Donor Simvastatin Treatment in Organ Transplantation (SIMVA)

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

Study Overview

• Status: Completed
• Conditions: Liver Failure; Heart Failure; Respiratory Failure; Kidney Failure; Transplantation
• Intervention / Treatment: Drug: Simvastatin 80mg; Drug: Control Rx

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, FI-00029
    • Cardiac Surgery, Heart and Lung Center, Helsinki University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Simvastatin 80 mg group; The transplant recipients who have received an organ from donors treated with simvastatin 80 mg.	Drug: Simvastatin 80mg; The transplant recipients who have received an organ from donors treated with simvastatin 80 mg.; Other Names: simvastatin
EXPERIMENTAL: Control Rx; The transplant recipients who have received an organ from non-treated donors.	Drug: Control Rx; The transplant recipients who have received an organ from non-treated donors.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: University of Helsinki; Academy of Finland
• Investigators: Principal Investigator: Karl B Lemstrom, MD, PhD, Cardiac Surgery, Heart and Lung Center, Helsinki University Hospital

Publications and helpful links

General Publications

• Nykanen AI, Holmstrom EJ, Tuuminen R, Krebs R, Dhaygude K, Kankainen M, Jokinen JJ, Lommi J, Helantera I, Raisanen-Sokolowski A, Syrjala SO, Lemstrom KB. Donor Simvastatin Treatment in Heart Transplantation. Circulation. 2019 Aug 20;140(8):627-640. doi: 10.1161/CIRCULATIONAHA.119.039932. Epub 2019 Jul 29.

Helpful Links

• Website of Heart and Lung Center, Helsinki University Hospital
• Website of Transplantation Laboratory, University of Helsinki

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2010
• Primary Completion (ACTUAL): August 1, 2016
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: July 12, 2010
• First Submitted That Met QC Criteria: July 12, 2010
• First Posted (ESTIMATE): July 13, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 19, 2017
• Last Update Submitted That Met QC Criteria: September 17, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Rejection; Transplantation; Ischemia-reperfusion injury; Simvastatin treatment
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Respiratory Tract Diseases; Respiration Disorders; Kidney Diseases; Urologic Diseases; Liver Diseases; Liver Failure; Respiratory Insufficiency; Renal Insufficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: T1020SIMVASTATIN