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

Phase 2TerminatedNCT03031470

Dompé Farmaceutici S.p.A40 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Ischemia-reperfusion Injury in Liver Transplant Early Allograft Dysfunction

Interventions

ReparixinDRUG

Reparixin was administered as a continuous intravenous infusion for 7 days (Day 0 to Day 6) (168 hours). Reparixin was provided as 33 mg/ml concentrated solution to be diluted for i.v. infusion, packaged into 250 mL clear glass vials. To give a final concentration of 11 mg/mL, the content of a vial (250 ml) was diluted with 500 ml of 0.9% sterile saline to a total volume of 750 ml. The dosing solution was placed in a 1000 ml sterile empty Infusion Bag. Dosing solutions were to be used within 72 h from preparation, unless more restrictive rules. Reparixin infusion started approximately 60-90 minutes before the anticipated time of OLT. Infusion interruption was allowed for no more than 60 min. All patients received standard immunosuppressive therapy in accordance with the Russian Transplant Society Guidelines for liver transplantation. Patients and allograft survival were monitored up to 1 year after OLT.

ControlOTHER

The patients who were randomized in the control group, did not receive any study therapy. The patients of both groups received the standard immunosuppressive therapy with Tacrolimus only or together with mycophenolates, or a combination of Tacrolimus/Cyclosporine with mycophenolates and/or glucocorticosteroids. The patients with hepatocellular carcinoma and impaired renal function could receive a combination of drugs that includes everolimus. Basiliximab in association with methylprednisolone was used for the induction of immunosuppression.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (7)

Healthcare Organization "9th City Clinical Hospital"

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

Krasnodar, Krasnodar Territory, Russia

Outcomes

Primary Outcomes

Incidence of EAD (Early Allograft Dysfunction) Within 7 Days After OLT (PP Population)

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.

Time frame: within 7 day after the OLT

Incidence of EAD (Early Allograft Dysfunction) Within 7 Days After OLT (mITT Population)

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.

Time frame: within 7 day after the OLT

Secondary Outcomes

Number of Patients With/Without Primary Allograft Nonfunction 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.

Time frame: Within 7 days after OLT

Number of Patients With/Without Overall Indicators of Allograft Dysfunction During the Early Postoperative Period

Data from ClinicalTrials.gov

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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

Saint Petersburg, Sankt-Peterburg, Russia

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

Moscow, Russia

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

Moscow, Russia

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

Moscow, Russia

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

Novosibirsk, Russia

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.