Clinical trial NCT01967888
Conditions: Pancreatectomy for Chronic Pancreatitis
Keywords: Pancreatic islet auto-transplantation
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2014-02-01; Completion date: 2018-01-01
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a phase 2/3, multicenter, double-blind, parallel assignment study. It involves 100 adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT).

The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by the proportion of insulin-independent patients following IAT. The safety of reparixin in the specific clinical setting will be also evaluated.

Detailed description:
In contrast to allo-transplantation in type 1 diabetes patients, where immunological mechanisms involving allo- and auto-antibodies affect long-term graft function, outcome in IAT (Islet Auto-Transplantation) is independent from immunological processes and does not require immunosuppression management. On the other hand, early inflammatory events intrinsic to the intra-portal islet infusion have been demonstrated to impact islet engraftment. Among possible mechanisms, PMNs have been found to be the predominant cell types infiltrating the liver in a syngeneic model of islet transplantation in mice.

Data obtained in experimental models of islet transplantation in mice demonstrate a clear effect of reparixin in improving graft survival and function. Protection from the loss and/or deterioration of transplanted islets was evident regardless of the immunological mechanisms involved in islet damage, suggesting that the ability of reparixin to modulate early inflammatory responses readily impact graft outcome.

Thus, the use of reparixin may emerge as a potential useful medication in the control of non specific inflammatory events surrounding the early phases of IAT.

The goal of this study is to reach a total of 100 adult patients who are randomized and receive IAT after total or completion pancreatectomy. Patients will be randomly (1:1) assigned to receive either reparixin \[continuous i.v. infusion for 7 days (168hrs)\], or matched placebo (control group),starting approximately 12hrs before islet infusion. The two groups will be balanced within each centre. All patients who are randomized and receive the Investigational Product (either reparixin or placebo) will be included in the ITT analysis. Patients will be in the ITT analysis whether or not they receive IAT, because exclusions cannot be made for events occurring after randomization that could be influenced by the randomized assignment.

Recruitment will be competitive among the study sites, until 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 transplant rate among study sites. Each centre will enroll patients as rapidly as possible, up to a maximum of 40 patients (as per the randomization list). A maximum of 48 patients is allowed for the site of the Primary Investigator.

Each patient will be involved in the study for 7 day hospital stay during pancreatectomy followed by islet transplantation, for all required measurements up to hospital discharge and for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the transplant.

Arms: arm 1: Solution for intravenous (IV) infusion with active compound arm 2: Physiologic solution
Interventions: intervention 1: Reparixin intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour intervention 2: Physiologic solution administered at 0.25 mL/kg/hour

Protocol documents:
Prot_003.pdf: 
Study REP0112 –Amendment No. 1 
Reparixin in IAT 
Page 1 of 4 
 
 
 
 
 
AMENDMENT No. 1 
To the CLINCIAL STUDY PROTOCOL version No. 1 – Final 11 October 2013 
APPLICABLE TO SITE No. 01 ONLY 
[Schulze Diabetes Institute; University of Minnesota Medical School] 
 
 
Study Number: 
REP0112 
 
IND Number: 
 117390 
 
Investigational Product: 
Reparixin 
 
 
Title: 
A phase 2/3, multicenter, randomized, double-blind, placebo-controlled, 
parallel assignment study to assess the efficacy and safety of reparixin in 
pancreatic islet auto-transplantation. 
 
 
 
 
Amendment No. 1 Version – Date Version No. 1 – final 18 July 2016 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this amendment and accompanying documents contains privileged or 
confidential information that is the property of Dompé farmaceutici s.p.a. It is understood 
that the information will not be used, divulged, or published without prior written consent of 
Dompé, except to the extent such disclosure is required by applicable laws and regulations. 
 
 
 
 
 
 
 
NOTES:  
This Amendment does not result in a change to either the CRF or the ICF. 
 
Version No. 1 – final 18 July 2016 
CONFIDENTIAL 
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Study REP0112 –Amendment No. 1 
Reparixin in IAT 
Page 2 of 4 
 
PROTOCOL AMENDMENT APPROVAL SIGNATURES 
 
SPONSOR:  
Medical Expert 
 
Signature:  _____________________________ 
Date: 
 ______________________  
Pier Adelchi Ruffini, MD – Development Director 
 
 
 
 
 
CLINICAL CENTRE:  PRINCIPAL INVESTIGATOR [PRIMARY INVESTIGATOR] 
I have read study protocol REP0112 “A phase 2/3, multicenter, randomized, double-blind, 
placebo-controlled, parallel assignment study to assess the efficacy and safety of reparixin in 
pancreatic islet auto-transplantation”.  
 
Name of Principal Investigator: 
Melena Bellin, MD 
 
Signature:  _____________________________ 
Date: 
 ______________________  
 
 
 
 
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Study REP0112 
Reparixin in IAT 
Page 1 of 68 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL - CONFIDENTIAL 
 
 
 
Study Number: 
REP0112 
 
IND Number: 
 117390 
 
Investigational Product: 
Reparixin 
 
 
Title: 
A phase 2/3, multicenter, randomized, double-blind, placebo-controlled, 
parallel assignment study to assess the efficacy and safety of reparixin in 
pancreatic islet auto-transplantation. 
 
 
Protocol Version – Date Version No. 2 – Final 18 July 2016 
APPLICABLE TO SITE No. 01 ONLY 
[Schulze Diabetes Institute; University of Minnesota Medical School] 
  
This protocol version results from revision of protocol version No. 1 (Final, 11 October 2013) 
according to Amendment No. 1 (final 18 July 2016).  
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential 
information that is the property of Dompé s.p.a. It 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 required by applicable laws and regulations. 
 
Version No. 2 – final 18Jul2016 
CONFIDENTIAL 
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REP0112 
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Page 2 of 68 
 
CONTACT INFORMATION 
 
SPONSOR 
Dompé s.p.a. [Dompé] 
 
Via Campo di Pile; 67100 L'Aquila, Italy 
 
Milan Offices: Via S. Lucia 6, 20122 Milan, Italy 
 
Phone: +39 02 583831; Fax: +39 02 58383324 
 
 
Medical Expert 
Pier Adelchi Ruffini, MD - Development Director 
 
 
Dompé s.p.a. - Milan Offices;  
 
 
Direct line: +39 02 58383500; Mobile: +39 346 8745908 
 
 
e-mail:  
 
 
Clinical Trial Manager 
Luisa Daffonchio, PhD - Clinical Development Manager 
 
 
Dompé s.p.a. - Milan Offices;  
 
 
Direct line: +39 02 58383246;  
 
 
e-mail: luisa.daffonchio@dompe.it 
 
 
Pharmacovigilance 
Dr. Laura Boga, QPPV 
 
 
Dompé s.p.a. - Milan Offices 
 
 
Direct line: +39 02 58383462; Mobile: +39 335 219580 
 
 
Fax: +39 02 36026913 
 
 
e-mail:  
 
 
 
CLINICAL RESEARCH 
inVentive Health Clinical [inVentive] 
ORGANIZATION 
504 Carnegie Center; Princeton, NJ 08540, USA 
 
Phone: +1 609 951 6800; Fax: +1 609 514 0390 
 
 
Project Manager 
Fiona Wingrave - Manager, Clinical Research 
 
 
5515 North Service Rd, Suite 200; Burlington, ON  L7L 6G4, 
 
 
Canada 
 
 
Phone: +1 289 313 3037; Fax: +1 937 637 9086 
 
 
e-mail: fiona.wingrave@inventivhealth.com 
 
 
 
 
INVESTIGATIONAL SITES 
 
Primary Investigator 
Melena Bellin, MD; Assistant Professor, Pediatric Endocrinology and Diabetes 
Schulze Diabetes Institute; University of Minnesota Medical School 
MMC 404, 420 Delaware St SE - Minneapolis, MN 55455 
Phone:  612-625-4686 or 612-626-5716 
Fax:  612-624-0420 (SDI), 612-626-5262 (Pediatric Endocrinology) 
Full list of investigational sites will be kept in the Trial Master File. Updated versions, if any, will be 
filed chronologically.  
 
 
CENTRALIZED LABORATORIES  
 
List of centralized laboratories will be kept in the Trial Master File. Updated versions, if any, will be 
filed chronologically.  
 
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Study REP0112 
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Page 3 of 68 
 
PROTOCOL APPROVAL SIGNATURES 
 
SPONSOR:  
Medical Expert 
 
Signature:  _____________________________ 
Date: 
 ______________________  
Pier Adelchi Ruffini, MD - Development Director 
 
 
Clinical Trial Manager 
 
Signature:  _____________________________ 
Date: 
 ______________________  
Luisa Daffonchio, PhD – Clinical Development Manager 
 
 
 
CLINICAL CENTRE:  PRINCIPAL INVESTIGATOR [PRIMARY INVESTIGATOR] 
I have read study protocol REP0112 “A phase 2/3, multicenter, randomized, double-blind, 
placebo-controlled, parallel assignment study to assess the efficacy and safety of reparixin in 
pancreatic islet auto-transplantation”.  
 
Name of Principal Investigator: 
Melena Bellin, MD 
 
Signature:  _____________________________ 
Date: 
 ______________________  
 
 
 
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TABLE OF CONTENTS 
1. 
STUDY SYNOPSIS AND OVERALL DESIGN ............................................................. 8 
2. 
BACKGROUND INFORMATION ............................................................................... 11 
2.1. 
RELEVANT NON-CLINICAL PHARMACOLOGY ...................................................... 11 
2.2. 
A SUMMARY OF TOXICOLOGY DATA ..................................................................... 12 
2.3. 
PHARMACOKINETICS AND PRODUCT METABOLISM .......................................... 12 
2.4. 
A SUMMARY OF CLINICAL DATA ............................................................................. 13 
2.4.1. 
Pharmacokinetics and product metabolism in humans ...................................................... 13 
2.4.2. 
Efficacy .............................................................................................................................. 13 
2.4.3. 
Safety ................................................................................................................................. 15 
2.5. 
DISEASE REVIEW AND STUDY RATIONALE ........................................................... 16 
2.5.1. 
Selection of dose and treatment schedule in the study ...................................................... 17 
2.5.2. 
Alternative treatments ........................................................................................................ 17 
2.5.3. 
Risk - benefit evaluation .................................................................................................... 17 
3. 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION....................................... 20 
3.1. 
STUDY DESIGN .............................................................................................................. 20 
3.2. 
STUDY TIME TABLE ..................................................................................................... 20 
3.3. 
END OF STUDY ............................................................................................................... 20 
4. 
OBJECTIVES AND ENDPOINTS ................................................................................ 21 
4.1. 
STUDY OBJECTIVES ..................................................................................................... 21 
4.2. 
STUDY ENDPOINTS ....................................................................................................... 21 
4.2.1. 
Primary efficacy endpoint .................................................................................................. 21 
4.2.2. 
Secondary efficacy endpoints ............................................................................................ 21 
4.2.3. 
Safety endpoints ................................................................................................................ 21 
4.2.4. 
Exploratory endpoints ........................................................................................................ 22 
4.2.5. 
Pharmacokinetic endpoints ................................................................................................ 23 
5. 
STUDY POPULATION .................................................................................................. 24 
5.1. 
INCLUSION CRITERIA .................................................................................................. 24 
5.2. 
EXCLUSION CRITERIA ................................................................................................. 24 
5.3. 
ASSIGNMENT OF PATIENT NUMBER ........................................................................ 25 
6. 
INVESTIGATIONAL PRODUCT ................................................................................ 26 
6.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING ................................. 26 
6.1.1. 
Presentation of Investigational Products............................................................................ 26 
6.1.2. 
Manufacturing, Packaging and Labelling of Investigational Product ............................... 26 
6.1.3. 
Supply, Storage and Handling of Investigational Product ................................................. 26 
6.1.4. 
Preparation of the Dosing Solution .................................................................................... 27 
6.1.5. 
Blinding ............................................................................................................................. 27 
6.2. 
DOSE, ROUTE AND SCHEDULE OF INVESTIGATIONAL PRODUCT 
ADMINISTRATION ......................................................................................................... 28 
6.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION/ 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT ........................................ 28 
6.3.1. 
Criteria for schedule adjustment or dose modification ...................................................... 28 
6.3.2. 
Criteria for discontinuation of Investigational Product ..................................................... 28 
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6.4. 
ACCOUNTABILITY ........................................................................................................ 29 
6.4.1. 
Assessment of compliance ................................................................................................. 30 
6.5. 
CONCOMITANT THERAPY .......................................................................................... 30 
6.5.1. 
Other treatments................................................................................................................. 31 
7. 
STUDY PROCEDURE AND ASSESSMENTS ............................................................ 32 
7.1. 
HOSPITAL STAY............................................................................................................. 32 
7.1.1. 
Screening and randomization ............................................................................................ 32 
7.1.2. 
Start of infusion with the Investigational Product ............................................................. 32 
7.1.3. 
Islet isolation and transplantation ...................................................................................... 33 
7.1.4. 
Drug administration during hospital stay........................................................................... 34 
7.1.5. 
Post-operative assessments ................................................................................................ 34 
7.2. 
FOLLOW-UP PROCEDURES AND ASSESSMENTS ................................................... 35 
7.3. 
EARLY PATIENT WITHDRAWAL ............................................................................... 36 
7.3.1. 
Criteria for withdrawal from the study .............................................................................. 36 
7.3.2. 
Replacement policy ........................................................................................................... 36 
8. 
ADVERSE EVENTS ....................................................................................................... 37 
8.1. 
DEFINITIONS .................................................................................................................. 37 
8.1.1. 
Definition of an Adverse Event ......................................................................................... 37 
8.1.2. 
Definition of a Serious Adverse Event .............................................................................. 37 
8.2. 
EMERGENCY PROCEDURES ....................................................................................... 37 
8.3. 
RECORDING .................................................................................................................... 37 
8.3.1. 
AE recording period .......................................................................................................... 38 
8.3.2. 
Relationship of AEs to the Investigational Product ........................................................... 38 
8.3.3. 
Severity of AEs .................................................................................................................. 38 
8.4. 
SERIOUS ADVERSE EVENT REPORTING .................................................................. 39 
8.4.1. 
Reporting Procedure for Investigators to Dompé (or designee) ........................................ 39 
8.4.2. 
Reporting Procedure for Investigators to IRB ................................................................... 39 
8.4.3. 
Reporting Procedures to the FDA ...................................................................................... 39 
8.5. 
ADVERSE EVENT EXEMPTION ................................................................................... 40 
9. 
STATISTICAL ISSUES .................................................................................................. 41 
9.1. 
SAMPLE SIZE .................................................................................................................. 41 
9.2. 
RANDOMIZATION ......................................................................................................... 42 
9.3. 
ANALYSIS POPULATION ............................................................................................. 42 
9.4. 
STATISTICAL METHODOLOGY .................................................................................. 43 
9.4.1. 
Demographic and baseline characteristics ......................................................................... 43 
9.4.2. 
Primary and Secondary Endpoint analysis ........................................................................ 43 
9.4.3. 
Safety analysis ................................................................................................................... 44 
9.4.4. 
Analysis of exploratory endpoints ..................................................................................... 44 
9.4.5. 
Interim analysis .................................................................................................................. 45 
9.4.6. 
Missing data ....................................................................................................................... 45 
9.4.7. 
Methods for multiplicity correction in analyses ................................................................ 46 
10. 
ETHICAL CONSIDERATIONS ................................................................................... 47 
10.1. 
INSTITUTE REVIEW BOARD (IRB) ............................................................................. 47 
10.2. 
INFORMED CONSENT ................................................................................................... 47 
10.3. 
CONFIDENTIALITY ....................................................................................................... 48 
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10.4. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND 
INDEMNIFICATION ....................................................................................................... 48 
11. 
DATA HANDLING AND RECORD KEEPING .......................................................... 49 
11.1. 
CASE REPORT FORMS COMPLETION........................................................................ 49 
11.2. 
DIARY CARD .................................................................................................................. 49 
11.3. 
DATA MANAGEMENT .................................................................................................. 49 
11.4. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING 
THE STUDY ..................................................................................................................... 49 
11.5. 
ESSENTIAL DOCUMENT RETENTION ....................................................................... 50 
12. 
STUDY MANAGEMENT ............................................................................................... 51 
12.1. 
REGULATORY BODY APPROVAL .............................................................................. 51 
12.2. 
STAFF INFORMATION & RESPONSIBILITIES .......................................................... 51 
12.3. 
MONITORING ................................................................................................................. 51 
12.3.1. 
Access to records ............................................................................................................... 51 
12.4. 
AUDIT AND INSPECTION ............................................................................................. 51 
12.5. 
DATA MONITORING COMMITTEE ............................................................................. 52 
12.6. 
PROTOCOL DEVIATIONS/AMENDMENTS ................................................................ 53 
12.7. 
DISCONTINUATION OF THE STUDY ......................................................................... 53 
12.8. 
PUBLICATIONS .............................................................................................................. 53 
13. 
REFERENCES ................................................................................................................ 54 
14. 
APPENDICES .................................................................................................................. 56 
14.1. 
APPENDIX 1 – CUMULATIVE SUMMARY OF ADVERSE DRUG 
REACTIONS1.................................................................................................................... 56 
14.2. 
APPENDIX 2 - PACKAGING AND LABELING DETAILS.......................................... 58 
14.3. 
APPENDIX 3 - STUDY DRUG INFUSION RATE BY BODY WEIGHT ..................... 60 
14.4. 
APPENDIX 4 - STUDY FLOW CHART ......................................................................... 62 
14.5. 
APPENDIX 5 - ACCEPTABLE TIME WINDOWS FOR ASSESSMENTS/ 
PROCEDURES ................................................................................................................. 63 
14.6. 
APPENDIX 6 - METHODOLOGICAL DETAILS .......................................................... 64 
14.6.1. 
Islet determination ............................................................................................................. 64 
14.6.2. 
Calculation of creatinine clearance .................................................................................... 64 
14.6.3. 
Handling of samples for centralized assays and assay methods ........................................ 64 
14.6.4. 
Mixed Meal Tolerance Test ............................................................................................... 66 
14.6.5. 
β-score calculation ............................................................................................................. 67 
14.7. 
APPENDIX 7 – SAMPLE DIARY CARD ....................................................................... 68 
 
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List of Abbreviations and Definitions of Terms  
 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ALT 
Alanine Aminotransferase 
ATG 
Anti-Thymocyte Globulin 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUC0-t 
Area under the plasma concentration-time curve from time zero to time t (time of last quantifiable 
plasma concentration) of reparixin and metabolites 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to infinity of reparixin and 
metabolites 
BP 
Blood Pressure 
C 
Degrees Celsius 
CL 
Clearance of reparixin and metabolites 
CLcr 
Calculated Creatinine Clearance (Cockcroft - Gault formula) 
Cinitial 
Plasma concentration of reparixin and metabolites just prior to the end of administration 
Cmax 
Maximum Plasma Concentration 
CMED 
Concomitant Medication 
cmH2O 
Centimeters of Water 
CPB 
Cardiopulmonary Bypass 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRP 
C-reactive Protein 
Css 
Steady State Concentration 
CXCL8 
CXC ligand 8 [formerly interleukin (IL)-8] 
ddPCR 
Droplet Digital PCR 
DMC 
Data Monitoring Committee 
g 
Grams 
GCP 
Good Clinical Practice 
HbA1c 
Glycated hemoglobin 
HR 
Heart rate 
kg 
Kilogram 
IAT 
Islet Auto-Transplantation 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IEQ 
Islet Equivalent 
IND 
Investigation New Drug 
INR 
International Normalized Ratio 
ITT 
Intent to Treat 
i.v. 
Intravenous 
LD50 
Lethal Dose50 
mg 
Milligram 
miR-375 
microRNA-375 
mL 
Millilitre 
mmHg 
Millimeters of mercury 
MMTT 
Mixed Meal Tolerance Test 
ng 
Nanogram 
NGSP 
National Glycohemoglobin Standardization Program 
NSAID 
Non Steroidal Anti-Inflammatory Drug 
PICD 
Patient Informed Consent Document 
PMN 
Polymorphonuclear leukocyte 
p.o. 
per os (taken by mouth) 
PTT 
Partial Thromboplastin Time 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
t½ 
Elimination half life 
tmax 
Time of maximum plasma concentration of reparixin and metabolites 
TPN 
Total Parenteral Nutrition 
U-CRA 
Unblinded-CRA 
ULN 
Upper Limit of Normal 
Vz 
Volume of distribution of reparixin  
XDP 
Fibrin Degradation Products 
μg 
Microgram 
λz 
Terminal phase rate constant reparixin and metabolites 
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1. 
STUDY SYNOPSIS AND OVERALL DESIGN 
 
Study title 
A phase 2/3, multicenter, randomized, double-blind, placebo-controlled, parallel assignment study to 
assess the efficacy and safety of reparixin in pancreatic islet auto-transplantation. 
Study Number 
REP0112          [US IND # 117390] 
 
Study period 
Projected starting date (first-patient-in): December 2013 
 
Projected completion of patient accrual (last-patient-in): March 2015 
 
Projected study end date (last-patient-last-visit): March 2016 
 
Study design 
The study will be a phase 2/3, multicenter, double-blind, parallel assignment study.  It will involve 100 
adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT).   
Patients will be randomly (1:1) assigned to receive either reparixin treatment (continuous i.v. infusion 
for 7 days – treatment group) or placebo (control group).  The two groups will be balanced within 
centres.  Recruitment will be competitive among the study sites, until the planned number of patients 
is enrolled.   
 
Objectives/endpoints 
The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome 
as measured by the proportion of insulin-independent patients following IAT.  The safety of reparixin 
in the specific clinical setting will be also evaluated. 
 
Efficacy endpoints will be:  
• The proportion of insulin-independent patients following IAT [Primary endpoint. time frame: 
day 365+14 after the transplant]. 
• Area Under the Curve (AUC) for the serum C-peptide level during the first 4 hours of an MMTT, 
normalized by the number of Islet Equivalent (IEQ)/kg [Time frame: day 75+14 and 365+14 after 
the transplant]. 
• Average daily insulin requirements [time frame: day 75+14 and 365+14 after the transplant]. 
• Basal (2 basal samples in the range between -20 to 0) to 240 min time course of glucose, C-
peptide and insulin derived from the MMTT [time frame: day 75+14 and 365+14 after the 
transplant]. 
• β-cell function as assessed by β-score [time frame: day 75+14 and 365+14 after the transplant]. 
• The proportion of patients with an HbA1c <6.5% [time frame: day 365+14 after the transplant]. 
• Cumulative number of severe hypoglycemic events [time frame: from day 75+14 to day 365+14 
after the transplant]. 
• The proportion of patients with an HbA1c <6.5% at day 365+14 AND are free of severe 
hypoglycemic events from day 75+14 to day 365+14 inclusive [time frame: day 365+14 and from 
day 75+14 to day 365+14 after the transplant].   
 
Safety endpoints will be:  
• Incidence and severity of Adverse Events and Serious Adverse Events [time frame: throughout 
the study up to day 365+14 after the transplant]. 
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• Standard laboratory tests including hematology (hematocrit, hemoglobin, red blood cells, 
platelets, white blood cells, differential white blood cells count), clinical chemistry (sodium, 
potassium, serum creatinine, blood urea nitrogen, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and coagulation (International Normalized Ratio (INR), partial 
thromboplastin time (PTT))  [time frame: pre-transplant hospital admission and post-transplant 
hospital discharge]. 
• Vital signs, i.e. blood pressure (BP) and heart rate (HR) [time frame: pre-transplant hospital 
admission and post-transplant hospital discharge]. 
• ALT/AST, INR/PTT, fibrin degradation products (XDPs), C-reactive protein (CRP) [time frame: 
all daily from day 1 up to day 7 after the transplant; ALT/AST also on day 75+14 after the 
transplant]. 
• Weight loss from pre-transplant value [time frame: day 75+14 and 365+14 after the transplant]. 
• Serum level of albumin and pre-albumin (absolute and change from pre-transplant value) [time 
frame: day 75+14 and 365+14 after the transplant]. 
• Severity of steatorrhea [time frame: day 75+14 and 365+14 after the transplant]. 
• Malnutrition risk (poor prognosis, significant risk, increased risk, normal) according to pre-
albumin level [time frame: day 75+14 and 365+14 after the transplant].  
• Cumulative number of episodes of documented hypoglycemia (documented symptomatic; 
asymptomatic) [time frame: from day 75+14 to day 365+14 after the transplant]. 
• Cumulative number of diabetic ketoacidosis-related events [time frame: from day 75+14 to day 
365+14 after the transplant]. 
 
Exploratory endpoints will be: 
• Time course of inflammatory chemokines/cytokines as assessed by serum level of CXCL8, CCL2 
(MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10, INF-γ, TNF-α, and IL-1β 
[time frame: pre-infusion hospital admission (2 basal samples collected 6 to 24 hrs apart; both 
samples will be obtained before surgery and before Investigational Product administration is 
started) and 6, 12, 24, 72, 120 and 168hrs after the end of islet infusion]. 
• Proportion of patients who are randomized but do not receive IAT [time frame: transplant day]. 
• Time course of serum microRNA-375 (miR-375) [time frame: pre-infusion hospital admission 
(sample will be obtained before surgery and before Investigational Product administration is 
started) and 6, 12, 24, 72, 120 and 168hrs after the end of islet infusion]. 
 
Pharmacokinetic endpoints will be: 
• 
Plasma levels of reparixin (total and unbound) and relevant metabolites (DF2243Y and 
ibuprofen) [time frame: post-operative day 1, 3, and 5 (steady state) in all patients; just prior to, 
and then at 1, 3, 5, 6, 8, and 12 hrs after termination of Investigational Product administration in 
a subset of at least 20-24 patients]. 
 
Number of patients 
The goal of this study is to reach a total of 100 patients who are randomized and receive IAT after 
total or completion pancreatectomy. 
 
Inclusion/exclusion criteria 
Patients aged > 18 years given written informed consent who are eligible for an IAT following total (or 
completion) pancreatectomy will be included in this study. 
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Recipients of a previous IAT (if completion pancreatectomy) as well as patients undergoing total 
pancreatectomy due to pancreatic cancer or pancreatic benign diseases (e.g. pancreatic pseudocystis, 
insulinomas, etc.) will be excluded.   
Patients who have inadequate renal reserve (calculated creatinine clearance < 60 mL/min according to 
the Cockcroft-Gault formula), hepatic dysfunction (increased ALT/AST > 3 x upper limit of normal or 
increased total bilirubin above upper limit of normal at local laboratory, except patients with Gilbert’s 
syndrome), a preoperative International Normalized Ratio (INR) > 1.5 or any known coagulopathy, 
hypersensitivity to ibuprofen or to more than one non steroidal anti-inflammatory drug or to more than 
one medication belonging to the class of sulfonamides (e.g. sulfamethazine, sulfamethoxazole, 
sulfasalazine, nimesulide or celecoxib - hypersensitivity to sulphanilamide antibiotics alone, e.g.  
sulfamethoxazole, does not qualify for exclusion) will be also excluded. 
Also, patients will be excluded from study participation if they have concurrent sepsis (as per positive 
blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome), have received a 
treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use for physiological 
replacement only), or any investigational agent (including any anti-cytokine/chemokine agents) or any 
immune modulators in the 4 weeks prior to enrolment, if they have pre-existing diabetes or evidence of 
impaired β-cells function (pre-operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%) or 
require treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 weeks 
prior to enrollment, if they have past or current history of alcohol abuse, if they have evidence of pre-
operative portal hypertension (clinical history and abdominal/liver imaging by ultrasound techniques). 
Pregnant or breast-feeding women or patients unwilling to use effective contraceptive measures 
(females and males) will not participate in the study. 
 
Investigational Product 
The investigational drug will be reparixin or matching placebo.  Reparixin will be administered as a 
continuous i.v. infusion into a (high flow) central vein at a dose of 2.772 mg/kg body weight/hour for 
7 days (168hrs), starting approximately 12hrs (6-18 hrs) before pancreatic islet infusion.  Placebo 
(0.9% w/v sodium chloride solution) will be infused at matching volume/rate.  
 
Procedures 
Each patient will be involved in the study for a 7 day hospital stay during pancreatectomy followed by 
islet transplantation, for all required measurements up to hospital discharge and for 2 post-transplant 
visits scheduled at day 75+14 and 365+14 after the transplant. 
 
Statistics 
All patient data collected on the CRF and on the Diary will be listed by patient, treatment group and 
centre.  The data will be presented in the Clinical Study Report.   
Appropriate descriptive statistics will be produced, according to the variable.  
For the primary efficacy endpoint, the proportion of insulin-independent patients following IAT over 
the time frame of day 365+14 after the transplant, the differences in proportions will be assessed using 
the Pearson Chi-square statistic, stratified by the three groups at baseline: < 2500 IEQ/kg vs. 2500-
5000 IEQ/kg vs. > 5000 IEQ/kg.   
A Statistical Analysis Plan will be issued describing details of all the statistical methods and analysis 
to be applied to trial results.  Any deviations from the original statistical plan will be described in the 
Clinical Study Report. 
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2. 
BACKGROUND INFORMATION 
Reparixin is a specific inhibitor of CXC ligand 8 [CXCL8; formerly interleukin (IL)-8] biological 
activity, stemming from a program of drug design of molecules intended to modulate chemokine 
action.  
Reparixin is the first low molecular weight blocker of CXCL8 biological activity in clinical 
development.  Relevant pre-clinical, toxicological and phase 1 and 2 clinical data are summarized 
below.  Please also refer to the Investigator’s Brochure for more detailed information.  
Reparixin (formerly repertaxin) was granted orphan drug designation for the “prevention of delayed 
graft function after (solid) organ transplantations” by the European Commission of Orphan Medicinal 
Products in September 2001 and by the Food and Drug Administration in January 2003.  More 
recently orphan drug designation has been granted in EU (Septemebr 2011) for the “prevention of 
graft loss in pancreatic islet transplantation” and in the US (September 2012) for the “prevention of 
graft loss in islet cell transplantation”. 
2.1. 
RELEVANT NON-CLINICAL PHARMACOLOGY 
Reparixin is in vitro a potent and specific inhibitor of CXCL8 biological activity.  In vitro chemotaxis 
experiments have shown that reparixin inhibits CXCL8-induced chemotaxis of human 
polymorphonuclear leukocytes (PMN) in the low nanomolar range.  Studies to elucidate the 
mechanism of action have shown that reparixin is a non-competitive allosteric inhibitor of the CXCL8 
receptors CXCR1 and CXCR2.  Interaction of reparixin with CXCL8 receptors inhibits the 
intracellular signal transduction events activated by binding of CXCL8 to CXCR1 and CXCR2 
[Bertini, 2004; Allegretti, 2005].  
In vivo, reparixin prevented PMN infiltration into the transplanted kidney and reduced creatinin levels 
in a rat model of kidney transplantation.  Similarly, in a rat model of lung transplantation, reparixin 
improved isolated graft oxygenation, decreased pulmonary oedema, and significantly reduced 
neutrophil infiltration into transplanted lungs.  Moreover, reparixin prevented PMN infiltration and 
tissue damage in other animal models of ischemia/reperfusion injury of liver, brain, intestine, heart 
and spinal cord.  In these models, in vivo inhibition of PMN recruitment ranged from 40 to 90%, and 
inhibition of tissue damage ranged from 50 to 80%.  Efficacy was seen in all models at reparixin dose 
of 9.90 mg/kg [Bertini, 2004; Cugini, 2005; Souza, 2004; Cavalieri, 2005; Garau, 2005; Villa, 2007; 
Gorio, 2007].  
More recently, reparixin lysine salt was evaluated in different models of intrahepatic pancreatic islet 
transplantation in mice, which include syngeneic and allogeneic settings.  Reparixin was administered 
by s.c. continuous infusion for 7 or 14 days starting from day -1 of islet transplantation.  A dose of 
5.28 mg/kg/hour was administered in all experiments.  Reparixin was able to significantly improve 
islet engraftment, as demonstrated by its ability to increase the likelihood of and to reduce the time to 
gain non-fasting blood glucose levels less than 200 mg/dl (normo-glycaemia) in marginal mass 
syngeneic islet transplantation model.  In the fully mismatched allogeneic model, reparixin not only 
protected islets from early graft failure, but was also able to increase the time to rejection, as shown by 
post-transplant prolongation of normo-glycaemia.  Graft function was indefinitely prolonged in 
20/30% of mice treated with reparixin and rapamycin, suggesting possible tolerance induction.  In 
parallel, reparixin treatment reduced intrahepatic infiltration of PMNs, macrophages, T helper and 
dendritic cells [Citro, 2012a].  
Reparixin also delayed the onset of diabetes induced in mice by multiple low doses of streptozotocin.  
Also, mice treated with reparixin retained a better glycemic control (lower glycemic levels) even after 
diabetes development [Citro, 2012b]. 
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2.2. 
A SUMMARY OF TOXICOLOGY DATA 
Reparixin was tested for toxicity in rodent and non-rodent animal species after single and repeated i.v. 
doses.  The repeated dose administration studies were conducted by i.v. continuous infusion, 
according to the intended human administration route.  
The general toxicological profile of i.v. reparixin, in the studies conducted to date, is characterized by 
a low toxicity after single or repeated dose administrations in rats (LD50 = 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 reparixin to the male and female rat at dose levels of up to 660.00 
mg/kg/day did not have any significant adverse effects on mating performance and fertility. 
Reparixin poses no genotoxic hazard for humans. 
Reparixin 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 systems of rats and dogs.  
The local tolerability of reparixin lysine salt was assayed in the rabbit ear lateral vein.  The compound 
was well tolerated in concentrations up to 4.95 mg/mL (1 mL/kg) infused over a minute. 
In order to provide evidence of the safety of DF2243Y, the main metabolite of reparixin excreted in 
urine in humans, safety pharmacology and toxicity studies have been performed at doses 2 to 3 times 
higher than those reached in man, as may occur during the treatment of patients receiving kidney 
transplantation. 
2.3. 
PHARMACOKINETICS AND PRODUCT METABOLISM 
PK studies by i.v. injection revealed that reparixin is very rapidly eliminated in rats and humans (t1/2 
0.5-3hrs and 1.0-1.5hrs, respectively) whereas elimination is slower in dogs (12-28hrs).  The PK of 
reparixin was linear in rats and in dogs but linearity was less evident in humans.   
Reparixin undergoes complete metabolism (oxidation + conjugation) in all the species tested. The in 
vitro human hepatic, phase I metabolism of reparixin is catalysed by CYP2C9 and to a lesser extent by 
CYP2C19.  DF2243Y, DF2188Y, methanesulfonamide and ibuprofen are the metabolites detected in 
human plasma and urine, with DF2243Y being the major metabolite.  Exposure to ibuprofen after 
administration of reparixin 2.77 mg/kg/h for 48hrs (the highest dose tested in humans) was similar or 
lower than that obtained after a standard therapeutic single dose of ibuprofen (300mg). 
Due to extensive metabolism, unchanged reparixin was poorly or not excreted into the urine of rat, 
dogs and humans so that the PK profile of reparixin is not influenced by renal impairment.   
In vitro protein binding of [14C]-reparixin showed that reparixin is highly bound (approximately 99%) 
to plasma proteins in rats, dogs, rabbits, cynomolgus monkeys and humans.  Albumin is likely to be the 
major binding protein in plasma in all species, accounting for 99.2% in humans.  
Reparixin has some potential in vitro for a non-competitive inhibition of the human hepatic enzyme 
CYP3A4 that is involved in the metabolism of cyclosporine A, tacrolimus and rapamycin.  However, 
since inhibition is evident at concentration far higher than the free plasma concentration of reparixin at 
steady state in humans, it is predicted that the clinical relevance of such inhibition is remote.  Indeed, 
reparixin does not affect to a clinically relevant extent the activity of CYP3A4 and CYP2C9 (enzyme 
involved in reparixin metabolism), as revealed by an interaction study where the PK of midazolam and 
tolbutamide (probe substrates for these enzymes) was evaluated in healthy subjects receiving single 
oral doses of the probes alone or in combination with reparixin.   
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2.4. 
A SUMMARY OF CLINICAL DATA  
Clinical development includes phase 1 pharmacokinetics, tolerability and pharmacodynamic studies 
and 2 phase 2 studies conducted in lung and kidney transplant patients.  An independent study was 
also carried out in cardiopulmonary bypass (CPB) patients.    
To date, a total of 363 subjects were involved in completed clinical studies, of whom 230 were 
exposed to reparixin.  
A pilot phase 2 study is ongoing in islet transplantation and is addressed below.  
2.4.1. 
Pharmacokinetics and product metabolism in humans 
Three phase 1 PK/safety studies were performed which included 30min to 48h i.v. infusion of 
ascending doses in healthy male subjects and 6h i.v. infusion of a selected dose in male and female 
subjects with normal to severely impaired renal function [REP0101; REP0102; REP0203].  An 
additional interaction study was also conducted in healthy subjects [REP0103].  PK results are 
discussed in paragraph 2.3. 
2.4.2. 
Efficacy 
In the first US-Canada phase 2 study [REP0104], 101 patients (46 on reparixin, 55 on placebo) 
undergoing single or bilateral lung transplant were included in the intent to treat (ITT) and safety 
population out of 114 enrolled.  The patients were randomized to receive 48h i.v. continuous infusion 
(loading: 4.488 mg/kg/h for 30min, maintenance: 2.772 mg/kg/h for 47.5hrs) of either reparixin or 
placebo starting a few hours before the transplant.  The study failed to show any statistically 
significant difference between the reparixin and placebo groups in the primary efficacy variable 
(PaO2/FiO2 ratio) and in any of the secondary efficacy variables assessed up to month 12 post-
transplant, except survival.  Indeed, there was a statistically significant difference in patient survival at 
Month 12 post-transplant between the placebo (7 deaths) and reparixin (no deaths) groups (p-value = 
0.0111 [Log-Rank]). 
The second phase 2 study [REP0204] was conducted in US, Italy, Spain and France and involved 
patients undergoing kidney transplantation at increased risk of developing Delayed Graft Function. 
This was a pilot study designed to explore the efficacy and safety of two different dosing schedules 
selected to minimize the impact of possible post-transplant renal dysfunction on reparixin PK.  Out of 
80 patients randomized, 74 patients (25 reparixin continuous infusion; 23 reparixin intermittent 
infusion; 26 pooled placebo) and 73 patients (24 reparixin continuous infusion; 23 reparixin 
intermittent infusion; 26 pooled placebo) were included in the safety and ITT analysis, respectively.  
The patients were randomized to receive reparixin or placebo as continuous infusion of 2.772 mg/kg/h 
for 12hrs or 12 intermittent i.v. infusions of 2.244 mg/kg for 30min with 1.5 hour intervals over a total 
period of 22.5hrs or matched placebo.  Overall, the study failed to show a significant difference 
between the treatment groups in the primary efficacy variable (early CLcr) and in any of the 
secondary efficacy variables assessed up to month 12 post-transplant.  However, a trend for a better 
graft function, measured by early (1-3 and 10-12hrs after transplant) CLcr and day 1 to 7 serum Cr 
was observed in the reparixin intermittent infusion group, which however did not reach a statistical 
significance.  Also a higher, even not significant, percentage of patients in this group had immediate 
graft function, with only one patient experiencing graft failure.     
The Medical University of Vienna conducted an additional independent placebo-controlled, 
randomized pilot trial in 32 patients undergoing elective coronary artery bypass grafting with CPB.  
Reparixin was infused at a loading dose of 4.488 mg/kg/h for 30min followed by a maintenance dose 
of 2.772 mg/kg/h for 8h.  The rise in neutrophil count after CPB was less marked in the reparixin than 
in the placebo group (p < 0.05).  Significant group differences were also detected at 4 hours post-CPB.   
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2.4.3. 
Safety 
A total of 230 subjects have been exposed to reparixin in the clinical studies completed to date which 
include 103 adult healthy subjects (100M/3F), 17 patients with different grades of renal impairment 
(12M/5F), 16 patients undergoing cardiopulmonary by pass (10M/6F), 46 patients undergoing lung 
transplantation (23M/23F) and 48 patients undergoing kidney transplant (31M/17F).  Exposure 
included short or prolonged i.v. infusion up to 10.6 mg/kg over 30min or 133 mg/kg over 48h. 
Overall, reparixin was safe and well tolerated in both healthy subjects and critically ill patients.   
In phase 1 studies, no deaths, Serious Adverse Events (SAEs) or Adverse Event (AE)-related 
withdrawals were reported.  The majority of AEs reported were of mild intensity.  All subjects had 
recovered completely or had ongoing adverse events of mild intensity when they were discharged.  
The safety of reparixin was confirmed also in patients with different grades of renal impairment.  In 
the 
interaction 
study 
no 
safety 
concerns 
were 
raised 
during 
co-administration 
of 
midazolam/tolbutamide with reparixin. 
During phase 2 studies, AE and SAE profile was similar for both placebo and reparixin groups and no 
particular safety concerns were raised.   
In the lung transplant study there were no AE-related withdrawals or deaths for either placebo or 
reparixin groups.  A total of 28 patients experienced SAEs.  Death occurred in 7 patients, all in the 
placebo group.  Death was due to infections in 4 patients leading to sepsis/bacteraemia (3 patients) or 
pneumonia (1 patient).  One patient died due to a cardiovascular accident.  Coronary artery disease or 
unknown origin was the cause of death reported for the other 2 patients for whom minimal information 
was available.     
In the kidney transplant study there was 1 AE-related withdrawal in the reparixin continuous infusion 
group.  AEs leading to discontinuation of study drug were reported for 3 patients in the reparixin 
continuous infusion group and for 1 patient in the placebo group.  One patient in the placebo group 
had an AE (septic shock, pneumonia) leading to death.  SAEs were reported in 21 patients.  Death 
occurred in 2 patients, 1 in the placebo group (septic shock, pneumonia) and 1 in the reparixin 
intermittent infusion group (no information available).   
No SAEs were reported from the CPB study.   
As to Adverse Drug Reactions (ADRs), infusion site reactions, mainly erythema or aseptic 
thrombophlebitis, were one of the most common ADRs.  The relatively high frequency was due to a 
cluster of events occurring in cohort 1 of the phase 1 48h-infusion study.  Local toxicity was clearly 
related to drug concentration since the use of a more diluted solution at a higher infusion rate 
markedly reduced the incidence, type and severity of infusion site reactions.   
Cumulative summary tabulations of ADRs are reported in Appendix 14.1.   
The most frequent (>10%) ADRs observed in the phase 1 and phase 2 studies were: 
Nervous system disorders (about 27%), including headache, dizziness, hypoaesthesia, somnolence. 
General disorders and administration site conditions (about 23%), including cannula site reaction, 
injection site thrombosis, infusion site oedema and peripheral oedema, fatigue, lethargy. 
Gastrointestinal disorders (about 14%), including nausea, vomiting, abdominal pain, dyspepsia, 
flatulence, gastroesophageal reflux disease. 
Overall, there was no correlation between the incidence of ADRs and the extent of exposure.  
Moreover, the incidence of ADRs was variable among studies regardless of the clinical condition of 
the population exposed to reparixin, i.e. patients under critical care (lung/kidney transplant or CPB 
patients) did not experience increased frequency of adverse events attributable to reparixin. 
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Preliminary data obtained in the ongoing pilot trial in islet allo-transplantation further support the 
safety of reparixin in this clinical setting.  In patients treated with a 7 day course of reparixin a few 
AEs were reported which were judged to be at least possibly related to reparixin treatment.  Most 
frequent ADRs were erythema, hypotension, nausea, vomiting; great majority of these were mild to 
moderate in nature and none required discontinuation if the Investigational Product.  A total of 5 SAEs 
were reported to date in 4 patients.  Two patients (one randomized to the control group, one to the 
reparixin group) experienced intraperitoneal bleeding which was judged to depend on the islet infusion 
procedure (not-related to the study treatment) in both cases.  One patient who had received reparixin 
during the first islet transplant was hospitalized for diabetic ketoacidosis (due to graft failure) and 
diarrhea (possibly due to MMF administration).  Nausea, vomiting and severe gastrointestinal bleeding 
associated with anaemia developed in a female patient early after the beginning of reparixin infusion; 
upon case evaluation, a medical error was evidenced, i.e. the patient received a dose of reparixn 3 
times as high as that foreseen in the protocol; infusion of reparixin was immediately discontinued and 
the patient recovered.  About 2 months later, this same patient required hospitalization for diarrhea and 
worsening of kidney function which were due to immunosupressive medications (MMF, tacrolimus).   
2.5. 
DISEASE REVIEW AND STUDY RATIONALE 
Total pancreatectomy is a surgical procedure to treat end-stage pancreatic diseases, including, but not 
limited to, chronic pancreatitis.  Despite improvement in surgical techniques, total pancreatectomy is 
associated with long term complications which are mostly accounted for by endocrine insufficiency.  
While exocrine insufficiency is considered easier to overcome, the ensuing surgical brittle diabetes 
presents with a high risk of hypoglycemic unawareness that is a leading cause of patient death [Sarr, 
1993; Berney, 2000; Gruessner, 2004; Garcea, 2009].   
After total pancreatectomy, the absence of endogenous insulin is coupled with the lack of other regulatory 
hormones, such as glucagon, resulting in the well known poor post-operative diabetes control [Farley, 
1995; Linhean, 1988].  Segmental pancreatic or islet auto-transplantation (IAT) has therefore been 
considered since the 1970s as feasible adjunctive procedures to prevent severe post-surgical diabetes in 
patients undergoing total pancreatectomy for chronic pancreatitis. IAT offers advantages over heterotopic 
pancreas auto-transplantation as intraportal islet infusion is a smaller procedure and should be favoured 
whenever the patient has lost pancreatic exocrine function [Sutherland, 1978; Hogle, 1978; Gruessner, 
2004; Dong, 2011].   
Despite β-cell mass, as estimated by Islet Equivalent (IEQ)/kg body weight, is less than for islet 
allografts, long term successful auto-graft function can be achieved in most patients, with a rate of 
insulin independence as high as >80% of recipients, even if lower figures have been reported, 
according to the total amount of IEQ infused [Sutherland, 2012; Pollard, 2011; Dong, 2011]. 
In addition to end-stage chronic pancreatitis, IAT post pancreatectomy has been utilized for an 
expanded series of pancreatic benign diseases including, pancreatic pseudocystis, insulinomas, etc.  More 
recently, patients bearing pancreatic cancer were admitted to IAT with no evidence of hepatic 
recurrence of pancreatic disease up to almost one year follow-up, offering some neoplastic patients a 
chance for post-pancreatectomy glycemic control [Dong, 2011; Balzano, 2011].  
In contrast to allo-transplantation in type 1 diabetes patients, where immunological mechanisms 
involving allo- and auto-antibodies affect long-term graft function, outcome in IAT is independent 
from immunological processes and does not require immunosuppression management.  On the other 
hand, early inflammatory events intrinsic to the intra-portal islet infusion have been demonstrated to 
impact islet engraftment.  Among possible mechanisms, PMNs have been found to be the predominant 
cell types infiltrating the liver in a syngeneic model of islet transplantation in mice.  Also, the intra-
hepatic mRNA for CXCL1/KC, the murine counterpart of human CXCL8, was strongly induced 
immediately after islet infusion.  Consistent with this results, transplanted CXCR2 knock out mice had 
a significant improvement in islet function [Citro, 2011].  Thus, CXCL8 might represent a relevant 
therapeutic target to prevent early graft failure after IAT. 
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Data obtained in experimental models of islet transplantation in mice demonstrate a clear effect of 
reparixin in improving graft survival and function.  Protection from the loss and/or deterioration of 
transplanted islets was evident regardless of the immunological mechanisms involved in islet damage, 
suggesting that the ability of reparixin to modulate early inflammatory responses readily impact graft 
outcome.  Results obtained with reparixin in the experimental model of multiple low doses of 
streptozotocin further emphasize the ability of reparixin to protect β-cells from an inflammatory 
damage which appears to impact subsequent graft outcome. 
Thus, the use of reparixin may emerge as a potential useful medication in the control of non specific 
inflammatory events surrounding the early phases of IAT.   
Preliminary data obtained in transplanted patients recruited in the ongoing pilot trial coupled with the 
safety shown in human phase 1 and 2 studies provide a sound rationale for further development of 
reparixin also in IAT and prompt the conduct of this phase 2/3 clinical study aimed at assessing the 
efficacy and safety of reparixin in improving graft outcome in patients undergoing total (or 
completion) pancreatectomy followed by IAT.   
2.5.1. 
Selection of dose and treatment schedule in the study 
The dose of reparixin proposed for this trial (2.772 mg/kg body weight/hour) is the same being 
administered in the ongoing clinical trials in islet allo-tranplantation.  It was originally derived from 
the effective reparixin concentrations found both in “in vitro” inhibition of CXCL8-induced 
chemotaxis of human PMN and in experiments in mouse models of syngeneic and allogeneic 
transplantation.  Such a dose was found safe in previous phase 1 and 2 studies.  Also, preliminary data 
obtained in the ongoing pilot trial in islet allo-transplantation confirm the efficacy and the safety of 
such a dose.   
Consistent with experimental data in animals and preliminary data in the ongoing pilot trial in islet 
allo-transplantation, the proposed schedule of administration (continuous infusion for 7 days) is 
intended to expose the patient to reparixin throughout the time-window of relevant inflammatory post-
transplant events after both allo-transplantation and IAT [Pollard, 2011; Citro, 2011]. 
2.5.2. 
Alternative treatments 
There are no specific pharmacologic treatments addressed to the prevention of graft failure after IAT.  
A trial is currently ongoing to test the potential effect of sitagliptin in IAT (NCT01186562).  Because 
of this, patients not willing to participate in the study may either be offered to participate in another 
trial of experimental treatment or will not be offered any specific alternative treatment.   
All patients, regardless of study participation, will receive the standard of optimal care for the 
transplanted organ (procurement, storage, isolation, infusion) and the recipient.   
2.5.3. 
Risk - benefit evaluation 
2.5.3.1. 
General risks 
Transplantation of islets is associated with several potential risks.  These are intrinsic to the procedure 
and may result from the intra-hepatic islet infusion as well as testing involved in the care and 
evaluation of transplanted subjects.  All patients receiving IAT are at risk of complication regardless 
of study participation.  
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2.5.3.2. 
Risk related to the Investigational Product 
Results from preclinical studies support the level of drug exposure planned in this study.  Also, past 
clinical experience with the same dose as planned in this study provides a clear cut evidence of 
reparixin safety.  Very few SAEs were reported with this dose even from clinical trials conducted in 
severe clinical conditions such as patients undergoing lung or kidney transplantation. 
Preliminary data obtained in the ongoing pilot trial in islet allo-transplantation further support the 
safety of reparixin in this clinical setting.  In patients treated with a 7 day course of reparixin a few 
AEs were reported which were judged to be at least possibly related to reparixin treatment.  Most 
frequent ADRs were erythema, hypotension, nausea, vomiting; great majority of these were mild to 
moderate in nature and none required discontinuation if the Investigational Product.  A total of 5 SAEs 
were reported to date in 4 patients.  Two patients (one randomized to the control group, one to the 
reparixin group) experienced intraperitoneal bleeding which was judged to depend on the islet infusion 
procedure (not-related to the study treatment) in both cases.  One patient who had received reparixin 
during the first islet transplant was hospitalized for diabetic ketoacidosis (due to graft failure) and 
diarrhea (possibly due to MMF administration).  Nausea, vomiting and severe gastrointestinal bleeding 
associated with anaemia developed in a female patient early after the beginning of reparixin infusion; 
upon case evaluation, a medical error was evidenced, i.e. the patient received a dose of reparixn 3 
times as high as that foreseen in the protocol; infusion of reparixin was immediately discontinued and 
the patient recovered.  About 2 months later, this same patient required hospitalization for diarrhea and 
worsening of kidney function which were due to immunosupressive medications (MMF, tacrolimus).   
The very short half life of reparixin (t1/2 1.0-1.5hrs) represents an important safety factor as plasma 
levels decline rapidly after drug discontinuation.  This PK profile, coupled with the mechanism of 
reparixin action (reversible inhibition), makes readily effective appropriate stopping rules.   
Administration via a high flow central vein, which was proven to be safe in lung and kidney recipients, 
as well as in patients undergoing islet transplant, is proposed for the study to minimize the risk of 
infusion-site toxicity seen in a cohort of volunteers receiving i.v. infusion via a peripheral vein.   
2.5.3.3. 
Central line 
The study drug will be administered as a continuous i.v. infusion over 7 days with a catheter inserted 
in a (high flow) central vein.  The risks of a central line are not considered study-related risks since a 
central line is routinely placed in patients undergoing post-pancreatectomy IAT for their routine 
clinical care.  This required access will be maintained for a period of time that might be slightly longer 
than that routinely used.  Nevertheless, central line care as routinely practiced by the participating sites 
will minimize the risk of thrombosis and infections. 
2.5.3.4. 
Blood sampling 
In addition to the routine blood sampling, participation in the study will require an amount of blood 
slightly higher than routine sampling at some time points (not exceeding 5mL at each time point), to 
allow study specific measurements and centralized assay of C-peptide, HbA1c, inflammatory 
chemokines/cytokines, miR-375 and PK samples.  
2.5.3.5. 
Other study related procedures 
No other procedures specifically associated to the study are required.  Type, timing and frequency of 
some measurements, e.g. stimulation test by a Mixed Meal Tolerance Test (MMTT), might be guided 
by the protocol, but such measurements are basically part of standard patient care and would be 
performed regardless of study participation. 
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2.5.3.6. 
Potential benefit 
To the patients: 
According to preliminary data obtained in islet allo-transplantation, patients 
receiving reparixin are likely to benefit with improved auto-graft function, but this 
is to be confirmed.  Patients assigned to the control arm are expected to obtain no 
additional benefit other than that established in IAT recipients.      
To society: 
This study may identify a useful medication that will make post-pancreatectomy 
IAT more effective for future recipients. 
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3. 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION 
3.1. 
STUDY DESIGN 
The study will be a phase 2/3, multicenter (US), randomized, double-blind, placebo-controlled, 
parallel assignment pilot study.   
The goal of this study is to reach a total of 100 adult patients who are randomized and receive IAT 
after total or completion pancreatectomy.  Patients will be randomly (1:1) assigned to receive either 
reparixin [continuous i.v. infusion for 7 days (168hrs)], or matched placebo (control group),starting 
approximately 12hrs before islet infusion.  The two groups will be balanced within each centre.  All 
patients who are randomized and receive the Investigational Product (either reparixin or placebo) will 
be inlcuded in the ITT analysis.  Patients will be in the ITT analysis whether or not they receive IAT, 
because exclusions cannot be made for events occurring after randomization that could be influenced 
by the randomized assignment. 
Recruitment will be competitive among the study sites, until 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 transplant rate among study sites.  Each centre will enroll patients as rapidly as 
possible, up to a maximum of 40 patients (as per the randomization list). A maximum of 48 patients is 
allowed for the site of the Primary Investigator. Each patient will be involved in the study for 7 day 
hospital stay during pancreatectomy followed by islet transplantation, for all required measurements 
up to hospital discharge and for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the 
transplant. 
3.2. 
STUDY TIME TABLE 
The planned patients are expected to be recruited in a 12 month period.  A follow-up of 12 months is 
planned for each patient. Overall study timelines are reported below. 
• 
Projected starting date (first-patient-in): 
December 2013 
• 
Projected completion of patient accrual (last-patient-in):  
March 2015 
• 
Projected study end date (last-patient-last-visit):  
March 2016 
3.3. 
END OF STUDY 
 
For the purpose of this trial, the end of study is defined as the date of the last visit of the last patient.  
 
 
 
 
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• Standard laboratory tests including hematology (hematocrit, hemoglobin, red blood cells, platelets, 
white blood cells, differential white blood cells count), clinical chemistry (sodium, potassium, 
serum creatinine, blood urea nitrogen, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and coagulation (International Normalized Ratio (INR), partial 
thromboplastin time (PTT))  [time frame: pre-transplant hospital admission and post-transplant 
hospital discharge]. 
• Vital signs, i.e. blood pressure (BP) and heart rate (HR) [time frame: pre-transplant hospital 
admission and post-transplant hospital discharge]. 
• ALT/AST, INR/PTT, fibrin degradation products (XDPs), C-reactive protein (CRP) [time frame: 
all daily from day 1 up to day 7 after the transplant; ALT/AST also on day 75+5 after the 
transplant]. 
• Weight loss from pre-transplant value [time frame: day 75+14 and 365+14 after the transplant]. 
• Serum level of albumin and pre-albumin (absolute and change from pre-transplant value) [time 
frame: day 75+14 and 365+14 after the transplant]. 
• Proportion of patients falling into one of the following levels of steatorrhea severity [time frame: 
day 75+14 and 365+14 after the transplant]. 
For the purpose of this protocol, levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75+14 
and 365+14), are defined as: 
- No steatorrhea; 
- Steatorrhea few times per week; 
- Steatorrhea daily; 
 
- Stool incontinence. 
• Proportion of patients falling into one of the following malnutrition risk levels (poor prognosis, 
significant risk, increased risk, normal) according to pre-albumin level [time frame: day 75+14 and 
365+14 after the transplant]. 
For the purpose of this protocol, malnutrition risk levels are defined as [adapted from Bernstein, 1995]: 
- Poor prognosis = pre-albumin level <5.0 mg/dL 
- Significant risk = pre-albumin level 5.0 to 10.9 mg/dL 
- Increased risk = pre-albumin level 11.0 to 15.0 mg/dL 
- Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL 
• Cmulative number of episodes of documented hypoglycemia (documented symptomatic; 
asymptomatic) [time frame: from day 75+14 to day 365+14 after the transplant]. 
For the purpose of this protocol, the following definition applies [Diabetes Care, 2005]: 
- 
Documented symptomatic hypoglycemia = An event during which typical symptoms of hypoglycemia 
are accompanied by a measured plasma glucose concentration <70mg/dL. 
- 
Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia, but 
with a measured plasma glucose concentration <70mg/dL. 
• Cumulative number of diabetic ketoacidosis-related events [time frame: from day 75+14 to day 
365+14 after the transplant]. 
For the purpose of this protocol, a diabetic ketoacidosis event is defined as the presence of [Pediatrics, 
2004]: 
- 
hyperglycemia (blood glucose >200 mg/dL); 
- 
pH <7.3 or HCO3 <15; 
- 
ketones positive in the serum or urine. 
4.2.4. 
Exploratory endpoints 
• 
Time course of inflammatory chemokines/cytokines as assessed by serum level of CXCL8, 
CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10, INF-γ, TNF-α, and 
IL-1β [time frame: pre-infusion hospital admission (2 basal samples collected 6 to 24 hrs apart; 
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both samples will be obtained before surgery and before Investigational Product administration is 
started) and 6, 12, 24, 72, 120 and 168hrs after the end of islet infusion]. 
• 
Proportion of patients who are randomized but do not receive IAT [time frame: transplant day]. 
• 
Time course of serum microRNA-375 (miR-375) [time frame: pre-infusion hospital admission 
(sample will be obtained before surgery and before Investigational Product administration is 
started) and 6, 12, 24, 72, 120 and 168hrs after the end of islet infusion]. 
4.2.5. 
Pharmacokinetic endpoints 
• 
Plasma levels of reparixin (total and unbound) and relevant metabolites (DF2243Y and 
ibuprofen) [time frame: post-operative day 1, 3, and 5 (steady state) in all patients; just prior to, 
and then at 1, 3, 5, 6, 8, and 12 hrs after termination of Investigational Product administration in a 
subset of at least 20-24 patients].  This number of patients should guarantee post-treatment 
sampling in at least 10-12 patients randomized to reparixin (base on a 1:1 randomization).  These 
patients will be enrolled at 2 of the participating sites.   
 
 
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5. 
STUDY POPULATION 
The goal of this study is to reach a total of 100 patients who are randomized and receive IAT after 
total (or completion) pancreatectomy, each being randomised (1:1) to receive either reparixin or 
placebo.   
Patients will be selected from those eligible for IAT following total or completion pancreatectomy.  In 
addition to locally accepted eligibility criteria for the IAT (see below), each prospective patient will be 
randomized provided that (s)he fully meets all of the study-specific Inclusion Criteria and none of the 
study-specific Exclusion Criteria described in Sections 5.1. and 5.2. below.      
5.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil ALL of the following inclusion 
criteria.  
1. 
Patients eligible for an IAT following total (or completion) pancreatectomy.   
Eligibility to both total (or completion) pancreatectomy and IAT will be based on locally 
accepted criteria and guidelines (see also exclusion below).  The most restrictive criteria will be 
applied .   
2. 
Ages > 18 years.  
3. 
Patients willing and able to comply with the protocol procedures for the duration of the study, 
including scheduled follow-up visits and examinations. 
4. 
Patients who have given written informed consent, prior to any study-related procedure not part 
of normal medical care, with the understanding that consent may be withdrawn by the patient at 
any time without prejudice to their future medical care. 
5.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for participation in the study. 
1. 
Recipients of a previous IAT (if completion pancreatectomy). 
2. 
Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic benign 
diseases other than chronic pancreatitis, including insulinomas, etc.  
3. 
Patients with inadequate renal reserve as per calculated creatinine clearance (CLcr) < 60 mL/min 
according to the Cockcroft-Gault formula (1976). 
4. 
Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x upper limit of normal 
(ULN) or increased total bilirubin above the upper limit at local laboratory).  Patients with 
Gilbert’s syndrome (elevated unconjugated bilirubin levels in the absence of any evidence of 
hepatic or biliary tract disease) are not excluded. 
5. 
Patients with a preoperative International Normalized Ratio (INR) > 1.5 or any known 
coagulopathy. 
6. 
Hypersensitivity to: 
 
a) 
ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID). 
 
b) 
more than one medication belonging to the class of sulfonamides, such as sulfamethazine, 
sulfamethoxazole, sulfasalazine, nimesulide or celecoxib; hypersensitivity to sulphanilamide 
antibiotics alone (e.g. sulfamethoxazole) does not qualify for exclusion. 
7. 
Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other signs of 
systemic sepsis syndrome). 
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8. 
Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use of <5mg 
prednisone daily or equivalent dose of hydrocortisone, for physiological replacement only) or 
with any immune modulators in the 4 weeks prior to enrolment.  
9. 
Patients with pre-existing diabetes or evidence of impaired β-cells function, based on pre-
operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%, or requiring treatment with 
any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 weeks prior to enrolment. 
10. 
Use of any investigational agent in the 4 weeks prior to enrolment, including any anti-
cytokine/chemokine agents.  
11. 
Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures 
(females and males). (NB: pregnancy should be avoided in patients or partners during the first 
month after completing the treatment with the Investigational Product; no other specific 
warnings are described, considering the treatment course of the Investigational Product, its PK 
profile, and the lack of significant adverse effects on mating performance and fertility in animal 
studies). 
12. 
Patients with past or current history of alcohol abuse based on clinical history and/or past 
treatment for alcohol addiction. 
13. 
Patients with evidence of pre-operative portal hypertension as per clinical history and 
abdominal/liver imaging by ultrasound techniques. 
Sites will comply with any additional or more restrictive exclusion criteria locally accepted, as per 
centre practice.  
5.3. 
ASSIGNMENT OF PATIENT NUMBER 
Patient number will be assigned in a sequential manner as a patient is found to be eligible for entry 
into the study and is randomized.  It will consist of the site number, and the patient number e.g. 0102, 
where first 2 digits represent site number, last 2 digits patient number.  If a patient is dropped from the 
study for any reason, the patient’s number will not be reassigned.   
 
