Clinical trial NCT03764020: Trial of Oral Melatonin in Elevated Blood Pressure
Official title: A Triple Blinded Randomized Controlled Trial of Oral Melatonin in Elevated Blood Pressure Individual (MRCTEBP)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Elevated Blood Pressure
Keywords: melatonin
inflammatory biomarkers
Lead sponsor: Tehran University of Medical Sciences
Sponsor class: OTHER
First posted: 2018-12-04
Enrollment: 320
Sex: ALL
Minimum age (years): 30
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Melatonin 3 Mg or placebo associated with life style modification according to 2013ACC/ AHA guideline has been planned in parallel fashion for three weeks of follow up. Participants allocated to each group will stay at the same interventional group for entire follow up period of three weeks.
Primary purpose: TREATMENT

Brief summary: Since, lowering blood pressure (BP) in elevated blood pressure individuals represents an excellent opportunity to for primary prevention of hypertension (HTN). Therefore, it is planned to use a safe treatment option - oral melatonin supplementation - associated with lifestyle interventions according to the American college of cardiology/American heart association (ACC/AHA) 2013 guideline in elevated blood pressure individuals to mitigate systolic and diastolic BP and ultimately, to prevent the development of HTN.

Hypothesis:

Melatonin therapy can lower the systolic and diastolic BP of elevated blood pressure individuals Melatonin can attenuate levels of circulatory biomarkers of Hs- CRP, Cholesterol, LDL-c and triglyceride

Detailed description: Study design: Randomized controlled trial (RCT)

Study population: Elevated blood pressure individuals who present themselves at the outpatient clinics of Tehran Heart Centre(THC) , seeking blood pressure treatment and who have a systolic blood pressure of 120-129 mmHg or a diastolic blood pressure of =80 mmHg.

Treatment groups: Melatonin 3 mg versus placebo

sample size: 160 per group ( 320 overall)

Treatment allocation: After completing informed consent and prior to randomization, all participants undergo complete physical examination and laboratory test. Baseline levels of inflammatory biomarkers and pregnancy test (for women in reproductive age) will be performed. Sleep quality, actual sleep time, and sleep latency will be recorded.

Treatment plan: Three weeks melatonin 3 Mg 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, instruction for avoidance of tobacco use and maintenance of a healthy body mass index (BMI) according to 2013ACC/ AHA guideline.

Follow up: Three weeks

Eligibility criteria: Inclusion Criteria:

* Individuals with systolic blood pressure120-129 and/or diastolic blood pressure =80mmHg
* 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, (i.e. coronary artery disease), and diabetes mellitus, epilepsy and other physician documented diseases
* Use of beta-blockers, sleep aids, warfarin, flaxseed, soy and supplements

Primary outcomes:
measure: Mean change in systolic blood pressure from baseline
timeFrame: From enrollment to end of treatment at 3 weeks
measure: Mean change in diastolic blood pressure from baseline
timeFrame: From enrollment to end of treatment at 3 weeks
measure: Mean change in cholesterol
timeFrame: From enrollment to end of treatment at 3 weeks
measure: Mean change in low density lipoprotein
timeFrame: From enrollment to end of treatment at 3 weeks
measure: Mean change in fasting blood sugar
timeFrame: From enrollment to end of treatment at 3 weeks
measure: Mean change in inflammatory biomarker
timeFrame: From enrollment to end of treatment at 3 weeks
Secondary outcomes:
measure: Mean change in sleep quality score from baseline
timeFrame: From enrollment to end of treatment at 3 weeks
Other outcomes:
Locations:
Study officials:
affiliation: Tehran University of Medical Sciences
name: zinat Hatmi, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ekmekcioglu C, Thalhammer T, Humpeler S, Mehrabi MR, Glogar HD, Holzenbein T, Markovic O, Leibetseder VJ, Strauss-Blasche G, Marktl W. The melatonin receptor subtype MT2 is present in the human cardiovascular system. J Pineal Res. 2003 Aug;35(1):40-4. doi: 10.1034/j.1600-079x.2003.00051.x.
citation: Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin--a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011 Mar;93(3):350-84. doi: 10.1016/j.pneurobio.2010.12.004. Epub 2010 Dec 28.
citation: Jonas M, Garfinkel D, Zisapel N, Laudon M, Grossman E. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press. 2003;12(1):19-24.
citation: Girotti L, Lago M, Ianovsky O, Elizari MV, Dini A, Perez Lloret S, Albornoz LE, Cardinali DP. Low urinary 6-sulfatoxymelatonin levels in patients with severe congestive heart failure. Endocrine. 2003 Dec;22(3):245-8. doi: 10.1385/ENDO:22:3:245.
citation: Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia MJ, Sanchez J, Marrero F, de Armas-Trujillo D. Decreased nocturnal melatonin levels during acute myocardial infarction. J Pineal Res. 2002 Nov;33(4):248-52. doi: 10.1034/j.1600-079x.2002.02938.x.
citation: Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, Kaski JC, Reiter RJ. Melatonin and circadian biology in human cardiovascular disease. J Pineal Res. 2010 Aug;49(1):14-22. doi: 10.1111/j.1600-079X.2010.00773.x. Epub 2010 Jun 1.
citation: Arangino S, Cagnacci A, Angiolucci M, Vacca AM, Longu G, Volpe A, Melis GB. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Am J Cardiol. 1999 May 1;83(9):1417-9. doi: 10.1016/s0002-9149(99)00112-5.
citation: Cagnacci A, Arangino S, Angiolucci M, Maschio E, Longu G, Melis GB. Potentially beneficial cardiovascular effects of melatonin administration in women. J Pineal Res. 1997 Jan;22(1):16-9. doi: 10.1111/j.1600-079x.1997.tb00297.x.
citation: Cagnacci A, Arangino S, Angiolucci M, Maschio E, Melis GB. Influences of melatonin administration on the circulation of women. Am J Physiol. 1998 Feb;274(2):R335-8. doi: 10.1152/ajpregu.1998.274.2.R335.
citation: Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004 Feb;43(2):192-7. doi: 10.1161/01.HYP.0000113293.15186.3b. Epub 2004 Jan 19.
citation: Cagnacci A, Cannoletta M, Renzi A, Baldassari F, Arangino S, Volpe A. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens. 2005 Dec;18(12 Pt 1):1614-8. doi: 10.1016/j.amjhyper.2005.05.008.
citation: Grossman E, Laudon M, Yalcin R, Zengil H, Peleg E, Sharabi Y, Kamari Y, Shen-Orr Z, Zisapel N. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med. 2006 Oct;119(10):898-902. doi: 10.1016/j.amjmed.2006.02.002.
citation: Gubin DG, Gubin GD, Gapon LI, Weinert D. Daily Melatonin Administration Attenuates Age-Dependent Disturbances of Cardiovascular Rhythms. Curr Aging Sci. 2016;9(1):5-13. doi: 10.2174/1874609809666151130220011.
citation: Mesri Alamdari N, Mahdavi R, Roshanravan N, Lotfi Yaghin N, Ostadrahimi AR, Faramarzi E. A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res. 2015 Jun;47(7):504-8. doi: 10.1055/s-0034-1384587. Epub 2014 Aug 15.
citation: Kozirog M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M. Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J Pineal Res. 2011 Apr;50(3):261-6. doi: 10.1111/j.1600-079X.2010.00835.x. Epub 2010 Dec 8.
citation: Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR. Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J Pineal Res. 2014 May;56(4):427-38. doi: 10.1111/jpi.12134. Epub 2014 Apr 5.
citation: Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol. 2000 May;49(5):423-7. doi: 10.1046/j.1365-2125.2000.00195.x.
citation: Rechcinski T, Trzos E, Wierzbowska-Drabik K, Krzeminska-Pakula M, Kurpesa M. Melatonin for nondippers with coronary artery disease: assessment of blood pressure profile and heart rate variability. Hypertens Res. 2010 Jan;33(1):56-61. doi: 10.1038/hr.2009.174. Epub 2009 Oct 30.
citation: Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves JW, Hill MN, Jones DH, Kurtz T, Sheps SG, Roccella EJ; Council on High Blood Pressure Research Professional and Public Education Subcommittee, American Heart Association. Recommendations for blood pressure measurement in humans: an AHA scientific statement from the Council on High Blood Pressure Research Professional and Public Education Subcommittee. J Clin Hypertens (Greenwich). 2005 Feb;7(2):102-9. doi: 10.1111/j.1524-6175.2005.04377.x. No abstract available.
citation: Fuchs SC, Poli-de-Figueiredo CE, Figueiredo Neto JA, Scala LC, Whelton PK, Mosele F, de Mello RB, Vilela-Martin JF, Moreira LB, Chaves H, Mota Gomes M, de Sousa MR, Silva RP, Castro I, Cesarino EJ, Jardim PC, Alves JG, Steffens AA, Brandao AA, Consolim-Colombo FM, de Alencastro PR, Neto AA, Nobrega AC, Franco RS, Sobral Filho DC, Bordignon A, Nobre F, Schlatter R, Gus M, Fuchs FC, Berwanger O, Fuchs FD. Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER-Prevention Randomized Clinical Trial. J Am Heart Assoc. 2016 Dec 13;5(12):e004248. doi: 10.1161/JAHA.116.004248.
citation: Collier SR, Landram MJ. Treatment of prehypertension: lifestyle and/or medication. Vasc Health Risk Manag. 2012;8:613-9. doi: 10.2147/VHRM.S29138. Epub 2012 Nov 15.
citation: Pandi-Perumal SR, BaHammam AS, Ojike NI, Akinseye OA, Kendzerska T, Buttoo K, Dhandapany PS, Brown GM, Cardinali DP. Melatonin and Human Cardiovascular Disease. J Cardiovasc Pharmacol Ther. 2017 Mar;22(2):122-132. doi: 10.1177/1074248416660622. Epub 2016 Jul 27.
citation: Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Melatonin and cardiovascular disease: myth or reality? Rev Esp Cardiol (Engl Ed). 2012 Mar;65(3):215-8. doi: 10.1016/j.recesp.2011.10.009. Epub 2012 Jan 13. No abstract available. English, Spanish.