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

NCT03031470 | Terminated Phase 2 Results DMC

• 1 other identifier: TPL-RPX-01
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 7

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).

Conditions

Ischemia-reperfusion Injury in Liver Transplant; Early Allograft Dysfunction

Keywords

Liver Transplant; Ischemia-reperfusion injury; Early allograft dysfunction

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  within 7 day after the OLT

Secondary Outcomes (20)

• Number of Patients With/Without Primary Allograft Nonfunction Within 7 Days After OLT

  Within 7 days after OLT

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

  Within 14 days after OLT

• Overall Indicators of the Allograft Dysfunction During the Early Postoperative Period - Extracorporeal Detoxification

  Within 14 days after OLT

• Frequency of Identification of Laboratory Examination Values

  within 3 day after the OLT

• 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

Study Arms (2)

Reparixin

EXPERIMENTAL

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.

Drug: Reparixin

Control

OTHER

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.

Other: Control

Interventions

Reparixin DRUG

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.

Reparixin

Control OTHER

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.

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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),
• 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.

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead

Study Sites (7)

Healthcare Organization "9th City Clinical Hospital"

Minsk, 220045, Belarus

Location

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, 350086, Russia

Location

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, 197022, Russia

Location

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

Moscow, 123182, Russia

Location

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

Moscow, 123182, Russia

Location

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

Moscow, 129090, Russia

Location

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

Novosibirsk, 630087, Russia

Location

MeSH Terms

Conditions

Reperfusion Injury

Interventions

reparixin

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Clinical Development & Operations
• Organization: Dompé farmaceutici s.p.a.

clinical.trials@dompe.com

+39 02 583831

Study Officials

• Sergey Vladimirovich Zhuravel, MD

  Moscow Scientific Research Institute of Emergency, NV Sklifosovskiy of Moscow Healthcare Department

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2016
• First Posted: January 25, 2017
• Study Start: March 10, 2015
• Primary Completion: February 9, 2017
• Study Completion: March 31, 2017
• Last Updated: January 7, 2025
• Results First Posted: December 11, 2024

Record last verified: 2024-12

Locations

BE (1); RU (6)