiac defects: non-cyanotic congenital heart defects such as atrial septal defect, ventricular septal defect, etc. • Availability of a central vascular access. • Otherwise healthy children as determined by medical assessment consisting of a medical history, physical examination, an ECG, and a laboratory evaluation, all performed within the clinical routine, that all show no clinically relevant abnormalities. • Minor deviations of laboratory values from the normal range may be acceptable in the pre-operative assessment, if judged by the investigator to be of no clinical relevance for this trial. Criteria include, but are not limited to o Alanine transaminase (ALT) = Upper limit of the normal (ULN) x 1.1 o Aspartate transaminase (AST) = ULN x 1.2 o Bilirubin = ULN x 1.2 (this will not apply to patients with Gilbert’s syndrome) o Creatinine = ULN + 0.1 mg/dl o Haemoglobin > 10 g/dl (pre- and postoperatively). • Both parents (or legal representatives) have to be able to communicate well with the investigator, to understand and comply with the requirements of the trial. • Voluntarily signed informed consent after full explanation of the trial to both parents (or legal representatives) of the participant. The informed consent will be obtained after the surgery. Are the trial subjects under 18? yes Number of subjects for this age range: 20 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: • Intake of a substance known to induce or inhibit drug metabolizing enzymes or drug transporters within a period of less than 10 times the respective elimination half-life or two weeks, whatever is longer. • Simultaneous treatment with anticoagulants (i.e. phenprocoumon, warfarin, heparin (prior intake of heparin is allowed if more than 24 h prior to the start of study)). • Active, clinical relevant bleeding. • Any hepatic disease which could lead to coagulopathy or clinical relevant risk of bleeding • Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities • Uncontrolled severe hypertension/hypotension • Severe respiratory insufficiency • Tachycardic arrhythmias • Renal/Liver insufficiency • Glaucoma • Gastrointestinal ulceration • Clinical relevant mental disorder. Any physical disorder that could interfere with the participant’s safety during the clinical trial or with the trial objectives. • Bodyweight lower than 7 kg. • Allergies (except for mild forms of hay fever) or history of hypersensitivity reactions/ intolerance to the study drugs. • Any acute or chronic illness or clinically relevant finding during the clinical course known or expected to modify absorption, distribution, metabolism, or excretion of the drug under investigation. • Any participation in an interventional clinical trial within 30 days before inclusion. Specific exclusion criteria for Midazolam • Administration of midazolam less than 48 h prior to the start of study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the PKs of rivaroxaban, apixaban and edoxaban, when co-administered as a cocktail of microdoses (apixaban 12,5 µg, rivaroxaban 12,5 µg, edoxaban 50 µg) in children with congenital heart defect, aged 6 month to 6 years.;Secondary Objective: •To compare the PKs in children with adults (healthy and patients from literature). •To characterise the CYP3A activity by means of a MDZ microdose in children. •To characterise the CYP2D6 activity by means of a yohimbine microdose in children. •To evaluate tolerability and safety of this microdose cocktail in children. ;Primary end point(s): This is a pharmacokinetic trial. The primary endpoint is the geometric mean of AUC in children after single dose of microdoses of apixaban, rivaroxaban and edoxaban.;Timepoint(s) of evaluation of this end point: Pharmacokinetics Apixaban: Blood samples (Li-Hep) will be obtained before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 25 h after intake of the oral solution. Rivaroxaban: Blood samples (Li-Hep) will be obtained before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 25 h after intake of the oral solution. Edoxaban: Blood samples (Li-Hep) will be obtained before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 25 h after intake of the oral solution. If patient´s body weight is lower than 10kg, a reduced sampling will be performed. This reduced sampling excludes the following timepoints: 0.75, 1.5, 6, and 25 h | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints include further pharmacokinetic parameters of apixaban, rivaroxaban and edoxaban (AUC0-t, Cmax, Tmax, CLF, Vz/F, and t1/2). Also the pharmacokinetic parameters of yohimbine (AUC0 ?, AUC0-t, Cmax, Tmax, CLF, Vz/F, and t1/2) are secondary endpoints. The CYP3A activity will be calculated by a published mathematical equation using the AUC2-4 of midazolam. Coagulation parameters (Quick/INR, PTT, TZ) will be assessed as safety endpoints as well. ;Timepoint(s) of evaluation of this end point: Apixaban/Rivaroxaban/Edoxaban Blood samples (Li-Hep) will be obtained before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 25 h after intake of the oral solution. Midazolam: Blood samples (Li-Hep) will be obtained before and 2, 2.5, 3, and 4 h after intake. Yohimbine: Blood samples (Li-Hep) will be obtained before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, and 12 h after intake. If patient´s body weight is lower than 10kg, a reduced sampling will be performed. This reduced sampling excludes the following timepoints: 0.75, 1.5, 6, and 25 h for Apixaban, Rivaroxaban and Edoxaban 0.75, 1.5, 1.75, 6, and 25 h for Yohimbine | — |
Countries
Germany
Contacts
Public ContactPaediatric and Congenital Cardiolog
University Hospital Heidelberg
Outcome results
None listed