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Cardiac Allograft Remodeling and Effects of Sirolimus (CAR)

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.
 
ClinicalTrials.gov Identifier: NCT01889992
Recruitment Status : Suspended (PI left University and project not continued)
First Posted : July 1, 2013
Last Update Posted : December 11, 2019
Sponsor:
Information provided by (Responsible Party):
University of Nebraska

Brief 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.


Condition or disease Intervention/treatment Phase
Cardiac Hypertrophy Immunosuppression Radiation: Cardiac MRI Procedure: Coronary angiography with IVUS Other: Cardiac Allograft Remodeling Drug: M-TOR Immunosuppression Procedure: Cardiac Biopsy C4D stain Genetic: Genetic Mechanism of M-TOR Other: Cardiopulmonary Exercise Test (CPET) Phase 1

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cardiac Allograft Remodeling and Effects of Sirolimus on Its Progression
Actual Study Start Date : April 2013
Actual Primary Completion Date : September 2018
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arm Intervention/treatment
Active Comparator: Cardiac biopsy C4D stain
A procedure that removes a very small sample of your heart muscle so that it can be evaluated in the lab. This procedure may be done to determine the cause of cardiac myopathy (a weakened heart muscle) or to check for rejection after a heart transplant.
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.
Other Name: heart biopsy

Experimental: 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.

Sirolimus dosage is based on blood levels.

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.

Active Comparator: Cardiac MRI
Cardiac Magnetic Resonance Imaging (MRI) produces no side effects from the magnetic fields and radio waves and doesn't carry a risk of cancer or birth defects. Serious reactions to the special contrast dyes used for MRI are very rare. The MRI examination poses almost no risk to the average patient when appropriate safety guidelines are followed, however side effects are possible and include headache, nausea, dizziness, change in taste and allergic reaction. Such reactions usually are mild and easily controlled by medication.
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%.

Active Comparator: 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.

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.


Active Comparator: Cardiopulmonary Exercise Test (CPET)
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.
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.
Other Name: Stress test

Experimental: MTor Immunosuppression

Sirolimus

Sirolimus dosage is based on blood levels.

To assess the potential of mTOR immunosuppressant Sirolimus in attenuation of CAR in HTx recipients and therefore, improve pre-existing cardiac allograft function, vasculopathy, and exercise capacity.

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.
Other Name: heart hypertrophy

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.

Other Name: Sirolimus

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




Primary Outcome Measures :
  1. Assessment in left ventricular hypertrophy [ Time Frame: One year ]
    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.


Secondary Outcome Measures :
  1. Assess outcomes [ Time Frame: One year ]
    The secondary end points will be changes from baseline in LV function.

  2. Access outcomes [ Time Frame: One year ]
    Exercise performance (peak VO2, equivalent for carbon dioxide (VE/VCO2)and coronary vessel intimal thickening.


Other Outcome Measures:
  1. Safety end points [ Time Frame: Three years ]
    Safety end points will be SRL side effects and prevalence of acute cellular cardiac rejection (ISHLT ≥ 2R) and AMR.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   19 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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 ClinicalTrials.gov identifier (NCT number): NCT01889992


Locations
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United States, Nebraska
The Nebraska Medical Center
Omaha, Nebraska, United States, 68198-2265
Sponsors and Collaborators
University of Nebraska
Investigators
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Principal Investigator: Eugenia Raichlin, MD University of NE Medical Center/The Nebraska Medical Center
Publications of Results:
Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O'Connell J, Rogers J, Ross H, Russell S, Vanhaecke J; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010 Aug;29(8):914-56. doi: 10.1016/j.healun.2010.05.034.

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Responsible Party: University of Nebraska
ClinicalTrials.gov Identifier: NCT01889992    
Other Study ID Numbers: 339-12-FB
First Posted: July 1, 2013    Key Record Dates
Last Update Posted: December 11, 2019
Last Verified: December 2019
Keywords provided by University of Nebraska:
Heart transplantation
Cardiac allograft remodeling
Immunosuppression
Cardiac MRI
M-TOR inhibitor
Additional relevant MeSH terms:
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Cardiomegaly
Hypertrophy
Pathological Conditions, Anatomical
Heart Diseases
Cardiovascular Diseases
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs