Cardiac Allograft Vasculopathy
Conditions
Keywords
cardiac allograft vasculopathy, pioglitazone, insulin resistance, heart transplant
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.
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.
Interventions
DRUGPioglitazone
15mg pioglitazone taken daily for one month, 30mg pioglitazone taken daily for another month, 45mg pioglitazone taken daily for remaining ten months
DRUGPlacebo
placebo taken daily for one year
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Levels Area Under Curve(AUC) | Baseline and 1 year | Change from baseline in Insulin Levels During Oral Glucose Tolerance test at 1 year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Levels of Fasting Glucose at Baseline and 1 Year | 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. |
| Change From Baseline in TG/HDL Ratio at One Year | Baseline and 1 year | Triglyceride ratio to High Density Lipoprotien |
| Change in Intimal Volume | 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) |
| Change From Baseline in ADMA (Asymmetric Dimethylarginine) at One Year. | Baseline and 1 year | Competitive ELISA assay in Stanford laboratory. |
| Change From Baseline in High-sensitivity C-reactive Protein (HsCRP) at One Year | Baseline and 1 year | measure of low levels of C-reactive protein to identify low but persistent levels of inflammation |
| Change in Maximal Intimal Thickness(MIT) by Intravascular Unltrasound(IVUS) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone
Pioglitazone: 15mg pioglitazone taken daily for one month, 30mg pioglitazone taken daily for another month, 45mg pioglitazone taken daily for remaining ten months | 9 |
| Placebo Placebo
Placebo: placebo taken daily for one year | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Placebo | Pioglitazone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 8 Participants | 16 Participants |
| Age, Continuous | 49.2 years | 50.8 years | 50.0 years |
| Region of Enrollment United States | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pioglitazone | Insulin Levels Area Under Curve(AUC) | -47.7 h*pmol/L |
| Placebo | Insulin Levels Area Under Curve(AUC) | 10.7 h*pmol/L |
Secondary
Change From Baseline in ADMA (Asymmetric Dimethylarginine) at One Year.
Competitive ELISA assay in Stanford laboratory.
Time frame: Baseline and 1 year
Population: One participant in one arm did not have Baseline or one year data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in ADMA (Asymmetric Dimethylarginine) at One Year. | -0.05 umol/L | Standard Deviation 0.1 |
| Placebo | Change From Baseline in ADMA (Asymmetric Dimethylarginine) at One Year. | -0.02 umol/L | Standard Deviation 0.1 |
Secondary
Change From Baseline in High-sensitivity C-reactive Protein (HsCRP) at One Year
measure of low levels of C-reactive protein to identify low but persistent levels of inflammation
Time frame: Baseline and 1 year
Population: participant drop put
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in High-sensitivity C-reactive Protein (HsCRP) at One Year | -3 mg/L | Standard Deviation 3 |
| Placebo | Change From Baseline in High-sensitivity C-reactive Protein (HsCRP) at One Year | 2 mg/L | Standard Deviation 4 |
Secondary
Change From Baseline in TG/HDL Ratio at One Year
Triglyceride ratio to High Density Lipoprotien
Time frame: Baseline and 1 year
Population: One drop out
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in TG/HDL Ratio at One Year | -0.03 ratio | Standard Deviation 6 |
| Placebo | Change From Baseline in TG/HDL Ratio at One Year | -1.2 ratio | Standard Deviation 3.3 |
Secondary
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
Population: The number of participants enrolled were not all included in the intimal volume analysis because the Angiographic diagnostic evaluation needed for intimal volume measurement was clinically inappropriate for 3 in the pioglitazone arm and 5 in the Placebo arm at 12 months post transplant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change in Intimal Volume | 12.2 mm^3 | Standard Deviation 39.9 |
| Placebo | Change in Intimal Volume | -26.8 mm^3 | Standard Deviation 46.7 |
Secondary
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
Population: One participant in each group did not complete the OGTT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change in Levels of Fasting Glucose at Baseline and 1 Year | 2.1 mg/dL | Standard Deviation 19 |
| Placebo | Change in Levels of Fasting Glucose at Baseline and 1 Year | 11 mg/dL | Standard Deviation 33 |
Secondary
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.
Time frame: Baseline and 1 year
Population: number participants analyzed contained drops out due to clinical reasons
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change in Maximal Intimal Thickness(MIT) by Intravascular Unltrasound(IVUS) | -0.01 mm | Standard Deviation 0.3 |
| Placebo | Change in Maximal Intimal Thickness(MIT) by Intravascular Unltrasound(IVUS) | -0.02 mm | Standard Deviation 0.1 |