A Triple Blinded Randomized Controlled Trial of Oral Melatonin in Elevated Blood Pressure Individual (MRCTEBP)
Phase: PHASE3
Conditions: Elevated Blood Pressure
Sponsor: Tehran University of Medical Sciences

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A Triple Blinded Randomized Controlled Trial of Oral Melatonin in Elevated 
Blood Pressure Individual 
 
 
 
 
NCT number: IR.TUMS.MEDICINE.REC.1397.438                Approval date: 2018-9-17 
 
Document date: December first 2018  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Introduction:  
Prescription of exogenous melatonin has been proved to decrease nocturnal hypertension, the 
pulsatility index of internal carotid artery, platelet aggregation, and catecholamine levels (1). 
Melatonin effects are both receptor mediated and receptor independent. Receptor-mediated effects of 
melatonin comprise of membrane melatonergic receptors (MT1 and MT2) located in vascular system 
and heart. And also could be find in cardiomyocytes, left ventricle, and coronary arteries (2, 3). 
Antioxidant and mitochondrial-protecting effects are receptor independent effects of melatonin (4). 
Melatonin levels decreased in pathological conditions including hypertension with no dipper pattern, 
(5) congestive heart failure (CHF) (6) Ischemic heart disease (4)   acute myocardial infarction (7), 
coronary artery disease (CAD) (1) and low level of LDL-c (8).  Melatonin attenuates blood pressure 
(BP), vascular reactivity, and circulating catecholamine versus placebo in healthy individuals (9-11).  
Besides, antioxidant effect, anti-inflammatory properties, and metabolic regulator activity of 
melatonin are also play an important role in introduction of melatonin as a potential therapeutic agent 
in hypertension and cardiovascular disease (CVD). Accordingly, Clinical trials have been conducted 
to evaluate antihypertensive effects of melatonin in different settings including:  
 A double-blind, placebo-controlled study in 2004 demonstrated that oral daily melatonin therapy with 
2.5 Mg for 3 weeks significantly decreased systolic and diastolic BP in 16 male hypertensive patients 
(12).   In a crossover randomized double blinded placebo controlled trial in 2005 eighteen women 
with normal BP or treated essential hypertension allocated to a 3-week course of slow-release 3Mg 
melatonin pill or placebo one hour before bedtime. They concluded that melatonin may improve the 
day–night rhythm of BP, particularly in women with a blunted nocturnal BP decline (13). 
Effectiveness and safety of melatonin on nocturnal hypertension was investigated in an RCT in 2006. 
Thirty eight treated hypertensive patients underwent four weeks controlled release melatonin 2 mg or 
placebo two hours before bedtime.  Bottom line was significant anti- hypertensive effects of 
controlled-release melatonin. Whereas fast-release did not control nocturnal hypertension (14) 
In a placebo controlled trial effects of 1.5 Mg melatonin for two weeks in 97 hypertensive and 
normotensive individuals have been investigated in 2015 results have been shown that both systolic 
and diastolic BP was significantly mitigated (15). 
In an RCT among 44 women in 2015 bedtime prescription of 6 Mg melatonin  significantly decreased 
mean serum level of; Hs-CRP, TNF-alpha and IL-6 versus placebo (16).   
Decreased level of plasma norepinephrine and blood pressure (BP) were found in an RCT study in 14 
men after 90 minutes of prescribing 2 Mg melatonin versus placebo (17).  
In a clinical trial in twenty healthy volunteers in 2014 to evaluate the safety and tolerability of 20, 30, 
50, and 100 Mg oral doses of melatonin. Apart from transient drowsiness no adverse effects have 
been reported. Sleeping pattern has not been changed with melatonin prescription (18). 
 Therefore, melatonin is appealing in medical practice both in primary and secondary prevention arena 
because of lack of side effect and availability of this medication.    
In a cross over double blinded trial 5Mg melatonin versus placebo was given to 47 mild to moderate 
hypertensive outpatients associated with Nifedipine 30 or 60 Mg a day. Results have been shown that 

