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Metabolic Effects of Melatonin Treatment

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ClinicalTrials.gov Identifier: NCT03859934
Recruitment Status : Recruiting
First Posted : March 1, 2019
Last Update Posted : September 30, 2019
Sponsor:
Collaborator:
University of Copenhagen
Information provided by (Responsible Party):
University of Aarhus

Tracking Information
First Submitted Date  ICMJE February 18, 2019
First Posted Date  ICMJE March 1, 2019
Last Update Posted Date September 30, 2019
Actual Study Start Date  ICMJE September 26, 2019
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Change of insulin sensitivity [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment and compared afterwards with a paired T-tes ]
    Insulin sensitivity is assessed by a hyperinsulinemic euglycemic clamp, unit: mg/kg/min (mg of glucose to maintain euglycemia per kilogram of weight per minuts)
  • Change of insulin secretion change [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Insulin secretion is assessed by an intravenous glucose tolerance test, unit: pmol/L (insulin)
  • MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion [ Time Frame: The outcome will be measured after 3 months of placebo treatment and again after 3 months of melatonin treatment ]
    MTNR1a rs10830963 genotype influence on insulin sensitivity and insulin secretion (see outcome 1 + 2)
  • Change of insulin signalling [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Insulin signalling in muscle and adipose tissue assessed by western blot
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Change of ambulatory blood pressure [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Ambulatory blood pressure assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (Unit: mmHg)
  • Change of arterial stiffness [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Arterial stiffness assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (unit: m/s)
  • Change of gut microbiome [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Feces analysis of microbial mRNA
  • Change of sleep evaluation 1 [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Pittsburg Sleep Quality Index Questionnaire (Points on a scale: range 0-57)
  • Change of sleep evaluation 2 [ Time Frame: After 3 months treatmentThe outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Epworth Sleepiness Scale Questionnaire (Points on a scale: range 0-24)
  • Change of psychological health 1 [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Major Depression Inventory Questionnaires (points on a scale: range 0-65)
  • Change of psychological health 2 [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    World Health Organization 5 Questionnaires (points on a scale: range 0-25)
  • Hormonal changes [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Ghrelin, HbA1c, GLP-1, GLP-2, GIP, free fatty acids (FFA), leptin, cytokines, adiponectin, growth hormone, cortisol, hsCRP, CD163, MBL, IGF-1 and proinsulin measured by ELISA, RIA, or routine biochemical analysis. Unit: pmol/L
  • Change of glucose and palmitate kinetics [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Tracer technique with infusion of radioactive labeled glucose and palmitate for determination of rate of appereance. Unit: mikromol/min
  • Change of regional glucose and palmitate uptake [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Forearm model with arteriovenous differences of glucose and palmitate (Arterial glucose minus venous glucose = forearm uptake (unit mmol/l). The same applies for palmitate
  • Change of DEXA-scans [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Evaluation of body composition and bone mineral density by DEXA-scan
  • Change of assessment of respiratory quotient (RQ) [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Assessment of respiratory quotient (RQ) with indirect calorimetry (unit: VCO2/VO2)
  • Change of assessment of resting energy expenditure (REE) [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Assessment of resting energy expenditure (REE) with indirect calorimetry (Unit J/s)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metabolic Effects of Melatonin Treatment
Official Title  ICMJE Metabolic Effects of Melatonin Treatment
Brief Summary Modern living is associated with an epidemic of type 2 diabetes mellitus (T2DM). Sleep disturbances such as insomnia or frequent awakenings are strong risk factors for T2DM with several studies indicating a central role of melatonin. Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM. Due to treatment of, among other things, insomnia, the use of melatonin is increasing rapidly in Denmark with a 100-fold increase from 2007-2012 in children and adolescents. No previous studies have thoroughly assessed changes in glucose and fatty acid metabolism after 3 months of melatonin treatment in patients with T2DM.
Detailed Description

Modern living is associated with an epidemic of type 2 diabetes mellitus (T2DM). Sleep disturbances such as insomnia or frequent awakenings are strong risk factors for T2DM with several studies indicating a central role of melatonin. Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM. Due to treatment of, among other things, insomnia, the use of melatonin is increasing rapidly in Denmark with a 100-fold increase from 2007-2012 in children and adolescents. No previous studies have thoroughly assessed changes in glucose and fatty acid metabolism after 3 months of melatonin treatment in patients with T2DM.

