Trial Outcomes & Findings for The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients (NCT NCT01355523)

Last Updated: 2014-05-06

Results Overview

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

Recruitment status

TERMINATED

Study phase

PHASE2/PHASE3

Target enrollment

54 participants

Primary outcome timeframe

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.

Results posted on

2014-05-06

Participant Flow

The recruitment period was from July 2011 till December 2012. The location was The Department of Breast Surgery - Herlev Hospital, Copenhagen - Denmark.

Participant milestones

Participant milestones
Measure	Melatonin 6 mg oral melatonin daily	Placebo 6 mg oral placebo daily
Overall Study STARTED	28	26
Overall Study COMPLETED	27	16
Overall Study NOT COMPLETED	1	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Melatonin 6 mg oral melatonin daily	Placebo 6 mg oral placebo daily
Overall Study Withdrawal by Subject	1	4
Overall Study Lost to Follow-up	0	2
Overall Study Protocol Violation	0	2
Overall Study Adverse Event	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=26 Participants 6 mg oral placebo daily	Total n=54 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	20 Participants n=5 Participants	16 Participants n=7 Participants	36 Participants n=5 Participants
Age, Categorical >=65 years	8 Participants n=5 Participants	10 Participants n=7 Participants	18 Participants n=5 Participants
Age, Continuous	54.50 years STANDARD_DEVIATION 10.69 • n=5 Participants	58.23 years STANDARD_DEVIATION 11.36 • n=7 Participants	56.30 years STANDARD_DEVIATION 11.07 • n=5 Participants
Sex: Female, Male Female	28 Participants n=5 Participants	26 Participants n=7 Participants	54 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Denmark	28 participants n=5 Participants	26 participants n=7 Participants	54 participants n=5 Participants
Type of surgery Mastectomy + axillary dissection +/- SN	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Type of surgery Mastectomy + SN	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Type of surgery Lumpectomy + axillary dissection +/- SN	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Type of surgery Lumpectomy + SN	16 Participants n=5 Participants	12 Participants n=7 Participants	28 Participants n=5 Participants
Type of surgery Lumpectomy converted to mastectomy + SN	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Type of surgery Bilateral lumpectomy + axillary dissection + SN	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Surgery duration	92 Minutes n=5 Participants	125 Minutes n=7 Participants	110 Minutes n=5 Participants
Anaesthesia duration	155 Minutes n=5 Participants	190 Minutes n=7 Participants	171 Minutes n=5 Participants
Oncological treatment None	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Oncological treatment Radiation	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Oncological treatment Chemotherapy	16 Participants n=5 Participants	7 Participants n=7 Participants	23 Participants n=5 Participants
Oncological treatment Chemotherapy + radiation	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Oncological treatment Radiation x 1 only	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Oncological treatment Drop-out before chemo/radiation	1 Participants n=5 Participants	9 Participants n=7 Participants	10 Participants n=5 Participants
Anti-hormone therapy NO	20 Participants n=5 Participants	10 Participants n=7 Participants	30 Participants n=5 Participants
Anti-hormone therapy YES	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Anti-hormone therapy Drop-out before anti-hormone therapy	1 Participants n=5 Participants	9 Participants n=7 Participants	10 Participants n=5 Participants
MDI - Major Depression Inventory	6.5 Scores on a scale n=5 Participants	7 Scores on a scale n=7 Participants	7 Scores on a scale n=5 Participants
Menopausal status Premenopausal	14 Participants n=5 Participants	10 Participants n=7 Participants	24 Participants n=5 Participants
Menopausal status Postmenopausal	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=20 Participants 6 mg oral placebo daily
Major Depression Inventory (MDI)- Depression at One Point in the Study NO	24 participants	11 participants
Major Depression Inventory (MDI)- Depression at One Point in the Study YES	3 participants	9 participants

PRIMARY outcome

Timeframe: Per protocol - depression at one point in the study period (not baseline)

Population: Includes only patients who have taken the study medication as planned

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.

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Per Protocol - Depression at One Point in the Study Period YES	3 participants	5 participants
Per Protocol - Depression at One Point in the Study Period NO	24 participants	11 participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=26 Participants 6 mg oral placebo daily
Intention to Treat (Underestimate) - Depression at One Point in the Study Period YES	3 participants	5 participants
Intention to Treat (Underestimate) - Depression at One Point in the Study Period NO	25 participants	21 participants

PRIMARY outcome

Timeframe: Intention to treat (overestimate) - depression at one point in the study period (not baseline)

Population: All missing data have been analyzed as "YES" depression.

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.

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=26 Participants 6 mg oral placebo daily
Intention to Treat (Overestimate) - Depression at One Point in the Study Period NO	23 participants	11 participants
Intention to Treat (Overestimate) - Depression at One Point in the Study Period YES	5 participants	15 participants

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=22 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period	85 mm*day Interval 44.0 to 160.0	140 mm*day Interval 46.0 to 341.0

SECONDARY outcome

Timeframe: 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.

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 %

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period	14 mm*2 weeks Interval 4.0 to 31.0	19 mm*2 weeks Interval 8.0 to 100.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=22 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period	35 Units on KSS*day Interval 26.0 to 48.0	39 Units on KSS*day Interval 31.0 to 55.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period	13 Units on KSS*2 weeks Interval 11.0 to 17.0	14 Units on KSS*2 weeks Interval 12.0 to 20.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=22 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period	307 mm*day Interval 93.0 to 399.0	300 mm*day Interval 146.0 to 429.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period	90 mm*2 weeks Interval 58.0 to 147.0	88 mm*2 weeks Interval 41.0 to 133.0

SECONDARY outcome

Timeframe: 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.

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 %

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=22 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period	282 mm*day Interval 211.0 to 436.0	372 mm*day Interval 180.0 to 450.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period	95 mm*2 weeks Inter-Quartile Range 141 • Interval 52.0 to 141.0	89 mm*2 weeks Inter-Quartile Range 44 • Interval 44.0 to 142.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=22 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period	97 mm*day Interval 45.0 to 181.0	130 mm*day Interval 46.0 to 421.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period	13 mm*2 weeks Interval 2.0 to 48.0	22 mm*2 weeks Interval 8.0 to 76.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=28 Participants 6 mg oral melatonin daily	Placebo n=22 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period	279 mm*day Interval 203.0 to 466.0	355 mm*day Interval 194.0 to 441.0

SECONDARY outcome

Timeframe: 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 %

Outcome measures

Outcome measures
Measure	Melatonin n=27 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period	101 mm*2 weeks Interval 51.0 to 148.0	116 mm*2 weeks Interval 51.0 to 133.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Melatonin n=26 Participants 6 mg oral melatonin daily	Placebo n=21 Participants 6 mg oral placebo daily
HPER3 Genotype 4/4 genotype	14 Participants	10 Participants
HPER3 Genotype 4/5 genotype	10 Participants	10 Participants
HPER3 Genotype 5/5 genotype	2 Participants	1 Participants
HPER3 Genotype Missing	2 Participants	5 Participants

SECONDARY outcome

Timeframe: App. 2 weeks postoperatively

Population: Analysis includes only patients who completed all parts of the neuropsychological test battery at baseline and 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

Outcome measures

Outcome measures
Measure	Melatonin n=26 Participants 6 mg oral melatonin daily	Placebo n=20 Participants 6 mg oral placebo daily
Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively.	0 Percentage of patients	0 Percentage of patients

SECONDARY outcome

Timeframe: App. 10 weeks postoperatively

Population: Analysis includes only patients who completed all parts of the neuropsychological test battery at baseline and 10 weeks postoperatively.

Outcome measures

Outcome measures
Measure	Melatonin n=26 Participants 6 mg oral melatonin daily	Placebo n=16 Participants 6 mg oral placebo daily
Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively	0 Percentage of patients	6.25 Percentage of patients

Adverse Events

Melatonin

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

MD Melissa Voigt Hansen

Herlev Hospital, Department of Surgery

Phone: +45 20661119

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Melatonin n=27 participants at risk 6 mg oral melatonin daily	Placebo n=24 participants at risk 6 mg oral placebo daily
Nervous system disorders Headache	11.1% 3/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	16.7% 4/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Ear and labyrinth disorders Dizziness	14.8% 4/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Nervous system disorders Sleepiness	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
General disorders Difficulty falling asleep	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	8.3% 2/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
General disorders More awakenings at night	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
General disorders Tiredness	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Nervous system disorders Paraesthesia (mouth region, arms/legs)	11.1% 3/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Nervous system disorders Memory problems	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Breathing difficulties	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Pneumonia	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Cardiac disorders Atrial fibrillation	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Nausea	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	8.3% 2/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Reflux	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Abdominal pain	0.00% 0/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Skin and subcutaneous tissue disorders Dry mouth	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Obstipation	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Vomitus	0.00% 0/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Diarrhoea	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Renal and urinary disorders Urinary urgency	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Gastrointestinal disorders Diffuse pain in the lower abdomen	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Musculoskeletal and connective tissue disorders Lower back pain	0.00% 0/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Musculoskeletal and connective tissue disorders Joint pain	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Skin and subcutaneous tissue disorders Flushing/sweating	7.4% 2/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	4.2% 1/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.
Musculoskeletal and connective tissue disorders Itch (arms)	3.7% 1/27 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.	0.00% 0/24 • From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively) Only includes patients who have at least taken 1 dose of the study drug.