Cardiac Allograft Remodeling and Effects of Sirolimus

Immunosuppression Clinical Trial

— CAR  

Official title:

Cardiac Allograft Remodeling and Effects of Sirolimus on Its Progression

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01889992
• Other study ID #: 0339-12-FB
• Status: Terminated
• Phase: Phase 1
• Start date: April 24, 2013
• Est. completion date: September 27, 2018

Study information

• Verified date: August 2023
• Source: University of Nebraska
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Cardiac allograft remodeling causes poor quality of life, allograft failure and increased mortality after heart transplantation. Risk factors for cardiac allograft remodeling and its progression are poorly defined and there is a need for effective interventions.This is a multi-factorial phenomenon, associated with various immunological and non-immunological factors. Animal studies suggest M-TOR inhibition attenuates cardiac allograft remodeling secondary to down-regulation of M-TOR downstream targets and increased autophagy. There is a paucity of data regarding effect of Sirolimus, a M-TOR inhibitor, on human heart remodeling.

This aim of the proposal to identify the prevalence of cardiac allograft remodeling on current immunosuppressive strategies and determine risk factors for its development. It will also identify molecular pathways associated with cardiac allograft remodeling and determine the impact of Sirolimus on these pathways.

Description:

Heart transplantation has become a well-established treatment option for patients with end-stage heart disease and currently has a one-year survival rate of 90%, a five-year survival rate of 70%, and 10-year survival rate of 50%. The introduction of anti-rejection treatment thirty years ago with drugs known as calcineurin inhibitors have resulted in a significant improvement in the survival of heart transplant recipients. However, most of this improvement occurs during the first year after transplantation. Beyond the first year, the mortality rate of heart transplant recipients has not changed, which indicates that the causes of late complications have not been affected in the last three decades by improvements in post-transplant care. It becomes apparent that in order to improve the late outcomes, the focus in heart transplant research needs to be shifted to the prevention and the treatment of late complications.

Cardiac allograft remodeling (CAR), or changes in heart's geometric pattern, is one of the common complications after heart transplantation and often inflicts poor quality of life, heart failure, and decreased survival. The risk factors and mechanism for the development and progression of CAR are poorly defined, and there is no effective treatment for this condition. In the proposed study, we will identify the prevalence, risk factors, and effect of CAR on physical capacity, cardiac vascular disease, and patient survival after a heart transplant. For assessment of heart geometry, we will use cardiac magnetic resonance imaging (CMRI), a techniques used to visualize the internal structures of the body in detail. CMRI is considered as being a "gold standard" for evaluating the heart's structure and function. We will also evaluate the molecular and genetic markers associated with development and progression of CAR after heart transplantation.

The drug Sirolimus, a new anti-rejection agent, can be used in place of calcineurin inhibitors after heart transplantation. Recent experimental and animal studies indicate that Sirolimus can attenuate the changes in the heart's geometry after a transplant (i.e., CAR) and improve heart function. We will assess the effect of Sirolimus on CAR in humans and will evaluate molecular and genetic markers associated with this effect.

It is our goal to provide an important insight into the nature of CAR after heart transplantation and its response to new anti-rejection drug Sirolimus. This information will have a significant impact on the treatment of heart transplant recipients and thus improve quality of life and prolong survival after heart transplantation.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: September 27, 2018
• Est. primary completion date: September 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 70 Years

Eligibility

Inclusion Criteria:

• All adult cardiac transplant recipients undergoing heart transplantation at UNMC/TNMC.

Exclusion Criteria:

• Adult cardiac transplant recipients with acute rejection (ISHLT R> grade 2) or acute infection.

Related Conditions & MeSH terms

• Cardiac Hypertrophy
• Cardiomegaly
• Hypertrophy
• Immunosuppression

Intervention

Radiation:
• Cardiac MRI
1 month post HTx, year 1 and year 2 annual post HTx eval. CMRIs completed using 1.5-Tesla Whole Body MRI system. Scout images will determine short & long-axis views of the heart. ECG-gated cine MR of 3 long axis and a contiguous short axis orientation will be obtained. T1-weighted delayed enhancement images will be obtained 10 minutes after injection of a gadolinium-based contrast agent. Measurements from each slice will be summed using the method of disks. Myocardial mass will be estimated by multiplying the myocardial wall volume at end diastole by the specific gravity of muscle (1.05gm/ml) and LV hypertrophy will be defined as LV mass indexed to height in meters 2.7 >/=35.8 g/m 2.7) (18). Delayed Gadolinium enhancement will be defined as any enhancement pattern greater than 0%.

Procedure:
• Coronary angiography with IVUS
Coronary angiography is a test that uses dye and special x rays to show the insides of your coronary arteries. The coronary arteries supply oxygen-rich blood to your heart. Intravascular ultrasound is a test that uses sound waves to see inside blood vessels. This article discusses intravascular ultrasound to see inside the coronary arteries, the blood vessels that supply the heart.

Other:
• Cardiac Allograft Remodeling
A surgical procedure in which a diseased heart is replaced with a healthy heart from a deceased person.

Drug:
• M-TOR Immunosuppression
Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B-cells by inhibiting their response to interleukin-2 (IL-2). Sirolimus dosage based on blood levels.

Procedure:
• Cardiac Biopsy C4D stain
A long, thin tube called a biopsy catheter is inserted through a vein in your neck or grion and guided through your blood vessels to your heart.

Genetic:
• Genetic Mechanism of M-TOR
To identify the molecular and genetic mechanisms associated with development of early post-transplant CAR, and to evaluate the impact of mTOR-inhibitor Sirolimus on this process.

Other:
• Cardiopulmonary Exercise Test (CPET)
The Cardiopulmonary Exercise Test is a highly sensitive, non-invasive stress test. It is considered a stress test because the exercise stresses your body's systems by making them work faster and harder. A disease or condition that affects the heart, lungs or muscles will limit how much faster and harder these systems can work. A CPET assesses how well the heart, lungs, and muscles are working individually, and how these systems are working in unison. Your heart and lungs work together to deliver oxygen to your muscles, where it is used to make energy, and to remove carbon dioxide from your body.

Locations

Country	Name	City	State
United States	University of Nebraska Medical Center	Omaha	Nebraska

Sponsors (1)

Lead Sponsor	Collaborator
University of Nebraska

Country where clinical trial is conducted

United States, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety end points	Safety end points will be SRL side effects and prevalence of acute cellular cardiac rejection (ISHLT = 2R) and AMR.	Three years
Primary	Assessment in left ventricular hypertrophy	The primary end point will be the change from baseline in LV mass indexed to height in meters 2.7 and LV concentricity as assessed by MRI during 12 months of the treatment.	One year
Secondary	Assess outcomes	The secondary end points will be changes from baseline in LV function.	One year
Secondary	Access outcomes	Exercise performance (peak VO2, equivalent for carbon dioxide (VE/VCO2)and coronary vessel intimal thickening.	One year