Reparixin in Prevention of Delayed Graft Function After Kidney Transplantation

Study Overview
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Brief Summary
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The chemokine CXCL8 plays a key role in the recruitment and activation of polymorphonuclear neutrophils in post-ischemia reperfusion injury after solid organ transplantation. Reparixin is a novel, specific inhibitor of CXCL8. This study is configured to explore the safety and efficacy of reparixin in preventing the delayed graft function (DGF) after kidney transplantation.

Detailed Description
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Delayed graft function (DGF) is the most common allograft complication in the immediate kidney post-transplant period, affecting 25-35% of all patients who receive a cadaver graft, but rates up to 50% have been reported, especially in recipients of kidneys from marginal donors. It is an important clinical complication as it requires dialysis, prolongs hospitalisation, raises the cost of transplantation, and makes more difficult the management of immunosuppressive therapy. Although the effects of DGF on long-term graft function are still debated, there is overall increasing evidence that DGF reduces long-term graft survival. Moreover, given the well documented impact of acute rejection on long-term graft survival, it is conceivable that DGF and acute rejection synergize in negatively influencing long-term graft survival. Kidney reperfusion, after long cold ischemia period, is associated with an inflammatory reaction characterized by massive polymorphonuclear leukocyte (PMN) infiltration both at the glomerular and tubular levels. The importance of CXCL8 in recruiting PMN in kidney tissue during the ischemic time and after reperfusion has been clearly documented. The efficacy of reparixin in preventing PMN infiltration and tissue damage in rat models of kidney transplantation and lung transplantation, as well as the safety shown in human phase 1 studies, provide the rationale for a clinical study aimed at evaluating the effect of reparixin in preventing DGF after kidney transplantation

Official Title
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Randomized, Double-blind, Placebo-controlled, Parallel-group Pilot Study to Assess Efficacy, Safety and Pharmacokinetics of 2 Schedules of Reparixin in the Prevention of Delayed Graft Function After Kidney Transplant in High Risk Patients

Conditions
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Ischemia-Reperfusion Injury, Kidney Diseases

Intervention / Treatment
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* Drug: Reparixin continuous infusion
* Drug: reparixin intermittent infusion
* Other: placebo infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients accepted and listed for renal transplantation due to end stage renal disease (ESRD) Planned isolated single kidney transplant from a non-living donor with brain death Recipients of a kidney maintained in cold storage Recipients at risk of developing DGF Planned induction with steroids + mycophenolate mofetil (MMF) or mycophenolic acid + biological induction Patient willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations Patient given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care Exclusion Criteria: Recipients of an intended multiple organ transplant Recipients of a kidney from a living donor Recipients of a kidney from a non-heart beating donor Recipients of double kidney transplant Re-transplant >2 Recipients of a kidney maintained by pulsatile machine perfusion Concurrent sepsis Recipients with hepatic dysfunction at the time of transplant Clinical contraindications to central line access, or arteriovenous fistula, if any, not suitable for infusion of investigational product Hypersensitivity to non steroidal anti-inflammatory drugs (NSAIDs) Patients simultaneously participating in any other clinical trials involving an investigational drug not yet authorized for use in kidney transplant Pregnant or breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: reparixin group - continuous infusion<br>Continuous iv infusion into a (high flow) central vein (or through an arterio-venous fistula) by an infusion pump. A dose of 2.772 mg/kg/h was administered for12 hours. | Drug: Reparixin continuous infusion<br>* The Investigational Product was administered as an intravenous infusion into a (high flow) central vein or through an arterio-venous fistula, by an infusion pump adequate to provide reliable infusion rates, as per treatment schedule. Total infusion volume did not exceed 500 mL/24 hours. A dose of 2.772 mg/kg body weight/hour was to be administered for 12 hours. Placebo was volume/schedule matched saline.<br>* Other names: REP;|
| Experimental: reparixin group - intermittent infusion<br>Intermittent iv infusion into a (high flow) central vein (or through an arterio-venous fistula) by an infusion pump. A dose of 2.244 mg/kg was administered over a 30-minute period, followed by a 1.5-hour interval. Twelve doses were administered over a total period of 22.5 hours. | Drug: reparixin intermittent infusion<br>* A dose of 2.244 mg/kg body weight was to be administered over a 30-minute period, followed by a 1.5-hour interval. Twelve doses were to be administered over a total period of 22.5 hours. Placebo was volume/schedule matched saline.<br>* Other names: REP;|
| Placebo Comparator: placebo infusion<br>Continuous/intermittent iv infusion of a volume/schedule matched saline into a (high flow) central vein (or through an arterio-venous fistula) by an infusion pump. | Other: placebo infusion<br>* placebo was volume/schedule matched saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Creatinine Clearance (CrCl) in the Immediate Post-transplant Period | CrCl was determined by two 60 minute urine collections, during the time intervals 1-3 and 10-12 hours of allograft reperfusion. Blood was withdrawn at the midpoint of each urine collection. CrCl at each timepoint was calculated according to the formula: creatinine clearance (mL/minutes) = urine creatinine (mmol/L) x urine volume (mL) / serum creatinine (mmol/L) x time of collection (minutes) An average was to be calculated from the two 60 minute values in each interval. | 1-3 and 10-12 hours post allograft reperfusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function Tests - Serum Creatinine | Serum creatinine (SrCr) was measured daily from Day 1 up to 7 days post-transplant or up to hospital discharge, whichever occurred earlier; in patients undergoing dialysis, SrCr values were measured immediately before dialysis. | daily up to day 7 post-transplant or hospital discharge | 
| Renal Function Tests - Calculated Glomerular Filtration Rate | Calculated glomerular filtration rate (GFR) was measured daily from Day 1 up to 7 days post-transplant or up to hospital discharge, whichever occurred earlier; in patients undergoing dialysis, SrCr values were measured immediately before dialysis | from Day 1 up to 7 days post-transplant or up to hospital discharge | 
| Renal Function Tests - Urine Output | Urine output, measured in the interval from transplant to 8:00 of Day 1, and then daily from Day 2 up to 7 days post-transplant or up to hospital discharge, whichever occurred earlier | from Day 1 up to 7 days post-transplant or up to hospital discharge | 
| Number of Patients Requiring Dialysis Within 7 Days Post-transplant | The number of patients who required dialysis within 7 days post-transplant was evaluated. | up to day 7 post-transplant | 
| Number of Days on Dialysis Before Resuming Kidney Function | the number of days on dialysis before resuming kidney function was evaluated. | up to Day 7 post-transplant | 
| Number of Patients With Immediate, Slow and Delayed Graft Function | The number of patients who required dialysis within 7 days post-transplant was evaluated. Immediate graft function: SrCr ≤3 mg/dL on post operative day 5) Slow graft function: SrCr >3 mg/dL dL on post operative day 5, no need of dialysis) Delayed graft function: Dialysis needed in the first week) | day 5 post-transplant | 
| Duration of Hospital Stay | The mean duration of hospital stay was evaluated. | first 30 days post-transplant | 
| Mortality | Mortality in the first 30 days post-transplant was evaluated. | first 30 days post-transplant | 
| Serum Creatinine at Month 1, Month 6 and Month 12 | Serum creatinine (SrCr) was measured at Month 1, Month 6 and Month 12. | at Month 1, Month 6 and Month 12 | 
| Calculated Serum Creatinine Clearance at Month 1, Month 6 and Month 12 | Creatinine clearance (CrCl) is the volume of blood plasma cleared of creatinine per unit time. It is a rapid and cost-effective method for the measurement of renal function. | at Month 1, Month 6 and Month 12 | 
| Acute Rejection Episodes at Month 6 and Between Month 6 and Month 12 | Acute rejection defined as an increase in serum creatinine level after exclusion of other causes of graft dysfunction, accompanied by a sudden decline in glomerular filtration rate and renal function and well-established diagnostic features on kidney allograft biopsy which can be either antibody-mediated and/or T cell-mediated and can occur at any time after transplant. | at Month 6 and between Month 6 and Month 12 | 
| Patient Survival Rate | Numbers of patients alive, dead, and lost to follow up are reported. | at Month 1, Month 6 and Month 12 | 
| Graft Survival Rate | Graft failure was defined as the failure of graft function for any reason, ultimately requiring renal replacement therapy and/or retransplantation (United States Renal Data System [USRDS] 2017. | at Month 1, Month 6 and Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplantation, Reperfusion Injury, Survival