Essential HypertensionPhase 2MIPAENCT05257291
Study MIPAE - Melatonin and Essential Arterial Hypertension
A Phase 2 study testing Melatonin in people with Essential Hypertension, run by Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia at 1 site in Italy.
Trial summary
Study MIPAE - Melatonin and essential arterial hypertension. Study with dietary supplement, prospective and monocentric (randomized control trial). 1 mg/day of melatonin has been administered for one year to a group of patients suffering from essential hypertension (from at least one year) and who are already on… Read more about this study
- Who is it for?
- Ages 40 to 50 years
- Conditions the study is for
- Essential Hypertension
- What is being tested?
- Melatonin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteItaly
- Study dates
- 2 Feb 2018to Aug 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Caucasian race;
- Age 40-50;
- Signed written informed consent
- Normal weight;
- Blood pressure: PAD >90 mmHg and PAS >140 mmHg;
- Blood pressure in the above mentioned range from at least 1 years
Show all 13Show fewer
- Fasting blood sugar < 100 mg/dL;
- Total cholesterol < 200 mg/dL and triglycerides < 150 mg/dL;
- Intake of antihypertensive therapies (except nitrates, statins and β-blockers);
- Non-smoking;
- No night shift workers (at least in the last 3 months before recruitment);
- With a regular sleep/wake rhythm;
- No pregnant/nursing women.
Who cannot join
- Blood pressure: PAD <90 mmHg and PAS <140 mmHg
- Heart disease of any kind;
- Autoimmune or rheumatological or vascular diseases other than essential hypertension;
- Anti-hypertensive therapies with nitrates, statins or β-blockers;
- Pregnancy/nursing;
- < 40 or > 50 years;
- Worker with night shifts (for a period of less than 3 months before recruitment);
- Continuous irregular sleep/wake rhythm.
Trial locations and contacts
1 site in 1 country.
Italy1 site
Anatomy and Physiopathology Division, Department of Experimental and Clinical Sciences, University of Brescia (Italy), Viale Europa 11, 25123 Brescia, Italy
Brescia, 23125
About this study
Official title: Melatonin and Essential Arterial Hypertension
Study MIPAE - Melatonin and essential arterial hypertension.
Study with dietary supplement, prospective and monocentric (randomized control trial). 1 mg/day of melatonin has been administered for one year to a group of patients suffering from essential hypertension (from at least one year) and who are already on antihypertensive therapy. This group has been compared with as many hypertensive patients on antihypertensive therapy to whom melatonin has not been administered. Each of the participants have been evaluated at the beginning of the study and after one year considering:
Read more
- systolic and diastolic blood pressure;
- echocardiographic values (Vivid Q, GE Healthcare);
- applanation tonometry (SphygmoCor, AtCor Medical);
- peripheral arterial tonometry (EndoPAT-2000, Itamar);
- melatonin levels and total circulating antioxidant capacity after peripheral venous blood sampling.
The aim of the study was to evaluate the antioxidant and vasoprotective effects of melatonin, evaluating both plasma changes and directly studying the possibility of a real remodeling and improvement of cardiac structures.
Read the detailed description
Hypertension is a pathological condition characterized by a constant and not occasional increase in systolic and diastolic blood pressure values. This pathology represents one of the most important public health problems in industrialized countries, as it affects more than 25-30% of the adult population and can cause serious and even fatal complications. It is in fact considered the major risk factor of mortality and pathological effect at cardiovascular, encephalic and renal level.
