Induction of HO-1; a Therapeutic Approach to Reduce Ischaemia Reperfusion Injury (IRI) Following Deceased Donor Renal Transplantation (HOT)

A Randomised Placebo-Controlled Trial to Investigate the Effect of Pre-treatment With Haem Arginate (Normosang) on Heme-Oxygenase 1 (HO-1) Upregulation in Recipients of Deceased Donor Kidneys

This is a blinded, placebo-controlled, randomised controlled trial looking at the effects of Heme arginate (HA) on cadaveric renal transplantation. The investigators know that HA can upregulate HO-1, which has been shown to have a protective effect on animal transplants.

The investigators will be giving HA/placebo to participants prior to transplant and repeat again on day 2 post-transplant and compare outcomes.

Study Overview

• Status: Completed
• Conditions: Ischemia-reperfusion Injury; Graft Failure
• Intervention / Treatment: Drug: Heme arginate (Normosang); Drug: 0.9% sodium chloride

Detailed Description

Patients will be recruited from the East of Scotland transplant waiting list and consent when they arrive in the hospital. The investigators will randomise them to drug or placebo and give the infusion prior to induction for their transplant.

A blood sample will be taken prior to infusion and a renal biopsy will be taken before the graft is implanted. These will be used as baseline values.

Patients will receive standard care from our unit. The investigators will use the routine blood test results (urea and creatinine) to determine the function of the graft.

The investigators will take blood samples 24 hours after infusion of drug/placebo and use this to determine the primary outcome. Blood tests will be taken daily and a renal biopsy taken on day 5 to fulfil secondary objectives.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Lothian
    • Edinburgh, Lothian, United Kingdom, EH16 4TJ
      • Royal Infirmary of Edinburgh/ University of Edinburgh

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

Inclusion Criteria:

• all patients receiving a cadaveric single kidney transplant
• patients on a standard immunosuppressive regime

Exclusion Criteria:

• patients on different immunosuppressives
• patients receiving 3rd or subsequent kidney transplant
• patients are fully anti-coagulated
• patients unable to take Heme Arginate
• patients unable to give informed consent
• patients on combined anti-platelet agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Heme arginate (Normosang); This arm will receive 2 doses of Heme Arginate (trade name Normosang); 1 dose prior to transplant and another on day 2. This is a product derived from human hemin and has been used for over 20 years in clinical practice with few side-effects.	Drug: Heme arginate (Normosang); 3mg/kg as a single IV infusion prior to transplant over 30 mins and same dose repeated on day 2 post-transplantation. Each drug infusion will be followed by 100ml saline IV to flush the line.; Other Names: Heme Arginate; Hemin
PLACEBO_COMPARATOR: 0.9% saline; The saline will be given as an IV infusion in the same manner as the Heme Arginate (active comparator) infusion.	Drug: 0.9% sodium chloride; Solution for infusion, this will be given prior to transplantation and again on day 2; the same as active drug.; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrophage/monocyte HO-1 protein levels	We will measure the level of HO-1 protein in isolated macrophages/ monocytes in a peripheral blood sample taken at 24 hours after drug infusion	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrophage/monocyte HO-1 mRNA levels	We will measure HO-1 mRNA levels in macrophages/monocytes from a peripheral blood sample taken at 24 hours.	24 hours
HO-1 protein in kidney transplant	We will measure the level of HO-1 protein in kidney tissue from a biopsy sample taken 5 days after drug infusion. This will be compared to baseline	5 days
Effect on transplanted kidney function	We will record how the kidney functions by determining presence or absence of delayed graft function.	daily for 5 days
Urinary biomarkers as markers of injury	We will collect urine to measure the presence of specific urinary biomarkers and correlate with renal function.	daily for 5 days

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Study Director: Lorna Marson, MD, Senior Lecturer, Transplant Surgery, University of Edinburgh; Principal Investigator: Rachel Thomas, MBChB, Clinical Research Fellow, University of Edinburgh; Principal Investigator: Stephen McNally, PhD, University of Edinburgh; Principal Investigator: David Kluth, PhD, University of Edinburgh

Publications and helpful links

General Publications

• Thomas RA, Czopek A, Bellamy CO, McNally SJ, Kluth DC, Marson LP. Hemin Preconditioning Upregulates Heme Oxygenase-1 in Deceased Donor Renal Transplant Recipients: A Randomized, Controlled, Phase IIB Trial. Transplantation. 2016 Jan;100(1):176-83. doi: 10.1097/TP.0000000000000770.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): August 1, 2013

Study Registration Dates

• First Submitted: August 30, 2011
• First Submitted That Met QC Criteria: September 6, 2011
• First Posted (ESTIMATE): September 7, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): May 27, 2015
• Last Update Submitted That Met QC Criteria: May 26, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Renal Transplantation; Ischemia-reperfusion injury; Heme-oxygenase 1; Heme arginate
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Ischemia; Reperfusion Injury
• Other Study ID Numbers: HOT-2011; 2011-004311-23 (EUDRACT_NUMBER)