E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
We want to find out whether the body eliminates tobramycin from the bloodstream more quickly if it is administered in the morning (at 0800h) compared to the evening (at 2000h). In recent years, a once daily dose of tobramycin has become a standard of care. Once daily aminoglycosides are easier for the patient and clinical staff, and are safer for the patient. We want to build on this improvement in care by being able to recommend the time of day for administration which will also minimise toxicity. We have data from a previous study which indicates that there is a daily rhythm in the rate at which patients eliminate tobramycin. Overnight, elimination may be slower than doses administered in the day time. A slower elimination would increase exposure, and hence increase the risk of toxicity. Therefore we will allocate patients randomly to one of two groups, and administer the tobramycin as either a morning dose or an evening dose, and see which group eliminates the tobramycin |
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E.2.2 | Secondary objectives of the trial |
The secondary research questions address other indicators of toxicity. We will measure urinary and blood levels of biomarkers of kidney injury, which may further support our hypothesis that tobramycin is safer when administered in the morning. Some of the individual differences in tobramycin elimination may be genetically determined (e.g. mice with a mutation of the gene megalin do not get aminoglycoside related kidney toxicity), so we will plan to examine this as a pilot for future studies. The other secondary research question is to establish the biological rhythm related to sleep awake pattern. This will be done by measurement of a salivary levels of a hormone related to sleep and by asking questions about sleep pattern. This will help us establish variation in daynight cycle and its effect on the elimination of Tobramycin. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Collection of samples for genetics is an optional component of this study, though it is not a formal sub-study. |
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E.3 | Principal inclusion criteria |
i) Diagnosis of CF (defined as clinical features of CF plus a positive sweat test OR the presence of 2 genes known to be associated with CF disease. ii) Infection with P. aeruginosa (chronic or intermittent) iii) Patient or parent / legal guardian able to give informed consent |
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E.4 | Principal exclusion criteria |
i) Previous episode of acute kidney injury ii) Solid organ transplantation iii) Evidence of impaired renal function (raised serum creatinine above the normal range for age) iv) Once daily aminoglycoside unsuitable because of hypersensitivity or previous high trough levels on once daily dosing. v) Pregnancy |
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E.5 End points |
E.5.1 | Primary end point(s) |
Kelr - the renal elimination rate constant of tobramycin |
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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 | Yes |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Time of day of administration |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
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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Last visit of the last subject. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |