Melatonin for Fatigue and Other Symptoms in Patients With Advanced Cancer

BACKGROUND:

Patients with advanced cancer often suffer from fatigue and other symptoms and problems such as insomnia, appetite loss and pain. Problems that may have great consequences for their quality of life. Several studies suggest that a supplement of the hormone melatonin (MLT) may have a beneficial effect on these symptoms/problems. This needs further investigation.

AIM:

To investigate if a supplement of melatonin have an effect on a) fatigue (the primary outcome of the trial), b) the symptoms insomnia, appetite loss, depression and pain, and c) overall quality of life.

METHODS AND PATIENTS:

The trial takes place in the Department of Palliative Medicine, Bispebjerg Hospital, and 50 patients will participate. The participants have to be 18 years or above, have advanced cancer, and suffer from quite a bit or very much fatigue.

The study consists of two parts. In part I it is investigated if melatonin has a better effect than placebo on the outcomes mentioned above. This part is a consecutive, prospective, double blinded, randomized (MLT vs. placebo), cross-over study where the patients serve as their own control. In part II the effect of melatonin over time is investigated. Part II is a consecutive, prospective, open-label study.

The outcomes are assessed with weekly questionnaires (MFI-20 and EORTC QLQ-C15PAL) and a few daily diary questions.

Melatonin has been used in several studies, and the general conclusion is that it is a safe substance with few adverse drug reactions.

PERSPECTIVES:

If melatonin has the potential to alleviate fatigue and other symptoms in patients with advanced cancer and enhance the quality of life of these patients, this will be of benefit to many future patients. Trials such as this are important both nationally and internationally to develop an evidence-based palliative medicine.

Study Overview

• Status: Completed
• Conditions: Cancer; Fatigue
• Intervention / Treatment: Drug: Melatonin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Department of Palliative Medicine, Bispebjerg Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Answered "quite a bit" or "very much" to the question "were you tired?" (from EORTC QLQ-C15-PAL)
• Cancer in a palliative phase
• Written informed consent
• Age 18 years or above

Exclusion Criteria:

• Not capable of understanding or judging information, or fill out a questionnaire
• Untreated anemia (Hb <= 6,0 mmol/L)
• Untreated hypocalcaemia
• Systolic blood pressure < 100
• In treatment with coumadin
• Receiving unstable doses of methylphenidate, corticosteroids or sleeping medicine the past two weeks
• TSH < 0.50 or > 5.50 mcL/mL
• Pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo tablet orally every evening about one hour before bedtime for one week. After having participated in the cross-over part of the trial (one week of placebo followed by one week of melatonin, or the other way around), the participant may receive melatonin for 6 weeks.
Experimental: Melatonin; 20 mg	Drug: Melatonin; 20 mg melatonin orally every evening about 1 hour before bedtime for one week. After having participated in the cross-over part of the trial (one week of melatonin followed by one week of placebo, or the other way around), the participant may receive melatonin for 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue as Measured by the Physical Fatigue Scale in the The Multidimensional Fatigue Inventory (MFI) (Smets EM, Garssen B, Bonke B, et al., J Psychosom Res 39:315-325, 1995)	Primary outcome: Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). The physical fatigue scale conists of four item each ranging from one to five. The four item were summed and the scae was converted to 0 to 100, where 100 indicated maximum fatigue.	One week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insomnia Measured by the Insomnia Item in the Questionnaire EORTC QLQ-C15-PAL	Primary outcome: Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). Insomnia was converted to a 0 til 100 scale according to the scoring manual for EORTC QLQ C15-PAL where 100 indicated maximum insomnia.	One week
Emotional Function as Measured by the Questionnaire EORTC QLQ-C15-PAL (Groenvold M, Petersen MA, Aaronson NK, et al, Eur J Cancer 42:55-64, 2006)	Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). Emotional function was converted to a 0 til 100 scale according to the scoring manual for EORTC QLQ C15-PAL where 100 indicated the best possible emotional function. Note outcome reported for complete compliers	One week
Pain as Measured by the Questionnaire EORTC QLQ-C15-PAL (Groenvold M, Petersen MA, Aaronson NK, et al, Eur J Cancer 42:55-64, 2006)	Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). Pain was converted to a 0 til 100 scale according to the scoring manual for EORTC QLQ C15-PAL where 100 indicated maximum pain. Note outcome reported for complete compliers	One week
Quality of Life as Measured by the Questionnaire EORTC QLQ-C15-PAL (Groenvold M, Petersen MA, Aaronson NK, et al, Eur J Cancer 42:55-64, 2006)	Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). Quality of Life was converted to a 0 til 100 scale according to the scoring manual for EORTC QLQ C15-PAL where 100 indicated best possible quality of life. Note outcome reported for complete compliers	One week
Appetite Loss as Measured by the Questionnaire EORTC QLQ-C15-PAL (Groenvold M, Petersen MA, Aaronson NK, et al, Eur J Cancer 42:55-64, 2006)	Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). Appetite loss was converted to a 0 til 100 scale according to the scoring manual for EORTC QLQ C15-PAL where 100 indicated maximum appetite loss (worst possible). Note outcome reported for complete compliers	One week
General Fatigue Measured by the The Multidimensional Fatigue Inventory (MFI)	Change from baseline to week one in intervention group minus change from baseline to week one in control group. Because it was a cross-over trial this was calculated the following way: Outcomes for arm 1 (melatonin then placebo) were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 (placebo then melatonin) were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1). The general fatigue scale that consits of four items was converted to a 0 til 100 scale where 100 indicated maximum (worst possible) fatigue. Note outcome reported for complete compliers	One week

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: Danish Cancer Society; Aase and Ejnar Danielsens Foundation; Beckett Foundation; I.M Daehnfeldt Foundation; The Andersen-Isted Foundation
• Investigators: Principal Investigator: Lise Pedersen, MD, DMSc., Department of Palliative Medicine, Bispebjerg Hospital

Publications and helpful links

General Publications

• Lund Rasmussen C, Klee Olsen M, Thit Johnsen A, Petersen MA, Lindholm H, Andersen L, Villadsen B, Groenvold M, Pedersen L. Effects of melatonin on physical fatigue and other symptoms in patients with advanced cancer receiving palliative care: A double-blind placebo-controlled crossover trial. Cancer. 2015 Oct 15;121(20):3727-36. doi: 10.1002/cncr.29563. Epub 2015 Jul 15.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: June 19, 2009
• First Submitted That Met QC Criteria: June 19, 2009
• First Posted (Estimate): June 22, 2009

Study Record Updates

• Last Update Posted (Actual): April 20, 2017
• Last Update Submitted That Met QC Criteria: March 10, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Melatonin; Quality of life; Randomized controlled trial; Palliative care; Advanced cancer; Symptoms
• Additional Relevant MeSH Terms: Fatigue; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: Feldt-01