Dose Assessment of Melatonin in Sepsis Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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Dose Assessment of Melatonin in Sepsis Trial

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Melatonin


Participation Criteria
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Eligibility Criteria
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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: Core temperature <36 or >38°C; tachycardia: heart rate > 90 beats/min; tachypnoea: respiratory rate > 20 breaths/min or ventilated; 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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melatonin<br>Melatonin at a dose of either 50mg (50ml) or 100mg (100ml) to be decided after an initial PK study to be given at intervals to be decided after PK data is available, for 72h. Oral liquid via nasogastric tube. | Drug: Melatonin<br>* Oral liquid<br>* Other names: N-acetyl-5-methoxytryptamine;|
| Placebo Comparator: Placebo<br>Placebo at a dose of either 50ml or 100ml (to be decided after an initial PK study) to be given at intervals to be decided after PK data, is available for 72h. Oral liquid via nasogastric tube. | Drug: Melatonin<br>* Oral liquid<br>* Other names: N-acetyl-5-methoxytryptamine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Completion of enrollment of 10 patients to Stage 1 | Stage 1= first 5 patients 50mg, second 5 patients 100mg oral melatonin liquid, open label | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite pharmacokinetic measures for each dose in Stage 1 (T max, CMax and AUC) | T max, CMax and AUC of melatonin and 6-hydroxymelatonin sulphate levels at two doses of melatonin. | 6 months | 
| Composite biomarker measures in Stage 2 ( linear discriminant analysis, hierarchical regression and hierarchical cluster analysis) | Multiplex biomarker analysis will be used; linear discriminant analysis, hierarchical regression and hierarchical cluster analysis will be used to explore relationships between biomarkers | 2 years | 
| 28d all cause mortality in Stage 2 | Survival status at 28d | 2 years | 
| Arterial blood lactate (stage 1 and stage 2) | Absolute arterial lactate measures at various time points; change over time. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, antioxidant, melatonin, inflammation