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

Phase 2

Terminated

Conditions: Ischemia-reperfusion Injury in Liver Transplant
Early Allograft Dysfunction

Interventions: Other: Control
Drug: Reparixin

Registration Number: NCT03031470

Lead Sponsor: Dompé Farmaceutici S.p.A

Brief Summary: The objective of the study is to evaluate the efficacy and safety of Reparixin treatment (2.772 mg/kg body weight/hour intravenous continuous infusion for 7 days) based on incidence of early allograft dysfunction within the first 7 days after orthotopic liver transplantation (OLT) and overall indicators of allograft dysfunction in the early postoperative period (within 14 days after the OLT).

Detailed Description: The study is a phase 2, multicenter, open-label, randomized pilot study to evaluate the efficacy and safety of Reparixin for prevention of early allograft dysfunction in patients undergoing orthotopic liver transplantation.

All the patients who participated in the study received standard immunosuppressive therapy in accordance with the Russian Transplant Society Guidelines for liver transplantation (2013). The study was planned to be conducted at 5-8 transplantation sites in Russia and Belarus. Recruitment was competitive among the study sites so that patients were screened and if eligible, randomized consecutively until the randomization was stopped.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Male and female patients aged 18 years and older needing a whole organ OLT, listed on the waiting list for liver transplantation.
Severity score of the initial condition of the patient (hepatocellular dysfunction) according to the scales of Child-Turcotte-Pugh ≥ 7 points or MELD 15-40 points (or both).
The possibility of insertion of a central catheter for infusion of the study drug.
Signed Patient Informed Consent Form.
Ability to comply with all the requirements of the protocol.
Consent to use adequate contraception means throughout the study. The adequate contraception methods include use of condom with spermicide.

Exclusion Criteria

Patients with any of the following conditions shall not be included in the study:

Split-liver transplantation or transplantation from a living donor.
Re-transplantation or multivisceral transplantation.
The presence of extrahepatic tumor foci or sepsis.
Gastrointestinal bleeding caused by portal hypertension within 3 months prior to screening.
BMI less than 18.5 or more than 40 kg/m2.
HIV infection.
Significant cardiovascular disease at the present time or within 6 months prior to screening, including: class III or IV chronic heart failure (the New York Heart Association), myocardial infarction, unstable angina, hemodynamically significant cardiac arrhythmias, ischemic or hemorrhagic stroke, uncontrolled arterial hypertension.
Preoperative renal impairment (glomerular filtration rate estimated with the Cockcroft-Gault formula ≤ 45 mL/min).
Significant, in the opinion of the Investigator, drug or alcohol abuse within 6 months prior to screening.
Hypersensitivity to:
1. ibuprofen or to more than one non-steroidal anti-inflammatory drug (NSAID),
2. more than one medication belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib; hypersensitivity to sulphanilamide antibiotics alone (e.g. sulfamethoxazole) does not qualify for exclusion.
Pregnant or lactating women, or women planning a pregnancy during the clinical study, fertile women not using adequate contraception methods.
Participation in another clinical study currently or within 30 days prior to screening, use of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to screening.
The patient's and his/her relatives' failure to understand the need for lifelong immunosuppressive therapy, as well as the risk and difficulty of the pending operation and the subsequent dynamic treatment.
Inability to read or write; unwillingness to understand and comply with the procedures of the study protocol; failure to comply with the treatment, which, in opinion of the Investigator, may affect the results of the study or the patient's safety and prevent the patient from further participation in the study; any other associated medical or serious mental conditions that make the patient unsuitable for participation in the clinical study, limit the validity of informed consent or may affect the patient's ability to participate in the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Control	The patients, who were randomized in the control group, did not receive any study therapy. All patients of the study received standard immunosuppressive therapy in accordance with the Russian Transplant Society Guidelines for liver transplantation.
Reparixin	Reparixin	Patients in the group of the study therapy received Reparixin at dose of 2.772 mg/kg/hour for 7 days (168 hours). The prepared solution of Reparixin 11 mg/ml was administered as a continuous infusion into a central vein using an automatic infusion pump that provides a constant rate of infusion. All patients of the study received standard immunosuppressive therapy in accordance with the Russian Transplant Society Guidelines for liver transplantation.

Primary Outcome Measures

Name	Time	Method
Incidence of EAD (Early Allograft Dysfunction) Within 7 Days After OLT (PP Population)	within 7 day after the OLT	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.
Incidence of EAD (Early Allograft Dysfunction) Within 7 Days After OLT (mITT Population)	within 7 day after the OLT	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.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With/Without Primary Allograft Nonfunction Within 7 Days After OLT	Within 7 days after OLT	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.
Frequency of Identification of Laboratory Examination Values	within 3 day after the OLT	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)
Number of Patients With/Without Overall Indicators of Allograft Dysfunction During the Early Postoperative Period	Within 14 days after OLT	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.
Overall Indicators of the Allograft Dysfunction During the Early Postoperative Period - Extracorporeal Detoxification	Within 14 days after OLT	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.
Number of Patients With Early Allograft Dysfunction (EAD) in Case of Transplantation of Donor Organs, by the Degree of Steatosis	Within 14 days after OLT	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 Differing by the Time (in Hours) of Allograft Removal From the Donor and up to Its Reperfusion (Duration of Cold Ischemia)	Within 14 days after OLT	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.
Number of Patients With EAD in Case of Transplantation of Donor Organs Differing by the Duration (in Min) of Warm Ischemia	Within 14 days after OLT	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.
Number of Patients With EAD in Transplantation From Donors Having Additional Adverse Factors	Within 14 days after OLT	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.
Number of Patients With EAD in Transplantation With Regard to the Interval (in Hours) Between the Diagnosis of Brain Death and Removal of the Liver Graft From a Donor	Within 14 days after OLT	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.
Number of Patients With EAD in Transplant Recipients With Each of the Different Liver Disease Etiology	Within 14 days after OLT	The number of patients with EAD in transplant recipients with liver diseases of different etiology (viral, alcoholic, autoimmune, etc.) was assessed.
Incidence of Early Allograft Dysfunction (EAD) in Transplant Recipients With Liver Diseases of Different Etiology and With Different Baseline Characteristics	Within 14 days after OLT	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 Patients With EAD in Transplant Recipients With Liver Diseases (HBV and HCV Virus) and With Different Baseline Characteristics	Within 14 days after OLT	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.
Incidence of Early Allograft Dysfunction in Transplant Recipients (Creatinine Clearance, ClCr)	Within 14 days after OLT	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.
Incidence of Early Allograft Dysfunction in Transplant Recipients - Severity of Recipient's Liver Disease Through MELD Index	Within 14 days after OLT	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
Number of Patients With EAD in Transplant Recipients Via Child-Turcotte-Pugh Score (CTP)	Within 14 days after OLT	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 Liver Function Normalization of Liver Function Parameters	Within 1 Year after OLT	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	within 1 year after OLT	Patient survival within 1 year after OLT was assessed. Please note the data are not available due to insufficient number of participants with events.
Mortality Within 1 Year After the OLT	Within 1 Year after OLT	Number of deaths within 1 year after the OLT was assessed.
The Incidence of Hyperacute, Acute and Chronic Liver Allograft Rejection .	Within 1 Year after OLT	Hyperacute or acute transplant rejection were determined by biopsy; chronic transplant rejection was defined by histological evaluation in both treatment groups.
Summary of Adverse Events up to 1 Year After the OLT	up to 1 year after the OLT	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.

Trial Locations

Locations (7): Healthcare Organization "9th City Clinical Hospital"
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Minsk, Belarus
State Budgetary Health Institution "Scientific Research Institute - Regional Clinical Hospital # 1 n.a. professor S.V. Ochapovskiy" of the Ministry of Health of the Krasnodar Territory
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Krasnodar, Krasnodar Territory, Russian Federation
State Budgetary Educational Institution of Higher Professional Education "First Saint Petersburg State Medical University n.a. I.P. Pavlov" of the Ministry of Health of the Russian Federation
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St. Petersburg, Saint Petersburg, Russian Federation
Federal State Budgetary Institution "Academician V.I. Shumakov Federal Research Center of Transplantology and Artificial Organs" Ministry of Health of the Russian Federation
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Moscow, Russian Federation
Federal State Budgetary Institution "State Research Centre of the Russian Federation - Federal Medical Biophysical Centre n.a. A.I. Burnazyan"
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Moscow, Russian Federation
State Budgetary Health Institution of Moscow "Scientific Research Institute of Emergency n.a. N.V. Sklifosovskiy of Moscow Healthcare Department"
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Moscow, Russian Federation
State Budgetary Health Institution of Novosibirsk Region "State Novosibirsk Regional Clinical Hospital"
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Novosibirsk, Russian Federation
Healthcare Organization "9th City Clinical Hospital"
🇧🇾Minsk, Belarus