Circadian Phase Adjustment and Improvement of Metabolic Control in Night Shift Workers

Study Overview
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Brief Summary
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EuRhythDia II is a multicenter, randomized, double-blind controlled study. The rationale of EuRhythdia is to explore the effects of 12 weeks of timed melatonin treatment on circadian rhythm, metabolic control and cardiovascular function in night shift workers. The 12 weeks of intervention will be followed by 12 weeks of washing out.

Detailed Description
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Modern lifestyle has dramatically changed the daily rhythms of life. Physical activity, diet and light exposure are no longer restricted to daytime hours due to increased shift work. Recent scientific reports have shown that shift work leads to disruption of circadian rhythms and promotes diabetes, obesity and cardiovascular disease. Until now only few studies investigating circadian rhythm disturbances in the context of type 2 diabetes and obesity have been conducted in man. Thus, knowledge of the molecular pathways and the responsibles genes in man are missing and have been identified only in animal studies. The objective of the project is to achieve breakthroughs in the understanding of the causality between inner clock rhythm disturbances and the development of type 2 diabetes and obesity. The provided data on the interaction between genes, epigenetics, metabolism, cardiovascular function and the internal clock are intended to contribute to identify novel biomarkers and novel therapeutic approaches focusing on circadian rhythms to reduce the occurence of diabetes and obesity in shift worker.

Official Title
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Multicenter, Randomized, Double-blind, Placebo Controlled Trial of 2 mg Melatonin for Circadian Phase Adjustment and Improvement of Metabolic Control in Night Shift Workers

Conditions
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Sleep Disorders, Circadian Rhythm

Intervention / Treatment
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* Drug: Melatonin 2mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female above the age of 18 Night shift workers on regular night shifts (at least 6 months before inclusion into the study and at least 4 night shifts per month during the study period Exclusion Criteria: pregnancy or breast feeding Known autoimmune disease Current or relevant history of physical or psychiatric illness Evidence of renal insufficiency or liver disease Known or suspected intolerance or hypersensitivity to the study medication Use of certain drugs within 4 weeks prior to the inclusion to the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Melatonin 2mg<br>The study medication will be compared to placebo control. | Drug: Melatonin 2mg<br>* once daily, 0.5-1 hours before going to bed and 1-2 hours after the last meal for 12 weeks.<br>* Other names: Circadin®;|
| Placebo Comparator: Placebo<br>The study medication will be compared to placebo control. | Drug: Placebo<br>* once daily, 0.5-1 hours before going to bed and 1-2 hours after the last meal for 12 weeks.<br>* Other names: None active substances;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy (AUC) | The change in the area under the curve (AUC) of blood glucose during an oral glucose tolerance test between baseline and 12 weeks of intervention. | baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy BMI | The change in body weight, BMI, abdominal circumference, biomarkers and vascular function between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy expression pattern of clock genes | The change in the gene expression patterns of Clock genes in peripheral blood monocytic cells (PBMC) between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy glucose homeostasis (HOMA-index) | The change in the HOMA-index (Homeostasis Model Assessment) between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy glucose homeostasis (QUICKI-index) | The change in the QUICKI-index (quantitative insulin sensitivity check index) between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy glucose homeostasis (Stumvoll ISI-index) | The change in HbA1c between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy glucose homeostasis (HbA1c) | The change in the Stumvoll ISI (Stumvoll insulin sensitivity index) between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy epigenetic profiles | The differences in epigenetic profiles of genes involved in circadian rhythm between the study groups after 12 weeks of intervention and between week 12 and 24. | 12 weeks and 24 weeks | 
| Efficacy biomarkers | The differences in plasma and serum biomarkers between baseline and 12 weeks of intervention and between week 12 and 24. | baseline, 12 weeks and 24 weeks | 
| Efficacy AUC Insulin 24 weeks | The change in the area under the curve (AUC) of blood insulin during an oral glucose tolerance test between week 12 and week 24 (= after 12 weeks without intervention). | 12 weeks and 24 weeks | 
| Efficacy AUC glucose 24 weeks | The change in the area under the curve (AUC) of blood glucose during an oral glucose tolerance test between week 12 and week 24 (= after 12 weeks without intervention). | 12 weeks and 24 weeks | 
| Efficacy AUC insulin 12 weeks | The change in the area under the curve (AUC) of blood insulin during an oral glucose tolerance test between baseline and 12 weeks of intervention. | baseline and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, metabolic control, Metabolomics, Circadian Rhythm, Melatonin, Biomarker, Clock Gene, PBMC, Cardiovascular function, Epigenetic modification, Lifestyle Intervention