Effect of Melatonin on Cardiometabolic Risk- FULL
试验速览
- 阶段
- 3 期
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- change in insulin sensitivity
研究概览
简要总结
In a 12 week double-blind, placebo-controlled randomized trial, 120 subjects with obesity (BMI≥30 kg/m2) and pre-diabetes (HbA1c, 5.7-6.4%) will be randomly assigned 1:1 to receive either placebo or 2 mg of controlled-release melatonin, taken orally every evening 1 hour before bed. The investigators will assess melatonin's effect on insulin sensitivity by performing a hyperinsulinemic euglycemic glucose clamp and β-islet cell function measured using a hyperglycemic clamp, as a primary endpoint. The investigator will also evaluating melatonin supplementation's effect on mean 24-hour ambulatory blood pressure, nocturnal blood pressure, and potential intermediates including endothelial function using brachial ultrasound, catecholamine production using 24-hour epinephrine and norepinephrine excretion, and renin-angiotensin system activation using measurements of plasma renin activity, angiotensin II, and urine aldosterone excretion. The final endpoint will be to evaluate melatonin supplementation's effect on cellular cytokine and CC family chemokine expression as well as high sensitivity C-reactive protein, IL-6, and TNF-α.
There will be a 24 week cohort phase as an extension of the trial. This will be an open-label prospective study of 50 subjects recruited from the trial who will take 2 mg of controlled-release melatonin nightly for 24 weeks after completion of the 12-week trial. At the end of the cohort-phase (36 weeks after entry in the trial), the investigators will again assess the extended use of melatonin supplementation on 24-hour BP, and glycemic control (HbA1, fasting glucose).
详细描述
All participants will be recruited locally in the Boston area, and all study visits and procedures will be conducted through Partners and the Harvard Catalyst.
Briefly, the trial-phase will consist of four visits, two as outpatient, and two as inpatient. The cohort-phase will consist of two additional outpatient visits. The screening outpatient visit will involve history taking, physical examinations (when appropriate), phlebotomy to measure circulating factors and urine pregnancy testing for female subjects. The 6-week outpatient check-up visit will be with a study coordinator. In addition to evaluating for adverse effects, the coordinator will perform a pill-count. Phlebotomy will be performed to measure circulating factors. The two inpatient visits will require two overnight stays each; the procedures performed for these two inpatient stays will be identical, and will include: timed urine collection, measurement of brachial artery flow mediated dilation, phlebotomy (including an IV protocol using low dose heparin), hyperinsulinemic euglycemic clamp, hyperglycemic clamp, central blood pressure, and placement of an ambulatory blood pressure monitor that the participant will wear home for 24 hours and return by pre-paid FedEx mailer. We will take blood samples at each visit, collecting about 54 tablespoons (798.5 mL) of blood over the 36-week course of the study.
Outpatient visits: A screening visit will be scheduled when a participant expresses interest in the study and is deemed potentially eligible by the study coordinator after a telephone interview. At the screening visit, a study physician will obtain informed consent. Thereafter, a study physician will conduct a history and physical examination, and phlebotomy will be performed. Female subjects will provide urine for pregnancy testing. The purpose of the screening visit is to evaluate potential volunteers based upon the inclusion and exclusion criteria listed above, and to explain the purpose and procedures of the study to the volunteers. If someone is eligible and willing, a baseline inpatient visit will be scheduled.
A 6-week check up will be scheduled after the subject completes the initial inpatient visit. In addition to evaluating for adverse effects, the coordinator will perform a pill-count. Phlebotomy will be performed to measure circulating factors.
For the cohort phase, 24- and 36-week check up visits will be scheduled after the subject completes the final inpatient visit. At these visits, in addition to evaluating for adverse effects, the coordinator will perform a pill-count. Phlebotomy will be performed to measure circulating factors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •age ≥18 years
- •body mass index (BMI) >30
- •HbA1c 5.4-6.4%
- •if hypertensive, BP <150/90
排除标准
- •Use of a melatonin supplement
- •Current use of anticoagulants
- •Use of hypoglycemic or antihypertensive meds
- •Current or prior history of diabetes mellitus, or random serum glucose ≥ 200 mg/dL
- •Major bleeding event in the past 60 days
- •Recent (past 2 weeks) or upcoming travel across time zones
- •Known obstructive sleep apnea or use of continuous positive airway pressure
- •Known heparin allergy
- •Hepatic impairment
- •Estimated GFR <60 mL/min/1.73m2
- •Job requires rotating night shifts
- •Preexisting lung disease requiring oxygen
- •Active chronic or acute infection
- •Preexisting CVD
- •Known melatonin allergy
- •Bariatric surgery within the prior 12 months
- •Preexisting hemoglobinopathy
- •Use of weekly or daily NSAID for chronic pain
- •Use of cholesterol lowering medications
- •Active or uncontrolled psychotic disorder
- •Use of hypnotic medications
- •Active or uncontrolled bipolar illness
- •Active or uncontrolled depression
- •Recent (within the past three months) blood donation or plan to donate blood during study period
- •Use of a phosphodiesterase inhibitor
- •Active malignancy within the prior 5 years
- •Hypertension (>150/90)
- •Currently lactating (women)
- •History of stroke
- •Hematocrit <36 (women) or <41 (men)
- •Thrombocytopenia or other bleeding disorders
- •Surgery in the past 60 days
研究组 & 干预措施
Placebo
Placebo tablet identical to Circadin by mouth each day before bedtime for 12 weeks
干预措施: Placebo (Drug)
Melatonin
Circadin, controlled release melatonin tablet 2mg by mouth each day before bedtime for 12 weeks
干预措施: Melatonin (Drug)
结局指标
主要结局
change in insulin sensitivity
时间窗: 12 weeks
measure insulin sensitivity using hyperinsulinemic clamp
change in beta-islet cell function
时间窗: 12 weeks
measure beta-iset cell function measured using a hyperglycemic clamp
次要结局
- change in plasma renin level(12 weeks)
- change in CC family chemokine expression(12 weeks)
- change in IL-6 level(12 weeks)
- change in 24 hour ambulatory blood pressure(12 weeks)
- change in catecholamine production(12 weeks)
- change in endothelial independent vasodilation(12 weeks)
- change in angiotensin II level(12 weeks)
- change in cellular cytokine level(12 weeks)
- change in TNF-alpha(12 weeks)
- change in nocturnal blood pressure(12 weeks)
- change in high sensitivity CRP(12 weeks)
- change in endothelial dependent vasodilation(12 weeks)
研究者
John P. Forman
Principal Investigator
Brigham and Women's Hospital