Donor Simvastatin Treatment in Organ Transplantation

Study Overview
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Brief Summary
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The aim of the study is to investigate the effects of donor simvastatin treatment on ischemia-reperfusion injury after heart transplantation.

Detailed Description
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The study hypothesis of the single center randomized double-blinded clinical trial is that donor simvastatin treatment reduces ischemia-reperfusion injury after heart transplantation. Also, it potentially decreases natural immune activity, rejection activation and thus improves long-term prognosis. Simvastatin is administered to heart and/or lung donors through the nasogastric tube 4-6 hours prior to organ harvesting. Control organ donors do not receive simvastatin. The randomization and donor hospital instruction of the donor simvastatin treatment is performed by the transplant coordinator. All other caregivers and the transplant recipient are blinded to the treatment group allocation. The impact of donor simvastatin treatment is investigated and analyzed by several specific blood samples and biopsies that are taken from the recipient at the various time-points during the perioperative and postoperative phase. In heart transplant recipients (n=42 in the donor simvastatin treatment group and n=42 in the control group), the primary end-point is postoperative cardiac enzyme serum levels (TnT, TnI, and CK-MB 1 hour, 6 hours, 12 hours and 24 hours after transplantation) and primary graft failure. Secondary end-points include peri- and postoperative parameters hemodynamics, short- and long term survival, biopsy-proven rejections, rejection treatments, and chronic rejection at 1, 5, 10, and 20 years after transplantation. Lung, kidney and liver transplant recipients that have received organs from donors randomized to the control group or donor simvastatin group will also be followed for ischemia-reperfusion injury, perioperative organ function, innate and adaptive immunity and patient survival.

Official Title
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Donor Simvastatin Treatment in Organ Transplantation

Conditions
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Heart Failure, Respiratory Failure, Liver Failure, Kidney Failure, Transplantation

Intervention / Treatment
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* Drug: Simvastatin 80mg
* Drug: Control Rx


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for a donor: Heart transplant donor Age 18-60 years Previously healthy No cholesterol medication Normal ECHO with LVEF >45%, normal right ventricle and normal coronary angiography PiO2/FiO2 > 40kPA, normal chest radiograph and normal bronchoscopy in lung donors Exclusion Criteria for the heart/lung donor: Severe left ventricular hypertrophy > 14 mm High dose of inotropes (dopamine or dobutamine > 20ug/kg/min or norepinephrine >0.2 ug/kg/min) at the time of procurement Donor outside of the study country Finland Inclusion criteria for a transplant recipient: Age between 18-70 for heart transplant recipients Male or female Listed for heart, lung, kidney, or liver transplantation Exclusive Criteria for the recipient systemic sepsis a positive cross match

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simvastatin 80 mg group<br>The transplant recipients who have received an organ from donors treated with simvastatin 80 mg. | Drug: Simvastatin 80mg<br>* The transplant recipients who have received an organ from donors treated with simvastatin 80 mg.<br>* Other names: simvastatin;|
| Experimental: Control Rx<br>The transplant recipients who have received an organ from non-treated donors. | Drug: Control Rx<br>* The transplant recipients who have received an organ from non-treated donors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor treatment with simvastatin reduces ischemia-reperfusion injury after heart transplantation | Recipient plasma release of cardiac troponins and creatinine kinase-MB and P-lactate, S-hs-CRP, peripheral blood leukocytes and neutrophils after heart transplantation | 1-24 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative hemodynamics | Arterial line and pulmonary artery catheter measurements 6, 12, 24, 48, and 72 hours | 0-72h | 
| Postoperative use of inotropes and hemodynamic support | Postoperative use of inotropes and hemodynamic support at 6, 12, 24, 48, and 72 hours and the length of inotropic support | 0-72h | 
| Heart transplant function | Heart transplant function analyzed by P-ProBNP and echocardiogram | 0-20 years | 
| Cardiac allograft vasculopathy | Cardiac allograft vasculopathy analyzed coronary angiogram | at 1, 3, and 5 years | 
| Biopsy proven acute rejection | Grade of rejection at endomyocardial biopsy | 0-20 years | 
| Rejection treatments | Any rejection treatments | 0-20 years | 
| Short- and long-term survival | Time to all-cause mortality | 0-20 years | 
| Substudy 1 | Outcome of kidney transplant recipients | 0-20 years | 
| Substudy 2 | Outcome of liver transplant recipients | 0-20 years | 
| Substudy 3 | Outcome of lung transplant recipients | 0-20 years | 
| Substudy 4 | Development of biomarkers for ischemia-reperfusion injury after heart transplantation | 0-24 h | 
| Substudy 5 | Development of molecular profiling for endomyocardial biopsy after heart transplantation | 0-1 years | 
| Substudy 6 | Effect of donor and recipient genomic backgroud on long term outcomes after heart transplantation | 0-20 years | 
| Substudy 7 | Effect of donor and recipient genomic backgroud on long term outcomes after kidney transplantation | 0-20 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transplantation, Simvastatin treatment, Ischemia-reperfusion injury, Rejection