Pioglitazone vs Placebo in Combination With Niacin Extended Release on Low HDL

Study Overview
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Brief Summary
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We will test our primary hypothesis that combining niacin extended release (niacin-ER), at a daily dosage of up to 2.0 g with pioglitazone, at a daily dosage of 45 mg will result in a 12% greater increase in HDL-C when compared to niacin-ER monotherapy over 12 weeks in non-diabetic patients with the metabolic syndrome (see Table 1).

Detailed Description
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This is a two-arm, parallel, double-blind randomized prospective clinical trial. The subjects will be asked to provide informed consent, and then undergo screening for enrollment criteria at the first visit (-5 weeks). The subjects who are eligible, and provide informed consent will return for Visit 2 baseline data (-4 weeks), and then begin the unblinded niacin-ER titration. Specifically, subjects will receive a starting dose of niacin-ER of 500 mg per day, which will be increased in 500 mg increments every week up to a dose of 2000 mg per day. Subjects will need to tolerate at least 1500 mg per day of niacin-ER in order to remain in the study and be randomized. Thus subjects who are unable to tolerate the 2000 mg daily dose of niacin-ER will be taken back to 1500 mg per day for one week and then randomized. Subjects who develop prohibitive side effects at doses less than 1500 mg per day will be discontinued from the study. All subjects who are able to take the target dose of niacin-ER will continue that dose of niacin-ER and come to the General Clinical Research Center (GCRC) to be randomized in a 1:1 fashion to either niacin-ER plus pioglitazone or niacin-ER plus matching placebo for 12 weeks. Pioglitazone will be started at 30 mg and then increased to 45 mg at week 6. This entry design is designed to minimize the differences in mean dose of niacin-ER and dropout rate between study groups.

Official Title
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A Randomized, Double Blind, Placebo Controlled Trial of Pioglitazone and Niacin Extended Release in Non-diabetic Patients With Metabolic Syndrome

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Drug: Pioglitazone
* Other: Placebo
* Drug: Niacin ER
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages of 18 and 75 HDL-C ≤ 40 mg/dL for Men and HDL-C < 50 mg/dl for Women* At least two of the following criteria (a, b, c, or d) listed below: Abdominal obesity (waist circumference: men 40 inches and women 35 inches)** Blood pressure > 130/>85 mmHg in untreated patients OR use of any antihypertensive agent. Fasting glucose > 100 mg/dL but < 126 mg/dL Fasting triglycerides > 150 mg/dL Exclusion Criteria: Diabetes or use of anti-hyperglycemic medication in the last 3 months (subjects with a fasting blood glucose of > 110 mg/dL will have an oral glucose tolerance test (OGTT) to rule out diabetes mellitus). Subjects on statin therapy may be enrolled, but only if they have been on a stable dose for at least 3 months, and are not expected to require titration of statin therapy during the course of the study. Uncontrolled hypertension (defined as systolic bp > 180, diastolic BP > 100). Triglycerides > 400 mg/dL LDL-cholesterol level > 190 mg/dl History of chronic renal insufficiency (serum creatinine >2.0 mg/dl). History of liver disease or abnormal liver function tests (LFTs) (>2x upper limit normal) Hemoglobin < 10 mg/dL History of congestive heart failure (NYHA Class III or IV) Women who are pregnant or lactating History of a non-skin malignancy within the previous 5 years Any major active rheumatologic, pulmonary, or dermatologic disease or other chronic inflammatory condition Surgery in the last 90 days History of HIV positive Active alcohol or drug abuse Active peptic ulcer disease Gout attack within the past 6 months Participation in an investigational drug study within 6 weeks Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful study participation Subjects on warfarin may be enrolled, but they will be excluded from the optional adipose biopsy.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Pioglitazone + Open-Label Niacin<br>Intervention: Pioglitazone, initially 30mg, then titrated to 45mg + niacin ER 2.0 g/day + aspirin 325 mg/day | Drug: Pioglitazone<br>* Pioglitazone, initially 30 mg, then titrated to 45 mg/day<br>* Other names: Actos;Drug: Niacin ER<br>* Niacin ER 2.0 g/day<br>Drug: Aspirin<br>* asprin 325 mg/day<br>|
| Placebo Comparator: Placebo +Open-Label Niacin<br>Intervention: Pioglitazone Placebo + 2.0 g/day Open-Label Niacin + 325 mg/day Aspirin | Other: Placebo<br>* Pioglitazone placebo<br>Drug: Niacin ER<br>* Niacin ER 2.0 g/day<br>Drug: Aspirin<br>* asprin 325 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks | Mean increase in HDL-C from baseline (week -4) to 12 weeks post randomization in non-diabetic subjects with low HDL-C and metabolic syndrome. After baseline, all subjects titrated niacin extended release (ER) to 2 grams (g) daily over 4 weeks. Subjects were also given 325 mg aspirin to take 30 minutes before the niacin ER. After 4 weeks, half of the subjects added blinded pioglitazone 30mg/day (milligrams/day) for 6 weeks followed by 45 mg/day for 6 weeks; the other half added placebo. HDL-C was was assessed at baseline and 12 weeks post randomization | Baseline, after 12 weeks of pioglitazone vs placebo | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HDL cholesterol, Metabolic syndrome