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melatonin can impair antihypertensive effect of calcium channel blockers, suggesting caution in 
concomitant use of melatonin and antihypertensive agents (19).  
A clinical trial in 60 coronary artery disease (CAD) patients and non- dippers has been conducted to 
evaluate efficacy of 5 Mg melatonin versus placebo along with previous treatment of CAD. After, 
completing 90 days of follow up they concluded that prescription of melatonin in patients with high 
normal value of BP is not recommended because of the nocturnal decrease and daytime increase in 
BP observed in melatonin intervention group (20). 
 An RCT in 63 patients with metabolic syndrome has been conducted to evaluate the efficacy of 5 Mg 
melatonin for two months. Results revealed that BP and lipid profile significantly decreased and anti- 
oxidative defence significantly improved after two months of melatonin therapy (21). 
 In a small sample size clinical trial in 12 young women cardiovascular effects of one Mg melatonin 
versus placebo has been assessed along with a fixed dose of monophasic contraceptive pill. Melatonin 
significantly reduced systolic and diastolic BP and pulsatility index of internal carotid artery (22).  
Therefore, large scale clinical trials are needed to evaluate the efficacy of melatonin on decreasing 
systolic and diastolic blood pressure. Aforementioned evidences have been shown the safety and 
efficacy of melatonin prescription in different clinical settings. Moreover, prescription of melatonin in 
hypertensive patients (20) and associated with other antihypertensive medications (19) have not been 
recommended. Therefore, we are going to evaluate the efficacy of melatonin versus placebo in pre 
hypertensive individuals who have been recognized as at higher risk of developing future 
hypertension.  
BP consists of systolic (the upper number) BP which indicates how much pressure the blood is 
exerting against artery walls when heart beats. And diastolic BP (the lower number) is indicative of 
the amount of pressure that blood is exerting against artery walls when the heart is resting between 
beats. Diagnosis and treatment of hypertension (HTN) depend on accurate measurement of blood 
pressure and also an average level of BP over a long duration. The last Classification of BP is:  
Normal blood pressure(systolic blood pressure(SBP) <120 mmHg or diastolic blood 
pressure(DBP)<80 mmHg),elevated blood pressure(SBP=120-129 mmHg or DBP<80 
mmHg),hypertension (stage 1; SBP=130-139 mmHg or  DBP=80-89 mmHg),(stage2; SBP>=140 
mmHg or DBP>=90mmHg)(23).  
Elevated BP defined as SBP=120-129 mmHg or DBP<80 mmHg), is associated with higher incidence 
of hypertension (HTN), cardiovascular events and other end-organ damages such as renal, 
cerebrovascular and ocular (24,25). It has been shown that life style intervention in elevated BP 
people can prevent incidence of hypertension. Elevated BP individuals who will not reach optimal BP 
after receiving lifestyle modification are candidate for more aggressive anti-hypertensive treatment 
strategies. So, lowering blood pressure in elevated BP people will provide an excellent opportunity to 
prevent the incidence of HTN. Therefore, we are planning to use a safe treatment option of melatonin 
associated with life style intervention according to ACC/AHA 2013 guideline (26) in elevated BP 
individuals to mitigate systolic and diastolic BP to prevent the incidence of HTN.   
Ongoing researches:  
IMPACT ongoing trial designed in 2014 to test intracoronary versus systemic melatonin in an RCT 
among patients with acute myocardial infarction (AMI) undergoing primary percutaneous cardiac 
intervention (27).    

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          Objectives: 
     Main objective: To determine the efficacy of melatonin in attenuating blood pressure among elevated 
BP individuals  
Specific objectives:   
To determine the efficacy of melatonin in attenuation of Systolic and diastolic BP  
To determine the effect of melatonin on Hs- CRP level, LDL-c, total cholesterol level and fasting 
blood sugar (FBS) 
To determine the effect of melatonin on sleeping pattern, drowsiness  
Hypothesis  
Melatonin therapy can lower the systolic and diastolic BP of elevated BP individuals  
Melatonin can attenuate levels of circulatory biomarkers such as Hs- CRP 
Melatonin can decline the level of total Cholesterol, LDL-c and FBS  
 
Materials, subjects and methods: 
 
Study design: Triple blinded randomized controlled trial (RCT)  
Study population: Elevated BP individuals who have systolic blood pressure of 120-129 mmHg or 
diastolic blood pressure of 80 mmHg  
Study sample: Patients admitted in Tehran Heart Centre (THC) 
Sampling method: Eligible patients will be recruited with simple random sampling  
Inclusion criteria:  
-Individuals with blood pressure120-129 / 80 mmHg 
- Age range of 30-60  
-Negative pregnancy test for women at productive age 
-Baseline melatonin and biomarkers level and complete liver function tests within normal range    
Exclusion criteria: 
 -Previous history of hypersensitivity of melatonin 
- Past history of using antihypertensive treatment 
- Past medical history of hypertension, cardiovascular diseases and diabetes mellitus, epilepsy and 
other physician documented diseases   

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- Use of beta-blockers, sleep aids, warfarin, flaxseed, soy and supplements  
 -Non- compliance  
Sample size:    
Sample size calculation is based on the following equation and efficacy of melatonin in reducing 
systolic and diastolic blood pressure published in an RCT in 2004 by Scheer F et.al: 
 
N= (1/1-f) (zα+zβ) 2    (s12 +s22) 2    / (X1-X2)2 
N=160 per arm 
N total= 320 
Informed consent: 
Written consent form according to Helsinki Declaration will provide participants with information 
about intervention including: benefits and harms, cost, methods of measuring out comes, follow up 
intervals, physician visits, and study team. Participants who accept to randomly assign to the trial 
arms are going to allocate to treatment versus placebo arm.  
Study design:  Randomized controlled trial (RCT), parallel two arms study   
 
 
Intervention plan: 
Recruitment: 320 cases of elevated BP will recruit to the study based on eligibility criteria with a 
simple random sampling method during screening visits by the physicians from THC.  
Treatment plan: Three weeks melatonin 3Mg or placebo one hour before bedtime has been planned. 
All of the melatonin and placebo capsules will be supplied from a single hospital pharmacy and free 
of charge to the participants. Melatonin and placebo capsules will be identical. Participants will 
receive a three weeks supply at the assignment time. Besides, all participants will receive a careful 
plan of adherence to a heart-healthy diet, regular exercise, avoidance of tobacco use and maintenance 
of a healthy body mass index (BMI) according to 2013ACC/ AHA guideline ( the last version).    
  Comprehensive written intervention protocol will be circulating at treatment assignment time.    
Treatment arms: Melatonin 3 mg versus placebo  
Treatment allocation: After completing informed consent and prior to randomization, all participants 
undergo complete physical examination and laboratory test. Baseline melatonin level, inflammatory 
biomarkers and pregnancy test (for women in reproductive age) will be performed. Sleep quality, 
actual sleep time, and sleep latency will be recorded.  
320 participants will be assigned to melatonin 3 mg versus placebo arm using balanced 
randomization.    

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Randomization scheme: Balanced randomization using computerized random digit table will be 
used.  
Blinding: Triple blinding is planned. All participants, medical providers and outcome evaluators will 
be blinded about treatment arms.    
Measurements:  
Two ambulatory blood pressure (BP) recording have been planned while using melatonin versus 
placebo during three weeks intervention period. First measurement will be at recruitment time and the 
second one at the end of three weeks intervention.  
 We have also planned to measure melatonin level at baseline, inflammatory biomarkers, liver 
function tests, lipid profile and sleep details.     
Follow up: 
Duration: Three weeks  
Active follow up:  
Written intervention protocol will be circulating at treatment assignment time. Weekly telephone 
contact with participants will assess adherence to the protocol and will obtain weekly counts of the 
melatonin or placebo capsules, recall for ambulatory BP measurement at the end of three weeks.  
 
Out comes:   
We will assess lowering blood pressure, sleep details using Pittsburgh sleep quality questionnaire  
(PSQI), inflammatory biomarkers, liver function test and adherence to ACC/AHA 2013 guideline 
regarding heart-healthy diet (step one national cholesterol education program), regular exercise 
(moderate level exercise 30 minutes a day five times a week), avoidance of tobacco use and 
maintenance of a healthy body mass index (BMI= 21-25) at baseline and after completion of the 3 
weeks follow up period. All clinical evaluations including efficacy of the treatments, side effects will 
be assessed by a different blinded clinician. Costs of a trial will be calculated by the research team. 
All blood samples will be fasting sample which will be processed, stored and assessed by one hospital 
laboratory.  
Laboratory methods: Standardized lab method using international or local kits will be used.     
Data collection: standardized questionnaire will be used to record the results of complete physical 
examination by physicians, anthropometric measurement, blood pressure measurement, ECG, and 
biological measurement such as inflammatory biomarkers and electrolytes and outcome variables 
such as BP, BMI, physical activity, ECG findings. Sleep quality and details of sleep will be detected 
with standard questionnaire.    
 
Data management plan: 
 Data coding, entry, cleaning, and analysis will be performed by data analyser team.  

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Data analysis protocol: 
Analysis plan: Normal distribution of the variables will be tested. We are going to conduct Univariate 
test including Log rank test and Mann Whitney or independent sample t-test, GLM, survival analysis 
and multivariable model of Cox proportional hazard model (CPHM). Statistical software of PASW 
version 21 and SAS will be used.  
 
 
 
 
 
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