Melatonin for Renal Protection in Patients Receiving Polymyxin B

This study has the objective to evaluate the effect in renal function of 30mg of Melatonin versus placebo in patients ≥18 years old treated with polymyxin B. The development of nephrotoxicity will be evaluated by RIFLE(Risk, Injury, Failure, Loss, End stage renal disease) score and KIM-1 urinary biomarker for the first 14 days of polymyxin B therapy.

This will be a randomized, double-blind, placebo controlled, phase 2 superiority trial.

Patients ≥18 years old admitted in two tertiary care hospitals from Porto Alegre-Brazil receiving intravenous polymyxin B (PMB) will be included after agreeing with the informed consent. Exclusion criteria will be use of PMB for less than 48 hours, chronic dialysis or glomerular filtration rate \<10ml/min or Intensive Care Unit (ICU) admission at baseline, previous regular use of melatonin, pregnancy, unability to receive oral medications or deprived from liberty individuals. All eligible patients will be consecutively recruited.

Primary outcome will be nephrotoxicity evaluated by RIFLE criteria. Secondary outcomes will be development of Renal Failure (by RIFLE criteria), Kidney Injury Molecule-1 (KIM-1) urinary biomarker evaluated at days 2,4 and 7 after the start of PMB and 30 day mortality. Potential confounding factors will be evaluated, such as: demographic variables, comorbidities, PMB dose, concomitant use of other antimicrobials, though concentration of PMB after the 4th dose of the antibiotic.

Patients will be randomized in a 1:1 ratio by a computer system in blocks of 4 for melatonin 30mg or placebo. Analysis will be stratified by center. Patients, attending physicians and researchers responsible for the intervention and data collection will be blinded.

Univariate analysis of variables that could potentially impact on nephrotoxicity will be done by T-test or Wilcoxon rank-sum and Fisher test according to the variables characteristics. A Cox regression model for time to nephrotoxicity during PMB therapy will be done, censoring patients if death, end of therapy or completion of 14 days of PMB therapy. The main analysis will be for intention- to-treat and a secondary per-protocol analysis will be done for patients that received at least 80% of the planned doses. All tests will be two-sided and P≤0.05 will be considered statistically significant.

A subgroup analysis is planned for patients with baseline glomerular filtration rate ≥60ml/min and ≥60years old.

The calculated sample size for this study is of 100 patients, 50 in each arm. An interim analysis is planned when half of the sample is recruited (25 in each arm). If the number of patients that achieve nephrotoxicity criteria is at least 30% less in one of the arms compared to the other, with a P≤0,01, the study will be interrupted.

Eligibility Criteria:
Inclusion Criteria:

1. Treatment with polymyxin B ( a second inclusion will be accepted if the end of the previous treatment was more than 30-days before enrollment)
2. Agreement with the consent form

Exclusion Criteria:

1. Suspension of polymyxin B therapy with \<48hs
2. Death in \<48hs
3. Dialysis or Glomerular Filtration Rate (GFR) \<10 ml/min at the beginning of treatment by the Modification in Diet in Renal Disease (MDRD) formula
4. Lactose intolerance
5. ICU admission at the beginning of therapy
6. Previous regular use of Melatonin
7. Pregnancy
8. Patients deprived from liberty
9. Unability to receive oral medication (i.e total parenteral nutrition)