Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis (CRITIC)

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Other: Tobramycin time of administration

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • Nottingham University Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Morning dose of tobramycin; Administration of tobramycin once daily dose in the morning	Other: Tobramycin time of administration; Random allocation to time of day of administration of tobramycin
ACTIVE_COMPARATOR: Evening tobramycin; Evening dose of tobramycin once daily	Other: Tobramycin time of administration; Random allocation to time of day of administration of tobramycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Nottingham

Publications and helpful links

General Publications

• Prayle AP, Jain K, Touw DJ, Koch BC, Knox AJ, Watson A, Smyth AR. The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison. J Cyst Fibros. 2016 Jul;15(4):510-7. doi: 10.1016/j.jcf.2015.07.012. Epub 2015 Aug 15.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): May 1, 2012
• Study Completion (ACTUAL): June 1, 2012

Study Registration Dates

• First Submitted: September 21, 2010
• First Submitted That Met QC Criteria: September 21, 2010
• First Posted (ESTIMATE): September 22, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): June 23, 2015
• Last Update Submitted That Met QC Criteria: June 22, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Cystic fibrosis; Toxicity; Tobramycin
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Tobramycin
• Other Study ID Numbers: 10076 (Other Identifier: CTEP); NIHR RfPB PB-PG-1207-15025 (OTHER_GRANT: National Institute of Health Research)