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

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

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).

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome
• Intervention / Treatment: Drug: Pioglitazone; Drug: Niacin ER; Drug: Aspirin; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women between the ages of 18 and 75
2. HDL-C ≤ 40 mg/dL for Men and HDL-C < 50 mg/dl for Women*

3. At least two of the following criteria (a, b, c, or d) listed below:

   1. Abdominal obesity (waist circumference: men 40 inches and women 35 inches)**
   2. Blood pressure > 130/>85 mmHg in untreated patients OR use of any antihypertensive agent.
   3. Fasting glucose > 100 mg/dL but < 126 mg/dL
   4. Fasting triglycerides > 150 mg/dL

Exclusion Criteria:

1. 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).
2. 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.
3. Uncontrolled hypertension (defined as systolic bp > 180, diastolic BP > 100).
4. Triglycerides > 400 mg/dL
5. LDL-cholesterol level > 190 mg/dl
6. History of chronic renal insufficiency (serum creatinine >2.0 mg/dl).
7. History of liver disease or abnormal liver function tests (LFTs) (>2x upper limit normal)
8. Hemoglobin < 10 mg/dL
9. History of congestive heart failure (NYHA Class III or IV)
10. Women who are pregnant or lactating
11. History of a non-skin malignancy within the previous 5 years
12. Any major active rheumatologic, pulmonary, or dermatologic disease or other chronic inflammatory condition
13. Surgery in the last 90 days
14. History of HIV positive
15. Active alcohol or drug abuse
16. Active peptic ulcer disease
17. Gout attack within the past 6 months
18. Participation in an investigational drug study within 6 weeks
19. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful study participation
20. Subjects on warfarin may be enrolled, but they will be excluded from the optional adipose biopsy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Kos Pharmaceuticals
• Investigators: Principal Investigator: Rick Samaha, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: March 6, 2006
• First Submitted That Met QC Criteria: March 6, 2006
• First Posted (Estimate): March 8, 2006

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: June 29, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Metabolic syndrome; HDL cholesterol
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Insulin Resistance; Hyperinsulinism; Syndrome; Metabolic Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Aspirin; Pioglitazone; Niacin
• Other Study ID Numbers: 803751; Pionir (Other Identifier: University of Pennsylvania)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED