A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): a structured summary of a study protocol for a randomized controlled trial

摘要

OBJECTIVES:? Primary objective: to evaluate the effect of intravenous melatonin (IVM) on mortality in adult patients admitted to the intensive care unit (ICU) with COVID-19. ? Secondary objectives: ? To evaluate the effect of IVM on ICU length of stay. ? To evaluate the effect of IVM on the length of mechanical ventilation (MV). ? To evaluate if the use of IVM is associated with an increase in the number of ventilator-free days. ? To evaluate if the use of IVM is associated with a reduced number of failing organs as determined by the sequential organ failure assessment (SOFA) scale. ? To evaluate if the use of IVM is associated with a reduction of the frequency and severity of COVID-19-associated thromboembolic phenomena. ? To evaluate if the use of IVM is associated with a decreased systemic inflammatory response assessed by plasma levels of ferritin, D-dimer, C-reactive protein, procalcitonin and interleukin-6. ? To evaluate if the use of IVM is associated with an improvement in hematologic parameters. ? To evaluate if the use of IVM is associated with an improvement in biochemical parameters. ? To evaluate if the use of IVM is associated with an improvement in blood gas analysis parameters. ? To evaluate adverse events during the 28 day study period.TRIAL DESIGN:Phase II, single center, double-blind, placebo-controlled randomized trial with a two-arm parallel group design and 2:1 allocation ratio.PARTICIPANTS:Only critically ill adult patients that fulfill all of the inclusion criteria and none of the exclusion criteria will be included. The study will be conducted in a mixed ICU of a publicly funded tertiary referral center in Madrid, Spain with a 30-bed capacity and 1100 admissions per year. ? Inclusion criteria: ? Patient, family member or legal guardian has provided written Informed Consent. ? Age ε 18 years. ? Confirmed SARS-CoV-2 infection with compatible symptoms AND a positive RT-PCR. ? Admission to the ICU with acute hypoxemic respiratory failure attributed to SARS-CoV-2 infection. ? ICU length of stay of less than 7 days prior to randomization with or without MV and without signs of improvement in respiratory failure (MURRAY score at randomization greater or equal to the MURRAY score at ICU admission). ? Exclusion criteria: ? Participant in a different COVID-19 study in which the study drug is under clinical development and hasn't been previously authorized for commercialization. ? Liver enzymes 5 times the upper normal range. ? Chronic kidney disease with GFR 30 mL/min/1.73 msup2/sup (stage 4 or greater) or need for hemodialysis. ? Pregnancy. A pregnancy test will be performed on every woman younger than 55 years of age prior to inclusion. ? Terminal surgical or medical illness. ? Autoimmune disease. ? Any patient condition that can prevent the study procedures to be carried out at the treating physician's judgement.INTERVENTION AND COMPARATOR:All patients will receive standard-of-care treatment according to the current institutional protocols. In addition, patients will be randomized in a 2:1 ratio to receive: ? Experimental group (12 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous melatonin every 6 hours. Maximum daily dose 500 mg per day. ? Control group (6 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous identically-looking placebo every 6 hours. After 3 days of treatment, 3 intensive care physicians will evaluate the participant and decide whether or not to complete the treatment based on their clinical assessment: ? If objective or subjective signs of improvement or no worsening of the general clinical condition, respiratory failure, inflammatory state or multi-organ failure are observed, the participant will continue the treatment until completion. ? If an adverse effect or clinical impairment is observed that is objectively or subjectively attributable to the study drug the treatment will be stopped.MAIN OUTCOME:Mortality in each study group represented in frequency and time-to-event at day 28 after randomization RANDOMIZATION: The randomization sequence was created using SAS version 9.4 statistical software (programmed and validated macros) with a 2:1 allocation. No randomization seed was pre-specified. The randomization seed was generated using the time on the computer where the program was executed.BLINDING (MASKING):Participants, caregivers and study groups will be blinded to arm allocation.NUMBERS TO BE RANDOMIZED (SAMPLE SIZE):A total of 18 patients will be randomized in this trial: 12 to the experimental arm and 6 to the control arm.TRIAL STATUS:Protocol version 2.0, June 5supth/sup 2020. Trial status: recruitment not started. The first patient is expected to be recruited in October 2020. The last patient is anticipated to be recruited in August 2021.TRIAL REGISTRATION:EU Clinical Trials Register. Date of trial registration: 10 July 2020. URL: https://www.clinicaltrialsregister.