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

A Multicenter, Open-label, Randomized Pilot Clinical Study of Efficacy and Safety of Reparixin for Prevention of Early Allograft Dysfunction in Patients Undergoing Orthotopic Liver Transplantation

Liver transplantation is currently the treatment of choice for end-stage liver cirrhosis of different origin, as well as for a number of inborn metabolism disorders and liver tumors. The need to perform a liver transplantation is high and amounts to 10 - 20 patients per 1 million population per year. Experimental and clinical evidence demonstrate the harmful short and long-term effects of ischemia-reperfusion injury (IRI) of the donor organ on the outcome of the intervention performed. Severe manifestations of IRI of the liver transplant (LT) is one of the main reasons for the increased length of hospitalization, the high cost of treating patients during the post- surgery period, the development of persistent early allograft dysfunction or loss, frequent crises of acute rejection, acute renal and multiple organ failure, and mortality of the operated patients. This pilot clinical study is designed to evaluate the efficacy and safety of Reparixin, which is a new, potent and specific inhibitor of chemokine CXCL8 (Interleukin-8), as an agent to prevent early allograft dysfunction caused by ischemia-reperfusion injury in patients undergoing orthotopic liver transplantation.

Liver transplantation is currently the treatment of choice for end-stage liver cirrhosis of different origin, as well as for a number of inborn metabolism disorders and liver tumors. The need to perform a liver transplantation is high and amounts to 10 - 20 patients per 1 million population per year. The indication for liver transplantation is the presence of irreversible liver disease with estimated life expectancy of less than 12 months, absence of another treatment, presence of chronic liver disease, significantly reducing the patient's quality of life and ability to work, as well as progressive liver disease with a life expectancy less than in the case of liver transplantation (after liver transplantation 85% of patients survive for 1 year and 70% - for 5 years). Currently, about 200 liver transplantations are performed annually in Russia, which is more than 10 times lower than the existing need and is far below the number of similar operations performed abroad. The vast majority of liver transplants for adult recipients are performed using liver allografts from cadaveric donors. The rigorous list of requirements for a transplant restricts significantly the use of cadaveric liver. Thus, the need to expand the pool of donor organs suitable for transplantation is a pressing issue. Experimental and clinical evidence demonstrate the harmful short and long-term effects of ischemia-reperfusion injury (IRI) of the donor organ on the outcome of the intervention performed. Severe manifestations of IRI of the liver transplant (LT) is one of the main reasons for the increased length of hospitalization, the high cost of treating patients during the post- surgery period, the development of persistent early allograft dysfunction or loss, frequent crises of acute rejection, acute renal and multiple organ failure, and mortality of the operated patients. IRI caused by the termination and subsequent restoration of blood flow is more or less inevitable for all donor organs. The mechanism of ischemia-reperfusion syndrome involves interaction between vascular endothelium, interstitial space, circulating cells and a variety of biochemical reactions, with the primary link in the chain of pathological processes of local and generalized nature being microcirculatory disorders. Early allograft dysfunction is an important predictor of severe complications and mortality after OLT. The incidence of early allograft dysfunction is approximately 25% (ranging from 9.3 to 43.7% subject to different definitions and classifications of the condition). Retrospective evaluation of the incidence of early allograft dysfunction performed in the Russian leading transplantation institution - N.V. Sklifosovsky Research Institute of Emergency Care, confirmed the development of this type of complication in 25% of cases (N = 202). Death has occurred in the population of patients with early allograft dysfunction at almost twice the rate of patients with normal functioning of the transplant during the first 7 days after OLT (p < 0.005). Therefore, as yet, the search of the drugs that may be effective in the prevention of early allograft dysfunction is still a relevant issue. Reparixin is a new, potent and specific inhibitor of chemokine CXCL8 (Interleukin-8). With regard to the mechanism of action of Reparixin, its early preclinical development was aimed at specific inhibition of migration of polymorphonuclear neutrophils and prevention of ischemia- reperfusion injury. Reparixin has received the orphan drug designation in EU in September 2001 and in USA in January 2003 for prevention of delayed graft function after solid organ transplantation. More recently orphan drug designation has been granted in EU (September 2011) for the "prevention of graft loss in pancreatic islet transplantation" and in the US (September 2012) for the "prevention of graft loss in islet cell transplantation". This pilot clinical study is designed to evaluate the efficacy and safety of Reparixin as an agent to prevent early allograft dysfunction caused by ischemia-reperfusion injury in patients undergoing orthotopic liver transplantation.

Overall indication of liver allograft disfunction, including: I) primary nonfuntion II) early allograft dysfunction defined as maximum alanine transferase (ALT) or aspartate transferase (AST) levels on days 1-7 of >2000 U/ml, day 7 bilirubin level ≥10 mg/dl, or a day 7 international normalized ratio (INR) ≥1.7, III) extracorporeal detoxification

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: ibuprofen or to more than one non-steroidal anti-inflammatory drug (NSAID), 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.

State Budgetary Health Institution of Moscow "Scientific Research Institute of Emergency n.a. N.V. Sklifosovskiy of Moscow Healthcare Department"

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

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

Federal State Budgetary Institution "Academician V.I. Shumakov Federal Research Center of Transplantology and Artificial Organs" Ministry of Health of the Russian Federation

Federal State Budgetary Institution "State Research Centre of the Russian Federation - Federal Medical Biophysical Centre n.a. A.I. Burnazyan"

State Budgetary Health Institution of Moscow "Scientific Research Institute of Emergency n.a. N.V. Sklifosovskiy of Moscow Healthcare Department"

State Budgetary Health Institution of Novosibirsk Region "State Novosibirsk Regional Clinical Hospital"