Early Allograft Dysfunction Clinical Trial
Official title:
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.
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