Cancer, Fatigue
Conditions
Keywords
Melatonin, Palliative care, Advanced cancer, Symptoms, Quality of life, Randomized controlled trial
Brief summary
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.
Interventions
DRUGMelatonin
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.
DRUGPlacebo
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.
Sponsors
I.M Daehnfeldt Foundation
Danish Cancer Society
Aase and Ejnar Danielsens Foundation
Beckett Foundation
The Andersen-Isted Foundation
Bispebjerg Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | One week | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | One week | 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 |
| 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) | One week | 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 |
| Insomnia Measured by the Insomnia Item in the Questionnaire EORTC QLQ-C15-PAL | One week | 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. |
| 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) | One week | 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 |
| General Fatigue Measured by the The Multidimensional Fatigue Inventory (MFI) | One week | 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 |
| 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) | One week | 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 |
Countries
Denmark
Participant flow
Pre-assignment details
72 patients were randomised in the study. 50 patients completed the first part of the stud, only 44 patients were complete compliers (having taking their melatonin and placebo for at least five days each week and having answered the questionnaires at all times). The primary analysis is of the 44 complete compliers.
Participants by arm
| Arm | Count |
|---|---|
| Melatonin, Then Placebo Melatonin then placebo: 20 mg melatonin orally every evening about 1 hour before bedtime for one week. Then 1 week placebo. | 34 |
| Placebo. Then Melatonin Placebo then melatonin: Placebo tablet orally every evening about one hour before bedtime for one week. Then one week melatonin 20 mg orally. | 38 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1 | Death | 1 | 2 |
| Part 1 | Withdrawal by Subject | 10 | 9 |
Baseline characteristics
| Characteristic | Melatonin, Then Placebo | Placebo. Then Melatonin | Total |
|---|---|---|---|
| Age, Continuous | 65 years | 62 years | 63 years |
| Sex: Female, Male Female | 24 Participants | 25 Participants | 49 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 34 | 0 / 38 |
| serious Total, serious adverse events | 0 / 34 | 0 / 38 |
Outcome results
Primary
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.
Time frame: One week
Population: The primary analysis was a per protocol analysis including only complete compliers, defined as those patients who had consumed at least 5 capsules per week for the 2 weeks in part 1 and who had answered the MFI-20 on days 1, 7, 10, and 17.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | 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) | -1.1 units on a scale | Standard Deviation 15.9 |
| Placebo Then Melatonin | 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) | -3.9 units on a scale | Standard Deviation 18.1 |
Secondary
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
Time frame: One week
Population: Complete compliers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | 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) | -0.8 units on a scale | Standard Deviation 25.4 |
| Placebo Then Melatonin | 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) | -3.2 units on a scale | Standard Deviation 21.6 |
Secondary
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
Time frame: One week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | 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) | -0.6 units on a scale | Standard Deviation 23.5 |
| Placebo Then Melatonin | 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) | 3.3 units on a scale | Standard Deviation 18.5 |
Secondary
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
Time frame: One week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | General Fatigue Measured by the The Multidimensional Fatigue Inventory (MFI) | -3.2 units on a scale | Standard Deviation 18.6 |
| Placebo Then Melatonin | General Fatigue Measured by the The Multidimensional Fatigue Inventory (MFI) | -2.1 units on a scale | Standard Deviation 24.8 |
Secondary
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.
Time frame: One week
Population: Complete compliers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | Insomnia Measured by the Insomnia Item in the Questionnaire EORTC QLQ-C15-PAL | -9.9 units on a scale | Standard Deviation 23.4 |
| Placebo Then Melatonin | Insomnia Measured by the Insomnia Item in the Questionnaire EORTC QLQ-C15-PAL | -4.6 units on a scale | Standard Deviation 30.9 |
Secondary
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
Time frame: One week
Population: Complete compliers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | 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) | 0.8 units on a scale | Standard Deviation 19.3 |
| Placebo Then Melatonin | 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) | 1.9 units on a scale | Standard Deviation 22.2 |
Secondary
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
Time frame: One week
Population: Complete compliers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melatonin Then Placebo | 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) | -0.8 units on a scale | Standard Deviation 13.6 |
| Placebo Then Melatonin | 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) | -3.2 units on a scale | Standard Deviation 19.2 |