Melatonin in sepsis
Research type
Research Study
Full title
Dose assessment of melatonin in sepsis trial (DAMSEL 2)
IRAS ID
160663
Contact name
Lee Allen
Contact email
Sponsor organisation
University of Aberdeen
Eudract number
2014-002840-42
ISRCTN Number
ISRCTN70688534
Duration of Study in the UK
1 years, 11 months, 30 days
Research summary
Research Summary
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) we 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 laboratory studies
DAMSEL 2 is a pilot Phase I/II study in patients with sepsis. Stage 1 will assess the pharmacokinetics of melatonin and its major metabolite after a single doses of either 50mg or 100mg melatonin in order to make dosing and dosing interval decisions for Stage 2. Stage 2 is a double blind randomised controlled pilot 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 analysis of mRNA changes. This study will inform a planned larger phase II trial.
Summary of Results
Sepsis is defined as a dysregulated host response to infection, and high-dose melatonin has been proposed as a treatment due to its antioxidant and anti-inflammatory properties. However, there are no data describing the pharmacokinetics of high-dose oral melatonin in critically ill patients. We undertook an open-label trial to determine the tolerance of melatonin administration in these patients and pharmacokinetic analysis, to inform a planned randomised controlled trial. Two groups of 5 critically ill patients with sepsis due to community-acquired pneumonia received either 20 or 50 mg oral melatonin liquid as a single dose. Blood samples and clinical measures were analysed over the next 24h. Melatonin was well tolerated and there were no adverse events. Maximum levels of melatonin were extremely high in patients receiving the 50 mg dose and levels of the major metabolite were much lower than expected and not different from those seen after 20 mg, suggesting saturation at the higher dose. We conclude that 20mg seems a suitable dose of liquid melatonin in patients with sepsis.
REC name
Scotland A: Adults with Incapacity only
REC reference
14/SS/1078
Date of REC Opinion
11 Dec 2014
REC opinion
Further Information Favourable Opinion