Heme Arginate in Transplantation Study

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Renal Transplant Rejection, Renal Transplant Failure

Intervention / Treatment
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* Drug: Heme Arginate 25 MG/ML
* Drug: 0.9% Sodium-chloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Interventional Model Description: Multi-centre, parallel group 1:1 randomised placebo controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Group<br>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<br>* 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).<br>|
| Placebo Comparator: Placebo Group<br>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<br>* 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).<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deceased donor renal transplantation, Heme Arginate, Delayed graft function