Clinical trial NCT05257291: Study MIPAE - Melatonin and Essential Arterial Hypertension
Official title: Melatonin and Essential Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Essential Hypertension
Keywords: Essential Hypertension
Melatonin
Antioxidant
Antihypertensive
Cardiovascular System
Lead sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Sponsor class: OTHER
First posted: 2022-02-25
Enrollment: 23
Sex: ALL
Minimum age (years): 40
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 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.

Eligibility criteria: Inclusion Criteria:

* 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
* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Blood pressure.
timeFrame: Baseline.
measure: Heart rate.
timeFrame: Baseline.
measure: Endothelial parameters.
timeFrame: Baseline.
measure: Arterial stiffness parameters.
timeFrame: Baseline.
measure: Echocardiographic parameters.
timeFrame: Baseline.
measure: Plasmatic melatonin levels.
timeFrame: Baseline.
measure: Total circulating antioxidant capacity in plasma.
timeFrame: Baseline.
measure: Blood pressure.
timeFrame: 1 year.
measure: Heart rate.
timeFrame: 1 year.
measure: Endothelial parameters.
timeFrame: 1 year.
measure: Arterial stiffness parameters.
timeFrame: 1 year.
measure: Echocardiographic parameters.
timeFrame: 1 year.
measure: Plasmatic melatonin levels.
timeFrame: 1 year.
measure: Total circulating antioxidant capacity in plasma.
timeFrame: 1 year.
Secondary outcomes:
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Anatomy and Physiopathology Division, Department of Experimental and Clinical Sciences, University of Brescia (Italy), Viale Europa 11, 25123 Brescia, Italy
Study officials:
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