Breast Cancer, Depression
Conditions
Keywords
Breast cancer surgery, Melatonin, Depression, Anxiety, Sleep disturbances, Cognitive function
Brief summary
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.
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%.
Interventions
6 mg oral melatonin daily 1 hour before bedtime
DRUGPlacebo
6 mg oral placebo daily 1 hour before bedtime
Sponsors
University of Copenhagen
Rigshospitalet, Denmark
Pharma Nord
Melissa Voigt Hansen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
30 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Depression Inventory (MDI)- Depression at One Point in the Study | 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. | 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 | Per protocol - depression at one point in the study period (not baseline) | 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 | Intention to treat (underestimate) - depression at one point in the study period (not baseline) | 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 | Intention to treat (overestimate) - depression at one point in the study period (not baseline) | 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
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period | Daily from inclusion till 8 days postoperatively | 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 | App. 14 days postoperatively till 10 weeks postoperatively | 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 | Daily from inclusion till 8 days postoperatively | 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 | App. 14 days postoperatively till 10 weeks postoperatively | 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 | Daily from inclusion till 8 days postoperatively | 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 | App. 14 days postoperatively till 10 weeks postoperatively | 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 Anxiety - Immediate Postoperative Period | Daily - from inclusion till 8 days postoperatively | 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 Sleep Quality - Long-term Postoperative Period | App. 14 days postoperatively till 10 weeks postoperatively | 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 | From inclusion till 14 days postoperatively | Actigraphy (total minutes asleep, sleep effectiveness, sleep latency, awakenings). A wrist actigraph will be worn from inclusion till 14 days postoperatively. |
| HPER3 Genotype | At inclusion = day-7 | 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. | App. 2 weeks postoperatively | 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 | App. 10 weeks postoperatively | 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 |
| Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period | Daily from inclusion till 8 days postoperatively | 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 Anxiety - Long-term Postoperative Period | App. 14 days postoperatively till 10 weeks postoperatively | 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 | Daily from inclusion till 8 days postoperatively | 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 | App. 14 days postoperatively till 10 weeks postoperatively | 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 % |
Countries
Denmark
Participant flow
Recruitment details
The recruitment period was from July 2011 till December 2012. The location was The Department of Breast Surgery - Herlev Hospital, Copenhagen - Denmark.
Participants by arm
| Arm | Count |
|---|---|
| Melatonin 6 mg oral melatonin daily | 28 |
| Placebo 6 mg oral placebo daily | 26 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Melatonin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 10 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 16 Participants | 36 Participants |
| Age, Continuous | 54.50 years STANDARD_DEVIATION 10.69 | 58.23 years STANDARD_DEVIATION 11.36 | 56.30 years STANDARD_DEVIATION 11.07 |
| Anaesthesia duration | 155 Minutes | 190 Minutes | 171 Minutes |
| Anti-hormone therapy Drop-out before anti-hormone therapy | 1 Participants | 9 Participants | 10 Participants |
| Anti-hormone therapy NO | 20 Participants | 10 Participants | 30 Participants |
| Anti-hormone therapy YES | 7 Participants | 7 Participants | 14 Participants |
| MDI - Major Depression Inventory | 6.5 Scores on a scale | 7 Scores on a scale | 7 Scores on a scale |
| Menopausal status Postmenopausal | 14 Participants | 16 Participants | 30 Participants |
| Menopausal status Premenopausal | 14 Participants | 10 Participants | 24 Participants |
| Oncological treatment Chemotherapy | 16 Participants | 7 Participants | 23 Participants |
| Oncological treatment Chemotherapy + radiation | 0 Participants | 0 Participants | 0 Participants |
| Oncological treatment Drop-out before chemo/radiation | 1 Participants | 9 Participants | 10 Participants |
| Oncological treatment None | 3 Participants | 3 Participants | 6 Participants |
| Oncological treatment Radiation | 5 Participants | 6 Participants | 11 Participants |
| Oncological treatment Radiation x 1 only | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Denmark | 28 participants | 26 participants | 54 participants |
| Sex: Female, Male Female | 28 Participants | 26 Participants | 54 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Surgery duration | 92 Minutes | 125 Minutes | 110 Minutes |
| Type of surgery Bilateral lumpectomy + axillary dissection + SN | 0 Participants | 2 Participants | 2 Participants |
| Type of surgery Lumpectomy + axillary dissection +/- SN | 6 Participants | 6 Participants | 12 Participants |
| Type of surgery Lumpectomy converted to mastectomy + SN | 1 Participants | 0 Participants | 1 Participants |
| Type of surgery Lumpectomy + SN | 16 Participants | 12 Participants | 28 Participants |
| Type of surgery Mastectomy + axillary dissection +/- SN | 1 Participants | 3 Participants | 4 Participants |
| Type of surgery Mastectomy + SN | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 27 | 9 / 24 |
| serious Total, serious adverse events | 0 / 27 | 0 / 24 |
Outcome results
Primary
Intention to Treat (Overestimate) - Depression at One Point in the Study Period
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.
Time frame: Intention to treat (overestimate) - depression at one point in the study period (not baseline)
Population: All missing data have been analyzed as YES depression.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Melatonin | Intention to Treat (Overestimate) - Depression at One Point in the Study Period | NO | 23 participants |
| Melatonin | Intention to Treat (Overestimate) - Depression at One Point in the Study Period | YES | 5 participants |
| Placebo | Intention to Treat (Overestimate) - Depression at One Point in the Study Period | NO | 11 participants |
| Placebo | Intention to Treat (Overestimate) - Depression at One Point in the Study Period | YES | 15 participants |
p-value: 0.002Chi-squared
Primary
Intention to Treat (Underestimate) - Depression at One Point in the Study Period
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.
Time frame: Intention to treat (underestimate) - depression at one point in the study period (not baseline)
Population: All missing MDI data have been analyzed as NO depression.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Melatonin | Intention to Treat (Underestimate) - Depression at One Point in the Study Period | NO | 25 participants |
| Melatonin | Intention to Treat (Underestimate) - Depression at One Point in the Study Period | YES | 3 participants |
| Placebo | Intention to Treat (Underestimate) - Depression at One Point in the Study Period | NO | 21 participants |
| Placebo | Intention to Treat (Underestimate) - Depression at One Point in the Study Period | YES | 5 participants |
p-value: 0.46Fisher Exact
Primary
Major Depression Inventory (MDI)- Depression at One Point in the Study
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
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.
Population: Includes all patients who have completed at least one other MDI than baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Melatonin | Major Depression Inventory (MDI)- Depression at One Point in the Study | NO | 24 participants |
| Melatonin | Major Depression Inventory (MDI)- Depression at One Point in the Study | YES | 3 participants |
| Placebo | Major Depression Inventory (MDI)- Depression at One Point in the Study | NO | 11 participants |
| Placebo | Major Depression Inventory (MDI)- Depression at One Point in the Study | YES | 9 participants |
p-value: 0.008Chi-squared
95% CI: [1.703, 11.024]
95% CI: [0.076, 0.797]
Primary
Per Protocol - Depression at One Point in the Study Period
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.
Time frame: Per protocol - depression at one point in the study period (not baseline)
Population: Includes only patients who have taken the study medication as planned
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Melatonin | Per Protocol - Depression at One Point in the Study Period | NO | 24 participants |
| Melatonin | Per Protocol - Depression at One Point in the Study Period | YES | 3 participants |
| Placebo | Per Protocol - Depression at One Point in the Study Period | NO | 11 participants |
| Placebo | Per Protocol - Depression at One Point in the Study Period | YES | 5 participants |
p-value: 0.125Fisher Exact
Secondary
Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period
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 %
Time frame: Daily from inclusion till 8 days postoperatively
Population: Patients were only included in the analysis if they had completed daily VAS on anxiety for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period | 282 mm*day |
| Placebo | Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period | 372 mm*day |
p-value: 0.93Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period
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 %
Time frame: Daily from inclusion till 8 days postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period | 35 Units on KSS*day |
| Placebo | Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period | 39 Units on KSS*day |
p-value: 0.446Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period
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 %
Time frame: App. 14 days postoperatively till 10 weeks postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period | 13 Units on KSS*2 weeks |
| Placebo | Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period | 14 Units on KSS*2 weeks |
p-value: 0.122Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period
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 %
Time frame: Daily - from inclusion till 8 days postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period | 85 mm*day |
| Placebo | Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period | 140 mm*day |
p-value: 0.264Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period
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 %
Time frame: App. 14 days postoperatively till 10 weeks postoperatively
Population: Patients were only included in the analysis if they had completed VAS on anxiety in the long-term postoperative period. Single missing data were filled out using last observation carried forward.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period | 14 mm*2 weeks |
| Placebo | Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period | 19 mm*2 weeks |
p-value: 0.351Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period
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 %
Time frame: Daily from inclusion till 8 days postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period | 307 mm*day |
| Placebo | Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period | 300 mm*day |
p-value: 0.907Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period
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 %
Time frame: App. 14 days postoperatively till 10 weeks postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period | 90 mm*2 weeks |
| Placebo | Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period | 88 mm*2 weeks |
p-value: 0.555Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period
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 %
Time frame: App. 14 days postoperatively till 10 weeks postoperatively
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period | 95 mm*2 weeks | Inter-Quartile Range 141 |
| Placebo | Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period | 89 mm*2 weeks | Inter-Quartile Range 44 |
p-value: 0.386Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period
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 %
Time frame: Daily from inclusion till 8 days postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period | 97 mm*day |
| Placebo | Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period | 130 mm*day |
p-value: 0.241Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period
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 %
Time frame: App. 14 days postoperatively till 10 weeks postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period | 13 mm*2 weeks |
| Placebo | Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period | 22 mm*2 weeks |
p-value: 0.339Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period
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 %
Time frame: Daily from inclusion till 8 days postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period | 279 mm*day |
| Placebo | Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period | 355 mm*day |
p-value: 0.578Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period
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 %
Time frame: App. 14 days postoperatively till 10 weeks postoperatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melatonin | Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period | 101 mm*2 weeks |
| Placebo | Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period | 116 mm*2 weeks |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
HPER3 Genotype
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
Time frame: At inclusion = day-7
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Melatonin | HPER3 Genotype | 4/4 genotype | 14 Participants |
| Melatonin | HPER3 Genotype | 5/5 genotype | 2 Participants |
| Melatonin | HPER3 Genotype | 4/5 genotype | 10 Participants |
| Melatonin | HPER3 Genotype | Missing | 2 Participants |
| Placebo | HPER3 Genotype | 4/5 genotype | 10 Participants |
| Placebo | HPER3 Genotype | 4/4 genotype | 10 Participants |
| Placebo | HPER3 Genotype | Missing | 5 Participants |
| Placebo | HPER3 Genotype | 5/5 genotype | 1 Participants |
Secondary
Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively
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
Time frame: App. 10 weeks postoperatively
Population: Analysis includes only patients who completed all parts of the neuropsychological test battery at baseline and 10 weeks postoperatively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Melatonin | Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively | 0 Percentage of patients |
| Placebo | Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively | 6.25 Percentage of patients |
Secondary
Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively.
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
Time frame: App. 2 weeks postoperatively
Population: Analysis includes only patients who completed all parts of the neuropsychological test battery at baseline and 2 weeks postoperatively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Melatonin | Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively. | 0 Percentage of patients |
| Placebo | Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively. | 0 Percentage of patients |
Secondary
Sleep Architecture
Actigraphy (total minutes asleep, sleep effectiveness, sleep latency, awakenings). A wrist actigraph will be worn from inclusion till 14 days postoperatively.
Time frame: From inclusion till 14 days postoperatively