Heme Arginate in Transplantation Study (HOT2)

Heme Arginate in Transplantation Study - a Multi-centre Blinded Parallel-group Randomised Trial of Heme Arginate Versus Placebo to Reduce Delayed Graft Function in Kidney Transplant Recipients

Organ shortage for transplant has necessitated use of kidneys from older donors, increasing the chance that the kidney will not work immediately or for as long as expected. The investigators gave the drug heme arginate (HA) to 20 kidney transplant patients in the first 24 hours after transplant, and showed that it may reduce kidney injury and is safe. The investigators plan to conduct a large study recruiting 600 patients to determine whether HA treatment increases the number of kidney transplants that work immediately. If successful, HA may be introduced into clinical practice at the end of this study.

Patients will be invited to take part in the study once listed for a kidney transplant. Further discussions will be had with them when admitted for transplant, and they will be offered the opportunity to participate. Consent will not be taken until the patient is admitted for transplantation. Following consent, participants will be randomised to receive either 2 doses of the study drug, HA, or a salt water solution, one at the time of transplant, and one approximately 24 hours later. Otherwise, treatment will be the same as any other patient undergoing a kidney transplant. Information about recovery from surgery, and specifically about kidney function, will be collected, but will not require additional blood tests. The study period ends after the first 7 days post-transplant, although longer term data will be collected from routine follow up appointments. Participants will be asked to complete a simple quality of life questionnaire 3 times: just before transplant, at approximately one week and three months after transplant.

Study Overview

• Status: Terminated
• Conditions: Renal Transplant Rejection; Renal Transplant Failure
• Intervention / Treatment: Drug: Heme Arginate 25 MG/ML; Drug: 0.9% Sodium-chloride

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4UX
    • Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh
  • Lothian
    • Edinburgh, Lothian, United Kingdom, EH16 4SA
      • NHS Lothian - Royal Infirmary of Edinburgh

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients undergoing a kidney only transplant, or a dual kidney transplant, from a deceased donor
• At least 18 years of age, no upper limit
• Receiving standard immunosuppression for the individual centre
• (where applicable) Meets co-enrolment criteria outlined in section 4.4 of the protocol

Exclusion Criteria:

• Kidney transplant patients as part of a multi-organ transplant e.g. with pancreas or liver
• Known hypersensitivity to heme arginate
• Unable to give informed consent
• Patients with porphyria, irrespective of whether they have received heme arginate or not, will be excluded
• Previous randomisation into this study (or HOT study)
• Women who are pregnant or lactating
• Kidneys that have undergone Ex-vivo Normothermic Perfusion (EVNP)
• Patients with known liver disease, epilepsy, brain injury or disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Group; Will receive Heme Arginate (IMP) at a dose of 3mg/kg over 30mins. Participants will receive infusions of the IMP at 2 time-points, the first prior to surgery (transplantation), and the second 20-28 hours later. At each infusion, the IMP will be followed by a 100ml infusion of 0.9% Sodium Chloride over 15mins.	Drug: Heme Arginate 25 MG/ML; IMP - to be administered at a dose of 3mg/kg to a maximum dose of 250mg over 30 mins. Participants will receive intervention twice during the trial, one on Day 0 (day of transplantation) and then again on D1 (20-28 hours after dose 1).
Placebo Comparator: Placebo Group; Will receive a 100ml infusion of 0.9% Sodium Chloride (placebo) over 30mins. Participants will receive infusions at 2 time-points, the first prior to surgery, and the second 20-28 hours later. At each infusion, the placebo will be followed by a further 100ml infusion of 0.9% Sodium Chloride over 15mins.	Drug: 0.9% Sodium-chloride; Placebo - 100ml of 0.9% Sodium Chloride will be given over 30 mins. Participants will receive intervention twice during the trial, one on Day 0 (day of transplantation) and then again on D1 (20-28 hours after dose 1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delayed Graft Function	The incidence of delayed graft function, defined as failure of a spontaneous fall in creatinine of >10% for each 3 consecutive day period in the first week following transplantation, with comparison between the two randomised groups.	1 week post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Requirement for dialysis	The number of participants requiring dialysis within the first week post-transplant	1 week post transplant
Time to functioning graft	The number of days to functioning graft, defined as the spontaneous fall in creatinine of greater than, or equal to 10% over a period of 3 consecutive days in the first 7 days post transplant	1 week
Length of hospital stay	The number of days spent in hospital, along with level of care (ward/HDU/ITU), for the index admission (transplantation admission)	3 months
Creatinine levels	Serum creatinine levels at 1 and 3 months post-transplant across both randomised groups	3 months
Acute rejection	The number of participants with biopsy-proven acute rejection within the first 3 months post-transplant	3 months
SF36 Quality of Life	A comparison of differences between groups in patient reported quality of life using the SF36	Up to 3 months post transplant
Cost per QALY gained	Using data derived from the SF36 to weight survival for quality of life, Quality Adjusted Life Year (QALY) will be assessed	Up to 3 months post transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
1 Year graft survival	Graft survival rates at 1 year post transplant will be obtained from routinely collected data and differences between treatment groups assessed.	1 year
1 year recipient survival	Recipient survival rates at 1 year post transplant will be obtained from routinely collected data and differences between treatment groups assessed.	1 year

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: Kidney Cancer UK
• Investigators: Principal Investigator: Lorna Marson, University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2019
• Primary Completion (Actual): March 17, 2020
• Study Completion (Actual): February 23, 2021

Study Registration Dates

• First Submitted: August 20, 2018
• First Submitted That Met QC Criteria: August 23, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Estimated): November 17, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Delayed graft function; Deceased donor renal transplantation; Heme Arginate
• Additional Relevant MeSH Terms: Pathologic Processes; Pathological Conditions, Signs and Symptoms; Delayed Graft Function; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; Sodium Chloride; heme arginate
• Other Study ID Numbers: AC17065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Following publication of the primary paper, a de-identified individual participant data set will be submitted to a data archive for sharing purposes. Access to this data set will be under a controlled access model in line with ECTU policies at that time.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No