Conditions: Ischemia-reperfusion Injury in Liver Transplant Early Allograft Dysfunction
Keywords: Liver Transplant Ischemia-reperfusion injury Early allograft dysfunction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

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).

Detailed description:
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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Reparixin intervention 2: Control
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
Prot_000.pdf: 
Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 1 of 81 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
TPL-RPX-01 
 
 
 
Study 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. 
Study Number: 
TPL-RPX-01 
Study Phase: 
2 
Name of the product: 
Reparixin 
Indications: 
Prevention of early allograft dysfunction in patients undergoing 
orthotopic liver transplantation 
Sponsor: 
Dompé farmaceutici s.p.a. 
Protocol Version - 
Date: 
Version No. 2 –Final 13 March 2015 
 
 
 
 
 
Confidentiality Statement 
 
Information in this protocol and accompanying documents contains privileged or confidential information that 
is the property of Dompé farmaceutici s.p.a. It is understood that the information will not be used, divulged, or 
published without prior written consent of Dompé farmaceutici s.p.a., except to the extent such disclosure is 
required by applicable laws and regulations. The fact of any disclosure of the information contained herein, 
either authorized or unauthorized, shall be immediately reported to Dompé farmaceutici s.p.a. 
 
 
 
 
Version No. 2 – Final 13 March 2015 
This protocol version results from the translation of the Russian version of the protocol dated 
18 February 2014, and revision according to Amendment No. 1 (Final, 3 March 2015). 


S1ud_v Tl'L-RPX-01 
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PROTOCOL APPROVAL l'AGE 
 
 
SPONSOR 
 
Developrnent Director•· Diahetes and Tra11spla11tation 
 
 
 
 
 
 
 
 
 
 
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PPD


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 3 of 81 
Version No. 2 – Final 13 March 2015 
 
 
 
PRINCIPAL INVESTIGATOR STATEMENT 
 
 
FULL NAME: 
I, the undersigned, hereby certify that I have read and understood the protocol TPL- 
RPX-01: “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”. 
I understand that, as Principal Investigator, I have ultimate responsibility for the 
protection of the rights and welfare of human subjects, conduct of the study and the ethical 
performance of the trial. I agree to accept responsibility for the conduct and supervision of 
this research and the protection of human subjects as set forth in the Declaration of Helsinki 
and the ICH GCP Guidelines, and as required by local regulatory requirements. 
DATE: 
SIGNATURE: 
CENTER NUMBER: 
TOWN: 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 4 of 81 
Version No. 2 – Final 13 March 2015 
 
 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
CONTACT INFORMATION ON THE CLINICAL STUDY 
 
 
SPONSOR 
Dompé farmaceutici s.p.a. 
Via S. Martino 12, 20122 Milan, Italy 
Phone +39 02 583831 
PPD 
 
Medical Expert 
PPD 
 
Clinical Trial Manager 
PPD 
 
Pharmacovigilance 
PPD 
 
CRO 
PPD 
 
2a, build. 1, Rabochaya str., Khimki 
Moscow Region, 141400, Russia 
PPD 
 
Project Manager 
PPD 
 
Medical Monitor 
and Safety Contact for 
SAE Reporting 
PPD 
 
 
INVESTIGATIONAL SITES 
Full list of investigational sites will be kept in the Trial Master File. Updated versions, if 
any, will be filed chronologically. Copies will be provided to the sites. 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 5 of 81 
Version No. 2 – Final 13 March 2015 
 
 
PPD 
PPD 
PPD 
INSTITUTIONS INVOLVED IN THE CLINICAL TRIAL 
 
 
CRO (site monitoring, medical 
monitoring, regulatory 
submissions, site audits) 
PPD 
PPD 
Centralized Laboratory for 
hematology, coagulation, 
biochemistry, serology and viral 
load 
PPD 
Centralized Laboratory for 
pharmacokinetic assays 
Biotech Unit 
Dompé farmaceutici s.p.a. 
Via Campo di Pile 
67100 L’Aquila – Italy 
PPD 
 
PPD 
 
Data Management, Biostatistics 
PPD 
 
Drug Depot 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 6 of 81 
Version No. 2 – Final 13 March 2015 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 10 
STUDY SYNOPSIS ................................................................................................................ 11 
1 INTRODUCTION ................................................................................................................ 17 
2 THE OBJECTIVES AND ENDPOINTS OF THE CLINICAL STUDY ............................ 19 
2.1 Study objective ............................................................................................................. 19 
2.2 Study endpoints ............................................................................................................ 19 
3 STUDY DESIGN ................................................................................................................. 21 
3.1 Overall design and study plan ...................................................................................... 21 
3.2 Study design ................................................................................................................. 21 
3.3 Screening...................................................................................................................... 21 
3.4 Study drug administration and surgery ........................................................................ 21 
3.5 Follow-up ..................................................................................................................... 22 
3.6 Rationale of the study design ....................................................................................... 26 
3.7 Duration of the study and the dates ............................................................................. 27 
3.8 Previous experience with Reparixin ............................................................................ 27 
3.8.1 Phase I Clinical Studies ...................................................................................... 29 
3.8.2 Phase II Clinical Studies ..................................................................................... 29 
3.8.3 Phase III Clinical Studies .................................................................................... 30 
3.8.4 Academic clinical studies ................................................................................... 31 
3.9 Risk/benefit ratio .......................................................................................................... 31 
3.9.1 General risks ....................................................................................................... 31 
3.9.2 Risks related to the administration of Investigational Product ........................... 31 
3.9.3 Central line .......................................................................................................... 32 
3.9.4 Potential benefits for patients.............................................................................. 32 
4 SELECTION OF THE STUDY POPULATION.................................................................. 33 
4.1 Study population .......................................................................................................... 33 
4.2 Inclusion criteria .......................................................................................................... 33 
4.3 Exclusion criteria ......................................................................................................... 33 
4.4 Criteria for selection of donor organ for OLT ............................................................. 34 
4.5 Retesting and rescreening ............................................................................................ 34 
5. STUDY DRUG .................................................................................................................... 35 
5.1 Description of study drug............................................................................................. 35 
5.2 Manufacturing, packaging and labeling ....................................................................... 35 
5.3 Preparation of the Dosing Solution .............................................................................. 37 
5.4 Dose, course and calculation of Reparixin administration........................................... 37 
5.4.1 Criteria for discontinuation of investigational product ....................................... 37 
5.5 Randomization ............................................................................................................. 38 
5.6 Blinding ....................................................................................................................... 38 
5.7 Assessment of compliance ........................................................................................... 38 
5.8 Supply, Storage and Handling of Investigational Product ........................................... 38 
5.9 Concomitant medications ............................................................................................. 39 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
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5.9.1 Standard immunosuppressive therapy ................................................................ 39 
5.10 Prohibited medications ............................................................................................... 40 
6 DESCRIPTION OF PROCEDURES .................................................................................... 41 
6.1 Informed consent ......................................................................................................... 41 
6.2 Patient registration ....................................................................................................... 41 
6.3 Demographic data and medical history........................................................................ 41 
6.4 Physical examination ................................................................................................... 41 
6.5 MELD and Child-Turcotte-Pugh scores ...................................................................... 42 
6.6 Vital signs, height and weight ...................................................................................... 42 
6.7 Electrocardiography ..................................................................................................... 42 
6.8 Doppler abdominal ultrasonography ............................................................................ 42 
6.9 Laboratory tests............................................................................................................ 42 
6.9.1 Laboratory parameters ........................................................................................ 43 
6.9.2 PK parameters ..................................................................................................... 44 
6.9.3 Collection, preparation, storage and shipment of biological samples................. 44 
6.9.3.1 Collection, preparation, storage and shipment of PK samples ........................ 44 
6.10 Assessment of efficacy .............................................................................................. 45 
6.11 Evaluation of Adverse Events (AEs) ......................................................................... 46 
6.11.1 Definitions of AEs ............................................................................................ 46 
6.11.2 Pregnancy .......................................................................................................... 46 
6.11.3 Reporting of AEs and SAEs ............................................................................. 47 
6.11.4 Assessment of the severity ................................................................................ 47 
6.11.5 Relationship between the AE and the Investigational Product ......................... 48 
6.11.6 Assessment of Expectedness ............................................................................. 48 
6.11.7 Reporting of SAEs/pregnancy........................................................................... 49 
6.11.8 Early patient withdrawal ................................................................................... 50 
6.11.9 Emergency response ......................................................................................... 50 
6.11.10 Terms of AE/SAE registration ........................................................................ 50 
6.11.11 Expected Adverse Events ............................................................................... 50 
6.11.12 Clinically significant abnormalities ................................................................ 50 
6.11.13 Adverse Event exemption ............................................................................... 51 
6.12 Early patient withdrawal and discontinuation of the study drug ............................... 51 
6.13 Patient replacement .................................................................................................... 52 
6.14 Validity of measurements .......................................................................................... 52 
7 STUDY PROCEDURES ...................................................................................................... 53 
7.1 Selection of the transplant ............................................................................................ 53 
7.2 Screening and Randomization, Day -1 ........................................................................ 53 
7.3 Study therapy, week 0 ............................................................................................ 54 
7.3.1 Day 0 ................................................................................................................... 54 
7.3.2 Day 1 after OLT .................................................................................................. 54 
7.3.3 Day 2 after OLT .................................................................................................. 54 
7.3.4 Day 3 after OLT .................................................................................................. 55 
7.3.5 Day 4 after OLT .................................................................................................. 55 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
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7.3.6 Day 5 after OLT .................................................................................................. 55 
7.3.7 Day 6 after OLT .................................................................................................. 55 
7.4 Completion of therapy, Day 7 after OLT (end of therapy) .......................................... 56 
7.5 Follow-up period .......................................................................................................... 56 
7.5.1 Week 2 after OLT(Time window  2 days) ........................................................ 56 
7.5.2 Week 4 after OLT (Time window  3 days) ....................................................... 56 
7.5.3 Weeks 12 and 24 after OLT (Time window  7 days) ........................................ 57 
7.5.4 Week 36 after OLT (Time window  7 days) ..................................................... 57 
7.5.5 Year 1 after OLT (Time window  14 days)....................................................... 57 
7.6 Unscheduled visits ....................................................................................................... 57 
7.7 Visit of early discontinuation (ED) .............................................................................. 57 
8 QUALITY ASSURANCE .................................................................................................... 59 
9 PLANNED STATISTICAL METHODS ............................................................................. 60 
9.1 General Terms.............................................................................................................. 60 
9.2 Determination of sample size....................................................................................... 60 
9.3 Populations for analysis ............................................................................................... 60 
9.3.1 Population per protocol ....................................................................................... 60 
9.3.2 MITT population ................................................................................................. 60 
9.3.3 Safety population ................................................................................................ 61 
9.4 Patient allocation, demographic and baseline characteristics ...................................... 61 
9.5 Investigational product administration ......................................................................... 61 
9.6 Statistical Methods ....................................................................................................... 61 
9.6.1 Demographic and Baseline Characteristics ......................................................... 61 
9.6.2 Efficacy analysis ................................................................................................. 61 
9.6.2.1 Primary efficacy analysis ................................................................................. 62 
9.6.2.2 Secondary efficacy analyses ............................................................................ 63 
9.7 Safety analysis ............................................................................................................. 64 
9.8 PK analysis................................................................................................................... 64 
10 ADMINISTRATIVE PROCEDURES ............................................................................... 65 
10.1 Legal aspects .............................................................................................................. 65 
10.2 Protocol Amendments ................................................................................................ 65 
10.3 Responsibilities of the Investigator ............................................................................ 65 
10.4 CRF data entry ........................................................................................................... 66 
10.5 Data Monitoring Committee ...................................................................................... 66 
10.6 Monitoring procedures ............................................................................................... 66 
10.7 Registration of data in the CRF ................................................................................. 67 
10.8 Essential Document retention .................................................................................... 67 
10.9 Ethical considerations ................................................................................................ 67 
10.9.1 Independent Ethics Committee ......................................................................... 67 
10.9.2 Ethical performance of the clinical study ......................................................... 67 
10.9.3 Informed Consent ............................................................................................. 67 
10.9.4 Discontinuation of the study ............................................................................. 68 
11 LIST OF REFERENCES .................................................................................................... 69 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
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Version No. 2 – Final 13 March 2015 
 
 
LIST OF TABLES 
Table 1 
Study TPL-RPX-01 flow chart .................................................................... 24 
Table 2 
Reparixin clinical trials ................................................................................ 28 
Table 3 
List of parameters for blood test .................................................................. 43 
Table 4 
List of parameters for urine test ................................................................... 44 
Table 5 
List of PK parameters .................................................................................. 44 
Table 6 
PK sampling schedule .................................................................................. 45 
Table 7 
Intensity (Severity) of the Adverse Event .................................................... 48 
Table 8 
Relationship between the AE and the Investigational Product .................... 48 
 
LIST OF FIGURES 
Figure 1. Design of clinical trial TPL-RPX-01 .................................................................. 22 
 
LIST OF APPENDICES 
Appendix 1. 
Classification of the New York Heart Association ............................ 70 
Appendix 2. 
MELD score ....................................................................................... 71 
Appendix 3. 
Child-Turcotte-Pugh score ................................................................. 72 
Appendix 4. 
Hepatic encephalopathy ..................................................................... 73 
Appendix 5. 
Table for calculating of the rate of Reparixin infusion ...................... 74 
Appendix 6. 
Calculation of creatinine clearance .................................................... 76 
Appendix 7. 
The Russian Transplant Society Guidelines for Liver Transplantation 
(2013) ................................................................................................. 77 
Appendix 8. 
Summary of Adverse Drug Reactions IV formulation1 ................................ 78 
Appendix 9. 
Sepsis criteria (2001 SCCM/ESICM/ACCP/ATS/SIS International 
Sepsis Definitions Conference) .......................................................... 80 
Appendix 10. 
Handling of samples for pharmacokinetic assay ............................... 81 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AP 
Arterial Pressure 
APTT 
Activated Partial Thromboplastin Time 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CLcr 
Creatinine Clearance 
CPB 
Cardiopulmonary Bypass 
CRF 
Case Report Form 
CXCL8; IL-8 
Interleukin-8 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ESR 
Erythrocyte Sedimentation Rate 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-glutamyltransferase 
HBV, HCV 
Hepatitis B and C 
HIV 
Human Immunodeficiency Virus 
ICH GCP 
Guidelines for Good Clinical Practice of the International Conference on 
Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRI 
Ischemia-reperfusion Injury 
i.v. 
Intravenous 
LDH 
Lactate Dehydrogenase 
LT 
Liver Transplant 
MELD 
Model for End-Stage Liver Disease 
MITT 
Modified population of patients who received treatment (Modified intent-to- 
treat) 
NSAID 
Non-steroidal Anti-inflammatory Drug 
OLT 
Orthotopic liver transplantation 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic 
PTT 
Prothrombin Time 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SADR 
Serious Adverse Drug Reaction 
t1/2 
Half-life 
WHO 
World Health Organization 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 11 of 81 
Version No. 2 – Final 13 March 2015 
 
 
STUDY SYNOPSIS 
Sponsor: Dompé farmaceutici s.p.a. 
Via San Martino 12, 20122, Milano, Italy 
Name of the study drug: Reparixin 
Active ingredient: R(-)-4-isobutyl-α-methyl-phenyl-acetyl-methanesulfonamide 
Study 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. 
Study number: TPL-RPX-01 
Study phase: 2 
Study objective: 
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 OLT). The safety of 
reparixin in the specific clinical setting will be also evaluated. 
Efficacy endpoints will be: 
• 
Incidence of early allograft dysfunction within 7 days after OLT (primary endpoint). 
• 
Primary nonfunction within 7 days after OLT. 
• 
Overall indicators of the liver allograft dysfunction during the early postoperative period 
(within 14 days after OLT), including: 
- Primary nonfunction, 
- Early allograft dysfunction, 
- Extracorporeal detoxification. 
• 
The frequency of identification of laboratory examination values corresponding to early 
allograft dysfunction, 3 days after the operation (Day 4 of the study drug administration). 
• 
The incidence of early allograft dysfunction in case of transplantation of donor organs 
differing by the degree of steatosis and by the time of allograft removal from the donor and 
up to its reperfusion after engraftment (duration of cold and warm ischemia). 
• 
The incidence of early allograft dysfunction in transplantation from donors having additional 
adverse factors (infectious complication, death of the brain, hypotension, etc.), and with regard 
to the interval between the diagnosis of brain death and removal of liver graft from a donor 
(in the case of the death of brain of the donor). 
• 
The incidence of early allograft dysfunction in transplant recipients with liver diseases of 
different etiology (viral, alcoholic, autoimmune, etc.) and with different baseline 
characteristics (age, activity of hepatitis B, kidney function, score in scales of end-stage liver 
disease (MELD), Child-Turcotte-Pugh, etc.). 
• 
Time for normalization of liver function parameters (alanine aminotransferase, aspartate 
aminotransferase and bilirubin levels, gamma-glutamyltransferase, lactate dehydrogenase, 
etc.) after OLT. 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 12 of 81 
Version No. 2 – Final 13 March 2015 
 
 
• 
The incidence of hyperacute, acute and chronic liver allograft rejection (defined by 
histological evaluation). 
• 
Mortality within 1 year after OLT. 
• 
Graft survival at 1 year after OLT. 
Safety endpoints will be: 
• 
The incidence of adverse events (AEs) and serious adverse events (SAEs) of different severity 
within 12 weeks and 1 year after OLT according to subjective complaints, physical 
examination, vital signs, laboratory tests (including liver and kidney function parameters), 
ECG, vascular ultrasound of the liver and kidneys with Doppler sonography. 
Pharmacokinetics endpoints will be: 
Reparixin (total and unbound) and relevant metabolites (DF2243Y and ibuprofen) 
• 
maximum plasma concentration (Cmax). 
• 
time of maximum plasma concentration (tmax). 
• 
terminal phase rate constant (z). 
• 
terminal half-life (t½). 
• 
area under the plasma concentration-time curve from time zero to time t (AUC0-t). 
• 
area under the plasma concentration-time curve from time zero to infinity (AUC0-). 
• 
volume of distribution (Vz). 
• 
clearance (CL). 
Rationale: 
Dompé farmaceutici s.p.a. (Italy) is developing a new drug Reparixin, which 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 the ischemia- reperfusion injury associated 
with solid organ transplantation. The clinical study of Reparixin was initially focused on the 
prevention of delayed allograft function and its primary nonfunction in transplantation of solid 
organs (kidneys, lungs) and pancreatic islets [1, 2, 3, 4]. 
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 post- orthotopic 
liver transplantation patients. 
Study Design: 
This is a 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. 
Patients will be accrued in this study using a two-stage Simon's design [5, 6]. Forty-four 
patients (22 per each group) will be enrolled in the first stage. If less than 5 patients from the study 
drug group will experience early graft dysfunction in the first stage, up to 34 patients (17 per group) 
will be enrolled in the second stage. If 5 or more patients from the study drug group will experience 
early graft dysfunction, the study will terminate enrollment early. 
Considering a possible 7% early discontinuation rate and the inability to assess the primary 
endpoint for some patents, up to 84 patients will be randomized in the study. This number of 
patients is based on a statistical power of 80% with an alpha of 0.05 and 1:1 randomization. In 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 13 of 81 
Version No. 2 – Final 13 March 2015 
 
 
total, considering a possible 15% screening failure rate, about 100 patients planned for OLT will 
need to be screened in the study. 
The study is planned to be conducted at 5-8 transplantation sites in Russia and Belarus. 
Recruitment will be competitive among the study sites, until the planned number of patients is 
enrolled. 
Patients admitted to the transplant center immediately before OLT, will be screened against 
the inclusion and exclusion criteria. Eligible patients will be randomized (randomization number 
assigned) by an Investigator (or designee) prior to start procedures for preparation of the dosing 
solution of the Investigational Product. 
Randomization will be performed before or at the day of the surgical operation. The patients 
will be randomized in a 1:1 manner into the Reparixin or the control group. 
In the group of the study therapy, Reparixin will be administered as a continuous infusion for 
7 days (168 hours). Infusion of the study drug will start approximately 60-90 minutes before the 
anticipated time of OLT. 
The control group will include patients who do not receive Reparixin therapy. All the patients 
who participate in the study will receive standard immunosuppressive therapy in accordance with 
the Russian Transplant Society Guidelines for liver transplantation (2013). 
The clinical study will consist of the following stages: 
Screening. The patients admitted to the transplant center immediately before OLT, will be 
screened (Day -1). The screening procedures may be performed within 24 hours before planned 
surgery. The results at screening will be considered as baseline values. 
Randomization. Patients fulfilling all the inclusion criteria and none of the exclusion criteria 
will be randomized in a 1:1 manner into the treated or the control group. 
Treatment. On Day 0, 60-90 minutes before OLT, the patients, who were randomized to the 
Reparixin group, will start to receive the infusion of the study drug, which will continue for 7 days 
(168 hours). OLT will be performed during the continuous infusion of Reparixin. Post- operative 
examinations will be performed daily within the first 7 days after OLT (from Day 0 to Day 6). The 
final assessment of safety parameters and of the primary endpoint will be performed after the end 
of the infusion of the study drug, on Day 7 after OLT. 
The patients, who will randomized to the control group, will not receive any study drug. 
The patients in both groups will receive 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 can receive a combination of drugs that includes everolimus. Basiliximab 
in association with methylprednisolone will be used for the induction of immunosuppression. 
Follow-up. The status of patients and allograft survival will be monitored up to 1 year after 
OLT. At Week 2 and Week 4 the patients will visit the center with mandatory control of the basic 
functions of the liver transplant and general condition of the patient. Then, the patients will visit 
the center on Week 12, Week 24 and 1 year after OLT in order to control the safety parameters. 
Study Population: 
Adult patients aged 18 years and older requiring OLT. 


Study TPL-RPX-01 
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Main inclusion/exclusion criteria 
To be enrolled in this clinical study, the patients shall meet the following 
inclusion/exclusion criteria. 
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: 
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 (Appendix 9). 
4. Gastrointestinal bleeding caused by portal hypertension within 3 months prior to screening. 
5. Body mass index (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 
classification), 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: 
a) ibuprofen or to more than one non-steroidal anti-inflammatory drug (NSAID), 
b) 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. 


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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. 
Investigational product, doses and mode of administration: 
Investigational product: Reparixin 
Active ingredient: R(-)-4-isobutyl-α-methyl-phenyl-acetyl-methanesulfonamide 
Dosage: 2.772 mg/kg/hour for 7 days (168 hours) 
Dosage form: Reparixin will be provided as 33 mg/ml concentrated solution to be diluted for 
i.v. infusion, 
 
The dosing solution will be placed in a 1000 ml sterile empty Infusion Bag. Dosing 
solutions will be prepared and used within 72 hours from preparation, unless the site has more 
restrictive rules. 
Mode of administration: continuous intravenous infusion into a central vein for 7 days (168 
hours). 
Manufacturer: PPD 
 
Reference product: 
None. 
Standard immunosuppressive therapy: 
The patients of both groups will receive 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 can receive a combination of drugs that includes everolimus. Basiliximab 
in association with methylprednisolone will be used for the induction of immunosuppression. 
Duration of the study: 
The overall duration of a patients' participation in the study will be approximately 1 year (1 
week of treatment and up to 1 year of post-transplant follow-up). The start of enrollment (first- 
patient-in) is expected for March 2015. It is planned that the last patient randomized in the first 
stage will complete all study visits by March 2017. The end of the study (last visit of the last patient 
randomized in the second stage of the study) is expected by December 2017. 
Statistical methods: 
Analysis of efficacy endpoints: 
The primary efficacy endpoint is the frequency of early allograft dysfunction after OLT (Week 
1) among patients who received Reparixin and patients in the control group. The frequency of 
early allograft dysfunction comprises about 25% (in the interval between 9,3 up to 43,7%; it 
depends on various specifications and classifications of the state). It is expected that Reparixin 
treatment can decrease the frequency of early allograft dysfunction. 
The analysis of the primary efficacy endpoint will be conducted in accordance with the 
Simon's minimax two-stage design [5, 6]. This model can trace the tendency in the efficacy 
parameters of the study drug in the small number of patients. Thus, it can assist in getting the 
results and making the decision on the following study of the drug. 
CCI 


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In accordance with this model, the analysis of the efficacy will be conducted in two stages: 
- During Stage 1 of the study the primary efficacy endpoint will be assessed in 22 patients in 
each group. In case of early allograft dysfunction in < 5 out of 22 patients from the group of the 
study drug, the transition to Stage 2 of the study will be deemed possible. In the case of early 
allograft dysfunction in ≥ 5 out of 22 patients from the group of the study drug, further study of 
Reparixin in this study population will be considered inappropriate. 
- During Stage 2 of the study, the primary efficacy endpoint will be assessed in additional 17 
patients in each group (in the total number of 39 patients in each group). Development of early 
allograft dysfunction in < 6 out of 39 patients from the group of the study drug gives grounds for 
a conclusion of the efficacy of Reparixin in this population and the appropriateness of the 
subsequent large-scale comparative Phase III clinical study. In case early allograft dysfunction 
develops in ≥ 6 out of 39 patients from the group of the study drug, further study of Reparixin in 
this study population can be considered inappropriate. 
Appropriate descriptive statistics will be produced for secondary efficacy endpoints. 
Analysis of safety endpoints: 
All AEs will be presented by primary system organ class systems and preferred term, in terms 
of the incidence, relationship to the study drug and severity. SAEs will be presented in the same 
way. 
Vital signs at each time point and laboratory parameters will be presented using descriptive 
statistics methods. 
PK analysis: 
Plasma levels of reparixin (total and unbound) and relevant metabolites (DF2243Y and 
ibuprofen) will be summarized using descriptive statistics. 
Sample size: 
Simon's minimax two-stage design for Phase II clinical trials was used to calculate the sample 
size [5, 6]. With an alpha level of 0.05 and 80% of power, a total of 39 evaluable patients treated 
with Reparixin are required to test the study hypothesis. Twenty-two patients will be treated at 
Stage I. In case of early allograft dysfunction in 5 or more patients in the first 22 patients, the study 
will early terminate enrollment. 
Data received from the control group will also be used in the study in order to control the 
validity of the information on frequency of early allograft dysfunctions. 
In case of early discontinuation of patients from the study prior to receiving study treatment 
or inability to evaluate the primary efficacy endpoint, the patient can be replaced (see paragraph 
6.13). Considering a possible 7% early discontinuation rate and the inability to assess the primary 
endpoint for some patents, up to 84 patients will be randomized in the study. This number of 
patients is based on a statistical power of 80% with an alpha of 0.05 and 1:1 randomization. In 
total, considering a possible 15% screening failure rate, about 100 patients planned for OLT will 
need to be screened in the study. 
Randomization: 
Patients will be randomized in a 1:1 manner into the treated or the control group (in 
accordance with a randomization list). 
Number and date of the current version of the protocol: 
Protocol Version No. 2 – Final 13 March 2015. 


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1 INTRODUCTION 
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. For example, in the USA, more than 4,000 liver transplantations (per 315 
million people) are performed annually, in the UK – 650 transplantations (per 63 million people), 
which satisfy the current demand by 75 – 85%. According to Gauthier S. and Tsirulnikova O.M. 
[7], mortality on the waiting list for liver transplantation in Russia is 57.4%. In Western Europe 
and the USA this figure is 4 – 10%. 
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 [8]. 
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. 
Dompé farmaceutici s.p.a. (Italy) is developing a new drug Reparixin, which 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. The clinical 
study of Reparixin was initially focused on the prevention of 


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delayed allograft function and primary nonfunction in transplantation of solid organs (kidneys, 
lungs) and pancreatic islets. 
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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2 THE OBJECTIVES AND ENDPOINTS OF THE CLINICAL STUDY 
2.1 Study objective 
To evaluate efficacy and safety of continuous intravenous infusion of Reparixin (2.772 mg/kg 
body weight/hour intravenous continuous infusion for 7 days) based on the incidence of early 
allograft dysfunction (within the first 7 days after OLT) and overall indicators of allograft 
dysfunction in the early postoperative period (within 14 days after OLT). The safety of reparixin 
in the specific clinical setting will be also evaluated. 
2.2 Study endpoints 
Efficacy endpoints will be: 
• 
Incidence of early allograft dysfunction (EAT) within the first 7 days after OLT (primary 
endpoint). 
• 
Primary nonfunction within 7 days after OLT. 
• 
Overall indicators of the liver allograft dysfunction during the early postoperative period 
(within 14 days after OLT), including: 
- Primary nonfunction (PNF), 
- Early allograft dysfunction, 
- Extracorporeal detoxification. 
• 
The frequency of identification of laboratory examination values corresponding to early 
allograft dysfunction, 3 days after the operation (Day 4 of the study drug administration). 
• 
The incidence of early allograft dysfunction in case of transplantation of donor organs 
differing by the degree of steatosis and by the time of allograft removal from the donor and 
up to its reperfusion after engraftment (duration of cold and warm ischemia). 
• 
The incidence of early allograft dysfunction in transplantation from donors having additional 
adverse factors (infectious complication, death of the brain, hypotension, etc.), and with regard 
to the interval between the diagnosis of brain death and removal of liver graft from a donor 
(in the case of the death of brain of the donor). 
• 
The incidence of early allograft dysfunction in transplant recipients with liver diseases of 
different etiology (viral, alcoholic, autoimmune, etc.) and with different baseline 
characteristics (age, activity of HBV, kidney function, score in scales of end-stage liver 
disease (MELD), Child-Turcotte-Pugh, etc.). 
• 
Time for normalization of liver function parameters (alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and bilirubin levels, gamma-glutamyltransferase (GGT), 
lactate dehydrogenase (LDH), etc.) after OLT. 
• 
The incidence of hyperacute, acute and chronic liver allograft rejection (defined by 
histological evaluation). 
• 
Mortality within 1 year after OLT. 
• 
Graft survival at 1 year after OLT. 
Safety endpoints will be: 
• 
The incidence of adverse events (AEs) and serious adverse events (SAEs) of different grade 
within 12 weeks and 1 year after OLT according to subjective complaints, physical 
examination, vital signs, laboratory tests (including liver and kidney function), ECG, vascular 
ultrasound of the liver and kidneys with Doppler sonography. 


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Pharmacokinetics endpoints will be: 
Reparixin (total and unbound) and relevant metabolites (DF2243Y and ibuprofen) 
• 
maximum plasma concentration (Cmax). 
• 
time of maximum plasma concentration (tmax). 
• 
terminal phase rate constant (z). 
• 
terminal half-life (t½). 
• 
area under the plasma concentration-time curve from time zero to time t (AUC0-t). 
• 
area under the plasma concentration-time curve from time zero to infinity (AUC0-). 
• 
volume of distribution (Vz). 
• 
clearance (CL). 


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3 STUDY DESIGN 
3.1 Overall design and study plan 
Dompé farmaceutici s.p.a. offers a program of clinical development of the drug Reparixin, 
which is a new, potent and specific inhibitor of the chemokine CXCL8 (Interleukin-8), as a drug 
for the prevention of early allograft dysfunction in patients undergoing orthotopic liver 
transplantation (OLT) patients. 
The aim of the present clinical phase 2 trial is to obtain preliminary efficacy data and evaluate 
the safety of Reparixin in terms of prevention of early allograft dysfunction after OLT. 
3.2 Study design 
This study is a multicenter, open-label, randomized pilot study to evaluate the efficacy and 
safety of Reparixin for prevention of early allograft dysfunction in patients undergoing OLT. All 
patients who participate in the study will receive standard immunosuppressive therapy in 
accordance with the Russian Transplant Society Guidelines for Liver Transplantation (2013). It is 
planned that the study will be conducted at 5-8 sites for liver transplantation in Russia and Belarus. 
Recruitment will be competitive among the study sites, until the planned number of patients is 
enrolled. 
Randomization will be performed before or at the day of the surgical operation. The patients 
will be randomized in a 1:1 manner into the Reparixin or the control group. 
Reparixin will be administered to patients as a continuous infusion for 7 days (168 hours). 
Infusion of the study product will start approximately 60-90 minutes before the anticipated time 
of OLT. The control group will include patients who do not receive Reparixin therapy. Follow- up 
of patients will last for approximately 1 year after OLT. 
3.3 Screening 
Patients admitted to the transplant center immediately before OLT surgery who signed the 
Patient Informed Consent Form will undergo screening procedures (Day -1). Screening can be 
carried out within 24 hours before planned surgery. The results at screening will be considered as 
baseline values. 
During the screening physical examination, assessment of vital signs, baseline scores 
according to MELD, Child-Turcotte-Pugh, laboratory tests and ECG, vascular ultrasound of the 
liver and kidneys with Doppler sonography will be performed. Patients fulfilling all the inclusion 
criteria and none of the exclusion criteria will be randomized. 
Considering a possible 7% early discontinuation rate and the inability to assess the primary 
endpoint for some patents, up to 84 patients will be randomized in the study. This number of 
patients is based on a statistical power of 80% with an alpha of 0.05 and 1:1 randomization. In 
total, considering a possible 15% screening failure rate, about 100 patients planned for OLT will 
need to be screened in the study. 
3.4 Study drug administration and surgery 
Patients who meet all inclusion criteria and do not conflict with the exclusion criteria will be 
randomized into the Reparixin or the control group. In the group of the study therapy, Reparixin 
will be administered as a continuous infusion for 7 days (168 hours). Infusion of the study drug 
will start approximately 60-90 minutes before the anticipated time of OLT. The patients, who will 
be randomized in the control group, will not receive any study therapy. 
The operation will be carried out according to the Russian Transplant Society Guidelines for 
liver transplantation and standard procedures adopted at the clinical sites (Appendix 7). In 


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addition to standard criteria approved by the health authorities of the Russian Federation to assess 
the extent of hepatodepression (liver problems), the Investigator will evaluate organ suitability for 
transplantation relying on histopathologic findings from biopsy. In this clinical setting, grafts with 
macrovesicular steatosis degree >50% will be considered as non-suitable for transplantation. 
During the study the patients of both groups will receive necessary concomitant medications, 
including immunosuppressive therapy in accordance with the Russian Transplant Society 
Guidelines for liver transplantation (Appendix 7). 
The patients of both groups will receive 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 can receive a combination of drugs that includes everolimus. Basiliximab 
in association with methylprednisolone will be used for the induction of immunosuppression. 
Post-operative examinations will be performed daily during 7 days after OLT (Day 0 – Day 
6). The final assessment of safety parameters and primary end-point will be conducted 7 days after 
OLT (in the group of the study therapy it will be held after the end of the infusion). 
3.5 Follow-up 
At the end of the 7-day period of the study therapy, the patients will receive the necessary 
prescription and recommendations for further treatment as appropriate for the standard 
management of patients after liver transplantation. The patients will be followed-up during 1 year 
after OLT. At Week 2 and Week 4 the patients will visit the center for mandatory control of the 
basic functions of the liver transplant and general condition of the patient. Then, the patients will 
visit the center on Weeks 12, 24 and 1 year after OLT in order to control safety parameters. 
At Week 36, the patients (or their families) will be contacted by the Investigator through 
telephone call to monitor graft and patient survival. The status of patient and allograft survival will 
be monitored up to 1 year from the date of OLT. The patient will receive all the necessary medical 
assistance in accordance with the standard of patient management after liver transplantation. 
Design of clinical trial TPL-RPX-01 is presented below. 
Figure 1. Design of clinical trial TPL-RPX-01 
 
Screening 
Study drug administration 
Follow-up 
Week 
W0 
W1 
W2 
W4 
W12 
W24 
W36 
Year1 
Day 
D-1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
↑ 
Randomization 
↑ 
 
 
↑OLT 
Telephone follow-up 
 
 
Study group 
 
 
Control group 
 
 
 
 
Both groups 
- 
 
Reparixin (continuous infusion 168 hours) 
 
Standard immunosuppressive therapy 


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The flow chart of the study is presented in Table 1. 


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Table 1 
Study TPL-RPX-01 flow chart 
 
Phase 
Screening and 
randomization 
Study drug administration 
Follow-up 
m 
ED 
Week 
W0 
W1 
W2 
W4 
W12 
W24 
W36 g 
Y1 
Day 
D(-1) 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Time window/ Visit period 
from 24 h up to 
90 min prior to 
planned surgery 
0 h (start 
of the 
Reparixin 
infusion) 
60-90 min 
from the 
start of the 
Reparixin 
infusion 
12 h from the start 
of the Reparixin 
infusion or 11 h 
after OLT 
(±30 min) 
 
±2 
days 
±3 
days 
±7 
days 
±7 
days 
±7 
days 
±14 
days 
Patient informed consent 
 
 
Patient registration 
 
 
Demographic data 
 
 
Medical history 
 
 
MELD and Child-Turcotte-Pugh Scores 
 
 
Complete physical examination 
 
 
 
 
 
 
 
 
Short physical examination 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Weight а 
 
 
 
 
 
 
 
 
ECG (12 leads) 
 
b 
 
 
 
 
 
 
 
 
 
Laboratory tests 
 
- Hematology 
 
 
 
 
 
 
 
 
 
 
 
- Biochemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Coagulation profile 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- HIV (express test) 
 
 
- Viral load: DNA HBV, RNA HCV c 
 
 
- Urinalysis 
 
 
 
 
 
 
 
 
 
 
- Pregnancy test d 
 
 
 
 
 
 
 
- PK sampling 
h 
h 
h 
k 
Doppler US of the abdomen 
 
 
 
 
 
 
 
 
 
 
Evaluation of inclusion/exclusion criteria 
 
 
Randomization 
 e 
 
Reparixin infusion (in the group of 
investigational therapy) 
168 hours continuous infusion 
 
OLT f 
 
 
Concomitant therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone follow-up 
 
 


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Abbreviations: 
W – week, 
D – day, 
Y – year, 
ECG – electrocardiography, 
OLT – orthotopic liver transplantation, 
US – ultrasound examination, 
ED – early discontinuation 
 
Footnotes: 
a Height will be measures only once during the trial (at screening). 
b On the operation day (Day 0) ECG data can be gathered via bedside monitor. 
c Viral load is determined only for patients with the past HBV/HCV. 
d Pregnancy test is carried out in the center with the help of test strips to women of childbearing potential only (including women in menopause of less than two 
years). 
e Patient randomization will be held before or on the day of surgical operation and only after confirmation of all inclusion/exclusion criteria. Inclusion/exclusion 
criteria, that depend on laboratory parameters, could be assessed on the basis of results obtained from a local laboratory of the center (without waiting for results 
from a centralized laboratory). 
f OLT will be carried in accordance with the Russian Transplant Society Guidelines for liver transplantation and as per center local standard clinical practice. All 
the patients that take part in the study will receive necessary concomitant medications, including standard immunosuppressant therapy. 
g Investigator will contact the patient on Week 36 for telephone follow-up to monitor status of patient and allograft survival. 
h Obtain PK ideally in the morning (on Day 1, 3, 5 after OLT), only in patients randomized to Reparixin in stage 1 of the study. 
k Obtain a PK sample just prior to the end of study drug administration, and then 1, 3, 5, 6, 8, and 12 hours after the end of study drug administration, only in 
patients randomized to Reparixin in stage 1 of the study. 
m The patient should attend the ED visit not later than in 4 weeks from the end of the study drug infusion (no later than 5 weeks after OLT for patients from the 
control group). In case of withdrawal from the study after Week 12, the ED visit is not needed. 


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3.6 Rationale of the study design 
Clinical study of Reparixin was initially focused on the prevention of delayed transplant 
function and primary graft nonfunction after the transplantation of solid organs (kidneys, lungs) 
and pancreatic islets. This multicenter, randomized, pilot open-label Phase 2 clinical study is 
aimed, first of all, to evaluate preliminary efficacy and safety of Reparixin treatment (2,772 mg/kg 
body weight/hour intravenous continuous infusion for 7 days) to prevent the development of early 
allograft dysfunction in patients undergoing OLT. The results of this study will allow conducting 
a subsequent study of Reparixin for this indication in the larger population of patients. In case of 
positive study results, an extension of donor criteria may be considered to expand the pool of 
potential organs for transplantation and to maximize donor organ utilization, minimizing waiting 
list delay. 
Reparixin is a specific inhibitor of chemokine CXCL8 (Interleukin-8), which plays an 
important role in ischemia-reperfusion injury of the transplant [9]. Safety of the drug was studied 
in Phase I studies in healthy volunteers and in patients with impaired renal function, and in phase 
II studies in patients with lung, kidney, and pancreatic islets transplants, as well as after coronary 
artery bypass surgery [10]. 
Relevant phase 1, 2 and 3 clinical data are summarized in paragraph 3.8. Please also refer to 
the Investigator’s Brochure for more detailed information. 
The dosage of the drug proposed in this study as a continuous 7-day infusion was studied in 
the clinical trial of pancreatic islets transplantation. The infusion will be conducted only at the time 
of hospital treatment under the strict supervision of the Investigator. 
In this study Reparixin is first used in a population of patients who underwent liver 
transplantation. The proposed design of the study with the use of Simon's minimax model [5, 6] 
will help to track the tendency in the parameters of drug efficacy in a small group of patients and 
thus will help to decide on further study of the drug for this indication in a large population of 
patients. 
Simon's minimax two-stage design for Phase II clinical trials was used to calculate the sample 
size. With the help of this model it is possible to receive preliminary data on presence or absence 
of drug effect in order to make a decision on further clinical development of the drug. This method 
is used worldwide in the sphere of clinical studies on oncology and transplantation [11, 12]. 
Simon’s minimax two-stage design is optimal for the first study of Reparixin among patients 
with OLT. The following aspects should be taken into account: 
1. 
The limited number of patients who undergo OLT (only about 200 surgeries per year 
in Russia). 
2. 
Ischemia-reperfusion syndrome is the acute reaction that is expressed in the early 
allograft dysfunction. Drugs of the standard immunosuppressive therapy, as well as 
other medications that are given to OLT patients, are currently not aimed at the 
correction of this syndrome and do not prevent early allograft dysfunction. Thus, there 
is no, so-called, gold standard treatment for such conditions or a possible alternative 
way of treatment that could be used like a reference drug. 
3. 
The usage of placebo as a reference substance is not possible due to ethical reasons and 
because of difficulties in administration of the drug (constant intravenous infusion 
during 168 hours and also during the surgical operation). Administration of placebo 
could be an unjustified risk for the patients that undergo operation and also in the early 
post-surgical period. 


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4. 
All the patients that participate in the study will receive standard immunosuppressive 
therapy and other essential medications. Thus, the participation in the study does not 
mean that patients will be left without drugs that are shown to be effective in the 
transplantation setting. However, it has already been stated that these drugs do not 
assist in correction and conducting preventive measures of states that are connected 
with ischemia-reperfusion syndrome and will not affect evaluation of study results. 
5. 
There is a global statistics concerning the frequency of early allograft dysfunction that 
matches the Russian data (Center of liver transplantation, N.V. Sklifosovsky Research 
Institute of Emergency Care). Early allograft dysfunction is observed in 25% of cases, 
i.e. in 50 patients out of 200 who undergo such a surgery in Russia (data for a period 
of 1 year). It doubles the risk of fatal case. 
6. 
During the previous studies that were connected with pancreas -cells transplantation 
Reparixin showed excellent efficacy and safety results for the same dose regime (2,772 
mg/kg body weight/hour intravenous continuous infusion for 168 hours). 
7. 
When the preliminary data concerning the presence of a certain effect are confirmed, 
a large-scale comparative study will be held to prove the drug’s efficacy. Otherwise 
further study of Reparixin in this study population will be considered inappropriate. 
8. 
Inclusion of the control group will help to map out any treatment effects more clearly, 
providing a better understanding of any effects of Reparixin. 
9. 
As a result of the study, it is expected to demonstrate the efficacy of the drug in the 
prevention of early allograft dysfunction caused by ischemia-reperfusion injury in 
patients undergoing OLT. Interim evaluation between two stages of patients’ 
enrollment in the study will provide preliminary data on presence of the expected effect 
of the study drug and will allow termination of the study in case of its absence. 
Early allograft dysfunction develops within one week after OLT. Therefore, the assessment 
of the primary end point will be held 7 days after surgery, and after the end of infusion of the study 
drug. Patients will visit the clinical site for 1 year to monitor the more remote indicators of liver 
transplant function. Survival rate of patients and the transplanted organs will be monitored up to 1 
year from the date of OLT. 
Safety parameters will be monitored during the study; and information on adverse events will 
be collected. More attention will be paid to parameters of liver function (liver enzymes, clotting 
parameters, albumin, glucose, and bilirubin). Renal function (creatinine, urea) and the 
cardiovascular system (vital signs, ECG) will also be evaluated. The Investigator may decide to 
early discontinue the patient from the study in case of development and progression of acute renal 
and hepatic failure. 
3.7 Duration of the study and the dates 
The overall duration of a patients' participation in the study will be approximately 1 year (1 
week of treatment and up to 1 year of post-transplant follow-up). 
The start of enrollment (first-patient-in) is scheduled for March 2015. It is planned that the 
last patient randomized in the first stage will complete all study visits by March 2017. The end of 
the study (last visit of the last patient randomized in the second stage of the study) is expected by 
December 2017. 
3.8 Previous experience with Reparixin 
A total of 404 subjects have been involved in phase 1 and phase 2 completed clinical studies. 
Among these, 266 subjects have been exposed to Reparixin. 


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CI 
Table 2 shows the clinical studies of Reparixin completed to date. Please also refer to the 
Investigator’s Brochure (Reparixin Final VersionCCCI 
information. 
Table 2 
Reparixin clinical trials 
) for more detailed 
 
 
Protocol 
number 
 
 
Design 
 
 
Subjects 
 
 
Dosage 
 
 
Treatment duration 
 
Phas 
e 
No. of subjects 
who received 
treatment with 
the drug 
 
CCI 


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Overall, Reparixin was safe and well tolerated in both healthy subjects and critically ill 
patients. 
3.8.1 Phase I Clinical Studies 
The safety and efficacy of Reparixin was evaluated in seven completed sponsor-initiated 
clinical studies. 
In the first of seven phase I clinical studies conducted to date, Reparixin L-lysine salt 1 to 16 
mg/kg was administered by short infusion (30min). The compound was well tolerated at all doses, 
with minor and unspecific AEs which were not dose-related. 
In the second study, the compound was administered as 48h i.v. infusion targeting to Reparixin 
steady-state concentrations (CSCs) of 10, 20 and 30 µg/mL. Reparixin resulted well tolerated; 
again AEs were minor and not dose related. The local reactions were observed to subside by 
administering a more diluted solution at a higher infusion rate. 
In the third study (interaction study), co-administration of midazolam/tolbutamide (probe 
substrates for CYP3A4 and CYP2C9) with Reparixin did not raise safety concerns. 
The fourth study was performed in subjects with different degree of renal impairment. The 
i.v. infusion of 2 mg/kg/h of Reparixin L-lysine salt was safe and well tolerated both in patients 
with different degree of renal impairment and in subjects with normal renal function. Very few 
AEs were reported, the majority of which were mild in intensity and unlikely due to Reparixin. 
Two studies were performed in the cantharidin blister model to assess if Reparixin can reduce 
the influx of PMNs inflammatory mediators, during acute inflammation. In the first study, there 
was a very high variability in the response to cantharidin. Only two out of 8 subjects were 
evaluable. The analysis did not detect any significant difference between treatments (Reparixin 
versus placebo) and unfortunately the blister volumes were not sufficient to evaluate the 
differences in the inflammatory mediators. The second of these two studies was to evaluate the 
effect of dexamethasone and Reparixin on inflammatory mediators in this model. There were no 
statistically significant differences observed in the inflammatory mediators from the two groups. 
Due to errors in sample handling with flow cytometry samples, no conclusion could be made 
regarding these data. The safety of Reparixin was confirmed in both of these studies. 
The seventh study in oncology was opened in July 2011 and the primary objective was to 
achieve the Proof of Concept that Reparixin targets CSCs in patients and that such targeting 
translates into potential for clinical benefit. Based on the aforementioned preclinical data, a Phase 
1b study to evaluate the safety and pharmacokinetic profile of Reparixin oral tablets in combination 
with paclitaxel, and to explore the effects of Reparixin on disease response and breast CSCs and 
the tumor microenvironment was initiated and has now completed enrollment. A Phase 2 study 
has also been initiated to evaluate the use of single agent Reparixin in the selective targeting of 
CSCs in breast cancer in the early stage setting. In addition, a new phase 2 study is in start up to 
evaluate Reparixin in combination with paclitaxel in metastatic triple- negative breast cancer. 
3.8.2 Phase II Clinical Studies 
Three Phase II studies have been completed to date. Two studies investigating the efficacy of 
Reparixin in the prevention of primary graft dysfunction/delayed graft function in lung/kidney 
transplantation were conducted with Reparixin administered by continuous intravenous infusion, 
up to a maximum of 48h. Neither of the two studies was able to show a statistically significant 
effect of Reparixin on short- and long- term functional and clinical outcomes after transplantation. 
In the lung study, a total of 7 patients died, all in the placebo group. The AE profile was similar 
for both placebo and Reparixin groups. Twenty-eight patients experienced SAEs; 8 SAEs in 6 
patients were judged possibly related to the study drug. During the renal 


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transplant study, one patient in the Reparixin intermittent infusion group and one patient in the 
placebo group died. The AE profile was similar for both Reparixin and placebo groups. SAEs were 
reported in 21 patients. SAEs possibly related to study drug were reported for only 2 patients, both 
in the Reparixin continuous infusion group. An assessment performed by DMC on a possible 
study-related higher incidence of thrombosis, excluded the potential relationship of Reparixin with 
these events. 
A phase II study evaluating the efficacy of Reparixin in improving transplant outcome in type 
1 diabetes patients undergoing pancreatic islet transplantation was conducted with Reparixin 
administered by intravenous infusion over 7 days. This study shows a clinical benefit of Reparixin 
in terms of improved β-cell function and islet transplant clinical outcomes, and provides a 
preliminary clinical proof of its potential in pancreatic islet transplantation in patients with type 1 
diabetes. Data obtained from this pilot trial further support the safety of Reparixin in this clinical 
setting. In patients treated with a 7 day course of Reparixin a few AEs were reported which were 
judged to be at least possibly related to Reparixin treatment. There were 11 reports of SAEs in 3 
patients taking Reparixin compared with 1 report in 1 patient in the control group. The safety 
profile was in line with previous clinical experience and there were no safety issues that would 
preclude further development of Reparixin in islet transplantation. 
3.8.3 Phase III Clinical Studies 
Due to encouraging data obtained in the pilot trial, a phase 3 study is ongoing in 8 sites in 4 
EU countries and 1 site in the US to further evaluate the efficacy and safety of Reparixin in 
pancreatic islet transplantation in T1D. A total of at least 42 (up to a maximum of 72) pancreatic 
islet transplant recipients will be randomly (2:1) assigned to receive either Reparixin [continuous 
i.v. infusion for 7 days (168hrs), starting approximately 12 hours before each islet transplant 
(treatment group)] or matched placebo (control group), administered as an added on treatment to 
the immunosuppressant regimen. Patients may receive up to 2 islet transplants, the 2nd one to occur 
between 3 and 12 months after the 1st one in patients who retain graft function (fasting C- peptide 
> 0.3 ng/mL). Primary endpoint is the AUC for the serum C-peptide level during the first 2 hours 
of a Mixed Meal Tolerance Test (MMTT), normalized by the number of IEQ/kg, calculated at day 
75+5 after the 1st islet infusion and day 365+14 after the last islet infusion. 
To date, 49 patients have been randomized, and 44 have gone on to treatment and transplant. 
23 patients have received a second islet infusion. 13 patients have completed one year follow-up 
after last transplant (either the 1st or the 2nd). 66 SAEs (excluding co-manifestations) have been 
reported to date in 30 patients. Most of the events involved the gastrointestinal system (e.g. 
abdominal pain, nausea, vomiting); blood and lymphatic system disorders (leukopenia, 
neutropenia, anemia, hemoperitoneum), other body system disorders (increased liver enzyme, 
hepatic hematoma, bleeding, raise in donor specific antibodies): overall the kind of SAEs reported 
were well known events associated to the transplant procedure. The following cases were 
considered by the investigator to be at least possibly related to the IP, either Reparixin or placebo: 
one case of neutropenia and leukopenia, one case of anemia, intra-abdominal haemorrhage and 
abdominal pain lower; one case of adenocarcinoma and cytomegalovirus colitis, two cases of 
transplant rejection, one case of pneumonia, one case of implant site haemorrhage. 
In addition, a phase 2/3 is being conducted at 6 centers in the US to assess the efficacy and 
safety of Reparixin in pancreatic islet auto-transplantation (IAT) in patients undergoing total 
pancreatectomy due to chronic pancreatitis. One Canadian center is going to be opened. The goal 
of this study is to reach a total of 100 adult patients who are randomized and receive IAT. Patients 
will be randomly (1:1) assigned to receive either Reparixin [continuous i.v. infusion for 7 days 
(168 hours)], or matched placebo (control group),starting approximately 12 hours before islet 
infusion. The primary endpoint is the proportion of insulin-independent patients at one year after 
the transplant. To date, 34 patients have been randomized and transplanted. 41 SAEs have 


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been reported to date in 26 patients. Most of the events involved the gastrointestinal system (e.g. 
abdominal pain, nausea, vomiting, clostridium difficile) and are known events associated to the 
transplant procedure. All cases were considered unrelated. 
3.8.4 Academic clinical studies 
Two academic independent clinical trials were conducted by the Medical University of 
Vienna. The results of the first study indicated that lipopolysaccharide -induced neutrophilia was 
not significantly affected by Reparixin in human volunteers. No AEs were reported. The second 
study was conducted in patients undergoing elective coronary artery bypass grafting with 
cardiopulmonary bypass. The rise of the neutrophil count after CPB was less marked in the 
Reparixin group. 
3.9 Risk/benefit ratio 
3.9.1 General risks 
OLT is the therapy of choice for terminal chronic liver disease and acute liver failure. OLT is 
associated with serious potential risk of patient’s life and health both during the operation and in 
the post-transplant period due to acute or chronic allograft rejection, regardless of study 
participation. 
3.9.2 Risks related to the administration of Investigational Product 
Results from preclinical studies support the level of drug exposure planned in this study. Also, 
past clinical experience with the same dose as planned in this study provides a clear cut evidence 
of Reparixin safety. 
The very short half-life of Reparixin (t1/2 1.0-1.5hrs) represents an important safety factor as 
plasma levels decline rapidly after drug discontinuation. This pharmacokinetic profile, coupled 
with the mechanism of Reparixin action (reversible inhibition), makes readily effective appropriate 
stopping rules. 
Administration via a high flow central vein, which was proven to be safe in lung and kidney 
recipients, as well as in patients undergoing islet transplant, is proposed for the study to minimize 
the risk of infusion-site toxicity seen in a cohort of volunteers receiving i.v. infusion via a 
peripheral vein. 
As to Adverse Drug Reactions (ADRs), infusion site reactions, mainly erythema or aseptic 
thrombophlebitis, were one of the most common ADRs. The relatively high frequency was due 
to a cluster of events occurring in cohort 1 of the phase 1 48h-infusion study. Local toxicity was 
clearly related to drug concentration since the use of a more diluted solution at a higher infusion 
rate markedly reduced the incidence, type and severity of infusion site reactions. 
Cumulative summary tabulation of ADRs is reported in Appendix 8. 
The most frequent (>10%) ADRs observed in the phase 1 and phase 2 studies completed to 
date were: 
Nervous system disorders (about 22%), including headache, dizziness, hypoaesthesia, 
somnolence. 
Gastrointestinal disorders (about 22%), including nausea, vomiting, abdominal pain, 
dyspepsia, flatulence, gastroesophageal reflux disease. 
General disorders and administration site conditions (about 19%), including cannula site 
reaction, injection site thrombosis, infusion site oedema and peripheral oedema, fatigue, lethargy. 
Data obtained in the pilot trial in islet transplantation further support the safety profile of the 


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proposed dose, even after a 7 days administration, repeated twice in a few patients. Most frequent 
ADRs were erythema, hypotension, nausea, vomiting; great majority of these were mild to 
moderate in nature and none required discontinuation of the Investigational Product. Nausea, 
vomiting and severe gastrointestinal bleeding associated with anaemia developed in a female 
patient early after the beginning of Reparixin infusion because the patient received a dose of 
reparixin 3 times as high as that foreseen in the protocol (medical error). These events were 
assessed as serious by the investigator and by the Sponsor. 
3.9.3 Central line 
The study drug will be administered as a continuous i.v. infusion over 7 days with a catheter 
inserted in a (high flow) central vein. The risks of a central line positioning are not considered 
study-related risks since it is routinely used during the early post-transplant period in patients 
undergoing orthotopic liver transplantation. In patients, who will receive the study drug, i.v. access 
may be maintained for a slightly longer time that routinely used. Nevertheless, routinely care of 
the catheter as practiced by the participating sites will minimize the risk of thrombosis and 
infections. 
3.9.4 Potential benefits for patients 
Preliminary pilot clinical study in patients with type I diabetes undergoing islet transplantation 
confirm that Reparixin improves function of the graft and prevents its early rejection. Taking into 
account the common mechanisms of ischemia-reperfusion injury after organ transplantation, it is 
expected that Reparixin will contribute to the prevention of early allograft dysfunction and 
improve graft survival rate and function. 


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4 SELECTION OF THE STUDY POPULATION 
4.1 Study population 
The study population will comprise adult patients aged 18 and older that require OLT. 
Considering a possible 7% early discontinuation rate and the inability to assess the primary 
endpoint for some patents, up to 84 patients will be randomized in the study. This number of 
patients is based on a statistical power of 80% with an alpha of 0.05 and 1:1 randomization. In 
total, considering a possible 15% screening failure rate, about 100 patients planned for OLT will 
need to be screened in the study. 
During Stage 1 of the study the primary efficacy endpoint will be assessed in 22 patients in 
each group. In case of early allograft dysfunction in < 5 out of 22 patients from the group of the 
study drug, the transition to Stage 2 of the study will be deemed possible. In the case of early 
allograft dysfunction in ≥ 5 out of 22 patients from the group of the study drug, further study of 
Reparixin in this study population will be considered inappropriate. 
During Stage 2 of the study, the primary efficacy endpoint will be assessed in additional 17 
patients in each group (in the total number of 39 patients in each group). Development of early 
allograft dysfunction in < 6 out of 39 patients from the group of the study drug gives grounds for 
a conclusion of the efficacy of Reparixin in this population and the appropriateness of the 
subsequent large-scale comparative Phase III clinical study. In case early allograft dysfunction 
develops in ≥ 6 out of 39 patients from the group of the study drug, further study of Reparixin in 
this study population can be considered inappropriate. 
4.2 Inclusion criteria 
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. 
4.3 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 (Appendix 9). 
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 


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classification), 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: 
a) ibuprofen or to more than one non-steroidal anti-inflammatory drug (NSAID), 
b) 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. 
4.4 Criteria for selection of donor organ for OLT 
In addition to standard criteria approved by the health authorities of the Russian Federation 
[13] for the assessment of the extent of hepatodepression (liver problems), the Investigator will 
evaluate organ suitability for transplantation relying on histopathologic findings from biopsy. 
In this clinical setting, grafts with macrovesicular steatosis degree >50% will be 
considered as non-suitable for transplantation. 
4.5 Retesting and rescreening 
In the case of ambiguous or equivocal results of laboratory studies during the screening, 
retest can be conducted with approval of the SponsorPPD 
Medical Monitor. 
In case of cancellation of surgery patients can undergo rescreening procedure. In this case, all 
screening procedures will be carried out again, including the procedure for obtaining informed 
consent and the assignment of a new identification number. 


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CCI 
CCI 
5. STUDY DRUG 
5.1 Description of study drug 
Investigational product is Reparixin 33 mg/ml; a concentrate solution to be diluted for i.v. 
infusion. Patients from control group will not receive the study therapy. 
 
 
5.2 Manufacturing, packaging and labeling 
Reparixin will be manufactured by PPD 
 
and packaged and labeled by 
PPD 
. Each vial of reparixin will be packed individually in a 34x10x20cm 
cardboard box together with 1 sterile CCI 
 Infusion Bag for preparation of infusion solution 
and label for Infusion Bag. 
The investigational product will be packaged and labeled in accordance with the current 
legislation of the Russian Federation and the Republic of Belarus and the applicable regulatory 
requirements, in particular with the Federal Law of the Russian Federation dated April 12, 2010 
No. 61-FZ “On Circulation of Medicines”. 
Labels for primary and secondary packaging and labelling are presented below. 
CCI 
 
Reparixin 
Study drug: 


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Primary packaging 
 
 
Secondary packaging 
 
CCI 
Sample label for Reparixin vial 
CCI 
Sample label for Infusion Bag 
CCI 
Sample label for Treatment Kit 


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5.3 Preparation of the Dosing Solution 
The dosing solution for infusion will be prepared at the designated Pharmacy or authorized 
location within each centre according to local guidelines for sterile re-constitution of i.v. injectable 
solutions. 
Preparation of investigational product solution begins after the confirmation of inclusion of 
the patient in the study immediately before the infusion of study drug. A self-adhesive label will 
be attached to each prepared Infusion Bag, reporting patient number and relevant information 
(preparation time and date and expiry time and date). 
 
 
 
The concentrated Reparixin solution has a pale yellow color. Sometimes during the 
preparation of the diluted Reparixin solution appears a temporary foaming surface layer that 
disappears in a short time. 
Prepared infusion solution should be used within 72 hours, unless the site has more restrictive 
rules. The Pharmacist (or designee) will make the Infusion Bags available to the hospital ward at 
the requested time. 
5.4 Dose, course and calculation of Reparixin administration 
Patients in the group of the study therapy will receive Reparixin CCI 
 
for 7 days (168 hours). The prepared solution of Reparixin CCI 
 will be administered as a 
continuous infusion into a central vein using an automatic infusion pump that provides a constant 
rate of infusion. 
Reparixin infusion will start 60-90 minutes before OLT. The Investigator shall accurately 
record the time of the beginning of Reparixin infusion in source documents and CRF. Infusion 
interruption is allowed for no more than 60 minutes. In case of interruption of the infusion for 
a longer period, the Investigator shall contact the Sponsor/PPD 
discuss tactics with regard to the patient’s condition. 
Medical Monitor to 
The pump rate will be adjusted to provide an infusion rate of approximately 0.25 ml/kg/hour. 
Actual infusion rate (mL/hour), adjusted to body weight, is tabulated in Appendix 5. 
5.4.1 Criteria for discontinuation of investigational product 
The investigational product should be immediately discontinued under any of the following 
conditions: 
1. An allergic reaction to Reparixin. 
2. Complications related to the surgery (OLT): intra-abdominal bleeding requiring a surgical 
reintervention, bile leak requiring a surgical reintervention, hepatic artery thrombosis 
confirmed by imaging techniques (e.g. ultrasound) or during surgery. 
3. Decrease of glomerular filtration rate (GFR) under 20 ml/min (estimated with the 
Cockcroft-Gault formula). 
4. Sepsis (Appendix 9), severe infectious complications (e.g., resulting in one or more 
organs failure, being considered life threatening or determining graft failure). 
5. Hyperacute or acute transplant rejection (determined by biopsy). 
6. Gastro-intestinal bleeding requiring a surgical or endoscopic intervention. 
7. Increasing hepatic encephalopathy (≥3rd grade). 
Withdrawal from the study will not interfere with patients’ future medical care. 
CCI 


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5.5 Randomization 
Randomization will be held before or on the day of the surgical operation. Patients fulfilling 
all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 manner into 
the Reparixin or the control group. 
Patients who do not meet the Inclusion Criteria or meet Exclusion Criteria will be considered 
screen failures (screen failure number assigned) and will not be allowed for inclusion into the 
study. 
The randomization will be carried out using a randomization list. Each site will receive a kit 
consisting of a list of randomization numbers and sealed randomization envelopes prior to the start 
of the study. The investigator will be instructed to consecutively allocate the lowest available 
randomization number, but open the randomization envelopes containing the information on the 
allocated treatment group only at randomization to avoid any possible biases that may derive from 
knowledge of the treatment group to which patient would be assigned. 
5.6 Blinding 
This study is an open-label with no blinding of investigators or participants. 
5.7 Assessment of compliance 
Study treatments will be administered only by study staff at clinical site. Compliance will be 
assured by the person(s) within the center in charge of Investigational Product administration. 
A self-adhesive label will be attached to each prepared Infusion Bag, reporting patient number 
to register actual date and time of infusion start and end. All used Infusion Bags will be retained 
at the centre to allow the Monitor to perform accountability of the study drug during monitoring 
visits and assess compliance with treatment. 
Actual date and time of infusion start and end for each Infusion Bag will be also recorded in 
the CRF, as well as the infusion rate(s). Temporary interruptions duration during drug 
administration should also be reported in the CRF. In case of Reparixin infusion halt for more 
than 60 minutes, the Investigator/Monitor shall contact the Sponsor/ PPD 
 
Monitor. 
Medical 
Compliance with the study product dosing schedule will be evaluated by the Monitor during 
on-site monitoring visits, as per records in the CRF versus accountability records and information 
reported on the labels of administered Infusion Bags, and by comparing the number of used and 
unused treatment kits available at site. 
The subject will be reminded of the importance of attending all scheduled follow-up visits on 
time. 
5.8 Supply, Storage and Handling of Investigational Product 
An appropriate number of supplies (Reparixin, Infusion Bags) will be initially sent to the site 
as soon as all essential documents and regulatory/ethics approvals have been obtained. Additional 
supplies will be sent on demand, according to enrolment rate. 
The Investigational Product must be kept at a temperature not exceeding 30°C. 
A temperature probe will accompany the drug on shipment. Temperature range reached during 
shipment will be verified on receipt, so that potential stability concerns during shipment can be 
investigated and appropriate action taken. 
Once received at the site, the Pharmacist (or designee) will check the package for accurate 
delivery and acknowledge receipt; any deviations from expected package content (inconsistency, 
damages) should be immediately reported to the CRO, and the use of the drug should be suspended 
until authorization for its continued use has been given by the Sponsor/CRO. 


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The Investigational Product must be stored in a secure location, in a temperature controlled 
room. Temperature records must be available for a Monitor to review during on-site monitoring 
visits. Any deviations from the recommended storage conditions should be immediately reported 
to the Sponsor/CRO and the use of the drug suspended until authorization for its continued use has 
been given by the Sponsor/CRO. 
The Investigational Product will be dispensed only by the Pharmacist (or authorized designee). 
The Investigator will ensure that study treatment is only administered by designated staff within 
the center. Pharmacists (or authorized designee) will be provided with the “Instructions to the 
Pharmacy”, a booklet detailing instructions for Investigational Product handling and preparation 
of the dosing solution. 
Immunosuppressive agents expected to be administered either for induction or maintenance 
therapy will not be supplied by the Sponsor since they are drugs routinely used to treat OLT 
patients and are part of the standard therapy. 
5.9 Concomitant medications 
All patients will receive appropriate concomitant therapy in accordance with the local 
standards. 
All the related medications and dietary supplements must be registered in source documents 
and CRF. This includes all medications and supplements that are not included in study therapy, 
used by patients one month prior to screening and at any time during the clinical study. Name 
(name of the active ingredient is preferred), dose, frequency, mode of administration, indications 
for use (including the underlying disease, comorbid conditions, adverse events or prevention), start 
and end date of concomitant medication use must be registered in source documents and CRF. If 
the patient continues to receive concomitant medications at the final study visit (defined as the last 
visit recorded by the Investigator for that patient), the corresponding note should be made in the 
CRF. 
The following drugs do not require registration in the CRF: 
- i.v. saline or other oral solutions (including electrolyte solutions ) used for hydration. 
- Parenteral and enteral nutrition. 
- Homeopathic medications. 
5.9.1 Standard immunosuppressive therapy 
All patients of the study will receive standard immunosuppressive therapy in accordance with 
the Russian Transplant Society Guidelines for liver transplantation (Appendix 7). The patients will 
receive 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 can receive a combination of drugs that 
includes everolimus. Basiliximab in association with methylprednisolone will be used for the 
induction of immunosuppression. 
Standard immunosuppressive therapy will be registered in source documents and in the CRF. 


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5.10 Prohibited medications 
The following drugs are prohibited in the study: 
• 
Other study drugs. 
• 
Anti-cytokine medicinal products (TNF- inhibitors, e.g. infliximab, adalimumab, 
etanercept; interleukin-1receptor antagonist, e.g. anakinra). 
• 
Low molecular weight dextran sulfates. 


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6 DESCRIPTION OF PROCEDURES 
The study will be performed according to the Good Clinical Practice-International Conference 
on Harmonization (GCP-ICH) regulations and conducted according to the principles of the 
Helsinki Declaration and any local regulatory requirements [14]. 
The Investigator should permit monitoring and auditing by the Sponsor/CRO, and inspections 
by appropriate regulatory authority(ies). Upon request of the Monitor, auditor, IEC, or regulatory 
authority, the Investigator should make available for direct access all requested trial-related 
records. 
6.1 Informed consent 
Informed consent shall be obtained at screening before conducting any procedures related to 
the study. 
6.2 Patient registration 
Every patient who has signed a Patient Informed Consent Form will have an unique 
registration number assigned, consisting of four digits: the first two digits correspond to the 
number of the clinical site, the second two digits will be the sequential number of this patient at 
this site (01, 02, 03, etc.). After randomization of the patient in one of the two groups, a letter will 
be added to the screening number of the patient that indicates the group (R – Reparixin, C – 
control). 
Thus, the number of the patient will consist of 4 numbers and 1 letter: 
-
-
. 
6.3 Demographic data and medical history 
To assess the compliance of patients with inclusion/exclusion criteria it is necessary to collect 
patient demographic data (gender, date of birth/age, ethnicity/race), and complete medical history, 
including liver disease history, significant acute and chronic diseases, conditions (e.g., 
menopause), surgical interventions, and allergic reactions. It is also necessary to gather 
information on hospitalizations and/or surgical procedures, in addition to the one planned in the 
study (if applicable). All new diagnoses and conditions identified at screening (including the 
results of laboratory and instrumental tests) shall be recorded to the patient's medical history. 
6.4 Physical examination 
A complete physical examination includes an assessment of the overall appearance, skin and 
mucous membranes condition (including the place of infusion), neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, extremities, lymph nodes, and neurological status. 
Short physical examination includes an assessment of the overall appearance, skin and mucous 
membranes condition (including the place of infusion), lungs, heart, stomach, lymph nodes, and 
neurological status. 
During each physical examination after OLT the state of post-operative wound will also be 
assessed. The assessment will focus primarily on the search for signs of bleeding, hematoma or 
bruising. Condition will be evaluated according to the scale: “better than usual”, “as usual”, “worse 
than usual”, “is difficult to define”. 
Clinically significant changes from the initial examination data, as well as an assessment of 
the state of the wound “worse than usual” shall be registered as an adverse event and recorded 
appropriately in source documents and CRF. 


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6.5 MELD and Child-Turcotte-Pugh scores 
The initial state of the patient and the severity of liver disease shall be evaluated according to 
MELD and Child-Turcotte-Pugh scores (Appendices 2 and 3). 
6.6 Vital signs, height and weight 
This examination includes the measurement of axillary temperature, as well as blood 
pressure, heart rate and respiratory rate in the supine position after 10 minutes of rest. 
Patient's weight and height (without shoes) will also be measured. Height will be measured 
only once during the study at Visit 1 (screening). 
Body mass index (BMI) is also calculated at screening as follows: 
BMI = weight/height2 (kg/m2), where the weight is in kg and the height is in meters. 
Clinically relevant changes in vital signs from baseline values should be registered as 
adverse events and recorded appropriately in source documents and CRF. 
6.7 Electrocardiography 
12-lead electrocardiography (ECG) is performed to the patient in the supine position after 10 
minutes of rest. The electrodes should be placed at the same points throughout the study. To record 
ECG it is recommended to use an electrocardiograph with automatic evaluation of intervals. At 
the day of operation (Day 0) the data can be collected from the bedside monitors. 
The Investigator shall review the ECG record, in case of abnormalities assess their clinical 
significance, sign and date the report. Significant changes in ECG shall be double-checked. 
Clinically significant ECG changes in comparison with the original data shall be registered as 
adverse events and recorded appropriately in source documents and CRF. 
6.8 Doppler abdominal ultrasonography 
Patients will undergo a comprehensive abdominal ultrasound with dopplerography of blood 
vessels of the liver and kidneys (Doppler ultrasound). This procedure shall be done by a doctor of 
functional or diagnostic ultrasound department with experience in ultrasound angiology of at least 
3 years. Ultrasound scanner of expert class shall be used to carry out this procedure. 
The Investigator shall review the conclusion of Doppler ultrasound, in the case of 
abnormalities assess their clinical significance, sign and date the report. Significant changes in the 
Doppler ultrasound shall be double-checked. Clinically significant changes in Doppler ultrasound 
in comparison with the original data shall be regarded as adverse events and recorded appropriately 
in source documents and CRF. 
6.9 Laboratory tests 
All laboratory tests described in the protocol, except for the tests for pregnancy and HIV, will 
be performed at the centralized laboratory level. Hematology, coagulation, biochemistry, serology 
and viral load testing will be carried out by the Independent Laboratory PPD   (Moscow, Russia) 
whereas pharmacokinetic analyses will be performed by Biotech Unit of Dompé farmaceutici s.p.a. 
(L’Aquila, Italy). 
Centralized laboratory PPD 
 will prepare a Laboratory Manual for the study that will be 
given to the clinical sites with special instructions for collection, preparation, storage and shipment 
of all biological samples. 
Prior to the initiation of the study, centralized laboratory PPD 
 will provide the required 
certificates and normal ranges of the laboratory. Centralized laboratory PPD 
 will be 
responsible for sending the lab reports for hematology, coagulation, biochemistry, serology and 
viral load to the clinical sites, as well as for reporting about the alarming laboratory tests to the 


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Investigators, Sponsor and PPD 
 Medical Monitor. The Investigator shall review the lab 
report, assess clinical significance of all abnormalities if any, sign and date the report. Clinically 
significant changes in laboratory parameters from baseline values are to be considered as adverse 
events and shall be recorded appropriately in source documents and CRF (apart from the 
exemptions listed in Paragraph 6.11.13). 
Screening tests will be performed in parallel at the centralized and local laboratories. HIV 
testing will be carried out only locally (express test). The decision on patient’s eligibility to 
participate in the study will be made based on the results obtained in the local laboratory of the 
site. Test results from the centralized laboratory will be used as baseline data. 
In case of significant differences between the results obtained from centralized and local 
laboratories, a follow-up test (re-test) may be performed at a centralized laboratory. 
Routine laboratory tests during and immediately after the surgery not covered by the protocol 
may be carried out or repeated at the local laboratory, when needed. 
Prior to initiation of the study the local laboratory will also provide the required certificates 
and normal ranges of the laboratory. Clinically significant changes in the parameters assessed at 
the local laboratory shall be regarded as adverse events and recorded appropriately in source 
documents and CRF (apart from the exemptions listed in Paragraph 6.11.13). 
6.9.1 Laboratory parameters 
The Investigator will obtain blood samples from patients. Sample preparation shall be carried 
out in accordance with the Laboratory Manual. The prepared samples of whole blood, serum and 
plasma, as well as urine will be sent to the centralized laboratory for analysis. Necessary laboratory 
tests will be carried out at certain visits in accordance with the Study flow chart (Table 1). 
Total volume of blood obtained from patients during the study period will be approximately 
200 ml in the control group, and 280 ml in the Reparixin group. Table 3 shows the parameters of 
blood tests, which will be assessed as part of this clinical study. 
Table 3 
List of parameters for blood test 
 
Hematology 
Biochemistry 
Coagulation 
profile 
Special tests 
General 
Liver status 
Renal status 
Hemoglobin 
Total protein 
ALT 
Urea 
APTT 
Screening: 
Hematocrit 
Red blood cells 
White blood cells 
Neutrophils 
Lymphocytes 
Monocytes 
Albumin 
Glucose 
Sodium 
Potassium 
Total cholesterol 
Triglycerides 
AST 
GGT 
LDH 
Total bilirubin 
Conjugated 
bilirubin 
Creatinine 
GFR (according 
to the Cockroft- 
Gault formula, 
Appendix 6) 
PTT 
INR 
Express HIV test 
(locally) 
Viral load: 
DNAHBV 
RNA HCV 
Eosinophils 
Basophils 
Platelets 
Erythrocyte 
sedimentation rate 
Determination of the viral load will be conducted only for the patients with HBV and/or HCV 
diagnosis in medical history via real-time PCR method. 


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Table 4 presents the urine tests which will be conducted in the study. 
Table 4 
List of parameters for urine test 
 
Urinalysis 
Special tests 
General parameters: color, transparency, specific 
gravity, pH, protein, glucose, bilirubin, urobilinogen, 
ketones, nitrites, hemoglobin 
Precipitate microscopy: epithelium, erythrocytes, 
leukocytes, cylinders, bacteria, salts 
Pregnancy test 
(the test is carried out directly in the center only in 
women able to bear children including menopausal 
women for less than two years) 
6.9.2 PK parameters 
Pharmacokinetic evaluation will be performed only in patients randomized to Reparixin in 
stage 1 of the study. Table 5 shows the PK parameters, which will be assessed as part of this 
clinical study. 
Table 5 
List of PK parameters 
 
6.9.3 Collection, preparation, storage and shipment of biological samples 
Collection, preparation, storage and shipment of biological samples will be carried out in 
accordance with regulatory requirements and Laboratory Manual. 
6.9.3.1 Collection, preparation, storage and shipment of PK samples 
PK samples preparation shall be carried out in accordance with the Laboratory Manual. The 
prepared samples of plasma will be sent with other biological samples to the centralized 
laboratory CCI 
 for temporary storage, and then to Biotech Unit of Dompé farmaceutici 
s.p.a. (L’Aquila, Italy) for analysis. 
Pharmacokinetic evaluation will be performed only in patients randomized to Reparixin in 
stage 1 of the study. Blood samples will be obtained during the treatment at Day 1, 3 and 5, just 
prior to the end of study drug administration, and then at 1, 3, 5, 6, 8, and 12 hours after termination 
of the study drug administration. Details on sample handling are reported in Table 6 below and 
Appendix 10. 
Cmax 
Maximum plasma concentration of reparixin and metabolites 
tmax 
Time of maximum plasma concentration reparixin and metabolites 
z 
Terminal phase rate constant of reparixin and metabolites 
t½ 
Terminal half-life of reparixin and metabolites 
AUC0-t 
Area under the plasma concentration-time curve from time zero to time t (time of last quantifiable 
plasma concentration) of reparixin and metabolites 
AUC0- 
Area under the plasma concentration-time curve from time zero to infinity of reparixin and metabolites 
Vz 
Volume of distribution of reparixin 
CL 
Clearance of reparixin 


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Table 6 
PK sampling schedule 
 
Week 
Day 
Time 
point No 
Time of sampling 
Week 1 
Day 1 
after OLT 
1 
This blood draw should be performed ideally in the morning (it is possible 
simultaneously with hematology and biochemistry) 
Day 3 
after OLT 
2 
This blood draw should be performed ideally in the morning (it is possible 
simultaneously with hematology and biochemistry) 
Day 5 
after OLT 
3 
This blood draw should be performed ideally in the morning (it is possible 
simultaneously with hematology and biochemistry) 
Day 7 
after OLT 
4 
This blood draw should be performed just prior to the end of study drug 
administration 
5 
This blood draw should be performed 1 hour after the end of study drug 
administration 
6 
This blood draw should be performed 3 hours after the end of study 
drug administration 
7 
This blood draw should be performed 5 hours after the end of study 
drug administration 
8 
This blood draw should be performed 6 hours after the end of study 
drug administration 
9 
This blood draw should be performed 8 hours after the end of study 
drug administration 
10 
This blood draw should be performed 12 hours after the end of study 
drug administration 
6.10 Assessment of efficacy 
Efficacy of the investigational therapy will be assessed based on the incidence of early allograft 
dysfunction after OLT. 
Early allograft dysfunction will be determined in accordance with the international standards 
(Olthoff et al. 2010), as having one of the following parameters obtained during one week after 
OLT (Day 7 of Week 1): 
- ALT > 2000 U/ml during first 7 days after OLT, 
- AST > 2000 U/ml during first 7 days after OLT, 
- Total bilirubin ≥ 10 mg/dl (on Day 7 only), 
- INR ≥ 1.6 (on Day 7 only). 
In addition, the incidence of primary nonfunction of the allograft will be assessed. Primary 
nonfunction is defined as absence of graft function leading to allograft loss, re-transplantation or 
death of the patient within 7 days after OLT for reasons not related to hepatic artery thrombosis, 
biliary complications, and acute exacerbations of chronic diseases or acute allograft rejection. 
Cumulative incidence of allograft dysfunction in early postoperative period will also be 
assessed within the first 2 weeks after OLT (Week 2), including: 
- Primary nonfunction, 
- Early allograft dysfunction, 
- Extracorporeal detoxification. 


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6.11 Evaluation of Adverse Events (AEs) 
6.11.1 Definitions of AEs 
Adverse Event (AE) – any untoward medical occurrence in a patient or clinical trial subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease. In this study, registration of AEs will 
commence from the moment the patient signs a Patient Informed Consent Form (before the first 
dose of study medication) and will continue during 1 year after OLT. 
Adverse Drug Reaction (ADR) – any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. “Reasonable possibility" means there is evidence 
to suggest a causal relationship between the drug (at any dose) and the adverse event. 
Serious Adverse Event (SAE), and/or Serious Adverse Drug Reaction (SADR) – any 
unfavorable medical event, which regardless of the dose of the study drug: 
- results in death, 
- is life-threatening (i.e. the patient was at risk of death at the time of the event), 
- requires inpatient hospitalization or prolongation of existing hospitalization, 
- results in persistent or significant disability/incapacity, 
- is a congenital anomaly/birth defect, 
- is an important medical event that may be not immediately life threatening or result in death 
or hospitalization but, based upon appropriate medical judgment, may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in the definition 
above. 
Significant medical events that do not pose an immediate threat to life, do not result in death 
or hospitalization, but put patients at risk or require interventions aimed at the prevention of the 
above outcomes can also be included in SAE/SADR. Examples of such events may include 
bronchospasm of allergic genesis, convulsions, malignant neoplasms. 
NOTE: Hospitalization for social reasons, visits to day in-patient department, as well as 
hospitalization or surgery scheduled before enrollment of the patient into the study to treat any 
previous condition are not considered as SAEs. 
Unexpected AE/ADR – AE/ADR, nature or severity of which is not consistent with the 
known information about the product (e.g., with the Investigator's Brochure). This group also 
includes AE/ADRs mentioned in the Investigator's Brochure as characteristic for this class of drugs 
or expected due to the pharmacological properties of the investigational product, but at a specificity 
or severity not previously observed. 
Serious and Unexpected Suspected Adverse Reaction: Any suspected adverse reaction that 
is both serious and unexpected (SUSAR). 
6.11.2 Pregnancy 
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are summarized in 
the protocol’s inclusion criteria in Section 4.2. 
Pregnancy is not an adverse event, but refers to events that require an urgent reporting to the 
Sponsor. In case of pregnancy during the study, either occurring in a female patient or in a male 
patient’s partner, the pregnancy status should immediately be reported to the Sponsor. Female 


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patient will be withdrawn from the study and will be monitored throughout pregnancy and up to 
30 days after its outcome. Health conditions of any newborn who was conceived during the study 
will also be followed up to 30 days after birth (including pregnancy of patient’s partner). Relevant 
information will be recorded in source documents, CRF and Pregnancy Report Form. Pregnancy 
reports should be completed and e-mailed/faxed following the procedure described in Paragraph 
6.11.7. 
6.11.3 Reporting of AEs and SAEs 
During each visit and examination patients shall report any adverse events in response to open, 
non-suggestive questions (e.g., “How did you feel after the last visit?”). For each adverse event 
marked by the patient, the Investigator shall collect and register as source documents and in the 
CRF all necessary information including the diagnosis or symptoms, start date and end date, 
outcome, severity, presence of severity criteria, circumstances that might indicate a possible 
relationship with the study medication or concomitant therapy, underlying diseases or concomitant 
conditions, study procedures or other causes, actions with respect to the study drug, concomitant 
medications, medical interventions, results of laboratory and instrumental studies about adverse 
events, as well as other circumstances which will help to maximize the event to be described. 
Increase in severity of the ongoing adverse event shall be considered a new AE. The date of 
further worsening in severity will be the start date of the new AE, and the previous day shall be 
the end date of the original AE. The start date of a SAE is the date of occurrence of seriousness 
criterion. Previous state must be registered as a non-serious AE, if applicable. 
If adverse event is serious, the Investigator shall also complete SAE Report Form (specifying 
the seriousness criteria) and promptly, within 24 hours from first knowledge, send it 
to the PPD 
 Medical Monitor. New information on the SAE, which become known later 
shall be recorded and sent to the PPD 
 Medical Monitor in the same manner and within the 
same timeline. Also, the PPD 
 Medical Monitor shall be provided with certified copies of 
source documents relevant to the SAEs (discharge summary, autopsy data, death certificate, etc.). 
AEs and SAEs shall be followed up and reported from the moment of signing of a Patient 
Informed Consent Form by patient and up to 1 year after OLT. 
In line with ICH E2A provisions on Post-Study events, although such information is not 
routinely sought or collected by the Sponsor, serious adverse events that occurred after the patient 
had completed a clinical study (including any protocol-required post-treatment follow- up) will 
possibly be reported by the Investigator to the Sponsor. Such “post-study cases” should be 
regarded for expedited reporting purposes as though they were study reports. Therefore, a causality 
assessment and determination of expectedness are needed for a decision on whether or not 
expedited reporting is required. 
The Monitor is responsible for source data verification of the CRF and SAE Report Forms. 
6.11.4 Assessment of the severity 
The Investigator will grade the severity of any AE using the definitions in Table 7. It shall be 
noted that severe adverse event does not always meet the criteria of seriousness and, vice versa, a 
SAE does not always have to be severe. 
Urgency of SAE reporting does not depend on the severity of the event. 
For each episode, the highest severity grade attained should be reported. 


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Table 7 
Intensity (Severity) of the Adverse Event 
 
Mild 
Grade 1 - does not interfere with patient’s usual function 
(awareness of symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - interferes to some extent with patient’s usual function 
(enough discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - interferes significantly with patient’s usual function 
(incapacity to work or to do usual activities [unacceptable]) 
 
6.11.5 Relationship between the AE and the Investigational Product 
For each AE the Investigator shall assess its relationship with the investigational product in 
accordance with categories shown in Table 8. 
Table 8 
Relationship between the AE and the Investigational Product 
 
None 
(Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational 
Product, e.g. patient is a passenger in a road traffic accident 
Unlikely 
(remote) 
Relationship is not likely e.g. a clinical event including laboratory 
test abnormality with temporal relationship to drug administration 
which makes a causal relationship improbable and in which other 
drugs, chemicals or underlying disease provide plausible 
explanations 
Possible 
Relationship may exist, but could have been produced by the 
patient’s condition or treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of 
Investigational Product and cannot be due to the patient’s condition 
Highly 
Probable 
Strong relationship, the event abates upon discontinuation of 
Investigational Product and, if applicable, re-appears upon repeat 
exposure 
6.11.6 Assessment of Expectedness 
Expectedness will be determined based on the contents of the Investigators’ Brochure. 
 
Expected 
An adverse reaction, the nature or severity of which is consistent with 
the applicable product information (e.g. Investigators’ Brochure) 
Unexpected 
An adverse reaction, the nature or severity of which is not consistent 
with information in the relevant source document (e.g. Investigators’ 
Brochure) 


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PPD 
PPD 
6.11.7 Reporting of SAEs/pregnancy 
The Investigator must report all SAEs, regardless of presumed causal relationship, and 
pregnancies to PPD 
 Medical Monitor and the Dompé Pharmacovigilance, by fax or e-mail 
within 24 hours of learning of the event. Contact details for SAE/pregnancy reporting are provided 
below and in the section “Contact Information”. 
PPD 
 Medical Monitor: 
PPD 
 
 
Dompé Pharmacovigilance: 
PPD 
 
 
 
PPD 
 
will be then responsible for verifying consistence of 
information reported and data included in SAE/Pregnancy Report Form, obtaining and reporting 
any additional information received from the Investigators, and forwarding fully completed 
SAE/Pregnancy Report Forms to the Dompé Pharmacovigilance, by e-mail immediately and 
anyway within 24 hours of knowledge of event. SAE reports with fatal outcome shall be 
transmitted to the Dompé Pharmacovigilance as soon as possible, and within a maximum of 
12 hours from the time PPD 
 has knowledge of the death. 
Information on SAEs will be recorded on a specific SAE Report Form. Electronic and blank 
paper copies will be provided to the Investigators. Follow-up reports (as many as required) should 
be completed and faxed/e-mailed following the same procedure above. 
Information on pregnancy will be recorded on a specific Pregnancy Report Form. If necessary, 
the Investigator can contact PPD 
 Medical Monitor for advice or clarification. 
The Investigator shall instruct each patient to immediately report the occurrence of SAEs or 
pregnancy during the study and for 1 year after OLT. The Investigator shall record all the available 
information about the event on the SAE/Pregnancy Report Form. Every SAE Report Form shall 
specify at least the following information: information on the patient, the event (signs or symptoms 
or diagnosis), the criterion of seriousness, the relationship with the investigational product, study 
drug administration dates and dosage, outcome at the time of the report and Investigator’s details. 
For the initial report the Investigator shall make the appropriate note on the SAE Report Form 
– “Initial report.” In case additional information on SAE becomes available (e.g., new information 
on the patient's condition or results of laboratory tests), the Investigator shall complete a new SAE 
Report Form with a note “Follow-up report” and number of follow up. The original SAE Report 
Forms shall be stored in the Investigator’s File. 
The Investigator (or an authorized staff member) will be responsible for reporting any 
SAEs/SUSARs to the Local Ethics Committee and local institutions in accordance with local 
regulations and requirements. CRO will be responsible periodic safety reporting to the Regulatory 
Authorities and Investigators, and expedited reporting of SUSARs to the local Regulatory 
Authorities, in accordance with local regulations and requirements. 


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6.11.8 Early patient withdrawal 
Patients will be informed that they have the right to withdraw from the study at any time, 
without prejudice to their medical care, and are not obliged to state their reasons. Any withdrawals 
must be fully documented in the CRF and should be followed up by the Investigator. 
A complete list of the reasons for early withdrawal is provided in Section 6.12. If possible, the 
Investigator shall preliminary consult the SponsorPPD 
Medical Monitor in advance 
of any withdrawal. Otherwise, the Investigator shall inform the Sponsor/PPD 
A 
Medical Monitor about patient withdrawal within 24 hours of knowledge of the event. 
Contact details of the Sponsor and PPD 
 
“Contact Information”. 
Medical Monitor are provided in the section 
Additionally, the Investigator may withdraw a patient at any time if (s)he considers this to be 
in the patient’s best interest. 
Also, a patient might be withdrawn from the study, at the Investigator’s judgment, in case of 
protocol violations, including (but not limited to) non-compliance with study procedures, patient 
lost to follow-up or administrative reasons. 
6.11.9 Emergency response 
The Investigator is responsible for obtaining information on all emergency medical conditions 
of patients during the study. Investigator’s contact information is present in a Patient Informed 
Consent Form. Patients will be encouraged to contact the Investigator in case of any emergency 
during the study. 
6.11.10 Terms of AE/SAE registration 
In this study registration of adverse events will be conducted from the moment of signing of 
a Patient Informed Consent Form by the patient and up to 1 year after OLT. 
In case of patient’s withdrawal from the study, the patient’s and graft survival will be followed 
up to 1 year after OLT. In case of the death after patient withdrawal from the study, the data and 
cause of death shall be recorded in the CRF. In case of liver re-transplantation, the date and reason 
for re-transplantation will be recorded (SAE Report Form will not be completed). 
In line with ICH E2A provisions on Post-Study events, although such information is not 
routinely sought or collected by the Sponsor, SAEs that occurred after the patient had completed 
a clinical study (including any protocol-required post-treatment follow-up) will possibly be 
reported by the Investigator to the Sponsor. Such “post-study cases” should be regarded for 
expedited reporting purposes as though they were study reports. Therefore, a causality assessment 
and determination of expectedness are needed for a decision on whether or not expedited reporting 
is required. 
6.11.11 Expected Adverse Events 
The most frequent adverse events recorded in the previous clinical studies of Reparixin are 
listed in Section 3.10 “Risk/benefit ratio”. 
6.11.12 Clinically significant abnormalities 
Any clinically significant abnormalities of laboratory parameters or results of the instrumental 
methods of examination noted at screening shall be registered in the patient's medical history. After 
screening, new or worsened clinically significant abnormalities (apart from the exemptions listed 
in Paragraph 6.11.13) shall be reported as adverse events in source documents and CRF. 


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6.11.13 Adverse Event exemption 
The following events will neither require recording nor reporting, as they are considered 
routinely associated to the transplant procedures: 
- 
Increased ALT/AST, bilirubin levels and other blood liver function tests if they are 
improving during 2 consecutive days, within 2 weeks post-transplant. 
- 
Abnormal electrolytes and INR values if they are improving on 2 consecutive days, 
within 2 weeks post-transplant. 
- 
Abnormal PTT values during prophylactic anticoagulation with unfractionated heparin. 
- 
Abnormal INR values during prophylaxis with warfarin (Coumadin®, Jantoven®, 
Marevan®, Uniwarfin®). 
6.12 Early patient withdrawal and discontinuation of the study drug 
In case of early discontinuation of the investigational product administration, the patient will 
be able to continue participation in the study (in the absence of other indications). However only 
patients who received not less than 70% of the total dose of Reparixin will be included in the 
efficacy analysis (not less than 120 hours of infusion). 
The patient has the right to refuse to participate in the study at any stage and for any reason. 
If during the course of study therapy any of the following conditions occurs, the investigational 
product administration will be discontinued, and the patient will be withdrawn from the study: 
• 
An allergic reaction to Reparixin, 
• 
Complications related to the surgery (OLT): intra-abdominal bleeding requiring a 
surgical reintervention, bile leak requiring a surgical reintervention, hepatic artery 
thrombosis confirmed by imaging techniques (e.g. ultrasound) or during surgery, 
• 
Decrease of glomerular filtration rate (GFR) under 20 ml/min (estimated with the 
Cockcroft-Gault formula), 
• 
Sepsis (Appendix 9), severe infectious complications (e.g., resulting in one or more 
organs failure, being considered life threatening or determining graft failure), 
• 
Hyperacute or acute transplant rejection (determined by biopsy), 
• 
Gastro-intestinal bleeding requiring a surgical or endoscopic intervention, 
• 
Increasing hepatic encephalopathy (≥3rd grade). 
 
The patient shall be withdrawn from the clinical study also in the following situations: 
• 
The patient is lost to follow-up, 
• 
Failure or refusal of the patient to follow the protocol requirements, 
• 
The patient's desire to withdraw from the study for any reason, 
• 
Any adverse event that according to Investigator opinion may prevent from patient’s 
further continuation in the study, 
• 
Graft loss, 
• 
Patient's death. 


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The following reasons require immediate withdrawal from the study: 
• 
The patient began receiving another study drug, 
• 
Pregnancy, 
• 
Significant protocol violations that may affect the safety of the patient and the integrity 
of the study data. 
In case of an early withdrawal from the study, the patient shall be invited to the clinical site, 
where he/she will undergo all procedures of the Early Discontinuation visit (ED visit). The patient 
should attend the ED visit not later than in 4 weeks from the end of the study drug infusion (no 
later than 5 weeks after OLT for patients from the control group). In case of withdrawal from the 
study after Week 12, the ED visit is not needed. 
The status of the patients withdrawn from the trial (patient and transplant survival) shall be 
followed for 1 year after OLT. The Investigator will contact the patient or his relatives not less 
than once every 3 months. 
The Investigator shall discuss any case of patient withdrawal with the Sponsor/PPD 
Medical Monitor. The reason for withdrawal shall be recorded in source documents and CRF. If 
the patient early discontinues from the study for more than one reason, only the main reason 
shall be listed. In case of consent withdrawal by the patient due to AE or SAE, occurrence of AE 
or SAE shall be given as a reason. 
AEs, SAEs and pregnancy present at the time of the study termination must be followed 
according to the Protocol, unless another procedure of follow-up is set by agreement between the 
Investigator and the Sponsor/CRO. 
6.13 Patient replacement 
Patients that will receive less than 70% (120 hours) of Reparixin treatment will not be 
included in the efficacy analyses and will be replaced except for the cases where the treatment 
will be discontinued due to AE (including conditions listed in paragraph 6.12) judged by the 
reporting investigator (and confirmed by the DMC) to be related to the study drug. 
6.14 Validity of measurements 
Evaluation of the efficacy and safety parameters in this study is the standard practice 
followed for Phase 2 clinical studies in patients with liver diseases. 


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7 STUDY PROCEDURES 
7.1 Selection of the transplant 
In addition to standard criteria approved by the health authorities of the Russian Federation 
[13] to assess the extent hepatodepression (liver problems), the Investigators will evaluate organ 
suitability for transplantation relying on histopathologic findings from biopsy. 
In this clinical setting, grafts with macrovesicular steatosis degree >50% will be 
considered as non-suitable for transplantation. 
7.2 Screening and Randomization, Day -1 
(Time window from 24 h up to 90 min prior to planned surgery) 
Patients admitted to the facility will undergo the screening procedure immediately before 
OLT surgery. Screening can be done on the day of surgery. 
• 
Procedure for obtaining of informed consent 
• 
Patient registration 
• 
Demographic data and medical history 
• 
Data collection for receiving concomitant therapy 
• 
 Collection of blood and urine samples for laboratory testing: hematology, biochemistry, 
coagulation profile, express HIV test, viral load in patients with HBV and/or HCV, 
urinalysis 
• 
Pregnancy test for women able to bear children (including women in menopause less 
than two years) 
• 
Complete physical examination 
• 
Assessment of vital signs 
• 
Measurement of weight and height 
• 
MELD and Child-Turcotte-Pugh scores 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
• 
Evaluation criteria for inclusion/exclusion 
The decision to include in the study will be made on the basis of the results of laboratory tests 
carried out in a local laboratory (hematology, biochemistry, coagulation profile, express HIV test, 
urinalysis). Laboratory tests (except the tests for pregnancy and HIV) will be repeated at the 
centralized laboratory level. Test results from a centralized laboratory will be used as baseline data. 
Randomization of patients should be conducted after the Investigator has checked the results 
of all the measurements that are needed for the assessment of inclusion/exclusion criteria. 
In case of ambiguous or equivocal results of laboratory tests re-test may be performed with 
the approval of the Sponsor/PPD 
Medical Monitor. 
Patients who did not meet all inclusion/exclusion criteria will not be included in the study. In 
case of cancellation of the surgery the patients can be re-screened. In this case, all screening 
procedures will be carried out again, including the procedure for obtaining informed consent and 
the assignment of a new identification number. 


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7.3 Study therapy, week 0 
7.3.1 Day 0 
 
60-90 minutes after the start of the Reparixin infusion (OLT) 
OLT will be conducted in accordance with the Russian Transplant Society Guidelines for liver 
transplantation (Appendix 7) and the standard procedure adopted in the research center. During 
and after OLT, patient will undergo all the necessary manipulations, including routine 
investigations, as well as prescription of immunosuppressive therapy and other concomitant 
therapy, as usual. 
12 hours from the start of the Reparixin infusion or 11 hours after OLT (Time window 
 30 min) 
• 
Evaluation of AEs and concomitant therapy 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
ECG (12 leads) – it’s possible to use the bedside monitor 
Continuation of the 168-hour uninterrupted infusion of Reparixin (in the group of the study 
therapy) 
7.3.2 Day 1 after OLT 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood samples for hematology, biochemistry, coagulation profile 
• 
Obtaining of blood samples for pharmacokinetic analyses (ideally in the morning; only in 
patients randomized to Reparixin in stage 1 of the study) 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
Doppler ultrasound of the abdomen 
Continuation of the 168-hour continuous infusion of Reparixin (in the group of the study 
therapy) 
7.3.3 Day 2 after OLT 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
ECG (12 leads) 
0 hours (start of the Reparixin infusion) 
• 
Evaluation of AEs and concomitant therapy 
• 
Assessment of vital signs 
• 
Start of the 168-hour continuous infusion of Reparixin (in the group of the study therapy) 


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• 
Continuation of the 168-hour continuous infusion of Reparixin (in the group of the study 
therapy) 
7.3.4 Day 3 after OLT 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood samples for biochemical blood analysis, coagulation profile 
• 
Obtaining of blood samples for pharmacokinetic analyses (ideally in the morning; only in 
patients randomized to Reparixin in stage 1 of the study) 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
Continuation of the 168-hour continuous infusion of Reparixin (in the group of the study 
therapy) 
7.3.5 Day 4 after OLT 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
• 
Continuation of the 168-hour continuous infusion of Reparixin 
7.3.6 Day 5 after OLT 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood samples for biochemistry, coagulation profile 
• 
Obtaining of blood samples for pharmacokinetic analyses (ideally in the morning; only in 
patients randomized to Reparixin in stage 1 of the study) 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
Continuation of the 168-hour continuous infusion of Reparixin (in the group of the study 
therapy) 
7.3.7 Day 6 after OLT 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood samples for biochemistry, coagulation profile 
• 
Short physical examination 
• 
Assessment of vital signs 
• 
Continuation of the 168-hour continuous infusion of Reparixin (in the group of the study 
therapy) 


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7.4 Completion of therapy, Day 7 after OLT (end of therapy) 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Full physical examination 
• 
Assessment of vital signs and body weight 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
• 
 Obtaining of blood samples for pharmacokinetic analyses just prior to the end of study 
drug administration, and at 1, 3, 5, 6, 8, and 12 hours after termination of the study drug 
administration (only in patients randomized to Reparixin in stage 1 of the study) 
In the group of the study therapy visit procedures should be conducted after completion of 168 
hour continuous infusion of Reparixin and catheter removal. 
7.5 Follow-up period 
While being in hospital and after discharge the patient will undergo procedures of follow-up 
visits on an outpatient basis. During this period the patient will receive necessary treatment in 
accordance with the standards of patient management after liver transplant. 
7.5.1 Week 2 after OLT(Time window  2 days) 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Complete physical examination 
• 
Assessment of vital signs and body weight 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
7.5.2 Week 4 after OLT (Time window  3 days) 
• 
Evaluation of AEs and concomitant therapy 
• 
 Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Pregnancy test for women able to bear children (including women in menopause less than 
two years) 
• 
Complete physical examination 
• 
Assessment of vital signs and body weight 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 


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7.5.3 Weeks 12 and 24 after OLT (Time window  7 days) 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Pregnancy test for women able to bear children (including women in menopause less than 
two years) 
• 
Complete physical examination 
• 
Assessment of vital signs and body weight 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
7.5.4 Week 36 after OLT (Time window  7 days) 
At Week 36, the patients (or their families) will be contacted by the Investigator through 
telephone call to monitor status of patient and allograft survival. 
7.5.5 Year 1 after OLT (Time window  14 days) 
• 
Evaluation of AEs and concomitant therapy 
• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Pregnancy test for women able to bear children (including women in menopause less than 
two years) 
• 
Complete physical examination 
• 
Assessment of vital signs and body weight 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
7.6 Unscheduled visits 
For safety reasons, in case of the need for re-examination or procedures there may be an 
unscheduled visit at any time during the clinical trial at the discretion of the Investigator. During 
unscheduled visits the Investigator may carry out the necessary procedures, including lab tests. 
Unscheduled visits shall be registered in source documents and CRF. Conducting of unscheduled 
visits shall not affect the schedule of planned visits in the protocol of the clinical trial. 
7.7 Visit of early discontinuation (ED) 
In case of early discontinuation of investigational product administration, the patient will be 
able to continue participation in the study (in the absence of other indications). However, the 
efficacy analysis will include only patients who received at least 70% of the total dose of Reparixin 
(infusion for at least 120 hours). 
In case of early withdrawal from the study, the patient will be invited to Early Discontinuation 
visit (ED visit) no later than 4 weeks after the end of the investigational product administration (no 
later than 5 weeks after OLT for patients from the control group). 
In case of patient withdrawal from the study after Week 12, ED visit is not necessary. 
The following procedures should be carried out during the ED visit: 
• 
Evaluation of AEs and concomitant medications 


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• 
Obtaining of blood and urine samples for laboratory tests: hematology, biochemistry, 
coagulation profile, urinalysis 
• 
Pregnancy test for women of reproductive age (including women with menopause for less 
than 2 years) 
• 
Complete physical examination 
• 
Assessment of vital signs and body weight 
• 
ECG (12 leads) 
• 
Doppler ultrasound of the abdomen 
If the ED visit cannot be carried out in full, the Investigator shall coordinate the actions with 
the PPD 
 Medical Monitor. 
Status of patients after early discontinuation (patient and allograft survival) will be monitored 
for 1 year after OLT at least once every 3 months. The patient will be given recommendations for 
following standard treatment. 
If possible, the Investigator shall preliminary consult the Sponsor/PPD 
 Medical 
Monitor in advance of any withdrawal. 
Otherwise, the Investigator shall inform the Sponsor/PPD 
Medical Monitor 
about patient withdrawal within 24 hours of knowledge of the event. Contact details of 
PPD 
 Medical Monitor are provided below and in the section “Contact Information”. 


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8 QUALITY ASSURANCE 
This clinical study will be conducted in accordance with standard operating procedures (SOPs) 
of the Sponsor/CRO, the Good Clinical Practice-International Conference on Harmonisation (GCP-
ICH) regulations and the principles of the Helsinki Declaration, and in respect of local regulatory 
requirements. Compliance with the requirements will be monitored by the Sponsor/CRO through 
carrying out audits of the clinical sites and the data obtained in the study. 
In accordance with the protocol the Investigator will record the required data in CRF provided 
by the CRO. Monitors with a frequency described in the monitoring plan will visit each clinical site 
to check on CRF completeness and accuracy. In case of missing or contradictory data, queries will 
be raised (per patient) in order to obtain consistent data. The queries should be answered by the 
Principal Investigator (or an authorized staff member). 
After CRF completion and resolution of all queries, the Investigator will sign and date the CRF 
of each patient. The completed CRF pages will be checked during the monitoring visits and 
submitted to Data Management. Upon study completion, the original CRF will be archived by the 
Sponsor, and a copy of the CRF will be stored at clinical sites. 


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9 PLANNED STATISTICAL METHODS 
9.1 General Terms 
This study is a multicenter, open-label, randomized pilot study of efficacy and safety of 
Reparixin for prevention of early allograft dysfunction in patients undergoing OLT. Methods of 
descriptive statistics will be used to evaluate the results of the study. Statistical analysis plan will 
be developed and finalized before closing the database. 
9.2 Determination of sample size 
The primary efficacy endpoint is the assessment of the incidence of early allograft dysfunction 
in patients undergoing OLT during therapy with Reparixin. 
Simon's minimax two-stage design for Phase II clinical trials was used to calculate the sample 
size [5, 6]. In this model, the study included patients to the total number = Ntotal (number of patients 
in each group for which an assessment of endpoint was conducted). Upon reaching the total 
number of patients who responded to treatment above Rtotal, the therapy will be found suitable for 
further study. Values of these parameters (with α = 0.05 and a power of 80%, P0 = 75% and P1 = 
90% for early allograft dysfunction) for a positive decision on the efficacy of treatment for further 
study are listed below. 
 
Efficacy endpoint 
P0 
P1 
r1 
n1 
Rtotal 
Ntotal 
α 
1-β 
No early allograft dysfunction 
0.75 
0.90 
> 17 
22 
> 33 
39 
0.05 
0.80 
Thus, 39 patients who underwent OLT and received treatment with Reparixin will provide 
80% of power to test the hypothesis of a preliminary assessment of the efficacy of the 
investigational product and the decision on the further study (α = 0.05). Data obtained in the control 
group will also be used in the study in order to control the correctness of data concerning the 
frequency of early allograft dysfunction. 
In case of early discontinuation of patients from the study prior to receiving study treatment 
or inability to evaluate the primary efficacy endpoint, the patient can be replaced (see paragraph 
6.13). Considering a possible 7% early discontinuation rate and the inability to assess the primary 
endpoint for some patents, up to 84 patients will be randomized in the study. This number of 
patients is based on a statistical power of 80% with an alpha of 0.05 and 1:1 randomization. In 
total, considering a possible 15% screening failure rate, about 100 patients planned for OLT will 
need to be screened in the study. 
9.3 Populations for analysis 
9.3.1 Population per protocol 
Per protocol population includes all patients who have received at least 70% of the dose of the 
study drug, with data sufficient for the primary efficacy analysis, and who are considered 
compliant. Patients are considered compliant in case of absence of any major protocol violations 
during the study. In the group of the study therapy the patients who received not less than 70% of 
the study drug dose will be considered compliant. Major protocol violations will be described in 
more detail in terms of statistical analysis and identified before closure of the database. 
9.3.2 MITT population 
Modified population of patients who received treatment (MITT = modified intent-to-treat) 
corresponds to all patients who received any dose of study drug. MITT population is the additional 
population for further evaluation. 


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9.3.3 Safety population 
Safety population will include all patients who received any dose of the study drug and also 
the patients from the control group who are included in the study. 
9.4 Patient allocation, demographic and baseline characteristics 
Allocation of patients, demographic and baseline characteristics will be presented in groups, 
using descriptive statistics. Number and percentage of patients taking concomitant medications 
will be presented in frequency tables for ATC class and the name of the active substance according 
to the State Register of Medicines of the Russian Federation. The number of patients with co-
morbidities and previous states will also be represented. 
9.5 Investigational product administration 
Information on dosing of Reparixin including the duration of exposure, interruptions in 
therapy and common doses will be presented descriptively. 
9.6 Statistical Methods 
Appropriate descriptive statistics will be produced, according to the nature of the variable. In 
general, categorical data will be presented using counts and percentages, whilst continuous 
variables will be presented using the mean, standard deviation, median, minimum, maximum and 
number of patients. Percentages will be rounded to the nearest integer. In tabulations, denominators 
for calculation of percentages will be taken as the number of non-missing responses in the specified 
analysis population and treatment group unless otherwise stated. 95% Confidence Interval of 
continuous and categorical variables will be presented. 
Unless otherwise specified, the significance level used for statistical testing will be 5% and 
two-sided tests will be used. 
All reasonable efforts will be made to reduce the rate of missing data, since any method used 
for imputation for missing observations would be based on untestable assumptions that likely 
would be invalid. Appropriate descriptive statistics will be produced for the rate and reason for 
missing data to allow comparison between the treatment groups. 
A Statistical Analysis Plan will be issued describing details of all the statistical methods and 
analysis to be applied to trial results. Any change in the planned analysis will be documented. The 
data will be presented in the clinical study report. 
9.6.1 Demographic and Baseline Characteristics 
Summaries of demographic and baseline characteristics data will be produced using the safety 
population and will be presented by treatment group. All baseline data will also be listed. 
9.6.2 Efficacy analysis 
Efficacy data will be reviewed on an ongoing basis by a Data Monitoring Committee (DMC). 
Full details of the activities and responsibilities of the DMC are provided in the study DMC 
Charter. 
Primary endpoint data will not be available until each patient reaches Day 7 post 
transplantation. The DMC will give careful consideration to the appropriateness of trial 
continuation if there is emerging evidence of futility of the Reparixin treatment. Main component 
of this assessment will be the rate of early graft dysfunctions. 
The DMC will consider the following guidelines regarding early termination based on the 
occurrence of early graft dysfunctions. Early termination will be considered if: 
• 
5 or more patients from the study drug group will experience early graft dysfunction in 
the first stage, 


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• 
 6 or more out of 39 patients from the group of the study drug group will experience early 
graft dysfunctions. 
The DMC will also consider early termination if the quality of conduct of the trial is such that 
the trial will not be able to provide a timely and reliable answer to the questions it was designed to 
address. 
9.6.2.1 Primary efficacy analysis 
The primary efficacy endpoint is the assessment of the incidence of early allograft dysfunction 
after OLT (Week 1) during the therapy with Reparixin. 
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. Sklifosovskiy Center of Liver Transplantation under Research Institute of 
Emergency Care, confirmed the development of this type of complications in 25% of cases (N = 
202). Death has occurred in the population of patients with early allograft dysfunction at almost 
twice the rate in patients with normal functioning of the transplant during the first 7 days after 
OLT (p < 0.005). 
Therefore, as a baseline index for the incidence of early allograft dysfunction was selected at 
the level of 25% (p0 = 0.75). The target level index for the incidence of early allograft dysfunction 
was selected at the level of 10% (p1 = 0.90). These data can be corrected after the first stage of the 
study in accordance with the results of the preliminary assessment of early allograft dysfunction 
rate in the Reparixin and control groups. 
The main purpose of this study is to give the primary assessment of Reparixin efficacy in 
accordance with Simon's minimax two-stage design. This model of statistical analysis in the phase 
2 pilot study was chosen to receive the primary efficacy data of Reparixin that is used during OLT 
for the first time. This model will follow a trend in the parameters of drug efficacy in a small group 
of patients, and thus, will decide on further study of the drug in the large-scale comparative studies. 
The analysis will be conducted by the primary efficacy endpoint, which is the incidence of early 
allograft dysfunction. The obtained preliminary evidence of the efficacy will decide on further 
studying of the drug for this indication. 
According to Simon's minimax model analysis of the efficacy will be conducted in two 
phases: 
- During Stage 1 of the study the primary efficacy endpoint will be assessed in 22 patients in 
both groups. In case of early allograft dysfunction in < 5 out of 22 patients from the group of the 
study drug, a transition to Stage 2 of the study will be deemed possible. In the case early allograft 
dysfunction develops in ≥ 5 out of 22 patients from the group of the study drug, further study of 
Reparixin in this study population will be considered inappropriate. 
- During Stage 2 of the study, the primary efficacy endpoint will be assessed in additional 17 
patients in each group (in total number of 39 patients in each group). Early allograft dysfunction 
in < 6 out of 39 patients from the group of the study drug gives grounds for a conclusion of the 
efficacy of Reparixin in this population and the appropriateness of subsequent large-scale 
comparative Phase III clinical trials. In case early allograft dysfunction develops in ≥ 6 out of 39 
patients in the group of the study drug, further study of Reparixin in this study population can be 
considered inappropriate. 


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The following statistical algorithm will be applied to the study: 
 
Experimental group 
Control group 
Stage 1 
22 patients 
22 patients 
≥ 5 early graft 
dysfunctions (≥23%) → 
no efficacy (stop) 
< 5 early graft 
dysfunctions (<23%) → 
potential efficacy 
(continue to Stage 2) 
< 7 early graft 
dysfunctions (<32%) → 
potential study failure 
due to lack of power 
Stage 2 
Up to 39 patients (total) 
Up to 39 patients (total) 
≥ 6 early graft 
dysfunctions (≥15%) → 
no efficacy (stop) 
< 6 early graft 
dysfunctions (13%) → 
potential efficacy 
< 12 early graft 
dysfunctions (<31%) → 
potential study failure 
due to lack of power 
 
9.6.2.2 Secondary efficacy analyses 
Secondary assessment of the efficacy includes the following parameters: 
• 
Primary nonfunction within 7 days after OLT. 
• 
Overall indicators of the liver allograft dysfunction during the early postoperative period 
(within 14 days after OLT), including: 
- Primary nonfunction, 
- Early allograft dysfunction, 
- Extracorporeal detoxification. 
All these parameters will be reported using appropriate descriptive statistics and 95% 
confidence intervals of difference between the Reparixin and control will be calculated 
• 
 The frequency of identification of laboratory examination values corresponding to early 
allograft dysfunction, 3 days after the operation (Day 4 of the study drug administration). The 
data for the treatment and control groups will be presented in a comparative table. 
• 
 The incidence of early allograft dysfunction in case of transplantation of donor organs 
differing by the degree of steatosis and by the time of allograft removal from the donor and 
up to its reperfusion after engraftment (duration of cold and warm ischemia). The data for the 
treatment and control groups will be presented in a comparative table. 
• 
 The incidence of early allograft dysfunction in transplantation from donors having additional 
adverse factors (infectious complication, death of the brain, hypotension, etc.), and with regard 
to the interval between the diagnosis of brain death and removal of liver graft from a donor 
(in the case of the death of brain of the donor). The data for the treatment and control groups 
will be presented in a comparative table. 
• 
 The incidence of early allograft dysfunction in transplant recipients with liver diseases of 
different etiology (viral, alcoholic, autoimmune, etc.) and with different baseline 
characteristics (age, activity of HBV, kidney function, score in scales of MELD, Child- 


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Turcotte-Pugh, etc.). The data for the treatment and control groups will be presented in a 
comparative table. 
• 
 Time for normalization of liver function parameters (ALT, AST and bilirubin levels, GGT, 
LDH, etc.) after OLT. The data will be presented with Kaplan-Meier curves. 
• 
 The incidence of hyperacute, acute and chronic liver allograft rejection (defined by 
histological evaluation). The data for the treatment and control groups will be presented in a 
comparative table. 
• 
Mortality within 1 year after OLT. The data for the treatment and control groups will be 
presented in a comparative table. 
• 
Graft survival at 1 year after OLT. The data for the treatment and control groups will be 
presented in a comparative table. 
9.7 Safety analysis 
Safety will be assessed on the basis of the analysis of the incidence of adverse events of 
different grade during 12 weeks and 1 year after OLT according to subjective complaints, physical 
examination, vital signs, laboratory tests (including liver and kidney function), ECG, vascular 
ultrasound of the liver and kidneys with Doppler sonography. The incidence of severe allograft 
dysfunction, which required extracorporeal detoxification and/or led to the death of the patient, 
will also be assessed. Data will be summarized and represented using descriptive statistics. 
Number and percentage of patients with adverse events in each group will be presented in 
tabular form according to the class of organ systems and preferred term, relation to the 
investigational product and severity. Life and laboratory parameters will be presented using 
descriptive statistics. 
9.8 PK analysis: 
Plasma levels of reparixin (total and unbound) and its metabolites (DF2243Y and 
ibuprofen)will be summarized using descriptive statistics. 


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10 ADMINISTRATIVE PROCEDURES 
10.1 Legal aspects 
All information obtained during the conduct of the study will be regarded as confidential. An 
agreement for disclosure will be obtained in writing by the patient and will be included in a Patient 
Informed Consent Form. Patient’s data collected during the study will be handled in accordance 
with applicable data protection laws and regulatory requirements. 
Life and health of patients participating in the clinical study will be insured according to the 
legislation of the Russian Federation (article 44 of the Federal Law on Drugs Circulation No 61- 
FZ of April 12, 2010 and other statutes in force) and the Republic of Belarus. 
The Sponsor is responsible for financing all clinical trial related activities. 
All data obtained in this study is confidential information belonging to Sponsor of the Study. 
The Sponsor will publicly disclose the results of the study in accordance with legislative and 
regulatory requirements. Publication policy for Investigators and clinical sites will be specified in 
the clinical trial agreement. 
10.2 Protocol Amendments 
Changes to the Protocol will be implemented only when written amendments have been signed 
by all individuals who signed the protocol. 
Any amendment will be sent to the appropriate IEC. No changes to the protocol will be 
implemented without documented approval of an amendment from the IEC which granted the 
original approval, except where necessary to eliminate an immediate hazard(s) to trial patient, or 
when the change(s) involves only logistical or administrative aspects of the trial. The changes to 
the protocol implemented to eliminate an immediate hazard to the trial patient and the proposed 
amendment, if appropriate, should be submitted to the IEC for review and approval as soon as 
possible. 
Any written amendment will be sent to all recipients of the protocol and to the Competent 
Authorities. 
10.3 Responsibilities of the Investigator 
The Investigator shall conduct clinical trials in accordance with the requirements of this 
protocol, the Good Clinical Practice-International Conference on Harmonisation (GCP-ICH) 
regulations and the principles of the Helsinki Declaration, and in respect of local regulatory 
requirements [14]. 
The Investigator (or an authorized staff member) will be responsible for reporting any 
SAEs/SUSARs to the Local Ethics Committee and local institutions in accordance with local 
regulations and requirements. 
The Investigator should permit monitoring and auditing by the Sponsor/CRO, and inspections 
by s appropriate regulatory authority(ies). Upon request of the Monitor, auditor, IEC, or regulatory 
authority, the Investigator/institution should make available for direct access all requested trial-
related records. 
The Investigator shall keep the originals of all signed during the study Patent Informed 
Consent Forms, as well as a full list of study subjects indicating the full name, given numbers, 
initials, date of birth, address and/or phone number to identify them if necessary. These documents 
shall not be copied for further transmission to the Sponsor. 
The Investigator is obliged to ensure the safety of study materials, including supporting 
documentation and copies of the CRF and Investigator’s File during at least 15 years after 
completion of the study or until the moment specified by the Sponsor. 


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10.4 CRF data entry 
The Investigator shall transfer the data obtained during the clinical study from source 
documents into the CRF, as required. No data will be recorded directly in the CRF. CRF 
completion guidelines will be studied by the Investigator during the Investigators Meeting and/or 
during the Site Initiation Visit. If the Investigator delegates the authority to complete the CRF to 
other clinical site employees, their names, titles, signatures and initials shall be entered in the Site 
Personnel Signature and Delegation Form and provided to the Sponsor/CRO. 
When a correction in CRF is made, there shall remain an audit trail, i.e. the data before and 
after the changes, reason (if applicable), date and initials of the one who makes changes shall be 
visible. The completed CRFs shall be signed by the Investigator. 
The completed CRF pages will be checked during the monitoring visits and submitted to Data 
Management. In case of missing or contradictory data, queries will be raised (per patient) in order 
to obtain consistent data. The queries should be answered by the Principal Investigator (or an 
authorized staff member). 
Upon study completion, original CRFs will be archived by the Sponsor, and copies of CRFs 
will be stored at clinical sites. 
10.5 Data Monitoring Committee 
An independent Data Monitoring Committee will be established to oversee study progress at 
regular intervals for the duration of the trial and make recommendations to the Sponsor on whether 
to continue, modify or stop the study. To contribute to enhancing the integrity of the trial, the DMC 
may also formulate recommendations to Dompé relating to the selection/recruitment/retention of 
participants, their management, improving adherence to protocol-specified regimens and retention 
of participants, and the procedures for data management and quality control. 
The DMC will operate independently of Dompé in accordance with a trial specific DMC 
Charter, and its members will not have connections to Dompé with the exception of the 
compensation to DMC members related to their activities. The DMC will report directly to Dompé 
who will convey the findings of the DMC to the investigators/CRO as applicable. 
The DMC: 
- Will be responsible for the ongoing review of efficacy data during the first recruitment 
stage and making appropriate recommendations regarding transition into stage 2 or 
stopping enrollment. In particular, the DMC will monitor the number of early graft 
dysfunctions to determine whether it is consistent with the expected rate. 
- Will be responsible for the ongoing review of efficacy and other study related data 
throughout the trial to enable the assessment of the acceptability of safety in the context of 
emerging evidence about efficacy. 
Will be advisory to Dompé and make recommendations to Dompé regarding the 
continuation/early discontinuation of the trial and potential modifications to the design and 
conduct of the trial. 
10.6 Monitoring procedures 
The Investigator shall provide direct access to all source documents, CRFs and Site 
Investigator File to the Sponsor/CRO, IEC and regulatory authorities. Source documentation 
includes but is not limited to medical records, hospital records, laboratory records, notes, 
questionnaires, drug dispensing records, readings of automatic recording devices, verified and 
certified true copies or discharge reports, photographic negatives, microfilm or magnetic carriers, 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 67 of 81 
Version No. 2 – Final 13 March 2015 
 
 
X-rays, any entries relating to the patient, including data stored in the pharmacy, laboratories and 
instrumental diagnostics departments used in clinical study. 
Monitoring will be conducted by PPD 
 
plan developed for this study. 
10.7 Registration of data in the CRF 
in accordance with its SOPs and Monitoring 
The CRO shall promptly inform the Sponsor about any issues related to early discontinuation 
of patients, interruption of the study drug infusion, early termination visit, and other important 
issues. The communication paths will be outlined in the Monitoring plan developed for this study. 
10.8 Essential Document retention 
The essential documents (source documents, the signed protocol, copies of the CRFs, Site 
Investigator File, Patient Informed Consent Forms from all patients who consented, etc.) shall be 
retained at clinical sites or another suitable archive with restricted access for at least 15 years after 
completion of the study or until the moment specified by the Sponsor. 
The Investigator should inform the Sponsor/CRO of the storage location, and take measures 
to prevent accidental or premature destruction of these documents. The Sponsor shall be informed 
in case of transfer of documents to other authorities or to other storage location. 
10.9 Ethical considerations 
10.9.1 Independent Ethics Committee 
Prior to the initiation of the clinical study all research centers will receive a written approval 
of the Independent Ethics Committees (IEC), in accordance with the Guidelines on Good Clinical 
Practice of the International Conference on Harmonization (ICH GCP), applicable laws and 
regulatory requirements. The following documents shall be provided to IEC for consideration: 
study protocol and amendments thereto, patient information sheet and informed consent form, 
written materials to be provided to the subjects of the research, current version of the Investigator’s 
Brochure, information on safety of the study drug, scientific biography of the Investigator and the 
other required documents. 
List of members of the IEC and the statement of compliance of its organization and operations 
with the principles of Good Clinical Practice and regulatory requirements shall be provided to the 
Sponsor/CRO. 
10.9.2 Ethical performance of the clinical study 
The study will be performed and monitored according to the Good Clinical Practice- 
International Conference on Harmonisation (GCP-ICH) regulations and conducted according to 
the principles of the Helsinki Declaration and any local regulatory requirements [14]. 
In addition to the other liabilities and responsibilities described in 10.2, the Investigator should 
permit monitoring and auditing by the Sponsor/CRO, and inspections by appropriate regulatory 
authority(ies). Upon request of the Monitor, auditor, IEC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial-related records. 
10.9.3 Informed Consent 
Prior to the clinical study the Investigator shall obtain the written approval of IEC on Patient 
Informed Consent Form and any on other written information to be provided to the subjects of the 
study. The written approval of IEC and approved documents shall be stored in the Investigator Site 
File. 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 68 of 81 
Version No. 2 – Final 13 March 2015 
 
 
The process of obtaining of informed consent shall be held in accordance with the Guidelines 
on Good Clinical Practice of the International Conference on Harmonization (ICH GCP), the 
principles outlined in the Declaration of Helsinki and in accordance with applicable law and 
regulatory requiremets. Patient Informed Consent Form shall be personally signed and dated by 
the patient before the start of any study procedures in two original copies. One original copy of the 
signed form will be provided to the patient, and the other original copy of the signed Patient 
Informed Consent Form will be retained and filed in the Investigator Site File. The process of 
obtaining informed consent shall be described in detail in source documents, including the fact of 
patient's consent to participate in this clinical study and the date of signing a Patient Informed 
Consent Form. 
10.9.4 Discontinuation of the study 
Dompé farmaceutici s.p.a. reserves the right to stop the study at any time on the basis of new 
information regarding safety or efficacy, or if study progress is unsatisfactory, or for other valid 
administrative reasons. 
After such a decision is made, the Investigator must inform all relevant persons e.g. study staff, 
potential patients etc. within 2 weeks. All delivered study materials must be collected and all CRFs 
completed to the extent possible. 


Study TPL-RPX-01 
Reparixin in Orthotopic Liver Transplantation 
Page 69 of 81 
Version No. 2 – Final 13 March 2015 
 
 
 
11 LIST OF REFERENCES 
1. Bertuzzi F, Marzorati S, Maffi P, Piemonti L, Melzi R, De Taddeo F, Valtolina V, 
D’Angelo A, Di Carlo V, Bonifacio E, Secchi A. Tissue factor and CCL2/Monocyte 
chemoattractant protein-1 released by human islets affect engraftment in type 1 diabetic 
recipients. J Clin Enocrinol & Metab 2004; 89:5724-28. 
2. Movahedi B, Gysemans C, Jacob-Tulleneers-Thevissen D, Mathieu C, Pipeleers D. 
Pancreatic duct cells in human islet cell preparations are a source of angiogenic cytokines 
interkeulin-8 and vascular endothelial growth factor. Diabetes 2008; 57:2128-2136. 
3. Shapiro AMJ, Ricordi C, Hering BJ, Hukincloss H, Lindblad R, et al. International trial of 
the Edmonton protocol for islet transplantation . N Engl J M 2005; 355:1318-30. 
4. Citro A, Cantarelli E, Maffi P, Nano R, Melzi R, et al. CXCR1/2 inhibition enhances 
pancreatic islet survival after transplantation. J Clin Invest 2012; 122:3647-51. 
5. Richard Simon. Optimal Two-Stage Designs for Phase II, Clinical Trials Controlled 
Clinical Trials 10:1-10, 1989, 
http://www.nihtraining.com/cc/ippcr/current/downloads/simon2stage.pdf 
6. Chung-Li Tsai. Two stage designs for Phase II clinical trials Institute of Statistics, 
National University of Kaohsiung, Taiwan, July 2006. 
7. Gauthier S., Konstantinov B., Tsirulnikova O. Liver transplantation. – Medical 
information agency, 2008; 14-15: 248 p. 
8. Johnson SR, et al: Primary nonfunction (PNF) in the MELD Era: an SRTR database 
analysis. Am J Transplant 2007, 7(4):1003–1009. 
9. Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines CXC 
and CC chemokines. Adv Immunol. 1994;55:97-179. 
10. Opfermann P1, Derhaschnig U, Felli A, Wenisch J, Santer D, Zuckermann A, Dworschak 
M, Jilma B, Steinlechner B. A pilot study on reparixin, a CXCR1/2 antagonist, to assess 
safety and efficacy in attenuating ischaemia-reperfusion injury and inflammation after on-
pump coronary artery bypass graft surgery. Clin Exp Immunol. 2015 Apr;180(1):131- 
142. doi: 10.1111/cei.12488. 
11. http://clinicaltrials.gov/show/NCT01764607 
12. http://clinicaltrials.gov/show/NCT00752479 
13. The Russian Transplant Society Guidelines for Liver Transplantation. – Moscow, 2013. 
14. National Standard of the Russian Federation GOST R 52379-2005. Good Clinical Practice. 
- Moscow, 2005. 
15. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong 
P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the 
American Association for the Study of Liver Diseases and the European Association for 
the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. doi: 10.1002/hep.27210. Epub 
2014 Jul 8. 
16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16:31-41. 

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CCICCI
PPD
PPD
PPD
Statistica! Analysis Pian 
-
TPL-RPX-01 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Name 
Version 
Study drug 
Study code 
litle of Study 
Sponsor 
CRO 
Version 
Version Date 
Reviewed/Approved by: 
I 
Statistica! Analysis Pian {SAP) on Protocol TPL-RPX-01 
Final Version, 3.0 
Reparixin 
TPL-RPX-01 
A multicenter, open-label, randomized pilot clinica! 
study of efficacy and safety of Reparixin for prevention 
of early allograft dysfunction in patients undergoing 
orthotopic liver transplantation. 
Dompé fannaceutici s.p.a. 
Version Control 
Change reason 
I 
The information contained in this document is confidenlial and the information contained within it 
may not be reproduced or otherwise disseminated without the approvai of KeyStat. 


Statistical Analysis Plan 
 
 
TPL-RPX-01 
 
CONFIDENTIAL 
Final Version 3.0 
 
Page 2 of 34 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS 
5 
2. 
INTRODUCTION 
7 
2.1 
Study Design 
7 
2.2 
Study Objectives 
7 
3. 
INTERIM ANALYSIS, FINAL ANALYSIS AND UNBLINDING 
8 
4. 
ENDPOINTS AND COVARIATES 
8 
4.1 
Efficacy endpoints 
8 
4.2 
Safety endpoints 
9 
4.3 
Pharmacokinetic endpoints 
10 
5. 
ANALYSIS SETS 
10 
5.1 
Efficacy Analysis Sets 
10 
5.1.1 
MITT population 
10 
5.1.2 
Per Protocol (PP) population 
10 
5.2 
Safety Analysis Set 
10 
5.3 
Protocol Deviations 
10 
6. 
HANDLING OF MISSING VALUES 
10 
6.1 
Efficacy Parameters 
10 
6.2 
Safety Parameters 
11 
6.2.1 
Missing onset dates in AE 
11 
6.2.2 
Pharmacokinetic Parameters 
11 
7. 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
11 
7.1 
Statistical Methods 
11 
7.2 
Statistical Analyses 
11 
7.2.1 
Primary Efficacy Analysis 
11 
7.2.2 
Secondary Efficacy Analyses 
11 
7.3 
Other 
13 
7.3.1 
Disposition of Subjects 
13 
7.3.2 
Demographic and baseline characteristics 
13 
7.4 
Safety Analysis 
13 
7.4.1 
Pharmacokinetics 
13 
7.4.2 
Adverse Events 
17 
7.4.3 
Laboratory Data 
17 
7.4.4 
Extend of exposure 
17 
7.4.5 
Vital Signs Data 
17 
7.4.6 
Physical Examination Data 
17 
7.4.7 
Concomitant Treatments 
17 
7.4.8 
Listings 
18 
7.5 
Changes in the planned analyses 
18 
8. 
REFERENCES 
18 
9. 
TABLE EXAMPLES 
19 
 
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LIST OF TABLE’S SHELLS 
Table 9.1 
Disposition 
19 
Table 9.2 
Demographic and other baseline characteristics.  MITT Analysis Set. Screening 
(baseline). N = xx 
19 
Table 9.3 
Creatinine clearance. MITT Analysis Set.  Screening (baseline). N = xx 
20 
Table 9.4 
Medical history. MITT Analysis Set. Screening (baseline). N = xx 
21 
Table 9.5 
Ongoing diseases/diagnosis/abnormalities. MITT Analysis Set. Screening 
(baseline). N = xx 
21 
Table 9.6 
Immunosuppressive therapy. Safety Set. During the study. N = xx 
21 
Table 9.7 
Concomitant medication. Safety Set. During the study.N = xx 
21 
Table 9.8 
Physical examination. Safety Set. N = xx 
21 
Table 9.9 
Vital signs. Safety Set. N = xx 
22 
Table 9.10 
Urine pregnancy test (females only). Safety Set. N = xx 
22 
Table 9.11 
12-lead electrocardiography. Safety Set. N = xx 
23 
Table 9.12 
Viral loading (for patients with HBV and/or HCV).  Safety Set. Screening. N = xx 
23 
Table 9.13 
State of post-operative wound. Safety Set. N = xx 
23 
Table 9.14 
Clinically significant changes in post-operative wound. 
24 
Table 9.15 
Doppler abdominal ultrasonography. Safety Set. N = xx 
24 
Table 9.16 
Laboratory parameters. Hematology. Deviation from normal values. Safety Set. N 
= xx 
24 
Table 9.17 
Laboratory parameters. Biochemistry. Deviation from normal values. Safety Set. 
N = xx 
24 
Table 9.18 
Laboratory parameters. Hematology. Absolute values. 
24 
Table 9.19 
Laboratory parameters. Biochemistry. Absolute values. 
25 
Table 9.20 
Biochemistry. ALT and AST deviation from normal values. 
25 
Table 9.21 
Biochemistry. ALT and AST absolute values comparison. 
26 
Table 9.22 
Extend of exposure. Safety Set. N = XX 
26 
Table 9.23 
Early allograft dysfunction. MITT Set. N = xx 
27 
Table 9.24 
Early allograft dysfunction. PP Set. N = xx 
27 
Table 9.25 
Efficacy assessment. MITT Set. N = XX 
28 
Table 9.26 
Logistic model of early allograft dysfunction and related risk factors. MITT Set. N 
= XX 
29 
Table 9.27 
Survival within 1 year. MITT Set. N = XX 
29 
Table 9.28 
ALT/AST > 2000 U/L and Early allograft dysfunction detected. MITT Set. N=XX 
29 
Table 9.29 
Early allograft dysfunction and potential prognostic factors. MITT Set. Nominal 
data. N=XX 
29 
Table 9.30 
Early allograft dysfunction and potential prognostic factors. MITT Set. Continuous 
data. N=XX 
30 
Table 9.31 
Early allograft dysfunction and additional adverse factors. MITT Set. Nominal 
data. N=XX 
30 
Table 9.32 
Early allograft dysfunction and interval between the diagnosis of brain death and 
removal of liver graft from a donor (in the case of the death of brain of the donor). 
MITT population. Nominal data. N=XX 
30 
Table 9.33 
Early allograft dysfunction in transplant recipients with liver diseases of different 
etiology and with different baseline characteristics. MITT Set. Nominal data. 
N=XX 
31 
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Table 9.34 
Time from the OLT normalization of liver parameters. 
31 
Table 9.35 
Hyperacute, acute and chronic transplant rejection (determined by biopsy). MITT 
Set. N = XX 
32 
Table 9.36 
PK data summary. Safety Set. (N = xx) 
33 
Table 9.37 
Adverse Events (AE/SAE). Up to 12 weeks after OLT. Safety Set. N = xx 
33 
Table 9.38 
Adverse Events (AE/SAE). Up to 1 year after OLT (all registered). Safety Set. N = 
xx 
33 
Table 9.39 
Adverse Events (AE/SAE) and severity. Up to 12 weeks after OLT. Safety Set. N = 
xx 
34 
Table 9.40 
Adverse Events (AE/SAE) and severity. Up to 1 year after OLT (all registered). 
Safety Set. N = xx 
34 
Table 9.41 
Adverse Events and relation to study drug(s). Up to 12 weeks after OLT. Safety 
Set. N = xx 
34 
Table 9.42 
Adverse Events and relation to study drug(s). Up to 1 year after OLT (all 
registered). Safety Set. N = xx 
34 
 
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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Arterial Pressure 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CLcr 
Creatinine Clearance 
CPB 
Cardiopulmonary Bypass 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CXCL8; IL-8 
Interleukin-8 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ESR 
Erythrocyte Sedimentation Rate 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-glutamyltransferase 
HBV, HCV 
Hepatitis B and C  
HIV 
Human Immunodeficiency Virus 
i.v. 
Intravenous 
IC 
Informed Consent 
ICH 
International Conference on Harmonization 
ICH GCP 
Guidelines for Good Clinical Practice of the International Conference 
on Harmonization 
IEC 
Independent Ethics Committee  
INR  
International Normalized Ratio 
IRI 
Ischemia-reperfusion Injury 
ITT 
Intent-to-treat 
LDH 
Lactate Dehydrogenase 
LME 
Linear Mixed Effect Model 
LOCF 
Last observation carried forward 
LT 
Liver Transplant 
Mean 
Mean value 
MELD 
Model for End-Stage Liver Disease 
MITT 
Modified Intent-to-Treat population 
N 
Number of observations 
NSAID 
Non-steroidal Anti-inflammatory Drug 
OLT 
Orthotopic liver transplantation  
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic 
PP 
Per Protocol 
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Abbreviation 
Explanation 
PTT 
Prothrombin Time 
p-value 
p-value for H0 of test performed 
RNA 
Ribonucleic Acid 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
t1/2 
Half-life 
TESS 
Treatment Emergency Sign and Symptom 
WHO 
World Health Organization 
 
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Final Version 3.0 
 
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2. 
INTRODUCTION 
This document contains further details to the statistical analyses described in the 
protocol TPL-RPX-01 and is the primary source of all statistical analyses for the study. 
2.1 
STUDY DESIGN 
This study is a multicenter, open-label, randomized pilot study to evaluate the efficacy 
and safety of Reparixin for prevention of early allograft dysfunction in patients 
undergoing OLT. All patients who participate in the study will receive standard 
immunosuppressive therapy in accordance with the Russian Transplant Society 
Guidelines for Liver Transplantation (2013). It is planned that the study will be 
conducted at 5-8 sites for liver transplantation in Russia and Belarus. Recruitment will 
be competitive among the study sites, until the planned number of patients is enrolled. 
Randomization will be performed before or at the day of the surgical operation. The 
patients will be randomized in a 1:1 manner into the Reparixin or the control group. 
Reparixin will be administered to patients as a continuous infusion for 7 days (168 
hours). Infusion of the study product will start approximately 60-90 minutes before the 
anticipated time of OLT. The control group will include patients who do not receive 
Reparixin therapy. Follow-up of patients will last for approximately 1 year after OLT. 
Figure 1. Design of clinical trial TPL-RPX-01 
 
Screening 
  
Study drug administration 
Follow-up 
Week 
 
W0 
W1 
W2 
W4 
W12 
W24 
W36 
Year1 
Day 
D-1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
                                                              ↑ 
 Randomization 
↑ 
  
↑OLT 
 
  
  
  
  
  
  
  
Telephone follow-up 
 
 
Study group 
 
Reparixin (continuous infusion 168 hours) 
  
  
  
  
 
Control group 
- 
 
 
 
 
 
 
Both groups 
 
Standard immunosuppressive therapy 
 
 
 
PK data should be obtained ideally in the morning (on Day 1, 3, 5 after OLT) and just 
prior (Day 7) to the end of study drug administration, and then 1, 3, 5, 6, 8, and 12 
hours after the end of study drug administration, only in patients randomized to 
Reparixin in stage 1 of the study. 
2.2 
STUDY OBJECTIVES 
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 OLT). The safety of Reparixin in the specific clinical setting will be also 
evaluated. 
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3. 
INTERIM ANALYSIS, FINAL ANALYSIS AND UNBLINDING 
One interim analysis is planned during the study flow. Such analysis is planned to 
review the data at some point of the study. All available data at the time of interim 
analysis will be presented with listings, tables and figures (see shells). Descriptive 
statistics will be used for summarize efficacy and safety data. Statistical tests will be 
done for all efficacy data available at the moment of interim database lock.  
The final analysis will be performed after Last patient had Last Visit and the Database 
lock. No unblinding procedures are necessary as this is an open label trial. 
4. 
ENDPOINTS AND COVARIATES 
 Incidence of early allograft dysfunction within 7 days after OLT (primary endpoint). 
 Primary nonfunction within 14 days after OLT. 
 Overall indicators of the liver allograft dysfunction during the early postoperative 
period (within 14 days after OLT), including: 
o Primary nonfunction, 
o Early allograft dysfunction, 
o Extracorporeal detoxification. 
 The frequency of identification of laboratory examination values corresponding to 
early allograft dysfunction, 3 days after the operation (Day 4 of the study drug 
administration). 
 The incidence of early allograft dysfunction in case of transplantation of donor 
organs differing by the degree of steatosis and by the time of allograft removal 
from the donor and up to its reperfusion after engraftment (duration of cold and 
warm ischemia). 
 The incidence of early allograft dysfunction in transplantation from donors having 
additional adverse factors (infectious complication, death of the brain, 
hypotension, etc.), and with regard to the interval between the diagnosis of brain 
death and removal of liver graft from a donor (in the case of the death of brain of 
the donor). 
 The incidence of early allograft dysfunction in transplant recipients with liver 
diseases of different etiology (viral, alcoholic, autoimmune, etc.) and with different 
baseline characteristics (age, activity of hepatitis B, kidney function, score in 
scales of end-stage liver disease (MELD), Child-Turcotte-Pugh, etc.). 
 Time for normalization of liver function parameters (alanine aminotransferase, 
aspartate aminotransferase and bilirubin levels, gamma-glutamyltransferase, 
lactate dehydrogenase, etc.) after OLT. 
 The incidence of hyperacute, acute and chronic liver allograft rejection (defined by 
histological evaluation). 
 Mortality within 1 year after OLT. 
 Graft survival at 1 year after OLT. 
4.1 
EFFICACY ENDPOINTS 
Primary efficacy endpoint 
 Incidence of early allograft dysfunction within 7 days after OLT 
Efficacy of the investigational therapy will be assessed based on the incidence of early 
allograft dysfunction after OLT. 
Early allograft dysfunction will be determined in accordance with the international 
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Page 9 of 34 
standards (Olthoff et al. 2010), as having one of the following parameters obtained 
during one week after OLT (Day 7 of Week 1): 
- 
ALT > 2000 U/ml during first 7 days after OLT, 
- 
AST > 2000 U/ml during first 7 days after OLT, 
- 
Total bilirubin ≥ 10 mg/dl (on Day 7 only), 
- 
INR ≥ 1.6 (on Day 7 only). 
Secondary efficacy endpoints 
 Primary nonfunction within 7 days after OLT. 
Primary nonfunction is defined as absence of graft function leading to allograft loss, re-
transplantation or death of the patient within 14 days after OLT for reasons not related 
to hepatic artery thrombosis, biliary complications, and acute exacerbations of chronic 
diseases or acute allograft rejection. 
 Overall indicators of the liver allograft dysfunction during the early postoperative 
period (within 14 days after OLT), including: 
o Primary nonfunction, 
o Early allograft dysfunction, 
o Extracorporeal detoxification. 
 The frequency of identification of laboratory examination values corresponding to 
early allograft dysfunction, 3 days after the operation (Day 4 of the study drug 
administration). 
 The incidence of early allograft dysfunction in case of transplantation of donor 
organs differing by the degree of steatosis and by the time of allograft removal 
from the donor and up to its reperfusion after engraftment (duration of cold and 
warm ischemia). 
 The incidence of early allograft dysfunction in transplantation from donors having 
additional adverse factors (infectious complication, death of the brain, 
hypotension, etc.), and with regard to the interval between the diagnosis of brain 
death and removal of liver graft from a donor (in the case of the death of brain of 
the donor). 
 The incidence of early allograft dysfunction in transplant recipients with liver 
diseases of different etiology (viral, alcoholic, autoimmune, etc.) and with different 
baseline characteristics (age, activity of hepatitis B, kidney function, score in 
scales of end-stage liver disease (MELD), Child-Turcotte-Pugh, etc.). 
 Time for normalization of liver function parameters (alanine aminotransferase, 
aspartate aminotransferase and bilirubin levels, gamma-glutamyltransferase, 
lactate dehydrogenase, etc.) after OLT. 
 The incidence of hyperacute, acute and chronic liver allograft rejection (defined by 
histological evaluation). 
 Mortality within 1 year after OLT. 
 Graft survival at 1 year after OLT. 
4.2 
SAFETY ENDPOINTS 
 The incidence of adverse events (AEs) and serious adverse events (SAEs) of 
different severity within 12 weeks and 1 year after OLT according to subjective 
complaints, physical examination, vital signs, laboratory tests (including liver and 
kidney function parameters), ECG, vascular ultrasound of the liver and kidneys 
with Doppler sonography. 
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4.3 
PHARMACOKINETIC ENDPOINTS 
Cmax 
Maximum plasma concentration of reparixin and metabolites 
tmax Time of maximum plasma concentration reparixin and metabolites 
z 
Terminal phase rate constant of reparixin and metabolites 
t½ 
Terminal half-life of reparixin and metabolites 
AUC0-t Area under the plasma concentration-time curve from time zero to time t (time 
of last quantifiable plasma concentration) of reparixin and metabolites 
AUC0- Area under the plasma concentration-time curve from time zero to infinity of 
reparixin and metabolites 
Vz Volume of distribution of reparixin 
CL Clearance of reparixin  
Pharmacokinetic evaluation will be performed only in patients randomized to Reparixin 
in stage 1 of the study.  
5. 
ANALYSIS SETS 
5.1 
EFFICACY ANALYSIS SETS 
Eligibility of patients (classification to populations) will be confirmed by the sponsor 
before the start of analysis. 
5.1.1 
MITT population 
Modified population of patients who received treatment (MITT = modified intent-to-
treat) corresponds to all patients who received any dose of study drug. MITT 
population is the additional population for further evaluation. 
5.1.2 
Per Protocol (PP) population 
Per protocol population includes all participants randomized into the trial, who were 
compliant with, and treated according to, the protocol, and who fulfil the following 
criteria: compliance with all inclusion criteria, absence of major clinical trial protocol 
violations with respect to factors likely to affect the efficacy of treatment, and adequate 
(not less than 70%) compliance with trial medication in the study treatment group.  
5.2 
SAFETY ANALYSIS SET 
Safety population will include all patients who received any dose of the study drug and 
also the patients from the control group who are included in the study. 
5.3 
PROTOCOL DEVIATIONS 
A full list of protocol deviations will be compiled and reviewed to identify major and 
minor deviations prior to database lock. 
6. 
HANDLING OF MISSING VALUES 
6.1 
EFFICACY PARAMETERS 
Replacement of missing data is not planned for efficacy parameters. 
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6.2 
SAFETY PARAMETERS 
6.2.1 
Missing onset dates in AE 
AE with missing onset date will be counted as TESS (Treatment Emergency Sign and 
Symptom). 
In case of AE date is incomplete following rules will be used: 
Day 
Month 
Year 
Condition 
Missing 
Missing 
In place 
In case of month and year of onset > date of 
start study time (IC date) - TESS 
Missing 
Missing 
In place 
In case of year of onset > year of start study 
time (IC date) - TESS 
Missing 
Missing 
Missing 
TESS 
Missing 
In place 
Missing 
TESS 
Missing 
Missing 
In place 
Year of onset > year of start study time (IC 
date) - TESS 
6.2.2 
Pharmacokinetic Parameters 
If a PK parameter cannot be derived from a subject’s concentration data, the 
parameter will be coded as NC (i.e., not calculated). (Note that NC values will not be 
generated beyond the day that a subject discontinues.) 
In summary tables, statistics will be calculated by setting NC values to missing; and 
statistics will be presented for a particular treatment with ≥ 3 evaluable measurements. 
For statistical analyses, PK parameters coded as NC will also be set to missing; and 
analyses will not be performed for a particular parameter if more than 50% of the data 
are NC. 
7. 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
7.1 
STATISTICAL METHODS 
Statistical analysis will be done using statistical software R (www.r-project.org). 
For the statistical analysis is planned to use descriptive statistics, ANOVA model, non-
parametric statistics – Mann-Whitney test, Fisher exact test, logistic regression model, 
survival curves and permutation tests (see section 8). 
7.2 
STATISTICAL ANALYSES 
7.2.1 
Primary Efficacy Analysis 
Primary efficacy analysis will be performed for the MITT and PP sets. 
 
Cases of early allograft dysfunction (EAD) within 7 days after OLT will be presented as 
nominal data. For proportions of EAD in treatment groups, 95% CI will be presented 
(exact Clopper-Pearson confidence interval). Treatments will be compared using exact 
Fisher test. Additionally, Kaplan-Meyer curves will be provided for time-to-event (EAD) 
with 95% CI. Treatment groups will be compared by time-to-event (time to EAD) using 
logrank test. 
7.2.2 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be performed for the MITT Set. 
 
Primary allograft nonfunction within 7 days after OLT and overall indicators of 
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allograft dysfunction within 14 days after OLT (primary nonfunction, early 
allograft dysfunction, extracorporeal detoxification) will be described by treatment 
groups as nominal data. Treatment groups will be compared for frequency of allograft 
nonfunction/dysfunction within 7/14days after OLT. Fisher exact test will be used for 
such purpose. Treatment groups also will be compared for prevalence of any type of 
allograft dysfunction (primary nonfunction, early allograft dysfunction, extracorporeal 
detoxification). For this specific purpose, permutation tests will be used. 
Secondary parameter defined in the protocol as “the frequency of identification of 
laboratory examination values corresponding to early allograft dysfunction, 3 
days after the operation (Day 4 of the study drug administration)” will be 
summarize with appropriate descriptive statistics. 
The frequency of identification of laboratory examination values corresponding 
to early allograft dysfunction, 3 days after the operation (Day 4 of the study drug 
administration) will be presented with a descriptive statistic of laboratory ALT and AST 
deviations more than 2000 U/L for time point Day 3 by early allograft dysfunction event 
(EAD) (see Table 9.28). 
The incidence of early allograft dysfunction in case of transplantation of donor 
organs differing by the degree of steatosis and by the time of allograft removal 
from the donor and up to its reperfusion after engraftment (duration of cold and 
warm ischemia) will be presented with a descriptive statistic by the EAD. Data will be 
presented as a nominal data and continuous data. Each variable will be cut to ranges 
with an idea to have approximately equal counts of patients in each range. 
Reparixin and Control groups will be compared for each of the parameter (degree of 
allograft steatosis and duration of cold ischemia as nominal data) using Cochran-
Mantel-Hensel (CMH) test with control EAD (see Table 9.29 and Table 9.30). 
The incidence of early allograft dysfunction in transplantation from donors 
having additional adverse factors (infectious complication, death of the brain, 
hypotension, etc.), and with regard to the interval between the diagnosis of brain 
death and removal of liver graft from a donor (in the case of the death of brain of 
the donor) will be presented with a descriptive statistic by the EAD, but without 
statistical inferential tests (see Table 9.32). 
The incidence of early allograft dysfunction in transplant recipients with liver 
diseases of different etiology (viral, alcoholic, autoimmune, etc.) and with 
different baseline characteristics (age, activity of hepatitis B, kidney function, 
score in scales of end-stage liver disease (MELD), Child-Turcotte-Pugh, etc.) will 
be presented with a descriptive statistic by the EAD, but without statistical inferential 
tests (see Table 9.33). 
Time for normalization of liver function parameters (alanine aminotransferase, 
aspartate aminotransferase and bilirubin levels, gamma-glutamyltransferase, 
lactate dehydrogenase, etc.) after OLT. 
Target parameters defined as: ALT, AST, GGT, LDH, total bilirubin, conjugated bilirubin. 
For each of the patients at each time point a flag of normality for all enumerated 
laboratory parameters will be derived. ALL of parameters must be in normal ranges to 
have the flag settled as NORMAL. In case of missing values in any of the parameter 
total flag will be counted as ABNORMAL. 
Time from the OLT to the date of normalization of ALL enumerated parameters will be 
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presented with a Kaplan-Mayer curves and median with 95% CI (if possible). See 
Table 9.34 and Figure 9.3. 
The incidence of hyperacute, acute and chronic liver allograft rejection (defined 
by histological evaluation) will be presented with a descriptive statistic according to 
the CRF flags (page 51 “REPARIXIN INFUSION” and page 87 “PRIMARY REASON 
FOR ENDING PARTICIPATION IN THE STUDY”). Data from such two pages (51 and 
87) will be additionally checked for consistency. 
Binary data will be described by risk ratio (RR) and 95% CI estimates and treatment 
groups were compared by exact Fisher's test (Table 9.35). 
General survival and graft survival (“graft loss” will be qualified as an event for “graft 
survival”) within 1 year will be presented with Kaplan-Mayer curves and survival time 
median with 95% CI. Treatment groups will be compared using logrank test. 
7.3 
OTHER 
7.3.1 
Disposition of Subjects 
Disposition of all subjects (enrolled, randomized, discontinued) in analyzed population 
will be presented.  
7.3.2 
Demographic and baseline characteristics 
This data will be presented for MITT analysis set by treatments group. 
Continuous data will be presented with number of non-missing values, mean, standard 
deviation, median, minimal and maximal values.  
Nominal data will be presented with absolute and relative (percent) frequencies. 
Between groups continuous data will be compared using unpaired Student’s t-test (for 
normally distributed data) or Mann-Whitney test (for free distribution data). Between 
groups binominal data will be compared using Fisher exact test, for categorical data 
Mann-Whitney test will be used. 
7.4 
SAFETY ANALYSIS 
7.4.1 
Pharmacokinetics 
7.4.1.1 
Calculation of PK parameters 
PK  
Parameter 
Definition 
𝐴𝑈𝐶0−𝑡 
Area under the plasma concentration-time curve from time zero to 
time t (time of last quantifiable plasma concentration) of reparixin and 
metabolites. Will be calculated using the linear trapezoidal rule.  If all 
concentrations are below the limit of quantification (BLQ),  
𝐴𝑈𝐶0−𝑡 will be reported as zero. 
𝐴𝑈𝐶0−𝑡= ∑𝐶𝑛+ 𝐶𝑛−1
2
(𝑡𝑛−𝑡𝑛−1) 
𝐴𝑈𝐶0−∞
 * 
Area under the plasma concentration-time curve from time zero to 
infinity of reparixin and metabolites.  
𝐴𝑈𝐶0−∞= 𝐴𝑈𝐶𝑡+
𝐶𝑙𝑎𝑠𝑡
𝜆𝑧, 
where Clast is the estimated concentration at the last measurable 
concentration (if possible). 
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PK  
Parameter 
Definition 
𝐶𝑚𝑎𝑥 
Maximum plasma concentration of reparixin and metabolites. 
Maximum observed plasma concentration obtained by inspection of 
the data.  If all observations are BLQ, 𝐶𝑚𝑎𝑥 will be reported as zero. 
𝑇𝑚𝑎𝑥 
Time of maximum plasma concentration reparixin and metabolites. 
First time at which 𝐶𝑚𝑎𝑥 is observed and is obtained by inspection of 
the data.  If all observations are BLQ, 𝑇𝑚𝑎𝑥 will be reported as not 
determined (ND). 
𝜆𝑧 
Terminal phase rate constant of reparixin and metabolites. 
Estimated as the absolute value of the slope of a linear regression 
during the terminal phase of the natural-logarithm (ln) transformed 
concentration-time profile (if possible). 
𝑡1/2* 
Terminal half-life of reparixin and metabolites. 
𝑡1/2 =
ln⁡(2)
𝜆𝑧⁡(if⁡possible) 
𝐴𝑈𝐶0−𝑡/𝐴𝑈𝐶0−∞ 
Ratio of 𝐴𝑈𝐶0−𝑡 to 𝐴𝑈𝐶0−∞ 
100 ∗𝐴𝑈𝐶0−𝑡
𝐴𝑈𝐶0−∞
 
𝑉𝑧 
Volume of distribution of reparixin. 
𝑉𝑧=
𝐹𝐷
𝐴𝑈𝐶0−∞𝜆𝑧, 
where D – dose, F – fraction of dose absorbed (assumed F=1); 
𝐶𝐿 
Clearance of reparixin. 
𝐶𝐿=
𝐹𝐷
𝐴𝑈𝐶0−𝑡
 
*=if data permits 
 
PK parameters for reparixin and its metabolites (DF2243Y and ibuprofen) will be 
summarized using descriptive statistics for the safety population (see  
Table 9.36). 
“Spaghetti” diagrams example for PK data for all subjects will be graphed using 
nominal sampling time (Figure 1). 
 
 
 
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Mean and Median profiles will be graphed on linear and log-linear scales. For
summary graphs a nominal time will be used. For individual graphs a real PK sample 
time will be used.
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Figure 3 
Mean of concentration (log scale) by time 
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Similar graphics will be produced for concentration medians. 
7.4.2 
Adverse Events 
Adverse Events will be summarized by treatment groups for two periods – up to 12 
weeks after OLT and up to 1 year after OLT (all AEs/SAEs). 
Relation of AE to the therapy will be defined by AE onset date and period start date for 
the patient. All AEs will be coded with MEDDRA dictionary. AEs will be summarized by 
SOC (System Organ Class) and PT (Preferred Terms). 
AE frequencies will be compared between treatment groups. For such comparisons 
MedDRA Preferred Terms (PT) will be used. Treatment groups will be compared by set 
of frequencies of PT terms using permutation tests. One p-value will be provided (H0: 
treatment groups are equal in set of AE frequencies). 
7.4.3 
Laboratory Data 
Laboratory data will be summarized by treatment group as clinical relevance 
(normal/abnormal, without clinical relevance/ abnormal, with clinical relevance) and as 
continuous data (absolute values).  
All laboratory data and changes from baseline will be described as continuous 
variables at each visit.  
Additionally, deviations from the normal values and absolute values for ALT and AST 
parameters will be compared between treatment groups at day 0-7, 14, 28, 84 and 
168. 
Proportion of patients with total bilirubin <1.1 mg/dL in reparixin and control group at 
day 7, 14, 28, 84 and 168 will be described and compared using Fisher exact test. 
 
7.4.4 
Extend of exposure 
Total duration of Reparixin infusion (hours), total Reparixin dose (mg/kg/hours) and 
deviations in infusion time/dose will be presented by descriptive statistics. 
7.4.5 
Vital Signs Data 
Vital signs data such as blood pressure, heart rate and body temperature will be 
summarized as continuous data by treatment group.  
All vital signs data and changes from baseline will be described at each visit.  
7.4.6 
Physical Examination Data 
Physical examination data will be summarized as normal/abnormal data. 
Physical examination data will be compared between treatment groups as each time 
point using permutation tests. 
7.4.7 
Concomitant Treatments 
Concomitant therapy and immunosuppressive therapy during the study time will be 
summarized by treatment groups. Drugs will be presented by ATC groups as nominal 
data (absolute and relative frequencies).  
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7.4.8 
Listings 
Additionally, combined listings from the database will be presented for: 
 Laboratory data 
 Adverse events and serious adverse events data. 
Laboratory data listings will be presented with patient number, age of patient, study 
period, group of treatment and laboratory data with units and flag of clinically 
significant abnormalities. Separately the same format listing will be presented for 
laboratory data but for patients who had abnormal values. 
7.5 
CHANGES IN THE PLANNED ANALYSES 
Any changes in the planned statistical methods will be documented and justified in the 
Clinical Study Report. 
8. 
REFERENCES 
Permutation Tests methodology for the section 7.1 is described in: 
 Helmut Strasser & Christian Weber (1999). On the asymptotic theory of 
permutation statistics. Mathematical Methods of Statistics *8*, 220-250. 
 Torsten Hothorn, Kurt Hornik, Mark A. van de Wiel & Achim Zeileis (2006). A 
Lego System for Conditional Inference. The American Statistician, *60*(3), 
257-263. 
 Torsten Hothorn, Kurt Hornik, Mark A. van de Wiel & Achim Zeileis (2008). 
Implementing a class of permutation tests: The coin package, Journal of 
Statistical Software, *28*(8), 1-23. http://www.jstatsoft.org/v28/i08 
 
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9. 
TABLE EXAMPLES1 
Table 9.1 
Disposition 
 
Reparixin 
n (%) 
Control 
n (%) 
Enrolled subject 
xx 
xx 
Randomized subjects 
xx (xx.x%) 
xx (xx.x%) 
MITT Analysis Set 
xx (xx.x%) 
xx (xx.x%) 
Safety Analysis Set 
xx (xx.x%) 
xx (xx.x%) 
Completed Study per protocol 
xx (xx.x%) 
xx (xx.x%) 
Discontinued prematurely 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
   Graft loss 
xx (xx.x%) 
xx (xx.x%) 
      Hyperacute transplant rejection 
xx (xx.x%) 
xx (xx.x%) 
      Acute transplant rejection 
xx (xx.x%) 
xx (xx.x%) 
      Chronic transplant rejection 
xx (xx.x%) 
xx (xx.x%) 
      Other 
xx (xx.x%) 
xx (xx.x%) 
   Death 
xx (xx.x%) 
xx (xx.x%) 
   Lost to follow-up 
xx (xx.x%) 
xx (xx.x%) 
   Consent withdrawn 
xx (xx.x%) 
xx (xx.x%) 
   Investigator decision 
xx (xx.x%) 
xx (xx.x%) 
   Protocol violation, including non-compliance 
xx (xx.x%) 
xx (xx.x%) 
   Protocol entry criteria not met 
xx (xx.x%) 
xx (xx.x%) 
   Study is stopped by Sponsor decision 
xx (xx.x%) 
xx (xx.x%) 
   Study is stopped by regulatory authorities / ethics committee 
xx (xx.x%) 
xx (xx.x%) 
   Other 
xx (xx.x%) 
xx (xx.x%) 
   Pregnancy 
xx (xx.x%) 
xx (xx.x%) 
 
Table 9.2 
Demographic and other baseline characteristics.  
MITT Analysis Set. Screening (baseline). N = xx 
Parameter 
Reparixin 
N = XX 
Control 
N = XX 
p-value 
Age (years) 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Gender 
 
 
 
   Male 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
   Female 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Race 
 
 
 
   Caucasian 
xx (xx.x%) 
xx (xx.x%) 
 
   Other 
xx (xx.x%) 
xx (xx.x%) 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Height (cm) 
 
 
 
   N 
xx 
xx 
--- 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Weight (kg) 
 
 
 
   N 
xx 
xx 
--- 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min – Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Ideal weight (kg) 
 
 
 
   N 
xx 
xx 
--- 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
                                            
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Parameter 
Reparixin 
N = XX 
Control 
N = XX 
p-value 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
Severity of recipient’s liver disease 
 
 
 
   MELD index 
 
 
 
      N 
xx 
xx 
=== 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
      40 or more -- 71.3% mortality 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
      30-39 -- 52.6% mortality 
xx (xx.x%) 
xx (xx.x%) 
 
      20-29 -- 19.6% mortality 
xx (xx.x%) 
xx (xx.x%) 
 
      10-19 -- 6.0% mortality 
xx (xx.x%) 
xx (xx.x%) 
 
      <9 -- 1.9% mortality 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
   Child-Turcot 
te-Pugh 
 
 
 
      N 
xx 
xx 
--- 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
5-6 points - Grade А (least severe liver disease) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
7-9 points - Grade В (moderately severe liver disease) 
xx (xx.x%) 
xx (xx.x%) 
 
10-15 points - Grade С (most severe liver disease) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Liver disease etiology 
 
 
 
      Viral 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
      Alcohol 
xx (xx.x%) 
xx (xx.x%) 
 
      Autoimunne 
xx (xx.x%) 
xx (xx.x%) 
 
      Other 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Degree of allograft steatosis 
 
 
 
      N 
xx 
xx 
0.xxx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Adverse factors 
 
 
 
   Infectious complications 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
   Hypotension 
xx (xx.x%) 
xx (xx.x%) 
 
   Death of the donor's brain 
xx (xx.x%) 
xx (xx.x%) 
 
   Other 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Express HIV test 
 
 
 
   Negative 
xx (xx.x%) 
xx (xx.x%) 
--- 
   Positive 
xx (xx.x%) 
xx (xx.x%) 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
Table 9.3 
Creatinine clearance. MITT Analysis Set.  
Screening (baseline). N = xx 
Parameter 
Reparixin 
N = XX 
Control 
N = XX 
p-value 
CC (mL/min). Males 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
CC (mL/min). Females 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
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Table 9.4 
Medical history. MITT Analysis Set. Screening (baseline). N = xx 
  MedDRA System Organ Class term 
 
MedDRA Preferred term 
Severity 
Reparixin 
n (%) 
Control 
n (%) 
 
x (%) 
 
Y 
x (%) 
 
Y 
BODY SYSTEM CODE 
 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 1 
Mild 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 2 
Moderate 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
Table 9.5 
Ongoing diseases/diagnosis/abnormalities. MITT Analysis Set. 
Screening (baseline). N = xx 
  MedDRA System Organ Class term 
 
MedDRA Preferred term 
Severity 
Reparixin 
n (%) 
Control 
n (%) 
 
x (%) 
 
Y 
x (%) 
 
Y 
BODY SYSTEM CODE 
 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 1 
Mild 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 2 
Moderate 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
Table 9.6 
Immunosuppressive therapy. Safety Set. During the study. N = xx 
ATC code 
   Drug 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
  
 
  
Group 
 
 
   Total 
xx (xx.x%) 
xx (xx.x%) 
   DRUG (ATC) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
Table 9.7 
Concomitant medication. Safety Set. During the study.N = xx 
ATC code 
   Drug 
Reparixin 
n (%) 
N = XX 
Standard 
n (%) 
N = XX 
  
 
  
Group 
 
 
   Total 
xx (xx.x%) 
xx (xx.x%) 
   DRUG (ATC) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
Table 9.8 
Physical examination. Safety Set. N = xx 
Category 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
p-value 
Screening (baseline) 
 
 
0.xxx 
   Overall appearance 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
   Eyes, ears, nose, throat 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
   Neck (including thyroid) 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
.. 
 
 
 
Week 0. Day 0 (12 HRS) 
 
 
0.xxx 
… 
 
 
 
Week 0. Day 1 
 
 
0.xxx 
… 
 
 
 
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Category 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
p-value 
Week 0. Day 2 
 
 
0.xxx 
… 
 
 
 
 
Table 9.9 
Vital signs. Safety Set. N = xx 
 
Reparixin 
N = XX 
Control 
N = XX 
Screening (baseline) 
 
 
   Body temperature (°C) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
   HR (beats/min) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
   RR (/min) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
   Systolic blood pressure (Hg mm) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
   Diastolic blood pressure (Hg mm) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
Week 0. Day 0 
 
 
… 
 
 
Week 0. Day 0. Change from baseline 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
0.xxx 
0.xxx 
 
 
 
Week 0. Day 1 
 
 
… 
 
 
Week 0. Day 1. Change from baseline 
 
 
… 
 
 
 
Table 9.10 Urine pregnancy test (females only). Safety Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Screening 
 
 
      Positive 
xx (xx.x%) 
xx (xx.x%) 
      Negative 
xx (xx.x%) 
xx (xx.x%) 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Follow-up. Week 24 
 
 
      Positive 
xx (xx.x%) 
xx (xx.x%) 
      Negative 
xx (xx.x%) 
xx (xx.x%) 
      No data 
xx (xx.x%) 
xx (xx.x%) 
PPD


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Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
 
 
 
Follow-up. 1 year 
 
 
      Positive 
xx (xx.x%) 
xx (xx.x%) 
      Negative 
xx (xx.x%) 
xx (xx.x%) 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
Table 9.11 12-lead electrocardiography. Safety Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Screening (baseline) 
 
 
     Abnormal 
xx (xx.x%) 
xx (xx.x%) 
     Normal 
xx (xx.x%) 
xx (xx.x%) 
     No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Week 0. Day 1 (12 HRS) 
 
 
     Abnormal 
xx (xx.x%) 
xx (xx.x%) 
     Normal 
xx (xx.x%) 
xx (xx.x%) 
     No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Week 0. Day 2 
 
 
     Abnormal 
xx (xx.x%) 
xx (xx.x%) 
     Normal 
xx (xx.x%) 
xx (xx.x%) 
     No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Week 0. Day 4 
 
 
… 
 
 
Week 1. Day 7 
 
 
… 
 
 
 
Table 9.12 Viral loading (for patients with HBV and/or HCV).  
Safety Set. Screening. N = xx 
 
Reparixin 
N = XX 
Control 
N = XX 
Screening (baseline) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
Table 9.13 State of post-operative wound. Safety Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Week 0. Day 0 (12 HRS after OLT) 
 
 
     Better than usual 
xx (xx.x%) 
xx (xx.x%) 
     As ususal 
xx (xx.x%) 
xx (xx.x%) 
     Worse than ususal 
xx (xx.x%) 
xx (xx.x%) 
     Is difficult to define 
xx (xx.x%) 
xx (xx.x%) 
     No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Week 0. Day 1 
 
 
… 
 
 
Week 0. Day 2 
 
 
… 
 
 
 
PPD


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Table 9.14 Clinically significant changes in post-operative wound.  
Safety Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Week 0. Day 0 (12 HRS after OLT) 
 
 
     Bleeding 
xx (xx.x%) 
xx (xx.x%) 
     Hematoma 
xx (xx.x%) 
xx (xx.x%) 
     No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Week 0. Day 1 
 
 
… 
 
 
Week 0. Day 2 
 
 
… 
 
 
 
Table 9.15 Doppler abdominal ultrasonography. Safety Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Screening (baseline) 
 
 
     Abnormal 
xx (xx.x%) 
xx (xx.x%) 
     Normal 
xx (xx.x%) 
xx (xx.x%) 
     No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Week 0. Day 1 
 
 
… 
 
 
Week 0. Day 4 
 
 
… 
 
 
 
Table 9.16 Laboratory parameters. Hematology. Deviation from normal values. 
Safety Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control  
n (%) 
N = XX 
Screening (baseline) 
 
 
   Hemoglobin 
 
 
      CS deviation 
xx (xx.x%) 
xx (xx.x%) 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
   Leukocytes 
 
 
      CS deviation 
xx (xx.x%) 
xx (xx.x%) 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
Week 0. Day 1 
 
 
… 
 
 
 
Table 9.17 Laboratory parameters. Biochemistry. Deviation from normal 
values. Safety Set. N = xx 
Similar 
 
Table 9.18 Laboratory parameters. Hematology. Absolute values.  
Safety Set. N = xx 
 
Reparixin 
N = XX 
Control 
N = XX 
Screening (baseline) 
 
 
   Hemoglobin (g/L) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
   Leukocytes (109/ml) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
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Reparixin 
N = XX 
Control 
N = XX 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
Week 0. Day 0 
 
 
… 
 
 
Week 0. Day 0. Change from baseline 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
0.xxx 
0.xxx 
 
 
 
Week 0. Day 1 
 
 
… 
 
 
Week 0. Day 1. Change from baseline 
 
 
… 
 
 
 
Table 9.19 Laboratory parameters. Biochemistry. Absolute values.  
Safety Set. N = xx 
Similar 
 
Table 9.20 Biochemistry. ALT and AST deviation from normal values.  
Safety Set. N=XX 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
p-value1 
Screening and randomization (Day -1) 
 
 
 
   ALT 
 
 
0.xxx 
      Lower 
xx (xx.x%) 
xx (xx.x%) 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Higher 
xx (xx.x%) 
xx (xx.x%) 
 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
   AST 
 
 
0.xxx 
      Lower 
xx (xx.x%) 
xx (xx.x%) 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Higher 
xx (xx.x%) 
xx (xx.x%) 
 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
   Total bilirubin 
 
 
0.xxx 
      < 1.1 ng/mL 
xx (xx.x%) 
xx (xx.x%) 
 
      ≥ 1.1 ng/mL 
xx (xx.x%) 
xx (xx.x%) 
 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Study therapy (WEEK 0) Day 1 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 2 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 3 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 4 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 5 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 6 
 
 
 
… 
 
 
 
Study therapy (WEEK 1) Day 7 
 
 
 
… 
 
 
 
Follow-up (WEEK 2) 
 
 
 
… 
 
 
 
Follow-up (WEEK 4) 
 
 
 
… 
 
 
 
Follow-up (WEEK 12) 
 
 
 
… 
 
 
 
                                            
1 Mann-Whitney test 
PPD


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Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
p-value1 
Follow-up (WEEK 24) 
 
 
 
 
Table 9.21 Biochemistry. ALT and AST absolute values comparison. 
Safety Set. N=XX 
 
Reparixin 
N = XX 
Control 
N = XX 
p-value1 
Screening and randomization (Day -1) 
0.xxx 
   ALT (U/L) 
 
 
 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
   AST (U/L) 
 
 
 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Study therapy (WEEK 0) Day 1 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 2 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 3 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 4 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 5 
 
 
 
… 
 
 
 
Study therapy (WEEK 0) Day 6 
 
 
 
… 
 
 
 
Study therapy (WEEK 1) Day 7 
 
 
 
… 
 
 
 
Follow-up (WEEK 2) 
 
 
 
… 
 
 
 
Follow-up (WEEK 4) 
 
 
 
… 
 
 
 
Follow-up (WEEK 12) 
 
 
 
… 
 
 
 
Follow-up (WEEK 24) 
 
 
 
… 
 
 
 
 
Table 9.22 Extend of exposure. Safety Set. N = XX 
 
Reparixin 
N = XX 
Reparixin infusion duration (hours) 
 
      N 
xx 
      Mean (SD) 
xx.x (xx.x) 
      Median 
xx.x 
      Min – Max 
xx.x – xx.x 
 
 
Total Reparixin dose (mg/kg/hours) 
 
      N 
xx 
      Mean (SD) 
xx.x (xx.x) 
      Median 
xx.x 
      Min - Max 
xx.x – xx.x 
 
 
Reparixin infusion stopped prematurely 
 
   No 
xx (xx.x%) 
   Yes 
xx (xx.x%) 
      An allergic reaction to Reparixin 
xx (xx.x%) 
      Complications related to the surgery (OLT) 
xx (xx.x%) 
      … 
 
                                            
1 ANOVA or Mann-Whitney test 
PPD


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Table 9.23 Early allograft dysfunction. MITT Set. N = xx 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Has early allograft dysfunction been determined within 7 days after OLT? 
   No 
xx (xx.x%) 
xx (xx.x%) 
   Yes 
xx (xx.x%) 95% CI [xx.x%; xx.x%] 
xx (xx.x%) 95% CI [xx.x%; xx.x%] 
   p-value 
 
0.xxx 
   
 
 
      ALT > 2000 U/L 
xx (xx.x%) 
xx (xx.x%) 
      AST >2000 U/L 
xx (xx.x%) 
xx (xx.x%) 
      Total bilirubin > 10 mg/dl 
xx (xx.x%) 
xx (xx.x%) 
      INR ≥ 1.6 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
      Resolved 
xx (xx.x%) 
xx (xx.x%) 
      Ongoing 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Median time to early allograft dysfunction 
    Median time 
xx.x 95% CI [xx.x; xx.x] 
xx.x 95% CI [xx.x; xx.x] 
    p-value 
 
0.xxx 
 
Figure 9.1 Time to early allograft dysfunction. MITT Set. N = XX 
 
 
Table 9.24 Early allograft dysfunction. PP Set. N = xx 
Similar 
 
Figure 9.2 Time to early allograft dysfunction. PP Set. N = XX 
Similar 
 
0
50
100
150 
0.0 
0.2 
0.4 
0.6 
0.8 
1.0 
Hours
PPD
·--:-, 
: 
I 
: 
I 
: 
I 
: 
__ ;-~, 
: 
I 
: 
I 
: 
I ·-, 
·--l+ l+, 
I 
I 
'··: 
I '--+, 
I 
I 
I 
I 
I 
I 
I "--
~; 
----+ 


Statistical Analysis Plan 
 
 
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Table 9.25 Efficacy assessment. MITT Set. N = XX 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Has primary nonfunction been determined within 7 days after OLT? 
   No 
xx (xx.x%) 
xx (xx.x%) 
   Yes 
xx (xx.x%) 
xx (xx.x%) 
   p-value 
 
0.xxx 
 
Has allograft dysfunction been determined within 14 days after OLT? 
   No 
xx (xx.x%) 
xx (xx.x%) 
   Yes 
xx (xx.x%) 
xx (xx.x%) 
   p-value 
 
0.xxx 
   
 
 
Specify signs of allograft nonfunction 
      Primary nonfunction allograft 
xx (xx.x%) 
xx (xx.x%) 
      Early allograft dysfunction 
xx (xx.x%) 
xx (xx.x%) 
      Extracorporeal detoxification 
xx (xx.x%) 
xx (xx.x%) 
      p-value 
 
0.xxx 
 
PPD


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Table 9.26 Logistic model of early allograft dysfunction and related risk 
factors. MITT Set. N = XX 
For the statistician’s decision 
 
Table 9.27 Survival within 1 year. MITT Set. N = XX 
 
Reparixin 
n (%) 
N = XX 
Control 
n (%) 
N = XX 
Patient survival 
   Median 95% CI 
xx (xx.x%) 95% CI [xx.x%; xx.x%] 
xx (xx.x%) 95% CI [xx.x%; xx.x%] 
   p-value 
 
0.xxx 
   
 
 
Graft survival 
   Median 95% CI 
xx (xx.x%) 95% CI [xx.x%; xx.x%] 
xx (xx.x%) 95% CI [xx.x%; xx.x%] 
   p-value 
 
0.xxx 
 
Table 9.28 ALT/AST > 2000 U/L and Early allograft dysfunction detected. MITT 
Set. N=XX 
Parameter 
Reparixin 
n (%) 
N = xx 
Control 
n (%) 
N = xx 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
Study therapy (WEEK 0) Day 3 
 
 
 
 
   ALT  2000 U/L 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   AST  2000 U/L 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   ALT and AST  2000 U/L 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
 
Table 9.29 Early allograft dysfunction and potential prognostic factors. 
MITT Set. Nominal data. N=XX 
Parameter 
Reparixin 
n (%) 
N = xx 
Control 
n (%) 
N = xx 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
Degree of allograft steatosis 
  0-10%1 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  10-30% 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  30-50% 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
p-CMH 
0.xxx 
 
 
 
Duration of cold ischemia 
   less than 5 hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   (5,6]2 hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   (6,7] hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   more than 7 hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
p-CMH 
0.xxx 
 
 
 
Duration of warm ischemia 
   less than 30 minutes 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   (30-45] minutes 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   (45-60] minutes  
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   more than 60 minutes 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
p-CMH 
0.xxx 
 
 
 
 
                                            
1 Right side is included (xx, xx]. 
2 Right side is included (xx, xx]. 
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Table 9.30 Early allograft dysfunction and potential prognostic factors. 
MITT Set. Continuous data. N=XX 
Parameter 
Reparixin 
N = xx 
Control 
N = xx 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
Degree of allograft steatosis (%) 
   N 
xx 
xx 
xx 
xx 
   Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Duration of cold ischemia (hours) 
   N 
xx 
xx 
xx 
xx 
   Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Duration of warm ischemia (hours) 
   N 
xx 
xx 
xx 
xx 
   Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
Table 9.31 Early allograft dysfunction and additional adverse factors. MITT 
Set. Nominal data. N=XX 
Parameter 
Reparixin 
n (%) 
N = xx 
Control 
n (%) 
N = xx 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
Infectious complication 
  No 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
  Yes 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
  No data 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
Death of the brain 
  No 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
  Yes 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
  No data 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
Hypotension 
  No 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
  Yes 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
  No data 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
Other 
 
 
 
 
   Other 1 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
   Other 2 
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%) 
   … 
 
 
 
 
 
Table 9.32 Early allograft dysfunction and interval between the diagnosis of 
brain death and removal of liver graft from a donor (in the case of the death 
of brain of the donor). MITT population. Nominal data. N=XX 
Parameter 
Reparixin 
n (%) 
N = xx 
Control 
n (%) 
N = xx 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
less than 1 hour 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
(1,2] hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
(2,3] hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
(3,4] hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
(4,6] hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
(6,8] hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
more than 8 hours 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
 
PPD


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Table 9.33 Early allograft dysfunction in transplant recipients with liver 
diseases of different etiology and with different baseline characteristics. 
MITT Set. Nominal data. N=XX 
Parameter 
Reparixin 
n (%) 
N = xx 
Control 
n (%) 
N = xx 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
Viral disease etiology 
  No 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  Yes 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  No data 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
Alcoholic disease etiology 
  No 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  Yes 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  No data 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
Autoimmune disease etiology 
  No 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  Yes 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
  No data 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
Other disease etiology 
 
 
 
 
   Other 1 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   Other 2 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   … 
 
 
 
 
Age of recipient (years) 
   N 
xx 
xx 
xx 
xx 
   Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
HBV and/or HCV virus loading at screening Day -1 
   N 
xx 
xx 
xx 
xx 
   Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
Creatinine clearance at screening Day -1 (mL/min) 
   N 
xx 
xx 
xx 
xx 
   Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
Severity of recipient’s liver disease. MELD index 
   <9 - 1.9% mortality 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   10-19 - 6.0% mortality 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   20-29 - 19.6% mortality 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   30-39 - 52.6% mortality 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   40 or more - 71.3% mortality 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
Severity of recipient’s liver disease. Child-Turcotte-Pugh 
   5-6 points 
   Grade А 
   (least severe liver disease) 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   7-9 points 
   Grade В 
  (moderately severe liver disease) 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
   10-15 points 
   Grade С 
   (most severe liver disease) 
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)   
 
Table 9.34 Time from the OLT normalization of liver parameters. 
MITT Set. N = xx 
Parameter 
Repariin 
Control 
Early allograft dysfunction detected 
Early allograft dysfunction detected 
No 
Yes 
No 
Yes 
Median with 95% CI1 
xx.x [xx.x; xx.x] 
xx.x [xx.x; xx.x] 
xx.x [xx.x; xx.x] 
xx.x [xx.x; xx.x] 
 
                                            
1 if possible 
PPD


Statistical Analysis Plan 
 
 
TPL-RPX-01 
 
CONFIDENTIAL 
Final Version 3.0 
 
Page 32 of 34 
Figure 9.3 Time from the OLT normalization of liver parameters. 
MITT Set. N = xx1 
 
 
Table 9.35 Hyperacute, acute and chronic transplant rejection (determined by 
biopsy). MITT Set. N = XX 
Hyperacute or acute transplant rejection (determined by biopsy) 
Reparixin 
n (%) 
N = xx 
Control 
n (%) 
N = xx 
Hyperacute or acute transplant rejection 
xx (xx.x%)   
xx (xx.x%)   
Relative risk Reparixin/Control with 95% CI 
 
xx.x [xx.x; xx.x] 
p-value (Fisher) 
 
0.xxx 
 
 
 
Chronic transplant rejection 
xx (xx.x%)   
xx (xx.x%)   
Relative risk Reparixin/Control with 95% CI 
 
xx.x [xx.x; xx.x] 
p-value (Fisher) 
 
0.xxx 
 
 
 
Hyperacute or acute or chronic transplant rejection2 
xx (xx.x%)   
xx (xx.x%)   
Relative risk Reparixin/Control with 95% CI 
 
xx.x [xx.x; xx.x] 
p-value (Fisher) 
 
0.xxx 
 
                                            
1 Figure is generated for illustration purposes only 
2 All cases acute or hyperacute or chronic 
0.00
0.25
0.50
0.75
1.00
0
250
500
750
1000
time
surv
strata
trt=Treatment 1, EAD=No 
trt=Treatment 1, EAD=Yes
trt=Treatment 2, EAD=No 
trt=Treatment 2, EAD=Yes
PPD
-+-
-+-
-+-
-+-


Statistical Analysis Plan 
 
 
TPL-RPX-01 
 
CONFIDENTIAL 
Final Version 3.0 
 
Page 33 of 34 
Table 9.36 PK data summary. Safety Set. (N = xx) 
Parameter 
Reparixin 
DF2243Y 
Ibuprofen 
AUC0-t 
 
 
 
   N 
xx 
xx 
xx 
   CV (%) 
xx% 
xx% 
xx% 
   Mean (SD; SE) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
100 * AUC0-t/AUC0-∞ 
 
 
 
   N 
xx 
xx 
xx 
   CV (%) 
xx% 
xx% 
xx% 
   Mean (SD; SE) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
Cmax 
 
 
 
   N 
xx 
xx 
xx 
   CV (%) 
xx% 
xx% 
xx% 
   Mean (SD; SE) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
Tmax 
 
 
 
   N 
xx 
xx 
xx 
   Median 
xx.xx; xx.xx; xx.xx 
xx.xx; xx.xx; xx.xx 
xx.xx; xx.xx; xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
t½ (hours-1) 
 
 
 
   N 
xx 
xx 
xx 
   Mean (SD; SE) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
Vz 
 
 
 
   N 
xx 
xx 
xx 
   Mean (SD; SE) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
CL 
 
 
 
   N 
xx 
xx 
xx 
   Mean (SD; SE) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
xx.xx (xx.xx; xx.xx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
   Min; Max 
xx.xx; xx.xx 
xx.xx; xx.xx 
xx.xx; xx.xx 
 
 
 
 
 
 
Table 9.37 Adverse Events (AE/SAE). Up to 12 weeks after OLT. Safety Set. N 
= xx 
  MEDDRA System Organ Class term 
 
MEDDRA Preferred term 
Reparixin 
n (%) 
Control 
n (%) 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
 
Preferred term 1 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
 
Preferred term 2 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
p-value = 0.xxx 
 
Table 9.38 Adverse Events (AE/SAE). Up to 1 year after OLT (all registered). 
Safety Set. N = xx 
PPD


Statistical Analysis Plan 
 
 
TPL-RPX-01 
 
CONFIDENTIAL 
Final Version 3.0 
 
Page 34 of 34 
Similar 
 
Table 9.39 Adverse Events (AE/SAE) and severity. Up to 12 weeks after OLT. 
Safety Set. N = xx 
  MEDDRA System Organ Class term 
 
MEDDRA Preferred term 
Severity 
Reparixin 
n (%) 
Control 
n (%) 
 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
 
Preferred term 1 
Mild 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
 
Preferred term 2 
Moderate 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
 
Table 9.40 Adverse Events (AE/SAE) and severity. Up to 1 year after OLT (all 
registered). Safety Set. N = xx 
Similar 
 
Table 9.41 Adverse Events and relation to study drug(s). Up to 12 weeks 
after OLT. Safety Set. N = xx 
Similar 
 
Table 9.42 Adverse Events and relation to study drug(s). Up to 1 year after 
OLT (all registered). Safety Set. N = xx 
Similar 
 
PPD