Main research questions:

  1. Does chronic melatonin treatment change insulin secretion in T2DM patients?
  2. Does chronic melatonin treatment change insulin sensitivity in T2DM patients?
  3. Does the MTNR1B rs10830963 risk allele alter the insulin secretion and insulin sensitivity compared with carries of the normal variant after chronic melatonin treatment?
  4. Does chronic melatonin treatment change insulin signalling in muscle - and adipose tissue? Design: A randomized, double-blinded, placebo controlled, crossover study, including 18 participants with T2DM. We aim to recruit 9 homozygous carriers of the normal allele and 9 hetero - or homozygous for the risk allele.

Participants will be examined on two occasions, 1) after 3 months of daily melatonin treatment before bedtime (10 mg), and 2) after 3 months of daily placebo treatment before bedtime.

On the study days, participants will initially undergo a basal period with glucose - and palmitate tracer infusions to assess endogenous glucose production and free fatty acid production. Afterwards a Botnia clamp, which combines an intravenous glucose tolerance test and a hyperinsulinemic euglycemic clamp, will be performed to assess β-cell function and insulin sensitivity. On both study days muscle - and fat biopsies will be performed under both basal and hyperinsulinemic euglycemic conditions.

Perspectives: It is highly relevant to evaluate the chronic effects of melatonin on glucose - and fat metabolism given the increase in melatonin consumption. Furthermore, the study may open for new treatment options of T2DM if beneficial effects of oral melatonin are detected.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Randomized, placebo controlled, double blinded crossover study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Metabolic Disease
  • Insulin Sensitivity
  • Glucose Metabolism Disorders (Including Diabetes Mellitus)
  • Type 2 Diabetes Mellitus
  • Blood Pressure
  • Inflammation
Intervention  ICMJE
  • Drug: Melatonin
    Melatonin treatment
    Other Name: Melatonin treatment
  • Drug: Placebo Oral Tablet
    Placebo treatment
    Other Name: Placebo treatment
Study Arms  ICMJE
  • Active Comparator: Melatonin
    10 mg melatonin each day 1 hour before bedtime for 3 months
    Intervention: Drug: Melatonin
  • Placebo Comparator: Placebo
    Placebo each day 1 hour before bedtime for 3 months
    Intervention: Drug: Placebo Oral Tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 28, 2019)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2022
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male sex
  • Caucasian race
  • Type 2 Diabetes Mellitus (T2DM)
  • T2DM duration of maximum 20 years
  • Age 40-70 years
  • BMI between 25-35 kg/m2 at T2DM debut
  • Written consent prior to study participation

Exclusion Criteria:

  • > 3 daily antihypertensive drugs
  • Blood pressure > 160/100 mmHg
  • Insulin treatment
  • > 3 daily oral antidiabetic drugs
  • > 1 lipid lowering drug
  • HbA1c > 65
  • Heart failure (New York Heart Association Class III or IV), liver disease (alanine aminotransferase (ALAT) > twice the upper limit of normal serum concentration), plasma creatinine > 130 µmol/L and/or albuminuria, goiter, active cancer, acute or chronic pancreatitis
  • Treatment with antidiabetic medicine that cannot be paused on study days (or for a week if the participants is treated with longtime-acting GLP-1 analogs)
  • Shift work within the last year
  • Travel across >4 time zones planned within the next 6 months
  • Use of melatonin on a regular basis within the last year
  • Severe illness
  • > 14 units of alcohol/week
  • Previous diagnosis of a sleep disorder
  • Present or earlier alcohol or drug abuse
  • Unable to give informed consent
  • Allergy towards melatonin
  • Daily consumption of benzodiazepines, fluvoxamine, amiodarone, efavirenz, fluoroquinolones, rifampicin, and carbamazepine due to interactions with the pharmacokinetics of melatonin.
  • Severe sleep apnea (>30 respiration breaks/hour over 10 seconds)
  • Medical treated depression or anxiety disorders within the last 3 years
  • Daily consumption of selective serotonin reuptake inhibitors or tricyclic antidepressants
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Esben Stistrup Lauritzen, MD +4523608465 esben.lauritzen@clin.au.dk
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03859934
Other Study ID Numbers  ICMJE 2019-000213-37
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Aarhus
Study Sponsor  ICMJE University of Aarhus
Collaborators  ICMJE University of Copenhagen
Investigators  ICMJE
Principal Investigator: Esben Stistrup Lauritzen, MD Medical Research Laboratory
Principal Investigator: Ulla Kampmann Opstrup, MD, PhD Aarhus University Hospital
Principal Investigator: Julie Støy, MD, PhD Aarhus University Hospital
PRS Account University of Aarhus
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP