Dose Assessment of Melatonin in Sepsis Trial
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Completion of enrollment of 10 patients to Stage 1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •<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
研究组 & 干预措施
Melatonin
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.
干预措施: Melatonin (Drug)
Placebo
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.
干预措施: Melatonin (Drug)
结局指标
主要结局
Completion of enrollment of 10 patients to Stage 1
时间窗: 6 months
Stage 1= first 5 patients 50mg, second 5 patients 100mg oral melatonin liquid, open label
次要结局
- Composite pharmacokinetic measures for each dose in Stage 1 (T max, CMax and AUC)(6 months)
- 28d all cause mortality in Stage 2(2 years)
- Arterial blood lactate (stage 1 and stage 2)(2 years)
- Composite biomarker measures in Stage 2 ( linear discriminant analysis, hierarchical regression and hierarchical cluster analysis)(2 years)