The classification of hypertension suggested by the ESC/ESH Guidelines defines diastolic blood pressure (PAD) values of 80-84 mmHg and systolic blood pressure (PAS) values of 120-129 mmHg as "normal" in a healthy adult. Blood pressure values between 90-99 mmHg (PAD) and 140-159 mmHg (PAS) define grade 1 hypertension.Between 100-109 mmHg (PAD) and 160-179 mmHg (PAS) define grade 2 hypertension. For values above 110 mmHg (PAD) and 180 mmHg (PAS), determine grade 3 hypertension (after 60 years of age slightly higher values are accepted). Although many antihypertensive drug therapies exist today, patients often show a lack of response to pharmacological treatment due to numerous factors of both genetic and environmental nature that contribute to determine the clinical picture and the poor response to the set therapeutic regime. Recent studies aimed at clarifying the pathophysiology of resistant hypertension are highlighting new pathophysiological mechanisms potentially involved in the genesis of this clinical condition. Since essential hypertension and vascular and cardiac dysfunctions seem to be closely related, the identification of molecules/substances that can at least help to reduce the alterations induced by the pathogenetic process of essential hypertension is a priority. In recent years, melatonin has shown important and interesting antihypertensive therapeutic potential. It has also been demonstrated by some authors of this project, in an animal model of arterial hypertension, that melatonin, thanks to its antioxidant properties, is able to regress structural alterations of both the aorta and small mesenteric resistance arteries in an animal model of arterial hypertension.
It is therefore necessary to investigate, also in humans, the correlation among essential arterial hypertension, levels of circulating melatonin and onset of cardiovascular events.
Furthermore, it is of fundamental importance to remember that, to date, following treatment with melatonin, even at high doses, show only rare and minimal adverse effects, including daytime drowsiness, dizziness and headaches.
The aim of the study was, therefore, to evaluate the antihypertensive, antioxidant and vasoprotective effects of melatonin in adult patients suffering from at least 1 year essential hypertension and in antihypertensive therapy. In a broad sense, the aim will be to contribute to current knowledge in terms of effective treatment and reduced impact of cardiovascular changes related to hypertension.
To do this, a total of 23 adult patients (mean age 54 years old) suffering from essential arterial hypertension and undergoing concurrent antihypertensive therapy were enrolled by the Cardiology Unit of the Spedali Civili di Brescia (Italy). The participants were randomly divided into a group to which melatonin was administered orally (1 mg/day for one year - "melatonin" group). This group of patients was then compared with a group of hypertensive patients on antihypertensive therapy who did not take melatonin ("control" group). In particular, patients with essential hypertension for at least 1 year were selected and enrolled.
With regard to the number of samples, reference has been made to recent studies conducted at our Institute. The sample size (alpha 0.05, power 80%) needed to catch a 2 tissue strain modification of the ascending aorta is 6.2% of the longitudinal 2D strain of the left ventricle 21, 0.1 of VAC is 10, 0.25 of RH-PAT index 17, 0.5 m/s in cfPWV is 12. In addition, patients after enrolment have been randomized 1:1 in the two groups; randomization by random number generation minimizes selection prejudices/errors in subdivising into groups and allows to better evaluate the possible effects of melatonin treatment on hypertensive patients (on antihypertensive therapy) compared to hypertensive patients (on antihypertensive) therapy who have not taken melatonin, while the other variables and the analysis to be performed have been kept constant.
All patients with essential hypertension (in antihypertensive therapy) enrolled in the study received the informed consent document and the information document together with clear and understandable explanations/information about the study. In addition, the investigating physician is available to enlisted patients for all necessary information and also for any subsequent questions/curiosities, as well as for the reporting of any adverse effects that he or she undertakes to notify promptly.
In addition, the supply of melatonin tablets required for 30 ± 3 days of treatment (35 tablets of 1 mg melatonin) have been delivered by the investigating physician only to patients enrolled in the "melatonin" group at the time of enrolment and for the following 11 months of the trial.
At the time of enrolment, the investigator has also provided all enlisted subjects a diary on which to record the time of melatonin intake (only for the "melatonin" group), the number of hours of sleep at night, the systolic and diastolic blood pressure values measured weekly by the patient himself and the onset of any adverse effects. At the end of the study, the investigator collected the diaries of all patients enrolled in the study in order to analyze and archive the data together with the evaluation of the previous medical history.
