Clinical trial NCT03904836: Tobramycin Administered at the Beginning of Dialysis
Official title: Pharmacokinetics of Tobramycin Administered at the Beginning of Intermittent Hemodialysis Session
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Dialysis
Renal Failure, Chronic
Keywords: Chronic Renal Diseases
Kidney Failure, Chronic
Renal Failure, Chronic
Tobramycin
Aminoglycosides
Pharmacokinetics
Infection
Anti-Bacterial Agents
Antibiotics
Renal Insufficiency, Chronic
Lead sponsor: Maisonneuve-Rosemont Hospital
Sponsor class: OTHER
First posted: 2019-04-05
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of the study is to evaluate whether the administration of a full tobramycin dose (5 mg/kg) during the first 30 minutes of a hemodialysis session provides favorable pharmacokinetic parameters in subjects with end-stage renal disease who are suspected or has been diagnosed with Gram-negative rod-type infection.

It is anticipated that the administration of a single 5 mg/kg dose of tobramycin during the first 30 minutes of a hemodialysis session will achieve an optimal ratio of maximum tobramycin concentration to minimal inhibitory concentration (Cmax/CMI) of 8 to 10 while limiting the accumulation (trough \< 2 mg/L before the next hemodialysis session) in end-stage renal disease subjects requiring intermittent hemodialysis sessions.

Detailed description: STUDY DESIGN:

Prospective, monocentric, non-randomized, uncontrolled pharmacokinetic study

End-stage renal disease subjects who have been involved in an intermittent hemodialysis program and who have suspected or diagnosed Gram-negative rod-type infection.

Pharmacokinetic parameters: Tobramycin concentration analyses done at the beginning of hemodialysis session (before tobramycin administration), 30 minutes after completion of the infusion (will allow us to calculate the peak), during hemodialysis session (additional), at the end of hemodialysis session, between hemodialysis sessions (optional) and just before the next hemodialysis session (will allow us to analyse the trough).

RECRUITMENT PROCESS:

A systematic daily screening for hemodialysis hospitalized subjects or subjects followed at the outpatient clinic who have a suspicion or diagnosis of Gram-negative rod type infection will be made by the research coordinators. Software routinely used in the clinic at Maisonneuve-Rosemont Hospital (Gesphar, NumeRx, Oacis and Medurge) will be used to ensure the identification of potential subjects. The pharmacists responsible for validation of prescriptions at the pharmacy department will collaborate with the research team to help identifying eligible candidates. An eligibility assessment tool will be used and subjects who meet the inclusion criteria and do not meet any exclusion criteria will be considered as eligible candidates. Thereafter, additional baseline information will be collected from the medical file (e.g. ethnicity) or by questioning the subject. A member of the research team will addressed the eligible subject, will explain the study and present the Information Form and Informed Consent (FIC), that will document informed consent of the subject.

DATA COLLECTION:

A minimum of four blood samples and a maximum of six blood samples will be collected. The sampling scheme is as follows: at the beginning of hemodialysis session (before tobramycin administration), 30 minutes after completion of the infusion, during hemodialysis session (additional), at the end of hemodialysis session, between hemodialysis sessions (optional) and just before the next hemodialysis session.

A member of the research team will provide the tubes to the nursing, will write sampling times and will ship the blood samples to the laboratory.

STUDY SAMPLE:

Since the objective is to obtain robust pharmacokinetic parameters, the calculation of the sample size aims at a sufficient number of participants to obtain a convergence of facilitated pharmacokinetic parameters, thus obtaining values of coefficients of variation of less than 40%, while maintaining a statistical power of 80%. The calculation uses the variability of the parameters obtained by Veinstein et al. In this study, the residual clearance (Clnhd) is the parameter with the greatest variability (average of 10.4 mL / min with a standard deviation of 6.4 mL / min). Thus, the variability used in calculating the sample size is that of the parameter with the greatest variability, the residual clearance. The sample studied by Veinstein et al. not having the same characteristics as the subjects of the study, the variability could be greater than the reference sample and a safety margin of 30% is added. A total of 12 subjects to be recruited is therefore planned. No correction is applied for losses at the follow-up or withdrawal of consent considering the short duration of the study.

Eligibility criteria: Inclusion Criteria:

* Subjects aged 18 and over;
* Subjects with end-stage renal disease who are on an intermittent hemodialysis program (three times a week, 3-4 hours) at the Hôpital Maisonneuve-Rosemont hemodialysis unit for at least one month;
* Subjects with suspicion or diagnosis of Gram-negative rod-type bacteria infection for which an antibiotic is prescribed;
* Subjects able to consent to the study (consent form read and signed by the subject).

Exclusion Criteria:

* Contraindication or possible medical hazard related to the administration of tobramycin or to any ingredient in the formulation (e.g. sulphites), such as severe allergies or aminoglycoside-reported previous intolerances;
* Variable residual renal function (e.g. acute or transient renal failure requiring occasional hemodialysis sessions, post-renal transplantation);
* Conditions sensitive to the side effects of tobramycin (e.g. history of myasthenia gravis, Parkinson's disease, vestibular or auditory disorder);
* Subjects with impaired volume of distribution (ie, severe burns \[\> 20%\], significant ascites, decompensation for acute heart failure requiring hospitalization, admission to the critical care unit, cystic fibrosis, morbid obesity \[dry weight greater than 50% of ideal weight\]);
* Pregnant or breastfeeding women;
* Unstable hemodynamic status (risk of not tolerating / completing a 3-4 hour dialysis session);
* Recent treatment with an aminoglycoside (\<1 month);
* Participation in another research protocol;
* Inability to give free and informed consent.

Primary outcomes:
measure: Ratio of maximum tobramycin concentration to minimal inhibitory concentration
timeFrame: The timeframe for data collection for this outcome is 48 hours to 72 hours
Secondary outcomes:
measure: Tobramycin trough level
timeFrame: The timeframe for data collection for this outcome is 48 hours to 72 hours
measure: Residual clearance
timeFrame: The timeframe for data collection for this outcome is 48 hours to 72 hours
measure: Clearance associated with hemodialysis
timeFrame: The timeframe for data collection for this outcome is 48 hours to 72 hours
measure: Volume of distribution
timeFrame: The timeframe for data collection for this outcome is 48 hours to 72 hours
measure: Total area under the curve
timeFrame: The timeframe for data collection for this outcome is 0 to 48 or 72 hours (depending on time between the two dialysis)
measure: Area under the curve between 0 to 24h after administration
timeFrame: The timeframe for data collection for this outcome is 0 to 24 hours
measure: Tobramycin concentration
timeFrame: The timeframe for data collection for this outcome is 24 hours to 72 hours
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: Maisonneuve-Rosemont Hospital
state: Quebec
Study officials:
affiliation: Maisonneuve-Rosemont Hospital
name: Jean-Philippe Lafrance, MD
role: PRINCIPAL_INVESTIGATOR
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