E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Aminoglycoside-induced nephrotoxicity |
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E.1.1.1 | Medical condition in easily understood language |
Kidney injury caused by a type of antibiotic called an aminoglycoside |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10069022 |
E.1.2 | Term | Kidney injury molecule-1 |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067571 |
E.1.2 | Term | Nephrotoxicity |
E.1.2 | System Organ Class | 100000004857 |
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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 |
Does rosuvastatin protect against kidney damage caused by aminoglycoside antibiotics?
This will be assessed by comparing the difference in the change in the urine biomarker KIM-1 from baseline to 'highest concentration' concentration during exposure to tobramycin between the rosuvastatin treated arm and control arm. |
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E.2.2 | Secondary objectives of the trial |
1. Change in serum concentration of creatinine and eGFR during tobramycin exposure between rosuvastatin treated arm and the control arm. 2. Change in other urinary and plasma biomarkers of renal injury during tobramycin exposure between rosuvastatin treated arm and the control arm. 3. Difference in serious adverse events between rosuvastatin treated arm and the control arm. 4. Difference in tobramycin concentrations between rosuvastatin treated arm and the control arm to identify any pharmacokinetic interaction between rosuvastatin and the tobramycin. 5. Difference in Forced Expiratory Volume in 1 second (FEV1) and C-Reactive Protein, between rosuvastatin treated arm and the control arm to identify any pharmacodynamics interaction between rosuvastatin and the tobramycin 6. Assessment of plasma rosuvastatin concentrations achieved in children randomised to the intervention arm. 7. Difference in biomarkers of Pseudomonas aeruginosa between rosuvastatin treated arm and the control |
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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 |
Title: Molecular genetics of aminoglycoside-induced nephrotoxicity Date: 6th June 2014 Version 1.2
All children who are invited to participate in the PROteKT study will also be invited to participate in a substudy to assess the molecular genetics of aminoglycoside-induced nephrotoxicity.
There exists a considerable degree of inter-individual variability in susceptibility to aminoglycoside-induced nephrotoxicity, and the reasons for this are not clear from the available literature. In particular, whether there is any genetic component to this variability has not been investigated previously in a genome-wide approach.
During this study all participants will be exposed to IV tobramycin as part of their routine clinical care. We will collect a sample for molecular genetic analysis from each child who consents to do so, and identify aminoglycoside-induced nephrotoxicity using novel biomarkers and serum creatinine.
The samples collected in this study will be combined with: 1. Samples collected through the MAGIC study (Molecular Genetics of Adverse Drug Reactions in Paediatric Patients), Research Ethics No: 10/H1002/57. 2. Samples collected through worldwide efforts to evaluate genetic factors predisposing to drug-induced renal injury.
In the future, we will conduct a genome wide association study (GWAS) to identify genetic risk factors for aminoglycoside-induced nephrotoxicity. Any positive hits will be further investigated using functional approaches to elucidate mechanisms and identify causal variants.
We will aim to assess the feasibility of carrying out a molecular genetic study in this group of children, and to address the following objectives: (1) Identify genetic risk factors for aminoglycoside-induced nephrotoxicity in children with CF in order to provide better preventive strategies in the future. (2) Identify causal mechanisms of aminoglycoside-induced AKI by exploring genotype/phenotype correlations, in order to provide better interventional strategies in future.
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E.3 | Principal inclusion criteria |
1. Age 10 to 18 years inclusive. 2. Diagnosis of cystic fibrosis (established by sweat test or genotype). 3. Planned, clinically indicated, course of treatment with IV tobramycin. 4. Ability to give informed consent. 5. Willingness to comply with all study requirements. 6. Able to take tablets.
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E.4 | Principal exclusion criteria |
1. Existing treatment with a statin. 2. Previous adverse reaction to a statin. 3. Co-enrolment in other drug trials*, or completion of a previous CTIMP within the last 30 days 4. Previous randomisation in the PROteKT trial 5. Patients taking any of the following medications: Ciclosporin, Protease Inhibitors, Fibrates, Ezetimibe, Erythromycin (but not other macrolides), Eltrombopag, Dronedarone, Itraconazole, Coumarins, Oral contraceptives, nicotinic acid, fusidic acid and Simepravir. 6. Female participants who are pregnant or lactating (female participants of childbearing potential must use a barrier method of contraception if sexually active whilst taking rosuvastatin and for 7 days afterwards). 7. Patients of Asian ancestry (Japanese, Chinese, Filipino, Vietnamese, Korean and Indian). 8. Patients with renal disease (eGFR<60ml/min/1.73m², using the Schwartz formula, in the 6 months preceding randomisation). 9. Patients with current elevation in transaminases exceeding 3x the upper limit of normal. 10. Family history, or personal history, of hereditary muscular disorders. 11. Patients with myopathy. 12. Patients with a history of, or active alcohol abuse. 13. Patients with hypothyroidism. 14. Patients with galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption. 15. Patients who are Hepatitis C positive or HIV-positive.
*Patients who are currently taking part in TORPEDO-CF are allowed to take part in PROteKT as long as their date of randomisation into TORPEDO-CF is not within the previous six months of the screening date for PROteKT.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is difference in mean fold-change in urinary KIM-1 from baseline to 'highest concentration' concentration during exposure to tobramycin between the rosuvastatin treated arm and control arm. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Urine samples, for measurement of urinary KIM-1, will be collected from each child at baseline, and on each day of aminoglycoside treatment (usually lasting 2 weeks). A further sample will be collected at the 4 week follow-up visit.
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E.5.2 | Secondary end point(s) |
1. Difference in serum concentration of creatinine and eGFR during tobramycin exposure between rosuvastatin treated arm and the control arm. 2. Difference in other urinary and plasma biomarkers of renal injury during tobramycin exposure between rosuvastatin treated arm and the control arm. 3. Difference in serious adverse events between rosuvastatin treated arm and the control arm. 4. Difference in tobramycin concentrations between rosuvastatin treated arm and the control arm to identify any pharmacokinetic interaction between rosuvastatin and the tobramycin. 5. Difference in Forced Expiratory Volume in 1 second (FEV1) and C-Reactive Protein, between rosuvastatin treated arm and the control arm to identify any pharmacodynamics interaction between rosuvastatin and the tobramycin 6. Relationship between plasma rosuvastatin concentrations achieved in children randomised to the intervention arm and change in urinary KIM-1. 7. Difference in biomarkers of Pseudomonas aeruginosa between rosuvastatin treated arm and the control arm.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood samples, for secondary endpoints 1, 2, 4, 5, 6, and 7, will be collected at baseline (T0), T+1 day, T+8 days, T+13 days, and the 4 week follow-up visits.
Urine samples, for secondary endpoints 2 and 7, will be collected at baseline, on each day of aminoglycoside treatment (usually lasting 2 weeks), and the 4 week follow-up visit.
FEV1, for secondary endpoint 5, will be measured at baseline (T0), T+8 days, T+13 days, and the 4 week follow-up visits. |
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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 | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
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 | 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 | No |
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 |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
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 | Yes |
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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The end of the trial is defined to be the date on which data for all participants has been finalised and all data has been entered onto the database. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |