Melatonin and Zinc Administration on Cardinal Symptoms in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Study Overview
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Brief Summary
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The aim of the study is to investigate the effects of oral melatonin and zinc supplementation on core features in individuals with ME/CFS

Detailed Description
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Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous condition characterized mainly by debilitating and prolonged fatigue, post-exertional malaise (physical, mental and emotional), unrefreshing sleep, cognitive impairment, and orthostatic intolerance with prolonged recovery that is not relieved by rest. Currently, the etiopathogenic mechanisms of ME/CFS are unknown. At present, there is no diagnostic test or effective treatment. MelatoZinc is a food supplement composed of melatonin and zinc, which could contribute to the circadian rhythm homeostasis and regulation of redox imbalance and immune response. The aim is to evaluate the efficacy and safety of oral treatment with MelatoZinc on the symptomatic complex of fatigue in a larger Spanish ME/CFS population. This is a single-center, randomized, double-blind, placebo controlled clinical trial. It will include a total of 106 ME/CFS patients who met 2011 ICC criteria for ME/CFS. All patients will take one capsule daily for 16 weeks. Group A will receive MelatoZinc (1 mg melatonin plus 10 mg zinc), and group B will receive a placebo (excipients: isomaltose and magnesium stearate). Clinical symptoms will be evaluated, and standardized questionnaires will be applied to assess the impact of fatigue, pain, anxiety-depression symptoms, sleep quality, dysautonomia, and quality of life. Heart rate variability (HRV) and orthostatic intolerance (10-min NASA Lean Test) will be performed to evaluate autonomic dysfunction. Sleep efficiency will be estimated through an actigraph sensor

Official Title
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Effect of Melatonin Plus Zinc Supplementation on Fatigue, Pain, Sleep Disturbances, Anxiety and Depression, and Autonomic Dysfunction in ME/CFS: a Randomized, Double-blind, Placebo-controlled Study

Conditions
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Chronic Fatigue Syndrome, Myalgic Encephalomyelitis

Intervention / Treatment
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* Dietary Supplement: melatonin plus zinc
* Other: isomaltose and magnesium stearate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients between 18 and 65 years of age. Patients with ME/CFS who met the diagnostic criteria (2011 ICC criteria) from the Central Sensitization Syndrome Unit (USSC) at the Vall d'Hebron University Hospital. Patients who freely give written consent. Exclusion Criteria: Any active medical condition that explained chronic fatigue (untreated hypothyroidism, sleep apnea, narcolepsy, medication side-effects). Previous diagnosis not unequivocally resolved (chronic hepatitis, malignancy). Past or current psychiatric disorders (major depressive disorder with psychotic or melancholic features, bipolar disorder, schizophrenia, delusional disorder, dementias, anorexia nervosa, bulimia nervosa). Participation in another clinical trial of the same or different nature in the 30 days prior to study inclusion. In the judgment of the investigator, inability to follow the instructions or to complete the treatment satisfactorily. Failure to provide signed informed consent. Current consumption of medications that may interfere with the results and/or whose withdrawal may be a relevant problem. Anticoagulant treatment. Pregnancy or breast-feeding, or had not used oral contraceptives or other hormonal preparations in the previous 6 months. Smoking, alcohol intake or substance abuse. Severe obesity (class 3 BMI ≥ 40 kg/m2). Hypersensitivity to melatonin and/or zinc dietary supplements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melatonin plus Zinc<br>Dietary Supplement: 53 patients treated with melatonin 1 mg plus Zinc 10 mg | Dietary Supplement: melatonin plus zinc<br>* One capsule with melatonin 1mg plus zinc 10 mg o.d. 30 minutes before bedtime, at least 1 hour after dinner during 4 months<br>* Other names: MelatoZinc;|
| Placebo Comparator: Placebo<br>53 patients treated with isomaltose and magnesium stearate (excipients) | Other: isomaltose and magnesium stearate<br>* One capsule with excipients o.d. 30 minutes before bedtime, at least 1 hour after dinner during 4 months<br>* Other names: excipients;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self-reported fatigue as assessed by the 40-item Fatigue Impact Scale (FIS-40) over the baseline in the study participants. | The FIS-40 includes three subscales of the perceived impact of fatigue: cognitive (10 items), physical (10 items) and psychosocial functions (20 items), each item being scored from 0 (no fatigue) to 4 (severe fatigue). The total score is calculated by adding together the responses from the 40 questions (range 0-160). Higher scores indicate more functional limitations due to fatigue. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The health-related quality of life (HRQoL) as assessed by the Short-Form 36-Item Health Survey (SF-36) over the baseline in the study participants. | The SF-36 is a broadly-based self-reported survey on health-related physical and mental functioning status. It assesses functioning on eight subscales, including domains of physical functioning, physical role, bodily pain, general health, social functioning, vitality, emotional role and mental health, and two general subscales covering the physical and mental health domains on a 0-100 score. Lower scores indicate a more negative impact of an individual's health on functioning. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Sleep disturbances as assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire over the baseline in the study participants. | The PSQI is the self-administered 19-item questionnaire. PSQI scores are obtained on each of seven components of sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep perturbations, use of sleeping medication and daytime dysfunction. Each item is scored from 0 to 3 (0 = no sleep problems and 3 = severe sleep problems). The global PSQI score ranges from 0 to 21 points, with scores of >5 indicating poorer sleep quality. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Sleepiness as assessed by the Epworth Sleepiness Scale (ESS) over the baseline in the study participants. | The ESS is a short, self-administered questionnaire that consists of eight questions asking to rate how likely it is to fall asleep in everyday situations (each question can be scored from 0 to 3 points: '0' indicates no sleepiness, and '3' indicates significant sleepiness). It provides a total score which has been shown to relate to the subject's level of daytime sleepiness (total score is ranging from 0 to 24 points). | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Sleep latency as assessed by an actigraph sensor over the baseline in the study participants. | An actigraph (Actiwatch Spectrum Plus® from Philips Respironics, Linton Instrumentation, UK) on the wrist of the non-dominant arm is continuously recording for seven days. The same device was programmed to collect data on motor activity (accelerometer) and light type/intensity (lux) at one minute intervals. These variables were recorded and stored in the device's memory for data analysis. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Sleep onset as assessed by an actigraph sensor over the baseline in the study participants | An actigraph (Actiwatch Spectrum Plus® from Philips Respironics, Linton Instrumentation, UK) on the wrist of the non-dominant arm is continuously recording for seven days. The same device is programmed to collect data on motor activity (accelerometer) and light type/intensity (lux) at one minute intervals. These variables will be recorded and stored in the device's memory for further data analysis. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Sleep efficiency as assessed by an actigraph sensor over the baseline in the study participants. | An actigraph (Actiwatch Spectrum Plus® from Philips Respironics, Linton Instrumentation, UK) on the wrist of the non-dominant arm is continuously recording for seven days. The same device is programmed to collect data on motor activity (accelerometer) and light type/intensity (lux) at one minute intervals. These variables will be recorded and stored in the device's memory for further data analysis. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Total sleep time as assessed by an actigraph sensor over the baseline in the study participants. | An actigraph (Actiwatch Spectrum Plus® from Philips Respironics, Linton Instrumentation, UK) on the wrist of the non-dominant arm is continuously recording for seven days. The same device is programmed to collect data on motor activity (accelerometer) and light type/intensity (lux) at one minute intervals. These variables will be recorded and stored in the device's memory for further data analysis. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Wake time as assessed by an actigraph sensor over the baseline in the study participants. | An actigraph (Actiwatch Spectrum Plus® from Philips Respironics, Linton Instrumentation, UK) on the wrist of the non-dominant arm is continuously recording for seven days. The same device is programmed to collect data on motor activity (accelerometer) and light type/intensity (lux) at one minute intervals. These variables will be recorded and stored in the device's memory for further data analysis. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Number of awakenings as assessed by an actigraph sensor over the baseline in the study participants. | An actigraph (Actiwatch Spectrum Plus® from Philips Respironics, Linton Instrumentation, UK) on the wrist of the non-dominant arm is continuously recording for seven days. The same device is programmed to collect data on motor activity (accelerometer) and light type/intensity (lux) at one minute intervals. These variables will be recorded and stored in the device's memory for further data analysis. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Heart rate variability (HRV) as recorded by the FitLab software over the baseline in the study participants. | Changes in the cardiovagal autonomic dysfuntion will be continuously assessed and recorded for the R-R intervals over 5-min periods at rest and in the supine position on different days using the FitLab software. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Orthostatic intolerance as assessed by the active standing test (10-minute NASA Lean test) over the baseline in the study participants. | The 10-minute NLT is a well-established non-invasive procedure used to assess impaired cardiovascular responses to standing and to diagnose OI phenotypes. It records objective hemodynamic parameters (blood pressure and heart rate). The participants will be first asked to lie down during 5 minutes and then to stand and lean against a wall, with heels 6-8 inches from the wall. Throughout the recording, participants will be asked to remain motionless, quiet and any talking or movement will be discouraged, except for reporting any symptoms of concern. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Pain intensity as assessed by a visual analog scale (VAS) over the baseline in the study participants. | The pain VAS is a continuous and unidimensional measure of pain intensity. It comprised of a horizontal line of 10-centimeters in length, anchored by 2 verbal descriptors, one for each symptom extreme. No pain (score of 0) and pain as bad as it could be or worst imaginable pain(score of 10). | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Anxiety and depression symptoms as assessed by the Hospital Anxiety and Depression Scale (HADS) over the baseline in the study participants. | The HADS is a validated self-reported tool composed of 14 items (seven related to anxiety symptoms and seven to depression). Each item is scored from 0-3, and thus, scores range from 0 to 21; scores of 0-7 are interpreted as normal, 8-10 as mild, 11-14 as moderate, and 15-21 as severe for either anxiety or depression. The total HADS score ranges from 0 (no anxiety or depression) to 42 (severe anxiety and depression). | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 
| Side effect of treatment | Treatment side effects will be collected from each participant during clinical trial. | During 4 months of treatment and 8 weeks after discontinuation of dietary therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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actigraphy, melatonin, zinc, fatigue, sleep quality, quality of life, pain, anxiety and depression, heart rate variability, orthostatic intolerance