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6. 
INVESTIGATIONAL PRODUCT 
The Investigational Product will be either reparixin [R(-)-4-Isobutyl-alpha-methylphenylacetyl-
methanesulfonamide] or matched placebo. 
6.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING 
6.1.1. 
Presentation of Investigational Products 
Reparixin will be provided as concentrate for solution for i.v. infusion packaged into 250 mL clear 
Glass Vials with the following composition per single (250 mL) unit: 
Reparixin composition - 33mg/mL 
NAME OF INGREDIENT 
PER-UNIT 
FORMULA 
FUNCTION OF 
INGREDIENT 
REFERENCE  TO QUALITY  STANDARDS 
Reparixin (DF1681Y) 
8.25 g 
Drug substance 
Manufacturer monograph and specification 
Sodium Dihydrogen 
Phosphate Dihydrate 
1.96 g 
Buffer 
European Pharmacopoeia - current edition 
L-lysine monohydrate 
4.78 g 
Solubilizer 
German Pharmacopoeia - current edition 
Sodium hydroxide 
qs to pH 8.0  
Buffer 
European Pharmacopoeia - current edition 
Water for injections 
qs to 250 mL 
Solvent 
European Pharmacopoeia - current edition 
 
Placebo will be physiologic salt solution (0.9% w/v sodium chloride solution) provided as 
commercially available 250 mL clear Glass Vials. 
Batch release certificate will be provided together with the Investigational Products. 
6.1.2. 
Manufacturing, Packaging and Labelling of Investigational Product 
Reparixin will be manufactured by Patheon (Italy).  Both Investigational products will be packaged 
and labelled by an authorized facility which will be identified before trial commencement.   
Reparixin and placebo vials will be supplied along with sterile empty Infusion Bags and corresponding 
Infusion Bag labels.   
All the materials will have trial-specific labels.  Details of packaging and labelling are reported in 
Appendix 14.2.  
6.1.3. 
Supply, Storage and Handling of Investigational Product 
An appropriate number of packages will be initially sent to the site as soon as all essential documents 
and FDA/ethics approvals have been obtained.  Additional supplies (reparixin, placebo, Infusion Bags) 
will be sent on demand, according to enrolment rate.  
The Investigational Product must be kept at a temperature not exceeding 30°C and must not be frozen.  
A temperature probe will accompany the drug on shipment.  Temperature range reached during 
shipment will be verified on receipt, so that potential stability concerns during shipment can be 
investigated and appropriate action taken. 
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Once received at the site, the Pharmacist (or designee) will check the package for accurate delivery 
and acknowledge receipt; any deviations from expected package content (inconsistency, damages) 
should be immediately reported to Dompé (or designee) and the use of the drug suspended until 
authorization for its continued use has been given by Dompé (or designee).   
The Investigational Product must be stored in a secure location, in a temperature controlled room.  
Temperature records must be available for the Unblinded-CRA (U-CRA) to review at monitoring 
visits; any deviations from the recommended storage conditions should be immediately reported to 
Dompé (or designee) and the use of the drug suspended until authorization for its continued use has 
been given by Dompé (or designee). 
The Investigational Product will be dispensed only by the Pharmacist (or designee).  The Investigator 
will ensure that study treatment is only administered by designated staff within the centre. 
Pharmacists will be provided with the ‘Instructions to the Pharmacy’, a booklet detailing instructions 
for Investigational Product handling and preparation of the dosing solution.   
6.1.4. 
Preparation of the Dosing Solution 
The dosing solution for infusion will be prepared at the designated Pharmacy or authorized location 
within each centre according to local guidelines for sterile re-consitution of i.v. injectable solutions. 
For each 750 mL dosing solution volume, the content of a Vial (250 mL) will be diluted with 500 mL 
of 0.9% sterile saline to dispense reparixin as 11.00 mg/mL solution.  The dosing solution will be 
placed in a 1000 mL sterile empty Infusion Bag.  Dosing solutions will be prepared and used within 72 
hours from preparation, unless the site has more restrictive rules. 
A double-tear off label will be attached to each prepared bag, reporting patient number and relevant 
blinded information.  Infusion Bags for the same patient/administration course will be numbered in a 
sequential manner, starting from No. 1.  Labels for the Investigation product administration during the 
2nd islet infusion will be clearly identified as such. 
The Pharmacist (or designee) will make the Infusion Bags available to the hospital ward at the 
requested time. 
6.1.5. 
Blinding 
Reparixin solution in the vial (33mg/mL) has a slightly different appearance (pale yellow colour) as 
compared with placebo.  Also, a transient foamy layer occasionally results from the preparation of the 
reparixin dosing solution.  However, once the foamy layer, if any, had subsided, the dosing solution of 
reparixin in the Infusion Bag will be indistinguishable from that of placebo.  
Individual treatment codes will be provided in tamper-resistant system (either sealed envelopes or 
scretch cards) to the Pharmacist (or designee).  They must be kept in a secure location accessible only 
to designated staff in order to prevent dissemination of the treatment to personnel involved in study 
conduct who must remain blind.  
The Pharmacist (or designee) will break the treatment code only after the patient-specific “IP 
Preparation Order Form” is received from the Investigator.  The individual code matching the patient 
randomization number will be opened to prepare the dosing solution matching the patient 
randomization number.       
The Investigators can request to an independent facility (either by telephone or web based system) an 
individual code in the event of an emergency only, where knowledge of the blinded treatment for that 
patient could influence further patient care.  Any potential unauthorized code break and the reason 
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behind it will be recorded.   
6.2. 
DOSE, ROUTE AND SCHEDULE OF INVESTIGATIONAL PRODUCT 
ADMINISTRATION 
Patients will receive either reparixin at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hrs) or 
matched (flow rate/length of infusion) placebo, according to the randomization number.   
The dosing solution (if reparixin, 11mg/mL) will be administered as a continuous i.v. infusion into a 
(high flow) central vein, by an infusion pump adequate to provide reliable infusion rates (see below), 
as per treatment schedule.  
Infusion of the Investigational Product will start approximately 12hrs (allowed range 6-18hrs) before 
the anticipated time when islet infusion is started.  The Investigator will identify the time to start study 
drug administration.  
The pump rate will be adjusted to provide an infusion rate of approximately 0.25mL/kg/hour.  Actual 
infusion rate (mL/hour), adjusted to body weight, is tabulated in Appendix 14.3.  Figures in the 
appendix represent mathematical rounding of original infusion rates derived from the following 
formula: 
Infusion rate (mL/hour)    =  
dose (mg/kg/hour) x body weight (kg) 
11.00 mg/mL 
Such a rounding affects actual administered dose/kg/hour by less than 1%. 
6.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION/ 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
6.3.1. 
Criteria for schedule adjustment or dose modification 
No schedule adjustment and/or dose modification is foreseen, except for discontinuation of drug as 
detailed below. 
6.3.2. 
Criteria for discontinuation of Investigational Product 
Phase 1 studies in patients with end stage renal disease have shown that renal function has a profound 
effect on plasma concentrations of a major, marginally active metabolite, carboxy-reparixin 
(DF2243Y), which 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 concern, limited 
experience in humans recommends discontinuation of the drug in case of renal impairment as it would 
not be possible to predict the risk associated with elevated plasma levels.   
Because reparixin undergoes extensive hepatic metabolism, hepatic dysfunction should also be 
monitored to avoid an increase in plasma levels.  An asymptomatic, self-limited transaminitis is 
consistently seen after islet transplantation into the liver.  This is characterized by elevation in 
AST/ALT which peaks at about 7 days post transplant and spontaneously normalizes within 4 weeks.  
Bilirubin and other liver function tests remained within the normal range, suggesting no major hepatic 
dysfunction that would impact reparixin metabolism.  [Rafael, 2003; Barshes, 2005]. 
Therefore, the Investigational Product should be immediately discontinued in case the patient 
develops renal or hepatic dysfunction defined as: 
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Renal dysfunction: 
the occurrence of both CLcr < 60 mL/min and urine output < 0.5 mL/kg/hour 
on two consecutive samplings.  Transient alterations of serum creatinine or 
urine output, other than defined above, do not indicate a renal dysfunction 
that would cause impaired excretion of DF2243Y.   
Hepatic dysfunction: 
the occurrence of ALT/AST > 3 x ULN and total bilirubin > 3mg/dL [> 51.3 
µmol/L].   
Renal and hepatic function will be evaluated daily from post-operative day 1 during Investigational 
Product infusion.  Samples will be processed immediately and results made available as soon as 
possible to the Investigator. 
Additionally, the Investigational Product should be immediately discontinued in the event of any 
other possibly drug related occurrences that the Investigator believes might compromise patient 
safety. 
Lastly, the Investigational Product will be immediately discontinued in the case the patient withdraw 
his/her consent or has not received the transplant.  
Patients who discontinue the treatment with the Investigational Product will not be withdrawn from 
the study by default, but will complete observations as per the protocol, unless otherwise they 
withdraw their consent. 
If the Investigational Product therapy is prematurely discontinued the primary reason for 
discontinuation must be recorded in the CRF.   
6.4. 
ACCOUNTABILITY 
All supplies will be maintained under adequate security by the responsible member of the Pharmacy 
staff.  The Investigator will ensure that study treatment is only administered by those named as sub-
investigators on the FDA form 1572 and designated staff.  
When the Investigational Product is received by the Pharmacist (or designee), (s)he will check for 
accurate delivery and acknowledge receipt by signing and dating the documentation provided by 
Dompé (or designee) and returning it to Dompé (or designee).  A copy will be retained for the 
Investigator/Pharmacy file. 
The dispensing of the Investigational Product will be carefully recorded on appropriate drug 
accountability forms provided by Dompé (or designee) and an accurate accounting will be available 
for verification by an U-CRA at each monitoring visit. 
Drug accountability records will include: 
• 
confirmation of receipt of the Investigational Product at the trial site, 
• 
the inventory at the site (vials), 
• 
details of each bag preparation, 
• 
the use by each patient,  
• 
disposition of unused vial(s), 
• 
account of any Investigational Product accidentally or deliberately destroyed. 
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They should include dates, quantities, batch numbers, use by date information, and any unique code 
numbers assigned to the Investigational Product and/or patients.   
Records should be maintained to adequately document that: 
• 
the patients were provided the doses specified by the protocol/amendment(s), 
• 
all Investigational Product provided was fully reconciled. 
The U-CRA will review the drug accountability forms for consistency with drug administraiton (as per 
CRF) and remaining unused Investigational Product vials. 
Investigational Product which has been dispensed to a patient and returned unused will not be 
re-dispensed to a different patient.  
Unused Investigational 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 designee) or 
disposed of, as determined by Dompé (or designee). 
6.4.1. 
Assessment of compliance 
Compliance will be assured by the person(s) within the centre in charge of Investigational Product 
administration.   
Immediately before the use of an Infusion Bag is started, the removable label on the bag will be 
detached and attached to the relevant page of the CRF.  Actual date and time of infusion start and end 
for each container will be recorded in the CRF, as well as the infusion rate(s).  Temporary interruption 
of > 30 min duration (cumulative within each 24 hours) during drug administration should also be 
reported. 
Compliance with the study product dosing schedule will be verified by a CRA during on-site 
monitoring visits, 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 given at the discretion of 
the Investigator, except for drugs described in paragraphs below. 
Administration of all prior (4 weeks prior to enrolment) and concomitant medications (CMEDs), apart 
from the agents listed below, during hospital stay will be reported in the appropriate section of the 
CRF.  Only medications used for SAE, oral hypoglycemic drugs as well as medications that should not 
be used (see Section 6.5.1 below) will be reported after hospital discharge.   
All the details as per the CRF fields (sequential number, drug name, indication, starting dose, 
start/stop date, route of administration) will be recorded.  Change in dose will not be tracked. 
The following agents do not need to be recorded: 
 
Saline and other hydration solutions (including additional electrolytes) 
 
Total parenteral nutrition and enteral feeds 
 
Homeopatic medications 
 
Elective vitamins and minerals 
 
Topical agents with no or negligible systemic absorption 
 
Osmotic laxatives and locally acting antacids 
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6.5.1. 
Other treatments 
Drugs required during surgery will be administered as per centre practice. 
The following prophylactic anticoagulation is suggested to be used in patients enrolled in this study  
- Heparin will be administered at a dose of 70 U/kg, divided equally between the islet bags, followed 
by 3 U/kg/hour infused i.v. for the next 4 hours.  From the 5th to the 48th hour post-transplant, 
heparin will be titrated to achieve and maintain PTT in the range 50-60 seconds.  Comparable 
marker other than PTT will be used as per site experience. 
- Enoxaparin will be administered at a dose of 30 mg subcutabeously from day 2 to 7 post-transplant.    
Prophylactic anticoagulation management (choice of medication and/or doses) might be adjusted on 
the basis of clinical requirements (e.g. occurrence of bleeding) and/or centre practice.  Low Molecular 
Weight Sulfate Dextran cannot be used in this trial.   
Glycemic control in the early post-transplant period will be achieved by insulin administration to 
target glucose levels in the range 80-180mg/dL. Patients will be tested for blood sugar by fingerstick a 
minimum of 4 times per day. Insulin will be titrated to maintain fasting and pre-meal blood sugars in 
the range 80-125 mg/dL, and 2 hour post-prandial glucoses <180 mg/dL. For patients on continuous 
enteral or parental feeds, insulin will be titrated to maintain glucose in the range 80-140 mg/dL. 
 
The following medications should not be used in this study: 
- Systemic steroids (i.e. intravenous, intramuscular, oral; intra-articular injection allowed): from 2 
weeks prior to enrolment up to the end of the study; use of <5mg prednisone daily or equivalent 
dose of hydrocortisone, for physiological replacement only is allowed. 
- Any investigational agents: from 4 weeks prior to enrolment up to the end of the study; 
- Any anti-cytokine/chemokine medications (e.g. anti-TNFα): from 4 weeks prior to enrolment up to 
the end of the study; 
- Any immune modulators: from 4 weeks prior to enrolment up to the end of the study; 
- Low Molecular Weight Sulfate Dextran; 
- Oral hypoglycemic agents and any drugs that influence insulin sensitivity. 
 
Since exposure to ibuprofen after administration of reparixin 2.772 mg/kg/h for 48hrs is in the range 
of that obtained after a standard therapeutic single dose of ibuprofen (300mg), concomitant 
administration of NSAIDs, including cyclo-oxygenase-2 specific inhibitors, should be considered with 
caution during infusion with the Investigational Product, as this may increase the risk of cyclo-
oxygenase-dependent adverse affects. 
 
