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

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).

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.

Inclusion Criteria:

1. Male and female patients aged 18 years and older needing a whole organ OLT, listed on the waiting list for liver transplantation.
2. 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).
3. The possibility of insertion of a central catheter for infusion of the study drug.
4. Signed Patient Informed Consent Form.
5. Ability to comply with all the requirements of the protocol.
6. 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:

1. Split-liver transplantation or transplantation from a living donor.

2. Re-transplantation or multivisceral transplantation.

3. The presence of extrahepatic tumor foci or sepsis.

4. Gastrointestinal bleeding caused by portal hypertension within 3 months prior to screening.

5. BMI less than 18.5 or more than 40 kg/m2.

6. HIV infection.

7. 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.

8. Preoperative renal impairment (glomerular filtration rate estimated with the Cockcroft-Gault formula ≤ 45 mL/min).

9. Significant, in the opinion of the Investigator, drug or alcohol abuse within 6 months prior to screening.

10. 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.

11. Pregnant or lactating women, or women planning a pregnancy during the clinical study, fertile women not using adequate contraception methods.

12. 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.

13. 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.

14. 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.