Clinical trial NCT00224406
Conditions: Ischemia-Reperfusion Injury Lung Transplantation
Keywords: Lung transplantation Reperfusion Injury Survival
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2005-05-01; Completion date: 2007-09-13
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical study was to evaluate whether CXCL8 (CXC ligand 8 \[formerly interleukin (IL)-8\]) inhibition with repertaxin leads to reduced severity of primary graft dysfunction, as the result of improved functional and clinical outcomes in lung transplantation patients.

The safety of repertaxin in the specific clinical setting was also evaluated.

The ability of repertaxin to reduce target cells (polymorphonuclear leukocyte \[PMN\]) infiltration into the graft was evaluated to confirm its mechanism of action.

Detailed description:
This was a phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group (two arms) study.

A total of 100 patients accepted and listed for lung transplantation, who met all of the study inclusion and none of the exclusion criteria described in Sections 9.3.1 and 9.3.2 of this report, were planned to be enrolled in the study. These patients were randomly assigned in a 1:1 ratio to receive either repertaxin or placebo, by continuous intravenous infusion for a period of 48 hours to start approximately 2 hours before reperfusion of the (first) transplanted lung occurred.

The experimental treatment was additional to the standard treatment of lung transplant recipients.

An initial 'loading dose' of repertaxin of 4.488 mg/kg body weight/hour was to be administered over 30 minutes followed by a maintenance dose of 2.772 mg/kg body weight/hour lasting 47.5 hours.

Placebo was to be volume matched saline. Total infusion volume was not to exceed 500 mL/24 hours. Study medication was to be provided as clear glass class I ampoules, each containing 10 mL of the following products: repertaxin (33 mg/mL aqueous injectable solution) and placebo (9 mg/mL aqueous injectable solution of NaCl).

The double-blind was to be maintained for the main part of the study only, i.e. up to the Month 1 (at least 30 days post-transplant) follow-up visit of the last patient in. After database lock of Month 1 data the study proceeded in an open fashion.

Arms: arm 1: Both repertaxin and placebo were aqueous solutions packaged into identical clear glass Type I ampoule single dose units. Each ampoule contained 10 mL of either repertaxin or placebo.The dosing solution for infusion was prepared aseptically at the designated Pharmacy within each center and dispensed as 12.65 mg/mL solution in appropriate size infusion bags. An initial 'loading dose' of Repertaxin of 4.488 mg/kg body weight/hour was administered over 30 minutes followed by a maintenance dose of 2.772 mg/kg body weight/hour lasting 47.5 hours.The loading and maintenance doses were administered using the same dosing solution (Repertaxin 12.65 mg/ml), but with the pump rate altered to provide an infusion rate of approximately 0.35 mUkg/hour and 0.22 ml/kg/hour, respectively. arm 2: Both repertaxin and placebo were aqueous solutions packaged into identical clear glass Type I ampoule single dose units. The dosing solution for infusion was prepared aseptically at the designated Pharmacy within each center and dispensed as 12.65 mg/mL solution in appropriate size infusion bags. ampoule contained 10 mL of either repertaxin or placebo. An initial 'loading dose' of 9 mg/ml sodium chloride (NaCl) solution was administered over 30 minutes, followed by a maintenance dose lasting 47.5 hours.
Interventions: intervention 1: Repertaxin intervention 2: Placebo
Intervention descriptions: intervention 1: An initial 'loading dose' of repertaxin was administered over 30 minutes by intravenous infusion followed by a maintenance dose lasting 47.5 hours.The infusion was to start approximately 2 hours prior to the anticipated time of reperfusion and was to continue during the ICU/hospital stay. The study medication was administered as a continuous intravenous infusion into a (high flow) central vein, by an infusion pump adequate to provide reliable infusion rates , as per treatment schedule. Total infusion volume was not to exceed 500 mL/24 hours. intervention 2: An initial 'loading dose' of placebo was administered over 30 minutes by intravenous infusion followed by a maintenance dose lasting 47.5 hours.The infusion was to start approximately 2 hours prior to the anticipated time of reperfusion and was to continue during the ICU/hospital stay. The placebo was administered as a continuous intravenous infusion into a (high flow) central vein, by an infusion pump adequate to provide reliable infusion rates , as per treatment schedule. Total infusion volume was not to exceed 500 mL/24 hours.

Protocol documents:
Prot_000.pdf: 
Study REPO 104 
Repertaxin in Lung Transplantation 
Page 1 of73 
PPD 
CLINICAL STUDY PROTOCOL • CONFIDENTIAL 
Study Number: 
Investigational Product: 
Title: 
Protocol Version 
Date of protocol: 
REP0104 
Repertaxin 
A phase 2, multi-center, randomized, double-blind, placebo-
controlled, parallel-group study of repertaxin in the 
prevention of primary grafi dysfunction after lung 
transplantation. 
Final Revision No. 3 
20 March 2006 
This protocol results from revision of "Final Revised Protocol No. 2 (30 August 2005)" 
according to Amendment No. 2 dated 20 March 1006. 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential 
information that is the property of Dompé pha.r.ma s.p.a. lt is understood that the 
information will not be used, divulged, or published without prior written consent of Dompé, 
except to the extent such disclosure is requìred by applicable laws and regulations. 
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Study REP0104 
Repertaxin in Lung Transplantation 
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CONTACTINFORMATION 
SPONSOR 
Dompé pha.r.ma s.p.a. [Dompé] 
Via Campo di Pile; 67100 L'Aquila, Italy 
Milan Offices: Via S. Martino 12-12/ A, 20122 Milan, Italy 
Phone: +39 02 583831; Fax: +39 02 58383324 
Medicai Director, 
Coordinator 
Clinical Trial Manager 
CLINICAL RESEARCH 
ORGANIZATION 
Project Leader 
Pharmacovigilance 
Contact 
PD 
PD 
PRIMARY INVESTIGATOR PPD 
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Study REP0l04 
Repertaxin in Lung Transplantation 
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INVESTI GATOR A GREEMENT SIGNATURES: 
CLINICAL CENTER: PRlNCIPAL lNVESTIGATOR 
I have read study protocol REP0104 "A phase 2, multi-center, randomized, double-blind, 
placebo-controlled, para11el-group study of repertaxin in the prevention of primary graft 
dysfunction after lung transplantation" and agree to conduct the study as outlined in the 
protocol, and in accordance with ICH-GCP and any local regulations. 
Name of Principal Investigator: 
Signa ture: 
Date: 
PROTOCOL APPROVAL SIGNATURES: 
DOtvfPÉ 
PPD 
Signing of this page of the protocol by the Sponsor and CRO indicates that the protocolformat and content have 
been agreed arul approved by both partìes; and that it ìs agreed that no further changes to the protocol are 
required at the time of sìgning. 
A plzotocopy of thi!t fully signed page will be provided to all participatitig fovestigational Sites for filing. 
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Study REP0104 
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TABLE 014"' 
CONTENTS 
1. 
STUDY SYNOPSIS AND OVERALL DESIGN ................................................ 
9 
2. 
BACKGROUND INFOR.l\1A 
TION ................................................................... 
12 
2.1. 
RELEV ANT PRE-CLINICAL RESULTS ........................................................... 12 
2.2. 
A SUMMARY OFTOXICOLOGY DATA ......................................................... 13 
2.3. 
A SUMMA.RY OFPHASE 1 DATA .................................................................... 14 
2.4. 
DISEASE REVIEW AND STUDY RATIONALE .............................................. 15 
2.4.1. 
Selectìon of dose and treatment schedule in the study .......................................... 16 
2.4.2. 
Alternative treatments ............................................................................................ 17 
2.4.3. 
Risk - benefit evaluation ........................................................................................ 17 
3. 
OVERALL STUDY DESIGN AN'D PLAN DESCRIPTION .......................... 19 
3.1. 
STUDYDESIGN .................................................................................................. 19 
3.2. 
STUDYTIME TABIB ......................................................................................... 19 
4. 
OB.JECTIVES AND ENDPOINTS .................................................................... 
20 
4.1. 
STlJDY OBJECTIVES ......................................................................................... 20 
4.2. 
STUDYENDPOINTS ........................................................................................... 20 
4.2.1. 
Efficacy endpoints ................................................................................................. 20 
4.2.2. 
Mechanism of action-targeted endpoints ............................................................... 21 
4.2.3. 
Pharmaco.kinetic endpoints .................................................................................... 21 
4.2.4. 
Safety endpoints ..................................................................................................... 21 
5. 
STUDY PO PULA TI ON .......................................................................................................
22 
5.1. 
lNCLUSION CRIIBRIA ...................................................................................... 22 
5.2. 
EXCLUSION CRITERIA ..................................................................................... 22 
5.3. 
ASSIGNMENT OFPATIENT NUMBER ............................................................ 23 
6. 
Srf"UDY 
MEDICA1"'ION 
.......................................................................................................
24 
6.1. 
PRESENTATION, STO RAGE, PAC.K.A.GING AND LABELING ..................... 24 
6.1.1. 
Presentation of Investigational Products ............................................................... 24 
6.1.2. 
Receipt of drug at the center/Stability during shipment ........................................ 24 
6.1.3. 
Preparatìon of the Dosing So!ution ........................................................................ 25 
6.1.4. 
Storage/Stability of Investìgational Products ........................................................ 25 
6.1.5. 
Packaging/Labeling of Investigatìonal Products ................................................... 25 
6.1.6. 
Blinding ................................................................................................................. 26 
6.2. 
DOSE, ROUTE AND SCHEDULE OF INVESTIGATIONAL PRODUCT 
AD:tv1INJSTRA.TION 
............................................................................................. 26 
6.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION/ 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT ........................... 27 
6.3.l. 
Criteria for schedule adjustment or dose modification .......................................... 27 
6.3.2. 
Criteria for discontinuation of Investigational Product ......................................... 27 
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6.4. 
ACCOUNT ABILITY ............................................................................................ 
28 
6.4.1. 
Assessment of compliance ..................................................................................... 29 
6.5. 
CONCOMITANTTIIBRAPY .............................................................................. 29 
6.5.1. 
Immunosuppressive therapy .................................................................................. 29 
6.5.2. 
Prophylaxis of opportunistic ìnfections ................................................................. 30 
6.5.3. 
Other treatrnents ..................................................................................................... 30 
7. 
STUDY PROCEDURE ANO ASSESSMENTS ................................................ 31 
7 .1. 
SCREENING AND RANDOMIZATION ............................................................ 31 
7.2. 
7.3. 
7.4. 
7.5. 
7.5.1. 
7.5.2. 
7.5.3. 
7.6. 
7.7. 
7.8. 
7.9. 
7.10. 
7.10.1. 
7.10.2. 
8. 
8.1. 
8.1.1. 
8.1.2. 
8.2. 
8.3. 
8.3.1. 
8.3.2. 
8.3.3. 
8.3.4. 
8.4. 
8.4.1. 
8.4.2. 
8.4.3. 
8.5. 
9. 
9.1. 
ORGAN PROCUREMENT .................................................................................. 32 
OPERATIVE COlJRSE ........................................................................................ 32 
ADMli'l"ISTRATION OF INVESTIGATIONAL PRODUCT IN THE 
OPERATIN'G ROOM ............................................................................................ 33 
ADMISSION 1'0 rc·u ........................................................................................... 33 
Arri val to the ICU .................................................................................................. 33 
Assessment in the ICU ........................................................................................... 33 
\Veaning mechanical ventilation ............................................................................ 34 
ICU DISCHARGE - HOSPIT AL STA Y .............................................................. 35 
DRUG ADMINISTRATION Ll\f THE ICU/HOSPITAL AND BLOOD 
SAIVIPLING FOR PHARNIACOKINETIC ASSA Y ............................................ 35 
MONTH 1 POST-TRANSPLANT ....................................................................... 35 
MONTHS 6 AND 12 POST-TRANSPLANT ....................................................... 36 
EARLY PATIENT WITHDRA W AL ................................................................... 36 
Withdrawal cri te.ria ................................................................................................ 36 
Replacement policy ............................................................................................... 36 
AD'1"ERSE EVENTS ........................................................................................... 38 
DEFINITIONS ...................................................................................................... 38 
Definiti on of an Ad verse Event ............................................................................. 38 
Definiti on of a Serious Adverse Event .................................................................. 38 
E:tvfERGENCY PROCEDURES ........................................................................... 38 
.RECORDlNG ........................................................................................................ 39 
AE reporting peri od ............................................................................................... 39 
Relatìonship of AEs to the InvestigationaJ Product. .............................................. 39 
Seve1ity of AEs ...................................................................................................... 40 
Frequency of AEs .................................................................................................. 40 
SERIOUS AD VERSE EVENT REPORTll~G ...................................................... 40 
Reporting Procedure for Investigators to PPD 
................................................. 
40 
Reporting Procedure for Investigators to IRB/REB ............................................. .41 
Reporting Procedure for Regulatory Authorities .................................................. .41 
DATA MONITORINO COMMlTTEE ................................................................. 41 
STA T.ISTICAL ISSUES ...................................................................................... 43 
SAl\.1PLE SIZE ...................................................................................................... 43 
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9.2. 
9.3. 
9.4. 
9.4.1. 
9.4.2. 
9.4.3. 
9.4.4. 
9.4.5. 
9.4.6. 
10. 
10.1. 
10.2. 
10.3. 
10.4. 
11.. 
11.1. 
11.2. 
11.3. 
11.4. 
11.5. 
12. 
12.1. 
12.2. 
12.3. 
12.3.1. 
12.4. 
12.5. 
12.6. 
12.7. 
13. 
14. 
14.1. 
14.1.1. 
14.1.2. 
14.1.3. 
14.2. 
RANDOMIZATION ............................................................................................. 43 
ANAL YSIS POPULATION ................................................................................. 43 
STATISTICAL METHODOLOGY ...................................................................... 44 
Demographic and baseline characteristics ............................................................. 44 
Primary efficacy analysis ....................................................................................... 44 
Secondary efficacy analysis ................................................................................... 45 
Analysis of the endpoint targeted to the mechanism of action .............................. 45 
Analysis of pharmacok.inetic endpoints ................................................................. 45 
Safety analysi.s ....................................................................................................... 46 
ETHICAL CONSIDERATIONS ....................................................................... 47 
L~STITUTIONAL REVIEW BOARD/RESEARCH ETHICS BOARD ............. 47 
INFORMED CONSENT ....................................................................................... 48 
CONFIDENTIALITY ........................................................................................... 48 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND 
INDElVIN'IFICATION ........................................................................................... 48 
DATA HANDLJNG AND RECORD KEEPING ............................................. 50 
CASE REPORT FOR.MS COìvlPLETION ........................ , .................................. 50 
DATA 1/fANAGEMENT ...................................................................................... 50 
DOCUME~1T ATI ON REQUIRED PRIOR TO INITIATION ............................. 51 
DOCUMENTATION REQUIRED DURINO THE STUDY ............................... 51 
ESSENTIAL DOClJMENT RETENTION ........................................................... 52 
STlJDY ~IANAGEl\lIBNT .................................................................................. 
53 
REGULATORY BODY APPROVAL. ................................................................. 53 
STAFF Il\1FORMATION & RESPONSIBILITIES .............................................. 53 
MO~TIORlNG ...................................................................................................... 53 
Access to records ................................................................................................... 54 
AUDIT AND IN"SPECTION ................................................................................. 54 
PROTOCOL DEVIATIONS/AMENDMENTS .................................................... 54 
DISCONTINUATION OF THE STUDY ............................................................. 54 
PlJBLICATIONS ................................................................................... , .............. 55 
REFEREN CES .................................................................................................... 56 
APPENDICES ...................................................................................................... 59 
APPEl'{DIX 1 - 11:ETHODOLOGICAL DET AILS .............................................. 59 
PGD score - ISHL T system for grading of severity of primary graft 
dysfunction [ Christie et al, 2004] .......................................................................... 59 
Bronchoalveolar la vage methods ........................................................................... 59 
Handling of samples for pharmacokinetic assay ................................................... 60 
APPENDL'X 2-PACKAGING AL'ID LABELJ.i'.TG 
DETAILS ............................. 62 
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14.3. 
APPENDIX 3 - STUDY DRUG INFUSION RATE BY BODY WEIGHT ......... 66 
14.4. 
APPENDIX 4 - STUDY FLOW CHART ............................................................. 69 
14.5. 
APPENDIX 5 - WORLD MEDICAL ASSOCIA TION DECLARATION 
OF lIBLSlL~KI. ...................................................................................................... 70 
14.6. 
APPENDIX 6 - ACCEPTABLE TIME WINDOWS POR ASSESSMENTS/ 
PROCEDURES ..................................................................................................... 73 
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Study REP0104 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ALT 
AE 
ADR 
A.i--iOVA 
AST 
AUC 
BAL 
BOS 
BP 
oc 
CLcr 
Cmax 
CO 
CRA 
CRF 
Css 
CVP 
CXCL8 
DGF 
DMC 
EMEA 
ESRD 
FDA 
FEV1 
Fi02 
FVC 
g 
GCP 
HR 
ICH 
ICU 
IND 
IRB/REB 
ISHLT 
Ì.V. 
kg 
mg 
mL 
mml-Ig 
ng 
NSAID 
PA 
Pa02 
PCWP 
PEEP 
PGD 
PMN 
p.o. 
PVR 
SAE 
s.c. 
SOP 
Sp02 
SVR 
t½ 
~tg 
UNOS 
Alanine Aminotransferase 
Ad verse Event 
Adverse Drug Reaction 
Analysis ofVariance 
Asparlate Aminotransferase 
Area Under the Curve 
Bronchoalveolar Lavage 
Bronchioli.tis Obliterans Syndrome 
Blood Pressure 
Degrees Celsius 
Calculated Creatinine Clearance (Cockcroft - Gault formula) 
Maximum Plasma Concentration 
Cardiac Output 
Clinica! Research Associate 
Case Report Form 
Steady State Concentration 
Right Atrial Pressure 
CXC ligand 8 [formerly interleukin (IL)-8] 
Delayed Graft Function 
Data Monitoring Committee 
European Medicines Evaluation Agency 
End Stage Rena! Disease 
Food and Drug Adrninistration 
Forced Expiratory Volume in One Second 
Fraction of Inspired Oxygen 
Forced Vital Capacity 
Grams 
Good Clinica! Practice 
Heart Rate 
Internatìonal Conference on Hannonization 
Intensive Care Unit 
Investìgational New Drug 
Instìtutìonal Review Board/Research Ethics Board 
International Society of Heart and Lung Transplantation 
Intravenous 
Kilogram 
Milligram 
Millilitre 
Millimeters mercury 
Nanogram 
Non Steroidal Anti-Inì1ammatory Drug 
Pulmonary Artery 
Partial Pressure of Arteria! Oxygen 
Pulrnonary Capillary Wedge Pressure 
Positive End Expiratory Pressure 
Primary Graft Dysfunction 
Polymorphonuclear leukocyte 
per os (taken by mouth) 
Pulmonary Vascu!ar Resistance 
Serious Adverse Event 
Subcutaneous 
Standard Operating Procedure 
Peripheral Oxygen Saturation 
Systemic Vascular Resistance 
Elìrnination half life 
Microgram 
United Network for Organ Sharing 
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Page 8 of 73 


Study REP0104 
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Page 9 of73 
1. 
STUDY SYNOPSIS AND OVERALL DESIGN 
Study title 
A phase 2, multi-center, randornized, double-blind, placebo-controlled, parallel-group study 
of repertaxin in the prevention of primary graft dysfunction after lung transp]antation. 
Study Number REP0104 
Study period 
Study design 
Actua1 starting date (first-patient-in): 1 May 2005 
Projected completi on of patient accrual (last-patient-in): September 2006 
Projected study end date (last-patient-last-visit): September 2007 
The study will be a phase 2, multi-center, randomìzed, double-blind, placebo-controlled, 
parallel-group (two arms) study. It will involve 100 lung transplant recipients. 
Objectives/endpoints 
The objectìve of this clinìcal trial is to evaluate whether CXCL8 inhibition with repertaxin 
leads to reduced severity of PGD. The safety of repertaxin in the specìfic clìnical setting will 
be also evaluated. 
Ptimary efficacy endpoint will be: PaO2/FiO2 ratio measured on ICU admission and at 24 
hours after ICU admission. 
, 
Secondary efficacy endpoints will be: the time profile of Pa0 2/FiO2 ratio (ICU adrnission, 
then q24 hours up to extubation or up to 72 hours; addìtional data obtained as per center 
standard of care will be collected in patients wìth clinica) diagnosis of PGD up to the clinica I. 
recovery of the condition); PGD score (ICU admission, 24 hours, 48 hours, and 72 hours after 
ICU admission; in patients with clinical diagnosis of PGD additional scoring will be 
calculated up to the clinica) recovery of the condition from available data); time to freedom 
from mechanical ventilation; duration of ICU stay; ICU mortality; mortality in the first 30 
days post-transplant; FEV 1 and FVC at month 1, 6, and 12 post-transplant; BOS score at 
month 6 and 12 post-transplant; cumulative acute rejection episodes at month 6 and 12 post-
transplant; patient survival rate evaluated at month 6 and 12 post-transplant. Any additional 
information from BAUbiopsies performed according to center standard of care in patients 
with clinica! diagnosis of PGD will be collected up to the clinical recovery of the condition. 
PMN count in BAL specimen obtained during mechanical ventìlation, in the inter-val between 
12 and 24 hours after reperfusion will be evaluated as a "mechanism of action-targeted" 
endpoint. Also. plasma levels of repe1iaxin and its major metabolite, DF2243Y, will be 
evaluated at steady state conditions (24±6 hours and 48 hours from the start of infusion) and 
then in the interval 2-6 hours after the end of drug infusjon. 
Safety endpoints will be; AE recordìng; standard laboratory tests performed at screening and 
at hospital discharge; vita} signs (BP & HR) evaluated at screening, at ICU admission and 
then q12 hours up to ICU discharge or up to 5 days after ICU admission; cardiopulmonary 
physiologic measurements (CO, PA pressure, SVR, PVR, PCWP, CVP), when PA catheter is 
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Study REP0l04 
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present, at ICU admission and then q12 hours up to ICU dìscharge or up to 5 days after ICU 
admìssion. 
Additiona1 cardiopulmonary data obtained as per standard of care will be 
collected in patients with clinical dìagnosis of PGD up to the clinica} recovery of the 
conditi on. 
Number of patients One-hundred patients undergoing single or bilatera} lung transplant. 
Inclusion/exclusion criteria 
Patients accepted and listed for transplantation (planned isolated lung transplant from a non-
livìng donar with brain death), ages 18-65 years, body weight 30-95 kg, given written 
informed consent will be included. Patient must have normai renai function (as per calcu.lated 
creatinìne clearance 
60 mUmin). 
Patients will be excluded if they are: recipients of an intended multiple organ transp1ant, 
including heart-lung and liver-lung transplantation; recipients of a lung from a living lobar 
donor or a Iung from a non-heart beatìng donor; recipìents of a re-do lung transplantatìon. 
Patients requiring mechanical ventilation at the time of transplant, or with extra-respiratory 
tract site of infection, or with hepatic dysfunction at the time of transpla.nt, or with 
hypersensitivity to ibuprofen orto more than one NSAID, orto medìcations belonging to the 
class of sulfonamides wìll be excluded as well. Also, patients planned to receive Orthoclone 
OKT3 or Campath induction immunosuppression or planned to receive sirolìrnus in the first 
three months after transplantation, or simultaneously participating in any other studies 
ìnvolving a study drug to be administered concomitantly with the Investìgational Product 
and/or a study dmg intended to prevent ischemia/reperfusìon injury will be excluded. 
Pregnant or breast feeding women will be exc]uded. 
Investigational drug 
Repertaxin: 33 mg/mL aqueous injectable solution of repertaxin (per single 10 m.L ampoule). 
Placebo: 
9 rng/rnL aqueous injectable solution of sodium chloride (NaCI) (per single 10 
mLampoule) 
For each 24 hour administration period, a dosing soJution will be prepared from the contents 
of 23 ampoules (230 mL), cliluted with 370 mL of 0.9 % sterile saline. 
The study drugs wìll be administered as a contìnuous i.v. infusion into a (high flow) central 
vein, by an infusion pump, starting approximately 2 hours before reperfusion of the (first) 
transplanted lung occurs. 
An initial 'loading dose' of repertaxin of 4.488 mg/kg body 
weight/hour will be administered over 30 min followed by a maintenance dose of 2.772 
mg/kg body weight/hour lasting 47 .5 hours. Placebo will be volume matched saline. Total 
infusion volume wìll not exceed 500 mU24 hours. 
Statistics 
Data for the double-blind (maìn) phase of the study (up to 30 days post-treatment) will be 
presented in the clinica] study report. Data collected during the open phase of the study (from 
l month up to 12 months) will be presented in an addendum to the cHnica1 study report. 
Appropriate descriptive statistics will be produced, accordìng te the variable. 
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Study REPO 104 
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The ptimary endpoint will be analyzed by ANOV A and separate comparisons at two time 
points (O hours on ICU admission and 24 hours after ICU admission). 
Appropriate descriptive statìstics wilJ be produced for all secondary endpoints. Inferential 
tests will be applied only to PaOi/FiO2 ratio, PGD Score, time to freedom from mechanical 
ventilati on and durati on of ICU stay. 
Safety data will be presented with the appropriate desc1iptive statistics. 
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Study REP0104 
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2. 
BACKGROUNDINFORMATION 
Repertaxin (DF1681 Y) is a specific inhìbitor of CXC lìgand 8 [CXCL8; fo1merly interleukin 
(IL)-8) bio]ogìcal activity, stemming from a program of drug design of molecules intended to 
modulate chemokine action. 
Repertaxin is the first low molecula:r weight blocker of CXCL8 biologica! activity jn clinical 
development. 
Dompé is currently committed to evaluating the clinical use of repertaxin in the prevention of 
Delayed Graft Function (DGF) after solid organ transplantations, a clinical condition that can 
be consìdered a paradìgrn of ischernìa/reperfusion injury. 
Repertaxin received the orphan drug designation by the European Committee of Orphan 
Medicinal Products in September 2001 and by the Food and Drug Administrntion (FDA) in 
January 2003 for such clinica! condition. In the 4th quarter of 2003, Dompé has obtained 
protocol assistance by the European Medicines EvaJuation Agency (EN.lEA) for the 
development of repertaxin, and a pre-Investìgation New Drug (IND) meeting was held with 
the Food and Drng Administration (FDA) to discuss IND submission. 
Relevant pre-clinical, toxicological and phase 1 clini e al data are summarized below. Please 
also referto the Investigator's Brochure for more detailed information. 
As mentioned in the Investigator's Brochure, all previous non clinical and clinica! (phase 1) 
studies were performed with the lysine salt of repertaxin. Repertaxin (free acid) formulated in 
a lysine buffer will be used for this phase 2 Clinical Trial. In order to allow a readi1y-
accessed infonnation and easy understanding of the study protocol, any doses of the 
experimental drug mentioned in this protocol are reported as repertaxin. 
2.1. 
RELEV ANT PRE-CLINICAL RESULTS 
Repertaxin is in vitro a potent and specific inhibitor of CXCL8 biologica} activity. In vitro 
chemotaxis experiments have shown that repertaxin inhibits CXCL8-induced chemotaxis of 
human polymorphonuclear leukocytes (PMN) in the low nanomolar range. Studies to elucidate 
the mechanism of action have shown that repertaxin is a non-competitive allosteric inhibitor 
of the CXCL8 receptors CXCRl and CXCR2. 
Interaction of repertaxìn with CXCL8 
receptors inhibits the intracellular signal transduction events activated by binding of CXCL8 
to CXCRI and CXCR2 [Bertini, 2004; Souz,a, 2004]. 
In vivo, treatment of rats with repertaxin lysine sa1t prevented PJ\,1N infìltration ìnto the 
reperfused transplanted kìdney and reduced kidney damage, as assessed by an increase in 
serum creatinine Levels. Moreover, repertaxìn prevented PMN infiltration and tissue damage 
in animai models of ischemia/reperfusion injury of lìver, brain, intestine, heart and spinal 
cord. In these models, repertaxin inhibition of PMN recruitment ranged from 40 to 90%, and 
inhìbìtion of functional damage ranged from 50 to 80%. Efficacy was seen in all rnodels at 
repertaxin dose of 9 .90 mg/kg. 
More recently, repertaxin 1ysine salt has been evaluated in a rat model of lung transplantation. 
Doses of repertaxin of 9.90 and 19.80 mg/kg given i.v. 15 nùn before and s.c. 2 and 4 hours 
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after the reperfusion, reduced PMN infiltration, along with organ damage (]ung edema) and 
functional impainnent (decreased PaO2) induced by ischemia/reperfusion. 
The phannacokinetics of repertaxin was evaluated after i.v. or p.o. single dose in rats, after 
i.v. single dose in dogs and after i.v. repeated bolus or i.v. continuous infusìon as part of 
toxicity studìes in both species. In rats, repertaxin is rapidly eliminated with a half-lìfe (tiri) 
of between 0.5 and 3 hours. lt is elìminated mainly by rnetabolism with negligible amounts of 
parent compound excreted in the urine. Phaimacokinetìcs were linear over a wide range of 
doses in rats. In dogs, a different pharmacokinetic profile was observed, i.e. repertaxin was 
less rapidly eliminated (t 112 12-28 hours) both after single bolus i.v. administration and i.v. 
continuous infusion. 
Metabolic studies inclicated the presence of 8 and 10 metabolites in rats and dogs, 
respectively. Ibuprofen is an expected mìnor metabolite. 
Repertaxin inhibited in vitro the isoenzymes CYP3A4 and, to a minor extent, CYP2Cl9. A 
phase I metabolism study of [14C]-repe1taxin indicated that repertaxin is catalysed by 
CYP2C9 and to a lesser extent by CYP2Cl 9 with the production of two major metabolites. 
In vitro protein bincling of [14C]-repertaxìn showed that repe1taxin is highly bound 
(approxirnately 99%) to plasma proteins in rats, dogs, rabbits, cynomolgus monkeys and 
humans. Albumìn ìs likely to be the mirjor binding protein in plasma in ali species. 
2.2. 
A SlTh'lMARY OF TOXICOLOGY DATA 
Repeitaxin was tested for toxicity in rodent and non-rodent anima! species after single and 
repeated ì.v. doses. 
The repeated dose administration studies were conducted by i.v. 
continuous infusion, according to the foreseen human admìnistratìon route. 
The genera] toxicological profile of i.v. repertaxin, in the studies conducted to date, is 
characterized by a low toxicity after sìngle or repeated dose administrations in rats (L.Dso = 
229.68 mg/kg i.v.; 660.00 mg/kg/day as No Observed Adverse Effect Level from 4 weeks 
studies) and mice (401.94 mg/kg i.v.). Continuous i.v. administration to dogs for 2 weeks 
resulted in a safe dose of 39.60 mg/kg/day. 
Continuous i.v. infusion of repettaxin to the male and fema1e rat at dose levels of up to 660.00 
mg/kg/day did not have any sìgnificant adverse effects on mating performance and fertilìty. 
Repertaxìn poses no genotoxìc hazard for humans. 
Repertaxin lysine salt, at doses in excess of those intended to be used in humans, has a safe 
pharmacology profile in the renal, cardiovascular and respiratory systerns of rats and dogs. 
The locai tolerabìlity of repertaxin lysine salt was assayed in the rabbit ear lateral vein. The 
compound was well tolerated in concentrations up to 4.95 mg/mL (1 mlJkg) infused over a 
minute. 
In order to provide evidence of the safety of DF2243Y, the main metabolite of repertaxin 
excreted in urine in hurnans, safety pharmaco1ogy and toxicity studies have been ìmplemented 
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at doses 2 to 3 tirnes higher that those reached in man, as may occur during the treatment of 
patients receiving kidney transplantation. 
2.3. 
A SUJ\t1MARY OFPHASE 1 DATA 
Four phase 1 pharmacokinetics/safety studies have been implemented: three healthy 
volunteers studies have been completed, and one study is ongoing in patients with chronic 
renal disease. 
In the first study _, 
single doses of repertaxin of 0.66 to 10.56 mg/kg were 
administered by 30-min i.v. infusion. Each dose group consisted of 4 subjects treated wìth 
repertaxin and 2 with placebo. The compound was well tolerated at all doses, with minor and 
unspecific adverse events that were not dose-related. Repertaxin peak plasma concentrations 
were achieved at approximately 30 min post-dose. Linear kinetics were observed over the 
dose range of 0.66-5.28 mg/kg. Repertaxin was eliminated from plasma with a terminal half-
life ranging from 0.94 to 1.28 hours. Total body clearance and volume of distribution 
appeared to be ìndependent of dose. Unchanged repertaxin was unmeasurable in urine and a 
very small amount was excreted in the f eces over 72 hours. 
In a second study -
repertaxin was adminìstered as 48-hour i.v. infusions of doses 
targeted to achieve repertaxin plasma steady state concentrations (Css) of 10, 20 and 30 
µ,g/mL. Three dose levels were administered: 2.05 mg/kg/h x 30 min fo1lowed by 0.66 
mg/kg/h x 47.5 h; 2.51 mgfk.g/h x 30 min followed by 1.32 mg/kg/h x 47.5 h; and 4.49 
mg/kg/h x 30 min fotlowed by 2.77 mg/kg/h x 47.5 h. Twelve subjects (9 active, 3 placebo) 
were dosed in each dose level. These treatment schedules were chosen in order to closely 
mimi e the possible dose regimen to be used in efficacy trials. Plasma levels of repe11axin, and 
its metabolites ibuprofen, DF2243Y and DF2188Y were determined. Repettaxin free fraction 
appeared to increase with total concentration. 
Elimination from plasma was rapid with 
terminal half-Iìfe of approximately 1.2-1.5 hours. The pham1acokinetics of repertaxin did not 
appear to be Jinear, with total clearance and volume of distribution increasing with dose, 
while maximum plasma concentration (Cmax) and area under the curve (AUC) appeared to be 
less than dose proportional. Repertaxin was metabolized and excreted into urine as ibuprofen 
(about 1 % of the dose), DF2243Y (30-40% of the dose), DF 2188Y (18-25% of the dose) and 
methanesulfonamide (10-12% of the dose). Renal clearance for repertaxin and ibuprofen was 
dose-dependent, but not for DF2243Y and DF2188Y. The total recovery of rnetabolites in 
urine accounted far 60-75% of the admìnistered dose. Repertaxin and ibuprofen were 
detectable in the feces over 60 hours at very low arnounts and only in few subjects. The 
metabolite DF2188Y had a terminal half-life similar to repertaxin, while tenninal half-lives 
for ibuprofen and DF2243Y were longer than that for repertaxin, suggesting elimination-rate 
limited pharmacokinetics for these two metabolìtes. Overall, the pharmacok.inetic profiles of 
repertaxin and its major metabolites are sirrrilar in rats and humans. Repertaxìn was well 
tolerated again, resulting in adverse events that were minor and not dose related. The local 
reactions observed have been reduced by administering a more dilute solution at a higher 
infusion rate. The study showed that, in healthy volunteers, the proposed dose regimen that 
gives rise to target concentrations expected to be clinically effective is feasible, reproducible 
and safe. 
A third study -
was performed to verify whether repertaxin, at plasma 
concentrations egual to or exceedìng that thought to be required for therapeutic efficacy, 
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Study REP0104 
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could affect drug metabolism through CYP3A4 and CYP2C9 ìn a clinically significant 
manner. 
No clinically significant pharrn.acokinetic interaction was observed between 
repertaxin and rnidazolam or tolbutamide, probe substrates for CYP3A4 and CYP2C9 
respectively. Repertaxin free fraction appeared to increase by at least 50% over the infusion 
period, after mìdazolam/tolbutarnide co-adminìstration, while tota! repertaxin concentrations 
remained stable. 
The fourth study design -
was implemented to obtain initial information on the 
safety and phannacokinetics of repertaxìn in subjects with renal impairment by exposing a 
very few subject.s with the most severe degree of renai impairment, i.e. patients with end stage 
renal disease (ESRD) undergoing hemodìalysis (stage A) to a limited dose of the compound. 
After determìning appropriate dosing for renal failure, a more complete evaluation of the 
safety and phannacokinetics of repertaxin was obtained by administering the appropriate dose 
to a representative number of subjects with various degrees of renal impairment and to male 
and female heaJthy volunteers (stage B). 
A dose of 1.32 mg/kg/h for 6 hours by i.v. 
continuous infusion is being adminìstered in both ESRD patients and healthy volunteers. 
Results obtained indicate that the pharmacokinetics profile of repertaxin is not influenced, as 
expected, by the degree of renai function. On the other hand, rena] function had a profound 
effect on plasma concentrations of the two major metabolites, which were found to increase 
over time along with the increase of the e]imination half-life. Based upon the .limited number 
of subjects there appears to be no apparent gender differences in the phannacokinetics profile 
of repertaxin and its metabolites. Repertaxin was well tolerated also in ESRD patients. Very 
few adverse events were reported, the majority of which was mìld in intensity and unlikely 
due to repe1taxìn. 
2.4. 
DISEASE REVIE'\iV 
AND STUDY RA TIONALE 
Lung transplantation has become a standard therapy for patients with end-stage lw1g disease. 
Within last decades, donor management, organ preservation, immunosuppressive regimens 
and controJ of infectious complications have been substantially improved. In addition, the 
operative techniques of transplantation procedures have been developed to an intemational 
standard of high quality [Lau & Patterson, 2003]. 
However, despite these refinernents, significant reperfusion injury occurs in up to 10-20% of 
Iung transplant recipients as the consequence of unavoìdable processes of procurement, 
preservation and restoring bJood flow. This clinica! condition, recently termed primary graft 
dysfunction (PGD), remains an important problem after lung transplantation [Christie, 1998; 
King, 2000], and still represents the single bìggest cause of early morbidity and mortality for 
lung recipients [Fischer, 2001; Thabut. 2002]. In additi on, there is some evidence to suggest 
a relationship between repe1fusìon ìnjury, acute rejection, and the subsequent development of 
chronic graft dysfunction [Waddell, 1996; Fìser, 2002]. 
Prediction of PGD is made difficuJt by the complexity of the interactions between the donor 
lung and the recipient [Sommers, 1996; McRae, 2000]. 
In post-ischemia reperfusion, restoration of the blood supply (reperfusion) after prolonged 
tissue ischemia is associated with an inflammatory reaction characterized by massive 
polymorphonuclear neutrophil infiltration into the reperfused tissue [de Perrot 2003]. The 
infiltrating inflammatory cells can perpetuate the initial inflarnmatory reactìon and induce 
further injuries. 
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Study REP0104 
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CXCL8 is a member of a class of chemokines involved in leukocyte recruitment and 
activatjon in tissues [Baggiolini, 1994]; this chemokine is believed to play a key role in the 
recruitment and activation of polymorphonuclear neutrophils in post-ischemia repe.rfusion 
injury [Welbourn, 1991; Lefer, 1991; Matsumoto, 1997]. The importance of CXCL8 in lung 
tissue during the ischemie time and after reperfusion has been clearly demonstrated. 
Reperfusion of ischemie lung in a rabbit model of lung reperfusion injury caused neutrophil 
infiltration and tissue damage, as well as a local production of CXCL8. The admìnistration of 
a neutralizing monoclonal antibody against CXCL8 prevented neutrophil infiltration and 
tissue injury, providing a causal role of locally-produced CXCL8 in this model [Sekido, 
1993]. The release of CXCL8 early after reperfusion could initiate neutrophil recruìtment and 
thus induce secondary lung injury [de Perrot, 2002]. 
As a resu1t of these findings, the modulati on or inhibition of CXCL8 acti vity ìs considered a 
valid target for the development of innovative treatments for a vaiiety of severe clinical 
conditions, including ischemia/reperfusion injury occurring after solid organ transplantation. 
No cmTently avai1able pharmacological treatments are intended to cure or to prevent the 
occurrence of ischemia/reperfusion injury after lung transplantation. The current standard of 
care in preventing this clinica} condition focuses on prevention by way of surgical techniques 
in the procurement, storage and implantation of grafi lungs. 
The efficacy of repertaxin in preventing polymorphonuclear neutrophil infiltration and tissue 
damage in rat models of kidney transplantation and lung transplantation, as well as the safety 
shown in human phase 1 studìes, provide the rationale for a clinical study aimed at evaluating 
the effect of repertaxìn in preventing PGD after lung transplantation. 
2.4.1. 
Selection of dose and treatment schedule in the study 
"In vitro", repertaxin inhibits CXCL8-induced chemotaxis of human PMN wìth an ICso of 1 
nM, corresponding to about 0.3 ng/mL. 
CXCL8 ìs a key mediator of P:tvll'-i infiltration (and hence of tissue damage) in post-
ischemia/reperfusion injury. 
In anima! models of ischemia/reperfusion, CXCL8 (and 
corresponding proteins in animals) is upregulated in the reperfused tissue within minutes from 
reperfusion, peaks after 4-6 hours and drops to undetectable levels within 24-48 hours from 
reperfusion [Sekido, 1993; Yamaguchi, 2000; Miura, 2001; Morita, 2001; DeVries, 2003]. 
Repe1taxin lysine sa.lt was tested in several anirnal models of ischemia/reperfusion. 
Repertaxin was admìnistered either by repeated bolus treatments (s.c. and/or i.v.) or by 
continuous i.v. infusion and was paired with observations of PMN infiltration and assessment 
of tissue damage (routineJy 24 hours after reperfusion). In both circumstances, repertaxin 
treatment was started before reperfusion occurred. For convenience and ease of treatment of 
animals, most expetiments were carried out by repeated bolus treatments. 
In repeated bolus treatments, repertaxìn was most efficacious in inhibiting PMN infiltratìon 
and reducing tissue damage in the reperfused tissue at doses ranging from 9.90 to 19.80 
mg/kg. Furthennore, there was no overt increase in efficacy at doses of 19.80 vs. 9.90 mg/kg. 
At the dose of 9.90 mg/kg, Cmax of total plasma repertaxin was 34 ~tg/rnL, corresponding to 
68 ng/mL of protein unbound (free) repertaxin. 
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Study REP0104 
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In continuous i.v. infusion animai experiments, repertaxin was found to be efficacìous at total 
plasma concentrations of 15 and 3.6 µg/mL, corresponding to 140 and 10 ng/mL of protein 
unbound (free) repertaxin, respectìvely. Repertaxìn was less efficacious at 0.5 ~tg/mL tota! 
repertaxin, corresponding to approx. 1-2 ng/mL of protein unbound drug. 
Although repertaxin was efficacious in animals when given either by repeated boluses or by 
continuous i.v. infusion, the proposed treatment in humans will be by continuous infusion in 
order to expose target cells (polymorphonuclear neutrophils) to steady state concentrations in 
the pharmacological range, thus maximizing the pharmacological activity. It should also be 
emphasized that repertaxin ìs a reversible inhibitor of CXCRI/2 activation induced by 
CXCL8 and that repertaxin has a short plasma ha]f Jife (0.95 to 1.28 hours in humans). 
The proposed dose in this clinical study was found safe in -previous phase l studies and should 
produce total plasma concentrations of 30 µg/mL, coITesponding to 30 ng/mL of protein 
unbound (free) repertaxin. Thus, the target plasma concentration of repertaxin obtainable in 
patients with the proposed dose ìs in the range found efficacious in both in vitro studies of 
CXCL8 inhibition and in animai rnodels of ischemia/reperfusion. The proposed schedule of 
administration (48 hours) is intended to expose the patient to repertaxin for the lag time when 
CXCL8 is believed to be upregulated in ischemia/reperfusion [Sekido, 1993; Yamaguchi, 
2000; Miura, 2001; Monta, 2001; DeVries, 2003]. 
2.4.2. 
Alternative treatments 
Because there is no other standard of care pharmacologic agent to prevent or treat PGD, 
patients not willing to participate in the study will not be offered any specific alternative 
treatment for the prevention of ischemia/reperfusion 
injury. Ali patients, regardless of study 
participation, will receive the standard of optimal care for the transplanted organ 
(procurement, storage, reperfusion) and the recipìent. 
Treatment of lung dysfunction, jncJucling the use of supporti ve measures, as well as overall 
management of lung transplant recipients will be the same, regardless of partìcipation in the 
study, 
2.4.3. 
Risk - benefit evaluation 
2.4.3.1. 
Treatment-related risks 
Results from preclinical studies support the level of drug exposure planned in this study. 
Furthennore, the sarne dose regimen that is proposed for this study has been tested in healthy 
volunteers without observing any significant, systemic adverse events. 
The tisk of toxicity at the infusion site, reported in a cohort of volunteers adrninistered by i.v. 
infusion via a peripheral vein, will be minimized by administe1ing the experimental drug via a 
high flow centrai vein. 
2.4.3.2. 
Centrai line 
The study dmg will be adrninistered as a continuous i.v. infusion aver 48 hours with a 
catheter inserted in a (high flow) centra! vein. The risks of a central line are not considered 
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Stud y REPO 104 
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study-related risks since preliminary survey reveals that centrai line will be routinely placed in 
all patients undergoing lung transplantation for their clirucal care. This clinically required 
access line will be maintained for a period of time that is longer than that required for the 
administration of the Investigational Product. Centrai line care as routinely practiced by the 
participating sites will mìnimize the risk of thrombosis and infections. 
2.4.3.3. 
Bronchoalveolar Lavage 
Broncoalveolar lavage (BAL) is an invasive procedure used to monitor emerging problems in 
lung transplant recipients. A BAL specimen wiII be obtaìned from all study patients on 
mechanical ventilation, in the interval between 12 and 24 hours after reperfusion, to explore 
the repe11axin effect in reducing target cells polymorphonuclear neutrophil trafficking. To 
nùnimize the additional risk of the stucly specific BAL, the procedure will not be performed in 
patients with any clinical conditions which would be worsened by BAL procedures, accorcling 
to the Investigator's judgment. 
2.4.3.4. 
Blood sampling 
In addition to the routine blood sa:mpling, participation in the study will require three 
pharmacological blood samplings (18 mL total), to detennine plasma concentrations of 
repertaxin (total and unbound) and its major metabolite, DF2243Y, in the specific clinical 
setting. Blood sampling will be performed at steady state conditions (24±6 hours and 48 hours 
from the start of infusion) and then in the interval 2-6 hours after the end of infusion. To 
maintain the study blind, blood samples will be obtained from all patients recruited in the 
study. 
Moreover, the study will require additional blood samplings at 12, 24, and 36 hours after the 
beginning of Investigational Product administration, to ensure that rena] and hepatic function 
are compatible with the ongoing jnvestigational treatment. 
2.4.3.5. 
Other study relateci procedures 
No other procedures specifically related to the study are required. The specific timing of some 
measurements such as blood gas measurements will be guided by the protocol, but such 
measurements are firmly entrenched as pare of standard patient care and would undoubtedly 
be perforrned regardless of study partici patì on. 
2.4.3.6. 
Potential benefit 
To the patients: It is qui te likely that there will be no direct benefit to individual patients 
participating in the trial. Half the patients will be receiving placebo and will 
therefore obtain no benefit other than the potential benefit of increased 
scrutiny and monito1ing that comes with being part of a clinical ttial The 
patients receiving the Investigational Product may possibly benefit with 
improved early lung function, but that is not certain. 
To society: 
This study may identify a useful medication that will make lung 
transplantation safer and more effecti ve for future recipients. 
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3. 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION 
3.1. 
STUDY DESIGN 
The study will be a phase 2, multi-center, randomized, double-blind, placebo-controlled, 
parallel-group (two arms) study. 
It wil1 involve 100 lung transplant recipients, randomly assigned in a 1:1 ratio to receive 
repertaxin or placebo, by contìnuous i.v. infusion for a per:iod of 48 hours starting 
approximately 2 hours before reperfusion of the (first) transplanted Iung occurs. 
The 
experimental treatment will be additional to the standard treatment of lung transplant 
recipients. 
Recruitment will be competitive among the study sjtes, unti I the planned number of patients is 
enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and to 
account for any difference in t:ransplant rate among study sites. 
Each patient will be involved in the study for 48 hour treatment, for measurements up to 
hospital discharge, and then for three visits (@ 1, 6, and 12 months post-transp1ant). 
The double-blind will be maintained for the main part of the study only, i.e. up t:o the 1 rnonth 
(at least 30 days post-transplant) follow-up visit of the last patient in. After database lock the 
randonnzation code will be broken and the results of the blìnd phase will be analyzed and the 
study will proceed in an open fashion. 
3.2. 
STUDY TIME TABLE 
• 
Actual starting date (first-patient-in): 
• 
Projected completion of patient accrual (last-patient-in): 
• 
Projected study end date (last-patient-last-visit): 
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Study REP0104 
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4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
STUDY OBJECTIVES 
The objective of this clinical trial is to evaluate whether CXCL8 inhibition with repertaxin 
leads to reduced seve1ity of PGD, as the result of improved functional and clinical outcomes 
in lung transplantatìon patìents. The safety of repertaxin in the specific clinical setting will be 
also evaluated. 
The ability of repertaxin to reduce target cells (PMN) infiltration into the graft will be 
evaluated to confinn its mechanism of action. Plasma levels of repertaxin and its major 
metabolite will be measured at steady state conditions to provide population pharmacokinetic 
profile in this specìfic clinical setting. 
4.2. 
STUDY ENDPOINTS 
4.2.1. 
Efficacy endpoints 
4.2.1.1. 
Prirnary efficacy endpoint 
• 
Pa02/FiO 2 ratio measured at FiO2 = 1 during mechanical ventìlation on ICU admission 
(time O) and at 24 hours after ICU admission. Patients on FiO2 < 1 will be tumed back 
to FiO2 = l for 5 minutes before gas measurement. 
4.2.1.2. 
Secondary efficacy (exp1oratory) endpoints 
• 
Time profile of PaO2/FìO2 ratio measured at FiO2 = 1 during mechanical ventilation at 
four potential time points: ICU admission (time O) and then q24 hours, up to extubation 
or up to 72 hours after ICU admission, whichever occurs earlier. 
Additional data 
obtained as per center standard of care will be collected in patients with clinical 
diagnosis of PGD up to the clinica! recovery of the conditi on. 
• 
PGD score (stratified by single or bilateral transplant), evaluated accordìng to the 
scming system described by Christie et al. of the working group on primary lung graft 
dysfunction in the Scientific Council on Pulmonary Transplantation, Intemational 
Society for Hea1t and Lung transplantation (2005; see Appendix 1 for methodological 
details). Specific planned comparison of PGD scores will be made at four time points: 
ICU admission (time O), 24 hours, 48 hours, and 72 hours after ICU admissìon. In 
patients with clinical diagnosis of PGD additional scoring will be calculated up to the 
clinica! recovery of the condition from available data as per center standard of care. 
• 
Time to freedom from mechanical ventilation, defined as time between admissjon to the 
ICU and the initial time of first extubation (breathing off mechanical venti lati on without 
a tube) which is maintained far more than 24 hours. 
• 
Duration ofICU stay. 
• 
ICU mortality, defined as vita] status at the ICU dìscharge. 
• 
Mortality, defined as any death occurring in the first 30 days post-transplant, regardless 
of hospital discharge. 
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Study REP0104 
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• 
FEV1 and FVC (stratìfied by single or bilatera] transplant) measured at month 1, 6, and 
12 post-transplant. 
• 
BOS score (stratified by single or bilateral transplant) evaluated according to Estenne et 
al. (2002). BOS score will be measured at month 6, and 12 post-transplant. 
• 
Cumulative acute rejection episodes, biopsy proven, evaluated accordìng to Yousem et 
al. (1996) at month 6 and 12 post-transplant. 
• 
Patient survival rate evaluated at month 6 and 12 post-transplant. 
• 
Any additional infonnation from BAUbiopsies pe1formed according to standard of care 
in patients with clinica} diagnosis of PGD will be collected up to the clinica! recovery of 
the condition. 
4.2.2. 
Mechanism of action-targeted endpoints 
• 
PMN count in BAL specimen obtained during mechanical ventilation, in the interval 
between 12 and 24 hours after reperfusion. 
4.2.3. 
Pharmacokinetic endpoints 
• 
Plasma Jevels of repertax.in (tota! and unbound) and its major metabolite, DF2243Y, at 
steady state conditions (24±6hours and 48 hours from the start of infusion) and then in 
the interval 2-6 hours after the end of study drug infusi on. 
4.2.4. 
Safety endpoints 
• AE recording. 
• 
Standard laboratory tests including hematology (hematocrit, hemoglobin, red blood 
cells, platelets, white blood cells, differential white blood cells count), and clinical 
chenùstry (sodium, chloride, potassium, bicarbonate, serum creatinine, blood urea 
nitrogen, total bilirubin, alanine arn.inotransferase (ALT), aspartate aminotransferase 
(AST), prothrombin time or intematìonal normalized ratio, partial thromboplastin time). 
Laboratory tests will be performed at screening and at hospital discharge. 
• 
Vita] signs, i.e. blood pressure (BP) and heart rate (HR), assessed at screening, on ICU 
admission, and then q 12 hours up to ICU discharge or up to 5 days after ICU ad.missi on, 
whichever occurs earlier. 
• 
Cardiopulmonary physiologic measurements, ìncluding cardiac output (CO), pulmonary 
artery pressure (PA pressure), systemic vascular resìstance (SVR), pulmonary vascular 
resjstance (PVR), pulmonary capillary wedge pressure (PCWP), right atrial pressure 
(CVP). Assessment will be perfonned on ICU admission, and then ql2 hours when PA 
catheter is present, up to ICU discharge or up to 5 days after ICU admission, whichever 
occurs earlier. Additional cardiopulmonary data obtained as per center standard of care 
will be collected in patients with clinical diagnosis of PGD up to the cHnical recovery 
of the condition. 
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S. 
STUDYPOPULATION 
One hundred patients, receiving lung transplantation, will be included in the study, each one 
being randomized to receive either repertaxin or placebo. 
Patients will be selected from those on the lung transplant waiting list. Each prospective 
patient will be enrolled provided that (s)he fully meets ali of the study Inclusion and none of 
the Exclusion Criteria described in Sections 5.1. and 5.2. 
5.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into thìs study, each patient must fulfill the following inclusion 
criteri a: 
1. 
Patients accepted and listecl for transplantatìon due to irreversìble, progressive disabling, 
end-stage pulmonary disease. 
2. 
Ages 18-65 years 
3. 
Body weight 30 - 95 kg, inclusive (i.e. up to 95.99 kg). 
4. 
Planned isolated (single and bi-lateral) lung transplant from a non-living donor with brain 
death. This includes lobar lung transplant involving excisjon and sizing of a cadaver 
donor lobe to meet the thoracic dimension of the recipient before being transplanted. 
5. 
Normal renal function at the time of transplant as per calculated creatinine clearance ,2:. 60 
mUmin. Creatinine clearance will be calculated (CLcr) accordìng to the Cockcroft-Gault 
formula (1976; see section 7.1). 
6. 
Patìent willing and able to comply with the protocol procedures for the duration of the 
study, including scheduled follow-up visits and examinations. 
7. 
Patient given wrìtten infom1ed consent, prior to any study-related procedure not part of 
norma! medical care, with the understanding that consent may be withdrawn by the 
patient at any tjme without prejudice to their future medica! care. 
5.2. 
EXCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must not fulfill any of the following: 
J. 
Recipients of an intended multiple organ transplant, including heart-lung and liver-lung 
transplantatìon. 
2. 
Recipients of a lung from a living lobar donor. 
3. 
Recipients of a lung from a non-heart beating donor. 
4. 
Re-do lung transplantation. 
5. 
Recipients requiring mechanical ventilation at the time of transplant. 
6. 
Recipients with extra-respiratory tract site of infection (positive blood culture(s) ancl/or 
fever, associated with other signs of systemic sepsis syndrome). The criterion is not 
meant to exclude bacteremic cystic fibrosis patients with or without fever, unless they 
present with other signs of sepsis. 
7. 
Recìpients with hepatic dysfunction (bilirubin exceeding 3 mg/dL and/or transaminases 
>3X upper limit of nonna I) at the time of transplant. 
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Study REP0104 
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8. 
Hypersensitivìty to: 
a) ibuprofen orto more than one non steroidal anti-inflammatory drug (NSAID). 
b) medications belonging to the class of sulfonamides, such as sulfamethazine, 
sulfamethoxazole, sulfasalazine, nimesulide or celecoxib. 
9. 
Patients simultaneously partìcipating in any other studies involving a study drug to be 
administered concomitantly with the Investigational Product and/or a study drug 
intended to prevent ischernia/reperfusìon injury. 
10. 
P1anned use of anti-CD3 monoclonal antibody (Orthoclone OKT3) or alemtuzumab 
(Campath) induction immunosuppression. 
11. Planned use of sirolimus in the first three months after transplantation. 
12. 
Pregnant or breast-feeding women. (NB: pregnancy should be avoided in patients or 
partners during the first month of participation in the study; no other specific wamings 
are desc1ibed, considering even stiicter general recommendations concerning pregnancy 
in transplanted patients, the treatment course of the Investigational Product, its 
phrumacokinetic profile, and the lack of significant adverse effects on mating 
performance and fertility in animal studies). 
5.3. 
ASSIGNMENT OF PATIENT NUMBER 
The randomization number will be assigned in a sequen6al manner as patients are found to be 
ehgible for entry into the study and are enrolled. It will consìst of the site number, and the 
patient number e.g. 0210, where first 2 digìts represent site number, last 2 digits patient 
number. Ifa patìent is dropped from the study for any reason, the patient's number will not be 
reassigned. 
From the sìgning of the Patient Informed Consent Document until t.he allocation of a 
randomizatìon number, patients will be identified by their initials and date of bìrth. 
Final Revision No. 3, 20-March-2006 


