Clinical trial NCT02451293: The Effect of MElatonin on Depression, Anxiety, CIrcadian and Sleep Disturbances in Patients After Acute Myocardial Syndrome
Official title: The Effect of MElatonin on Depression, Anxiety, CIrcadian and Sleep Disturbances in Patients After Acute Myocardial Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Depression
Acute Coronary Syndrome
Keywords: Depression
Acute Coronary Syndrome
Anxiety
Sleep
Circadian
Lead sponsor: Zealand University Hospital
Sponsor class: OTHER
Collaborators: name: Psychiatric Research Unit, Region Zealand, Denmark
name: University of Copenhagen
name: Pharma Nord
First posted: 2015-05-21
Enrollment: 252
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the study is to investigate whether prophylactic treatment with melatonin has an effect on depressive symptoms. Secondarily melatonin's effect on anxiety, sleep and circadian disturbances will be investigated.

The MEDACIS trial is a randomised, placebo-controlled, double-blinded multicenter trial investigating the effect of 25 mg exogenous melatonin (intervention group) against placebo (control group) and the study is designed as a parallel group superiority trial.

Detailed description: AIM Depression after Acute coronary syndrome (ACS - myocardial infarction and unstable angina) is highly prevalent and associated with a 2.5 fold increased in all-cause morbidity and mortality. Sleep disturbances is an integrated part of the pathology of depression and have severe consequences for quality of life.

Melatonin has shown potential to reduce depressive symptoms and anxiety. Likewise melatonin has shown sleep improving effects in several populations and also in patients with depression. Melatonin can potentially reduce the incidence of depression and sleep disturbances in patients after myocardial infarction.

The project sets to answer the following hypotheses:

1. Melatonin will due to its antidepressant effect prevent or reduce the incidence of depressive symptoms in patients after an ACS.
2. Melatonin will due its anxiolytic effect prevent or reduce the incidence of anxiety in patients after an ACS.
3. Melatonin will due to its hypnotic and circadian effects prevent development of sleep and circadian disturbances in patients after an ACS.

BACKGROUND In Denmark about 8600 each year suffered an acute myocardial infarction. An acute myocardial infarction is a life-changing event that affects people's lives long after the blood clot. 20% develop a moderate to severe depression requiring pharmacological treatment and up to 50% experience depressive symptoms after the initial treatment. Depression after a acute coronary syndrome is associated with 2.5-fold increased mortality, and 1.5-fold increased risk of a recurrence of thrombosis. Screening of patients for depression has therefore been recommended by both the Danish cardiology Association and the American Heart Association.

Depression in itself requires treatment because depression after myocardial infarction is associated with reduced quality of life, reduced compliance with medication, reduced participation in cardiac rehabilitation, and less likelihood of occupational activity.

Medical treatment of depression would traditionally be a selective serotonin reuptake inhibitor (SSRI) as first-line treatment. SSRI are associated with side-effects such as sleep disorders, sexual disorders and heart rhythm disturbances.

As an alternative to SSRIs, the investigators focus on the endogenous hormone melatonin which is virtually side-effect free. Previous experiments have shown that 1000 mg of melatonin daily for one month was only associated with mild drowsiness increased. Melatonin regulates the body's circadian rhythm and plays an important role as a hypnotic and in stabilizing the sleep during the night. Sleep disorders are an integral part of the pathogenesis of depression and is important for the development of depression.

Method The investigators will perform a double-blind, placebo-controlled, randomized trial in which patients allocated to either melatonin or placebo in a prophylactic setup. Participants will be followed for 12 weeks, where they have three clinical visits and depression measurements every two weeks.

Depression in the study is measured by Major Depression Inventory (MDI), a self-rating form with 12 questions. The questionnaire is well studied and validated in a Danish population. The questions covers the 10 ICD-10 symptoms of depression, and is recommended for use in general practice. MDI is a flexible tool that can be used as a diagnostic tool and at the same time as measuring instrument for severity of depressive disorder. MDI will be administered during clinic visits and used in the outpatient phase, so the patients are followed continuously every two weeks throughout the study. Should there be a treatment demanding depression (moderate/severe) the participant will be referred to a dedicated psychiatrist who will perform a Hamilton evaluation and make treatment recommendations.

Participants are also assessed for depression and anxiety by using the Hospital anxiety and depression scale (HADS). A large Danish study of patients after myocardial infarction was shown have a prevalence of depression in 20%, and HADS will also be used to compare included with non-participating patients (external validity).

Melatonin has been shown ameliorative effect on sleep and circadian rhythm. Sleep and circadian rhythm disorders are an integral part of the development and maintenance of depression. These will be monitored intensively with actigraphy (objective sleep measurements), Pittsburgh sleep quality index (PSQI), sleep diaries and visual analog scales from inclusion meeting to first clinical control. Afterwards subjective sleep measurements will be performed every two weeks.

Sample size is calculated on the basis of a conservative assumption that, 31 % of patients following ACS will develop depressive symptoms, which the investigators assume can be reduced to 15.5 % by Melatonin treatment. Power calculation is based on two-sided test, and with a power of 0.80 and the significance level 5 % (alfa= 0.05), the required sample size in each group is 116. There are no interim efficacy analyses planned. The study will proceed until 120 patients have been enrolled in each arm.

MEFACS subtrial (single center)

The objective of the MEFACS study is to investigate whether prophylactic treatment with melatonin has an effect on endothelial dysfunction. Secondarily, our objective is to investigate the effect of melatonin on inflammation markers.

The MEFACS trial is a sub-trial of the MEDACIS trial, and The MEFACS trial will be carried out as a single center trial on a subpopulation of the patients enrolled in the MEDACIS trial.

The MEFACS trial will include 2 x 15 patients.

Eligibility criteria: Inclusion Criteria:

1. Patients should be admitted to a coronary care unit for acute coronary syndrome (ACS), and should be enrolled within 4 weeks after the primary ACS.
2. Participants should be 18 years or older.
3. No sign of depression on Major Depression Inventory (MDI) at the point of enrolment.
4. Participants must sign an informed consent form
5. Females not in menopause (defined as no menstruation during the last 12 months) should have a negative pregnancy test.

Exclusion Criteria:

1. Known allergic reaction to melatonin.
2. Ongoing or previous pharmacological treated depression or bipolar disorder.
3. No dementia as determined by mini mental state examination score (MMSE) \< 24
4. At the point of inclusion no participation in another pharmacological intervention trial is allowed.
5. No diagnose of Rotor or Dubin-Johnson syndrome, epilepsy, sleep apnoea syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or multiple sclerosis is allowed.
6. Severe liver disease defined as transaminases above X 3 normal levels, and severe kidney disease defined as eGRF under 40 ml/min.
7. Ongoing hypnotic treatment.
8. Known sleep disorder (e.g. insomnia, restless legs etc.)
9. Work involving nightshifts.
10. Daily alcohol consumption above 5 units of alcohol (1 unit = 12 g alcohol)
11. Predictable poor compliance ( e.g. not speaking fluent Danish)
12. Pregnant or breastfeeding.
13. Severe, life-threatening medical condition, that implies that the patient cannot participate in a the study course. (e.g. cancer, stroke, )
14. Indication for coronary artery bypass graft (CABG).

    For the MEFACS subtrial - (single center)
15. Conditions that preclude/make impossible the measurement of reliable RHI (e.g. patient with only one arm, known side-difference in brachial arterial blood pressure and other factors).

Primary outcomes:
measure: Major Depression Inventory (MDI)
timeFrame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 14.
measure: Major Depression Inventory (MDI)
timeFrame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 28
measure: Major Depression Inventory (MDI)
timeFrame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 42
measure: Major Depression Inventory (MDI)
timeFrame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 56
measure: Major Depression Inventory (MDI)
timeFrame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 70
measure: Major Depression Inventory (MDI)
timeFrame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 84
Secondary outcomes:
measure: Actigraphy - Sleep outcomes - Time in bed
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - total sleep time
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - sleep effetiveness
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - wake after sleep onset
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - sleep latency
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - number of awakenings
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - time awake
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - time asleep
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - Sleep outcomes - number of naps
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - circadian outcomes - Mesor
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - circadian outcomes - Acrophase
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - circadian outcomes - Amplitude
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - circadian outcomes - F-statistics
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - circadian outcomes - Inter-daily stability
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Actigraphy - circadian outcomes - Inter-daily variability
timeFrame: From inclusion to first clinical visit (app. 14 days)
measure: Anxiety measured by Hospital anxiety and depression scale (HADS-A)
timeFrame: Anxiety at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
measure: Depression measured by Hospital anxiety and depression scale (HADS-D)
timeFrame: Depression at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
measure: Subjective sleep quality measured by Pittsburgh sleep quality index (PSQI)
timeFrame: Subjectie sleep at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
measure: Sleep diary
timeFrame: From inclusion to first clinical visit each day (day 0 - 14). After the first clinical visit (day 14) the sleep diary will be filled out on day 28, day 42, day 56, day 70 and day 84 of the study.
measure: UKU side effect rating scale
timeFrame: The UKU will be filled out a total of 6 measurements at app. day 14, day 28, day 42, day 56, day 70 and day 84 of the study
measure: VAS Data on Anxiety
timeFrame: From inclusion to first clinical visit each day (day 0 - 14). After the first clinical visit (day 14) the VAS will be filled out on day 28, day 42, day 56, day 70 and day 84 of the study.
measure: VAS Data on Fatigue
timeFrame: From inclusion to first clinical visit each day (day 0 - 14). After the first clinical visit (day 14) the VAS will be filled out on day 28, day 42, day 56, day 70 and day 84 of the study.
measure: VAS Data on Pain
timeFrame: From inclusion to first clinical visit each day (day 0 - 14). After the first clinical visit (day 14) the VAS will be filled out on day 28, day 42, day 56, day 70 and day 84 of the study.
measure: VAS Data on Sleep Quality
timeFrame: From inclusion to first clinical visit each day (day 0 - 14). After the first clinical visit (day 14) the VAS will be filled out on day 28, day 42, day 56, day 70 and day 84 of the study.
measure: VAS Data on General Well-being
timeFrame: From inclusion to first clinical visit each day (day 0 - 14). After the first clinical visit (day 14) the VAS will be filled out on day 28, day 42, day 56, day 70 and day 84 of the study.
measure: Endothelial function (EndoPAT)
timeFrame: From inclusion (day 0), first clinical visit (day 14), and final visit (day 84).
Other outcomes:
measure: Blood sample
timeFrame: Blood sample will be drawn at day 0 and at day 84.
measure: Oxidative-stress markers
timeFrame: Blood sample will be drawn at day 0 and at day 84
Locations:
city: Køge
country: Denmark
facility: Roskilde and Køge Hospital, Department of Surgery.
state: Danmark
city: Holbæk
country: Denmark
facility: Department of internal Medicin, Holbaek Sygehus
state: Zealand
city: Roskilde
country: Denmark
facility: Department of Cardiology, Roskilde Sygehus
state: Zealand
city: Køge
country: Denmark
facility: Department of internal medicin, M5
state: Zeland
city: Hvidovre
country: Denmark
facility: Department of Cardiology, Hvidovre Hospital,
city: Slagelse
country: Denmark
facility: Department of Cardiology, Slagelse Sygehus
Study officials:
affiliation: Department of surgery. Koege and Roskilde Hospital
name: Michael Tvilling Madsen, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of surgery. Koege and Roskilde Hospital
name: Ismail Gögenur, M.D. Professor
role: STUDY_CHAIR
affiliation: Psychiatric Research Unit, Region Zealand
name: Erik Simonsen, M.D. Professor
role: STUDY_CHAIR
References:
citation: Madsen MT, Juel K, Simonsen E, Gogenur I, Zwisler ADO. External validity of randomized clinical trial studying preventing depressive symptoms following acute coronary syndrome. Brain Behav. 2021 Aug;11(8):e02132. doi: 10.1002/brb3.2132. Epub 2021 Jun 17.
citation: Madsen BK, Zetner D, Moller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database Syst Rev. 2020 Dec 8;12(12):CD009861. doi: 10.1002/14651858.CD009861.pub3.
citation: Madsen MT, Isbrand A, Andersen UO, Andersen LJ, Taskiran M, Simonsen E, Gogenur I. The effect of MElatonin on Depressive symptoms, Anxiety, CIrcadian and Sleep disturbances in patients after acute coronary syndrome (MEDACIS): study protocol for a randomized controlled trial. Trials. 2017 Feb 23;18(1):81. doi: 10.1186/s13063-017-1806-x.