Rosiglitazone And Fenofibrate Additive Effects on Lipids (RAFAEL) (RAFAEL)

April 8, 2014 updated by: Ahmad Slim
The design of the study will be randomized, double blind trial, which will examine the effects of Rosiglitazone on the fasting triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and plasma concentrations of apolipoproteins A-I, A-II, and C-III as compared to Fenofibrate and placebo. This study will also assess the synergistic effect of Rosiglitazone and Fenofibrate on the same parameters. Data from this study will help clarify whether Rosiglitazone favorably impacts plasma lipid and lipoprotein concentrations through improving insulin sensitivity and glycemic control, or by directly influencing the synthesis of the apolipoproteins that are responsible for very-low-density lipoprotein (VLDL) and HDL metabolism.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Treatment of patients with type 2 Diabetes Mellitus (DM) consists of reducing hyperglycemia through diet, exercise, oral drug therapy or insulin (1). The Thiazolidinedione (TZDs), which include Troglitazone (withdrawn by the FDA), Rosiglitazone, and Pioglitazone, correct hyperglycemia by increasing insulin sensitivity in both the liver (2, 3) and skeletal muscles (4,5). Although TZDs improve glycemic control in type 2 diabetic subjects, when these agents are administered to non-diabetic subjects they do not affect fasting plasma glucose levels. Nolan et al. (6) observed no effect on the plasma glucose levels of non-diabetic subjects treated with Troglitazone 200 mg twice daily.

Clinical trials using TZDs in type 2 diabetic subjects have observed that these agents also favorably impact plasma lipid and lipoprotein concentrations. A recent study comparing the efficacy of adding Metformin (850 mg, once or twice daily) or Troglitazone (200 mg, once or twice daily) to Glyburide (10 mg, twice daily) on glycemic control in type 2 diabetic patients (n=22), reported that after 4 months of treatment, Metformin did not induce significant changes in LDL-C, LDL size, HDL-C, Triglycerides or Plasminogen Activator Inhibitor-1 (PAI-1), but decreased C-reactive protein (CRP) by 33%. Interestingly, Troglitazone increased the size of LDL and the mean LDL-C level (+10%), but decreased the Triglyceride (-22%) and CRP (-60%) concentrations (7). Following eight weeks of treatment with Rosiglitazone (4mg, twice daily) in 243 type 2 diabetic patients, the mean HDL-C increased by 6% and TG by 2%. The increase in the LDL-C concentration (9%) was accompanied by a shift in small, dense LDL to large, buoyant LDL in 52% of the treated subjects. The shift in LDL size occurred independent of a significant Triglyceride reduction, which is in contrast to several studies reporting that increases in LDL size are significantly correlated with a decrease in the plasma concentrations of total and very low density lipoproteins (VLDL) Triglycerides (8-10).

The mechanism involved in the plasma lipid and lipoprotein changes induced by TZDs remains unclear. It is possible that these agents indirectly alter plasma lipid and lipoprotein levels indirectly by improving insulin sensitivity and glycemic control, or directly by influencing lipoprotein synthesis and/or catabolism.

In type 2 Diabetes Mellitus, hepatic synthesis of Triglycerides is increased and peripheral catabolism is decreased. The primary metabolic defect causing the hypertriglyceridemia is peripheral insensitivity to the action of insulin, accompanied by hyperinsulinemia. The insulin insensitivity inhibits the synthesis and activity of lipoprotein lipase and consequently impairs peripheral catabolism of Triglyceride-rich lipoproteins (VLDL and Chylomicrons) (11-12). Since hepatocytes remain sensitive to the action of insulin, the hyperinsulinemia suppresses beta-oxidation and shunts free fatty acids entering the liver into the synthesis of Triglycerides. Therefore, hepatic production of Triglycerides (i.e. VLDL) is increased at the same time peripheral catabolism is impaired. The result is hypertriglyceridemia with a reciprocal decease in HDL-C concentration. By reducing insulin resistance and plasma insulin levels, TZDs would decrease hepatic Triglyceride production and enhance peripheral catabolism of Triglycerides, resulting in plasma reduction and a reciprocal increase in the HDL-C level.

Recently, it has been recognized that circulating levels of Triglyceride and HDL-C are influenced by the activities of Peroxisome Proliferator Activator Receptors (PPARs). PPARs constitute a super family of nuclear hormone receptors and are ligand-activated transcription factors. When activated, they transmit signals from intra-cellular lipid-soluble factors (e.g. fatty acids, hormones, vitamins) to genes in the nucleus by binding to DNA at specific response elements (13). Three distinct PPARs, termed alpha, beta, and gamma modulate intracellular lipid and glucose metabolism through controlling gene expression when activated (14). Specifically when PPAR-alpha is activated, gene expression for the synthesis of ApoC-III, lipoprotein lipase, ApoA-I and ApoA-II are impacted. ApoC-III is a specific inhibitor of peripheral lipoprotein lipase and competes with ApoE for space on the surface of VLDL. Reduced amounts of ApoC-III will result in a larger representation of ApoE on the VLDL particle, and as a consequence, the ApoE mediated hydrolysis of Triglycerides is enhanced. Activation of PPAR-alpha leads to decrease production of ApoC-III, which in turn results in enhanced clearance of Triglycerides. Activation of PPAR-alpha also increases the synthesis of lipoprotein lipase, which increases Triglyceride catabolism. Gene expression for the synthesis of ApoA-I and ApoA-II is also enhanced by activation of PPAR-alpha, resulting in increase in HDL concentration. Fibric acid derivatives (Gemfibrozil and Fenofibrate) induce their Triglyceride lowering and HDL-C augmenting properties by binding to the PPAR-alpha nuclear receptor.

TZDs are PPAR-gamma ligands that stimulate the gene expression of GLUT1 and GLUT4 (cellular glucose transport proteins) leading to increased insulin sensitivity in the target cells (15,16). The three PPAR receptors possess some degree of structural homology. Therefore, while TZDs have high affinity to PPAR-gamma, they may also bind to a lesser degree to PPAR-alpha or beta. Saliel and Olefsky (17) have determined in cell culture studies that Troglitazone can activate all three PPAR nuclear receptors. Lehmann et al. (18) observed in vitro that TZDs are high affinity ligands for PPAR-gamma yet also bind to PPAR-alpha (to a small degree). Binding PPAR-alpha would directly enhance the catabolism of Triglycerides (i.e. reduced ApoC-III plasma concentrations and increased lipoprotein lipase activity) and increase HDL-C plasma concentration through enhancing the expression of lipoprotein lipase and ApoA-I and ApoA-II. Therefore, administration of TZDs to non-diabetic normoglycemic individuals should not change plasma glucose concentrations, but by binding to PPAR-alpha it would result in decrease in the plasma concentration of ApoC-III, and an increase in ApoA-I and ApoA-II, with a subsequent rise in HDL-C and reduction in Triglyceride concentration.

In a recent animal study assessing Rosiglitazone's mode of action on lipids using male Sprague-Dawley rats, serum total, free and HDL cholesterol concentrations were monitored. In rats given Rosiglitazone, serum Triglyceride levels decreased in a dose-dependent manner, dropping to less than 50% of that of the control rats at the highest dose tested (5 mg/kg/d). Serum glucose concentrations did not change after Rosiglitazone treatment, which is in agreement with previous studies showing that thiazolidinediones do not exert a hypoglycemic action in the normoglycemic, non-diabetic rat. (18)

Study Type

Interventional

Enrollment (Actual)

41

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • San Antonio, Texas, United States, 78234
        • Brooke Army Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion criteria:

  1. Fasting plasma glucose <100 mg/dl
  2. Fasting LDL <160 mg/dl and Triglyceride <400 mg/dl.

Exclusion criteria:

  1. Congestive heart failure
  2. Evidence of renal impairment (serum creatinine> 1.4mg/dL)
  3. Liver disease (ALT and/or AST above the upper level of normal)
  4. Known diabetes mellitus or impaired fasting glucose (fasting glucose ≥ 100mg/dL)
  5. LDL of ≥160mg/dL and/or triglycerides of ≥400mg/dL
  6. Pregnant or breast feeding women
  7. Prior history of an acute coronary syndrome, myocardial infarction or revascularization procedures in the past
  8. Life-threatening disease with a survival prognosis <3 years
  9. Inability to take rosiglitazone and/or fenofibrate
  10. Already on statin therapy or have been on statin therapy in the last 3 months

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Rosiglitazone + Placebo
Rosiglitazone 8 mg daily + Placebo (Fenofibrate) 145 mg daily for 12 weeks
Drug: Rosiglitazone
Rosiglitazone 8mg daily for 12 weeks
Other Names:
  • Avandia
Drug: Placebo (Fenofibrate)
Placebo (Fenofibrate) 145 mg daily for 12 weeks
Active Comparator: Fenofibrate + Placebo
Fenofibrate 145mg daily + Placebo (Rosiglitazone) 8mg daily for 12weeks
Drug: Placebo (Rosiglitazone)
Placebo (Rosiglitazone) 8mg daily for 12 weeks
Drug: Fenofibrate
Fenofibrate 145 mg daily for 12 weeks
Other Names:
  • Tricor, Triglide, Fenoglide, Lipofen and Lofibra
Experimental: Rosiglitazone +Fenofibrate
Rosiglitazone 8mg daily + Fenofibrate 145mg daily for 12 weeks
Drug: Rosiglitazone
Rosiglitazone 8mg daily for 12 weeks
Other Names:
  • Avandia
Drug: Fenofibrate
Fenofibrate 145 mg daily for 12 weeks
Other Names:
  • Tricor, Triglide, Fenoglide, Lipofen and Lofibra
Placebo Comparator: Placebo Therapy Daily
Placebo (Rosiglitazone) 8mg daily + Placebo (Fenofibrate) 145 mg daily for 12 weeks
Drug: Placebo (Fenofibrate)
Placebo (Fenofibrate) 145 mg daily for 12 weeks
Drug: Placebo (Rosiglitazone)
Placebo (Rosiglitazone) 8mg daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change in Triglyceride (TG) Levels Post Treatment
Time Frame: 12 weeks from initial visit (day 0) to final visit (12 weeks)
The reported percent change is the difference between TG levels obtained on initial visit (day 0) and TG levels obtained at final visit (week 12) as per protocol
12 weeks from initial visit (day 0) to final visit (12 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post-treatment Percent Change in High-Density Lipoprotein (HDL) Levels
Time Frame: 12 weeks from initial visit (day 0) to final visit (12 weeks)
The reported percent change is the difference between HDL levels obtained on initial visit (day 0) and HDL levels obtained at final visit (week 12) as per protocol
12 weeks from initial visit (day 0) to final visit (12 weeks)
Post-treatment Percent Change in Low-Density Lipoprotein (LDL) Levels
Time Frame: 12 weeks from initial visit (day 0) to final visit (12 weeks)
The reported percent change is the difference between LDL levels obtained on initial visit (day 0) and LDL levels obtained at final visit (week 12) as per protocol
12 weeks from initial visit (day 0) to final visit (12 weeks)
Post-treatment Percent Change in Apolipoprotein A-I (Apo AI), Apolipoprotein A-II (Apo AII) and Apolipoprotein C-III (Apo CIII) Levels
Time Frame: 12 weeks from initial visit (day 0) to final visit (12 weeks)
Post-treatment median change in Apo AI, Apo AII and Apo CIII levels reported in mg/dL with Interquartile ranges provided
12 weeks from initial visit (day 0) to final visit (12 weeks)
Mean Levels of Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) at Initial Visit and Final Visit
Time Frame: 12 weeks from initial visit (day 0) to final visit (12 weeks)
The mean Levels of AST and ALT measured at initial visit (Day 0) and final visit (Week 12) annotated as AST 1, AST 12, and ALT 1 and ALT 12, respectively.
12 weeks from initial visit (day 0) to final visit (12 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ahmad Slim

Collaborators

GlaxoSmithKline

Investigators

  • Study Chair: Laudino Castillo-rojas, MD, Brooke Army Medical Center
  • Study Director: Jennifer N Slim, DO, Brooke Army Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2008

Primary Completion (Actual)

May 1, 2010

Study Completion (Actual)

May 1, 2010

Study Registration Dates

First Submitted

January 8, 2009

First Submitted That Met QC Criteria

January 8, 2009

First Posted (Estimate)

January 9, 2009

Study Record Updates

Last Update Posted (Estimate)

April 24, 2014

Last Update Submitted That Met QC Criteria

April 8, 2014

Last Verified

April 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • C.2007.122

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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