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7. 
STUDY PROCEDURE AND ASSESSMENTS 
A schedule for the tests and evaluations to be conducted in this study is found in the flow chart in 
Appendix 14.4.  A list of acceptable assessment/procedure time windows is detailed in Appendix 
14.5.  Methodological details are reported in Appendix 14.6. 
7.1. 
HOSPITAL STAY 
7.1.1. 
Screening and randomization 
Potential study patients will be identified among those referring to the investigational site and found 
eligible as per site standard criteria for total (or completion) pancreatectomy followed by IAT.  
Consented patients will undergo the following screening evaluation, within 72 hours prior to 
randomization.  
BP, HR, body weight (kg) and height (m) will be measured. 
A baseline blood sample will be taken prior to any intervention for safety laboratory tests (assay as per 
centre practice).  These include hematocrit, hemoglobin, red blood cells, platelets, white blood cells, 
differential white blood cells count, sodium, potassium, serum creatinine, blood urea nitrogen, total 
bilirubin, ALT, AST, INR, PTT.  Albumin and pre-albumin will be also measured.  
Pregnancy test (urine dipstick or blood test) will be performed, if appropriate. 
Renal reserve will be assessed by CLcr (Cockcroft-Gault; 1976; see details in Appendix 14.6.2).  
Hepatic function will be assessed by ALT/AST and bilirubin. 
Concurrent sepsis will be diagnosed by blood culture(s) and/or fever associated with other signs of 
systemic sepsis syndrome.  
Pre-operative portal hypertension will be diagnosed as per clinical history and abdominal/liver 
imaging (e.g. presence/absence of varices, splenomegaly, Doppler waveforms and flow direction) by 
ultrasound techniques (e.g. duplex ultrasonography, spectral Doppler imaging and Color Doppler 
imaging, power Doppler imaging). 
Two basal serum samples collected 6 to 24 hrs apart will be stored for centralized assay of pre-
transplant chemokines/cytokines; similarly, a basal sample will be stored for centralized assay of pre-
transplant miR-375 (see Appendix 14.6.3).  All basal samples will be obtained before surgery and 
before Investigational Product administration is started. 
Compliance with inclusion/exclusion criteria will be verified vs demographic, laboratory test results 
and clinical history/information available as per local standard clinical practice.   
Eligible patients will be randomized (randomization number assigned) by an Investigator (or designee) 
before starting the infusion of the Investigational Product. 
A screening form will be completed for all patients who signed the Patient Informed Consent 
Document, regardless of subsequent entry into the study.  Patients will be identified by their age and 
sex; patient number if enrolled or reasons for exclusion from the study will be recorded. 
7.1.2. 
Start of infusion with the Investigational Product 
Infusion of the Investigational Product will start approximately 12hrs (6-18hrs) before the anticipated 
time of islet infusion.  The Investigator will identify the time to start study drug infusion.  Infusion may 
be halted during pancreatic surgery if required, provided that interruption is not longer than 6 hours.   
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The infusion pump will be set to provide the infusion rate corresponding to the planned dose.  Infusion 
rate (mL/hour) corresponding to each unit increment (kg) of body weight, is reported in Appendix 14.3.  
Immediately before the start of infusion, the removable label on the Infusion Bag No. 1 will be detached 
and attached to the relevant page of the CRF.  Starting time of drug administration and infusion rate will 
be recorded in the CRF. 
7.1.3. 
Islet isolation and transplantation 
Techniques for pancreas removal will be used, as per centre practice, including requirement for 
concomitant splenectomy.   
Islet preparation: Site will process islets by enzymatic digestion using an FDA approved collagenase 
and neutral protease as per site specific standards.  The pancreas will be distended by 
intraductal infusion of collagenase/neutral protease; if duct disruption prohibits 
intraductal infusion, enzyme will be manually injected into the pancreatic 
parenchyme.   Pancreatic digestion will be performed using the semi-automated 
method of Ricordi.  Purification will be performed when necessary to reduce tissue 
volume, dependent on site specific standards for islet manufacturing, using density 
centrifugation with COBE 2991.  Samples will be taken from the pancreatic 
preservation solution and final islet product for sterility testing by gram stain and 
culture.   
 
Islet mass will be assessed by manual counts as detailed in Appendix 14.6.1 and 
quantified as total IEQ and IEQ/kg body weight.  The final product is suspended in a 
200 mL suspension of CMRL 1066 Transplant Media or equivalent solution.  The 
final product is supplied in one to three 200 mL infusion bags, containing a 
minimum dose of >10,000 IEQ total. 
Islet infusion: 
At all sites, islets will be transplanted on the same day as the total pancreatectomy 
procedure. 
 
The islet mixture will be delivered slowly by gravity drainage into the portal vein or 
a tributary of the portal vein.  Access to the portal vein may be obtained by direct 
cannulization during laparotomy or by percutaneous access by fluoroscopic, 
ultrasonographic, or real-time CT guidance.   
 
At minimum, portal venous pressure will be monitored (direct venous measurement) 
before initiation, mid-way, and after completion of islet infusion. In case the portal 
pressure reaches >35 cmH2O, islet infusion will be put on hold, and restarted when 
portal pressure has dropped.  In the rare event that portal pressure does not lower 
(within a 30 min interval), infusion is definitely stopped and any remaining tissue 
either discarded or placed in another tissue (e.g. peritoneal cavity, duodenal wall, 
underneath the kidney capsule, etc.). 
The following isolation and operative details will be recorded in the CRF, as per documentations 
provided by the local Islet Processing Facility and centre information: 
 
• Date and time of isolation (procedure completed).  
• Date and time of infusion (start and end of infusion); 
• IEQ/kg infused.  Islet will be counted as detailed in Appendix 14.6.1; 
• Total islet infusion volume; 
• Pre-, mid-way, and post- infusion portal pressure. 
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7.1.4. 
Drug administration during hospital stay 
Administration of the Investigational Product will continue during hospital stay.  
Infusion Bags will be used in a sequential manner (No. 1, No. 2, No. 3 etc.) and infusion of the 
Investigational Product will progress non-stop up to a total of 7 day (168hrs) administration.   
The removable label on each new Infusion Bag will be detached and attached to the relevant page of 
the CRF.  Start date/time and stop date/time for each Bag will be recorded in the CRF, along with 
accidental interruptions of study drug infusion for > 30min (cumulative within each 24 hours). 
7.1.5. 
Post-operative assessments 
The following will be assessed during hospital stay and recorded in the CRF.  Measurement will be 
performed as per centre practice, unless otherwise specified.  
 
• Renal function (CLcr, urine output):  Renal function will be assessed daily from post-operative day 1 
up to the end of study drug infusion.  Details of Clcr calculation are reported in Appendix 14.6.2.  
There is no need to have a urine catheter in place, if this is not required by standard of care.  Urine 
volume will be measured at urination (measuring cylinder); corresponding collection time will be 
calculated from the previous urination.  Depending from feasibility and patient compliance, ideally 
more than one measurement should be done over a 24-hour period to get the best estimate of urine 
output.  
• Total bilirubin:  Total bilirubin will be assessed daily from post-operative day 1 up to the end of 
study drug infusion as part of hepatic function evaluation.   
• XDP, ALT/AST, INR/PTT, C-reactive protein (CRP):  These will be measured daily from day 1 up 
to day 7 post-transplant.  
• Chemokines/cytokines [CXCL8, CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), 
IL-6, IL-10, INF-γ, TNF-α, and IL-1β]: A blood sample will be obtained @ 6, 12, 24, 72, 120 and 
168hrs after the end of islet infusion.  Samples will be handled and stored for the centralized assay, 
as detailed in Appendix 14.6.3. 
• miR-375: A blood sample will be obtained @ 6, 12, 24, 72, 120 and 168hrs after the end of islet 
infusion.  Samples will be handled and stored for the centralized assay, as detailed in Appendix 
14.6.3. 
• Pharmacokinetics [plasma levels of reparixin (total and unbound) and relevant metabolites 
(DF2243Y and ibuprofen)]: A blood sample will be obtained in all patients randomized and treated 
with the Investigational product on post-operative day 1, 3 and 5, ideally in the morning.  In a subset 
of at least 20-24 patients, treated at 2 selected sites, a blood sample will be also obtained just prior 
to, and then at 1, 3, 5, 6, 8, and 12 hrs after termination of Investigational Product administration.  
Samples will be handled and stored for centralized assay, as detailed in Appendix 14.6.3.    
• Safety laboratory tests: Laboratory tests will be performed before hospital discharge. 
• Vital signs, i.e. blood pressure (BP) and heart rate (HR) will be measured before hospital discharge. 
During hospital stay, all AEs (see details in Sections 8.2.) and CMEDs (see details in Sections 6.5.) 
will be recorded.   
For all measurements above, the actual date and time of assessment, including date of sampling, will 
be recorded in the CRF.  
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Apart from compliance with protocol procedures up to day 7 post-transplant, hospital discharge will 
be primarily based on criteria related to total pancreatectomy (the major surgical procedure in total 
pancreatectomy followed by IAT) and will comply with each site’s hospital standards.  However, at all 
sites, at least the following criteria will be complied with: “A patient will be discharged if he/she at 
least is ambulating, has adequate nutrition (oral, enteral, or Total Parenteral Nutrition (TPN), is not 
requiring any intravenous medications which require inpatient monitoring, pain is adequately treated, 
and he/she has a stable plan for glycemic control (management of blood glucose testing and insulin 
administration at home)”. 
7.2. 
FOLLOW-UP PROCEDURES AND ASSESSMENTS 
Since hospital discharge, patients will self monitor glucose levels and insulin intake according to 
standard clinical instructions at the site.  Insulin will be administered to target fasting and pre-meal 
glucose levels in the range 80-125 mg/dL, and 2 hour post-prandial glucoses <180 mg/dL. For patients 
on continuous enteral or parental feeds, insulin will be titrated to maintain glucose in the range 80-140 
mg/dL.   
The Investigator will identify if- and the date when- it is appropriate for the patient to stop insulin 
intake, according to standard of centre practice.  Regardless the patient is on or off insulin, he/she will 
report on a Diary Card (see Appendix 14.7) his/her self monitored glucose levels for 14 consecutive 
days prior to the follow-up visits on day 75+14 and 365+14 after the transplant: glucose levels will be 
measured at least two times a day: 1) after an overnight fast (or anyway before breakfast if the patient 
is still on a tube feed and TPN); 2) within 2 hours post-prandial.  Also, patients still on insulin will 
report on the Diary Card their daily insulin intake. 
Patients will attend the centre for study assessments on 2 follow-up visits scheduled on day 75+14 and 
365+14 after the transplant.   
At each visit, the following will be evaluated/measured in all patients as per centre practice, unless 
otherwise specified.  Measurements, including the actual date and time of assessment, or the date of 
sampling, will be recorded in the CRF. 
• Patient weight. 
• Retrospective self-measured glucose and insulin requirement data in the 2 weeks prior to the visit 
will be reviewed and average (previous week) insulin requirement at each time point as well as 
insulin-independence / insulin-dependence status will be assessed. 
• Retrospective episodes of severe hypoglycaemia in the interval will be assessed as per centre 
practice.  Events of documented  hypoglycemia in the interval will be obtained from review of the 
patient’s home glucometer download from between visits and/or patient glucose logs.   
• Retrospective severity of steatorrhea in the 4 weeks prior to the visit will be evaluated. 
• A blood sample will be taken prior to the meal administration to measure HbA1c, albumin and pre-
albumin.  ALT/AST will be also measured on day 75+5.   
• A MMTT test will be performed as detailed in Appendix 14.6.4.  Blood samples will be drawn @ 0 
(2 basal samples in the range between -20 to 0 prior to the meal) and 15, 30, 60, 90, 120, 180, 240 
min after the meal for glucose, C-peptide and insulin measurement. 
• β-score will be calculated according to Ryan (2005) (see Appendix 14.6.5 for details). 
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C-peptide and HbA1c will be measured by a centralized laboratory with CLIA certification and 
National Glycohemoglobin Standardization Program (NGSP) certified assay.  Details of handling and 
storage of samples as well as data handling are reported in Appendix 14.6.3. 
Any SAEs that occurred after hospital discharge will be recorded at the visits, as well as CMEDs, as 
appropriate.  
Patients should be strongly motivated to attend the centre for the planned follow-up visits.  However, if 
a patient cannot refer to the site for protocol assessments, the Investigator will try to obtain any relevant 
information from the patients, including documents/lab results available from local medical care.  
7.3. 
EARLY PATIENT WITHDRAWAL 
7.3.1. 
Criteria for withdrawal from the study 
Patients will be informed that they have the right at any time to withdraw from further participation in 
the study (withdrawal of consent), without prejudice to their medical care, and without being obliged 
to state their reasons.  However, during the consent process, patients will be also educated about the 
scientific relevance of their continued participation as well as the deleterious effect that missing data 
will have on trial integrity.  
If a patient fails to return to the centre for a scheduled visit, all reasonable attempts should be made to 
contact the patient to ensure that the reason for not returning is not a SAE.  Likewise if a patient 
declares his/her wish to discontinue from the study e.g. for personal reasons, an attempt should be 
made to establish that the true reason is not a SAE (bearing in mind the patient is not obliged to state 
his/her reasons).  The term withdrawal of consent should be used only when the patient no longer 
wishes to participate in the trial and no longer authorizes the Investigators to make efforts to continue 
to obtain his/her outcome data. Ideally, if patients withdraw their consent, it should be done in writing. 
Patients who have discontinued the study treatment should be anyway followed to ensure that primary 
and secondary outcome measures are assessed, unless they formally have withdrawn consent. 
It is important that any randomized patient remains in the study and is followed for both efficacy and 
safety outcomes, regardless he/she has completed or discontinued the study treatment.  Investigators 
will be trained about the importance of patient retention and full data capture.  Also, all reasonable 
attempts should be made by the Investigators to emphasize continued patient’s participation for the 
full duration of the trial.     
Any withdrawals must be fully documented in the CRF. 
7.3.2. 
Replacement policy 
No patient who has been randomized and withdraws from the study for any reason will be replaced. 
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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 medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal product, whether or not related to the medicinal product [Clinical safety data 
management: Definitions and Standards for Expedited Reporting].  
8.1.2. 
Definition of a Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (i.e. the patient was at risk of death at the time of the event.  It does not refer to 
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 congenital anomaly/birth defect, 
• is an important medical event that based upon appropriate medical judgment, may jeopardize the 
patient and may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
All AEs should be followed-up to determine the outcome of the reaction.  The Investigator should 
follow up the event until resolution or stabilization of the condition.  It is the Investigator's 
responsibility to assure that the subjects experiencing an AE receive definite treatment for any AE, if 
required. 
8.2. 
EMERGENCY PROCEDURES 
The treatment allocation for each patient will be provided in individual tamper-resistant decoding 
systems (sealed envelopes or scratch cards) to the Dompé Pharmacovigilance department.   
The Investigator can request treatment allocation for a patient to an independent facility (either by 
telephone or web based system) in case of emergency where knowledge of the double-blind treatment 
may influence the further care of the patient.   
If a code is opened for any reason, the reason behind it will be recorded . 
8.3. 
RECORDING 
AE data should be obtained through observation of the patient, from any information volunteered by 
the patient, or through patient questioning.  Specifically, patients will be asked about any episode of 
documented hypoglycemia and ketoacidosis-related events occurring from the transplant day up to day 
75+14 post-transplant.  Any episodes will be reported as an AE or SAE, as appropriate.  In addition, 
the Investigator will capture and report episodes of non-documented hypoglycemia throughout study 
participation.   
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All AEs (serious and non-serious) encountered during the clinical study will be recorded in the 
appropriate section of the CRF as per the recording period defined in paragraph 8.3.1.  It is important 
that this includes the duration of the AE (onset/resolution dates), the relationship to the drug, the 
severity, the outcome and relevant concomitant treatments dispensed (or other action taken) (see 
Sections 8.3.2. and 8.3.3. below).   
8.3.1. 
AE recording period 
All AEs (serious and non-serious) which occur during each hospital stay will be recorded in the CRF.  
In addition, SAEs and relevant untoward events that occur subsequent to each hospital discharge will 
be recorded in the CRF. 
8.3.2. 
Relationship of AEs to the Investigational Product 
The Investigator will assess the possible relationship between the AE and the investigational 
medication, according to the criteria in the Table below: 
Relationship of the Adverse Event to the Investigational Product 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational Product, 
e.g. a surgical intervention for nevus removal performed during the study, 
but planned before patient enrolment into the study 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test 
abnormality with temporal relationship to drug administration which makes 
a causal relationship improbable and in which other drugs, chemicals or 
underlying disease provide more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s 
condition or treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Investigational 
Product and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational 
Product and, if applicable, re-appears upon repeat exposure 
An Adverse Drug Reaction (ADR) is defined as an adverse experience which is a reasonably likely 
to have been caused by the drug.  Any AE reported in the study having a possible, probable or highly 
probable relationship to study drug will be considered as an ADR. 
8.3.3. 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the Table below. For each 
episode, the highest severity grade attained should be reported. 
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Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of 
symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to 
work or to do usual activities [unacceptable]) 
 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. 
Reporting Procedure for Investigators to Dompé (or designee) 
The Investigator must report all SAEs, regardless of presumed causal relationship, to Dompé (or 
designee) by fax or e-mail within 24 hours of learning of the event.  Contact details for SAE reporting 
are provided in the section “Contact Information”.     
Information on SAEs will be recorded on a specific Non-Carbon Repeat SAE form.  Both electronic 
and blank paper copies will be included in the Investigator’s Site File.  Follow-up reports (as many as 
required) should be completed and faxed/e-mailed following the same procedure above.   
Whenever more than one SAE is observed, the Investigator should identify which is the primary 
adverse event, i.e. the most relevant one.  If other events are listed in the same report, the Investigator, 
along with their relatedness to the Investigational Product, should identify which adverse events are 
serious and which are non-serious.  In any case, the Investigator is requested to record his/her opinion 
about the relatedness of the observed event(s) with the investigational medication. 
8.4.2. 
Reporting Procedure for Investigators to IRB  
In addition to reporting the SAE to Dompé, the Investigator must also comply with the requirements 
related to the reporting of SAEs to the IRB which approved the study. 
The requirements of IRB varies from one state and indeed one IRB to another; however, as a 
minimum requirement, the Investigators must promptly report all serious unexpected* ADRs, life-
threatening problems or deaths to their IRB. 
Dompé (or designee) will inform Investigators of all serious unexpected ADRs which are reported to 
Dompé from other Investigators.  These SAEs should also be reported promptly to the IRB in 
compliance with the local regulations.   
Copies of all correspondence relating to reporting of any SAEs to the IRB should be maintained in the 
Investigator’s Files. 
* For the purpose of this study, all ADRs are assumed to be unexpected.   
8.4.3. 
Reporting Procedures to the FDA 
During the course of the clinical trial, Dompé (or designee) shall inform the FDA of any serious 
unexpected ADR* as soon as possible and in no event later than: 
(a) seven calendar days after becoming aware of the information if the event is fatal or life 
threatening; and 
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(b) fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
Dompé (or designee) shall, within 8 days after having informed the FDA under paragraph (a), submit 
a complete report in respect of that information that includes an assessment of the importance and 
implication of any findings made.   
Furthermore, Dompé (or designee) shall follow up safety information and shall report final findings in 
a written safety report as soon as the relevant information is available. 
If the results of an investigation show that an adverse drug reaction not initially determined to be 
reportable is reclassified as reportable, Dompé (or designee) shall report such reaction in a written 
safety report as soon as possible, but in no event later than 7/15 calendar days after the determination 
is made. 
Dompé (or designee) will inform the FDA of all serious ADRs which are reported from other 
Investigators.   
8.5. 
ADVERSE EVENT EXEMPTION 
The following events will neither require recording nor reporting, as they are considered routinely 
associated to the pancreatectomy or to the transplant procedures: 
- 
Delayed Gastric Emptying requiring insertion of a central line for Total Parenteral Nutrition or 
insertion of a nasojejunal tube for Enteral Nutrition; 
- 
Increased ALT/AST levels up to 5 x ULN, inclusive, within 2 weeks post transplant;  
- 
Abnormal  PTT and INR values during prophylactic anticoagulation. 
   
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9. 
STATISTICAL ISSUES 
9.1. 
SAMPLE SIZE 
The primary efficacy endpoint of the clinical trial will be the proportion of insulin-independent 
patients following IAT over the time frame: day 365+14 after the transplant.   
In the following considerations, statistical significance for this endpoint will be achieved if the 
Pearson Chi-Square Statistic yields a two sided p-value less than 0.05.  The corresponding false 
positive error rate is (one-sided) 0.025.  In addition, 95% confidence interval for the difference of 
success (failure) rates between the reparixin and placebo groups will be provided, based on the normal 
distribution approximation to the standardized difference in estimated success rates. 
Based on published data from a retrospective series (Sutherland, 2012), it appears that the likelihood 
of achieving insulin independence at 12 month follow-up in the placebo control arm depends upon the 
number of IEQ/kg, with patients categorized in three groups: 
• 
< 2500 IEQ/kg: 
13% insulin independence 
• 
2500-5000 IEQ/kg: 23% insulin independence 
• 
> 5000 IEQ/kg: 
55% insulin independence 
In ther overall series, the yields were <2500 IEQ/kg in 36%, 2500-5000 IEQ/kg in 39% and > 5000 
IEQ/kg in 24% of patients.  In the more recent series of 217 patients receiving IAT from 2006 to 2011, 
corresponding yields were <2500 IEQ/kg in 34%, 2500-5000 IEQ/kg in 42% and > 5000 IEQ/kg in 
24%:  
We initially focus on the cohort that is in the range 2500-5000 IEQ/kg, since these participants will be 
the largest fraction of enrollees.  It is anticipated that the percentage of such patients achieving insulin 
independence will be increased from 23% in the placebo control arm to 55% in the reparixin arm.  
Using standard statistical formulas based on the approximation of the binomial distribution by the 
normal distribution, the sample size of 44 patients per arm provides 90% power to detect a 23% vs. 
55% true difference when using a Pearson Chi-Square Statistic having the traditional (one-sided) 2.5% 
false positive error rate. Even accounting for the discreteness, the power should be in the 87%-90% 
range.  Furthermore, with 44 patients per arm, statistical significance (i.e., one-sided p=0.025) will be 
obtained if the estimated difference is 22.7% (10/44) vs. 43.2% (19/44), which is an estimated 20.5% 
increase in patients achieving insulin independence.  Hence, with 44 patients per arm, statistical 
significance is achieved with an estimated effect size that is clinically meaningful.  
Even though the largest percentage of patients will be in the cohort receiving IEQ/kg in the range 
2500-5000 IEQ/kg, the trial will also enroll participants in two additional strata: <2500 IEQ/kg and 
>5000 IEQ/kg.  As noted above, we are presuming the middle strata would have an increase from 23% 
to 55% in percentage of patients achieving insulin independence. This is an odds ratio higher than 4.  
If we have an odds ratio of approximately 4.3 to 4.5 in the other 2 strata and if approximately ½ of the 
patients would be from the 2500-5000 IEQ/kg stratum, then only a modest increase of about 12 
additional patients beyond the 88 patient sample size would be needed to maintain the statistical power 
of the trial.  An increase in success rate from 13% to 40% in the <2500 IEQ/kg stratum would be an 
odd ration of 4.4 and an increase in success rate from 55% to 84% in the >5000 IEQ/kg stratum would 
be an odd ration of 4.3.  
Based on these considerations, it is planned to enroll 100 patients in this trial who receive IAT, with 
the expectation that there will be approximately 5 others who do not receive IAT.  Under such a plan, 
the trial would not be overpowered even if all participants were in the 2500-5000 IEQ/kg stratum since 
statistical significance (i.e., one-sided p=0.025) would be obtained with 52 patients per arm if the 
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estimated difference is 23.1% (12/52) vs. 42.3% (22/52), which is an estimated clinically significant 
19.2% increase in percentage of patients achieving insulin independence. 
The sample size of 100 to 105 patients also provides high statistical power for the key secondary 
endpoint, C-peptide AUC (MMTT) normalized by IEQ/kg.  Based on preliminary data reported from 
the ongoing pilot trial (see table on page 14), month 1 post transplant means and standard deviations 
for this endpoint are 1.92+1.62 in the reparixin group and 0.44+0.04 in the control group.  With 52 
patients in each treatment group, the trial will have greater than 95% power to detect a difference in 
means of at least 1.48 (the difference between a treated mean of 1.92 and a control mean of 0.44) 
assuming that the common standard deviation is 1.37 and using an 0.0025 two-sided significance 
level. 
9.2. 
RANDOMIZATION 
Patient will be randomized in a 1:1 fashion to either reparixin or placebo.   
The randomization list will be generated with a computer procedure by the method of random 
permuted blocks in which treatment (in blocks of 4) will be balanced within centres.  A master 
randomization list will be generated, randomizing an excess of patients (a maximum of 40 for each 
site – additional 8 patients for the site of the Primary Investigator) to allow competitive recruitment 
within each centre.    
The randomization list will be prepared by and independent statistician and provided to Dompé in a 
sealed envelope to prevent unblinding.   
Similarly, individual treatment codes will be provided as a tamper-resistant system (either a sealed 
envelope or a scratch card).  Such system will definite allow to recognize if the code has been broken 
and guarantees detection of any code misuse. Individual treatment codes will be provided to:  
- the Pharmacist (or designee) within each participating site for Investigational Product preparation; 
- the Dompé Pharmacovigilance department for safety procedures. 
The Investigators can request to an independent facility (either by telephone or web based system) an 
individual code in the event of an emergency only, where knowledge of the blinded treatment for that 
patient could influence further patient care.  Any potential unauthorized code break and the reason 
behind it will be recorded. 
The randomization codes will also be accessible to an Independent Statistician (liaison between the 
CRO database and DMC Biostatistician) who will generate the reports for the Data Monitoring 
Committee (DMC) evaluation (see Section 12.5). 
The randomization code will be broken at study completion, i.e. when the last patient has completed 
his/her last follow-up visit (planned 365 days after islet infusion), and once the database has been 
locked.  
9.3. 
ANALYSIS POPULATION 
The Intent to Treat (ITT) population will consist of all patients who are randomized and receive the 
Investigational Product (either reparixin or placebo); it will be based on the treatment randomized, 
regardless of the treatment actually received.  Patients will be in the ITT analysis whether or not they 
receive IAT, because exclusions cannot be made for events occurring after randomization that could 
be influenced by the randomized assignment.  The primary and secondary efficacy analyses will be 
presented primarily for the ITT Population. 
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The Safety population will consist of all randomized patients and will be based on the treatment 
actually received.  The Safety population will be used to present the demographic and baseline data, 
and all safety data.  
9.4. 
STATISTICAL METHODOLOGY 
All patient data collected on the CRF and on the Diary will be listed by patient, treatment group and 
centre.   
Appropriate descriptive statistics will be produced, according to the variable.  For continuous 
variables, the data will be presented according to a clinically relevant discretization.  For categorical 
data, frequencies and percentages will be presented.  If appropriate, confidence intervals around the 
mean or the proportions will be presented.  
All the AUC analyses will be based on actual rather than scheduled timings and will be calculated 
using the trapezoidal rule.  If the actual time is not recorded, the scheduled time will be used instead.  
For ease of interpretation, the AUC value obtained will be divided by the total time the scale is 
assessed for reporting purposes. 
The data will be presented in the Clinical Study Report.  A Statistical Analysis Plan will be issued 
describing details of all the statistical methods and analyses to be applied to trial results, including 
alpha spending and testing for multiple endpoints.  Any deviations from the original statistical plan 
will be described in the Clinical Study Report. 
All reasonable efforts will be made to prevent missing data.  Thoughtful methods for imputation of 
missing data will be presented in the Statistical Analysis Plan for the clinical trial 
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 and Secondary Endpoint analysis 
For the primary efficacy endpoint, the proportion of insulin-independent patients over the time frame 
of day 365+14 after the transplant, the differences in proportions will be assessed using the Pearson 
Chi-square statistic, stratified by the three groups at baseline: < 2500 IEQ/kg vs. 2500-5000 IEQ/kg 
vs. > 5000 IEQ/kg.  The significance level used for statistical testing will be 2.5% and one-sided test 
will be used.  The 95% confidence interval for treatment proportions and for the difference in 
treatment proportion between reparixin and placebo will be produced.  The primary analysis will be 
performed using both ITT population with PP analysis serving as a sensitivity analysis. 
For secondary endpoints that will be tested both at 75±14 and 365±14 days after the transplant, only 
the day 365±14 time point will be tested for superiority in the fixed sequence testing procedure. 
The C-peptide AUC after the MMTT normalized by IEQ/kg will be analyzed at the two time points by 
a repeated measurements model using PROC MIXED within SAS®, including terms for treatment, 
time point and center.  The treatment effect within each time point will be compared using a two-sided 
test at the 5% level.  The estimated treatment difference between reparixin and placebo at each time 
point will be presented together with the corresponding 95% confidence interval.  The confidence 
interval will be generated using α=0.05. 
The mean in average daily insulin requirements at the two time points will be analyzed using a 
repeated measurements model using PROC MIXED within SAS®.  The model will include fixed effect 
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terms for center, time point and treatment.  Time point will be specified as a repeated measurement.  
The treatment effect within each time point will be compared using a two sided test at the 5% level. 
The proportion of patients with an HbA1c <6.5% will be analyzed at day 365+14.  Additionally, the 
proportion of patients with an HbA1c <6.5% at day 365+14 will be analyzed again, but patients are 
included in this second analysis if they are also free of severe hypoglycemic events from day 75+14 to 
day 365+14 inclusive.  Treatment effect will be analyzed using Pearson Chi-square. 
The effect of treatment on the rate of recurrent episodes of severe hypoglycaemia will be evaluated 
using an Andersen-Gill analysis with robust sandwich-type variance estimate. 
The other secondary efficacy endpoints will be analysed using appropriate parametric and non-
parametric tests and appropriate 95% CI will be presented. 
9.4.3. 
Safety analysis 
Safety variables will be presented for the Safety population, by treatment group.  
All AEs will be coded using the most up-to-date version at the time of database lock of the MedDRA 
and will be presented by primary system organ class and preferred term.  AEs will be presented in 
terms of the incidence, severity and relationship to the study drug, overall and by body system and 
preferred term.  SAEs will be presented in the same way. 
Results for laboratory test at screening and hospital discharge will be assessed as being within the 
normal range or outside the normal range and clinically-significant outside results.  The following 
parameters will be also presented at different time points: AST/ALT, INR/PTT, fibrin degradation 
products (XDPs), C-reactive protein (CRP) will be presented for all daily from day 1 up to day 7 after 
transplant and on day 75+5 after transplant for AST/ALT. Serum level of albumin and pre-albumin 
will be summarized as absolute values and change from pre-transplant value at day 75+14 and 365+14 
after transplant.   
Vital signs at each time point and the change in vital signs from pre-transplant value, and weight loss 
will be presented using descriptive statistics.   
Steatorrhea and malnutrition risk will be graded as described in 4.2.3.  Analysis will be performed 
separately at day 75+14 and 365+14 after transplant. 2x4 contingency table will be performed at each 
time point. 95% confidence intervals of proportion will be also done. 
Analysis of documented hypoglycemia episodes and diabetic ketoacidosis-related events, recorded as 
cumulative number of episodes per patient, will be performed from day 75+14 to 365+14 after islet 
infusion. Mean, median, SD, min, max will be calculated for the interval 
9.4.4. 
Analysis of exploratory endpoints 
Chemokines/cytokines will be presented using appropriate descriptive statistics, by treatment group. 
The relationship between inflammatory chemokines/cytokines response and exposure to reparixin will 
be explored. 
Serum level of miR-375 will be presented using appropriate descriptive statistics, by treatment group. 
The comparison will be made between the reparixin and the placebo control arms regarding the rates 
of patients who are randomized but do not receive IAT. 
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9.4.5. 
Interim analysis 
Safety and efficacy 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.  
Primary endpoint data will not be available until each patient reaches one year post randomization.  
Hence, it is expected that the majority of enrolment and treatment will be completed before 
meaningful evidence is available regarding treatment effect on the primary endpoint.  Thus, traditional 
group sequential methods would have more limited utility in this setting. 
The DMC will give careful consideration to the appropriateness of trial continuation if there is 
emerging evidence that Reparixin is harmful.  One component of this assessment will be the rate of 
unexpected deaths.  Based on historical experiences from the published Minnesota series for 1977-
2011 that includes 356 adults, 217 underwent pancreatectomy and IAT from 2006-2011. There was 1 
unexpected death within 12 months of transplant.  This translates to an estimated 0.5% rate. 
The DMC will consider the following guidelines regarding early termination based on the occurrence 
of unexpected deaths.  Early termination will be considered if: 
• 
there are at least 2 unexpected deaths in the first 33 reparixin patients (an outcome with 1.2% 
chance if the true event rate is 0.5%); 
• 
there are at least 3 unexpected deaths in reparixin patients at any time in the trial (an outcome 
with 0.2% chance in 50 reparixin patients if the true event rate is 0.5%). 
In making any recommendations about termination, the totality of data will be considered, including 
the number of unexpected deaths in the control group, and the available evidence about efficacy and 
the overall safety profile.  
The DMC will also give particular attention to clinically significant coagulation abnormalities, 
including but not limited to intra-abdominal or gastrointestinal hemorrhage.  Early termination would 
be considered if the rate of clinically significant post-surgical complications that require reoperation 
reliably exceeds the rate expected currently in standard practice settings.  Insights about that rate in 
standard practice settings will be provided by a literature review, and will include the publication for 
the Minnesota series, where intra-abdominal as well as gastrointestinal hemorrhage have been reported 
to be the most common reasons for reoperation (Sutherland, 2012). 
The DMC will also consider early termination if the quality of conduct of the trial is such that the trial 
will not be able to provide a timely and reliable answer to the questions it was designed to address. 
9.4.6. 
Missing data 
All reasonable efforts will be made to reduce the rate of missing data, since any method used for 
imputation for missing observations would be based on untestable assumptions that likely would be 
invalid. 
Investigators will be trained about the importance of patient retention and full data capture.  Also, any 
reasonable attempts should be made by the Investigators to emphasize continued patient’s 
participation for the full duration of the trial (see details in Section 7.3.1 and 10.2).  However, in order 
to minimize missing data, if a patient cannot refer to the site for a planned follow-up visit, the 
Investigator will try to obtain any relevant information from the patients, including 
documents/laboratory results available from local medical care. 
Subjects who die before the primary endpoint assessment at 12 months will be treated as failures in the 
efficacy analysis.  Additionally, for the primary analysis, patients who are lost to follow-up by 12 
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months will be considered as failures, with the recognition that the procedures described in this section 
have been developed to ensure the number of patients who are lost to follow-up will be very small.   
9.4.7. 
Methods for multiplicity correction in analyses 
If the primary analysis of the primary endpoint leads to rejection of the null hypothesis, the null 
hypotheses for the secondary endpoints will be tested in a conditional sequential manner.  A null 
hypothesiswill be rejected if and only if the primary analysis of that endpoint and all primary analyses 
of preceding primary and secondary endpoints result in a rejection of the respective null hypotheses. 
This procedure protects the family-wise false positive error rate at the overall one-sided 0.025 level. 
