Remote Ischaemic Preconditioning in Transplantation (RIPTRANS)

Remote Ischaemic Preconditioning in Transplantation (RIPTRANS) - A Prospective Randomized Controlled Trial

Remote ischemic preconditioning (RIPC) is a concept where remotely induced ischemia produces protection against ischemia-reperfusion injury in a remote organ. RIPC has been studied extensively in animal models and heart surgery, but it's benefit in transplantation has been studied less. The primary aim of this study is to find out whether RIPC performed in a donor in donation after brain-death (DBD) could improve delayed graft function rate of kidney transplants.

Study Overview

• Status: Recruiting
• Conditions: Transplant Dysfunction
• Intervention / Treatment: Procedure: RIPC; Procedure: Sham-RIPC

• Study Type: Interventional
• Enrollment (Anticipated): 496
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ville Sallinen, MD, PhD; Phone Number: +358-9-4711; Email: ville.sallinen@helsinki.fi
• Study Contact Backup: Name: Aki Uutela, MD; Phone Number: +358-9-4711; Email: aki.uutela@hus.fi

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Recruiting
    • Helsinki University Hospital
    • Contact: Ville Sallinen, MD, PhD; Phone Number: +358-9-4711; Email: ville.sallinen@helsinki.fi
    • Contact: Aki Uutela, MD; Phone Number: +358-9-4711; Email: aki.uutela@hus.fi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Donor Inclusion Criteria:

• Brain-dead organ donor with a plan of harvesting at least one kidney

Donor Exclusion Criteria:

• Haemodynamically unstable donor
• Age below 18 years
• Planned organ recipients are recruited to another prospective trial, which prevents participation in this trial.

