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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01186250
Recruitment Status : Completed
First Posted : August 23, 2010
Results First Posted : August 18, 2016
Last Update Posted : August 18, 2016
Information provided by (Responsible Party):
Kiran Khush, Stanford University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cardiac Allograft Vasculopathy Drug: Pioglitazone Drug: Placebo Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Clinical Trial of Pioglitazone for Prevention of Cardiac Allograft Vasculopathy After Heart Transplantation
Study Start Date : July 2010
Actual Primary Completion Date : August 2013
Actual Study Completion Date : December 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Pioglitazone
Drug: Pioglitazone
15mg pioglitazone taken daily for one month, 30mg pioglitazone taken daily for another month, 45mg pioglitazone taken daily for remaining ten months
Other Name: Actos

Placebo Comparator: Placebo
Drug: Placebo
placebo taken daily for one year

Primary Outcome Measures :
  1. Insulin Levels Area Under Curve(AUC) [ Time Frame: Baseline and 1 year ]
    Change from baseline in Insulin Levels During Oral Glucose Tolerance test at 1 year.

Secondary Outcome Measures :
  1. Change in Intimal Volume [ Time Frame: baseline and 1 year ]
    Intimal volume is defined as external elastic membrane volume minus lumen (luminal) volume measured at the heart Catheterization and intravascular Ultrasound( IVUS)

  2. Change in Levels of Fasting Glucose at Baseline and 1 Year [ Time Frame: 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.

  3. Change From Baseline in TG/HDL Ratio at One Year [ Time Frame: Baseline and 1 year ]
    Triglyceride ratio to High Density Lipoprotien

  4. Change in Maximal Intimal Thickness(MIT) by Intravascular Unltrasound(IVUS) [ Time Frame: Baseline and 1 year ]
    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.

  5. Change From Baseline in ADMA (Asymmetric Dimethylarginine) at One Year. [ Time Frame: Baseline and 1 year ]
    Competitive ELISA assay in Stanford laboratory.

  6. Change From Baseline in High-sensitivity C-reactive Protein (HsCRP) at One Year [ Time Frame: Baseline and 1 year ]
    measure of low levels of C-reactive protein to identify low but persistent levels of inflammation

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01186250

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United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
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Principal Investigator: Kiran Khush Stanford University

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Responsible Party: Kiran Khush, Assistant Professor of Medicine, Stanford University Identifier: NCT01186250     History of Changes
Other Study ID Numbers: SU-05282010-6202
CTRU protocol 1314
IRB protocol 19373
First Posted: August 23, 2010    Key Record Dates
Results First Posted: August 18, 2016
Last Update Posted: August 18, 2016
Last Verified: July 2016
Keywords provided by Kiran Khush, Stanford University:
cardiac allograft vasculopathy
insulin resistance
heart transplant
Additional relevant MeSH terms:
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Vascular Diseases
Cardiovascular Diseases
Hypoglycemic Agents
Physiological Effects of Drugs