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Ciprofibrate and Pre-diabetes (FIT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03662984
Recruitment Status : Recruiting
First Posted : September 10, 2018
Last Update Posted : February 21, 2020
Sponsor:
Collaborator:
Maastricht University
Information provided by (Responsible Party):
Maastricht University Medical Center

Brief Summary:

Free fatty acids (FFA) are the main fuel source in a healthy adult heart, since they are responsible for 70-80% of the myocardial ATP production. Plasma FFA and triglycerides (TG) levels are elevated in obesity and diabetes, evoking substrate competition in the heart: the increased availability of lipids will lead to fat accumulation in the heart, which is associated with cardiac insulin resistance and will therefore restrain insulin-stimulated cardiac glucose oxidation. It is shown that a lower myocardial glucose uptake correlates with decreased diastolic function. The benefits of counterbalancing this lipid overload is proven by previous research in pre-diabetes, which showed the reversibility of impaired myocardial substrate metabolism and improvement of function and structure after modest weight loss induced by lifestyle changes.

Ciprofibrates are a ligand of the peroxisome proliferator-activated receptor (PPAR) α and are considered to be a major regulator of the lipid metabolism and promote fat oxidative capacity. They are not only effective in normalizing lipid-lipoprotein levels in patients with the metabolic syndrome, but improve also their insulin sensitivity. We therefore hypothesize that ciprofibrate administration in subjects with impaired glucose metabolism (IGM) influence the myocardial substrate metabolism (via the PPARα pathway) and thereby improve myocardial insulin sensivity.


Condition or disease Intervention/treatment Phase
Myocardial Insulin Sensitivity Impaired Glucose Metabolism Diastolic Dysfunction Drug: Ciprofibrate 100Mg Tablet Drug: Placebo Oral Tablet Phase 3

Detailed Description:

Objectives: The main objective of the study is to investigate whether ciprofibrate treatment can improve myocardial insulin sensitivity in subjects with IGM. As secondary objectives we want to investigate whether ciprofibrate treatment also improves diastolic and myocardial mitochondrial function and decreases intracardiomyocellular lipid content. Futhermore, since ciprofibrate could also affect cardiac metabolism indirectly, we want to investigate the effect of ciprofibrate on skeletal and hepatic glucose uptake, hepatic lipid storage and composition.

Study design: In a randomized, double-blind, cross-over design, the effects of ciprofibrate supplementation on myocardial insulin sensitivity will be compared to placebo in humans with IGM.

Study population: Twelve male, overweight (BMI > 27 kg/m2), insulin-resistant subjects, aged between 40 and 70 years, without cardiac disease, will participate in this study.

Intervention: Subjects will be asked to take one pill of ciprofibrate 100mg, or placebo, once daily (at dinner), for 35 days.

Main study parameters/endpoints: The main study endpoint is the difference in myocardial insulin sensitivity (measurement of glucose uptake using radio-active labeled 18F-FDG tracer in PET-MRI) after ciprofibrate administration compared to the placebo trial.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Effects of Ciprofibrate on Myocardial Insulin Sensitivity in Pre-diabetes
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : August 30, 2020
Estimated Study Completion Date : August 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy Prediabetes

Arm Intervention/treatment
Active Comparator: Ciprofibrate
1dd100mg at breakfast
Drug: Ciprofibrate 100Mg Tablet
Ciprofibrate is a PPARα ligand and is considered to be a major regulator of the lipid metabolism. PPARα regulates the genes involved in mitochondrial function and fat metabolism and is therefore abundantly expressed in tissues that require high rates of FFA oxidation, like for instance in the heart and activation of PPARα in the heart may have beneficial effects on mitochondrial function and fat oxidative capacity.
Other Name: PPARa agonist

Placebo Comparator: Placebo
1dd0mg at breakfast
Drug: Placebo Oral Tablet
To compare ciprofibrate




Primary Outcome Measures :
  1. Myocardial insulin sensitivity [ Time Frame: 1hour, day 35 ]
    measured by the insulin-stimulated myocardial glucose uptake by FDG-PET


Secondary Outcome Measures :
  1. Hepatic glucose uptake [ Time Frame: 1hour, day 35 ]
    measured by the insulin-stimulated myocardial glucose uptake by FDG-PET

  2. Skeletal muscle glucose uptake [ Time Frame: 1hour, day 35 ]
    measured by the insulin-stimulated myocardial glucose uptake by FDG-PET

  3. Brown adipose tissue (BAT) glucose uptake [ Time Frame: 1hour, day 35 ]
    measured by the insulin-stimulated myocardial glucose uptake by FDG-PET

  4. Insulin sensitivity [ Time Frame: 4hours, day 35 ]
    Glucose infusion rate (GIR) from the hyperinsulinemic euglycemic clamp

