Melatonin on Clock Genes in Parkinson's Disease

Study Overview
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Brief Summary
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Parkinson's disease (PD) is the second most important neurodegenerative disease that affects about 2% of the population over 60 years of age. About 40% of the Mexican population with PD suffer from sleep disorders, which has been linked to a deregulation of the circadian cycle and therefore of the clock genes. Melatonin is a hormone produced by the pineal gland that regulates the sleep-wake cycle, at pharmacological doses, it is used to decrease sleep disorders; it is suggested that is used could also normalize the levels of the clock genes expression. In rats with PD, a decrease in clock genes levels has been observed, which are restored by administering melatonin. The aim of the study is to evaluate the effect of melatonin on the expression of the PER1 and BMAL1 clock genes in patients with PD during 12 months. A controlled, double-blind, randomized clinical trial will be carried out in patients with a diagnosis of PD. A survey will be applied in order to know the course of the disease and two more tests to rule out some sleep disorder, at the beginning of the study, at the 6th month and at the 12th month. A blood sample (approximately 15 ml) will be taken every 3 months for a year. By random assignment, the participant will be given Melatonin or placebo, which should be taken every day in the morning and evening after meals for one year.

Detailed Description
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A controlled, double-blind, randomized clinical trial will be carried out in 58 patients with a diagnosis of PD. Twenty-nine patients will receive Melatonin and 29 placebo. A blood sample will be taken to determine the expression levels of the PER1 and BMAL1 clock genes by a real-time quantitative polymerase chain reaction (RT-qPCR), and as secondary variables, to determine the activity of the mitochondrial complex 1, the levels of malondialdehyde (MDA) and 4-hydroxyalkene (4-HDA) and the production of nitric oxide will be quantified by spectrophotometric methods. The SCOPA-Sleep and EPWORTH questionnaires will be applied to assess sleep. To evaluate the clinical evolution of PD in each patient, the UPDRS scale will be used. It will be given the assigned treatment, with the printed patient code. They will be supplemented with 50 mg of Melatonin at a dose of 25 mg orally every 12 hours for 12 months. The double-blind of the medication for this study will be maintained by the use of gels identical to the Melatonin supplement. The blind's break will only be authorized in case of emergency events that require it, and the date, time and reason for the break should be noted. It will be given a follow-up diary, and the patient will be explained how they should take the treatment and that they should record the date and time of administration, the description of adverse events that may occur, raising the patient's awareness that It is important to keep the diary and take it at each appointment to assess the attachment to treatment. Concerning the medications that patients ingest, before entering the protocol, it will be indicated to follow their usual administration. Finally, the patient will be instructed to schedule their appointment 3,6, 9 and 12 months later of starting treatment.

Official Title
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Effect of Melatonin Administration on the PER1 and BMAL1 Clock Genes in Patients With Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Melatonin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with diagnosis of PD in stages 1-3 of the classification by stages of Hoehn & Yahr Go with a companion to the appointments Patients who agree to participate in the study and sign the Informed Consent letter Exclusion Criteria: Patients with movement disorder other than PD Prior pallidotomy, thalamotomy or deep brain stimulation Pregnant Patients who consume alcohol or coffee Patients who consume an antioxidant supplement

Ages Eligible for Study
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Minimum Age: 20 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 group<br>Patients with PD who will receive 25 mg of melatonin gel at 12 hours a day and half an hour before sleeping for 12 months | Drug: Melatonin<br>* 25 mg of melatonin gel at noon and 25 mg of melatonin gel 30 minutes before sleeping for 12 months<br>|
| Placebo Comparator: Placebo group<br>Patients with PD who will receive 25 mg of placebo gel at 12 hours a day and half an hour before sleeping for 12 months | Drug: Placebos<br>* 25 mg of placebo gel at noon and 25 mg of placebo gel 30 minutes before sleeping for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression levels of clock genes | Relative ratio of messenger ribonucleic acid (mRNA) expression of PER1 and BMAL1 genes corresponding to a control (GAPDH) for each sample, measured by an RT-qPCR. | Change from baseline at third, sixth, ninth and twelfth month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SCOPA-Sleep scale | It is a specific instrument for the evaluation of sleep disorders in patients with PD. It is self-applicable and consists of two subscales; the first assess nighttime sleep and the second daytime sleepiness during the last month. The score greater than seven of five points respectively indicates abnormal sleepiness. Additionally, the SCOPA-Sleep scale has a question of global sleep evaluation. | Change from baseline at third, sixth, ninth and twelfth month | 
| Epworth scale | Is an eight-item self-applicable instrument developed to assess the propensity to fall asleep in eight situations, mostly monotonous. A total score of less than 10 was considered normal, 10-12 as indicative of marginal drowsiness and above 12 suggestive of excessive drowsiness. | Change from baseline at third, sixth, ninth and twelfth month | 
| Progression of PD | For the longitudinal follow-up of the PD course, the Unified Parkinson's Disease Rating Scale (UPDRS) will be applied through an interview. The scale is composed by four parts: mental, behavioral and mood; activities of daily living; motor evaluation; and motor complications. The scoring range is from 0 to 199, where 199 represents total disability and 0 without disability. | Change from baseline at third, sixth, ninth and twelfth month | 
| Anxiety | To assess the severity of a person's anxiety symptoms and discriminate between anxiety and depression symptoms the Beck anxiety inventory will be use. The rating is made through a likert scale of 0 to 3, where 0 means absence of the symptom and 3 maximum severity. The total score is obtained from the sum of the 21 reagents, 0 is the minimum and 63 is the maximum. In the Mexican population, a score of 0-5 points will be minimal anxiety, 6-15 mild anxiety, 16-30 moderate anxiety and 31-63 severe anxiety. | Change from baseline at third, sixth, ninth and twelfth month | 
| Depression | To evaluate the severity of depression symptoms the Beck's depression inventory will be use. The rating is made through a likert scale of 0 to 3, where 0 means absence of the symptom and 3 maximum severity. The total score is obtained from the sum of the 21 reagents, 0 is the minimum and 63 is the maximum. In the Mexican population, a score of 0-9 points will be considered normal, 10-16 mild depression, 17-29 moderate depression, and 30-63 severe depression. | Change from baseline at third, sixth, ninth and twelfth month | 
| Activity of the mitochondrial complex 1 | To measure the mitochondrial complex I, a spectrophotometric assay will be used, it measures the oxidation of rotenone-sensitive nicotinamide-adenine dinucleotide (NADH) at 340 nm in mitochondria-enriched fractions | Change from baseline at third, sixth, ninth and twelfth month | 
| Oxidative stress | Products of nitric oxide metabolism and products of lipoperoxidation such as malondialdehyde and 4-hydroxyalkene by spectrophotometry will be measured | Change from baseline at third, sixth, ninth and twelfth month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melatonin, clock genes, BMAL1 gene, PER1 gene