All organ recipients receiving organs (kidney, liver, pancreas-kidney, heart, lungs) from a randomized donor will be recruited providing that the recipient surgery is performed at Helsinki University Hospital, recipient is over 18 years old, and recipient gives written informed consent to participate in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RIPC; RIPC will consist of setting a tourniquet to donor thigh and inflating it to 300mmHg four times 5 minutes with 5 minutes deflating in between each. RIPC-intervention will be performed twice: First after brain death and second time before procurement procedure.	Procedure: RIPC; Remote Ischaemic Preconditioning
Sham Comparator: Sham-RIPC; Sham-RIPC will consist of setting a tourniquet to donor thigh without inflating it and keeping it in place for 35 min. Sham-RIPC-intervention will be performed twice: First after brain death and second time before procurement procedure.	Procedure: Sham-RIPC; Sham procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DGF	Delayed graft function of kidney allografts defined as postoperative dialysis within 1 week from transplantation	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney allografts: eGFR	Kidney allografts: estimated glomerular filtration rate	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Combined Pancreas-Kidney allografts: eGFR	Combined Pancreas-Kidney allografts: estimated glomerular filtration rate	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Kidney allografts: BPAR	Kidney allografts: Biopsy proven acute rejection	within 1 year
Combined Pancreas-Kidney allografts: Kidney BPAR	Combined Pancreas-Kidney allografts: Biopsy proven acute rejection in Kidney allograft	within 1 year
Kidney allografts: graft survival	Kidney allografts: time from transplantation to death, retransplantation or permanent dialysis	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Combined Pancreas-Kidney allografts: kidney graft survival	Combined Pancreas-Kidney allografts: time from transplantation to death, retransplantation of the kidney or permanent dialysis	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Kidney allografts: death-censored graft survival	Kidney allografts: time from transplantation to retransplantation or permanent dialysis, death-censored	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Combined Pancreas-Kidney allografts: death-censored kidney graft survival	Combined Pancreas-Kidney allografts: time from transplantation to retransplantation of the kidney or permanent dialysis, death-censored	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Liver allografts: MEAF-score at 3rd POD	Liver allografts: Model for Early Allograft Function Scoring (MEAF) (MEAF = (score ALTmax:3POD+ score INRmax:3POD+ score bilirubin3POD), score range 0 - 10, higher score indicates worse outcome)	3rd post-operative day
Liver allografts: Postoperative biliary complications	Liver allografts: Amount and type of postoperative biliary complications: stricture at anastomosis, bile leak, ischaemic type biliary lesions (ITBL)	within 1 year
Liver allografts: Posttransplantation kidney injury	Liver allografts: Posttransplantation kidney injury (acute kidney injury) according to ADQI (2010) criteria	within 1 week, at 3 months, 1 year
Liver allografts: BPAR	Liver allografts: Biopsy proven acute rejection	within 1 year
Liver allografts: graft survival	Liver allografts: graft survival: time from transplantation to death, retransplantation or explantation	at 1 year, 2 year, 5 year, 10 year, and 20 year
Pancreas allografts: HbA1c	Pancreas allografts: blood HbA1c measurement	at 3 months, 1 year, 2 year, 5 year, 10 year, and 20 year
Pancreas allografts: Acute rejection	Pancreas allografts: Either biopsy proven (allograft pancreas or duodenal biopsy) acute rejection or clinically treated suspected acute rejection	within 1 year
Pancreas allografts: Pancreatic allograft survival	Pancreas allografts: Time from transplantation to death, retransplantation, explantation or daily insulin dependance	at 1 year, 2 year, 5 year, 10 year, and 20 year
Pancreas allografts: Death-censored Pancreatic allograft survival	Pancreas allografts: Time from transplantation to retransplantation, explantation or daily insulin dependance, death-censored	at 1 year, 2 year, 5 year, 10 year, and 20 year
Heart allograft: TnI at 6 hours	Heart allograft: blood TnI measurement at 6 hours after transplantation	at 6 hours
Heart allograft: proBNP at 1 week	Heart allograft: blood proBNP measurement at 1 week after transplantation (12/09/2019 BNP changed to proBNP because of changes in Helsinki University Hospital HUSlab laboratory protocols)	at 1 week
Heart allograft: Primary graft dysfunction	Heart allograft: Primary graft dysfunction according to ISHLT (2014)	within 24 hours after transplantation
Heart allograft: acute rejection	Heart allograft: Biopsy proven or clinically treated acute rejection	within 1 year
Heart allograft: Vasculopathy-free survival	Heart allograft: Vasculopathy-free survival according to Mehra (2010)	at 1 year, 2 year, 5 year, 10 year, and 20 year
Heart allograft: graft survival	Heart allograft: time from transplantation to death, retransplantation or explantation	at 1 year, 2 year, 5 year, 10 year, and 20 year
Lung allograft: Primary graft dysfunction	Lung allograft: Primary graft dysfunction according to ISHLT	within 72 hours
Lung allograft: Acute rejection	Lung allograft: Biopsy proven or clinically treated acute rejection	within 1 year
Lung allograft: CLAD-free survival	Lung allograft: Chronic Lung Allograft Dysfunction (CLAD) free survival according to Verleden (2014)	at 1 year, 2 year, 5 year, 10 year, and 20 year
Lung allograft: graft survival	Lung allograft: time from transplantation to death, retransplantation or explantation (12/16/2019 secondary outcome measures for lung recipients redifined. Lung recipients recruitment started later than for other organs because of a conflicting trial which now has completed recruiting. Only four lung patients have thus far been included in the study and no results for lung recipients have been analyzed.)	at 1, 2, 5, 10 and 20 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcomes Kidney allograft miR-21	Measurement of reperfusion injury in blood and urine samples micro-RNA miR-21	peroperative blood samples before and after graft perfusion and urinary sample 6 hours after transplantion
Exploratory outcomes Kidney allograft miR-24	Measurement of reperfusion injury in blood and urine samples micro-RNA miR-24	peroperative blood samples before and after graft perfusion and urinary sample 6 hours after transplantion
Exploratory outcomes Kidney allograft NGAL	Measurement of reperfusion injury in blood and urine samples neutrophil gelatinase associated lipocain NGAL	peroperative blood samples before and after graft perfusion and urinary sample 6 hours after transplantion
Exploratory outcomes Kidney allograft KIM-1	Measurement of reperfusion injury in blood and urine samples kidney injury molecule -1 KIM-1	peroperative blood samples before and after graft perfusion and urinary sample 6 hours after transplantion
Exploratory outcomes Kidney allograft FABP-1	Measurement of reperfusion injury in blood and urine samples fatty acid binding protein -1 FABP-1	peroperative blood samples before and after graft perfusion and urinary sample 6 hours after transplantion
Exploratory outcomes Kidney allograft SLPI	Measurement of reperfusion injury in blood and urine samples secretory leucocyte proteinase inhibitor SLPI	peroperative blood samples before and after graft perfusion and urinary sample 6 hours after transplantion
Exploratory outcomes Liver allograft: Early allograft dysfunction	Exploratory outcomes Liver allograft: Early allograft dysfunction according to Olthoff (Bil >100, INR 1.6 or more, ALT or AST > 2000 at 7th POD	at 7 days
Exploratory outcomes Liver allograft: Highest ALT within 7th POD	Exploratory outcomes Liver allograft: The highest ALT measurement within 7th POD	within 7 days
Exploratory outcomes Liver allograft: Highest INR within 7th POD	Exploratory outcomes Liver allograft: The highest INR measurement within 7th POD	within 7 days
Exploratory outcomes Liver allograft: Highest Bil within 7th POD	Exploratory outcomes Liver allograft: The highest Bil measurement within 7th POD	within 7 days
Exploratory outcomes heart allografts: TnI	Exploratory outcomes heart allografts: TnI measurement	at 1 hour, 12 hours and 24 hours
Exploratory outcomes heart allografts: proBNP	Exploratory outcomes heart allografts: (12/09/2019 BNP changed to proBNP because of changes in Helsinki University Hospital HUSlab laboratory protocols)	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: crea	Exploratory outcomes heart allografts: crea	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: urea	Exploratory outcomes heart allografts: urea	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: eGFR	Exploratory outcomes heart allografts: eGFR	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: LVEF	Exploratory outcomes heart allografts: left ventricle ejection fraction	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: LV wall thickness	Exploratory outcomes heart allografts: left ventricle wall thickness measurements	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: tricuspidal leak	Exploratory outcomes heart allografts: grading of the tricuspidal valve leak	at 1 day, 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: Ischaemia-reperfusion injury	Exploratory outcomes heart allografts: The appearance of ischaemia-reperfusion injury in routine biopsies	at 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: fibrosis	Exploratory outcomes heart allografts: The appearance of fibrosis associated factors in routine biopsies	at 7 days, 14 days and 21 days
Exploratory outcomes heart allografts: long time follow-up of proBNP	Exploratory outcomes heart allografts: long time follow-up of proBNP (12/09/2019 BNP changed to proBNP because of changes in Helsinki University Hospital HUSlab laboratory protocols)	at 1 month, 3 months, 6 months, 12 months
Exploratory outcomes heart allografts: long time follow-up of LVEF	Exploratory outcomes heart allografts: long time follow-up of left ventricle ejection fraction in cardiac ECHO	at 1 month, 3 months, 6 months, 12 months
Exploratory outcomes heart allografts: CAD at 1 year	Exploratory outcomes heart allografts: Coronary Artery Disease in coronary angiography at 1 year	at 1 year
Exploratory outcomes heart allografts: MACE	Exploratory outcomes heart allografts: Major Adverse Cardiac Events (including death because of cardiac cause, graft loss, primary allograft dysfunction, rejection classified as 2R or more)	at 1 month, 3 months, 6 months, 12 months
Exploratory outcomes lung allografts: Severity of ischaemia/reperfusion injury standardized P/F-ratio	Severity of ischemia/reperfusion injury after transplantation: standardized P/F-ratio during mechanical ventilation	at 0 hours, 1 hour, 6 hours, 12 hours and 24 hours
Exploratory outcomes lung allografts: Severity of ischaemia/reperfusion injury: non-standardized P/F-ratio	Severity of ischemia/reperfusion injury after transplantation: non-standardized P/F-ratio during mechanical ventilation	at 0 hours, 1 hour, 6 hours, 12 hours and 24 hours
Exploratory outcomes lung allografts: Severity of ischaemia/reperfusion injury: lactate	Severity of ischemia/reperfusion injury after transplantation , plasma lactate,	at 0 hours, 1 hour, 6 hours, 12 hours and 24 hours
Exploratory outcomes lung allografts: Severity of ischaemia/reperfusion injury: CRP	Severity of ischemia/reperfusion injury after transplantation: serum highly sensitive C-reactive protein	at 0 hours, 1 hour, 6 hours, 12 hours and 24 hours
Exploratory outcomes lung allografts: Severity of ischaemia/reperfusion injury: leuc	Severity of ischemia/reperfusion injury after transplantation blood leukocyte count	at 0 hours, 1 hour, 6 hours, 12 hours and 24 hours
Exploratory outcomes lung allografts: Severity of ischaemia/reperfusion injury: neut	Severity of ischemia/reperfusion injury after transplantation neutrophil count	at 0 hours, 1 hour, 6 hours, 12 hours and 24 hours
Exploratory outcomes lung allografts: FEV1	Exploratory outcomes lung allografts: FEV1	at 1 month, 3 months, 6 months, 12 months
Exploratory outcomes lung allografts: FVC	Exploratory outcomes lung allografts: FVC	at 1 month, 3 months, 6 months, 12 months
Exploratory outcomes lung allografts: chronic rejection	Exploratory outcomes lung allografts: chronic rejection	at 1 month, 3 months, 6 months, 12 months
Exploratory outcomes lung allografts: infections	Exploratory outcomes lung allografts: infections after transplantation	at 1 month, 3 months, 6 months, 12 months

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Academy of Finland; Finska Läkaresällskapet (funding); Helsinki University Hospital Research Funds (funding)
• Investigators: Principal Investigator: Aki Uutela, MD, Helsinki University Central Hospital; Study Chair: Marko Lempinen, MD, PhD, Helsinki University Central Hospital

Publications and helpful links

General Publications

• Uutela A, Helantera I, Lemstrom K, Passov A, Syrjala S, Aberg F, Makisalo H, Nordin A, Lempinen M, Sallinen V; RIPTRANS Study Group collaborators. Randomised sham-controlled double-blind trial evaluating remote ischaemic preconditioning in solid organ transplantation: a study protocol for the RIPTRANS trial. BMJ Open. 2020 Nov 16;10(11):e038340. doi: 10.1136/bmjopen-2020-038340.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2019
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): February 1, 2042

Study Registration Dates

• First Submitted: February 11, 2019
• First Submitted That Met QC Criteria: February 24, 2019
• First Posted (Actual): February 27, 2019

Study Record Updates

• Last Update Posted (Actual): March 10, 2020
• Last Update Submitted That Met QC Criteria: March 6, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: RIPTRANS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: After the completion of the study the depersonalized data can be requested from the authors.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No