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Ciprofibrate and Pre-diabetes (FIT)

Primary Purpose

Myocardial Insulin Sensitivity, Impaired Glucose Metabolism, Diastolic Dysfunction

Status
Completed
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Ciprofibrate 100Mg Tablet
Placebo Oral Tablet
Sponsored by
Maastricht University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Myocardial Insulin Sensitivity

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • Nutrition and Movement Sciences

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Ciprofibrate

Placebo

Arm Description

1dd100mg at breakfast

1dd0mg at breakfast

Outcomes

Primary Outcome Measures

Myocardial insulin sensitivity
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET

Secondary Outcome Measures

Hepatic glucose uptake
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Skeletal muscle glucose uptake
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Brown adipose tissue (BAT) glucose uptake
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Insulin sensitivity
Glucose infusion rate (GIR) from the hyperinsulinemic euglycemic clamp
Intracardiomyocellular lipid content
Cardiac 1H-MRS: fasted & insulin-stimulated
Cardiac systolic function
Functional cardiac MRI: fasted & insulin-stimulated
In vivo myocardial mitochondrial function (PCr/ATP ratio)
Cardiac 31P-MRS: fasted
Cardiac diastolic function
Cardiac ultrasound
Intrahepatic lipid content and hepatic lipid composition
Hepatic 1H-MRS: fasted
Blood pressure
24-hour blood pressure monitor
Whole body (sleeping) energy metabolism (sleeping energy expenditure and substrate oxidation)
Respiration chamber: overnight
Whole body maximum aerobic capacity
VO2 max test
Total body mass and fat mass
Body composition
Ex vivo PPARalpha expression and downstream targets
Skeletal muscle biopsy
Postprandial lipid response
Meal test
Anti-inflammatory effects (in the long term on the immune cells; acute effect on postprandial response), circadian rhythm
PBMC
Cholesterol profile
Blood after venapunction

Full Information

First Posted
August 29, 2018
Last Updated
January 7, 2021
Sponsor
Maastricht University Medical Center
Collaborators
Maastricht University
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1. Study Identification

Unique Protocol Identification Number
NCT03662984
Brief Title
Ciprofibrate and Pre-diabetes
Acronym
FIT
Official Title
Effects of Ciprofibrate on Myocardial Insulin Sensitivity in Pre-diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
November 1, 2018 (Actual)
Primary Completion Date
November 6, 2020 (Actual)
Study Completion Date
November 13, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center
Collaborators
Maastricht University

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myocardial Insulin Sensitivity, Impaired Glucose Metabolism, Diastolic Dysfunction

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ciprofibrate
Arm Type
Active Comparator
Arm Description
1dd100mg at breakfast
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
1dd0mg at breakfast
Intervention Type
Drug
Intervention Name(s)
Ciprofibrate 100Mg Tablet
Other Intervention Name(s)
PPARa agonist
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Intervention Description
To compare ciprofibrate
Primary Outcome Measure Information:
Title
Myocardial insulin sensitivity
Description
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Time Frame
1hour, day 35
Secondary Outcome Measure Information:
Title
Hepatic glucose uptake
Description
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Time Frame
1hour, day 35
Title
Skeletal muscle glucose uptake
Description
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Time Frame
1hour, day 35
Title
Brown adipose tissue (BAT) glucose uptake
Description
measured by the insulin-stimulated myocardial glucose uptake by FDG-PET
Time Frame
1hour, day 35
Title
Insulin sensitivity
Description
Glucose infusion rate (GIR) from the hyperinsulinemic euglycemic clamp
Time Frame
4hours, day 35
Title
Intracardiomyocellular lipid content
Description
Cardiac 1H-MRS: fasted & insulin-stimulated
Time Frame
1hour, day 35
Title
Cardiac systolic function
Description
Functional cardiac MRI: fasted & insulin-stimulated
Time Frame
1hour, day 35
Title
In vivo myocardial mitochondrial function (PCr/ATP ratio)
Description
Cardiac 31P-MRS: fasted
Time Frame
1hour, day 28
Title
Cardiac diastolic function
Description
Cardiac ultrasound
Time Frame
1hour, day 34
Title
Intrahepatic lipid content and hepatic lipid composition
Description
Hepatic 1H-MRS: fasted
Time Frame
1hour, day 28
Title
Blood pressure
Description
24-hour blood pressure monitor
Time Frame
24hours, day 27
Title
Whole body (sleeping) energy metabolism (sleeping energy expenditure and substrate oxidation)
Description
Respiration chamber: overnight
Time Frame
12 hours, day 34
Title
Whole body maximum aerobic capacity
Description
VO2 max test
Time Frame
1hour, day 28
Title
Total body mass and fat mass
Description
Body composition
Time Frame
0.5 hour, day 35
Title
Ex vivo PPARalpha expression and downstream targets
Description
Skeletal muscle biopsy
Time Frame
0.5 hour, day 35
Title
Postprandial lipid response
Description
Meal test
Time Frame
5hour, day 34
Title
Anti-inflammatory effects (in the long term on the immune cells; acute effect on postprandial response), circadian rhythm
Description
PBMC
Time Frame
6hour, day 0-34-35
Title
Cholesterol profile
Description
Blood after venapunction
Time Frame
5hours, day 0,7,14,21,28,35

10. Eligibility

Sex
Male
Gender Based
Yes
Gender Eligibility Description
Females have a oestrogen receptor which interferes with the PPARa receptor
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Schrauwen, Professor
Organizational Affiliation
Maastricht University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nutrition and Movement Sciences
City
Maastricht
State/Province
Limburg
ZIP/Postal Code
6200MD
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Ciprofibrate and Pre-diabetes

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