Clinical Trial of Pioglitazone for Prevention of Cardiac Allograft Vasculopathy After Heart Transplantation

Stanford University18 enrolled

Overview

The purpose of this study is to determine the benefit of using the FDA-approved insulin-sensitizing agent, Pioglitazone, on human heart transplant recipients. The objectives of this project are to (1) determine if pioglitazone effectively treats insulin resistance in heart transplant recipients, and (2) to determine whether pioglitazone therapy after heart transplantation impacts the development or progression of cardiac allograft vasculopathy (CAV), a form of chronic rejection after heart transplantation.

CAV, a rapidly progressive obliterative disease involving the graft coronary arteries, is the leading cause of morbidity and mortality beyond the first year after heart transplantation. This common complication occurs in almost half of recipients within 3 years after heart transplantation, and is associated with high rates of graft failure and mortality. Clinical care of heart transplant recipients in the current era is greatly limited by the lack of effective treatment options to prevent or retard the progression of CAV. CAV appears to be strongly associated with the state of insulin resistance, which is present in over half of heart transplant recipients and is characterized by metabolic abnormalities including glucose intolerance, dyslipidemia, endothelial dysfunction, and high levels of circulating inflammatory markers. Insulin resistance can be effectively treated with pioglitazone, a TZD compound which directly affects tissue insulin sensitivity. In this study, we will enroll 32 insulin-resistant heart transplant recipients and will randomize them to pioglitazone or placebo for a one-year period. We will determine the efficacy of pioglitazone for the treatment of insulin resistance and prevention of the development and progression of CAV after heart transplantation. The data generated from this study will provide important preliminary data for future, larger-scale clinical investigations.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Cardiac Allograft Vasculopathy

Interventions

PioglitazoneDRUG

15mg pioglitazone taken daily for one month, 30mg pioglitazone taken daily for another month, 45mg pioglitazone taken daily for remaining ten months

PlaceboDRUG

placebo taken daily for one year

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Heart transplant recipients, years 1-4 post-transplant 2. Age \>= 18 years 3. Fasting TG/HDL ratio\>=3.0 or Fasting TG\>=150 mg/dL Exclusion Criteria: 1. Diabetes mellitus 2. Severe liver dysfunction (ALT\>=2.5 x upper limit of normal) 3. Severe renal dysfunction (GFR\<30 or Stage IV CKD) 4. Moderate-severe fluid retention 5. Clinical or echocardiographic signs of left ventricular dysfunction 6. Contraindication to coronary angiography and/or IVUS

Locations (1)

Stanford University School of Medicine

Stanford, California, United States

Outcomes

Primary Outcomes

Insulin Levels Area Under Curve(AUC)

Change from baseline in Insulin Levels During Oral Glucose Tolerance test at 1 year.

Time frame: Baseline and 1 year

Secondary Outcomes

Change in Intimal Volume

Intimal volume is defined as external elastic membrane volume minus lumen (luminal) volume measured at the heart Catheterization and intravascular Ultrasound( IVUS)

Time frame: baseline and 1 year

Change in Levels of Fasting Glucose at Baseline and 1 Year

Oral Glucose Tolerance Test : blood was drawn for fasting plasma glucose and insulin levels, followed by ingestion of a solution containing 75grams of glucose. Repeat blood samples were collected for glucose and insulin levels at 30, 90, and 120 minutes after glucose ingestion. All glucose measurements were performed by the Clinical Translational Research Unit (CTRU) Stanford University.

Time frame: Baseline and 1 year

Change From Baseline in TG/HDL Ratio at One Year

Triglyceride ratio to High Density Lipoprotien

Time frame: Baseline and 1 year

Change in Maximal Intimal Thickness(MIT) by Intravascular Unltrasound(IVUS)

The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery, the cross sections, predominantly in the left anterior descending coronary artery, from baseline to one-year follow-up, were studied. The IVUS cross sections were matched by using identifiable landmarks in the images, such as bifurcations or arterial calcification, or external landmarks, such as coronary veins or pericardium. In addition, the one-year IVUS studies were obtained with an angiographic roadmap of where the initial IVUS study was performed along the length of the vessel. The IVUS system auto pullback was performed at .5 mm/s from the mid-distal portion of the study vessel, where an easily identifiable landmark was visible (i.e., branchpoint). The following items were measured for each patient: maximal intimal thickness (MIT), intimal area (IA), and vessel area.

Data from ClinicalTrials.gov

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