Melatonin for Prevention of Delirium in Critically Ill Patients (MELLOW-1)
Feasibility of Melatonin for Prevention of Delirium in Critically Ill Patients: a Multi-centre, Randomized, Placebo-controlled Study.
研究概览
详细说明
The available evidence indicates melatonin may decrease the incidence of delirium in non-critically ill patient populations; however, trials in the critically ill are lacking. The investigators hypothesize that melatonin, administered on a scheduled nightly basis during ICU admission, will be efficacious and safe for the prevention of delirium in critically ill adults. The null hypothesis is that there is no difference in delirium incidence between placebo and melatonin. Prior to conducting an adequately powered multi-centre, blinded randomized, placebo-controlled trial in critically ill patients, there is a need for a better understanding of melatonin pharmacokinetics (PK) in critically ill patients. This will help to determine appropriate dosing, drug administration issues (specifically protocol adherence), adverse drug effects, and recruitment rates based on inclusion and exclusion criteria.
The specific aim is to conduct a phase II triple blind, placebo-controlled randomized trial comparing two doses of melatonin (low dose = 0.5 mg and high dose = 2.0 mg) to assess the feasibility of a future full-scale RCT. Feasibility of the larger trial will be based on protocol adherence and participant recruitment rates. Data on PK properties of melatonin will be assessed to determine dosing for future studies of melatonin for delirium prevention in the critically ill.
研究类型
注册 (预期的)
阶段
- 阶段2
联系人和位置
学习地点
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Ontario
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Toronto、Ontario、加拿大、M5G1X5
- 招聘中
- Mount Sinai Hospital
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接触：
- Lisa Burry, PharmD
- 邮箱：lisa.burry@sinaihealthsystem.ca
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首席研究员：
- Lisa Burry
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Toronto、Ontario、加拿大
- 招聘中
- Sunnybrook Health Sciences Centre
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接触：
- Damon Scales
- 邮箱：damon.scales@sunnybrook.ca
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首席研究员：
- Damon Scales, MD PhD
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首席研究员：
- Louise Rose, PhD
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Quebec
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Montréal、Quebec、加拿大
- 尚未招聘
- Hopital Du Sacre-Coeur
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接触：
- David Williamson
- 邮箱：david.williamson@umontreal.ca
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首席研究员：
- David Williamson, PhD
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首席研究员：
- Francis Bernard, MD
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
- Critically ill patients ≥18 years of age
- Anticipated ICU stay of >48 hours
- Able to receive enteral administration of study drug (i.e. by mouth or any feeding tube = naso- or oro- or percutaneous gastric or post-pyloric feeding tube)
- Consent to participate.
Exclusion Criteria:
- ICU admission of >48 hours prior to screening
- Unable to assess for delirium (e.g. comatose defined as SAS 1 or 2 or either 'No Response' Score A or B on ICDSC, chemically paralyzed with neuromuscular blocking drugs)
- Screened delirium positive prior to randomization (ICDSC score ≥4 out of 8)
- Anticipated withdrawal in next 48 hours
- Known history of severe cognitive or neurodegenerative disease (e.g. dementia, Parkinson's disease) or severe structural brain injury (e.g. traumatic brain injury, intracranial hemorrhage) as the ICDSC assessment tool has not been validated in these patient populations
- Unable to communicate in English or French (Montreal site)
- Contraindications to receiving any enteral medication (defined as absolute contraindication to enteral nutrition such as gastrointestinal obstruction, perforation, recent upper GI surgery, no enteral access)
- Active seizures
- Known pregnancy
- Legal blindness
- Known allergy to melatonin
学习计划
研究是如何设计的？
设计细节
- 主要用途：预防
- 分配：随机化
- 介入模型：并行分配
- 屏蔽：四人间
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
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有源比较器：Enteral melatonin 0.5 mg
Melatonin 0.5 mg from the 1mg/mL oral suspension qs to 5 mL with Oral Mix SF (sugar-free flavoured suspending vehicle) (final concentration of 0.1 mg/mL; final volume in the oral syringe will be 5 mL)
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Study drug will be given at 21:00 - 23:59 daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days, as most critically ill patients are at greatest risk of delirium in the first two weeks of admission.
The study medication will be given by mouth (PO or per os) or if needed, via the feeding tube followed by a flush with 20mL water.
Doses can be given up to midnight if administration needs to be delayed for procedures or investigations.
其他名称：
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有源比较器：Enteral melatonin 2 mg
Melatonin 2 mg from the 1mg/mL oral suspension qs to 5 mL with Oral Mix SF (sugar-free flavoured suspending vehicle) (final concentration 0.4 mg/mL; final volume in the oral syringe will be 5 mL)
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Study drug will be given at 21:00 - 23:59 daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days, as most critically ill patients are at greatest risk of delirium in the first two weeks of admission.
The study medication will be given by mouth (PO or per os) or if needed, via the feeding tube followed by a flush with 20mL water.
Doses can be given up to midnight if administration needs to be delayed for procedures or investigations.
其他名称：
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安慰剂比较：Enteral matched placebo
Melatonin 0 mg qs to 5 mL with Oral Mix SF (sugar-free flavoured suspending vehicle) (final concentration 0 mg/mL; final volume in the oral syringe will be 5 mL)
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Study drug will be given at 21:00 - 23:59 daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days, as most critically ill patients are at greatest risk of delirium in the first two weeks of admission.
The study medication will be given by mouth (PO or per os) or if needed, via the feeding tube followed by a flush with 20mL water.
Doses can be given up to midnight if administration needs to be delayed for procedures or investigations.
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研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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Feasibility: Study adherence
大体时间：1 year
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Investigators will calculate protocol adherence as the overall proportion of administered doses in the prescribed dose administration window (between 21:00 and to 23:59 hours) divided by total number of eligible study days.
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1 year
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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Feasibility: Trial recruitment
大体时间：1 year
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Proportion of ICU patients screened that meet study inclusion criteria, the number of patients excluded and reasons for exclusion, and the consent rate of eligible participants.
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1 year
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Feasibility: Time in motion (minutes)
大体时间：1 year
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Research coordinators at each site will capture the amount of time (minutes) taken to screen, consent, and enrol patients, complete study procedures, and collect data.
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1 year
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Pharmacokinetic: Peak melatonin concentration (Cmax)
大体时间：24 hours
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Peak melatonin concentration. Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
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Pharmacokinetic: Time of peak melatonin concentration (Tmax)
大体时间：24 hours
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Time of peak melatonin concentration (Tmax). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
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Pharmacokinetic: Morning melatonin concentration (C9AM)
大体时间：24 hours
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Morning melatonin concentration (C9AM). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
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Pharmacokinetic: Melatonin half-life (T½)
大体时间：24 hours
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Melatonin half-life (T½). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
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Pharmacokinetic: Mean apparent clearance (CL/F)
大体时间：24 hours
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Mean apparent clearance (CL/F). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
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Pharmacokinetic: Mean apparent volume distribution (V/F)
大体时间：24 hours
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Mean apparent volume distribution (V/F). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
|
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Pharmacokinetic: Area under the concentration-time curve (AUC)
大体时间：24 hours
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Area under the concentration-time curve (AUC). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site. On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours). |
24 hours
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Clinical: Adverse events
大体时间：14 days
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Adverse events reported by the participant, family, or treating team.
The following potential adverse effects will be collected: morning drowsiness (Sedation Agitation Scale (SAS) score <3 or patient's self report of drowsiness between 07:00h and 12:00h), headache, and vivid dreams.
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14 days
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Clinical: Delirium incidence
大体时间：14 days
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Intensive Care Delirium Screening Checklist (ICDSC) administered daily.
Delirium defined as an ICDSC score ≥4.
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14 days
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Clinical: Delirium time to onset and duration (days)
大体时间：14 days
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Time to onset of first ICDSC score ≥4, and number of days with ICDSC score ≥4.
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14 days
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Clinical: Sleep
大体时间：14 days
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Richards Campbell Sleep Questionnaire (RCSQ) administered daily, where possible.
Patients with or without the assistance of their nurse will be asked to complete the questions of the RCSQ each morning.
Nurses will not complete the RCSQ if the patient is unable to verbalize, as poor correlation has been shown between patient and nursing scores.
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14 days
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Clinical: Duration of mechanical ventilation
大体时间：ICU admission
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Duration of mechanical ventilation (days)
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ICU admission
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Clinical: ICU length of stay
大体时间：ICU admission
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Duration of stay for index ICU admission (days)
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ICU admission
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Clinical: Hospital length of stay
大体时间：1 year
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Duration of stay for admission involving trial enrolment (days)
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1 year
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Clinical: ICU mortality
大体时间：1 year
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Number of deaths during index ICU admission
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1 year
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Clinical: Hospital mortality
大体时间：1 year
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Number of deaths during hospital admission
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1 year
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合作者和调查者
调查人员
- 首席研究员：Lisa Burry, PharmD、Mount Sinai Hospital
出版物和有用的链接
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (预期的)
研究完成 (预期的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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