Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
Cystic fibrosis is the most common inherited life limiting condition which affects children. Patients with it develop lung infections which become difficult to clear, and damage the lungs. These are treated with antibiotics (such as tobramycin) into the vein (termed intravenous antibiotics). This has without doubt improved survival. However, all treatments have side effects. Tobramycin can cause kidney damage. The investigators have preliminary data that suggests that administering tobramycin in the morning may be safer for the kidneys than administering it in the evening. The investigators plan to approach children and adults with cystic fibrosis whose doctors have decided to administer a course of intravenous tobramycin. The investigators will randomly allocate them to receive it at either 0800h or 2200h. The investigators will measure the rate at which the body eliminates tobramycin from the bloodstream, by measuring the amount of tobramycin in the blood stream after administering the antibiotic. For each patient the study will last for the duration of the course of antibiotics. This is decided by the doctor looking after the patient (rather than the researcher), and would typically be 14 days. The investigators will also measure substances in the blood and urine (biomarkers) which are sensitive indicators of low levels of kidney injury. The investigators will monitor lung function and lung bacteria in both the groups to ensure that the patients in both groups improve by the same amount. If the preliminary data are proved correct, this research will allow investigators to improve the safety profile of tobramycin, one of the most widely prescribed drugs in cystic fibrosis.

Official Title
-----------------
Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis (CRITIC) A Randomized Pharmacokinetic Comparison of Tobramycin in Cystic Fibrosis

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Other: Tobramycin time of administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of cystic fibrosis (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) Males or female 5 years and older Treating doctor has decided to commence a course of tobramycin Patient or parent / legal guardian able to give informed consent Exclusion Criteria: Previous episode of acute kidney injury Solid organ transplantation Evidence of impaired renal function (raised serum creatinine above the normal range for age) Once daily aminoglycoside unsuitable because of hypersensitivity or previous high trough levels on once daily dosing. Pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 5 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morning dose of tobramycin<br>Administration of tobramycin once daily dose in the morning | Other: Tobramycin time of administration<br>* Random allocation to time of day of administration of tobramycin<br>|
| Active Comparator: Evening tobramycin<br>Evening dose of tobramycin once daily | Other: Tobramycin time of administration<br>* Random allocation to time of day of administration of tobramycin<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Elimination Rate Constant of Tobramycin |  | Days 1, 8 and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight |  | Day 1, 8, 14 | 
| Pulmonary Function |  | Day 1, 8, 14 | 
| Urinary Biomarkers | NAG, NGAL, IL-18, KIM1, Cystatin C | Days 1 and 14 | 
| Serum biomarkers | Serum creatinine Serum Cystatin C Estimated GFR | Days 1 & 14 | 
| Serum Electrolytes | Serum Potassium and Magnesium | Days 1 & 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cystic fibrosis, Tobramycin, Pharmacokinetics, Toxicity