  5. Intracardiomyocellular lipid content [ Time Frame: 1hour, day 35 ]
    Cardiac 1H-MRS: fasted & insulin-stimulated

  6. Cardiac systolic function [ Time Frame: 1hour, day 35 ]
    Functional cardiac MRI: fasted & insulin-stimulated

  7. In vivo myocardial mitochondrial function (PCr/ATP ratio) [ Time Frame: 1hour, day 28 ]
    Cardiac 31P-MRS: fasted

  8. Cardiac diastolic function [ Time Frame: 1hour, day 34 ]
    Cardiac ultrasound

  9. Intrahepatic lipid content and hepatic lipid composition [ Time Frame: 1hour, day 28 ]
    Hepatic 1H-MRS: fasted

  10. Blood pressure [ Time Frame: 24hours, day 27 ]
    24-hour blood pressure monitor

  11. Whole body (sleeping) energy metabolism (sleeping energy expenditure and substrate oxidation) [ Time Frame: 12 hours, day 34 ]
    Respiration chamber: overnight

  12. Whole body maximum aerobic capacity [ Time Frame: 1hour, day 28 ]
    VO2 max test

  13. Total body mass and fat mass [ Time Frame: 0.5 hour, day 35 ]
    Body composition

  14. Ex vivo PPARalpha expression and downstream targets [ Time Frame: 0.5 hour, day 35 ]
    Skeletal muscle biopsy

  15. Postprandial lipid response [ Time Frame: 5hour, day 34 ]
    Meal test

  16. Anti-inflammatory effects (in the long term on the immune cells; acute effect on postprandial response), circadian rhythm [ Time Frame: 6hour, day 0-34-35 ]
    PBMC

  17. Cholesterol profile [ Time Frame: 5hours, day 0,7,14,21,28,35 ]
    Blood after venapunction



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Females have a oestrogen receptor which interferes with the PPARa receptor
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Race: caucasian
  • Sex: male
  • Age: 40-70 years
  • BMI: 27-35 kg/m2
  • Stable dietary habits: no weight gain or loss > 5kg in the last three months
  • Insulin resistant: glucose clearance rate below < 360 ml/kg/min, as determined using OGIS120

Exclusion Criteria:

  • Patients with a cardiac disease or with instable angina
  • Patients with hepatic or renal failure
  • Haemoglobin <7.8 mmol/l
  • In case of an abnormal ECG in rest: this will be discussed with the responsible medical doctor
  • HbA1c > 6.5%
  • Diagnosed with type 1 or type 2 diabetes mellitus
  • Patients with alcohol abuse
  • Use of a fibrate
  • Medication use known to interfere with glucose homeostasis/metabolism
  • Use of anti-coagulants, excluding platelet aggregation inhibitors
  • Subjects who do not want to be informed about unexpected medical findings during the screening /study, or do not wish that their physician is informed, cannot participate in the study.
  • Subjects who intend to donate blood during the intervention or subjects who have donated blood less than three months before the start of the intervention.
  • Participation in another biomedical study within 1 month before the first screening visit
  • Any condition, disease or abnormal laboratory test result that, in the opinion of the Investigator, would interfere with the study outcome, affect trial participation or put the subject at undue risk
  • Any contra-indication to MRI scanning. These contra-indications include patients with following devices:

    • Electronic implants such as pacemakers or defibrillator or neurostimulator
    • Central nervous system aneurysm clip
    • Some hearing aids (such as cochlear implant) and artificial (heart) valves which are contraindicated for MRS
    • Iron containing corpora aliena in the eye or brains
    • Claustrophobia
  • Participation in earlier research or medical examinations in the past 3 months that included PET/MRI scanning

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03662984


Contacts
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Contact: Vera de Wit-Verheggen, MD 0031433882124 v.dewit@maastrichtuniversity.nl

Locations
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Netherlands
Nutrition and Movement Sciences Recruiting
Maastricht, Limburg, Netherlands, 6200MD
Contact: P Schrauwen, Prof    0031433882222    p.schrauwen@maastrichtuniversity.nl   
Sponsors and Collaborators
Maastricht University Medical Center
Maastricht University
Investigators
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Principal Investigator: Patrick Schrauwen, Professor Maastricht University

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Responsible Party: Maastricht University Medical Center
ClinicalTrials.gov Identifier: NCT03662984    
Other Study ID Numbers: NL.ABR.65583
First Posted: September 10, 2018    Key Record Dates
Last Update Posted: February 21, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Insulin Resistance
Prediabetic State
Hypersensitivity
Immune System Diseases
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Diabetes Mellitus
Endocrine System Diseases
Ciprofibrate
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents