The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients (MELODY)

This study has been terminated.
(Inclusion rate not as expected. Not financially possible to involve other centres.)
Sponsor:
Collaborators:
University of Copenhagen
Rigshospitalet, Denmark
Pharma Nord
Information provided by (Responsible Party):
Melissa Voigt Hansen, Herlev Hospital
ClinicalTrials.gov Identifier:
NCT01355523
First received: May 13, 2011
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to investigate the effect of 6 mg melatonin daily for 1 week preoperatively to 12 weeks postoperatively on depressive symptoms, anxiety, cognitive function and sleep disturbances in breast cancer patients. Furthermore the investigators will examine whether a specific clock-gene (HPER3) is correlated with an increased risk of depression, sleep disturbances or cognitive dysfunction.


Condition Intervention Phase
Breast Cancer
Depression
Drug: Melatonin (N-acetyl-5-methoxytryptamine)
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients

Resource links provided by NLM:


Further study details as provided by Herlev Hospital:

Primary Outcome Measures:
  • Major Depression Inventory (MDI)- Depression at One Point in the Study [ Time Frame: Depression at one point in the study (not including baseline) out of 4 measurements at app. day 21, day 35, day 63 and day 91 of the study. ] [ Designated as safety issue: No ]

    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 we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we 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


  • Per Protocol - Depression at One Point in the Study Period [ Time Frame: Per protocol - depression at one point in the study period (not baseline) ] [ Designated as safety issue: No ]

    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 we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.

    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 This analysis includes only patients who have taken study medication as planned.


  • Intention to Treat (Underestimate) - Depression at One Point in the Study Period [ Time Frame: Intention to treat (underestimate) - depression at one point in the study period (not baseline) ] [ Designated as safety issue: No ]

    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 we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.

    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 For this analysis all missing MDI data have been analyzed as "NO" depression.


  • Intention to Treat (Overestimate) - Depression at One Point in the Study Period [ Time Frame: Intention to treat (overestimate) - depression at one point in the study period (not baseline) ] [ Designated as safety issue: No ]

    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 we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.

    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 For this analysis all missing MDI data have been analyzed as "YES" for depression.



Secondary Outcome Measures:
  • Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period [ Time Frame: Daily - from inclusion till 8 days postoperatively ] [ Designated as safety issue: No ]

    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.

    Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %


  • Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period [ Time Frame: App. 14 days postoperatively till 10 weeks postoperatively ] [ Designated as safety issue: No ]

    Anxiety measured by VAS (visual analog scale). Completed every 14th day. A subjective feeling of anxiety was registered on a VAS going from "no anxiety", equivalent to 0mm to "worst possible anxiety", equivalent to 100mm.

    Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %


  • Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period [ Time Frame: Daily from inclusion till 8 days postoperatively ] [ Designated as safety issue: No ]

    Sleepiness measured by Karolinska Sleepiness Scale. KSS is a 9-point scale from 1 (very awake) to 9 (very sleepy) where a score of 7 or more reflects pathological sleepiness.

    Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %


  • Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period [ Time Frame: App. 14 days postoperatively till 10 weeks postoperatively ] [ Designated as safety issue: No ]

    Sleepiness measured by Karolinska Sleepiness Scale. KSS is a 9-point scale from 1 (very awake) to 9 (very sleepy) where a score of 7 or more reflects pathological sleepiness.

    Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %


  • Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period [ Time Frame: Daily from inclusion till 8 days postoperatively ] [ Designated as safety issue: No ]

    Fatigue on a Visual Analog Scale - filled out daily. A subjective feeling of fatigue was registered on a VAS going from "no fatigue", equivalent to 0mm to "worst possible fatigue", equivalent to 100mm.

    Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %


  • Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period [ Time Frame: App. 14 days postoperatively till 10 weeks postoperatively ] [ Designated as safety issue: No ]

    Fatigue on a Visual Analog Scale - filled out every 14th day. A subjective feeling of fatigue was registered on a VAS going from "no fatigue", equivalent to 0mm to "worst possible fatigue", equivalent to 100mm.

    Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %


  • Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period [ Time Frame: Daily from inclusion till 8 days postoperatively ] [ Designated as safety issue: No ]

    General well-being on a Visual Analog Scale - filled out daily. A subjective feeling of general well-being was registered on a VAS going from "very high well-being", equivalent to 0mm to "very low well-being", equivalent to 100mm.

    Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %


  • Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period [ Time Frame: App. 14 days postoperatively till 10 weeks postoperatively ] [ Designated as safety issue: No ]

    General well-being on a Visual Analog Scale - filled out every 14th day. A subjective feeling of general well-being was registered on a VAS going from "very high well-being", equivalent to 0mm to "very low well-being", equivalent to 100mm.

    Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %


  • Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period [ Time Frame: Daily from inclusion till 8 days postoperatively ] [ Designated as safety issue: No ]

    Pain on a Visual Analog Scale - filled out daily. A subjective feeling of pain was registered on a VAS going from "no pain", equivalent to 0mm to "worst possible pain", equivalent to 100mm.

    Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %


  • Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period [ Time Frame: App. 14 days postoperatively till 10 weeks postoperatively ] [ Designated as safety issue: No ]

    Pain on a Visual Analog Scale - filled out every 14th day. A subjective feeling of pain was registered on a VAS going from "no pain", equivalent to 0mm to "worst possible pain", equivalent to 100mm.

    Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %


  • Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period [ Time Frame: Daily from inclusion till 8 days postoperatively ] [ Designated as safety issue: No ]

    Subjective sleep score on Visual Analog Scale. Subjective sleep quality was registered on a VAS going from "best possible sleep", equivalent to 0mm to "worst possible sleep", equivalent to 100mm.

    Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %


  • Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period [ Time Frame: App. 14 days postoperatively till 10 weeks postoperatively ] [ Designated as safety issue: No ]

    Subjective sleep on a Visual Analog Scale. Subjective sleep quality was registered on a VAS going from "best possible sleep", equivalent to 0mm to "worst possible sleep", equivalent to 100mm.

    Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).

    Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %


  • Sleep Architecture [ Time Frame: From inclusion till 14 days postoperatively ] [ Designated as safety issue: No ]
    Actigraphy (total minutes asleep, sleep effectiveness, sleep latency, awakenings). A wrist actigraph will be worn from inclusion till 14 days postoperatively.

  • HPER3 Genotype [ Time Frame: At inclusion = day-7 ] [ Designated as safety issue: No ]
    A blood sample will be taken at inclusion and analysed for HPER3 genotype (4/4, 4/5, 5/5) and this will be investigated for a correlation with sleep, cognitive function and depressive symptoms 7 patients did not give blood samples

  • Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively. [ Time Frame: App. 2 weeks postoperatively ] [ Designated as safety issue: No ]

    Calculations for POCD were based on normative data from 133 females aged 40-60 years. We evaluated changes from the preoperative baseline to the 2 postoperative test sessions. In controls we calculated mean and standard deviations (SD) of these differences. The mean change in this group may be taken as estimated learning effects. For the individual patients, we compared baseline scores with the 2- and 12-week postoperative test results, subtracted the average learning effect from the changes and divided the result by the SD of the control group to obtain a Z score for the 7 individual test outcomes. A large positive Z score indicated deterioration in cognitive function from baseline in patients. We defined a composite Z score as the sum of the 7 Z scores and normalized this using the SD for that sum in the controls. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in at least 2 of the 7 subtests.

    Units of measure = % of patients with YES to POCD


  • Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively [ Time Frame: App. 10 weeks postoperatively ] [ Designated as safety issue: No ]

    Calculations for POCD were based on normative data from 133 females aged 40-60 years. We evaluated changes from the preoperative baseline to the 2 postoperative test sessions. In controls we calculated mean and standard deviations (SD) of these differences. The mean change in this group may be taken as estimated learning effects. For the individual patients, we compared baseline scores with the 2- and 12-week postoperative test results, subtracted the average learning effect from the changes and divided the result by the SD of the control group to obtain a Z score for the 7 individual test outcomes. A large positive Z score indicated deterioration in cognitive function from baseline in patients. We defined a composite Z score as the sum of the 7 Z scores and normalized this using the SD for that sum in the controls. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in at least 2 of the 7 subtests.

    Units of measure = % of patients with YES to POCD



Enrollment: 54
Study Start Date: July 2011
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Melatonin
6 mg oral melatonin daily
Drug: Melatonin (N-acetyl-5-methoxytryptamine)
6 mg oral melatonin daily 1 hour before bedtime
Other Names:
  • Melatonin
  • N-acetyl-5-methoxytryptamin
Placebo Comparator: Placebo
6 mg oral placebo daily
Drug: Placebo
6 mg oral placebo daily 1 hour before bedtime

Detailed Description:

About 1.4 million women are diagnosed with breast cancer every year. Breast cancer is the most common malignancy among women worldwide constituting about 1/5 of all cancer types. Breast cancer diagnosis and treatment, and the months following primary therapy are stressful times for most women. Aside from the actual "cancer threat" many women experience various degrees of depression, anxiety, sleep disturbances and memory/concentration problems (cognitive dysfunction). Naturally these factors influence the quality of life but also contribute to morbidity and mortality.

Melatonin is a regulatory circadian hormone having, among others, hypnotic, sedative, anxiolytic and possibly anti-depressive effects. It has very low toxicity and very few adverse effects.

The purpose of this project is to test melatonin (6 mg daily for 1 week preoperatively to 12 weeks postoperatively) on breast cancer patients and hopefully hereby be able to prevent depression, anxiety, sleep disturbances and cognitive dysfunction. On an overall perspective this will hopefully contribute to improving the quality of life for these patients and extend their lifetime. Furthermore the investigators will be examining whether a specific gene called a clock-gene (HPER3) is correlated with an increased risk of depression, sleep disturbances or cognitive dysfunction. If this is the case it could become possible to identify women with an increased risk and provide prophylactic treatment for those with a risk of developing a depression, sleep disturbances or cognitive disturbances.

Sample size calculations were based on our primary outcome parameter. Using a conservative estimate for the incidence of depression, the investigators expect to find a reduction from 30% to 15% with melatonin treatment. Sample size is sufficient to include our secondary and tertiary outcome parameters as well. The sample size calculations were calculated with a power of 80%, a type I error of 5% and a type II error of 20%.

  Eligibility

Ages Eligible for Study:   30 Years to 75 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women, age 30-75, with breast cancer who are admitted for a lumpectomy or mastectomy at Herlev Hospital
  • ASA score I-III
  • No sign of depression measured my Major Depression Inventory (MDI)
  • Not pregnant

Exclusion Criteria:

  • Neoadjuvant chemotherapy
  • Treatment with SSRI, Warfarin or other anticoagulants (except 75 mg ASA daily), MAO inhibitors or calcium blockers
  • Rotor or Dubin-Johnson syndrome
  • Epilepsy
  • Known allergic reaction to melatonin
  • Known and treated sleep apnea
  • Diabetes Mellitus - insulin treated
  • Ongoing or previous medically treated depression or bipolar disorder
  • Known autoimmune diseases - systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and sclerose
  • Incompensated liver cirrhosis
  • Severe kidney disease
  • Previous or current cancer
  • Known medically treated sleep-disorder (insomnia, restless legs etc)
  • Shift-work and night-work
  • Daily alcohol intake of more than 5 units
  • Pre-operative treatment with psychopharmacological drugs, opioids or anxiolytics (including all sleeping pills)
  • Predicted bad compliance
  • Pregnant or breast-feeding
  • Pre-operative Mini Mental State Evaluation (MMSE) score less than 24
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01355523

Locations
Denmark
Herlev Hospital
Copenhagen, Denmark, 2730
Sponsors and Collaborators
Melissa Voigt Hansen
University of Copenhagen
Rigshospitalet, Denmark
Pharma Nord
Investigators
Principal Investigator: Melissa V Hansen, MD Herlev Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Melissa Voigt Hansen, M.D., ph-D student, Herlev Hospital
ClinicalTrials.gov Identifier: NCT01355523     History of Changes
Other Study ID Numbers: MVH-03, 2010-022460-12, 2007-58-0015/HEH.750.89-12, H-4-2011-007
Study First Received: May 13, 2011
Results First Received: August 14, 2013
Last Updated: April 4, 2014
Health Authority: Denmark: Danish Dataprotection Agency
Denmark: The Danish National Committee on Biomedical Research Ethics
Denmark: Danish Medicines Agency

Keywords provided by Herlev Hospital:
Breast cancer surgery
Melatonin
Depression
Anxiety
Sleep disturbances
Cognitive function

Additional relevant MeSH terms:
Breast Neoplasms
Depression
Depressive Disorder
Dyssomnias
Parasomnias
Sleep Disorders
Behavioral Symptoms
Breast Diseases
Mental Disorders
Mood Disorders
Neoplasms
Neoplasms by Site
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Skin Diseases
Melatonin
Antioxidants
Central Nervous System Agents
Central Nervous System Depressants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014