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

• Sponsor: Melissa Voigt Hansen (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01355523
• Collaborator: University of Copenhagen (Other), Rigshospitalet, Denmark (Other), Pharma Nord (Industry)
• Enrollment: 54
• Location: 1
• Arms: 2
• Duration (Months): 18.1
• Patients Per Site Per Month: 3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Depression	Drug: Melatonin (N-acetyl-5-methoxytryptamine); Drug: Placebo	Phase 2/Phase 3

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%.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. 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

2. 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.

3. 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.

4. 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 Outcome Measures

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 %

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 %

3. 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 %

4. 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 %

5. 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 %

6. 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 %

7. 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 %

8. 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 %

9. 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 %

10. 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 %

11. 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 %

12. 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 %

13. 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.

14. 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

15. 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

16. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Melissa Voigt Hansen, M.D., ph-D student, Herlev Hospital
• ClinicalTrials.gov Identifier: NCT01355523
• Other Study ID Numbers: MVH-03; 2010-022460-12; 2007-58-0015/HEH.750.89-12; H-4-2011-007
• First Posted: May 18, 2011
• Last Update Posted: May 6, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Melissa Voigt Hansen, M.D., ph-D student, Herlev Hospital: Breast cancer surgery; Melatonin; Depression; Anxiety; Sleep disturbances; Cognitive function
• Additional relevant MeSH terms: Breast Neoplasms; Dyssomnias; Parasomnias; Depression; Depressive Disorder; Melatonin

Study Results

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.

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Period Title: Overall Study
STARTED	28	26
COMPLETED	27	16
NOT COMPLETED	1	10

Baseline Characteristics

Arm/Group Title	Melatonin	Placebo	Total
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily	Total of all reporting groups
Overall Participants	28	26	54
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 71.4%	16 61.5%	36 66.7%
>=65 years	8 28.6%	10 38.5%	18 33.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.50 (10.69)	58.23 (11.36)	56.30 (11.07)
Sex: Female, Male (Count of Participants)
Female	28 100%	26 100%	54 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Denmark	28 100%	26 100%	54 100%
Type of surgery (Number) [Number]
Mastectomy + axillary dissection +/- SN	1 3.6%	3 11.5%	4 7.4%
Mastectomy + SN	4 14.3%	3 11.5%	7 13%
Lumpectomy + axillary dissection +/- SN	6 21.4%	6 23.1%	12 22.2%
Lumpectomy + SN	16 57.1%	12 46.2%	28 51.9%
Lumpectomy converted to mastectomy + SN	1 3.6%	0 0%	1 1.9%
Bilateral lumpectomy + axillary dissection + SN	0 0%	2 7.7%	2 3.7%
Surgery duration (Minutes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Minutes]	92	125	110
Anaesthesia duration (Minutes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Minutes]	155	190	171
Oncological treatment (Number) [Number]
None	3 10.7%	3 11.5%	6 11.1%
Radiation	5 17.9%	6 23.1%	11 20.4%
Chemotherapy	16 57.1%	7 26.9%	23 42.6%
Chemotherapy + radiation	0 0%	0 0%	0 0%
Radiation x 1 only	3 10.7%	1 3.8%	4 7.4%
Drop-out before chemo/radiation	1 3.6%	9 34.6%	10 18.5%
Anti-hormone therapy (Number) [Number]
NO	20 71.4%	10 38.5%	30 55.6%
YES	7 25%	7 26.9%	14 25.9%
Drop-out before anti-hormone therapy	1 3.6%	9 34.6%	10 18.5%
MDI - Major Depression Inventory (Scores on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Scores on a scale]	6.5	7	7
Menopausal status (Number) [Number]
Premenopausal	14 50%	10 38.5%	24 44.4%
Postmenopausal	14 50%	16 61.5%	30 55.6%

Outcome Measures

1. Primary Outcome

Title	Major Depression Inventory (MDI)- Depression at One Point in the Study
Description	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.

Outcome Measure Data

Analysis Population Description

Includes all patients who have completed at least one other MDI than baseline

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	20
NO	24 85.7%	11 42.3%
YES	3 10.7%	9 34.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Number need to treat
	Estimated Value	2.95
	Confidence Interval	(2-Sided) 95%; 1.703 to 11.024
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; 0.076 to 0.797
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Per Protocol - Depression at One Point in the Study Period
Description	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)

Outcome Measure Data

Analysis Population Description

Includes only patients who have taken the study medication as planned

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
NO	24 85.7%	11 42.3%
YES	3 10.7%	5 19.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	Fisher Exact
	Comments

3. Primary Outcome

Title	Intention to Treat (Underestimate) - Depression at One Point in the Study Period
Description	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)

Outcome Measure Data

Analysis Population Description

All missing MDI data have been analyzed as "NO" depression.

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	26
NO	25 89.3%	21 80.8%
YES	3 10.7%	5 19.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments
	Method	Fisher Exact
	Comments

4. Primary Outcome

Title	Intention to Treat (Overestimate) - Depression at One Point in the Study Period
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	26
NO	23 82.1%	11 42.3%
YES	5 17.9%	15 57.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	22
Median (Inter-Quartile Range) [mm*day]	85	140

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
Median (Inter-Quartile Range) [mm*2 weeks]	14	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.351
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	22
Median (Inter-Quartile Range) [Units on KSS*day]	35	39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.446
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
Median (Inter-Quartile Range) [Units on KSS*2 weeks]	13	14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	22
Median (Inter-Quartile Range) [mm*day]	307	300

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.907
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
Median (Inter-Quartile Range) [mm*2 weeks]	90	88

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.555
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	22
Median (Inter-Quartile Range) [mm*day]	282	372

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.930
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
Median (Inter-Quartile Range) [mm*2 weeks]	95 (141)	89 (44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.386
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

13. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	22
Median (Inter-Quartile Range) [mm*day]	97	130

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.241
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
Median (Inter-Quartile Range) [mm*2 weeks]	13	22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.339
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	28	22
Median (Inter-Quartile Range) [mm*day]	279	355

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.578
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Secondary Outcome

Title	Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	27	16
Median (Inter-Quartile Range) [mm*2 weeks]	101	116

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Melatonin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

17. Secondary Outcome

Title	Sleep Architecture
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	HPER3 Genotype
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	26	21
4/4 genotype	14 50%	10 38.5%
4/5 genotype	10 35.7%	10 38.5%
5/5 genotype	2 7.1%	1 3.8%
Missing	2 7.1%	5 19.2%

19. Secondary Outcome

Title	Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively.
Description	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

Outcome Measure Data

Analysis Population Description

Analysis includes only patients who completed all parts of the neuropsychological test battery at baseline and 2 weeks postoperatively.

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	26	20
Number [Percentage of patients]	0	0

20. Secondary Outcome

Title	Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	6 mg oral melatonin daily	6 mg oral placebo daily
Measure Participants	26	16
Number [Percentage of patients]	0	6.25

Adverse Events

Time Frame	From inclusion (app. 1 week preoperatively) till the final visit (app. 10 weeks postoperatively)
Adverse Event Reporting Description	Only includes patients who have at least taken 1 dose of the study drug.
Arm/Group Title	Melatonin		Placebo
Arm/Group Description	6 mg oral melatonin daily		6 mg oral placebo daily
All Cause Mortality
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/27 (55.6%)		9/24 (37.5%)
Cardiac disorders
Atrial fibrillation	1/27 (3.7%)		0/24 (0%)
Ear and labyrinth disorders
Dizziness	4/27 (14.8%)		1/24 (4.2%)
Gastrointestinal disorders
Nausea	1/27 (3.7%)		2/24 (8.3%)
Reflux	1/27 (3.7%)		0/24 (0%)
Abdominal pain	0/27 (0%)		1/24 (4.2%)
Obstipation	1/27 (3.7%)		0/24 (0%)
Vomitus	0/27 (0%)		1/24 (4.2%)
Diarrhoea	1/27 (3.7%)		0/24 (0%)
Diffuse pain in the lower abdomen	1/27 (3.7%)		0/24 (0%)
General disorders
Difficulty falling asleep	1/27 (3.7%)		2/24 (8.3%)
More awakenings at night	1/27 (3.7%)		0/24 (0%)
Tiredness	1/27 (3.7%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Lower back pain	0/27 (0%)		1/24 (4.2%)
Joint pain	1/27 (3.7%)		0/24 (0%)
Itch (arms)	1/27 (3.7%)		0/24 (0%)
Nervous system disorders
Headache	3/27 (11.1%)		4/24 (16.7%)
Sleepiness	1/27 (3.7%)		1/24 (4.2%)
Paraesthesia (mouth region, arms/legs)	3/27 (11.1%)		0/24 (0%)
Memory problems	1/27 (3.7%)		0/24 (0%)
Renal and urinary disorders
Urinary urgency	1/27 (3.7%)		0/24 (0%)
Respiratory, thoracic and mediastinal disorders
Breathing difficulties	1/27 (3.7%)		0/24 (0%)
Cough	0/27 (0%)		1/24 (4.2%)
Pneumonia	1/27 (3.7%)		0/24 (0%)
Skin and subcutaneous tissue disorders
Dry mouth	1/27 (3.7%)		0/24 (0%)
Flushing/sweating	2/27 (7.4%)		1/24 (4.2%)

Limitations/Caveats

Premature termination (54/260). Only included about 8% (54/703) of the patients assessed for eligibility.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.