Clinical trial NCT02319265: Dose Assessment of Melatonin in Sepsis Trial
Official title: Dose Assessment of Melatonin in Sepsis Trial
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Sepsis
Keywords: sepsis
antioxidant
melatonin
inflammation
Lead sponsor: University of Aberdeen
Sponsor class: OTHER
First posted: 2014-12-18
Enrollment: 0
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: DAMSEL 2 is a pilot Phase II study in patients with sepsis. Stage 1 will assess the pharmacokinetics of melatonin and its major metabolite after a single dose of 50 or 100mg exogenous melatonin in two small groups of patients with sepsis in order to make dosing and dosing interval decisions for Stage 2.

Stage 2 is a double blind randomised controlled trial of melatonin in patients with sepsis at the dose and dosing interval decided after Stage 1. Measurements of melatonin and its major metabolite, and an array of biomarkers of inflammation and oxidative stress will be made, plus transcriptome (mRNA) analysis. This study will inform a planned larger phase II trial.

Detailed description: Antioxidant therapy targeted at mitochondria has the potential to reduce inflammation, mitochondrial damage and organ dysfunction in sepsis. Melatonin accumulates in mitochondria and both it and its metabolites have potent antioxidant and anti-inflammatory activity, preventing organ dysfunction in a rat model of sepsis. In a recent Phase I dose escalation study (DAMSEL 1) the investigators showed that oral doses of melatonin in healthy subjects were well tolerated with no adverse events and resulted in levels of circulating melatonin and its major metabolite which had beneficial anti-inflammatory and antioxidant actions in ex vivo studiesStage 1 will assess the pharmacokinetics of melatonin and its major metabolite after a single dose of 50 or 100mg exogenous melatonin in two small groups of patients with sepsis in order to make dosing and dosing interval decisions for Stage 2.

Stage 2 is a double blind randomised controlled trial of melatonin in patients with sepsis at the dose and dosing interval decided after Stage 1. Measurements of melatonin and its major metabolite, and an array of biomarkers of inflammation and oxidative stress will be made, plus transcriptome (mRNA) analysis. This study will inform a planned larger phase II trial.

Eligibility criteria: Inclusion Criteria:

Adult patients (16 years or over) on the ICU at Aberdeen Royal Infirmary with sepsis due to community acquired pneumonia who are within 24h of fulfilling the criteria for sepsis with clinical suspicion of pneumonia and the presence of chest X-ray changes consistent with pneumonia will be recruited. The criteria for sepsis are:

* clinical suspicion or evidence of acute infection
* systemic inflammatory response syndrome, defined by two or more of the following:

  1. Core temperature \<36 or \>38°C;
  2. tachycardia: heart rate \> 90 beats/min;
  3. tachypnoea: respiratory rate \> 20 breaths/min or ventilated;
  4. leucocyte count \>12 x 109/L or \<4 x 109/L.

Exclusion Criteria:

* \<16 years old,
* have a life expectancy \<24h,
* have metastatic cancer or immunosuppression,
* are receiving steroids (\>20mg/d prednisolone or equivalent, used regularly for \>2 weeks prior to ICU admission)
* women of child bearing potential without a negative pregnancy test or a history of surgical sterilization.
* patients receiving fluvoxamine or nifedipine,
* have overt hepatic failure
* unable to tolerate oral medication
* known to be hypersensitive to trial medication and/or excipients

Primary outcomes:
measure: Completion of enrollment of 10 patients to Stage 1
timeFrame: 6 months
Secondary outcomes:
measure: Composite pharmacokinetic measures for each dose in Stage 1 (T max, CMax and AUC)
timeFrame: 6 months
measure: Composite biomarker measures in Stage 2 ( linear discriminant analysis, hierarchical regression and hierarchical cluster analysis)
timeFrame: 2 years
measure: 28d all cause mortality in Stage 2
timeFrame: 2 years
measure: Arterial blood lactate (stage 1 and stage 2)
timeFrame: 2 years
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
Study officials:
affiliation: Univetsity of Aberdeen
name: Helen Galley
role: STUDY_DIRECTOR
References: