A Randomized, Double-Blind Trial Comparing the Efficacy and Safety of Fenofibrate, Metformin, Their Combination and Placebo in Patients With Metabolic Syndrome.

Study Overview
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Brief Summary
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The purpose of this study was to study the effect of different combinations of fenofibrate and metformin on the cluster of metabolic syndrome (MetS) biochemical abnormalities, and to determine the dose combination allowing normalization of MetS patients.

Official Title
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A Randomized, Double-Blind Trial Comparing the Efficacy and Safety of Fenofibrate, Metformin, Their Combination and Placebo in Patients With Metabolic Syndrome.

Conditions
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Patients With Metabolic Syndrome

Intervention / Treatment
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* Drug: Fenofibrate /Metformin
* Drug: Fenofibrate /Metformin
* Drug: Fenofibrate /Metformin
* Drug: Fenofibrate /Metformin
* Drug: Fenofibrate /Metformin
* Drug: Fenofibrate /Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged from 18 to 75 years old (at inclusion V1). With 3 of the following 5 criteria, including at least 2 biochemical abnormalities (glucose and one lipid abnormality) And having signed a written informed consent (at inclusion V1). Exclusion Criteria: known Type 1 diabetes, or treated type 2 diabetes [25], [26]; wth HbA1c > 8 % [27] at the first blood sample; body mass index (BMI) > 45 kg/m2; females who were not surgically sterilized or not using adequate contraceptive or not using adequate contraceptive precautions or not postmenopausal pregnant or lactating women; known hypersensitivity to fibrates; known hypersensitivity to metformin chlorhydrate; known abnormal thyroid hormone levels, or high thyroid stimulating hormone (TSH) level; having received an investigational drug in the last 30 days before the date of randomization; unable or unwilling to comply with the protocol; likely to withdraw from the study before its completion; treated with some concomitant medications: reporting a change within the last 6 weeks before randomization and during the study in the medications that could interfere with the lipid profile (i.e., anti-hypertensive drugs, oral corticosteroids, thyroid hormones, retinoids, thiazidic derivatives, hormone replacement therapies); presenting with the following disease or conditions: chronic respiratory insufficiency, patient with medical device for sleep apnea; current chronic pancreatitis, or identified risk or known history of acute pancreatitis; hepatic insufficiency, acute alcohol intoxication, alcoholism; known cholelithiasis without cholecystectomy; aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2 times the upper limit normal (ULN); musculoskeletal disease or increased creatine phosphokinase (CPK) > 3 times the ULN; renal failure or renal dysfunction defined by serum creatinine levels > 135 μmol/L in males and > 110 μmol/L in females [28]; acute conditions with the potential to alter renal function such as dehydration, severe infection, shock or intravascular administration of iodinated contrast agents; acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction (within 3 months prior to randomization), shock; known gastric or peptic ulcer or intestinal disease within the previous 3 months of randomization capable of modifying the intestinal absorption of the drugs; any other severe pathology such as cancer, mental illness, etc., which in the opinion of the investigator might pose a risk to the patient or confound the results of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Fenofibrate /Metformin<br>* fenofibrate 2 x 40 mg bid + metformin 850 mg bid (F160-M1700)<br>|
| Experimental: 2<br> | Drug: Fenofibrate /Metformin<br>* fenofibrate 2 x 40 mg bid + metformin 500 mg bid (F160-M1000)<br>|
| Experimental: 3<br> | Drug: Fenofibrate /Metformin<br>* fenofibrate 40 mg bid + metformin 850 mg bid (F80-M1700)<br>|
| Experimental: 4<br> | Drug: Fenofibrate /Metformin<br>* fenofibrate 40 mg bid + metformin 500 mg bid (F80-M1000)<br>|
| Experimental: 5<br> | Drug: Fenofibrate /Metformin<br>* fenofibrate 2 x 40 mg bid + metformin placebo (F160-M0)<br>|
| Experimental: 6<br> | Drug: Fenofibrate /Metformin<br>* fenofibrate placebo + metformin 850 mg bid (F0-M1700)<br>|
| Placebo Comparator: 7<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of normalized patients at V4 (fasting glucose < 6.1 mmol/L, TG < 1.69 mmol/L and HDL-C >= 1.03 mmol/L in males and >= 1.29 mmol/L in females) |  | End of study visit (V4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting blood insulin and fasting blood glucose, HbA1c. |  | End of study visit (V4) | 
| Area under the curve from 0 to 2h (AUC0-2h) of glucose, insulin, C-peptide and free fatty acids (FFA) during Oral Glucose Tolerance Test (OGTT). |  | End of study visit (V4) | 
| Insulin sensitivity assessed by the OGTT-derived composite whole-body Insulin Sensitivity Index (ISI) |  | End of study visit (V4) | 
| Fasting lipid parameters: FFA, TG, TC, HDL-C, measured LDL-C, VLDL-C, small dense LDL, apolipoprotein (Apo) A1, Apo A2, Apo CIII, LDL and HDL sizes, remna |  | End of study visit (V4) | 
| Plasminogen -1 Activation Inhibitor (PAI-1) activity, PAI-1 antigen, tissue-type Plasminogen Activator antigen (t-PA-ag), high sensitivity C-reactive protein (hsCRP), fibrinogen, tumor necrosing factor (TNF) alpha, interleukin (IL)1 and IL6. |  | End of study visit (V4) | 
| Body mass index (BMI), waist circumference, hip circumference, waist to hip ratio, and blood pressure. |  | End of study visit (V4) | 
| Percentage of patients who presented 0, 1, 2, 3, 4 or 5 MetS criteria. |  | End of study visit (V4) | 
| Adverse events (AEs). |  | End of study visit (V4) | 
| Biochemistry: creatinine phosphokinase (CPK), AST, ALT, GGT, alkaline phosphatase, serum creatinine, total bilirubin, blood urea nitrogen (BUN), uric acid, albumin and total homocysteine |  | End of study visit (V4) | 
| Hematology: white blood cells (WBC) and differential count, red blood cells (RBC), hemoglobin, hematocrit and platelets. |  | End of study visit (V4) | 
| Blood pressure. |  | End of study visit (V4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Hypertriglyceridaemia, Metabolic Syndrome