Stuòy REP0104 
Repertaxìn in Lung Transplantation 
Page24 of73 
6. 
STUDY MEDICATI ON 
Repertaxin is a new chemical entity with chernical narne R(-)-4-lsobutyl-alpha-
rneth ylphen ylacety 1-methanesulfonamìde. 
6.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING 
6.1.1. 
Presentation of Investigational Products 
In this study the Investigational Products will be repertaxin and placebo. 
They will be provided as clear glass class I ampoules, each containing 10 mL of the following 
products: 
Repertaxin: 
33 mg/mL aqueous injectable solution of repertaxin wìth the following 
composition (per single 10 mL unit): 
NAME0F 
INGREDIENT 
Repertaxin (DF 1681 Y) 
. 
. .. 
PER-IJNrr: 
• •• 
FORMULA. 
330mg 
F\JNCTI0NOF 
INGREDIENT 
Active substance 
REFERENCE T0 QUALITY 
STANDARDS 
Manufacturer monograph and 
s ecification 
Placebo: 
9 mg/mL aqueous injectable solution of sodiurn chloride (NaCl) with the 
following compositi on (per single 10 mL unit): 
NAMES0F 
PER·UNIT 
FuNCTION 0F 
• .REFERENCE T0 QUALffY 
· INGREDIENT · · 
FORMULA 
INGREDIENT 
STANDARDS. 
Sodium Chloride 
90mg 
Isotonizing agent 
European Phannacopoeia -
currenl edition 
Water for injections 
qstolOmL 
Solvent 
European Pharmacopoeia -
current eclition 
Certificates of Analysis will be provided together with the Investigational products. 
6.1.2. 
Receipt of drug at the center/Stability during shipment 
No Investigational Product wìll be sent to the Investigator before receiving Institutional 
Review Board (IRB)fResearch Ethics Board (REB) approvai. 
A temperature probe and data legger will accompany the drug on shipment. It is essentia] that 
centers read the graphical record on receipt in arder to verify the temperature range reached 
Final Revision No. 3, 20-March-2006 
' -- --- -- --
• -


Study REP0104 
Repertaxin in Lung Transplantation 
Page 25 of73 
duting shipment, so that potential stability concerns during shipment can be investigated and 
appropriate action taken. 
6.1.3. 
Preparation of the Dosing Solution 
The dosing solution for ìnfosìon wìll be prepared aseptically at the designated Pharmacy 
within each center. 
For each 24 hour administration period, the contents of 23 ampoules (230 mL) will be cliluted 
with 370 mL of 0.9 % sterile saline. This volume includes that needed for dead-space 
priming. Thus, repe1taxin will be dispensed as a 12.65 mg/mL solution. 
The dosing solution will be placed i11 a 1000 mL sterile empty infusion bag. Bags will be 
identified as Infusion Bag No. l (0-24 hour infusion) and Infusion Bag No. 2 (24 - 48 hour 
infusion). 
Detailed instrnction for the preparation of the dosing solution will be reported in the 
'Instrnctions to the Phrumacy' provided with each 'Patient Box' of medicati on (see below ). 
Dosing solutions will be prepared and used within 72 hours from preparation. 
6.1.4. 
Storage/Stability of Investigational Products 
Investigational Products must be stored not above 30°C (86°F). 
All Investigational Products must be stored in a secure locatìon, preferably in a temperature 
controlled locked room, and may be dispensed only by the Pharmacist or by a mernber of staff 
specifically authorized by the Investigator, as appropriate. 
Any deviations from the 
recommended storage conditions should be immediately rep01ted to PPD 
and the use of 
the drug suspended until authmization for its continued use has been given by Dompé. 
6.1.S. 
Packaging/Labeling of Investigational Products 
Investigational Products have been manufactured by 
Current Repertaxin/Placebo ampoules have been packaged by 
. Any 
~s 
will be packaged by 
, (formerly known as 
-----
All study medication is provided as 'Patient Boxes'. Each Patie11t 
Box wìll contain 2 'Treatment Boxes' (Treatment Box No. l = 0-24 hour infusion; Treatment 
Box No. 2 = 24-48 hour infusion) of 25 ampoules each, 23 to be used for the preparation of 
the dosing solution, 2 to be kept as reserve. Two sterile empty bags (lnfusion Bag No. 1 and 
Infusion Bag No. 2), plus an additional reserve bag, will be included in each Patient Box, 
along with the 'Instrnctions to the Pharmacy', a booklet detailing instrnctions for 
Investigational Product handlìng and preparati on of the dosing solution. 
If unused, the two ampoules in excess must remain in the Treatment Box. If they are used, 
the reasons for use must be documented. 
Dosing solutions will be prepared at the center Pharmacy. 
Final Revision No. 3, 20-March-2006 


Study REP0104 
Repertaxin in Lwrg Trcmsplanuuion 
Page26 ofi3 
Current labeling of all study materials has been provided by 
Any future 
labeling will be provided by -· 
Labeling is prepared to meet locai regulatory 
requirements. 
Details of packaging and labeling are reported in Appendix 2. 
6.1.6. 
Blinding 
In vesti gati onal Products 
Repertaxin and placebo will be packaged in identica! containers (boxes. ampoules. bags) 
displaying the same information on the labels so as to preserve the study blind. Moreover, 
solutions of repertaxin and placebo, either in the ampoules or in the bag (dosing solutìons), 
will be similar as per appearance and smell. 
Nevertheless, study Pharrnacists might not be fully blinded, since a transient foamy Jayer 
occasionally results from the preparation of the repertaxin dosing solution. Once the foamy 
layer, if any, has subsided, the dosing solution of repertaxin will be indistinguishable from 
that of placebo. 
Study blind 
After database lock of data recorded in the main part of the study, corresponding to the 1 
month follow-up visit of the last patient in, the b1ind code will be broken and the study will 
proceed in an open fashion. 
6.2. 
DOSE, ROUTE AND SCHEDULE OF INVESTIGATIONAL PRODUCT 
ADMINISTRA TION 
According to the parallel-group design, patients will receive either repertaxin or placebo as 
determined by a previously generated randomization schedule. 
An ìnitial 'loading dose' of repe1taxin of 4.488 mg/kg body weight/hour will be administered 
over 30 minutes followed by a maìntenance dose of 2.772 mg/kg body weight/hour lasting 
47.5 hours. Placebo will be volume matched saline. 
The study drugs will be administered as a continuous ì.v. infusion into a (high flow) centrai 
vein, by an infusion pump adequate to provide reliable infusion rates (see below), as per 
treatment schedule. Total infusion volume will not exceed 500 mU24 hours. 
The infusion will start approxìmately 2 hours before the anticipateci time of reperfusion. For 
the purpose of this trial, reperfusion is defined as "the time of resumption of blood flow after 
vascular de-clamping of the first allograft". If cardiopulmonary bypass is used, the time of 
reperfusion is when the patient comes off the bypass, unless partial de-clamping occurs prior 
to complete stop of cardiopulmonary bypass. The surgeon will identify the time to start study 
drug infusion. In most instances, this time will be close to the time of the incision that begins 
the operation. 
The loading and maintenance doses will be gi ven using the same dosing soluti on (repertaxin 
12.65 mg/mL), but t11e purnp rate will be altered to provide an infusion rate of approximately 
Final Revision No. 3, 20-March-2006 


Study REP0104 
Repertaxin in Lung Transplantatio11 
Page27 of73 
0.35 mLJkg/hour and 0.22 mIJkg/hour, respectively. Actual infusion rate (mUhour), adjusted 
to body weight, is tabulated in Appendix 3. Figures in the appendix represent mathematical 
rounding of origina! infusion rates derived from the following formula: 
Infusion rate (mL/hour) = 
dose (mg/kg/hour) x body weight (kg) 
12.65 mg/mL 
Such a rounding affects actua] administered dose/kg/hour by less than 1 %. 
Technical characteristics of the infusion pump should include ìnfusion rate covering the range 
from 6.6 to 31.9 mUhour, in 0.1 rnUhourincrements, and capacity ìn excess of 600 mL'day. 
6.3. 
6.3.1. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION/ 
DISCONTINUATION OF INv'ESTIGATIONAL PRODUCT 
Criteria for schedule adjustment or dose modification 
No schedule adjustment and/or dose modificatìon is foreseen, except for discontinuation of 
drug as detailed below. 
6.3.2. 
Criteria for discontinuation of Investigational Product 
Administration of the Investigatìonal Product should be immediately discontinued in case the 
patient develops renai or hepatic dysfunction defined as: 
renai dysftmction: 
the occurrence of both CLcr < 60 mL/min and urine output < 0.5 
mIJkg/hour on two consecutive sampling time points (12, 24, 36 hours 
after the begjnning of Investigational Product infusion). 
hepatic dys.function: bilirubin exceeding 3 mg/d.L and/or transarrùnases >3X upper limit of 
norma!). 
Phase 1 studies in patients with ESRD have shown that renal function has a profound effect 
on plasma concentrations of a major, marginally active metabolite, carboxy-repertaxin 
(DF2243Y), whìch was found to accumulate over time along with the increased elimination 
half-life. Even if toxicological results to date suggest that DF2243Y does not raise any safety 
concem, limited experience in humans recommends to discontinue the drug in case of renal 
impairment as it would not be possible to predi.et the risk assocìatcd with elevated plasma 
levels. However, transient alterations of serurn creatinine or urine output, as defined above, 
do not indicate a renai dysfunction that would cause impaired excretion of DF2243Y. 
Because repertaxin undergoes extensive hepatic metabolism, it is also recommended that the 
infusi on is discontinued in case of hepatic dysfunction to avoid an increase of plasma level of 
repertaxin, exceeding the target and safe concentration. 
CLcr, urine output, bilirubìn and transaminases will be evaluated at 12, 24 and 36 hours after 
the beginning of Investigational Product infusion. Samples will be processed imrnediately 
and results made available as soon as possible to the Investigator. Urine output will be 
calculated for each of the 12 hour periods: from start of infusion to 12 hours, 12-24 hours, and 
24-36 hours. 
Final Revision No.3, 20-March-2006 


Study REP0104 
Repertaxin in Lzmg Transplantation 
Page28 of73 
Investigational Product will also be immediately discontinued in the event of any other 
possibly drug related occun-ences that the Investigator believes might compromise patient 
safety. 
If the Investigational Product therapy is prematurely discontinued the primary reason for 
discontinuation must be recorded in the CRF. Patients who discontinue the treatment with the 
Investìgational Product will not be withdrawn from the study by default, but will complete 
observations as per the protocol, unless otherwise withdrawn at the Investigator's decision. 
6.4. 
ACCOUNTABILITY 
Ali supplies will be maintained under adequate security by the responsible member of the 
Pharmacy staff. 
The Investìgator wìll ensure that study treatment is only admin:istered by designated staff 
wìthin the center. In particula:r, for U.S. sites, the Investigator will ensure that study treatrnent 
is only administered by those named as sub-investigators on the FDA form 1572 and 
designated staff. 
When Investjgational Product is received by the Phannacist (or designee), he/she will check 
for accurate delìvery and acknowledge receìpt by signing and dating the documentation 
provided by or on behalf of PPD 
and retuming it to PPD 
. A copy will be retained for 
the Investigator/Pharmacy file. 
The dispensing of the Investigational Product will be carefully recorded on appropriate drug 
accountability fo1ms (these will be provided by PPD 
) and an accurate accounting will be 
available for verification by the CRA at each monitoring visit. 
Drug accountability records will include: 
• 
confinnation of delivery of the Investigati on al Product to the trial site, 
• 
the inventory at the site (ampoules/bags), 
• 
the use by each patient, 
• 
the retum to Dompé or alternative disposition of unused product(s), 
• 
accounts of any Investigational Product accidentally or deliberately destroyed, 
• 
accounts of an y reserve ampoules used. 
They should ìnclude dates, quantities, batch numbers, expiration dates (ff applicable), and any 
unique code numbers assigned to the Investigational Product(s) ancl/or patients. Investigators 
should maintain records which document adequately that: 
• 
the patients were provìded the doses specified by the protocoJ/amendment(s), 
• 
ali Investigational Product provided was fully reconciled. 
The PPD 
will review the drug accountability fonns and check ali Investigational 
Product ampoules (both unused and used) prior to making arrangements for their retum to 
Dompé, or authorizing their destruction by the study site. 
Investìgational Product which has been dispensed to a patient and retumed unused will not be 
re-dispensed to a dìfferent patient. 
Pina) Revision No. 3, 20-March-2006 


Study REP0 l 04 
Repertaxin in Lung Transplantation 
Page 29 of73 
Unused Investìgational Product must not be discarded or used for any purpose other than the 
present study. Any remaining test material at the end of the trial will be returned to Dompé or 
disposed of, as detennined by the Sponsor. 
6.4.1. 
Assessment of compliance 
Compliance will be assured by the person(s) within the center in charge of Investigational 
Product administration. 
Imn1ediately before the start of each 24-hours treatment period, the removable label on the 
Infusion Bag will be detached and attached to the relevant page of the CRF. Actual date and 
time of infusion start, switch of infusion rate (first 24 hours period only) and end of infusion 
will be recorded in the CRF, as well as infusion rates in each period. 
Compliance with the study product dosing schedule will be verified by a CRA during on-site 
monitoring visìts, as per records in the CRF, versus accountability records. 
6.5. 
CONCOMITANT THERAPY 
Any medications required for the patient's welfare are permitted and will be gi ven at the 
discretion of the Investigator, except for drugs described in paragraphs below. 
Administration of all prior and concomitant medications, apart frorn the agents lìsted below, 
from the time of enrolment until 10 days after the end of study drng admìnistratìon or until 
hospital discharge (whichever occurs earlier) will be reported in the appropliate section of the 
CRF. For the intervals between 10 days or hospìtal dìscharge up to 12 month vìsit, only 
medications used far immunosuppression, prophylaxis of inf ections, and AE that the 
Investigator assesses as at least possibly related to the Investigational Produci will be 
reported. 
Ali the details as per the CRF fi.elds (sequential number, drng name, indication, startìng dose, 
doses at month 1, 6, and 12, route of administratìon, start/stop dates) will be recorded for the 
medications used for immunosuppression and prophylaxis of infections. Only the sequential 
number, the drng name, the ìndication and the start date wi11 be recorded for ali the other 
concomitant medications. 
The following agents do not need to be recorded: 
Saline and other hydration solutìons (including additional electrolytes) 
TPN and enteral f eeds 
' 
Homeopatic medications 
Elective vitamins and minerals 
Topica! agents (apart from inhaled) with no or negligible systemic absorption 
Osmotic laxatì ves and locally acting antacids 
6.5.1. 
Imrnunosuppressive therapy 
Neither guidelines nor fonnal consensus on "best" or "standard" immunosuppressive 
strategies 
after human lung transplantation 
are currently available. 
Therefore, 
Final Revision No. 3, 20-March-2006 


Study REPO 104 
Repertaxin in lung Transplantation 
Page 30 of73 
irrummosuppression after lung transplantation is derived from the wider experience gained in 
renai and heart transplant recipients integrated by the results of specific lung trials. 
6.5.1.1. 
Induction 
Data from the Intemational Socìety for Heart and Lung Transplantation (ISHLT) registry 
indicate that about 45% of lung transplant recipients receive some type of induction therapy, 
mainly polyclonal antilymphocyte preparations or anti-ìnterleukin (IL)-2-receptor antibodies. 
The use of Orthoclone OKT3 has been frequently associated to a cytokine release syndrome, 
which may induce cardiopulmonary instability. Also, experience with anti-CD52 (Campath) 
in the specific clinica} setting is very limited. Therefore, induction ,vith Orthoclone OKT3 
or Campath will not be allowed in the trial. 
Induction therapy will not be mandatory in this trial and the decision, including the choice of 
the immunosuppressive agent, with the exclusion of Orthoclone OKT3 and Campath, will be 
based on center' s practice. 
6.5.1.2. 
Maintenance 
At the present time, maintenance with a triple-drug regimen can be considered the norm. 
Therefore, this study will follow the common practice currently in use, recommending a 
ttiple-drug regimen of either cyclosporin A or tacrolimus, plus steroids (at a moderate dose in 
the first seven days), plus either azathioprine or mycophenolate mofetil/mycophenolic acid. 
The use of sirolimus will be discouraged, at least in the first three rnonths after lung 
transplantation, as cases of branchia] anastomotic dehiscence, rnost fatai, bave been repo1ted 
in de novo lung transplant patients when the dmg has been used as part of an 
immunosuppressive regimen. Programs intendìng to use sirolìmus in the first three months 
should refrain from enrollìng such patients in the t:rial. 
Monitoring strategies for dose adjustment as well as strategies for weanìng steroids will be as 
per center' s practice. 
6.5.1.3. 
Treatment of acute and chronic rejection 
Treatment of acute rejections will be handled as per center practice. 
Treatment of established chronic rejection is currently net supported by evidence obtained in 
adequately designed clinical studies. Any strategy deemed useful by the Investigator will be 
allowed. 
6.5.2. 
Prophylaxis of opportunistic infections 
Prophylaxis of oppo1tunistic ìnfections will be handled as per center practice. 
6.5.3. 
Other treatments 
Nitric Oxide, Surfactant, Prostaglandin El will be administered as per center practice. 
Final Revìsion No. 3, 20-March-2006 


Study REP0104 
Repertaxin in Lung Transplantation 
Page 31 of73 
7. 
STUDY PROCEDURE AND ASSESS1"1ENTS 
A schedule for the tests and evaluations to be conducted in this study is found in the flow 
chart in Appendix 4. A list of acceptable assessment/procedure time windows is detailed in 
Appendix 6. 
7.1. 
SCREENING AND RANDOMIZATION 
Potential study patients will be identified whilst on the center transplant waiting list. On 
anival at the center for transplantatìon, consented patients will undergo confirmatory 
screening for the study. 
Compliance with inclusion/exclusion criteria will be verified vs demographic and clinica! 
inforrnation available as per Organ Procurement Agency - e.g. United Network for Organ 
Sharing (UNOS) - form and standard clinica! practice. 
Laboratory tests (hematocrit, hemoglobìn, red blood cells, plateJets, white blood cells, 
differential white blood cells count, sodium, chloride, potassium, bicarbonate, serum 
creatinine, blood urea nitrogen, total bilirnbin, ALT, AST, prothrombin time or intemational 
normalized ratio, partial thromboplastin time) will be performed by local laboratories. 
Screening also includes measurement of BP, HR, body weight (kg), and testing for renai and 
hepatic function, as well as for extra-respiratory tract site of infection. 
Renal function will be evaluated by CLcr, calculated according to the following formula 
( Cockcroft-Gault; 1976): 
[ 140 - age (years)J • Weight (kg) 
Male: CLcr = 
Female: CLcr = 
Serum Creatinine (mmol / L) • 815 
[140 - age (years)] • Weight (kg) 
-------------
• 0.85 
Serum Creatinine (mmol / L) • 815 
Hepatic function will be evaluated by bilirubin (mg/dL) and transaminases (ALT and AST). 
Extra-respiratory tract sites of infection will be diagnosed by blood culture(s) ancl/or fever 
associated with other signs of systemic sepsis syndrome. Previous results of blood cultures 
can be used to verify inc1usion criteria, provided that the sample has not been obtained earlier 
than 72 hours prior to randomization. 
Eligible patients will be randomized (randomìzation number assigned) by an Investigator or 
designee before proceeding to the operating room. The Investigator will forward to the 
Pharmacy an order to start preparati on of Investigational Product dosìng solution. 
A screening form will be completed for all patients who signed the Patient Informed Consent 
Document, regardless of sequent entry into the study. Patients will be identified by their 
Final Revision No.3, 20-March-2006 


Study REP0!04 
Repertaxin in Lung Tra11splantatio11 
Page 32 of73 
initials and date of birth; in addition their race, sex and reasons for exclusion from the study 
wiH be recorded. 
Jf entered into the study, the folJowing recipient data wi11 be recorded in the CRF: 
-
demographic, i.e. age, sex, race, weight, height, 
-
immediate pretransplant and transplant clinica! information as per Organ Procurement 
Agency - e.g. UNOS - form, 
-
results of laboratory tests. 
7.2. 
ORGAN PROCUREMENT 
Standard protocols for procuring and preserving donor lungs will be used. Lungs will be 
resected en bloc following systemic hepalinization. 
Lungs will be washed by anterograde plus retrograde perfusion via the pulmonary artery with 
Low Potassium Dextran (Pe1iadex®) - based solution (with or without additions as per center 
practice) at 4°C. The lungs will be transported in the partially inflated state immersed in 
Pe1fadex® solution at 4°C. 
Donor lung data will be recorded in the CRF as per Organ Procurement Agency - e.g. UNOS -
form. 
7.3. 
OPERATIVE COURSE 
In principle, standard surgery procedures, excluding possible graft reflush with leukocyte 
depleted blood, will be applied as per center practice. However, it is suggested to adopt 
whenever possible, the following strategks: 
-
Application of topìcal hypothermìa during implantation. 
-
After implantation, blood flow will be progressively, in a controJled way, restored over a 
period of up to 10 rrùnutes (minimum 2 uùn). 
-
Protective venti1ation strategy will be adopted during the initial period of repetfusion. It is 
suggested that the new]y implanted lung allograft is gently reinflated with a sustained 
airway pressure of 20 cmH20 before reperfusion and then ventilateci with Fi02 of 50%, 
PEEP =5 cmH2O, and pressure contro] ventilation limitìng peak airway pressures to 20 to 
25 cmH20. After reperfusion has occurred, changes of ventilation will be directed by the 
anesthesìologist according to his/her judgment of the functional status of the implanted 
lung. 
Relevant operative details wìll be recorded in the CRF, including gross abnonnalities of the 
donor lung(s), duration of cold and warm ischemia, time of reperfusion, use and duration of 
cardiopulmonary bypass, Jung reduction procedures, anastomotic difficulties, hypoxemia, and 
pulmonary edema, use of nitroglycerin/nitric oxide/inhaled prostacyc1in/suifactant. 
Final Revision No.3, 20-March-2006 
e ---- -- ·-- . -


Study REP0104 
Repertaxin ìn lung Transpla11tation 
Page 33 of73 
7.4. 
ADMINISTR.,i TION OF IlWESTIGATIONAL PRODUCT IN THE 
OPERA TING ROOM 
The infusion Bag No. I, containing the dosing solution matching the patient randomization 
number, should be available in the operating room prior to anesthesia induction. 
Infusion of the Investigationa1 Product will start approximately 2 hours before the anticipated 
time of reperlusion of first allograft. The surgeon will identify the time to start study drug 
infusi on. 
The infusion pump will be set to provide the infusion rate corresponding to the loading dose. 
The loading dose will be infused for 30 min. Thereafter, the infusion rate will be reduced to 
provide the maintenance dose. Infusion rate (mL/hour) corresponding to each unit increment 
(kg) of body weight, is reported in Appendix 3. 
Immediately before the start of infusion, the removable 1abel on the lnfusion Bag will be 
detached and attached to the relevant page of the CRF. Starting time of drug administratìon, 
time of switch to maintenance dose and infusion rates will be recorded in the CRF. 
7.5. 
ADMISSION TO ICU 
7.5.1. 
Anival to the ICU 
Date and time of ICU admission will be recorded in the CRF. 
All patients will be mechanically ventilated through a ora! endotracheal tube. The ventìlator 
mode and rate will be set as per center practice, to ensure best standard of patient care. 
Upon arriva! to the ICU, the patient wilJ be hemodynamically stabilized and p]aced on FiO2 
=1.0 and PEEP =5 cmH2O (or greater, if clinically necessary, to achieve SpO2 > 92% and 
PaO2 75mmHg). 
The following will be assessed as per center practice (unless otherwise specified) on affival to 
the ICU and recorded in the CRF, apart from SVR and PVR which wìll be calculated during 
data-management: 
• PaO2/FiO2 ratio (FiO2 =1; PEEP =5). 
• Chest X-rays (see Appendix 1 for methodological details). 
• BP,HR. 
• CO, PA pressure, SVR, PVR, PCWP, CVP. 
7.5.2. 
Assessment in the ICU 
The following will be assessed during ICU stay and recorded in the CRF, apart from SVR and 
PVR which will be calculated during data-management. Measurement will be performed as 
per center practice, unless otherwise specified. For the purpose of this study, clinically 
diagnosed PGD is defined as: 
Final Revision No.3, 20-March-2006 


Study REP0104 
Repert<.L~in in Lung Transplantation 
Page 34 of73 
-
An episode of decreased PaOf_FiO2 ratio and chest X-ray results consistent with a PGD 
score of grade 3, which is not the result of some other secondary cause of graft dysfunction 
[Christie, 2005]. When diagnosed, the condition is considered clinically recovered for a 
PGD score of 
1. 
• PaO2/FiO2 ratio. PaOiFiO2 ratio will be measured at FiO2 = 1 q24 hours, up to extubation 
or up to 72 hours after ICU admission, wbichever occurs earlier. Patients on FiO2 < 1 will 
be iurned back to FiO2 = 1 for 5 minutes before gas measurement. Addìtional PaO2/FiO2 
ratio values obtained as per center standard of care in patients with clinical diagnosis of 
PGD will be recorded in the CRF up to the clinica] recovery of the condition. 
• Chest X-rays. A chest X-rays will be obtained 24 hours, 48 hours, and 72 hours after ICU 
admission (see Appendix 1 for details). 
• BP, HR. Vita! signs wìll be measured q12 hours up to ICU dìscharge or up to 5 days after 
ICU admission, whichever occurs earlier. 
• CO, PA pressure, SVR, PVR, PCWP, CVP. Cardiopulmonary physiologic measurements 
will be assessed q12 hours when a PA catheter is present, up to ICU discharge or up to 5 
days after ICU admission, whichever occurs earlier. Additional measurements obtaìned as 
per standard of care in patients with clinica] diagnosis of PGD will be recorded in the CRF 
up to the clinica! recovery of the condition. 
For all measurements above, the actual date and time of assessment will be recorded in the 
CRF. 
• A BAL wm be perforrned during mechanical ventilation, in the interval between 12 and 24 
hours after reperfusion, unless the patient is suffering from any clinica] conditions which 
would be worsened by BAL procedures, in the opìnion of the Investigator (see Appendix 1 
for methodological details). Date and tìme of samp1ing will be recorded in the CRF along 
wìth location of BAL (lung, site) number of aliquots injected, amount recovered and 
summary of the most recent chest X-rays report. Specific reasons (hemodynamìc ìnstability, 
severe hypoxemia, etc.) for the decision to omit the BAL should be recorded in the CRF. 
Rena] (CLcr, urine output) and hepatic (bilirubin, transaminases) function wi11 be tested at 12, 
24, and 36 hours after the begjnning of Investigation Product infusion. 
Other clìnical findings, including bronchoscopic and/or BAL findings, repo1ts for all routine 
chest X-rays and thoracìc CT scans, and results of routine biopsy will be copied ìnto the CRF 
from the medical charts. AEs will be also recorded. 
7.5.3. 
Weaning mechanical ventilation 
\.Veaning procedures will be as per center practice. 
Every moming (@08:00) that a patient has not started weaning procedures, reasons for not 
weaning are recorded in the CRF. 
Date and time of first extubation which is maintained for more than 24 hours are recorded in 
the CRF. 
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7.6. 
ICUDISCHARGE • HOSPITAL STAY 
Date and time of ICU discharge will be recorded in the CRF, as well as vital status at ICU 
discharge. Every moming (@08:00) that a patient has not been discharged from the ICU, 
reasons for not discharging are recorded in the CRF. 
Rena! (CLcr, urine output) and hepatic (bilirubin, transaminases) function wìll be tested at 12, 
24, and 36 hours after the beginning of Investigati on Product infusi on. 
Before hospital discharge, laboratory tests will be pe1formed. Resu1ts will be recorded in the 
CRF. 
Length of hospital stay, vital status at hospitaJ discharge and AEs will be recorded. 
7.7. 
DRUG ADMINISTRATION IN THE ICU/HOSPITAL AND BLOOD 
SAMPLING FOR PHARMACOKINETIC ASSA Y 
Drug ad:mìnistration (maintenance dose) will continue during ICU/hospital stay. 
Twenty-four hours after the start of the infusion, Infusion Bag No. 1 will be replaced by 
Infusion Bag No. 2. The removable label on Bag No. 2 will be detached and attached to the 
relevant page of the CRF. A blood sample will be obtained for pharmacokìnetic assay @ 
24±6 hours. 
Infusion of Investigational Product will continue up to 48 hours. Immediately before the 
infusion is terminated, a blood sample will be obtained for pharmacokinetic assay. 
An additional blood sample will be obtained in the interval 2-6 hours after the end of infusi on. 
Blood sampling for phaimacokinetic assay will be vja an indwelling intravenous (or intra-
arterial, if already in place) cannula or by direct venipuncture. On each time poìnt, a 6 mL 
sarnple will be taken into lithium heparin monovettes. Details of sample handling are 
reported in Appendix 1. 
Time of bag replacement, end of ìnfusìon, and blood sampling will be recorded in the CRF. 
7.8. 
MONTH 1 POST•TRANSPLANT 
Patient will attend the center for study assessment at month 1 (at least 30 days post 
transplant). The following measurements will be performed as per center practice and 
recorded in the CRF: 
• FEV 1, FVC. Actua] date of assessment will be recorded in the CRF. 
Any AEs that occutTed du1ing the interval i.e. sìnce 10 days after the end of study drug 
administration or since hospital discharge (if applicable), and that the Investigator assesses as at 
least possibly related to the Investigational Product, will be recorded at this visit, as well as 
patient vita] status. 
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Study REP0 104 
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7.9. 
MONTHS 6 AND 12 POST~TRANSPLANT 
Patient will attend the center at months 6 and 12 +/- 2 weeks post-transplant. The fo11owing 
measurements will be perlonned as per center practice (unless otherwise specified) and 
recorded in the CRF: 
• FEV1. FVC. BOS score will be assessed at each visit. BOS score will be evaluated 
according to Estenne et al. (2002). 
• Acute, biops v proven rejection episodes diagnosed according to Y ousem et al. (1996). 
Cumulative assessment at each visit. 
Por all measurements above, actual date of assessment will be recorded in the CRF. Diagnosis 
and treatment of acute rejection, if any, will be also recorded in the CRF. 
Patient vital status, as well as any i\Es occuning during the intervals between study visits that 
the Investigator assesses as at least possibly related to the lnvestigational Product wiIJ be 
recorded at each visit. 
7.10. 
EARL Y PATIENT 'WITHDRA ,v AL 
7.10.1. 
vVithdrawal criteria 
Patients will be informed that they have the 1ight to withdraw from the study at any time, 
without prejudice to their medicai care, and are not obliged to state their reasons. Any 
withdrawals must be fu11y documented in the CRF and should be followed up by the 
Investigator. 
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. 
Patients must be annulled from the study for the following reasons: 
• 
Patient was randomized, but did not receive the Investigational Product, 
• 
Patient was randornized, but did not proceed to lung transplantation. 
If a patient fai 1s to return to the center for a scheduled visit, attempts should be made to 
contact the patient to ensure that the reason for not retuming is not an AE that may at least 
possibly be related to Investigatìonal Product. Likewise ifa patient declares his/her wish to 
discontinue from the study e.g. far persona! reasons, an attempt should be made to establish 
that the trne reason is not an AE (bearing in mind the patient is not obliged to state his/her 
reasons). 
7.10.2. 
Replacement policy 
Only patients withdrawn due to one of the following reasons will be replaced: 
• 
Patient was randomized, but did not receive any Investigatìonal Product, 
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\ -- --
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• 
Patient was randomized, but did not proceed to lung transplantation. 
Should a patient be replaced, his/her number will not be real1ocated. A new patient will be 
enrolled and assigned the next number available. 
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Study REPO 104 
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8. 
ADVERSE EVENTS 
8.1. 
DEFINITIONS 
8.1.1. 
Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medicai occurrence in a patient or clinica! 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causai relationship with this treatment. 
An AE can therefore be any unfavorable and 
unintended sign (including an abnorrnal laboratory finding), symptom, or disease temporally 
associated with the use of a medicina! (investigational) product, whether or not related to the 
medicina! (investigational) product [ Clinica/ safety data management: Definitions and 
Standardsfor Expedited Reporting]. 
8.1.2. 
Definition of a Serious Ad verse Event 
A Serious Adverse Event (SAE) is defined [ Clinica/ safety data management: Definitions and 
Standards far Expedited Reporting] as any untoward medicai occurrence that at any dose: 
• 
• 
• 
• 
• 
• 
8.2. 
results in death, 
is life-threatening (i.e. the patient was at risk of death at the time of the event. It 
does not referto an event which hypothetically might have caused death if it were 
more severe), 
requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity, 
is a congenita! anomaly/birth defect, 
is an important medicai event that based upon appropriate medicai judgment, may 
jeopardize the patient and may require medicai or surgical intervention to prevent 
one of the outcomes listed above. 
EMERGENCYPROCEDURES 
Ali AEs should be followed-up to determine outcome of the reaction. The Investigator should 
follow up the event unti! resolution or stabilization of the condition. It is the Investigator's 
responsibility to assure that the subjects experiencing AEs receive definite treatment for any 
AE, if required. 
The treatment allocation for each patient will be provided in individuai sealed envelopes. The 
locati on of these envelopes must be communicated to relevant study site staff and documented 
in the Investigator file. An envelope should only be opened in case of emergency where 
knowledge of the double-blind treatment may influence the further care of the patient. Ali 
such envelopes (both opened and unopened) will be collected by 
 as each patient 
completes the study. If an envelope is opened for any reason, the Investigator will notify 
 immediately and a record will be kept of when it was opened, by whom and why. 
Final Revision No. 3, 20-March-2006 
CONFIDENTIAL 
PPD
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8.3. 
RECORDING 
AE data should be obtained through observation of the patient, from any information 
volunteered by the patìent, or through patient questioning. 
All AEs encountered during the clinica! study, including SAEs wìll be reported in the 
appropriate section of the CRF. It is important that this ìncludes the duration of the AE 
(onset/resolution dates), the relationship to the drng, the severity, and relevant concomitant 
treatments dispensed (or other action taken) (see Sections 8.3.2., 8.3.3., and 8.3.4. below). 
8.3.1. 
AE reporting period 
All AEs which occur during the treatment period (i.e. the first to last day of Investigational 
Product administration) and up to 10 days after the end of Investigational Product 
adnùnistration or up to hospìtal discharge, whìchever occurs earlìer, will be recorded in the 
CRF. 
In addition, any known untoward event that occurs subsequent to the AE reporting period that 
the Investigator assesses as at least possìbly related to the Investigational Product shou1d also 
be reported as an AE. 
8.3.2. 
Relationship of AEs to the Investigational Product 
The Investigator wi11 assess the possible relationship between the AE and the investigational 
medication, according to the crite1ia in Table 1 below: 
Table 1: 
Relationship of the Adverse Event to the Investigational Product 
None (lntercurrent 
An event that is not and cannot be related to the Investigational Product, 
Event) 
e.g. patient js a passenger in a road traffic accident 
Relationship is not likely e.g. a clìnical event including laboratory test 
Unlikely (remote) 
abnormality with temporal relationship to drug administration which 
makes a causa! relationship improbable and in which ol11er drugs, 
chemicals or underlying disease provìde plausible explanatìons 
Possible 
ReJationship may exist, but could have been produced by the patient's 
conditi on or treatment or other cause 
Probable 
Relationship is likely, the AE ~bates upon discontinuati on of 
Investigational Product and cannot be due to the patient's conclition 
Strong relationship, 
the event 
abates upon cliscontinuation of 
H.ighly Probable 
Investigational Product and, ìf appJicable, re-appears upon repeat 
exposure 
An Ad verse Drug Reaction (ADR) is defined as an adverse experience which is a reasonably 
likely to have been caused by the drng. Any AE reported in the study having a possible, 
probable or highly probable relationship to study drug wil1 be considered as an ADR. 
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Study REP0104 
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8.3.3. 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in Table 2. For each 
epìsode, the highest seve1ity grade attained should be reported. 
Table 2: 
Severity of the Ad verse Event 
Mild 
Grade 1 - Does not interfere with patient's usual function (awareness of 
svmotoms or sjgns, but easilv tolerated [acceptable]). 
Moderate 
Grade 2 - Intetferes to some extent with patient's usual functi.on (enough 
discomfort to jnterfere with usnal activity [disturbing]). 
Severe 
C1Tade 3 - Interferes significantly with patient's usual function (ìncapacity 
to work orto do usual activities [unacceptable]) 
Life Threatening 
Grade 4 - Results .in risk of death, organ damage, or pennanent disabj]ìty 
( unacceptable] 
8.3.4. 
Frequency of AEs 
The frequency of AEs should be described as per Table 3. 
Table 3: 
Frequency of the Adverse Event 
Once 
The AE occurred only once and resolved in < 24 hours 
Occasionally 
The AE occmTed sporadìcally or episodically between the onset ancl 
resolutìon dates (and times) 
Continuously 
The AE was present for the entire time between onset and resolution dates 
(and times) and was > 24 hours duration 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. 
Reporting Procedure for Investigators to PPD 
The Investigator must report all SAEs, regardless of presumed causai relationship, to the 
PD 
Pharmacovigilance Depattment, by fax. within 24 hours of leaming of the event. 
Details of the relevant fax number for SAE repo1ting are provided in the section ''Contact 
Information". 
Infonnacion on SAEs wrn be recorded on a specific Non-Carbon Repeat SAE fonn. Blank 
copìes will be included in the Investigator's Site File. 
Follow-up reports (as many as required) should be completed and faxed following the sarne 
procedure above. 
A final report is required ìn any case once the condition is resolved or stabilized and no more 
information about the event ls expected. The final report should be completed and faxed 
following the same procedure above. 
PPD 
will report to Dompé alJ information received by the Investigators, by fax within 24 
hours of knowledge. 
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Study REP0104 
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in Lung Transplantation 
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8.4.2. 
Reporting Procedure for Investigators to IRB/REB 
In addition to reportìng the SAE to PPD 
, the Investigator rnust also comply with the 
requirements related to the reporting of SAEs to the IRB/REB which approved the study. 
The requirements of IRB/REB vaiies from one state and indeed one country to another, 
however as a minimum requirement a11 Investigators must promptly report all serious 
unexpected* ADRs, life-threatening problems or deaths to their IRB/REB. 
PPD 
will ìnforrn Investigators of all serious unexpected ADRs, which are reported to 
PPD 
from other Investigators. These SAEs should also be reported promptly to the 
IRB/REB in compliance with the locai regu1ations. Copies of all co1Tespondence relating to 
reporting of any SAEs to the IRB/REB should be maintained in the Investigator's Files and 
provided to PPD 
• 
* An unexpected ADR is defined as any adverse drug experience, the nature or seve1ity of 
which is not consìstent with the current Investigator's Brochure. 
8.4.3. 
Reporting Procedure for Regulatory Authorities 
This study is jntended to take place at centers in the USA and Canada and therefore should 
satisf y both FDA and Health Canada SAE reporting requirements. 
During the course of the clinica} tiial, Dompé (or designee) shall inform FDA/Health Canada 
of any serious unexpected ADR as soon as possible and in no event later than: 
(a) seven calendar days after becoming aware of the info11nation if it ìs fata] or !ife 
threatening; and 
(b) fifteen ca1endar days after becoming aware of the information ìf it is neither fatal nor life 
threatening. 
Dompé (or designee) shall, within eight days after having infonned Health Canada under 
paragraph (a), submit a complete report in respect of that information that includes an 
assessment of the impo:rtance and imphcation of any findings made. 
Furthermore Dompé shall promptly investigate all safety information received by it and 
follow up information to a safety report shall be submitted to the appropriate authorities as 
soon as the relevant information is available. 
If the results of an investìgation show that an adverse drug reaction not initially determined to 
be reportable is reclassified as reportable, Dompé (or designee) shall repo1t such reaction in a 
written safety report as soon as possible, but in no event later than 15 calendar days after the 
deterrnination is made. 
8.5. 
DATA MONITORINGCOMMITTEE 
An independent Data Monitoring Committee (DMC) wilJ be established to ensure patient 
safety, to consider patient risks against the potential for meeting tria! objectives, and to • 
previde recommendations to Dompé with respect to the conduct and analysis of the tiial. The 
DMC will operate independently of Dompé, and its members will not have connections to the 
Sponsor with the exception of the compensation to DMC members related to DMC activities. 
The DMC will comprise three voting members. They will be a multidisciplinary group that 
will include: 
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• 
A surgeon with extensive experience in lung transplantation, 
• 
A physician with relevant experience in pulmonary and criticai care medicine (e.g. a. 
Medical Director of a Lung Transplant Program), 
• 
A biostatistician. 
The DMC will perfonn the following major functions: 
• The DMC will be responsible for the ongoing review of safety data throughout the 
tria!. Primary among the safety data that will be reviewed are serious AEs, ADRs and 
relevant available clinica] laboratory results. 
• 
The DMC may review acute and additional safety data, on a patient-by-patìent basis, 
at their discretion. This review would be warranted if significant unexpected ADRs 
are observed. 
• 
The DMC may request additional safety data if, in the view of the Committee, these 
adclitional data are needed in order to make an informed, responsible decision about 
the conduct of the study. 
• 
The DMC will advìse Dompé regarding safety of patients and continuing validity and 
scientific merit of the trial. The DMC will also monitor the number of deaths for both 
arms of the study to ensure that mortality is consistent with historical data. 
Ali details of the conduct and responsibìlities of the study DMC will be described in the 
'DMC Charter' whkh will be finalized prior to the start of patient enrolment. 
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Stud y REP0 I 04 
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9. 
STATISTICAL ISSUES 
9.1. 
SAMPLE SIZE 
The sample size has been estimated based on PaO2/FiO2 ratios immediately and at 24 hours 
from the results of 700 lung transplant operations at the Washington University. The database 
reports means and standard deviations for this endpoint of 329±137 mmHg at the initial ICU 
assessment and 315±117 mmHg at 24 hours. 
A sample size of 50 in each group will have a 81 % power to detect a difference in means of 
70 mmHg (the difference between a placebo mean of 315 and a treated mean of 385, a 22% 
improvement) assuming that the common standard deviation is 137 using a two group t-test 
with a 0.05 one-sided significance leve!. Altematively, a sample size of 50 in each group will 
have a 56% power to detect a difference in means of 50 mmHg (the difference between a 
placebo mean of 315 and a treated mean of 365, a 15% improvement) assuming that the 
common standard deviation is 137 using a two group t-test with a 0.05 one-sided significance 
leve!. 
There is no currently available datato provide a knowledgeable estimate of the effect size in 
this study. If the effect size is smaller than 15%, the power of this study will be reduced and 
the chance of a Type II error is increased. Under such circumstances, this study would stili 
provide valuable data regarding the effect size in the primary outcome variable as well as the 
results in ali of the secondary, exploratory endpoints and subgroup analysis. 
9.2. 
RANDOMIZATION 
Patient will be randomized in a 1: 1 fashion to either repertaxin or placebo. Treatment will be 
balanced within centers. 
A master randomization list will be prepared, randomizing an excess of patients to allow 
flexible/competitive recruitment within each center. The randomization list will be prepared 
by 
 according to the current versi on of the Standard Operating procedure (SOP). 
The randomization code will be broken at completion of the main part of the study, i.e. when 
the last patient in has completed his/her 30 days follow-up visit, and once the database has 
been locked. 
9.3. 
ANALYSIS POPULATION 
The Safety population will consist of ali patients who received any study medication, and will 
be based on the treatment actually received. The Safety population will be used to present the 
demographic and baseline data, and ali safety data. 
The Intent to Treat (ITT) population will consist of ali patients who recei ved any study 
medication and the transplant, and will be based on the treatment randomized, regardless of 
the treatment actually received. 
The Per-Protocol (PP) population will consist of ali patients in the ITT population who did 
not have any major protocol violations, defined to be: 
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CONFIDENTIAL 
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• 
Patient who started study drug infusion after reperlusion, i.e. after vascular de-
clamping of the first allograft, 
• 
Patients who did not receì ve the study medicati on for at least 24 hours, 
• 
Patients without data for PaOiFiO 2 ratio at O and 24 hours, while on mechanical 
ventìlation, 
• 
Patients 
who 
receive 
Orthoclone 
OKT3 
or 
Campath 
induction 
immunosuppression, 
The primary and secondary efficacy analyses will be presented for the ITT population, 
primarily, and confinned by the PP population. 
9.4. 
STATISTICAL METHODOLOGY 
Appropriate descriptjve statistics will be produced, according to the variable. For continuous 
data the mean, standard deviation, medìan and range (minimum and maximum) will be 
presented. 
For categorica! data, frequencies and percentages wìll be presented. 
If 
appropriate, confidence intervals around the mean or the proportions will be presented. 
Ali patient data collected on the CRF will be listed by patient, treatment group and center. 
The data for the doubl.e-blind phase of the study (up to 30 days post-treatment) will be 
presented in the clinica! study report. Data collected during the open phase of the study (from 
1 month 
up 
to 
12 
months) 
will 
be 
presented 
in 
an addendum to the 
clinica] 
study 
report. 
Unless otherwise specìfied, the significance leve] used for statistical testing will be 5% and 
two-sided tests will be used. 
9.4.1. 
Demographic and baseline characteristics 
Demographic and baseline characteristics will be summarized for all patients in the Safety 
population, by treatment group. 
9.4.2. 
Primary efficacy analysis 
The PaO2/FiO2 ratio will be analyzed separately, at the two time points: O hours (ICU 
admission) and 24 hours after ICU admission. Analysis of variance wìll be used, including 
terms for treatment and center. The impo1iance of the treatment by center interaction wìll be 
investigated but if this is not significant at the 10% level, this term will be excluded from the 
final model. 
If a center by treatment interaction is detected, alternative methods of 
presentation will be explored. Treatment effect will be primariJy compared using a one-sided 
0.05 leve] test and then re-tested for consistency with a two-sided 0.05 level test. Type of 
transplant (single or bilateral) wi11 then be included in the model of the analysis to explore any 
possible, even unanticipated, differences due to the specific procedure. 
Primarily the data will be analyzed excluding missing data. As confinnatory analysis, the 
ANOV As wìll be performed substituting any missing values by the last observation ca1Tied 
forward (LOCF) method, in patients extubated before 24 hours. If the data are missing due to 
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patient death, the PaO2/FiO2 ratio will be given a zero va]ue. If the data are missing due to 
Jack of recording while on mechanical ventilation, these data will not be substituted. 
9.4.3. 
Secondary efficacy analysis 
The PaO2/FiO2 ratio will be analyzed, as described for the p1imary efficacy endpoint, at 48 
hours and 72 hours after ICU admission. Analysis of variance will be used, including te1ms 
for treatment and center. The ìmportance of the treatment by center interaction will be 
ìnvestigated but if this is not significant at the 10% level, this tenn will be excluded from the 
final model. 
If a center by treatment interaction is detected, alternati ve methods of 
presentation will be explored. Type of transplant (single or bilateral) wm then be inc1uded in 
the model of the analysis to ex.plore any possible, even unanticipated, differences due to the 
specific procedure. 
Analysis of PGD score will be performed separately at the four time poìnts (O, 24, 48, 72 
hours) to test for differences between treatments. Two analyses will be perforrned at each 
time-poìnt, using Cochran-Mantel Haenszel statistics, with the first analysis usìng type of 
transplant as a stratification factor, and the second using center as a strafrfication factor. 
The time to freedom from rnechanical ventilation and the duration of ICU stay will be 
presented using Kaplan-Meier plots, and wiH be analyzed using the Median test, to test for 
differences between treatments. 
Time to freedom from mechanical ventilation and the 
duration of ICU stay will also be presented by type of transplant, ancl the Median test will be 
performed on each type of transplant, if there are sufficient patient numbers in both 
categories. 
Ali other secondary endpoints wìll be presented using appropriate descriptive statistics, and 
no formal statistica] testing will be performed. 
ICU mo1tality and the number of patients who die within the first 30 days post transplant will 
be tabulated. 
FEV1 and PVC at 1 month post-transplant will be presented by type of 
transplant. 
FEV I and FVC, BOS score, cumulative acute rejection episodes and patient survival at 6 and 
12 months post-transplant will be presented in an addendum to the clinica! study report, usìng 
descriptive statistics. BOS score, cumulative acute rejection episodes and patient survival 
will also be presented by type of transplant. 
9.4.4. 
Analysis of the endpoint targeted to the mechanism of action 
PMN count in BAL specimen will be presented using descriptive statistics. 
9.4.5. 
Analysis of pharmacokinetic endpoints 
Plasma levels of repertaxin (total and unbound) and its major metabolite, DF2243Y, are 
recorded 24±6 hours anà 48 hours from the start of infusion, and then in the interval 2-6 hours 
after the end of infusion. Data will be summarised using descriptive statistics. 
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9.4.6. 
Saf ety analysis 
Safety variables will be presented for the Safety population. 
AEs will be presented, by treatment group, in tenns of the incidence, severity and relationship 
to the study drug, overall and by body system and preferred term. SAEs will be presented in 
the smne way. 
Laboratory tests are pe1formed at screening and at hospital discharge and shìft tables will be 
used to present shifts from within/outside the norma} range between screening and discharge. 
Vital signs at each time point, the change in vital signs from screening to each time point, and 
cardiopulmonary physìologic measurements at each time point will be presented using 
descri pti ve statisti es. 
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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INSTITUTIONAL REVIEW BOARD/RESEARCH ETHICS BOARO 
lt is the responsibility of the Investigator to obtain approvai of the trial protocol/amendments 
frorn the Institutional Review Board/Research Ethics Board (IRB/REB). 
Prior to the initiation of the study, the Investigator wìl1 submit to the approptiate IRB/REB for 
approva] the followings: 
• 
the study protocol, 
• 
the Patìent Informed Consent Document and any other w1itten documents to be 
provided to the patient, 
• 
the current version of the Investigator's Brochure, 
• 
Investigator's current curriculum vitae, 
• 
patient recruitment procedures e.g. advertisements, 
• 
any other requested document(s), 
A copy of the IRB/REB approva} will be sent to PPD 
along with ali other correspondence 
with the IRB/REB, including the submissìon documents. The Investigator should file all 
con-espondence with the IRB/REB in the Investigator Site File. PPD 
wìll promptly send to 
Dompé a copy of the IRB/REB approval. 
The study will not be started until full written approva] has been obtaìned from the 
appropriate IRB/REB. The letter of approval should be dated, and should specify the type 
(e.g. protocol number) and the date of the documents which were reviewed and approved. 
The Investigator will submit any future amendment to the protocol to the IRB/REB which 
granted the original approval (and other local authorities, according to local regulations). Any 
amendment will be implemented only when full approvai has been obrained from the 
approptiate IRB/REB, except for those amendments which involve only .logistica! or 
administrative aspects of the study. 
The Investigator wiU send to the IRB/REB any updated Investigator's Brochure. 
A dated list of the voting mernbers of the JRB/REB who were present when the 
protocol/amendment was reviewed and approved, including their titles/occupations and 
institutional affiliations should be provided where possible by the Investigator to PPD 
prior to study initiation. The Investigator will make all attempts to obtain a staternent from 
the IRB/REB that it is constituted and operates in accordance with the ICH-GCP and any 
locai regulations. 
The Investigator will submit required progress reports to the IRB/REB which approved the 
protocol at least annually, as well as report any serious unexpected ADRs, life-threatening 
problems or deaths. The Investigator will also infonn the IRB/REB of repo11s of serious 
unexpected ADRs (provided to him/her by PPD 
) occurred at other sites participating to 
this clinica! trial and/or in other clinicàl studies conducted with repertaxin. 
The Investigator must inform the IRB/REB of the tennination of the study. 
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10.2. 
INFORMED CONSENT 
No study-related procedures (including non-invasive and diagnostic procedures) will be 
undertaken prior to completion of the consenting process. Each potentially eligible patient 
will be informed of the study's objectives and overall requirements. The Investigator will 
explain the study fully to him/her using the Patient Informed Consént Document. If the 
patient is willing to participate in the study, (s)he will be requested to give written informed 
consent after being given sufficient time to consider his/her participation and the opportunity 
to ask for further details. 
The Patient Informed Consent Document will be signed and 
personally dated by both the patient and the Investigator. 
A copy of the signed form will be provided to the patient and the originai signed Patient 
Informed Consent Document will be retained and filed in the Investigator Site File. 
Although nursing staff may be involved in describing the tria] to a patient, the Investigator 
must participate in discussions with the patient and sign and personally date the Patient 
Informed Consent Document. 
Individuai (i.e. site specific) Patient Informed Consent Forms will be based on a master 
document provided by 
 and must be approved by 
 prior to submission 
to the IRB/REB. 
Any changes requested by the IRB/REB must be approved by 
 prior to the documents being used. A copy of the final, IRB/REB-approved 
Patient Informed Consent Document must be submitted to 
 prior to initiation of this 
study. 
Where applicable, patients next on the waiting list (max 25 patients) will be pre-consented, 
i.e. consent is provided before the patient is called into the hospital for transplantation. 
10.3. 
CONFIDENTIALITY 
The Investigator must ensure that the subjects' anonymity will be maintained. On the CRFs or 
other documents submitted to 
 patients should NOT be identified by their names, but 
by the assigned patient number if randomized plus their initials and date of birth (if not 
randomized). 
If patient names are included on copies of documents submitted to 
 the names (except 
for initials) will be obliterated or masked and the assigned patient number added to the 
document. 
The Investigator should keep a separate log (Patient Master List) of patient's codes, names, 
addresses, telephone number and hospital number (if applicable ). 
Documents that are 
collected but not required for submission to 
 (e.g. signed Patient Informed Consent 
Forms) should be maintained by the Investigator in strict confidence. 
10.4. 
COMPENSATI ON FOR MEDICINE-INDUCED INJURY AND 
INDEMNIFICATION 
Before the tria! formally starts, Dompé will take out an insurance contrae! covering the 
amount requested by the respective national/federal laws for patients participating in clinica] 
trials. The insurance contrae! will also cover the Investigator/Institution against claims arising 
from the tria!, except for claims that arise from malpractice and/or negligence, including 
violations of the study protocol. 
Final Revision No. 3, 20-March-2006 
CONFIDENTIAL 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Study REP0104 
Repertaxin in Lung Transplantation 
Page49 of73 
Should any patients suffer adverse effects as a direct consequence of the Investigational 
Product administration in accordance with the protocol, Dòmpé will reimburse for hospital 
medicai costs required for diagnosis and treannent. Medical treatment shall be provided 
primarily through the study center. 
Dompé will not provide for the costs of medica] care unrelated to the study. 
In case of questions about medical care, cost for medical care or insurance, patients can talk to 
their Investigator. Contact details will be given in the Patient Infonned Consent Document. 
Final Revision No.3, 20-March-2006 


Study REP0104 
Repertaxin in Lung Transplantation 
Page 50 of73 
11. 
DATA HANDLING ANO RECORD KEEPING 
11.1. 
CASE REPORT FORMS COMPLETION 
CRFs will be supplied by PPD •. CRFs are the sole property of PPD 
and should 
not be made available in any fonn to third parties, except for authorized representatives of 
appropriate Health/Regulatory Auth01ities, without w1itten perm.ission from PPD 
------
A CRF is required and should be completed for each included patient. The Investigator will 
be responsìble for the accuracy of the data entered ìn the CRFs. All entries must be written in 
ENGLISH in black ink. Source documents should be available to support ali the data 
recorded in the CRF. Location of source data, including those for whìch the CRF might be 
accepted as being the sole source document, will be specified and listed at the center Inìtìation 
Visit. 
The CRF must be available for review/collection to designated PPD 
representatives at 
each scheduled rnonito1ing visit. 
11.2. 
DATA MANAGE1\1ENT 
Data management of the CRFs will be perfonned by PPD 
distinct phases. 
and will be split into two 
For the blìnded (main) part of the study the CRF pages for all patients up to the month 1 visit 
wìl1 be data-entered (double data entry) into the study database, and the data will be verified 
for missing data, ìnconsistencies, and for any necessary medical clarifications. 
Queries arising from these checks will be sent to the Investigator for response and signature. 
All possible attempts should be made by the Investigator to complete and return the signed 
responses as instructed to PD 
within the requested timeframes. 
Once all data queries pertaining to the blinded part of the study have been resolved, the study 
will be declared to be "clean", and the study data will be locked ready for analysis. FoIJowing 
the data lock the study blind will be broken and each patient' s medicina] assignment (i .e. 
repertaxin or placebo) will be revealed to the appropriate Investigator. 
The CRF pages for both follow up visits i.e. months 6 and 12 will be entered ìnto a different 
location of the same database using the same procedure as described above. Furthermore 
when the last patient's month 12 visit has been "deaned" the database will be Iocked ready 
for the final analysis. 
After the database lock has been achieved, the Investigator may archive che copies of the 
CRFs retained at the center. The origina} CRFs collected by PPD 
will be archived by 
Dompé. 
Ali data management will be conducted in accordance with good clinical, scientific and data 
management principles and in compliance with current PPD 
SOP. 
Final Revision No, 3, 20-March-2006 
( 


Study REPO 104 
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PageSl of73 
11.3. 
DOCUMENTA TION REQUIRED PRIOR TO INITIATION 
In addition to the documents mentioned in Sections 10.1 and 12.1, the following will be 
required from the Investigator prior to the initiation visit: 
• 
• 
• 
• 
• 
• 
• 
• 
• 
11.4. 
Current, signed and dated Curriculum Vjtae of Principal Investigator and any 
Sub-In vesti gators/co-workers, 
Normal ranges of all laboratory tests to be performed at the study site and a recent 
certificatìon 
or 
accreditation 
of established 
quality 
control 
(or other 
documentation of established quality contro! or extemal quality assessment or 
other validation), 
A signed origina] of the final protocol and any amendments, 
Indemnìty / certificate of Insurance, 
A signed originai of the study Financial Agreement/Clinical Study Agreement 
with Dompé, including Phannacy, radiology etc (i.e. all study specific costs), 
Fonn 1572 (USA and Canada), Qualified Investigator Undertaking, Research 
Ethics Board Attestation, Clinica! Trial Site Infonnation Form (Canada only). 
Financial disclosure fo1m 3455 from all persons listed on the 1572, 
Data protection form (HJP AA in USA) signed by the Investigator (givìng the 
Investigator's approval and the patient's consent for persona! data to be kept on 
file at PD 
), 
List of delegated responsibility (Study Team Signature List / Delegatìon of 
Responsibilities fo1m). 
DOCUJ.\tlENTATION 
REQUIRED DURING THE STUDY 
The following will be required from the Investigator during the study: 
• 
CmTent, signed and dated Cuniculum Vitae of Principal Investigator and any 
Co-Investigators/co-workers who are delegated protocol related responsibilities 
after study initiation, 
• 
Updates of nonnal ranges (including the dates from which they become effective) 
of all laboratory tests to be pe1fom1.ed at the study site and updates in certification 
or accreditati on of established quality control ( or other documentation of 
established quality contro! or extema1 quahty assessment or other validation), 
• 
A signed original of any protocoJ amendments, 
• 
Copies of any new approvals from or correspondence with the IRB/REB, 
• 
Renewals of certificates of Insurance, as app]icable per country regulations, 
• 
Updated form 1572 (USA and Canada), Qualified Investigator Undertalcing, 
Research Ethics Board Attestation, Clinica! Trial Site Information Form (Canada 
only), 
• 
Financial disclosure fonn 3455 from all new persons listed on the 1572, 
• 
Updated list of delegated responsibility (Study Team Signature List / Delegation 
of Responsibilities fonn). 
Final Revision No.3, 20-March-2006 


Study REP0104 
Repertaxin in Lung Transplantation 
Page 52 of73 
11.5. 
ESSENTIAL DOCUMENT RETENTION 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP) 
unti] at Jeast 2 years after the last approvai of a marketing application in an ICH region, and 
until there are no pending or contemplateci marketing applications in an ICH regi on, or at least 
2 years have elapsed since the formai discontinuation of clinica! development of the 
Investigational Product. These documents should be retained for a longer period however if 
required by the apphcable regulatory requirements. The Investigator should take measures to 
prevent accidental or premature destruction of these documents. 
The essential documents include at least: the signed protocol, copies of the completed CRFs, 
signed Patient Informed Consent Forms from ali patients who consented, hospital records, and 
other source documents, IRB/REB approval and all related correspondence, including 
approved documents, and all other documentation included in the Investigator Site File and 
Phannacyillispensing File. 
The Investigator will inform PPD 
of the storage location of these essential documents and 
rnust contact PPD 
before clisposing of any. If the Investigator wishes to assjgn the 
files to someone else or to remove them to another location, the PPD 
Medicai 
Director should be consulted about this change. 
Dompé will infonn the Investigator in writing when these documents no Jonger need to be 
retained. 
Fina! Revision No.3, 20-March-2006 


Study REPO I 04 
Repertaxin in Lung Transplantatìon 
Page 53 of 73 
12. 
STUDY MANAGEMENT 
The study wiJl be performed in accordance with the protocol, the Declaration of Helsinki 
(Appendix 5), and ICH Harmonised Tripartite Guideline for Good Clinica! Practice (ICH-
GCP) and any local regulations. 
12.1. 
REGULATORY BODY APPROV AL 
The study will not be started until full written approval from the relevant reglllatory body 
(FDA and Health Canada) has been received by Dompé. PPD 
will then previde the 
Investigator with a copy of appropriate document on behalf of Dompé. 
PPD 
unde:rtakes to obtain (on behalf of Dornpé) the necessary approvai from the Health 
Canada p1ior to initìation of the study. The responsibìlity for gaining FDA approva] lies with 
an independent regulatory consultant employed by Dompé. 
12.2. 
STAFF INFORMATION & RESPONSIBILITIES 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully infonned of all relevant aspects of the study, including detailed knowledge of and 
training in all procedures to be followed. 
The Investigator will provide a list of delegated responsibility to PPD 
detailing the various 
study tasks to be performed by each member of hìs/her study staff. Bach staff mernber should 
sign in agreement to their perfonning each of the tasks delegateci to them on the list. 
12.3. 
MONITORING 
Monitoring will be canied out by ..._P_D 
___ 
_., according to the current version of PD 
SOP. 
Prior to study stait, the Investigator will be informed of the anticipated frequency of the 
monitoring visits. He/she will also receive a notification prior to each monitoring visit during 
the course of the study. It is expected that the Investigator and/or his/her sub-Investigator(s) 
and other appropriate staff will be available on the day of the visit to discuss study conduct 
and to cooperate with the monitor to ensure that auy problems detected during the course of 
these monitoring visits are resolved. 
The purpose of the monitoring visit .is to ve1ìfy that the rights and the wellbeing of the patient 
are protected, that the reported data are accurate, complete and verifiable from source 
documents and that the conduct of the tria! complìes with the currently approved protocol and 
any amendments, with ICH GCP, and with regulatory requirements. 
The CRA will complete a standard report following each Monitoring Visìt and provide this 
repo1t to the Project Leader for review within a specified tirneframe. 
Final Revision No. 3, 20-March-2006 


Study REPO 104 
Repertaxin in L1mg Transplantation 
Page 54 of73 
12.3.1. 
Access to records 
The Investigator will a1low designated PPD 
representatives, 
designated Dompé 
representatives, and regulatory bodies to have direct access to the source documents to verify 
the data reported in the CRFs. Source documents are the originals of any documents used by 
the Investigator or hospital/institution that allow verification of the existence of the patient 
and substantiate the ìntegtity of the data collected during the tria!. Source documents shoulcl 
be available to support all the data recorded in the CRF. Location of source data, including 
those for which the CRF might be accepted as being the sole source document, will be 
specified and listed at the center Initiation Visit. 
12.4. 
AUDIT AND INSPECTION 
Audìt activìties will be perlormed by PPD 
Quality Assurance group, except for audit of 
Protocol/ Amendments, Patient Informed Consent Document, and CRF, which will be 
perfonned by the Dompé Quality Assurance Unit. 
On one or more occasions the study site may be audited by PPD 
. The Investigator will be 
informed in advance of such a vìsit. All audits will be performed by 
PD 
personnel 
according to the current version of PPD 
SOP. 
Additionally the study site may be inspected by Dompé representatìves or a regulatory agency 
on one or more occasions. 
12.5. 
PROTOCOL DEVIATIONS/Al\tIENDMENTS 
Changes to the Protocol wìll be implemented only when written amendments have been 
signed by all individuals who sìgned the protocol. 
Any amendment will be sent to the appropriate IRB/REB. No deviations from or changes to 
the protocol wilJ be implemented without documented approvai of an amendment from the 
IRB/REB which granted the originai approval, except where necessary to eliminate an 
immediate hazard(s) to tria! patient, or when the change(s) invoJves only logistica! or 
administrative aspects of the trial. The devìations from or changes to the protocol 
implemented to eliminate an immediate hazard to the tria! patient and the proposed 
amendrnent, if appropriate, should be submitted to the IRB/REB for review and approva! as 
soon as possible. 
Any other deviation from the protocol that has not been approved by 
PD 
and the 
IRB/REB could result in a dìscontinuation from the study at the center involved. 
Any written amendment will be sent to all recipients of the protocol and to the regulatory 
authorities (FDA/Health Canada). 
12.6. 
DISCONTINUA TION OF THE STUDY 
Dompé 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 ali CRFs completed to the extent possible. 
Study discontinuation will be notified to FDA/Health Canada within 5 days from decìsion. 
Final Revision No.3, 20-March-2006 
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Study REP0104 
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12.7. 
PUBLICATIONS 
Any manuscript, abstract or other publication or presentation of results or information arising 
in connection with the study must be prepared in conjunction with Dompé and must be 
submitted to the Dompé Medical Director for review and comment at least 45 days prior to 
submìssìon for publication or presentation. 
Final Revision No. 3, 20-March-2006 


Study REP0104 
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Page 56 of73 
13. 
REFERENCES 
Baggiolini M, Dewald B, Moser B. lnterleukin-8 and related chemotactic cytokines CXC and 
CC chemokines. Adv Immunol 1994; 55:97-179. 
Be1tìni R et al. Non-competitive al1osteric inhibitors of the inflammatory chemokine receptors 
CXCR1 and CXCR2: prevention of reperfusion injury. PNAS 2004; 101: 11791-11796. 
Christie ID, Bavatia JE, Palevsky Hl, Litzky L, Blumenthal NP, Kaiser LR et al. Primary 
graft failure following lung transplantation. Chest 1998; 114(1 ): 51-60. 
Christìe JD, Carby M, Bag R, Conis P, Hertz M, Weill D. Report of the ISHLT Working 
Group on Prìmary Lung Graft Dysfunction Part Il. Definition. A consensus Statement of the 
International Society of Heart and Lung Transplantation. J Heart Lung Transplant 2005; 
24: 1454-1459. 
Christie ID at al., Impact of P1imary Graft Failure on outcomes following lung 
transplantation. Chest 2005; 127:161-165. 
Clinical safety data management: Definitions and Standards for Expedited Repo1ting (E2A -
Approved by the CPMP in November 1994 for studies commencing after 1st June 1995 [Note 
for Guidance 3C614A]; Approved by FDA with effective date 1st March 1995 [60 FR 
11284]). 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976; 16:31-41. 
de Perrot M, Sekine Y, Fischer S, Waddell T, McRae K, Liu M, Wig1e DA, Keshavjee S. 
Interleukin-8 release during early reperfusion predicts graft function in human lung 
transplantation. Am J Respir Crit Care Med 2002; 165: 211-215. 
de Perrot M, Liu M, \.Vaddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. 
Am J Respir Crit Care Med 2003; 167: 490-511. 
De Vries ME, Hosiawa KA, Cameron CM, Bosinger SE et al. The role of chemokine receptors 
in allogenic-independent anà allogenic-dependent transplantation injury. Sem Immunol 2003; 
15:33-48. 
Estenne M, Maurer JR, Boehler A, et aJ. Bronchìolitis obliterans syndrome 2001: an update of 
the diagnostic criteria. J Heart Lung Transplant 2002; 21:297-310. 
Fischer S, Matte-Martyn A, de Perrot M, Waddel1 TK, Sekine Y, Hutcheon M et al. Low-
potassium dextran preservation solution improves lung function after human lung 
transplantation. J Thorac Cardiovasc Surg 2001; 121(3):594-596. 
Fiser SM, Tribble CG, Long SM, Kaza AK, Kem JA, Jones DR, Robbins MK, Kron IL. 
Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis 
obliterans syndrome. Ann Thorac Surg 2002; 73:1041-1047. 
Final Revision No. 3, 20-March-2006 
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Study REP0104 
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ICH Hannonised Tripartite Guidehne for Good Clinical Practice (June 1996), as 
recommended for adoption to the three regulatory parties to ICH. Approved on l ih July 1996 
(CPMP/lCH/135/95). Approved by FDA on 9th May 1997 and effective 9th May 1997 (62 FR 
25692). Accepted and published by Health Canada, 1997. 
Keshavjee SH, Davis RD, Zamora MR, Schulman LL, de Perrot M, Patterson GA. A 
randomized placebo controlled tria! of complement inhibition in ischemia-reperfusion ìnjury 
after lung transplantation in humans. In press 
King RC, Binns OA, Rochiguez F, Kanithanon RC, Daniel TM, Spotnitz WD et al. 
Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. 
Ann Thorac Surg 2000; 69(6): 1681-1685. 
Lau CL, Patterson GA. Current status of lung transplantation. Eur Respir J 2003; 47:57s-64s. 
Lefer AM, Johnson G 3rd, Ma XL, Tsao PS, Thomas OR. Cardioprotectìve and endothelial 
protective effects of [Ala-IL8]77 in a rabbìt model of myocardial ischaemia and reperfusion. 
Br J Pharmacol 1991; 103(1):1153-9. 
Matsumoto T, Ikeda K, Mukaida N, Harada A, Matsumoto Y, Yamashita J, Matsushima K. 
Prevention of cerebral edema and infarct in cerebral reperfusion injury by an antibody to 
interleukin-8. Lab Invest 1997; 77(2):119-25. 
McRae KM, Pulmonary transplantation. Curr Opin Anaesthesiol 2000; 13:53-59. 
Meade MO, Granton Jt, Matte-Martyn A, McRae K, Weaver B, Ctipps P, Keshavjee SH and 
the Toronto Lung Transplant Program. A randornized trial of inhaled nitric oxide after lung 
transplantation. Arn J Repsir Crit Care Med 2003; 167:1483-1489. 
Mìura M, Fu X, Zhang QW, Remick DG, Fairchild RL. Neutralization of Groa and 
macrophage inflamrnatory protein-2 attenuates renal ischemia/reperfusion injury. Aro J Pathol 
2001; 159:2137-2145. 
Morita K, Miura M. Paolone DR, Engeman TM, Kapoor A, Remick DG, Fairchild RL. Early 
chemokine cascade in murine cardiac grafts regulate T celi recruitment and progressìon of 
acute allograft rejection. J Immunol 2001; 167: 2979-2984. 
Patterson GA, Cooper ID, Goldman B et al. Technique of successful clìnìcal double lung 
transplantation. Ann Thorac Surg 1988; 45:626-633. 
REP0l0l - Clìnical study ME0706; Dompé Internal Report (final). 
REP0102 - Clinical study 'ME0735; Dompé Interna] Report (final). 
REP0103 Clinica} stuyd ìv1E0757; Dompé Internal Report (final). 
REP0203 - Clinica} study ìv1E0761; Dompé Internal Report (final). 
Sekido N, Mukaida N, Harada A, Nakanishi I, Watanabe Y, Matsushima K. Prevention of 
lung reperfusion injury in rabbìts by a monoclonal antibody against interleukin-8. Nature. 
1993; 365(6447):654-7. 
Final Revision No. 3, 20-March-2006 


Study REPO 104 
Reperta,,ù1 in Lung Transplantation 
Page 58 of73 
Sommers KE, Giiffith BP, Hardesty RL, Keenan RJ. Early lung allograft function in twin 
recipients from the same donor: tisk factor analysis. Ann Thorac Surg 1996; 62(3):784-790. 
Souza DG, Bertinì R, Viera AT, Cunha Q, Poole S, Allegretti M, Calotta F, Teixeira M1'vL 
Repertaxin, a novel inhibitor of rat CXCR2 function, inhibits inflammatory responses that 
follow intestinal ischemia and reperfusion injury. Br J Pharmacol 2004; 143:132-142. 
Thabut G, Vinatier I, Stem J-B, Lesèche G, Loirat P, Fournier M, Mal H. Primary graft failure 
following lung transp1antation. Predictive factors of mortality. Chest 2002; 121: 1876-1882. 
Waddell TK, Gorczynsld RM, DeCampos KN, Patterson GA, Slutsky AS. Major 
histocompatibility complex expression and lung ischemia- reperfusion in rats. Ann Thorac 
Surg 1996; 62(3):866-872. 
Welbourn CR, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB. 
Pathophysiology of ischaemia reperlusìon injury: centra} role of the neutrophil. Br J Surg. 
1991; 78(6):651-5. 
Yamaguchi Y, Ohshiro H, Nagao Y, Odawara K, Okabe K, Hidaka H et al. Urinary trypsin 
inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion. J Surg Res 
2000; 94:107-115. 
Yousem SA, Be1Ty GJ, Cagle PT, et al. A revìsion of the 1990 working formulation for the 
cJassification of pulmonary allograft rejection: Lung rejection study group (LRST). J Heart 
Lung Transplant 1996; 15:1-15. 
Zamora MR, Davis RD, Keshavjee SH, Schulman L, Levin J, Ryan U and Patterson GA. 
Complement ìnhibition attenuates human lung transplant reperfusion ìnjury. Chest 1999; 
l 16:46S. 
Final Revision No. 3, 20-March-2006 


Study REPO 104 
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Page 59 of73 
14. 
APPENDICES 
14.1. 
APPENDIX 1 - METHODOLOGICAL DETAILS 
14.1.1. 
PGD score - ISHL T system for grading of severity of primary graft 
dysfunction [ Christie et al, 2004] 
Grade O 
PaOi/FiO2 >300 mmlfa; no radiograohic ìnfiltrates 
Grade 1 
PaO2'FiO2 2:,300 rnmHg + radiographic infiltrntes consistent 
with pulmonarv oedema 
Grade 2 
200 mmHg _:ç PaOz/FiO2 <300 mmHg + radiographic infiltrates 
consistent with oulmonarv oedema 
Grade 3 
PaOi/FiO2 <200 mmHg + radiographìc infiltrates consìstent 
with pulmonarv oedema 
Any patient with no infiltrate on chest X-rays is automatically grade O, regardless of 
PaO2/FiO2 value. If the patìent is on nasal cannula for oxygen or FiO2 <0.3, the patient is 
graded as O or 1, based on chest X-rays. 
Any patient on extra corporea] membrane 
oxygenation is automatìcally grade 3. Any subject mechanically ventilated with FiO2 greater 
than 0.5 or requiring nitric oxide beyond 48 hours from the time of trnnsplant should be 
considered grade 3. 
If multiple blood gas values are available, the worst Pa0i/FiO2 ratio will be used for the 
purpose of this grading scheme. 
PGD score will be evaluated at the following time points: 
-
Time-O (T0): defined as within 6 hours of final lung reperfusion. The first blood gas in 
ICU is idea! for this. ldeally, measurement should be done on FiO2 1.0 and PEEP =5 while 
stili on mechanìcal ventilation. 
-
T24, T48, T72: Later times being measured at potentially multiple time points after 24 
hours, up to 72 hours. Time will be measured following T0±6 hours. 
Chest X-rays will graded by an Investigator, and then validated by a (blinded) transplant 
radiologist. 
In patients with cJinical diagnosis of PGD additional time points will be considered up to the 
clinical recovery of the condition as per available data according to center standard of care. 
14.1.2. 
Bronchoalveolar lavage methods 
BAL specimen 
BAL sample will be taken from the allograft (first implanted allograft, in case of bi-latera1 
lung transplantation). 
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Study REP0104 
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The dìstal bronchoscope will be wedged in a subsegmental bronchus of either the right middle 
or left lingular lobe. Ifa prominent, focal infiltrate is present on chest X-rays, BAL will be 
perf ormed in the area of maximal radiographic abnormality. 
Approximately 50 mL aliquots of sterile, pre-warmed, non-pyrogenic, isotonic sodium 
ch]oride solution will be instilJed through the bronchoscope and immediately recovered by 
gentle suctìon (60 to 80 mmHg). This "back and fo1th" is repeated for a maximum of 4 
washes. 
The recovered fluid will be pooled and mixed thoroughly. Tota} recovered volume will be 
measured. BAL fluid will be transferred to the center laboratory on ice, but it can be 
transported at room temperature if processing wil1 be undertaken within 30 minutes. 
BAL processing 
The recovered ce11 suspension wìll be filtered through surgical cotton gauze to remove excess 
mucus. To determine the total cell yield, a small aliquot of the fluid will be used for counting 
the ce1Is on a hemacytometer. Red blood cells are not included in the total celi yield. 
The BAL fluid will be then placed in siliconized glass or non-cell-adherent plastic centrifuge 
tubes and will be centrifuged at 200 x g for 5 minutes. The supematant will be discharged, 
taking care not to disturb the cell pellet. The cells pel1et will be resuspended in and washed 
twice with Hanks' balanced salt solution (or another medium such as phosphate-buffered sa1t 
solution) without Ca2+ and Mg2+. 
To obtain differential cell counts the cell suspension (approximately lxl0 5 cells) will be 
cytocentrifuged at 800 g for 10 minutes. The slides will be stained as per center practice 
(May-Grunwald-Giemsa or Diff-Quick stain is suggested) and air dried at room temperature 
for 1 hour. Stained spot will be fixed (Entellan fixative is suggested), and slides covered by a 
microscope cover glass and stored until shìpment to Dompé pha.r.ma s.p.a. (see below). 
Detailed packaging and labeling instruction and shipment procedures will be communicated at 
each center at stucly initiation. 
Cell differentials wiH be petfonned by Dompé pha.r.ma s.p.a. - Preclinical Pharmacology 
Department. Two hundreds cells will be counted in each slide. 
14.1.3. 
Handling of samples for pharmacokinetic assay 
Samples will be centrifuged ideally within 15 minutes at 2500g (3350 rpm) at 4°C for 10 
minutes. If that is not possible then samples can be stored at room temperature for not more 
than 2 hours or at 4°C for not more than 24 hours before centrifugation. At least 3 m.L of 
plasma will be obtained and divided equally into 2 aliquots, one to be used for tota! repertaxin 
and DF2243 Y, the ot.her for the repertax.in unbound fraction. Plasma samples will be stored at 
approximately -80°C into stopped glass tubes, unti! shipment to the centra1ized analytical 
Iaboratory for assay. 
Samples will be shipped to the centralized laboratory in appropriate package in dry ice (solid 
C0 2) to maìntain frozen conditions. Detailed packaging and labelìng instruction and shipment 
procedures will be communicated at each center at study initiation. 
Analysis will be 
perlormed by a centralized laboratory according to standardized and validated methods as per 
Good Laboratory Practices. 
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Study REPO l 04 
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Page 61 of73 
PPD 
, has been identìfied as the centralized laboratory where 
phannacokìnetic analysis is pe1formed. 
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14.2. 
APPENDIX 2- PACKAGING AND LABELJNG DETAILS 
A "Patient Box" will be prepared for each patient. Each Patient Box will contain: 
• Two Treatment Boxes, each with 25 x 10 mL ampoules - either containing repertaxin or 
placebo. 
• Two (p]us one reserve) sterile empty infusion bags 
• Instructions to the Phannacy 
All items will have labels (English and French language forali, except ampoules); specimens 
of these are provided below. Only the Iabel of the infusion bag will be a "double - tear off' 
label. The Investigational Product already packaged to the date of thìs protocol revision, 
whether sent to the site or stored at Aptuìt, WILL NOT BE RE-LABELED. Labels of any 
additional future supplies will have the same format/information, apart from the name of the 
sponsor that will read "Dompé pha.r.ma s. p.a. ". 
NOTE: + 
Patient No. XXYY where 
XX= Study site 
YY = Patient sequential number within the site 
(The first patient at Study Site No.1 will have the number 0101). 
lnfusion Bag - "Preparation" date and time, as well as "Use by" date and time 
will be entered by the Phannacist. 
Use by date/time will be calculated as 
date/time of preparati on+ 72 hours (expiry date/time of the dosing solution). 
Patient Box and Infusion Bag - Patient initials will be entered by the 
Pharmacist. 
Specimen Label for exterior of each Patient Box 
STUDY (ESSAI) REP0104 
Sponsor (Promotew'): Dompe s.p.a.~ Via Campo di Pile, L'Aquila -- ltaly 
PATIENT BOX (BOITE pour PATIENT} 
PATIENT No. XXYY 
PATIENTN° 
PATIENT INITIALS 1-1-1-1 [to be entered by the Pharmadst] 
INITIALES DU PATIENT 
fàcomp!éterpar!ePharm~cienJ 
CONTAINS: 1WO TREATMENT BOXES [No. 1 (0·24 h); No. 2 (24-48 h)], 1WO STERILE EMPTY INFUSION BAGS (PLUS ONE 
RESERVE 
BAG), INSTRUCT1CNS 
TO THE PHARMACY 
CONTENfJ: 
DEUX 80/TES DE TRAITEMENT 
[N° 1 (0-24 h}; N° 2 (24-48 h}J, DEUX POC4ES DE' PE'RFUSION 
VIDES ET STERILES (PLUS UNE POCHE 
DE RE'SE.~VE}, 
LES INSTRUcnONS POUR lA PHARMAOE 
INVESTIGATIONAL PRODUCTS: REPERTAXIN OR PLACEBO INJECTABLE SOLUTION 
PRODUffS DE RECHERCHE: SOLIJTION INJECTABLE DE REPERTAXIN 0IJ DE PLACEBO 
BUNDED BATCH No. 
N" Oé LOT CODJffE 
For questions • CRO contact = 
Pour toute questton contacter la ORC= 
EXPIRY DATE mm/yyyy 
DATE Dé PERE'MP710N 
mm/aaaa 
I 
DO NOT STORE AT >30°C {86°F) 
NE PAS ENTREPOSER A >30°C (86•F) 
I 
DIRECTIONS: Use ampoules in Treatment Box No. 1 and Treatment Box No. 2 to prepare the dosing solution of Investigational 
Product for the 0-24 hours and 24-48 hours periods, respectively. 
INSTRllCTIONS: Utiliser respectivement !es ampoufes de la Bolle de Traltement N° 1 et de la Bofte de Ttattement N" 2 pour préparer !es doses de 
so!utlons du Produits de Recherche durant !es périodes de 0-2·1 heures et 2448 /Jevres. 
CAUTION: 
New Drug-Umited by Federai law to investigational use. Investigational drug to be used by a qualified investigator only. 
ATTENTION: 
Nouvelle substance • Umitée à la recherche par la foi Fédérate. Produft de recherche, ne dolt étre urìliSé que par un tnYestlgateur quali!Jé. 
Final Revision No.3, 20-March-2006 


Study REPOJ04 
Repertaxin in Lung Transplantation 
Page 63 of73 
Specimen Label for Treatment Box No. 1 [time period 0-24 hours] 
STUDY (ESSAI) REP0104 
Sponsor (Promoteur''): Dompé s.p.a.; Via Campo di Pile, L'Aquila - Italy 
TREATMENT BOX No. 1 {0·24 hours} 
BOITE DE TRAITEMENT N" 1 (0-24 heures} 
PATIENT No. XXYY 
PATIENTN~ 
CONTAINS: 
25 AMPOULES 
OF 10 ml REPERTAXIN 
(33 mg/ml) OR PLACEBO FOR INJECTABLE 
SOLUTION 
CONTENU: 
25 AMPOUlE5 OE 10 ml DE SOLUTION INJECTABLé DE REPERTAXIN (JJ mg/ml) OU Oé PLACEBO 
BLINDED BATCH No. 
N" DE LOT CO[JlfiE 
EXPIRY DATE mrn/yyyy 
VATE DE PERENPTION mm/aaaa 
DO NOT STORE AT >30°C (86°F) 
NE PAS ENTREPOSER 
A >30°C {86~F) 
For questions - CRO contact "' 
Pour toute question contacter la ORC:= 
PPo.----------------------
DJRECTIONS: 
Transfer into infusion BAG No. 1 the contents of 23 AMPOULES + 370 ml of 0.9% Naa, according to procedures 
detailed !n the "Jnstructions to the Pharrnac/'. Report preparation date and time, and use by date and time (72 
hours from preparat!on) on the bag !abel. 
NOTE: This box contains 2 AMPOULES ìn excess that are to be used as RESERVE ONLY. 
INSTRUCTIONS: 
Transférer le contenu de 23 ampoules dans la Pod1e de perfusion N° 1 + 370 ml de NaCI à 0.9%, comme Jnd!qué dans la procédure 
déloiliée « Instructions pour la Pharmade ». écrire /éJ dc1te et /'Mure de préparatlon ainsl que la date et l'heure de péremption (72 
heures à partir de fa préparation) s11r l'étlquette de la poche. 
NOTE: Celte boite conaent 2 AMPOULES supplémeotat,--es 
à n'utiliser que COM/IIE RESERVE. 
CAUTION: 
New Drug-Limited by Federai law to investigational use. Investigalional drug to be used by a qualified investlgator on!y. 
A TTENTION: Nouvelle substance - Umitée à la recherche par /éJ tal Fédérale. Produit de recherei/e, ne doit etre uti!isé que par un lnvestigateur qua/itìé. 
Specimen Label for Treatment Box No.2 [time period 24-48 hours] 
STUDY (ESSAI) REP0104 
Sponsor (Promoteur'): Dornpé s.p.a.; Via campo di Pile, L'Aquila - Jtaly 
TREATMENT BOX No.2 (24-48 hours) 
BOITE DE TRAITEMENT N° 2 (24-48 heures} 
PATIENT No. XXYY 
PATIENTN° 
CONTAINS: 
25 AMPOULES 
OF 10 ml REPERTAXIN 
(33 mg/ml) OR PLACEBO FOR INJECTABlE SOLUTION 
CONTENU: 
2S AMPOUlES DE 10 ml DE SOl/JTlON /NJECTABLE DE REPERTAXIN {33 mg/ml} OU DE PLACEBO 
BLINDED BATCH No. 
N° DE LOT CODIFIE 
For questions • CRO contact = 
Pour toute question contacter là ORC= 
EXPIRY DATE mm/y,fYY 
DATE DE PERéMPTION mm/a<1aa 
PD 
DO NOT STORE AT >30°C (86°F) 
NE PAS ENTREPOSER 
A >.30°C {86°F) 
OIRECTIONS: 
Transfer into infusion BAG No. 2 the contents of 23 AMPOULES + 370 ml of 0.9% NaO, according to procedures 
detaileò in the "Instructìons to the Pharmacy". Report preparation date and time, and use by date and time (72 
hours frorn preparation) on the bag label. 
NOTE: This box contains 2 AMPOULES In excess that are te be used as RESERVE ONLY. 
INSTRUCTIONS: 
Transférer le contenu de 23 r1mpo11les 
d,ms la Poche de perfusion N° 2 + 370 ml de Naa iJ 0.9%, comme im:liqué dans la procédure 
détatlfée « Instructions pour la Phannacie .», ferire la date et l'heure de prép,m1aon ainsi que fa date et l'heure de péremption (72 
lleures à partir de la préparation) sur l'étiquette de la poche. 
NOTE: Cette bcite contient 2 AMPOlJLES 
supplémentaires à n'utilìser que COMME RESERVE. 
CAUTION: 
New Drug-Limited by Federai law to investigalional use. Investigational drug to be used by a qualified investigator only. 
A TTENTION: Nouvelle substance • Limltée à fa recherclle par la loi rédérafe. Produit de recherche, ne doit étre utìlisé q11e par un investigateur quatifié. 
Final Revision No.3, 20-March-2006 


Study REPO 104 
Repertaxin in Lung Transplantation 
Page 64 of73 
Specimen double tear off Label for Infusion Bag No. 1 [time period 0-24 hours] 
STUDY (ESSAI) REP0104 
Sponsor (Promoteur): Dompé s.p.a.; Via campo dì Pile, L'Aquila - Italy 
INFUSION BAG No. 1 (0-24 hours) - POCHE DE PERFlJSION N° 1 (0-24 heures} 
PATIENT No. XXYY 
PATIENTN° 
PATIENT INITIALS 1-1-1-1 [to be entered by the Pharmadst] 
INITIALES DU PA TIENT 
{ii compléter par te Pflarmacien] 
CONTAINS: 
600 ml OF REPERTAXIN 
(12.65 mg/ml) OR PLACEBO INJECTABLE DOSING SOLUTION 
CONTENU: 
600 ml DE SOllfflON !NJECTABLE 
DE REPERrAX!N (12.65 mg/ml) ou DE PLACEBO 
PREPARED ON I_I_I/ l_!_I/ I_I_I_I_! 
PREPAREE LE 
dd (jj) / 
mm I WYY (aaaa) 
USE BY 
[_l_l/l_l_l/l_l_l_i_l 
lJTIUSERAVANTLE 
dd (ji) / 
mm / WYY(aaaa) 
For questions • CRO contact "' 
Pour toute question contàcter la ORC"' 
PD 
I_I_I : !_I_! 
[to be entered by the PharmacistJ 
h 
: 
min 
[à compléter par le Pharmacien] 
DO NOT STORE AT >30°C {86°F) 
NE PAS ENTREPOSER A >30°C (86°F) 
1-1-1 : I_J_I [to be entered by the Pharmacist] 
h 
min 
[à compléter par le Phannacien] 
DIRECTIONS: 
Administer as a continuous i.v. infusion into a (high flow) centrai vein, by an infusion pump. Infusion wil! start 
approximately 2 hours before reperfusion. Pump rate for the loading (0-30 min ìnfusion) and maintenance (30 min 
- 24 hours infusion) dose will be adjusted according to patient body weight as per Appendix 3 of Study Protocol. 
INSTRUCTIONS: Admfnlstrer 
à /'a/de d'une pompe 8 fnfusion en fntusion continue i. v, dens une veine centrò/e 
(haut debit}. L 7nfusio11 
doit commencer 
environ 2 heurcs 1want fa reperfusion. Le nux de la pompe pour la dose de charge (infusion 0-30 min) et d'équl!ibre (infusion 30 min 
- 24 heures) devra §tre a/usté en fonctfon du poids du patlent comme !nd!qué dans !'Appendice 3 du Protocole d'Essai. 
CAUTION: 
New Drug-Lirnited by Federai law to investigational use. Investigationa! drug to be used by a qualified investigator only. 
A TTENTION: 
Nouvelle svbstance - Llmltée a la recherche par la /of Fédérale. Prodult de recherche, ne doit etre utifisé que par un investigateur qu,1/ifié. 
Final Revision No.3, 20-March-2006 


Sludy REP0104 
Repertaxin in Lung Transplantation 
Page65 of73 
Specimen double tear off Label for Infusion Bag No.2 [time period 24-48 bours] 
STUDY (ESSAI) REP0104 
Sponsor (Promoteuf): Dompé s.p.a.; Via Campo di Pile, L'Aquila - ItalY 
INFUSION BAG No. 2 (24-48 hours) - POCHE DE PERFUSION N" 2 {24-48 heures) 
PATIENT No. XXYY 
PATIENTN" 
PATIENT INITIALS 1-1-1-1 [to be entered by the Pharmacist] 
INITIALES DU PA TIENT 
fa compléter par le Pharmacien] 
CONTAINS: 
600 ml OF REPERTAXIN 
(12.65 mg/ml) OR PLACEBO INJECTABLE DOSING SOLUTION 
CONTENU: 
500 mL DE SOLU7TON 
lNJECTABLE 
DE REPERTAXJN 
(1.l.65 mg/ml) OU DE PLACEBO 
PREPARED ON l_!_l/l_l_l/!_I_I_I_I 
PREPAREE LE 
dd Ui) / 
mm / WYY (aaaa) 
USE BY 
I_I_I/I_I_I/I_I_I_I_I 
UTILISERAVANTLE 
dd (jj) / 
mm / WYY (aaaa) 
For questions - CRO contact = 
Pour toute question contader la ORC= 
I_I_I : !_I_I 
[to be entered by the Pharmacist] 
h 
: 
min 
[à compléter par le PtJarmacien) 
DO NOT STORE AT >30°C (86°F) 
N& PAS ENTREPOSER A >30°C {86°F) 
LJ_I : I_I_I 
[to be entered by the Pharmacist] 
h 
min 
[à complérer par le Pharmaden] 
DIRECTIONS: Administer as a continuous i.v. infuslon into a (high flow) centrai vein, by an infusion pump. Pump rate far the 
maintenance dose (24-48 hours infusion) will be adjusted according to patient body weight as per Appendix 3 of 
Study Protoco!. 
INSTRUCTIONS: Administrer à /'a/de d'une pompe J infusion en infusion conanue i.v. dans une vetne centrale (haut déblt), Le /lux oc liJ pompe pçur 
mainter1ir te doSège (infusion 1448 heures) devra ètre aJusté en f'onction di.I polds du patient comme incliqué dill1$ l'Appendice 3 du 
Protocole d'Essai. 
CAUTION: New Drug-Limited by Federai law to investigational use. Investigational drug to be used by a qua!ified tnvestigator only. 
A rrENTION: 
Nouvelle substance • Umftée à la recherche par la loi Fédérale. Produit de recherche, ne doit étre utillsé que par un r,,vestigateur qua/ifié, 
Specimen label for each ampoule - repertaxin or placebo 
STUOY REP0104 
Dompé s.p.a., Jtaly 
PATIENT No. XXYY 
10 ml of repertaxin (33 mg/ml) or placebo 
DO NOT STORE AT >30°C (86°F) 
Blindecl batch No. 
Expiry date mm/yyyy 
New Drug•Llmlted by Federai law to 
investigational use. lmrestigational drug 
to be used by a qualified investlgator 
onlv. 
Final Revision No. 3, 20-March-2006 


Study REP0 I 04 
Repertaxin in Lung Transplantation 
Page 66 of 73 
14.3. 
APPENDIX 3 • STUDY DRUG INFUSI ON RA TE BY BODY WEIGHT 
Loading dose = 4.488 mg/kg /hour 
Dosing solution (repertaxin) = 12.65 mg/mL 
Maintenance dose= 2.772 mg/kg /hour 
BODY WEIGHT(kg) 
LOADING DOSE 
MAINTENANCE DOSE 
(each figure is from 0.00 to 0.99) 
(mL/hour x 30 min) 
(mL/hour x 47.5 hours) 
30 
10,6 
6,6 
31 
11,0 
6,8 
32 
11,4 
7,0 
33 
11,7 
7,2 
34 
12,1 
7,5 
35 
12,4 
7,7 
36 
12,8 
7,9 
37 
13,1 
8,1 
38 
13,5 
8.3 
39 
13.8 
8,5 
40 
14,2 
8,8 
41 
14,5 
9,0 
42 
14~9 
9,2 
43 
15,3 
9,4 
44 
15,6 
9,6 
45 
16,0 
9,9 
46 
16,3 
10,1 
47 
16,7 
10,3 
48 
17,0 
10,5 
49 
17,4 
10,7 
50 
17,7 
11,0 
51 
18,1 
11,2 
52 
18,4 
11,4 
53 
18,8 
11,6 
54 
19,2 
11,8 
55 
19.5 
12,1 
56 
19,9 
12.3 
57 
20,2 
12,5 
58 
20,6 
12,7 
59 
20,9 
12,9 
Final Revisìon No. 3, 20-March-2006 


Study REP0I04 
Repertaxin in Lung Tra11spla11tation 
Page 67 of73 
BODY WEIGHT(kg) 
LOADING DOSE 
MAINTENANCE DOSE 
(each ffaure is from 0.00 to 0.99) 
(mL/hour x 30 min) 
(mL/hour x 47.5 hours) 
60 
21,3 
13.1 
61 
21.6 
13.4 
62 
22,0 
13.6 
63 
22,4 
13.8 
64 
22.7 
14,0 
65 
23.1 
14.2 
66 
23.4 
14.5 
67 
23.8 
14.7 
68 
24.1 
14.9 
69 
24.5 
15.1 
70 
24.8 
15.3 
71 
25.2 
15.6 
72 
25.5 
15.8 
73 
25.9 
16.0 
74 
26.3 
16.2 
75 
26,6 
16.4 
76 
27.0 
16.7 
77 
27.3 
16.9 
78 
27.7 
17.1 
79 
28.0 
17,3 
80 
28.4 
17.5 
81 
28.7 
17.7 
82 
29.1 
18.0 
83 
29.4 
18.2 
84 
29.8 
18.4 
85 
30.2 
18.6 
86 
30.5 
18.8 
87 
30.9 
19.1 
88 
31.2 
19.3 
89 
31,6 
19.5 
90 
31.9 
19.7 
91 
32.3 
19.9 
92 
32.6 
20.2 
Final Revisìon No.3, 20-March-2006 


Study REP0104 
Repertaxin in Lw1g Transplantation. 
Page 68 of73 
BODY WEIGHT(kg) 
LOADING DOSE 
MAINTENANCE DOSE 
(each tiiwre is from 0.00 to 0.99) 
(mL/hour x 30 min) 
(mL/hour x 47.S hours) 
93 
33.0 
20.4 
94 
33.3 
20.6 
95 
33.7 
20.8 
Final Revision No. 3, 20-March-2006 


Study REP0104 
Reperwxin in Lung Tra11splcmtation 
Page 69 of73 
14.4. 
APPENDIX 4 - STUDY FLOW CHART 
ICU 
Test/Examination 
Screening 
Tx 
ICU 
Time after ICU admission 
Hospital 
1 month 
6 months 
admission 
12h 
24 h 
36h 
48 h 
54 h 60h 
72h 
disc.harge 
discharj:!e 
12 months 
Informed consent 
X 
Inclusion/exclusion criteria 1 
X 
Laboratorv tests 
X 
X 
Renal/hepatic function2 
X 
x2 
xi 
x2 
Studv d~ug administration 3 
X---------· .... -:------- ·---·---------·-----·-·· • •• ·-X
2 
Pharmacokinetic samoling 2 
Xl. 
xz 
xz 
PaOi/FiO 2 ratio 
X 
X 
X 
X 
Chest X-rav 
-
X 
X 
X 
X 
Vital signs (BP & HR) 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiopulmonary 
measurements 
4 
X 
X 
X 
X 
X 
X 
X 
X 
BAL5 
xs 
Vital status 
X 
X 
X 
X 
X 
FEV 1 &FVC 
X 
X 
X 
BOS score 
X 
X 
Cumulative acute reiection 
X 
X 
Adverse Events 6 
6 
X----·················-·····--·······-····-·········---------·---------------------··········-··········--·-
--X 
X ••••• ·-·· •••• ····----·--· --------·-•• X6 
Prior 
and 
concomìtant 
X---------------------···--------• ----•••• ••••• ····-···-······ --• -----·· ----------· ••••• ---------· -----· ---···· -·--· ---------·X 
7 
X----· ------·-·· ---·-··-· • ------·----· X
7 
medications 7 
I = ConfirmalOry screening to take piace upon admission to the center prior to randomìzation 
2 = (shadowed boxes) Time is frorn the start of study <lrug infosion. The '24 hours' sample is ta.ken @ 24±6 hours; the '54 hours' samplc is taken in the interval 2-6 hours after tbe infusion end 
3 "'Study drug infusion will start approximately 2 hours before the anticipated time of reperfusion 
4 = Vita! signs and cardiopulmonary measurements (when a PA catheter is present) will be measured up to ICU discharge or up to 5 days after ICU admission, whichever occurs earlicr 
5 "'BAL will be performed during mechanìcal vencilation, in thc interval between 12 and 24 hours afler rcperfusion 
6::: All AEs will be reported up to 10 days or hospital disch.arge. Thereafter, only untoward events that the lnvestigator assesses as at least pos,ibly rclated to lhe study drug will be rccorded 
7 = After IO days or hospital discharge, only drugs used for immunosuppression, infection prophylaxis, and AEs possibly related to the srudy drug (scc 6 above) will be recorded 
Final Revision No. 3, 20-March-2006 


Study REP0104 
Repertaxìn in Lung Transplantatian 
Page 70of73 
14.5. 
APPENDIX 5 - WORLD MEDICAL ASSOCIA TION DECLARA TION OF 
HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA Genera! Assembly Helsinki, Finland, June 1964 and amended by the 
29th WMA Genera! Assembly, Tokyo, Japan, October 1975 
35th WMA Generai Assembly, Venice, Italy, October 1983, 
41st WMA Generai Assembly, Hong Kong, September 1989, 
48th WMA Generai Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA Generai Assembly, Edinburgh, Scotland, October 2000 
Note of clarification on Paragraph 29 added by WMA Generai Assembly, Washington 2002 
A. 
INTRODUCTION 
The World Medicai Association has developed the Declaration of Helsinki as a statement of ethical principles to 
provide guidance to physicians and other participants in medicai research involving human subjects. Medicai research 
involving human subjecl':l includes research on identifiab\e human material or idenlifiable data. 
It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
The Declaration of Geneva of the World Medicai Association binds the physìcian with the words, "The health of my 
patient will be my fìrst consideration," and the Intemational Code of Medìcal Ethics declares that, "A physician shall 
act only in the patient's interest when providing medica! care which might have the effect of weakening the physical 
and menta! conditi on of the patient." 
Medicai progress is based on research which uitimately must rest in part on experimentation involving human 
subjects. 
In medicai research on human subjects, considerations related to the well-being of the human subject should take 
precedence over the interests of science and society. 
The primary purpose of medicai research involving human subjects is to improve prophylactic, diagnostic and 
therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best proven 
prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
In current medicai practice and in medica\ research, most prophytactic, diagnostic and therapeutic procedures involve 
risks and burdens. 
Medicai research is subject to ethical standards that promote respect for ali human beings and protect their health and 
rights. Some research populations are vulnerable and need special protection. The particular needs of the economically 
and medically disadvantaged must be recognised. Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit 
personally from the research and for those for whom the research is combined with care. 
Research Investigators should be aware of the ethical, lega! and regulatory requirements for research on human 
subjects in their own countries as well as applicable international requirements. No national ethical, legai or regulatory 
reguirement should be allowe<l to reduce or eliminate any of the protections for human subjects set forth in this 
Declaralion. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medica! research to protect the life, health, privacy, and dignity of the human subject. 
Medica\ research involving human subjects must confonn to generally accepted scientific principles, be based on a 
thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, 
where appropriate, animai experimentation. 
Appropriate caution must be exercised in the conduct of research which may affect the environmem, and the welfare 
of animals used for research must be respected. 
Final Revision No.3, 20-March-2006 


Study REP0104 
Repertaxin in Lung Transplantation 
Page 71 of73 
The design and performance of each experimental procedure involving human subjects should be clearly formulated in 
an experimental protocol. This protocol should be submitted for consideration, cornment, guidance, and where 
appropriate, approvai to a specially appointed ethical review commìttee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence. Thìs ìndependent committee should be in confomùty 
with the laws and regulations of the country in which the research experìment ìs performed. The committee has the 
right to monitor ongoìng trials. The researcher has the obligation to provide morùtoring information to the committee, 
especially any serious adverse evencs. The researcher should also submit to the committee, for review, information 
regardìng funding, sponsors. institutional affiliatioos, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contaìn a statement of the ethtcal considerations involved and should indicate 
that there is compliance with the principles enunciated in this Declaration. 
Medicai research involving human subjects should be conducted only by scientifically qualified persons and under the 
supervision of a clinically competent medica! person. The responsibility tor the human subject must always rest with a 
rnedically qualified person and never rest on the subject of the research, even though the subject has given consent. 
Every medicai research project involvìng human subjects should be preceded by careful assessment of predictable 
risks and burdens in comparison with foreseeable benefits to the subject or to others. This does nor preclude the 
participation of healthy volunteers in medicai research. The design of ali studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless they are confident that 
the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any 
investigation if the risks are found to outweigh the potential benefits or if Ll-iere is conclusive pmof of positive and 
beneficiai results. 
Medicai research involving hurnan subjects should only be conducted if the importance of the objective outweighs the 
inherent risks and burdens to the subject. This is especial1y important when the human subjects are healthy volunteers. 
Medica! research is only justified if there is a reasonable likelihood that the populations in which thc rcsearch is 
carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed particìpants in che research project. 
The right of research subjects to safeguard theìr integrity must always be respected. Every precaution should be taken 
to respect the privacy of the subject, the confidentiality of the patìent's information and to minimise the impact of the 
study on the subject's physical and mental integrìty and on the personality of the subject. 
1n any research on human beings, each potential subject must be adequately informed of the aims, rnethods, sources of 
funding, any possible cont1icts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain 
from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring thai 
the subject has understood the infomiation, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing. If t11e consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly cautious if the subject is 
in a dependent relationship with the physicìan or may consent under duress. In that case the informed consent should 
be obtained by a well-informed physician who is not engaged in lhe investigation and who is cornpletely independent 
of this relationship. 
For a research subject who is iegally incompetent, physically or mentally incapable of giving consent or is a legally 
incompetent minor, the investigator must obtain informed consent from the legally authorised representative in 
accordance with applicable law. These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and thìs research cannot instead be performed on legally competent 
persons. 
When a subject deemed iegally incompetent, such as a minor child, is able co give assent to decisions about 
participalion in research, the investigator must obtain that assent in addition to the consenc of the legally authorised 
representati ve. 
Research on individuals from whorn ìt is noc possible to obtain consent, including proxy or advance consent, should be 
done only if the physical/mental condition that prevents obtaining informed consent ìs a necessary characteristic of the 
research population. The specific reasons for involving research subjects with a condìtion that renders them unable to 
give informed consent should be stated in the experimental protocol for consideration and approvai of the review 
committee. The protocol should state that consent to remain in the research should be obtained as soon as possible 
from the ìndividual or a legally authorised surrogate. 
Final Revision No. 3, 20-March-2006 


Study REP0 104 
Repertaxin in Lung Transplantatio11 
Page 72 of73 
Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are 
obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise 
publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be 
declared in the publìcation. Reports of experimentation not in accordance with the principles laìd down in this 
Declaration should not be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
The physician may combine medicai research with medical care, only to the extent that the research is justified by its 
potential prophylactic, diagnostic or therapeutic value. When medica! research is combined wilh medical care, 
additional standards apply to protect the patients who are research subjects. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current 
prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies 
where no proven prophy!actic, diagnostic or therapeutic method exists. 
At the conclusion of the study, every patient entered into the study should be assured of access to the best proven 
prophylactic, diagnostic and therapeutic methods identified by the study. 
The physician should fully infonn the patient which aspects of the care are related to the research. The refusal of a 
patient to participate in a study must never interfere with the patient-physic.ian relationship. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been 
ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, 
diagnostic and therapeutic measures, if in the physician's judgement it offers hope of saving life, re-establishing health 
or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate 
their safety and effìcacy. In all cases, new information should be recorded and, where appropriate, published. The 
other relevant guidelines of this Declaration should be followed. 
Note of ç)arification on Paragi:aph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms ìts position that extreme care must be taken in making use of placebo-controlled trials 
and that in generai this methodology should only be used in the absence of existing proven therapy. However. a 
placebo-controlled tria! may be ethically acceptable, even if proven therapy is available, under the following 
circumstances: 
or 
• 
Where for compelling and scientifically sound methodological reasons its use is necessary to detenni ne the 
efficacy or safety of a prophylactic, dìagnostic or therapeutic method 
• 
Where a prophylactic, diagnostic or therapeutic method is being investigated fora minor condition and the 
patients who receive placebo will not be subject to any additional risk or serious irreversìble harm. 
All other provisions of be Declarntion of Helsinki must be adhered to, especially the need for appropriate ethìcal and 
scientific review. (6.10.02) 
Final Revisìon No. 3, 20-March-2006 


Study REP0104 
Repertaxin in Lung Transplantation 
Page 73 of73 
14.6. 
APPENDIX 6-ACCEPTABLE TIME WJNDOWS FOR ASSESSMENTS/ 
PROCEDURES 
Infusion Bag 1 begins approximately 2 hrs prior to 
re erfusìon 
> l hour prior to reperfusion 
Change 1oading dose to maintenance dose @ 30 30_35 mìnutes after statt of infusion 
mins 
Change Infusion Bag 1 to Infusion Bag 2 @ 24 hrs 
after start of infusion 
End of Infusìon @ 48 hrs 
PaO2/FiO2 ratio measurements 
± 1 hour 
± 1 hour 
@ ICU Admission 
± 2 hour 
@ 24 hrs 
± 2 hour 
@ 48 hrs 
± 4 hours 
@ 72 hrs 
± 4 hours 
1---------------------t, 
====~= 
X-ray to calculate PGD Score 
@ ICU Admission 
@ 24 hrs 
@ 48 hrs 
@ 72 hrs 
Vitals & Cardiopulmonary measurements @ ICU 
admission and every 12 hours after ICU admission 
for 5 days or ICU discharge (whichever occurs 
earJier) 
Renal & Hepatic Function after infusion start 
@ 12 hrs 
@ 24 hrs 
@ 36 hrs 
PKsamples 
After infusion start 
Just rior to end of infusion 
Post infusion end 
Mechanical Ventilation/Discharge 
@ 8 am ever rnornin 
Hospital discharge blood sample 
Month 1 visit post transplant 
Month 6 & Month 12 visits 
Final Revision No. 3, 20-March-2006 
±4 hour 
± 4 hours 
± 8 hours 
± 8 hours 
± 4 hours 
±4 homs 
Up to 24 hours prior to dìscharge 
30-35 days 
± 2 weeks 

SAP_001.pdf: 
PPD 
PPD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
Statistica! Analysis Pian Approvai Sheet 
REP0104 
A phase 2, multi-center, randomized, double-blind, placebo-controlled, 
parallel group study of repertaxin In the preventlon of prlmary graft 
dysfunctlon after lung transplantation. 
Month 1 
/ PD 
1.1 {Final) ____ 
.... 
The undersigned have reviewed this and find it to be consistent with the study requirements as it 
applies to their respective function: 
Version date: 29 Sep 2006 
Page 1 of25 
; 
1 .. 


Statistical Analysls Pian 
REP0104 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica! Ana/ysis Pian 
A phase 2, multi-center, randomized, double-blind, placebo-controlled, 
parallel group study of repertaxin in the preventlon of primary graft 
dysfunction after lung transplantation. 
Month 1 
Prepared for: 
Dompé pha.r.ma s.p.a. 
Version Number 
1.0 
1.1 
Version date: 29 Sep 2006 
Prepared by: 
CONFIDENTIAL 
Author 
PD 
Page 2 of25 


PD 
1 
1.1 
1.2 
1.3 
2 
3 
3.1 
3.2 
3.3 
4 
4.1 
4.2 
4.2.1 
4.2.2 
4.3 
5 
6 
6.1 
6.2 
6.3 
7 
8 
8. i 
8.2 
9 
9.1 
9.2 
9.3 
9.4 
9.4.1 
9.4.2 
9.4.3 
9.4.4 
9.4.5 
9.5 
9.5.1 
9.5.2 
9.6 
9.6.1 
9.6.2 
9.6.3 
9.6.4 
9.6.5 
9.6.6 
10 
11 
12 
13 
lntroduction 
Generai 
Changes from Protocol 
Changes from previous versions of SAP 
Study Objectives 
Study Design 
Overvìew 
Sample Size Considerations 
Randomization 
Study variables and covarìates 
Primary variable 
Secondary variables 
Efficacy 
Safety 
Predetermined Covariates and Prognostic Factors 
Definitions 
Analysis Populations 
lntention-to-treat (ITT) 
Per protocol (PP) 
Safety 
Interim Analyses 
Data Revìew 
Data handling and Transfer 
Data Review Meeting 
Statistica! Methods 
Generai Principles 
Patient Disposìtion 
Protocol deviations 
Demographic and Baseline Characteristics 
Demographic data 
Recipient lnformation 
Significant Medicai History 
Donar lnformation 
Transplantation 
Efficacy analyses 
Primary Variable 
Secondary Variables 
Safety analyses 
Extent of Study Drug Exposure 
Adverse events 
Serious Adverse Events 
Laboratory data 
Concomitant Medications 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
5 
5 
5 
5 
5 
5 
5 
6 
7 
7 
7 
7 
7 
7 
8 
8 
Vital Signs, Physìcal Findings and Other Observations Relateci lo Safety 
Validatìon 
10 
10 
10 
11 
11 
11 
11 
11 
11 
11 
11 
12 
12 
12 
12 
12 
12 
12 
12 
13 
14 
15 
15 
15 
16 
16 
17 
17 
17 
17 
20 
21 
List of tables, Figures and listings for Month 1 Report 
Data Presentation 
Table Shells 
Version date: 29 Sep 2006 
Page 3 of25 


PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysìs Pian 
GLOSSARY OF ABBREVIATIONS 
AE 
ALT 
APTT 
AST 
ATC 
BAL 
BOS 
BP 
CMV 
CO 
CRF 
CSR 
CVP 
CXCL8 
DMC 
Dompé 
FEV1 
FiO2 
FVC 
HR 
PaO2 
PCWP 
PGD 
PK 
PMN 
PP 
PT 
PVR 
SAP 
SAE 
soc 
SVR 
Adverse Event 
Alanine Aminotransferase 
Actìvated Partial Thromboplastin Time 
Aspartate Aminotransferase 
Anatomie Therapeutic Chemical Classification 
Bronchoalveolar Lavage 
Bronchiolitis Obliterans Syndrome 
Blood Pressure 
Cytomegalovirus 
Cardiac Output 
Case Report Form 
Clinica! Study Report 
Right Atrial Pressure 
CXC ligand 8 [formerly interleukin (IL)-8} 
Data Monitoring Committee 
Dompé pha.r.ma s.p.a 
Forced Expiratory Volume in One Second 
Fraction of lnspired Oxygen 
Forced Vital Capacity 
Heart Rate 
lntravenous 
Intensive Care Unit 
lntention-To-Treat 
Millimeters mercury 
PPD 
Pulmonary Artery 
Partial Pressure of Arteria! Oxygen 
Partial Capillary Wedge Pressure 
Primary Graft Dysfunction 
Pharmacokinetic 
Polymorphonuclear Leukocyte 
Per Protocol 
Prothrombin Time 
Pulmonary Vascular Resistance 
Statistica! Analysis Pian 
Serious Adverse Event 
System Organ Class 
Systemic Vascular Resistance 
Version date: 29 Sep 2006 
Page 4 of25 


PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
1 
INTRODUCTION 
1.1 
Generai 
This statistica! analysis pian (SAP) describes the statistica! methods to be used during the 
analysis and reporting of data collected under Dompé pha.r.ma s.p.a. (Dompé} Protocol 
REP0104. 
The study is splil into two phases: screening to one month post-transplant and greater than one 
month to 12 months post-transplant. This SAP applies to all outputs, in-text or post-text, 
produced for inctusion in the clinica! study report (CSR) far the Month 1 analyses. A separate 
SAP will be produced for the Month 12 analyses. This SAP should be read in conjunction with 
the study protocol and case report form (CRF). This version of the pian has been developed 
using the revised protocol dated 30 August 2005; the CRF dateci 01 March 2005 and the 
amended pages relating to the 30 August protocol amendment. Any further changes to the 
protocol or CRF may necessitate updates to the SAP. 
At the time of writing this version of the SAP, approximately 60 patients have been randomized 
into the study. 
The analysis pian will be finalized and approved by the sponsor and 'PD 
--,--,--------
p rio r to database lock. 
-------------------
1.2 
Changes from Protocol 
None. 
1.3 
Changes from previous versions of SAP 
For the primary analysis, the covariance matrix for the final model was wrongly defined as the 
matrix with the highest value for the Al<aike's lnformation Criterion. The selection criterion has 
been changed to the matrix with the lowest value for the Akaike's lnformation Crìterion. 
2 
STUDY OBJECTIVES 
To evaluate whether CXCL8 inhibìtion with repertaxin leads to reduced severity of primary graft 
dysfunction (PGD}, as the result of improved functional and clinica! outcomes in lung 
transplantation patients. 
The safety of repertaxin in the specific clinica! setting wìll also be evaluated. 
The ability of repertaxin to reduce target cells (PMN) infiltration into the grafi will be evaluated lo 
confìrm its mechanism of action. Plasma levels of repertaxin and its major metabolite will be 
measured al steady state conditions lo previde population pharmacokinetic (PK) profile in this 
dinical setting. 
3 
STUDY DESIGN 
3.1 
Overview 
This is a phase 2, multi-center, randomized, double blind, placebo-controlled, parallel group study 
of repertaxin in the prevention of PGD after lung transplantation. The study will involve 100 
Version date: 29 Sep 2006 
Page5 of 25 


PPD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
patients undergoing single or bilatera! lung transplant who will be randomized to receive either 
repertaxin or placebo via continuous intravenous (i.v.) infusion administered aver 48 hours. 
Patients randomized into the study who do not go on to receive study drug or lung transplant will 
be replaced therefore the tota! number of patients randomized may exceed 100. Patients will be 
followed for 12 months post-transplant but the majority of study assessrnents are performed 
during the intensive care unit (ICU) and hospital stay immediately after surgery. 
Patients will be selected far entry into the study from those listed on the center's lung transplant 
waiting list. lnclusion/exclusion criteria (as listed in protocol sections 5.1 and 5.2), disease 
history, extrapulmonary site of infection, significant medicai history, vita! signs, renai and hepatic 
function, laboratory safety tests and donor information will al! be assessed prior to randomìzatìon 
lo ensure patient eligibility. 
The lung transplant surgery will be performed according to the center's standard practice. The 
study drug infusion will start approximately 2 hours before the anticipated time of reperfusion of 
the first allograft. A loading dose will be administered tor the fìrst 30 minutes, followed by a 
maintenance dose tor the remaining 47.5 hours of administration. 
After completion of surgery, patlents will be admìtted to an ICU and blood gases (PaO2, FiO2 and 
PaO2/FiO2 ratio) will be measured on admission (time O) and at 24, 48 and 72 hours post ICU 
admission or unti! extubation whichever occurs earlier. Chest x-rays, renai and hepatic functlon 
and PK sampling will be measured at defined time poinls within the 72 hours following ICU 
admission. Vital slgns (BP and HR) and cardiopulrnonary measurements will be assessed at 
defined time points within the 5 days post ICU admission or unti! ICU discharge (or PA catheter 
removed) whichever occurs earlier. Further patient assessments are made at ICU discharge and 
hospital discharge. 
Patients will return to the center at least 30 days after the transplant for the Month 1 assessment 
and at 24-28 weeks and 50-54 weeks post transplant tor the Month 6 and Month 12 assessments 
respectìvely. Once data up to and including the Month 1 assessment has been collected, entered 
and cleaned, the Month 1 database will be locked, the study will be unblinded and the primary 
analysis of safety and effìcacy data will be performed. Data collected during the open phase of 
the study i.e. at Months 6 and 12 will be presented in an addendum to the main CSR. 
An independent Data Monitoring Committee (DMC) has been established to ensure patient 
safety, to consider patient risks agaìnst the potential for meeting tria! objectives, and to previde 
recommendations to Dompé with respect to the conduct and analysis of the trial. p PD 
will be 
responsible for providing the DMC statisticlan with listings of data relating to disposmon 
{randomization, completion and withdrawal), demography, adverse events (AEs) and occurrence 
of clinically diagnosed PGD. Full details of the responsibilities of the DMC are provided in the 
DMC Charter. 
3.2 
Sample Size Considerations 
Under the foliowing assumptions: 
1. A single prirnary endpoint - PaO,2'FiO2 ratio 
2. One prirnary comparison: repertaxin versus placebo at 24 hours post ICU admissìon 
(Ho: µR = µp; H,: PR > µp ). 
3. A one-sided two group t-test of statistica! significance 
4. a-leve! or probability of Type I error associated with the test of 0.05 
5. A placebo mean of 315 mmHg 
6. A common standard deviation of 137 mrnHg 
7. A sample size of 50 in each group 
Version date: 29 Sep 2006 
Page 6 of 25 


PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 statistica! Ana/ysis Pian 
the study has 81% power to detect a difference in means of 70 mmHg (µR = 385 mmHg) and 56% 
power to detect a difference in means of 50 mmHg (µR = 365 mmHg). The data for assumptions 
5 and 6 1s taken from the results of 700 lung transplant operations at the Washington University. 
However, there are currently no data available to provide an estimate of the treatment effect size 
for this study. 
3.3 
Randomization 
Prior to surgery, patients who meet all the entry criteria and who previde written informed consent 
will be randomized to receive either repertaxin or placebo according to a 1:1 randomization. 
A master randomization list was prepared far 352 patìents (44 at each of 8 centers) by lnsight 
Statistica! Consulting on behalf of PP07. 
A dummy randomization was reviewed by statisticians 
at both PD 
and Dompé prior toproduction of the final version. Since each patient should only 
ever require a single drug pack, the randomization number is identica! to the patient number. 
The randomization number is assigned sequentially at each site as patients are found to be 
elìgible tor entry to the study and are enrolled. Patients who are enrolled to replace patients who 
withdraw from the study prior to study drug infusìon or !ung transplantation wìlt be issued a new 
randomization/patient number. 
lf a patìent is allocateci a randomization number and either the transplant does not happen or the 
study drug is not administered, the relevant drug box should be annulled to avoid its re-use with 
another patient. 
4 
STUDY VARIABLES AND COVARIATES 
4.1 
Primary variable 
The primary variable within the study is PaO2'FiO2 ratio measured at ICU admission (time O) and 
24 hours post ICU admission. 
4.2 
Secondary variables 
4.2.1 Efficacy 
• 
• 
• 
• • • • 
• 
• • 
4.2.2 
• 
• • 
• • • 
Time profile of PaO2/FiO2 ratio measured ICU admission and at 24, 48 and 72 hours post 
ICU admìssion or until extubated whichever occurs earlier. 
PGD score 
Time to freedom from mechanical ventilation 
Duration of ICU stay 
ICU mortality 
Mortality in the first 30 days post-transplant 
FEV 1 and FVC at Months 1, 6 and 12 post-transplant 
8OS score at Months 6 and 12 post-transplant 
Cumulative acute rejection eplsodes at months 6 and 12 post-transplant 
Patient survival rate evaluated at Months 6 and 12 post-transplant 
Safety 
Study drug dosìng 
lncidence of adverse events 
lncidence of clinically significant results and shifts (relative to normai ranges) in 
hematology, clinica! chemistry and coagulation test results 
lncidence of concomitant medication use 
Vital signs 
Cardiopulmonary measurements 
Version date: 29 Sep 2006 
Page 7 of 25 


Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
4.3 
Predetermined Covariates and Prognostic Factors 
• 
Type of transplant (single or double) 
Data recorded only at Months 6 and 12 wHI not be covered within this document but will be 
discussed in the Month 12 SAP. 
Data for PMN count in bronchoalveolar lavage (BAL) and plasma levels of repertaxin and its 
major metabolita DF2243Y will not be analyzed fPD 
These data will be provided in 
separate stand alone reports by the responsible laboratories. These reports will be included as 
appendices to the CSR. 
5 
DEFINITIONS 
Time O 
This is defìned as date and time of ICU admission. 
Month 1 
This is defined as 30-35 days after date of lung transplant. 
Month 6 
This is defined as 24 - 28 weeks ( 168 - 196 days) after date of lung transplant. 
Month 12 
This is defined as 50 - 54 weeks (350- 378 days} after date of lung transplant. 
Age 
The integer age of the patient will be derived relative to the date of the screening visit usìng the 
following SAS code: 
age = INTCK('YEAR', dob, dos) - {(MONTH(dos) < MONTH{dob)) OR 
(MONTH(dos) = MONTH(dob) ANO DAY(dos) < DAY(dob))); 
where dob = date of birth and dos = date of screening visit. 
Transplant type 
This is defined as either single or double where a single transplant is defined as a single left lung 
or a single right lung and a double transplant is defined as a bilatera! sequential lung or an en• 
bloc double lung. 
Duration of cold ischemia 
This ìs the interval in hours between onset of organ ischemie time (date and time of cross•clamp 
on donor organ) and lhe removal of the donor organ from cold storage and ìs derìved as: 
(Date/time of organ removal from cold storage- date/time of cross clamp on donor organ)/3600 
Duration of warm ischemia 
This is the interval in hours between removal of donor organ from cold storage and the start of 
reperfusion or vascular de-clamping of the allograft and is derived as: 
(Date/time of start of reperfusion - date/lime of organ removal from cold storage)/3600 
Duration of cold and warm ischemia 
This is the interval in hours between onset of organ ischemie time and the start of repertusion and 
is derived as: 
(Date/time of start of reperfusion - date/time of cross clamp on donar organ)/3600 
Time to freedom from mechanical ventilation 
This will be measured in hours and wìll be derived as: 
Version date: 29 Sep 2006 
Page8 of 25 


PPD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
(date/time of extubation - date/time of ICU admission)/3600. The resu!t will be rounded to the 
nearest integer. 
Duration of ICU stay 
This is the interval in hours between ICU admission and ICU discharge and will be derived as: 
(date/time of ICU discharge- date/time of ICU admission)/3600. The result will be rounded to the 
nearest integer. 
PGD Score 
This is graded as an integer between O and 3 according to the following definitions: 
Grade O 
no radiographic infiltrates 
Grade 1 
PaOzfFiO2 :::300 mmHg + radìographic infìltrates consistent with 
pulmonary oedema 
Grade 2 
200 mmHg PaO2/FiO2 <300 mmHg + radiographic ìnfiltrates 
consistent with pulmonary oedema 
Grade 3 
PaO2'FiO2 <200 mmHg + radiographic infiltrates consistent with 
pulmonary oedema 
Duration of study drug infusion 
This is measured in hours and derived as follows: 
(date/time of termination of infusion - date/time of start of infusion}/3600. 
The duration should be adjusted for documented interruptions of at least one hour or cumulative 
interruptions of at least 2 hours. The CRF does not previde a piace to record inteiruptions so the 
clock times of infusion interruptions and infusion re-start will be provided via filenotes where 
applicable. 
Amount of study drug infused 
This is measured in milliliters and will be derived as the sum of each of the dosing intervals 
multiplied by the relevant infusion rate. Assuming that dosing is performed per protocol, the 
formula will be: 
(date/time of dose switch - date/time of start of infusion)/3600 x infusion rate tor loading dose 
+ 
(date/time of bag switch- date/time of dose switch)/3600 x infusion rate for maintenance dose 
+ 
(date/time of end of infusion - date/time of bag switch)/3600 x infusion rate for bag 2. 
lf the dose swìtch is not performed then it will be: 
(date/time of bag switch - date/time of start of infusion)/3600 x infusion rate far loading dose 
+ 
(date/time of end of infusion - date/time of bag switch)/3600 x infusion rate for bag 2. 
lf lhe bag switch is not performed then it will be: 
date/time of dose switch - date/time of start of infusion)/3600 x infusion rate for loading dose 
+ 
(date/time of end of infusion - date/time of dose switch)/3600 x infusion rate for maintenance 
dose. 
lf neither the dose switch nor the bag switch are performed then the formula will be: 
{date/time of end of ìnfusion - date/time of start of infusion)/3600 x infusion rate for loading dose. 
For repertaxin, the amount of sludy drug in milligrams will be derived as 12.65 x tota! volume 
transfused in milliliters. 
Treatment-emergent adverse events 
Version date: 29 Sep 2006 
Page 9 of 25 


PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
Treatment-emergent adverse events are those which first occur or increase in severity after the 
first dose of study drug. Adverse events with a start date greater than or equal to the start date of 
study drug infusion will be considered to be treatment emergent. lf the onset date is missing then 
the event will be assumed to be treatment-emergent. lf the start date is partial and only the 
month and year are populated then all events starting in the same month as the study drug 
infusion will be assumed to be treatment-emergent. lf the start date is partial and only the year is 
populated then all events starting in the same year as the study drug infusion will be assumed to 
be treatment-emergent. 
Systemic Vascular Resistance (SVR) 
This is measured in dyn·s·cm-5 and is derived as: 
80 x (MAP - CVP)/CO where MAP = mean arteria! pressure = DBP + (SBP - DBP}/3. 
Pulmonary Vascular Resistance (PVR) 
This is measured in dyn·s·cm-5 and is derived as: 
80 x {MPAP - PCWP)/CO 
where MPAP = mean pulmonary arteria! pressure 
= systolic PA pressure + (2 x diastolic PA pressure)/3. 
BOS Score 
This is an integer between O and 3 based on FEV1 categories defined as follows: 
BOS O 
FEV1 ~80% of baseline value 
8OS 1 
FEV1 66-80% of baseline value 
BOS 2 
FEV1 5i-65% of baseline value 
BOS 3 
FEV 1 s50% of baseline value 
The baseline value will be defined as per center practice as the best FEV 1 value following 
surgery. 
6 
ANAL YSIS POPULATIONS 
The primary analysis of the primary efficacy variable will be presented for the intention-to-treal 
(ITT) population. A secondary confirmatory analysis will be performed using the per protocol (PP) 
population. 
6, 1 
lntention-to-treat (ITT} 
The ITT population wìll consist of all randomized patients who received any study medication and 
a lung transplant. Patients will be analyzed according to the treatmen1 randomized regardless of 
which treatment was actually received. 
6.2 
Per protocol (PP) 
The PP population will consist of all patients in the ITT population who do noi meel any of the 
following criteria: 
• 
Started study drug infusìon after reperfusion i.e. after vascular de-clamping of the first 
allograft 
• 
Received study drug infusìon for less than 24 hours 
• 
Missing data for PaO2'FiO2 ratio at both time O and 24 hours post ICU admission while on 
mechanical ventilation 
• 
Received Orthoclone OKT3 or Campath induction immunosuppression at time of 
transplant. This will be recorded in the Month 1 Concomitant Medication pages if used. 
Further criteria for exc!usion from the PP population may be identified during the data review 
meeting held prior to database lock. 
Version date: 29 Sep 2006 
Page 10 of 25 


PPD 
6.3 
Safety 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysìs Pian 
The safety population will consist of ali patients who received any study medication and wlll be 
based on the treatment actually received. 
7 
INTERIM ANAL YSES 
No formai interim analyses of efflcacy are planned for this study. However, safety data will be 
reviewed on an ongoing basis by a DMC. Full details of the activities and responsibilities of the 
DMC are provided in the study DMC charter. 
8 
DATA REVIEW 
8.1 
Data handling and Transfer 
The data from this study will be entered, verified and cleaned by the Data Management group at 
PD 
in accordance with the study data handling manual and data clarification policies. The 
data will be provided to the staUstician as SAS datasets. The preferred term and system organ 
classification (SOC) from the relevant version of the MedDRA dictìonary will be provided tor all 
adverse events. The ATC group and sub-group from the relevant version of the WHO-DRUG 
dictionary will be provided for all prior and concomitant medications. 
8.2 
Data Review Meeting 
Programming of analysis datasets, tables, fìgures and listings wìll be ongoing during the data 
management of the study. When the Month 1 database is considered clean by data 
management, a set of blinded listings (using a dummy randomization) will be produced and 
distributed to the study team for review. A meeting will be held to review any data values 
requiring investigation or correction and also protocol deviations. Once ali data issues have been 
resolved, the Month 1 data will be locked. Treatment code unblinding and the full run of outputs 
will then take piace. 
9 
STATISTICAL METHODS 
9.1 
Generai Principles 
The statistica! package SAS (Version 8.1) will be used to produce all summary tables, graphs and 
listings. In generai, categorical data will be presented using co1.,mts and percentages, whìlst 
continuous variables will be presented using the mean, standard deviation, medlan, minimum, 
maximum and number of patients. Minima and maxima will usually be reported to the same leve! 
of accuracy as the raw data; means, medians and standard deviations will be presented to one 
further decimai piace; standard errors (if presented) will be presented to 2 decimai places more 
than the raw data. Percentages will be rounded to the nearest integer. 
In tabulations, denominators for calculation of percentages wil! be taken as the number of non-
missing responses in the specified analysis population and treatment group unless otherwise 
stateci. 
Ali data recorded in the CRF wìll be listed. 
9.2 
Patient Disposition 
The number and percentage of patients screened, randomized and treated in the study will be 
presented, together with the number and percentage of patients who withdrew from the study 
prematurely prior to Month 1 and a breakdown of the corresponding reasons for withdrawal. The 
number and percentage of patìents included in each of the ITT, PP and safety analysis 
populations will also be included. Screening data recorded far patients who do not proceed to 
transplant with study drug administration will be listed separately in the report. The exact format 
of the listings will be discussed with Dompé when the total number of patients randomized but not 
treated/transplanted is known. 
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PPD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica! Analysis Pian 
A tabulation of the number and percentage of patients randomized at each center will be 
presented. 
AII data relating to study completion or withdrawal and inclusion in the analysis populations wìll 
also be listed. 
9.3 
Protocol deviations 
Protocol deviations which exclude patients from the ITT or PP populations (see Sections 6.1 and 
6.2 for definitions) will be summarized by treatment group. 
9.4 
Demographic and Baseline Characteristics 
Summaries of baseline data will be produced using the safety population and will be presented by 
treatment group and overall. Data for parameters measured at screenìng that are also measured 
at subsequent time points post-randornization (e.g. vita! signs, renai and hepatic function) will not 
be presented in this section. AII baseline data will also be listed. 
9.4.1 Demographic data 
Summary statistics for age (see Section 5 far definition of derivation}, height and weight at 
screening will be presented, together with frequency counts and percentages for ethnic origin, 
race and gender. 
9.4.2 Reclpient lnformation 
Frequency counts and percentages will be presented for transplant procedure type, reasons tor 
transplant, medicai condition and CMV status. A footnote will be added to the iabie to clarify ihat 
multiple reasons for transplant may be indicated. Data relating to extra respiratory tract of 
infection will also be included. Frequency counts and percentages will be presented for blood 
culture results, fever and other signs of systemic sepsis syndrome. 
9.4.3 Slgnificant Medicai Hìstory 
The tota! number of patìents reporting any significant medicai history and the tota! number of 
patients reporting significant occurrences ongoing at screening will be presented. In addition, the 
number and percentage of patients reporting an item of signifìcant medicai history within each of 
the following 15 body systems will also be presented: Generai Appearance; Head, Ears, Eyes, 
Nose and Throat; Cardiovascular; Pulmonary; Gastrointestinal; Liver; Renai; Genitourinary; 
Endocrine; lmmune/Allergy; Psychiatric; Centrai Nervous System; Dermatologie; Musculoskeletal; 
Other. 
9.4.4 Donor lnformation 
Summary statistics will be presented tor the age of the donor, together with frequency counts and 
percentages of the gender of the donor, whether the donor was a brain dead heart beating donor 
and a breakdown of the reasons for brain death. lf multiple reasons are provided than a footnote 
should be added to the table explaining that the number of reasons gìven will exceed the number 
of patients. The number and percentage of donors whose transplant organ was flushed will be 
presented by type of solution (Perfadex or other) and category of flush (anterograde, retrograde, 
additional) and the number and percentage of donors whose transplant organ was stored in either 
Perfadex or other solution will also be presented. 
9.4.5 Transplantation 
The data for first and second allograft will be presented separately. For each allografl, the 
following data will be presented: summary statistics tor the duration of cold ischemia, the duration 
of warm ischemia and the duration of both cold and warm ischemia (see section 5 for definitions} 
will be presented, together with frequency counts and percentages for the number of patients who 
had cardiopulmonary bypass performed. Ali olher data relating to transplant will be listed only. 
9.5 
Efficacy analyses 
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PP 
9.5.1 PrJmary Variable 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Anafysis Pian 
The PaO2/FiO2 ratio will be analyzed at two time points: O hours (time of ICU admission) and 24 
hours after ICU admission. These analyses will be performed using both the ITT and PP 
populations with the ITT analysìs considered as the primary result. As this is nota pivotal study 
and the contrast estimates will be obtained from a repeated measurements model fitted for data 
at both time points, adjustments for multiplicity are not considered necessary. 
Primary analx:sis 
The ratio at the two time points will be analyzed using a repeated measurements model using 
PROC MIXED within SAS®. The model will include fixed effect terms for center, time point and 
treatment. Time point will be specified as a repeated measurement. In order to se!ect an 
appropriate matrix for the observations within each patient, 3 models will be fitted using the 
compound symmetry, Huynh-Feldt and unstructured structures. The matrix for the final model will 
be selected using Akaike's lnformation Criterion where lhe lowest value indicates the best fit 
Type lii sums of squares from the mixed procedure within SAS® will be used to assess the 
sìgnifìcance of individuai terms within the model using the selected matrix structure. The 
importance of the treatment-by-center interaction will be investigateci but if the term is not 
significant at the 10% leve!, it will be excluded from subsequent models. lf there are insufficient 
data within each center and treatment combination to allow estimation of effects. centers will be 
pooled based on similar surgical practices. 
The adjusted least squares means wìll be estimated for each combination of time point and 
treatment. The treatment effect within each time point will be compared using a one sided test at 
the 5% level. Missing data will be excluded. The primary analysis will be performed for the ITT 
population. 
The tests of the fixed effects will be presented, together with the estimateci least squares means 
and summary statistìcs of the raw PaO2/FiO2 ratio for each of the two treatments at each time 
point. The estimateci treatment difference between repertaxin and placebo at each time point will 
be presented together with the corresponding 95% confidence interval. The confidence interval 
will be generated using a=0.1 o and the lower limìt will be replaced by -oo. 
Sensitivity Analyses 
The primary analysis wìll be repeated using the PP population. 
The primary analysis will be repeated using a two-sided test at the 5% leve!. 
The primary analysis wìll be repeated usìng the last observation carried forward (LOCF) method 
to substitute a missing PaO21'FiO
2 ratio tor patients extubated wìthin 24 hours after ICU 
submission. Far patients who dìed wìthin 24 hours of ICU admissìon a ratio of O will be used at 
the 24 hour time point. Data far patients with a ratio mìssing for any other reason will not be 
substituted. 
The prìmary anatysis will be performed including the type of transplant (single or double) as a 
fixed effect covariate whose importance will be assessed at the 5% level. The ìnteraction term far 
type of transplant and treatment will also be fitted but if this is not signifìcant at the 10% level il 
will be excluded from the final model. The randomization has not been stratified by the type of 
transplant and therefore this analysis will only be performed ìf there are sufficient data wìthin each 
treatment, center and type of transplant combinatlon. 
In summary, the following presentations of PaOJFiO2 ratio at time O and 24 hours will be 
produced: 
Repeated Measurements Analysis using a one-sided test far the ITT population with missing data 
excluded. 
Repeated Measurements Analysis using a one-sided test for the PP population with missing data 
excluded. 
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PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
Repeated Measurements Analysis using a two-sided test for the ITT population with missing data 
excluded. 
Repeated Measurements Analysìs using a one-sided test for the ITT population w\th substitution 
of missing data. 
Repeated Measurements Analysis using a one-sided test far the ITT population including type of 
transplant but with missing data excluded. 
Repeated Measurements Analysis using a one-sided test for the PP population ìncluding type of 
transplant but with missing data excluded. 
Additional exploratory analyses may be performèd to further investigate the robustness of the 
primary efficacy data. 
9.5.2 Secondary Variables 
9.5.2.1 
PaO2/FiO2 ratio at 48 hours and 72 hours after ICU admission 
These data wm be analyzed as described for the primary analysis using a one-sided test at the 
5% level and wìth missing data excluded. A further analysis including type of transplant again 
using a one-sided test at the 5% leve! and with missing data excluded will also be performed 
provided there are sufficient data recorded. Both these analyses will be performed on the ITT 
and PP analysis populations. 
9.5.2.2 
PGD score 
Analysis of PGD score will be performed separately at time O and at 24, 48 and 72 hours after 
ICU admission. Two analyses, using Cochran-Mantel-Haenszel statistics frorn PROC FREQ 
within SAS, wi\l be performed at each time point. The first will use type of transplant (single or 
double) as a stratificatlon factor and will use the following SAS code: 
Proc freq data=data1 (where=(time=x}) noprint; 
table tran_typ*PGD*treat/cmh out=ct_typ; 
output out=cmhtype cmh ; 
run; 
As the randomization did not include type of transplant it is possible that that there will be 
insufficient data within each of the cells to perform the analysis. This will be assessed after the 
Month 1 database lock. 
The second analysìs will use center as a stratificatìon factor. 
Both analyses will be performed for bo1h the ITT and PP populations. Far each analysis, the 
number and percentage of patients within each table cell will be presented, together with the 
second of the three p-values provided by PROC FREQ {labeled as Row Mean Scores Differ). and 
the corresponding Mantel-Haenzsel odds ratio and the associateci 95% confidence interval. 
9.5.2.3 
Time to freedom from mechanical ventilatìon 
Time to freedom from mechanical ventilation will be derived as described in Section 5. Kaplan-
Meier summary statistics and plots will be used to illustrate time to freedom from mechanical 
ventilatìon for each treatment group. The analysis will be performed using PROC LIFETEST 
within SAS: 
proc lifetest plots=(s, Is, 11s) data=data2 method=km outsurv=estimates; 
time freetime•censor{1); 
strata treatment ; 
ods output ProductlimitEstìmates=file1 ; 
run; 
Patients who die while stili on mechanical ventilatlon will be censored at the time of death. 
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PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 statistica! Analysis Pian 
The risk set and number of events occurring within each 12-hour interval will be presented 
together with the event probability and standard errar. The estimated difference in event 
probability and corresponding 95% confidence interval will also be presented together with the 
log-rank and Wilcoxon tests for differences between treatments. 
The analysis will also be performed by treatment and type of transplant. 
Both analyses will be presented for both the ITT and PP populatìons. 
9.5.2.4 
Duration of ICU stay 
The duration of ICU stay will be derìved as described in Section 5. This duration is equivalent to 
time to ICU discharge. The duration of ICU stay will be analyzed as descrìbed far time to 
freedom from mechanical ventilation. 
9.5.2.5 
Mortality 
Frequency counts and percentages for the number of patients who die while in ICU and also the 
number and percentage of patients who die within the first 30 days post-transplant (derived as 
latest date of repertusion + 30) will be presented by treatment group. This table will be presented 
for the ITT populatìon only. 
9.5.2.6 
Pulmonary Function Tests 
Summary slatistics for FEV1 and FVC measured at Month 1 will be presented for the ITT 
population by treatment group and aiso for each treatment group and transplant type 
combinations. 
9.5.2.7 
Acute Rejection Episodes 
The number and percentage of patients reporting at least one acute rejection episode up to and 
including Month 1 will be reported by treatment group and also by treatment group and transplant 
type. The total number of episodes will also be reported for each treatment group and each 
treatment group and transplant type combination. This summary will be presented for the ITT 
population only. 
9.6 
Safety analyses 
9.6.1 Extent of Study Drug Exposure 
Summary statistics far duration of study drug infusion and amount of study drug infused (see 
Section 5 for definition) will be presented by treatment group. 
9.6.2 Adverse events 
A summary of treatment-emergent adverse events (see Section 5 for definition} reported between 
start of infusion and the Month 1 visit, including the tota( number of events reported, the number 
and percentage of patients reporting at least one adverse event, the number and percentage of 
patients withdrawing prematurely due to an adverse event, the nurnber and percentage of 
patients with at least one serious adverse event and the number and percentage of deaths, will 
be presented by treatment. In addition, a sumrnary of the event by each category of drug 
relationship will be presented for adverse events and also for serious adverse events. 
A breakdown of the number and percentage of patients reporting each adverse event, 
categorized by body system and preferred term coded according to the MedDRA dictionary, will 
be presented. Note that counling will be of patients not events and patients are only counted 
once within each preferred term. 
A further tabulation of these data, broken down by relatìonshìp to study drug, will be presented. 
Patients with multiple events within a particular body system or preferred term will be counted 
under the category of their most drug-related event within that body system or preferred term, 
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PPD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
Relationship lo study drug ìs categorized as none, unlìkely, possible, probable and highly 
probable as recorded on the CRF. Each category of relatìonship will be presented on a separate 
page. 
A summary of events reported, broken down by severlty (mild, moderate, severe, life 
threatening), will also be provided. Patients with multiple events within a particular body system 
or preferred term will be counted under the ca1egory of their most severe event within that body 
system or preferred term. Each category of severity will be presented on a separate page. 
A summary of adverse events leading to premature withdrawal wìll be provided, grouped by body 
system and preferred term. 
AII adverse events recorded on the CRF will be listed. 
9.6.3 Serious Adverse Events 
A breakdown of the number and percentage of patients reporting each serious adverse event 
(SAE) between the start of infusion and the Month 1 vislt, categorized by body system and 
preferred term coded according to the MedDRA dictionary, will be presented. 
A further tabulation of these data, broken down by relationship to study drug, will be presented. 
Patients with multiple SA Es within a particular body system or pref erred term will be counted 
under the category of their most drug-related SAE withln that body system or preferred term. 
Relationship to study drug is categorized as none, unlikely, possible, probable and highly 
probable as recorded on the CRF. Each category of reiationship will be presented on a separate 
page. 
A summary of SAEs reported, broken down by severity (mild, moderate, severe, life threatening), 
will also be provided. Patients with multiple SAEs withìn a partìcuiar body system or preferred 
term will be counted under the category of their most severe SAE withìn that body system or 
preferred term. Each category of severity will be presented on a separate page. 
A summary of SAEs leading to premature withdrawal will be provided, grouped by body system 
and preferred term. 
9.6.4 Laboratory data 
Samples for safety laboratory tests for hematology, clinica! chemistry and coagulation are taken 
at Screening and hospital discharge. The following parameters will be included in the summary 
data presentaUons: 
Hematology: hematocrit, hemoglobin, red blood cells, while blood cells, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils 
Clinica! chemistry: sodiurn, potassium, chlorlde, bicarbonate, blood urea nitrogen (BUN), total 
bilirubin, alanine aminotransferase {ALT), aspartate aminotransferase (AST), serum creatinine 
Coagulation: activated partial thromboplastin time (APTT), prothrombin time (PT), INR 
Note: patients will either have a value for PT or INR at each time point. 
Results for each parameter at screening and hospital discharge will be assessed as being below 
the lower limìt of the normai range, within the normai range or above the upper limit of the normai 
range. The number and percentage of patients with out-of-range results and the number and 
percentage of patients with clinically significant out-of-range results will be presented for each 
parameter al each ![me point, together with the number of patients with results for that parameter 
and time point. Shifts in laboratory parameters during the hospital stay will also be presented for 
each parameter. 
Creatinina clearance is calculated using Cockcroft-Gault formula at Screening and at 12, 24 and 
36 hours post ICU admission for the assessment of renai and hepatic function during the study. 
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PD 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Ana/ysis Pian 
These data are used for assessment of patient during the study conduct phase and will be listed 
only. 
9.6.5 Concomitant Medications 
Ali medications reported in the CRF as being taken prior to the Month 1 visit, categorized by 
medication group and subgroup according to WHO DRUG, will be summarized. The number and 
percentage of patients using at least one medication within each medication group and subgroup 
will be presented. 
9.6.6 Vital Signs, Physical Flndìngs and Other Observations Related to Safety 
Vital signs 
Vita! signs, induding systolic and diastolic blood pressure and heart rate, are measured at 
Screening, ICU admission, every 12 hours post ICU admission unti! 120 hours post ICU 
admission or until ICU discharge or PA catheter removed whichever occurs earliest. Summary 
statistics for each of these three parameters will be presented by treatment group at each time 
point. Summary statistics for the change from screening lo each post-screening time point will 
also be presented. 
Cardiopulmonary measurements 
Cardiopulmonary measurements consist of CVP, PCWP, CO and PA Pressure (systolic/diastolic) 
andare measured at ICU admission, every 12 hours post ICU admission untii 120 hours post ICU 
admission or until ICU discharge or PA catheter removed whichever occurs earliest. These data 
will be summarized by treatment group al each time point. Summary statistics for the derìved 
variables SVR and PVR (see Section 5 for detinitions) will also be provided. 
10 VALIDATION 
Ali summary tables and figures will be validated by independent programming within SAS. Any 
numerica! discrepancies will be resolved prior to finalization of the tables and figures. AII outputs 
will have the following checks performed: 
• 
Tìtles and footnotes are correct 
• 
No errors or wamings in SAS log file 
• 
Expected number of observations in dataset used for final output 
• 
Matches the specifications documented in this pian 
11 LIST OF TABLES, FIGURE$ ANO LISTINGS FOR MONTH 1 REPORT 
Output numbering may be further sub-divided in arder to allow tor logica! presentation of the data. 
Tables 
1.1 
1.2 
1.3 
1.4 
1.5 
1.6 
1.7 
1.8 
2.1.1 
2.1.2 
Patient Disposition (AII Screened Patients) 
Patient Randomization by Center (AII Randomized Patients) 
Protocol Deviations (Safety Population) 
Demographic Data (Safety Population) 
Recipient lnformation (Safety Population) 
Significant Medicai History (Safely Popu!ation} 
Donar lnformation (Safety Population) 
Transplantation (Safety Population) 
Repeated Measurements Anatysis of PaOdFiO2 ratio at O and 24 hours 
after ICU Admission using a one-sided test excluding mìssing data (ITT 
population) 
Repeated Measurements Analysis of PaO2/FiO2 ratio at O and 24 hours 
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PPD 
2.1.3 
2.1.4 
2.1.5 
2.1.6 
2.2.1 
2.2.2 
2.2.3 
2.2.4 
2.3.1. 
2.3.2 
2.3.3 
2.3.4 
2.4.1 
2.4.2 
2.4.3 
2.4.4 
2.5.1 
2.5.2 
2.5.3 
2.5.4 
2.6 
2.7 
2.8 
3.1 
3.2.1.1 
3.2.1.2 
3.2.1.3 
3.2.1.4 
3.2.1.5 
3.2.2.1 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
after ICU Admission using a one-sided test excluding missing data (PP 
populatìon) 
Repeated Measurements Analysis of PaO2'FiO2 ratio at O and 24 hours 
after ICU Admission using a two-sided test excluding missing data (ITT 
population) 
Repeated Measurements Analysis of PaO2/FiO2 ratio at O and 24 hours 
after ICU Admission using a one-sided test and subslitution of missing 
data {ITT population) 
Repeated Measurements Analysis of PaO2'FìO2 ratio at O and 24 hours 
after ICU Admission including type of transplant using a one-sided test 
and excluding missing data {ITT population) 
Repeated Measurements Analysìs of PaO2'FìO2 ratio at O and 24 hours 
after ICU Admission includìng type ot transplant using a one-sided test 
and excluding mìssing data (PP population) 
Repeated Measurements Analysis of PaO2/FiO2 ratio at 48 and 72 hours 
after ICU Admission using a one-sided test excluding missing data (ITT 
population) 
Repeated Measurements Analysis of PaO:/FiO2 ratio at 48 and 12· hours 
after ICU Admission using a one-sided test excluding missing data (PP 
population) 
Repeated Measurernents Analysis of PaO2/FiO2 ratio at 48 and 72 hours 
after ICU Admission including Type of Transplant using a one-sided test 
excluding missing data (ITT population) 
Repeated Measurements Analysis of PaO2/FiO2 ratio at 48 and 72 hours 
after ICU Admission including Type of Transplant using a one-sided test 
excluding missing data (PP population) 
Analysìs of PGD Score stratified by Type of Transplant (ITT Population). 
Analysis of PGD Score stratified by Type of Transplant (PP Population} 
Analysis of PGD Score stratified by Centre (ITT Population) 
Analysis of PGD Score stratified by Centra (PP Population) 
Time to Freedom from Mechanìcal Ventilatìon (ITT Populatìon) 
Time to Freedom from Mechanical Ventilation (PP Population) 
Time to Freedom from Mechanical Ventilation by Type of Transplant (ITT 
Population) 
Time to Freedom from Mechanical Ventìlation by Type of Transplant (PP 
Population) 
Duration of ICU Stay (ITT Population) 
Duration of ICU Stay (PP Population) 
Duration of ICU Stay by Type of Transplant (ITT Population) 
Duratìon of ICU Stay by Type of Transplant (PP Population) 
Mortality up to 30 Days Post-Transplant (ITT Poputation) 
Pulmonary Function Tests at Month 1 (ITT Population) 
Acute Rejectìon Episodes by Month 1 (ITT Population) 
Extent of Study Drug Exposure (Safety Population) 
Summary of Treatment-Emergent Adverse Events (Safety Population) 
Treatment-Emergent Adverse Events by Body System and Preferred 
Term (Safety Populatìon) 
Treatment-Emergent Adverse Events by Body System, Preferred Terrn 
and Relationship to Study Drug (Safety Population) 
Treatment-Emergent Adverse Events by Body System, Preferred Term 
and Severity of Event (Safety Population) 
Treatment-Emergent Adverse Events Leading to Premature Withdrawal 
(Safety Population) 
Treatment-Emergent Serious Adverse Events by Body System and 
Preferred Term (Safety Population} 
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3.2.2.2 
3.2.2.3 
3.2.2.4 
3.3.1.1 
3.3.1.2 
3.3.1.3 
3.3.2.1 
3.3.2.2 
3.3.2.3 
3.4 
3.5.1.1 
3.5.2 
3.5.3 
3.6 
Figures 
1.1 
1.2 
i.3 
1.4 
2.1 
2.2 
2.3 
2.4 
Listlngs 
2.1.1 
2.1.2 
2.1.3 
2.1.4 
2.2 
2.5.1 
2.5.2 
2.6.1 
2.6.2 
2.6.3 
2.6.4 
2.6.5 
2.6.6 
2.7.1 
2.7.2 
2.8.1 
2.8.2 
2.8.3 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
Treatment-Emergent Serious Adverse Events by Body System, Preferred 
Term and Relationship to Study Drug (Safety Population) 
Treatment-Emergent Serious Adverse Events by Body System, Preferred 
T erm and Severity of Event (Safety Population) 
Treatment-Emergent Serious Adverse Events Leading to Premature 
Withdrawal (Safety Population) 
Clinically Significant Results for Hematology (Safety Populalion) 
Clinically Significant Results tor Clinica! Chemistry (Safety Population) 
Clinically Significant Results for Coagulation (Safety Population) 
Shifts in Hematology Parameters (Safety Population) 
Shìfts in Clìnical Chemistry Parameters (Safety Population) 
Shifts on Coagulation Parameters (Safety Population) 
Prior and Concomitant Medications (Safety Population) 
Vital signs - Systolic Blood Pressure (Safety Population) 
Vita! signs - Diastolic Blood Pressure (Safety Population) 
Vital signs - Heart Rate (Safety Population) 
Cardiopulmonary Measurements (Safety Population) 
Kaplan-Meier Plot of Time to Freedom from Mechanìcal Ventilation (ITT 
Population) 
Kaplan-Meier Plot of Time to Freedom from Mechanical Ventilation (PP 
Population) 
Kaplan-Meier Plot of Time to Freedom from Mechanical Ventilation by 
Type of Transplant (ITT Population) 
Kaplan-Meier Plot of Time to Freedom from Mechanical Ventilation by 
Type of Transplant (PP Population) 
Kaplan-Meier Plot of Duration of ICU Stay (ITT Population) 
Kaplan-Meìer Plot of Duration of ICU Stay (PP Population) 
Kaplan-Meier Plot of Duration of ICU Stay by Type of Transplant (ITT 
Population) 
Kaplan-Meìer Plot of Duration of ICU Stay by Type of Transplant (PP 
Population) 
Patìent Dispositìon (Ali Randomized Pa1ients) 
Protocol Deviations (Ali Randomized Patients) 
Month 1 Completion and Reasons for Premature Withdrawal from Study 
(AII Randomized Patients) 
Reasons Screened but not Randomìzed (AII Screened Paiients) 
Demographìc Data 
Study Treatment Administration - Dates and Times 
Study Treatment Administration - Termination of lnfusion 
Individuai Efficacy Response Data - Pa0:2/FiO2 ratio 
Individuai Efficacy Response Data - PGD Score 
Individuai Efficacy Response Data - Time to Freedom from Mechanical 
Ventilation 
Individuai Efficacy Response Data - Duration of Hospìtal Stay 
Vital Status 
Pulmonary Function Tests 
Adverse Events Reported up to Month 1 
Serious Adverse Events Reported up to Month 1 
Laboratory Data: Hematology - Patìent Profiles 
Laboratory Data: Clinical Chemistry - Patient Profiles 
Laboratory Data: Coagulation - Patient Profìles 
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4.1 
4.2.1 
4.2.2 
4.3.1 
4.3.2 
4.4 
4.5.1 
4.5.2 
4.6.1 
4.6.2 
4.7 
4.8 
4.9 
4.10 
4.11.1 
4.11.2 
4.11.3 
4.11.4 
4.12 
4.13 
4.14 
4.15 
4.15.1 
4.15.2 
4.15.3 
4.15.4 
4.15.5 
4.16 
4.17.1 
4.17.2. 
4.18 
4.19 
4.20 
4.21.x 
Dompé pha.r.ma s.p.a. REP0104 
Month 1 Statistica/ Analysis Pian 
Visit Dates 
lnclusion Criteria 
Exclusion Criteria 
Recipient lnformation - Transplant type 
Recipient lnformatìon - CMV Status and Extrapulrnonary site of infection 
Significant Medicai History 
Donor lnformation - Demography and Cause of Death 
Donor lnformation - Lung Flush Solutions 
Transplant lnformation - Dates and Tìmes 
Transplant lnformation - Procedures and Complications 
Preparation of lnfusion Bags 
ICU Admission 
Bronchoalveolar Lavage 
ICU Discharge and Mechanical Ventilation Weaning Tracking 
Clinica! Diagnosis of PGD 
PaO2/FiO2 Ratio for Patients Diagnosed with PGD 
PGD Score for Patients Diagnosed with PGD 
Bronchoalveolar Lavage or Biopsy Patients Diagnosed with PGD 
First Extubation and ICU Discharge 
ICU Readmission and Hospital Discharge 
Patient Status at Month 1 
Death Report 
Laboralory Data: Hematology - Variable Profiles 
Laboralory Data: Clinica! Chemistry-
Variabte Profiles 
Laboratory Data: Coagulation - Variable Proftles 
Creatinine Clearance 
Renai and Hepatic Function 
Prior and Concomitant Medications Reported up to Month 1 
Vital Signs and Cardiopulmonary Measuremenls 
Cardiopulmonary Measurements for Patients Dìagnosed with PGD 
Pharmacokinetic Sample Colleclion 
lnvestigator's Declaration 
lnvestigator Comments 
Screening data for Patients Randomised but Not Treated/Transplanted 
12 DATA PRESENTATION 
Ali outputs will be produced using the following settings: 
Orientatlon 
Marains 
Font 
Headers 
Landscape 
Top: 1in/2.54cm 
SAS Monospace 
(Centered) 
Bottom: 1 in/2.54cm 
8pt 
Protocol Number 
Left: 0.5in/1.27cm 
Table/Listing 
Riaht: 0.5in/1.27cm 
Number and title 
Titles will be as follows: 
Oompé pha.r.ma s.p.a. Protocol REP0104 
Table tabno tabtitle 
Version date: 29 Sep 2006 
Footers 
(Left) 
Path and Filename 
Creation date 
Page20 of25 


PD 
13 TABLE SHELLS 
Tables 2.1.x and 2.2.x Repeated Measurements Analysìs 
Source 
Center 
Ti1_11e 
Treatment 
Center-by-treatment 
Version date: 29 Sep 2006 
Tests of Fixed Effects 
NDF 
DDF 
X 
X 
X 
X 
X 
X 
X 
X 
Type III F 
p 
X.XX 
o.xxxx 
x.xx 
o.xxxx 
X.XX 
o.xxxx 
x.xx 
O.xxxx 
Dompé pha.r.ma s.p.a. REP0104 
statistica/ Analysis Pian 
Page 21 of25 


PD 
Time 
o 
24 
Version date: 29 Sep 2006 
Sum~ary Statistics 
Repertaxin 
Placebo 
Time=O 
Least Squares Mean 
xx.xx 
xx.xx 
Mean 
xx.xx 
xx.xx 
so 
xx. xx 
xx.xx 
Median 
xx.xx 
xx.xx 
Range 
(xx.x; XX.X) 
(xx.x; XX.X) 
N 
X 
X 
Time=24 
Least Squares Mean 
xx.xx 
xx.xx 
Mean 
xx.xx 
xx.xx 
so 
xx.xx 
xx.xx 
r.tedian 
xx.xx 
xx.xx 
Range 
(xx.x; XX.X) 
(xx.x; XX.X) 
N 
X 
X 
Treatment Comparison 
Difference 
SE of 
959., confidence 
Compari son 
between Means 
dHference 
interval 
Repertaxin 
Placebo 
x.xxx 
X.XXX 
(-x.xx, 
X.XX) 
Repertaxin 
Placebo 
x.xxx 
X.XXX 
(-X.XX, 
X.XX) 
Dompé pha.r.ma s.p.a. REP0104 
Statistica/ Analysis Pian 
P-value 
o.xxxx 
o.xxxx 
Page 22 of25 


PD 
Table 2.3.x Analysis of PGD Score 
Repertaxìn 
N= 
N 
% 
Grade o 
xx 
xx 
Grade 
xx 
xx 
Grade 2 
xx 
xx 
Grade 3 
xx 
xx 
111 Odds ratio is Aepertaxin:Placebo 
Placebo 
Odds 
N= 
Ratio 
N 
% 
l 1 J 
xx 
xx 
X.XX 
xx 
xx 
xx 
xx 
xx 
xx 
95% CI for 
Odds Ratio 
(x.xx, x.xx) 
Dompé pha.r.ma s.p.a. REP0104 
Statistica/ Ana/ysis Pian 
P-value 
[2] 
o.xxx 
{2} The p-value is obtained froAI a Cochran-Mantel-Haenszel test of the treatment difference. 
Table 2.4.x Time to Freedom frorn Mechanical Ventilation 
TIME 
POINT 
24 hrs 
48 hrs 
72 hrs 
96 hrs 
etc 
Censored 
(N) 
Log-rank 
Repertaxìn 
N:a: 
Number of 
cumulative 
Patients 
Number of 
Remaining 
Events 
xx 
Version date: 29 Sep 2006 
Event 
Probabìlìty 
S.E. 
Placebo 
N" 
Number of 
Cumulative 
Patients 
Nu111ber 
of 
Event 
Remainìng 
Events 
Probability 
xx 
S.E. 
Oifference 
in Event 
Prob. 
Chi-sq 
statistic 
95% CI for 
Dìfference 
P-value 
Page23 of25 


PD 
Examples of adverse event presentations 
Table 3.2.1 .1 Summary of Treatment-Emergent Adverse Events (TEAEs) 
Total number of TEAEs 
Nu~ber of Patients with: 
At least one TEAE 
Withdrawing prematurely due to TEAE 
At least one Serious TEAE 
TEAE leading to death 
TEAEs - Most serious Relationship 
to Study Drug 
Unrelated 
Unlikely 
Possible 
Probable 
Highly Probable 
Serious TEAEs - Most Serious Relationship 
to Study Drug 
Unrelated 
Unlikely 
Possible 
Probable 
Highly Probable 
Version date: 29 Sep 2006 
Repertaxin 
xx 
xx (XX%) 
xx (XX%) 
xx (XX
96) 
xx (XX%) 
xx (XX%) 
xx {XX%) 
xx {XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
Dompé pha.r.ma s.p.a. REP0104 
Statistica/ Analysis Pian 
Treatment 
Placebo 
xx 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX%) 
xx (XX9o) 
Page 24 of 25 


PPD 
Dompé pha.r.ma s.p.a. REP0104 
Statìstical Analysis Pian 
Table 3.2.1.2 Treatment-Einergent Adverse EvHnts by Body Systea and Preferred Term 
Treatment 
MedDRA Body System & Preferred Term 
Repertaxin 
Placebo 
PAIN 
xx (XX%) 
xx (XX%) 
Pain- other 
xx (XX%) 
xx (XX%) 
Bone Pain 
xx (XX%) 
xx (XX%) 
Abdominal 
xx (XX%) 
xx (XX%) 
Headache 
xx (XX%) 
xx (XX%) 
Chest pain 
xx (XX%) 
xx (XX~ò) 
GASTROINTESTINAL 
xx (XX%) 
xx (XX~,;) 
Constipation 
xx (XX%) 
xx (XX%) 
Naw~ea 
xx (XX%) 
xx (XX%) 
Anorexia 
xx (XX%) 
xx (XX%) 
Vomiting 
xx (XX%) 
xx (XX%) 
Diarrhea 
xx (XX%) 
xx {XX%) 
Version date: 29 Sep 2006 
Page 25 of25