E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Age-related changes in drug absorption and metabolism in children |
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E.1.1.1 | Medical condition in easily understood language |
Age-related changes in processes involved in oral drug absorption and processing in children |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To describe the total apparent CYP3A mediated clearance (Cl/F) of midazolam in the paediatric intensive care population from the age of 0 to 6 years, as surrogate marker of intestinal and hepatic CYP3A activity. |
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E.2.2 | Secondary objectives of the trial |
To describe the oral bioavailability and other PK parameters of midazolam and metabolites. To explore the impact of age and severity of illness (PELOD score) on oral and IV midazolam pharmacokinetics. To explore the feasibility of a microdosing study in children.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age 0 to 6 years inclusive - At least 36 weeks of post conceptual age or body weight 2.5 kg or more - Receiving midazolam IV - Parental informed consent - Intravenous of intra-arterial access for blood sampling |
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E.4 | Principal exclusion criteria |
- Anticipated death in 48 hours - No informed consent - ECMO treatment - Circulatory failure * Receiving more than 1 vasporessor or * Increase of vasopressor drug dose in the last 6 hours - Chronic liver cirrhosis or chronic renal failure - Renal failure according to the pRIFLE criteria, i.e. estimated creatinine clearance decreased by 75% or an urine output of <0.3 ml/kg/h for 24h or anuric for 12 hours. - Acute liver failure AST/ALT >2 times the upper limit for age - Gastrointestinal disorders: Ileus, diarrhoea, short bowel disease, underlying inflammatory bowel disease, pancreatic insufficiency (e.g. cystic fibrosis), celiac disease. - Use of most relevant co-medication known to affect midazolam metabolism (according to the ‘Cytochrome P450 Drug Interactions Table’ )
INHIBITORS Indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem, cimetidine , amiodarone, chloramphenicol, ciprofloxacin, delaviridine, diethyldithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, star fruit, voriconazole
INDUCERS Efavirenz, nevirapine, barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Apparent clearance of midazolam (CL/F) to 1-OH-midazolam and 4-OH-midazolam.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time after completion of the last included patient |
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E.5.2 | Secondary end point(s) |
2. Following parameters will be estimated for both formulations (IV and PO) midazolam and metabolite plasma and urinary clearance, volume of distribution in relation to age and PELOD score. For oral midazolam also: AUC, Cmax, Tmax. Metabolites: 1-OH-midazolam (1-OHM), 1-OH-midazolam-glucuronide (1-OHMG), 4-OH-midazolam (4-OHM) 4-OH-midazolam-glucuronide (4-OHMG), Midazolam-glucuronide (M-G) In feces: midazolam and metabolite appearance. 3. Description of feasibility of microdosing study in pediatric population. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time after completion of the last included patient |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Microdosing study to elucidate the ontogeny of intestinal drugmetabolism pathway of midazolam |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Time after completion of the last included patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |