DepressionPhase 2/3MEDACISNCT02451293
The Effect of MElatonin on Depression, Anxiety, CIrcadian and Sleep Disturbances in Patients After Acute Myocardial Syndrome
A Phase 2/3 study testing Melatonin (N-acetyl-5-methoxytryptamine) in people with Depression and Acute Coronary Syndrome, run by Zealand University Hospital at 6 sites in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Depression, Acute Coronary Syndrome
- What is being tested?
- Melatonin (N-acetyl-5-methoxytryptamine)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 252 participants
- Where
- 6 sitesDenmark
- Study dates
- 18 Jan 2016to 20 Jul 2018
- Phase
- Phase 2/3
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- Participants should be 18 years or older.
- No sign of depression on Major Depression Inventory (MDI) at the point of enrolment.
- Participants must sign an informed consent form
- Females not in menopause (defined as no menstruation during the last 12 months) should have a negative pregnancy test.
Who cannot join
- Known allergic reaction to melatonin.
- Ongoing or previous pharmacological treated depression or bipolar disorder.
- No dementia as determined by mini mental state examination score (MMSE) < 24
- At the point of inclusion no participation in another pharmacological intervention trial is allowed.
- No diagnose of Rotor or Dubin-Johnson syndrome, epilepsy, sleep apnoea syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or multiple sclerosis is allowed.
- Severe liver disease defined as transaminases above X 3 normal levels, and severe kidney disease defined as eGRF under 40 ml/min.
Show all 16Show fewer
- Ongoing hypnotic treatment.
- Known sleep disorder (e.g. insomnia, restless legs etc.)
- Work involving nightshifts.
- Daily alcohol consumption above 5 units of alcohol (1 unit = 12 g alcohol)
- Predictable poor compliance ( e.g. not speaking fluent Danish)
- Pregnant or breastfeeding.
- Severe, life-threatening medical condition, that implies that the patient cannot participate in a the study course. (e.g. cancer, stroke, )
- Indication for coronary artery bypass graft (CABG).
- For the MEFACS subtrial - (single center)
- 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).
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Denmark6 sites
Department of internal Medicin, Holbaek Sygehus
Holbæk, Region Sjælland, 4300
Department of Cardiology, Hvidovre Hospital,
Hvidovre, 2650
Roskilde and Køge Hospital, Department of Surgery.
Køge, Danmark, 4600
Department of internal medicin, M5
Køge, Region Sjælland, 4600
Department of Cardiology, Roskilde Sygehus
Roskilde, Region Sjælland, 4000
Department of Cardiology, Slagelse Sygehus
Slagelse, 4200
About this study
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.
Read the 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:
- Melatonin will due to its antidepressant effect prevent or reduce the incidence of depressive symptoms in patients after an ACS.
- Melatonin will due its anxiolytic effect prevent or reduce the incidence of anxiety in patients after an ACS.
- 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.
- Conditions
- Depression, Acute Coronary Syndrome
- Being tested
- Melatonin (N-acetyl-5-methoxytryptamine), Placebo
- Keywords
- Depression, Acute Coronary Syndrome, Anxiety, Sleep, Circadian
- Medical subject headings
- Depression, Acute Coronary Syndrome, Anxiety Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Melatonin (N-acetyl-5-methoxytryptamine)Drug
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Melatonin (N-acetyl-5-methoxytryptamine) | Active comparator | Melatonin (N-acetyl-5-methoxytryptamine) 25 mg oral administration 1 hour before bedtime for 12 weeks. Receives: Drug: Melatonin (N-acetyl-5-methoxytryptamine) |
| Placebo | Placebo comparator | Comparable placebo pill, oral administration 1 hour before bedtime for 12 weeks. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Major Depression Inventory (MDI)
MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument. For inclusion the investigators used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements the investigators used the rating scale. Diagnostic scale using the ICD-10 algorithm: Mild depression: 2 core symptoms and 2 other symptoms Moderate depression: 2 core symptoms and 4 other symptoms Severe depression: 3 core symptoms and 5 other symptoms Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50
Measured: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 14.
Major Depression Inventory (MDI)
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Measured: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 28
Major Depression Inventory (MDI)
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Measured: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 42
Major Depression Inventory (MDI)
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Measured: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 56
Major Depression Inventory (MDI)
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Measured: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 70
Major Depression Inventory (MDI)
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Measured: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 84
Secondary outcomes (26)
Actigraphy - Sleep outcomes - Time in bed
Outcomes measured - Nightime: time in bed, (min)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - total sleep time
Outcomes measured - Nightime: total sleep time (min)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - sleep effetiveness
Outcomes measured - Nightime: sleep effectiveness (%)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - wake after sleep onset
Outcomes measured - Nightime: wake after sleep onset (min)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - sleep latency
Outcomes measured - Nightime: sleep latency (min)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - number of awakenings
Outcomes measured - Nightime: number of awakenings (duration of 5 min).
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - time awake
Outcomes measured - Daytime: Time awake (min)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - time asleep
Outcomes measured - Daytime: time asleep (min)
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - number of naps
Outcomes measured - Daytime: number of naps
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Mesor
Outcomes measured: Mesor - Adjusted mean of activity counts over 24 hours.
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Acrophase
Outcomes measured: Acrophase - Time of peak amplitude.
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Amplitude
Outcomes measured: Amplitude - Peak activity value above mesor.
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - F-statistics
Outcomes measured: F-statistics - Goodness of fit of general cosine model in summarizing the actual data.
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Inter-daily stability
Outcomes measured: Inter-daily Stability - The regularity of the rhythm from one day to next.
Measured: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Inter-daily variability
Outcomes measured: Intra-daily Variability - Fragmentation of the rhythm.
Measured: From inclusion to first clinical visit (app. 14 days)
Anxiety measured by Hospital anxiety and depression scale (HADS-A)
The HADS consists two subscales; one for anxiety (HADS-A) and one for depression (HADS-D), which can be used separately. Each scale consists of 7 questions which are graded on a 4 point scale (0-1-2-3) and is summed into a total score between 0-21. A score of 7 or lower is negative case, a score of 8 - 10 is a doubtful case, and a score of 11 or above is a positive case. The scale inquires about the presence of symptoms during the last week and, hence, should be administered at a maximum of weekly intervals].
Measured: Anxiety at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
Depression measured by Hospital anxiety and depression scale (HADS-D)
The HADS consists two subscales; one for anxiety (HADS-A) and one for depression (HADS-D), which can be used separately. Each scale consists of 7 questions which are graded on a 4 point scale (0-1-2-3) and is summed into a total score between 0-21. A score of 7 or lower is negative case, a score of 8 - 10 is a doubtful case, and a score of 11 or above is a positive case. The scale inquires about the presence of symptoms during the last week and, hence, should be administered at a maximum of weekly intervals].
Measured: Depression at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
Subjective sleep quality measured by Pittsburgh sleep quality index (PSQI)
The PSQI, which asses sleep quality during the last 4 weeks, and has a clinical established cut of 5 ≥ as poor sleeper and 8≥ as having sleep problems needing treatment
Measured: 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
Sleep diary
A sleep diary is the patient's own account of sleep data, and they are asked to fill in a diary page each morning after awakening.
Measured: 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.
UKU side effect rating scale
The UKU has been develop for use to monitor side effect of psychotropic drugs, and has been validated in several Nordic countries. The UKU consists of a single symptom rating scale (48 items), a global assessment of influence of side effect on patients daily lives (patient and doctor), and the side effect influence on continued medication treatment.
Measured: 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
VAS Data on Anxiety
Anxiety measured by VAS (visual analog scale). A subjective feeling of anxiety was registered on a VAS going from "no anxiety", equivalent to 0mm to "worst possible anxiety", equivalent to 100mm.
Measured: 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.
VAS Data on Fatigue
Fatigue measured by VAS (visual analog scale). A subjective feeling of Fatigue was registered on a VAS going from "no Fatigue", equivalent to 0 mm to "worst possible Fatigue", equivalent to 100mm.
Measured: 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.
VAS Data on Pain
Pain measured by VAS (visual analog scale). A subjective feeling of Pain was registered on a VAS going from "no Pain", equivalent to 0 mm to "worst possible Pain", equivalent to 100mm.
Measured: 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.
VAS Data on Sleep Quality
Sleep Quality measured by VAS (visual analog scale). A subjective feeling of Sleep Quality was registered on a VAS going from "best possible sleep", equivalent to 0 mm to "worst possible sleep", equivalent to 100mm.
Measured: 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.
VAS Data on General Well-being
General Well-being measured by VAS (visual analog scale). A subjective feeling of General Well-being was registered on a VAS going from "very high well-being", equivalent to 0 mm to "very low well-being", equivalent to 100mm.
Measured: 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.
Endothelial function (EndoPAT)
Endothelial function measured by EndoPAT with an outcome measure of reactive hyperemia index (RHI).
Measured: From inclusion (day 0), first clinical visit (day 14), and final visit (day 84).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2015 (estimated)
- Study start18 Jan 2016
- Primary completion18 Aug 2017
- Study completion20 Jul 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by Zealand University HospitalThe sponsor's other registered studies.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 252 participants (actual)
Sponsor and investigators
- Lead sponsor
- Zealand University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Psychiatric Research Unit, Region Zealand, Denmark, University of Copenhagen, Pharma Nord
- Responsible party
- Sponsor
- Investigators
- Michael Tvilling Madsen, M.D., Principal investigator, Department of surgery. Koege and Roskilde HospitalIsmail Gögenur, M.D. Professor, Study chair, Department of surgery. Koege and Roskilde HospitalErik Simonsen, M.D. Professor, Study chair, Psychiatric Research Unit, Region Zealand
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02451293
- Sponsor's protocol ID
- MTM-03
- Other IDs
- 2015-002116-32, 2015
- Acronym
- MEDACIS
- Status last verified
- Jan 2019
- First submitted
- 12 May 2015
- Last updated
- 15 Jan 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 34145796Madsen 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.
PubMed 33319916Madsen 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.
PubMed 28228148
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of MElatonin on Depression, Anxiety, CIrcadian and Sleep Disturbances in Patients After Acute Myocardial Syndrome
- ClinicalTrials.gov ID
- NCT02451293
- Acronym / sponsor ID
- MEDACIS / MTM-03
- Conditions
- Depression, Acute Coronary Syndrome
- Keywords
- Depression, Acute Coronary Syndrome, Anxiety, Sleep, Circadian
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 252 participants (actual)
- Lead sponsor
- Zealand University HospitalUniversity, hospital or other
- Collaborators
- Psychiatric Research Unit, Region Zealand, Denmark, University of Copenhagen, Pharma Nord
- Study start
- 18 Jan 2016 (actual)
- Primary completion
- 18 Aug 2017 (actual)
- Study completion
- 20 Jul 2018 (actual)
- First posted
- 21 May 2015 (estimated)
- 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.
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:
- Melatonin will due to its antidepressant effect prevent or reduce the incidence of depressive symptoms in patients after an ACS.
- Melatonin will due its anxiolytic effect prevent or reduce the incidence of anxiety in patients after an ACS.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Melatonin (N-acetyl-5-methoxytryptamine) | Active comparator | Drug: Melatonin (N-acetyl-5-methoxytryptamine)Melatonin (N-acetyl-5-methoxytryptamine) 25 mg oral administration 1 hour before bedtime for 12 weeks. |
| Placebo | Placebo comparator | Drug: PlaceboComparable placebo pill, oral administration 1 hour before bedtime for 12 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
- Participants should be 18 years or older.
- No sign of depression on Major Depression Inventory (MDI) at the point of enrolment.
- Participants must sign an informed consent form
- Females not in menopause (defined as no menstruation during the last 12 months) should have a negative pregnancy test.
Key exclusion criteria (16 listed)
- Known allergic reaction to melatonin.
- Ongoing or previous pharmacological treated depression or bipolar disorder.
- No dementia as determined by mini mental state examination score (MMSE) < 24
- At the point of inclusion no participation in another pharmacological intervention trial is allowed.
- No diagnose of Rotor or Dubin-Johnson syndrome, epilepsy, sleep apnoea syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or multiple sclerosis is allowed.
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 |
|---|---|---|
| Melatonin (N-acetyl-5-methoxytryptamine) | Drug | Melatonin (N-acetyl-5-methoxytryptamine) |
| Placebo | Drug | Placebo |
Primary outcome
Major Depression Inventory (MDI)
Time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 14.
MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument. For inclusion the investigators used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements the investigators used the rating scale. Diagnostic scale using the ICD-10 algorithm: Mild depression: 2 core symptoms and 2 other symptoms Moderate depression: 2 core symptoms and 4 other symptoms Severe depression: 3 core symptoms and 5 other symptoms Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50
Major Depression Inventory (MDI)
Time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 28
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Major Depression Inventory (MDI)
Time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 42
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Major Depression Inventory (MDI)
Time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 56
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Major Depression Inventory (MDI)
Time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 70
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
Major Depression Inventory (MDI)
Time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 84
MDI is a self-rating depression scale with 12 questions. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50.
26 secondary outcomes
Actigraphy - Sleep outcomes - Time in bed
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - total sleep time
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - sleep effetiveness
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - wake after sleep onset
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - sleep latency
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - number of awakenings
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - time awake
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - time asleep
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - Sleep outcomes - number of naps
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Mesor
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Acrophase
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Amplitude
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - F-statistics
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Inter-daily stability
Time frame: From inclusion to first clinical visit (app. 14 days)
Actigraphy - circadian outcomes - Inter-daily variability
Time frame: From inclusion to first clinical visit (app. 14 days)
Anxiety measured by Hospital anxiety and depression scale (HADS-A)
Time frame: Anxiety at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
Depression measured by Hospital anxiety and depression scale (HADS-D)
Time frame: Depression at one point in the study (not including baseline) out of 2 measurements at app. day 14 and day 84 of the study
Subjective sleep quality measured by Pittsburgh sleep quality index (PSQI)
Time frame: 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
Sleep diary
Time frame: 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.
UKU side effect rating scale
Time frame: 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
VAS Data on Anxiety
Time frame: 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.
VAS Data on Fatigue
Time frame: 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.
VAS Data on Pain
Time frame: 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.
VAS Data on Sleep Quality
Time frame: 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.
VAS Data on General Well-being
Time frame: 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.
Endothelial function (EndoPAT)
Time frame: From inclusion (day 0), first clinical visit (day 14), and final visit (day 84).
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2019.
- Derived from this study: PubMed 34145796Madsen 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.
- Derived from this study: PubMed 33319916Madsen 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.
- Derived from this study: PubMed 28228148Madsen 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.
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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.
Michael Tvilling Madsen, M.D. principal investigator
Department of surgery. Koege and Roskilde Hospital
Ismail Gögenur, M.D. Professor study chair
Department of surgery. Koege and Roskilde Hospital
Erik Simonsen, M.D. Professor study chair
Psychiatric Research Unit, Region Zealand
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Melatonin (N-acetyl-5-methoxytryptamine) in people with Depression and Acute Coronary Syndrome, run by Zealand University Hospital at 6 sites in Denmark.
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 5 inclusion and 16 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: finished, as of the sponsor's last update on 15 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Denmark. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined 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.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Major Depression Inventory (MDI) (time frame: Depression at one point in the study (not including baseline) out of 6 measurements at app. day 14.). The study lists 6 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 NCT02451293, which also lists 3 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 15 Jan 2019.