Trial Outcomes & Findings for Pilot Study of Reparixin for Early Allograft Dysfunction Prevention in Liver Transplantation (NCT NCT03031470)

Patients admitted to the transplant center immediately before OLT surgery who signed the Patient Informed Consent Form underwent screening procedures (Day -1). Screening can be carried out within 24 hours before planned surgery. The results at screening were considered as baseline values. During the screening physical examination, patients fulfilling all the inclusion criteria and none of the exclusion criteria were randomized.

Pilot Study of Reparixin for Early Allograft Dysfunction Prevention in Liver Transplantation

Assessment of the frequency of early allograft disfunction (EAD) after orthotopic liver transplantation (OLT) (Day 7 of Week 1) among patients who received Reparixin and patients in the control group. EAD was defined according to standard criteria as maximum Alanine Transferase (ALT) or Aspartate Transferase (AST) levels on days 1-7 of \>2000 U/L, day 7 Bilirubin level ≥10 mg/dl, or a day 7 International Normalized ratio (INR) ≥1.6. Taking into account that 5 out of 22 patients in the Reparixin group experienced EAD during the first stage of the study, according to the Protocol and the DMC conclusion, it was decided on the early termination of the study.

Assessment of the frequency of early allograft disfunction after orthotopic liver transplantation (OLT) (Day 7 of Week 1) among patients who received Reparixin and patients in the control group. EAD was defined according to standard criteria as maximum Alanine Transferase (ALT) or Aspartate Transferase (AST) levels on days 1-7 of \>2000 U/L, day 7 Bilirubin level ≥10 mg/dl, or a day 7 International Normalized ratio (INR) ≥1.6. Please note that taking into account that 5 out of 22 patients in the Reparixin group experienced EAD during the first stage of the study, according to the Protocol and the DMC conclusion, it was decided on the early termination of the study.

The number of patients in which: a) the primary allograft nonfunction within 7 day after the OLT was determined and not determined, and the number of patients in which 2)Appropriate data was not available in each of the two arms are reported.

The number of patients in which: a) the primary allograft dysfunction within 14 day after the OLT was determined and not determined, and the number of patients in which 2)Appropriate data was not available in each of the two arms are reported. The term "early allograft dysfunction" (EAD) identifies liver transplant (LT) allografts with initial poor function and portends poor allograft and patient survival.

Cumulative incidence of extracorporeal detoxification as an indicator of liver allograft dysfunction in early postoperative period within 2 weeks after OLT is reported. Extracorporeal liver support describes all measures of extracorporeal blood treatments, which are aimed at supporting any functions of the liver in order to reduce the number of failing organs as a consequence of liver failure. The ultimate goal of extracorporeal liver support is to prolong the survival time of patients with liver failure by preventing progression of secondary organ failure.

The frequency of identification of laboratory examination values corresponding to early allograft dysfunction within 3 days after the operation (Day 4 of the study drug administration)

Incidence of early allograft dysfunction in case of transplantation of donor organs differing by the degree of steatosis was reported. The investigators evaluated organ suitability for transplantation relying on histopathologic findings from biopsy. In this clinical setting, grafts with macrovesicular steatosis degree \>50% were considered as non-suitable for transplantation. Steatosis or fatty liver disease (NAFLD) is characterised by hepatic lipid accumulation. Nominal data for the MITT are reported.

Number of patients with EAD in case of transplantation of donor organs by the time of allograft removal from the donor and up to its reperfusion after engraftment (duration of cold ischemia) was assessed. Cold ischemia time during procurement is defined as the time after clamping of aorta until excision of the organ, which can last some hours. Prolonged cold ischemia time is an independent risk factor for the development of delayed function and primary nonfunction of the allograft. Although the exact mechanism is unknown, cold ischemia time is believed to affect graft function by contributing to ischemia-reperfusion injury. Nominal data for the MITT are reported.

The number of EAD patients in case of transplantation of donor organs differing by the time of allograft removal from the donor and up to its reperfusion after engraftment (duration of warm ischemia) was assessed. In surgery, warm ischemia is the time a tissue, organ, or body part remains at body temperature after its blood supply has been reduced or cut off but before it is cooled or reconnected to a blood supply. In the transplant setting, this term is used to describe two physiologically distinct periods of ischaemia: (1) Ischemia during implantation, from removal of the organ from ice until reperfusion, and (2) Ischemia during organ retrieval, from the time of cross clamping (or of asystole in non-heart-beating donors), until cold perfusion is commenced. Nominal data for the MITT are reported.

The number of patients with early allograft dysfunction in transplantation from donors having additional adverse factors like infectious complication, death of the brain, hypotension, etc. was reported. The correlation between EAD and additional adverse factors are showed. Nominal data for the MITT are reported.

The number of patients with allograft dysfunction in transplantation with regard to the interval between the diagnosis of brain death and removal of the liver graft from a donor (in the case of a brain-dead donor). This interval can last hours. Nominal data for the mITT are reported.

The number of patients with EAD in transplant recipients with liver diseases of different etiology (viral, alcoholic, autoimmune, etc.) was assessed.

The incidence of early allograft dysfunction in transplant recipients with liver diseases of different etiology and with different baseline characteristics. Herein the intent is reporting the number/percentage of subjects with EAD within 14 days after OLT, without distinction for disease etiology and baseline characteristics.

The number of EAD patients in transplant recipients with liver diseases detected, and with different baseline characteristics was assessed. Herein HBV and HCV viral load at screening visit are reported.

The incidence of early allograft dysfunction in transplant recipients with different baseline characteristics. Herein Creatinine clearance at screening Day - 1 (mL/min). 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. the normal range of CrCl is 110 to 150mL/min in males and 100 to 130mL/min in females. Serum creatinine level for men with normal kidney function is approximately 0.6 to 1.2mg/dL and between 0.5 to 1.1 mg/dL for women. Creatine levels above the normal range indicate renal dysfunction.

The incidence of early allograft dysfunction in transplant recipients with different score in scales of end-stage liver disease. The MELD score estimates a patient's chances of surviving their disease during the next three months. Practically, MELD is a reliable measure of mortality risk in patients with end-stage liver disease. It is used as a disease severity index to determine prognosis and help prioritize patients for organ allocation by estimating 3-month mortality risk. The MELD score ranges from 6 to 40 and is based on results from several lab tests. The higher the number, the more likely the subject is to receive a liver from a deceased donor when an organ becomes available. MELD Score= 11.2 x In INR + 9.57 x In Creatinine (mg/dL) + 3.78 (if the patient had dialysis at least twice in the past week, the value for serum creatinine needs to be adjusted to 4.0) x In Bilirubine (mg/dL) + 6.43

The incidence of early allograft dysfunction in transplant recipients with different allograft dysfunction based on CTP. This score assesses the severity of the disease, the risk of lethal outcome (during surgeries) and the prognosis in patients with cirrhosis. The CTP scoring system incorporates five parameters: serum bilirubin, serum albumin, prothrombin time, ascites, and grade of encephalopathy. Each of them can score between 1 and 3. Based on the sum of the points from these five parameters, the patient is categorized into one of three CTP classes/grades: A, B, or C. Score: • 5-6 points - Grade A (least severe liver disease) * 7-9 points - Grade B (moderately severe liver disease) * 10-15 points - Grade C (most severe liver disease)

Time to normalization of liver function parameters (alanine aminotransferase, aspartate aminotransferase and bilirubin levels, gamma-glutamyltransferase, lactate dehydrogenase, etc.) after the OLT was assessed. Please note the upper limit of IC is not available due to insufficient number of participants with events.

Patient survival within 1 year after OLT was assessed. Please note the data are not available due to insufficient number of participants with events.

Number of deaths within 1 year after the OLT was assessed.

Hyperacute or acute transplant rejection were determined by biopsy; chronic transplant rejection was defined by histological evaluation in both treatment groups.

An Adverse Event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.