At the beginning of the study and after one year, the patients were evaluated during a medical examination considering:
- blood pressure (weekly evaluation carried out by the patient and monthly check-up carried out by the investigating doctor during meetings with the patient);
- heart rate;
- endothelial parameters: RHI, LnRHI, peripheral AIx@75;
- arterial stiffness parameters: central blood pressure, AIx@75 radial, cfPWV, SEVR;
- echocardiographic parameters: dimensions of atria and ventricles, stenosis and valve insufficiencies, systolic function VS (FE) and VD (TAPSE, FAC, S' TSI), diastolic function VS and VD (E/A, DT, E/E', E'/A'), dimensions and elastic properties of the ascending aorta (compliance, distensibility, stiffness index, elastic modulus of Peterson, PWV, M-mode strain, tissue strain), elongated aortic (Ea) and ventricular telediastolic sinintra (Ees), ventricular-arterial coupling (VAC=Ea/Ees), 2D longitudinal/radial/circonferential strain of VS, longitudinal strain of VD and left atrium (LAA and LAS), torsion of VS;
- laboratory parameters: blood melatonin levels and total circulating antioxidant capacity.
- Conditions
- Essential Hypertension
- Being tested
- Melatonin
- Keywords
- Essential Hypertension, Melatonin, Antioxidant, Antihypertensive, Cardiovascular System
- Medical subject headings
- Essential Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MelatoninDrug
Supplementation with 1 mg/day of melatonin for 1 year
| Study group | Role | What they receive |
|---|---|---|
| Control group | No intervention | Group of essential hypertensive patients who have received no additional therapies in addition to their established treatment plan (each patient was on specific antihypertensive therapy that has not been changed). |
| Melatonin treated group | Active comparator | Group of essential hypertensive patients who have received additional therapies consisting in 1 mg/day of melatonin for 1 year, in addition to their established treatment plan. Receives: Drug: Melatonin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood pressure.
Value of ambulatory blood pressure obtained from the mean of three different misurations.
Measured: Baseline.
Heart rate.
Ambulatory recorder of the heart rate of the patient.
Measured: Baseline.
Endothelial parameters.
PAT signals were obtained using the EndoPAT-2000 device, which has been vali-dated and used previously to assess peripheral arterial tone in other populations. Endothelial function is measured via a reactive hyper-emia (RH) protocol: it consists of a 5 minutes baseline mea-surement, after which a blood pressure cuff on the test arm isinflated to 60 mm Hg above baseline systolic BP or at least200 mm Hg for 5 minutes. After 5 minutes, the cuff is deflated, and the PAT tracing isrecorded for a further 5 minutes. The cal-culated ratio is called RH-PAT index or RH index (RHI).
Measured: Baseline.
Arterial stiffness parameters.
The radial artery waveform was recorded using the SphygmoCor system. The tip of the tonometer was pressed gently against the radial artery at the site of maximum pulsation at the wrist. This micromanometer precisely records pressure within the artery. he augmentation pressure is defined as the height of the late systolic peak above the inflection point. Augmentation index is expressed as a percentage of PPAO. Augmentation index is a measure of the stiffness of the arterial walls, namely pulsatile load. Because there is a linear relationship between it and heart rate (HR), augmentation index was standardized to a HR of 75 bpm (AIx@75).
Measured: Baseline.
Echocardiographic parameters.
Bi-dimensional transthoracic echocardiographic examinations were performed using Vivid 9 and Vivid Q (GE Medical HealthCare, USA) with a probe of 3.5 MHz, to assess LV dimensions and systolic function, according to the guidelines. The main points were: the dimensions of atria and ventricles, stenosis and valve insufficiencies, systolic and diastolic function VS and VD, Dimensions and elastic properties of the ascending aorta (compliance, distensibility, stiffness index, elastic modulus of Peterson, PWV, M-mode strain, tissue strain).
Measured: Baseline.
Plasmatic melatonin levels.
Obtained with ELISA laboratory test.
Measured: Baseline.
Total circulating antioxidant capacity in plasma.
Obtained with ELISA laboratory test.
Measured: Baseline.
Blood pressure.
Ambulatory blood pressure obtained from the mean of three different misurations.
Measured: 1 year.
Heart rate.
Ambulatory recorder of the heart rate of the patient.
Measured: 1 year.
Endothelial parameters.
PAT signals were obtained using the EndoPAT-2000 device, which has been vali-dated and used previously to assess peripheral arterial tone in other populations. Endothelial function is measured via a reactive hyper-emia (RH) protocol: it consists of a 5 minutes baseline mea-surement, after which a blood pressure cuff on the test arm isinflated to 60 mm Hg above baseline systolic BP or at least200 mm Hg for 5 minutes. After 5 minutes, the cuff is deflated, and the PAT tracing isrecorded for a further 5 minutes. The cal-culated ratio is called RH-PAT index or RH index (RHI).
Measured: 1 year.
Arterial stiffness parameters.
The radial artery waveform was recorded using the SphygmoCor system. The tip of the tonometer was pressed gently against the radial artery at the site of maximum pulsation at the wrist. This micromanometer precisely records pressure within the artery. he augmentation pressure is defined as the height of the late systolic peak above the inflection point. Augmentation index is expressed as a percentage of PPAO. Augmentation index is a measure of the stiffness of the arterial walls, namely pulsatile load. Because there is a linear relationship between it and heart rate (HR), augmentation index was standardized to a HR of 75 bpm (AIx@75).
Measured: 1 year.
Echocardiographic parameters.
Bi-dimensional transthoracic echocardiographic examinations were performed using Vivid 9 and Vivid Q (GE Medical HealthCare, USA) with a probe of 3.5 MHz, to assess LV dimensions and systolic function, according to the guidelines. The main points were: the dimensions of atria and ventricles, stenosis and valve insufficiencies, systolic and diastolic function VS and VD, Dimensions and elastic properties of the ascending aorta (compliance, distensibility, stiffness index, elastic modulus of Peterson, PWV, M-mode strain, tissue strain).
Measured: 1 year.
Plasmatic melatonin levels.
Obtained with ELISA laboratory test.
Measured: 1 year.
Total circulating antioxidant capacity in plasma.
Obtained with ELISA laboratory test.
Measured: 1 year.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2022
- Study start2 Feb 2018
- Primary completion14 Jul 2022
- Study completionAug 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for Essential HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Rita Rezzani, Università degli Studi di Brescia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05257291
- Sponsor's protocol ID
- NP 2717
- Acronym
- MIPAE
- Status last verified
- Jan 2023
- First submitted
- 6 Oct 2021
- Last updated
- 1 Feb 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Scientific publication in an international peer-reviewed journal
Publications
Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado ME, Lima-Cabello E, Lopez LC, Rosales-Corral S, Tan DX, Reiter RJ. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014 Aug;71(16):2997-3025. doi: 10.1007/s00018-014-1579-2. Epub 2014 Feb 20.
PubMed 24554058Agabiti-Rosei C, De Ciuceis C, Rossini C, Porteri E, Rodella LF, Withers SB, Heagerty AM, Favero G, Agabiti-Rosei E, Rizzoni D, Rezzani R. Anticontractile activity of perivascular fat in obese mice and the effect of long-term treatment with melatonin. J Hypertens. 2014 Jun;32(6):1264-74. doi: 10.1097/HJH.0000000000000178.
PubMed 24751595Andersen LP, Gogenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-0368-5.
PubMed 26692007Arangino 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.
PubMed 10235107Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):168-75. doi: 10.1161/01.atv.0000051384.43104.fc.
PubMed 12588755Cagnacci 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.
PubMed 9062865Cagnacci A, Arangino S, Angiolucci M, Melis GB, Facchinetti F, Malmusi S, Volpe A. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clin Endocrinol (Oxf). 2001 Feb;54(2):261-6. doi: 10.1046/j.1365-2265.2001.01204.x.
PubMed 11207642Chen CH, Fetics B, Nevo E, Rochitte CE, Chiou KR, Ding PA, Kawaguchi M, Kass DA. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol. 2001 Dec;38(7):2028-34. doi: 10.1016/s0735-1097(01)01651-5.
PubMed 11738311Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res. 2000 May;28(4):193-202. doi: 10.1034/j.1600-079x.2000.280401.x.
PubMed 10831154Favero G, Rodella LF, Reiter RJ, Rezzani R. Melatonin and its atheroprotective effects: a review. Mol Cell Endocrinol. 2014 Feb 15;382(2):926-37. doi: 10.1016/j.mce.2013.11.016. Epub 2013 Nov 28.
PubMed 24291636Goor DA, Sheffy J, Schnall RP, Arditti A, Caspi A, Bragdon EE, Sheps DS. Peripheral arterial tonometry: a diagnostic method for detection of myocardial ischemia induced during mental stress tests: a pilot study. Clin Cardiol. 2004 Mar;27(3):137-41. doi: 10.1002/clc.4960270307.
PubMed 15049379Hardeland 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.
PubMed 21193011Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001 Sep;38(3 Pt 2):581-7. doi: 10.1161/hy09t1.096249.
PubMed 11566935Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res. 1987 Sep;21(9):678-87. doi: 10.1093/cvr/21.9.678.
PubMed 3328650Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015 Mar 13;116(6):1007-21. doi: 10.1161/CIRCRESAHA.116.303596.
PubMed 25767286
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Melatonin and Essential Arterial Hypertension
- ClinicalTrials.gov ID
- NCT05257291
- Acronym / sponsor ID
- MIPAE / NP 2717
- Conditions
- Essential Hypertension
- Keywords
- Essential Hypertension, Melatonin, Antioxidant, Antihypertensive, Cardiovascular System
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di BresciaUniversity, hospital or other
- Study start
- 2 Feb 2018 (actual)
- Primary completion
- 14 Jul 2022 (actual)
- Study completion
- Aug 2024 (estimated)
- First posted
- 25 Feb 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Study MIPAE - Melatonin and essential arterial hypertension.
Study with dietary supplement, prospective and monocentric (randomized control trial). 1 mg/day of melatonin has been administered for one year to a group of patients suffering from essential hypertension (from at least one year) and who are already on antihypertensive therapy. This group has been compared with as many hypertensive patients on antihypertensive therapy to whom melatonin has not been administered. Each of the participants have been evaluated at the beginning of the study and after one year considering:
- systolic and diastolic blood pressure;
- echocardiographic values (Vivid Q, GE Healthcare);
- applanation tonometry (SphygmoCor, AtCor Medical);
- peripheral arterial tonometry (EndoPAT-2000, Itamar);
- melatonin levels and total circulating antioxidant capacity after peripheral venous blood sampling.
The aim of the study was to evaluate the antioxidant and vasoprotective effects of melatonin, evaluating both plasma changes and directly studying the possibility of a real remodeling and improvement of cardiac structures.
Detailed description
Hypertension is a pathological condition characterized by a constant and not occasional increase in systolic and diastolic blood pressure values. This pathology represents one of the most important public health problems in industrialized countries, as it affects more than 25-30% of the adult population and can cause serious and even fatal complications. It is in fact considered the major risk factor of mortality and pathological effect at cardiovascular, encephalic and renal level.
The classification of hypertension suggested by the ESC/ESH Guidelines defines diastolic blood pressure (PAD) values of 80-84 mmHg and systolic blood pressure (PAS) values of 120-129 mmHg as "normal" in a healthy adult. Blood pressure values between 90-99 mmHg (PAD) and 140-159 mmHg (PAS) define grade 1 hypertension.Between 100-109 mmHg (PAD) and 160-179 mmHg (PAS) define grade 2 hypertension. For values above 110 mmHg (PAD) and 180 mmHg (PAS), determine grade 3 hypertension (after 60 years of age slightly higher values are accepted). Although many antihypertensive drug therapies exist today, patients often show a lack of response to pharmacological treatment due to numerous factors of both genetic and environmental nature that contribute to determine the clinical picture and the poor response to the set therapeutic regime. Recent studies aimed at clarifying the pathophysiology of resistant hypertension are highlighting new pathophysiological mechanisms potentially involved in the genesis of this clinical condition. Since essential hypertension and vascular and cardiac dysfunctions seem to be closely related, the identification of molecules/substances that can at least help to reduce the alterations induced by the pathogenetic process of essential hypertension is a priority. In recent years, melatonin has shown important and interesting antihypertensive therapeutic potential. It has also been demonstrated by some authors of this project, in an animal model of arterial hypertension, that melatonin, thanks to its antioxidant properties, is able to regress structural alterations of both the aorta and small mesenteric resistance arteries in an animal model of arterial hypertension.
It is therefore necessary to investigate, also in humans, the correlation among essential arterial hypertension, levels of circulating melatonin and onset of cardiovascular events.
Furthermore, it is of fundamental importance to remember that, to date, following treatment with melatonin, even at high doses, show only rare and minimal adverse effects, including daytime drowsiness, dizziness and headaches.
The aim of the study was, therefore, to evaluate the antihypertensive, antioxidant and vasoprotective effects of melatonin in adult patients suffering from at least 1 year essential hypertension and in antihypertensive therapy. In a broad sense, the aim will be to contribute to current knowledge in terms of effective treatment and reduced impact of cardiovascular changes related to hypertension.
To do this, a total of 23 adult patients (mean age 54 years old) suffering from essential arterial hypertension and undergoing concurrent antihypertensive therapy were enrolled by the Cardiology Unit of the Spedali Civili di Brescia (Italy). The participants were randomly divided into a group to which melatonin was administered orally (1 mg/day for one year - "melatonin" group). This group of patients was then compared with a group of hypertensive patients on antihypertensive therapy who did not take melatonin ("control" group). In particular, patients with essential hypertension for at least 1 year were selected and enrolled.
With regard to the number of samples, reference has been made to recent studies conducted at our Institute. The sample size (alpha 0.05, power 80%) needed to catch a 2 tissue strain modification of the ascending aorta is 6.2% of the longitudinal 2D strain of the left ventricle 21, 0.1 of VAC is 10, 0.25 of RH-PAT index 17, 0.5 m/s in cfPWV is 12. In addition, patients after enrolment have been randomized 1:1 in the two groups; randomization by random number generation minimizes selection prejudices/errors in subdivising into groups and allows to better evaluate the possible effects of melatonin treatment on hypertensive patients (on antihypertensive therapy) compared to hypertensive patients (on antihypertensive) therapy who have not taken melatonin, while the other variables and the analysis to be performed have been kept constant.
All patients with essential hypertension (in antihypertensive therapy) enrolled in the study received the informed consent document and the information document together with clear and understandable explanations/information about the study. In addition, the investigating physician is available to enlisted patients for all necessary information and also for any subsequent questions/curiosities, as well as for the reporting of any adverse effects that he or she undertakes to notify promptly.
In addition, the supply of melatonin tablets required for 30 ± 3 days of treatment (35 tablets of 1 mg melatonin) have been delivered by the investigating physician only to patients enrolled in the "melatonin" group at the time of enrolment and for the following 11 months of the trial.
At the time of enrolment, the investigator has also provided all enlisted subjects a diary on which to record the time of melatonin intake (only for the "melatonin" group), the number of hours of sleep at night, the systolic and diastolic blood pressure values measured weekly by the patient himself and the onset of any adverse effects. At the end of the study, the investigator collected the diaries of all patients enrolled in the study in order to analyze and archive the data together with the evaluation of the previous medical history.
At the beginning of the study and after one year, the patients were evaluated during a medical examination considering:
- blood pressure (weekly evaluation carried out by the patient and monthly check-up carried out by the investigating doctor during meetings with the patient);
- heart rate;
- endothelial parameters: RHI, LnRHI, peripheral AIx@75;
- arterial stiffness parameters: central blood pressure, AIx@75 radial, cfPWV, SEVR;
- echocardiographic parameters: dimensions of atria and ventricles, stenosis and valve insufficiencies, systolic function VS (FE) and VD (TAPSE, FAC, S' TSI), diastolic function VS and VD (E/A, DT, E/E', E'/A'), dimensions and elastic properties of the ascending aorta (compliance, distensibility, stiffness index, elastic modulus of Peterson, PWV, M-mode strain, tissue strain), elongated aortic (Ea) and ventricular telediastolic sinintra (Ees), ventricular-arterial coupling (VAC=Ea/Ees), 2D longitudinal/radial/circonferential strain of VS, longitudinal strain of VD and left atrium (LAA and LAS), torsion of VS;
- laboratory parameters: blood melatonin levels and total circulating antioxidant capacity.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control group | No intervention | –Group of essential hypertensive patients who have received no additional therapies in addition to their established treatment plan (each patient was on specific antihypertensive therapy that has not been changed). |
| Melatonin treated group | Active comparator | Drug: MelatoninGroup of essential hypertensive patients who have received additional therapies consisting in 1 mg/day of melatonin for 1 year, in addition to their established treatment plan. |
Who may qualify
- Ages
- 40 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- Caucasian race;
- Age 40-50;
- Signed written informed consent
- Normal weight;
- Blood pressure: PAD >90 mmHg and PAS >140 mmHg;
Key exclusion criteria (8 listed)
- Blood pressure: PAD <90 mmHg and PAS <140 mmHg
- Heart disease of any kind;
- Autoimmune or rheumatological or vascular diseases other than essential hypertension;
- Anti-hypertensive therapies with nitrates, statins or β-blockers;
- Pregnancy/nursing;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MelatoninSupplementation with 1 mg/day of melatonin for 1 year | Drug | Melatonin treated group |
Primary outcome
Blood pressure.
Time frame: Baseline.
Value of ambulatory blood pressure obtained from the mean of three different misurations.
Heart rate.
Time frame: Baseline.
Ambulatory recorder of the heart rate of the patient.
Endothelial parameters.
Time frame: Baseline.
PAT signals were obtained using the EndoPAT-2000 device, which has been vali-dated and used previously to assess peripheral arterial tone in other populations. Endothelial function is measured via a reactive hyper-emia (RH) protocol: it consists of a 5 minutes baseline mea-surement, after which a blood pressure cuff on the test arm isinflated to 60 mm Hg above baseline systolic BP or at least200 mm Hg for 5 minutes. After 5 minutes, the cuff is deflated, and the PAT tracing isrecorded for a further 5 minutes. The cal-culated ratio is called RH-PAT index or RH index (RHI).
Arterial stiffness parameters.
Time frame: Baseline.
The radial artery waveform was recorded using the SphygmoCor system. The tip of the tonometer was pressed gently against the radial artery at the site of maximum pulsation at the wrist. This micromanometer precisely records pressure within the artery. he augmentation pressure is defined as the height of the late systolic peak above the inflection point. Augmentation index is expressed as a percentage of PPAO. Augmentation index is a measure of the stiffness of the arterial walls, namely pulsatile load. Because there is a linear relationship between it and heart rate (HR), augmentation index was standardized to a HR of 75 bpm (AIx@75).
Echocardiographic parameters.
Time frame: Baseline.
Bi-dimensional transthoracic echocardiographic examinations were performed using Vivid 9 and Vivid Q (GE Medical HealthCare, USA) with a probe of 3.5 MHz, to assess LV dimensions and systolic function, according to the guidelines. The main points were: the dimensions of atria and ventricles, stenosis and valve insufficiencies, systolic and diastolic function VS and VD, Dimensions and elastic properties of the ascending aorta (compliance, distensibility, stiffness index, elastic modulus of Peterson, PWV, M-mode strain, tissue strain).
Plasmatic melatonin levels.
Time frame: Baseline.
Obtained with ELISA laboratory test.
Total circulating antioxidant capacity in plasma.
Time frame: Baseline.
Obtained with ELISA laboratory test.
Blood pressure.
Time frame: 1 year.
Ambulatory blood pressure obtained from the mean of three different misurations.
Heart rate.
Time frame: 1 year.
Ambulatory recorder of the heart rate of the patient.
Endothelial parameters.
Time frame: 1 year.
PAT signals were obtained using the EndoPAT-2000 device, which has been vali-dated and used previously to assess peripheral arterial tone in other populations. Endothelial function is measured via a reactive hyper-emia (RH) protocol: it consists of a 5 minutes baseline mea-surement, after which a blood pressure cuff on the test arm isinflated to 60 mm Hg above baseline systolic BP or at least200 mm Hg for 5 minutes. After 5 minutes, the cuff is deflated, and the PAT tracing isrecorded for a further 5 minutes. The cal-culated ratio is called RH-PAT index or RH index (RHI).
Arterial stiffness parameters.
Time frame: 1 year.
The radial artery waveform was recorded using the SphygmoCor system. The tip of the tonometer was pressed gently against the radial artery at the site of maximum pulsation at the wrist. This micromanometer precisely records pressure within the artery. he augmentation pressure is defined as the height of the late systolic peak above the inflection point. Augmentation index is expressed as a percentage of PPAO. Augmentation index is a measure of the stiffness of the arterial walls, namely pulsatile load. Because there is a linear relationship between it and heart rate (HR), augmentation index was standardized to a HR of 75 bpm (AIx@75).
Echocardiographic parameters.
Time frame: 1 year.
Bi-dimensional transthoracic echocardiographic examinations were performed using Vivid 9 and Vivid Q (GE Medical HealthCare, USA) with a probe of 3.5 MHz, to assess LV dimensions and systolic function, according to the guidelines. The main points were: the dimensions of atria and ventricles, stenosis and valve insufficiencies, systolic and diastolic function VS and VD, Dimensions and elastic properties of the ascending aorta (compliance, distensibility, stiffness index, elastic modulus of Peterson, PWV, M-mode strain, tissue strain).
Plasmatic melatonin levels.
Time frame: 1 year.
Obtained with ELISA laboratory test.
Total circulating antioxidant capacity in plasma.
Time frame: 1 year.
Obtained with ELISA laboratory test.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2023.
- Background: PubMed 24554058Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado ME, Lima-Cabello E, Lopez LC, Rosales-Corral S, Tan DX, Reiter RJ. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014 Aug;71(16):2997-3025. doi: 10.1007/s00018-014-1579-2. Epub 2014 Feb 20.
- Background: PubMed 24751595Agabiti-Rosei C, De Ciuceis C, Rossini C, Porteri E, Rodella LF, Withers SB, Heagerty AM, Favero G, Agabiti-Rosei E, Rizzoni D, Rezzani R. Anticontractile activity of perivascular fat in obese mice and the effect of long-term treatment with melatonin. J Hypertens. 2014 Jun;32(6):1264-74. doi: 10.1097/HJH.0000000000000178.
- Background: PubMed 26692007Andersen LP, Gogenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-0368-5.
- Background: PubMed 10235107Arangino 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.
- Background: PubMed 12588755Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):168-75. doi: 10.1161/01.atv.0000051384.43104.fc.
- Background: PubMed 9062865Cagnacci 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.
- Background: PubMed 11207642Cagnacci A, Arangino S, Angiolucci M, Melis GB, Facchinetti F, Malmusi S, Volpe A. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clin Endocrinol (Oxf). 2001 Feb;54(2):261-6. doi: 10.1046/j.1365-2265.2001.01204.x.
- Background: PubMed 11738311Chen CH, Fetics B, Nevo E, Rochitte CE, Chiou KR, Ding PA, Kawaguchi M, Kass DA. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol. 2001 Dec;38(7):2028-34. doi: 10.1016/s0735-1097(01)01651-5.
- Background: PubMed 10831154Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res. 2000 May;28(4):193-202. doi: 10.1034/j.1600-079x.2000.280401.x.
- Background: PubMed 24291636Favero G, Rodella LF, Reiter RJ, Rezzani R. Melatonin and its atheroprotective effects: a review. Mol Cell Endocrinol. 2014 Feb 15;382(2):926-37. doi: 10.1016/j.mce.2013.11.016. Epub 2013 Nov 28.
- Background: PubMed 15049379Goor DA, Sheffy J, Schnall RP, Arditti A, Caspi A, Bragdon EE, Sheps DS. Peripheral arterial tonometry: a diagnostic method for detection of myocardial ischemia induced during mental stress tests: a pilot study. Clin Cardiol. 2004 Mar;27(3):137-41. doi: 10.1002/clc.4960270307.
- Background: PubMed 21193011Hardeland 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.
- Individual participant dataSharing planned: Yes. Scientific publication in an international peer-reviewed journal
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Melatonin in people with Essential Hypertension, run by Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 1 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood pressure. (time frame: Baseline.). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05257291, which also lists 25 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2023.