It is noted that for secondary endpoints that will be tested both at 75±14 and 365±14 days after the 
transplant, only the day 365±14 time point will be tested for superiority in the fixed sequence testing 
procedure. 
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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INSTITUTE REVIEW BOARD (IRB) 
It is the responsibility of the Investigator to obtain approval of the trial protocol/amendments from the 
appropriate IRB. 
Prior to the initiation of the study, the followings will be submitted to the IRB for approval: 
• 
the study protocol, 
• 
the Patient Informed Consent Document, 
• 
the current version of the Investigator’s Brochure, 
• 
Investigator’s current curriculum vitae, 
• 
any other requested document(s). 
A copy of the IRB approval will be sent to Dompé along with all other correspondence with the IRB, 
including the submission documents.  The Investigator should file copies of all correspondence with 
the IRB in the Investigator Site File.   
The study will not be started until full written approval has been obtained from the appropriate IRB.  
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 which granted the 
original approval.  Any amendment will be implemented only when full approval has been obtained 
from the appropriate IRB, except for those amendments which involve only logistical or 
administrative aspects of the study. 
The Investigator will send to the IRB any updated Investigator’s Brochure received from Dompé (or 
designee). 
The Investigator will submit required progress reports to the IRB which approved the protocol at least 
annually, as well as report any serious ADRs, life-threatening problems or deaths.   
The Investigator will also inform the IRB of reports of serious ADRs occurred at other sites 
participating to this clinical trial and/or in other clinical studies conducted with reparixin.   
The Investigator must inform the IRB of the termination of the study. 
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 Consent Document 
(PICD).  Although patients will be informed that they can withdraw consent at any time, the 
Investigator will also emphasize that missing data diminish the scientific value of all patients’ 
contributions.  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.   
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The PICD will be signed and personally dated by both the patient and the Investigator.  Although 
nursing staff may be involved in describing the trial to a patient, the Principal Investigator (or a Sub-
Investigator) must participate in discussions with the patient and sign and personally date the PICD. 
A copy of the signed form will be provided to the patient, and the original signed PICD will be 
retained and filed in the Investigator Site File.  Patient consent will be documented in the hospital 
records. 
Individual (i.e. site specific) PICD will be based on a master document provided by Dompé and must 
be approved by Dompé prior to submission to the IRB.  Any changes requested by the IRB must be 
approved by Dompé prior to the documents being used.  Translation into a language different from 
English will be provided, if required.   
10.3. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential.  An 
agreement for disclosure will be obtained in writing by the patient and will be included in the PICD.  
Patient’s data collected during the study will be handled in accordance with applicable data protection 
laws and regulations.  The patient’s privacy associated with the use and disclosure of the patient’s 
protected health information will be safeguarded under applicable country laws (e.g. HIPAA). 
On the CRFs or Diary Cards, patients will be identified ONLY by the assigned patient number.  If 
patient names are included on copies of documents submitted to Dompé (or to the CRO appointed by 
Dompé), the names 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 and 
addresses. 
10.4. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND 
INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance contract covering the 
amount requested by the respective national laws for patients/Investigators/Institutions participating in 
the clinical trial.   
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 PICD. 
Insurance and any updates will be provided to the Investigator before trial commencement for filing 
into the Investigator Site File.  
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11. 
DATA HANDLING AND RECORD KEEPING  
11.1. 
CASE REPORT FORMS COMPLETION 
CRFs will be supplied by the CRO appointed by Dompé.  CRFs are the sole property of Dompé and 
should not be made available in any form to third parties, except for authorized Dompé’designee or 
representatives of appropriate Health/Regulatory Authorities, without written permission from Dompé. 
A CRF is required and should be completed for each included patient.  The Investigator will be 
responsible for the accuracy of the data entered in the CRFs.  All entries must be written in ENGLISH 
in black ink.  Source documents should be available to support all the data recorded in the CRF.  
The CRF must be available for review/collection to designated Dompé’s representatives at each 
scheduled monitoring visit.  
11.2. 
DIARY CARD 
Diary Cards will be supplied by the CRO appointed by Dompé.  They are the sole property of Dompé 
and should not be made available in any form to third parties, except for authorized Dompé’designee 
or representatives of appropriate Health/Regulatory Authorities, without written permission from 
Dompé. 
A sample Diary Cards is provided in Appendix 14.7.  Translation into a language different from 
English, will be provided, if required.   
Diary Cards are required and should be completed for each patient.  It is responsibility of the 
Investigator to explain to each patient how to enter the data in the Diary Card.   
11.3. 
DATA MANAGEMENT 
Data management of the CRFs and Diary Cards will be performed by the CRO appointed by Dompé. 
The CRF and Diary Card pages for all patients will be data-entered (double data entry) into the study 
database, and the data will be verified for missing data, inconsistencies, and for any necessary medical 
clarifications.  Queries arising from these checks will be sent to the Investigator for response and 
signature.     
Once all data queries have been resolved, the study will be declared to be “clean”, and the study data 
will be locked ready for analysis.   
After the database lock has been achieved, the Investigator may archive the copies of the CRFs and 
Diary Card retained at the centre.  The original CRF and Diary Card collected by the CRO appointed 
by Dompé will be transferred to Dompé for archiving.  
11.4. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND 
DURING THE STUDY 
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: 
• Current, signed and dated Curriculum Vitae, GCP qualification, and Financial Disclosure 
Statement of Principal Investigator and any Sub-Investigators.  Updates should be provided at lest 
every two years. 
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• Normal ranges of all laboratory tests to be performed at the study site and a recent certification or 
accreditation of established quality control (or other documentation of established quality control 
or external quality assessment or other validation).  Updates should be provided as soon as any 
reference value has changed. 
• A signed page of the final protocol and any amendments. 
• A signed original of the study Financial Agreement/Clinical Study Agreement with Dompé, 
including Pharmacy, laboratory etc (i.e. all study specific costs). 
• List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form).  
• Form 1572 and financial disclosure form 3455 from all the persons listed on the 1572. 
11.5. 
ESSENTIAL DOCUMENT RETENTION 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP) until at 
least 2 years after the last approval of a marketing application in an ICH region, and until there are no 
pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the Investigational Product.  These 
documents should be retained for a longer period however if required by the applicable 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, and 
Diary Cards, signed Patient Informed Consent Forms from all patients who consented, hospital records 
and other source documents, and all other documentation included in the Investigator Site File and 
Pharmacy/Dispensing File. 
The Investigator will inform Dompé of the storage location of these essential documents and must 
contact Dompé before disposing of any.  If the Investigator wishes to assign the files to someone else 
or to remove them to another location, he/she should consult with Dompé about this change. 
Dompé will inform the Investigator in writing when these documents no longer need to be retained. 
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12. 
STUDY MANAGEMENT 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (59th WMA 
General Assembly, Seoul, October 2008) and ICH Harmonised Tripartite Guideline for Good Clinical 
Practice (ICH-GCP) and any local regulations. 
12.1. 
REGULATORY BODY APPROVAL 
The study will not be started until review from FDA has been positively completed. 
12.2. 
STAFF INFORMATION & RESPONSIBILITIES 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are fully 
informed 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 the CRO appointed by Dompé 
detailing the various study tasks to be performed by each member of his/her study staff.  Each staff 
member should sign in agreement to their performing each of the tasks delegated to them on the list. 
12.3. 
MONITORING 
Monitoring will be carried out by CRAs of the CRO appointed by Dompé.  
Prior to study start, the Investigator will be informed of the anticipated frequency of the monitoring 
visits.  (S)He 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 any problems detected during the course of these monitoring visits are resolved. 
The purpose of the monitoring visit is to verify 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 trial complies with the currently approved protocol and any amendments, with ICH 
GCP, and with regulatory requirements.  
Monitoring at the Pharmacy will be carried out by the U-CRA in order to maintain study blind with all 
other CRO/site staff involved. 
12.3.1. 
Access to records 
The Investigator will allow 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 integrity of the data collected during the trial.  Source 
documents should 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 centre Initiation Visit.   
12.4. 
AUDIT AND INSPECTION 
Audit activities will be performed by the Quality Assurance of the CRO appointed by Dompé, except 
for audit to Protocol/Amendments, Patient Informed Consent Document (template) and CRF that will 
be done by the Dompé Quality Assurance Unit.  
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On one or more occasions the study site may be audited by the CRO appointed by Dompé. The 
Investigator will be informed in advance of such a visit.   
Additionally the study site may be inspected by a regulatory agency on one or more occasions. 
12.5. 
DATA MONITORING COMMITTEE  
An independent Data Monitoring Committee (DMC) will be established and will be responsible for 
safeguarding the interests of trial participants, and for enhancing the integrity and credibility of the 
trial. The DMC will assess the safety and efficacy of the interventions during the trial, and will 
monitor the overall conduct of the clinical trial.  The DMC will provide recommendations to Dompé 
about stopping or continuing the trial.  To contribute to enhancing the integrity of the trial, the DMC 
may also formulate recommendations to Dompé relating to the selection/recruitment/retention of 
participants, their management, improving adherence to protocol-specified regimens and retention of 
participants, and the procedures for data management and quality control. 
The DMC will operate independently of Dompé, and its members will not have connections to Dompé 
with the exception of the compensation to DMC members related to their activities.  
The DMC will comprise three members. They will be a multidisciplinary group that will include: 
• Two surgeons/physicians with extensive experience in islet transplantation and critical care 
medicine (e.g. a. Medical Director of a Transplant Program); 
• A Biostatistician with substantial experience in the DMC process. 
The DMC: 
• Will review unblinded data. To this purpose, an Independent Statistician will liaise with the CRO 
statistician and will have access to those components of the database necessary to generate the 
reports to the DMC. 
• Will be responsible for the ongoing (at least every 4 months) review of safety data throughout the 
trial.  Primary among the safety data that will be reviewed are Serious AEs. In particular, the 
DMC will monitor the number of deaths for both arms of the study to assess whether mortality is 
consistent with historical data. The DMC also will give attention to post-surgical reoperation and 
clinically significant coagulation abnormalities (intra-abdominal as well as gastrointestinal 
hemorrhage have been reported to be the most common reasons for reoperation). 
• Will review efficacy data in an ongoing manner to enable the assessment of the acceptability of 
safety in the context of emerging evidence about efficacy, i.e. measures of metabolic control and 
graft function.   
• Will be advisory to Dompé and make recommendations to Dompé regarding the continuation of 
the trial and potential modifications to the design and conduct of the trial.  These 
recommendations will be made in a manner to maintain confidentiality of emerging information 
about efficacy and safety, unless access to certain data is needed to enable Dompé to make 
decisions about the DMC recommendations.  Dompé will be responsible for promptly reviewing 
the DMC recommendations, to decide whether to continue or terminate the trial, and to determine 
whether amendments to the protocol or changes in the study conduct are required 
All details of the conduct and responsibilities of the DMC will comply with Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees and will 
be described in the ‘DMC Charter’ to be finalized during the set-up phase of the study and prior to the 
initiation of enrollment. 
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12.6. 
PROTOCOL DEVIATIONS/AMENDMENTS 
Changes to the Protocol will be implemented only when written amendments have been signed by all 
individuals who signed the protocol.   
Any amendment will be sent to the appropriate IRB.  No deviations from or changes to the protocol 
will be implemented without documented approval of an amendment from the IRB which granted the 
original approval, except where necessary to eliminate an immediate hazard(s) to trial patient, or when 
the change(s) involves only logistical or administrative aspects of the trial.  The deviations from or 
changes to the protocol implemented to eliminate an immediate hazard to the trial patient and the 
proposed amendment, if appropriate, should be submitted to the IRB for review and approval as soon 
as possible.  
Any other deviation from the protocol that has not been approved by Dompé and the IRB could result 
in a discontinuation from the study at the centre involved. 
Any written amendment will be sent to all recipients of the protocol and to the Competent Authorities. 
12.7. 
DISCONTINUATION 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 all CRFs 
completed to the extent possible. 
Study discontinuation will be notified to the FDA within 5 days from decision. 
12.8. 
PUBLICATIONS 
As this study is part of a multicentre trial, publications derived from this study will be planned and 
agreed with the participating Investigators.  Publications will include input from the Investigators, 
his/her colleagues, other investigators in this trial and Dompé personnel.  Such input will be reflected 
in publication authorship.  Criteria for selection of authors will be agreed.  Subsequent to the 
multicentre publication or one year after completion of the study, whichever occurs first, an 
Investigator and/or his/her colleagues may publish the results of Investigator’s part of the study 
independently.  
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 for review and comment at least 45 days prior to submission for publication or presentation.  If 
such draft contains confidential patentable information, the Investigator will refrain from publishing 
any such information for a period not exceeding 180 days, to enable Dompé to file for the protection 
of any intellectual or proprietary property interest. 
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13. 
REFERENCES 
Allegretti M et al. 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive 
CXCL8 inhibitors. J Med Chem 2005; 48:4312-4331. 
American Diabetes Associacion. Defining and reporting hypoglycemia in diabetes. Diabetes care 2005; 28:1245-
1249. 
Balzano et al. Autologous pancreatic islet transplantaiton (IAT) as endocrine tissue rescue in patients undergoing 
complete pamcreatectomy because of surgical complicaiton after Whipple resection. Transplant Int 2011; 
abstract O-174 page 49. 
Barshes NR et al. Transaminitis after pancreatic islet transplantation. J Am Coll Surg 2005; 200:353-361. 
Berney T et al. Long-term metabolic results after pancreatic resection for severe chronic pancreatitis. Arc Sur 
2000; 135: 1106 
Bernstein L et al. Measurement of visceral protein status in assessing protein and energy malnutrition: standard 
of care. Prealbumin in Nutritional Care Consensus Group. Nutrition 1995; 11:170. 
Bertini R et al. Non-competitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and 
CXCR2: prevention of reperfusion injury. PNAS 2004; 101:11791-11796. 
Caumo A et al. Transplant Estimated Function. Diabetes Care 2008; 31:301-305. 
Cavalieri B et al. Neutrophil recruitment in the reperfused-injured rat liver was effectively attenuated by 
repertaxin, a novel allosteric non-competitive inhibitor of CXCL8 receptors: a therapeutic approach for the 
treatment of post-ischemic hepatic syndrome. Int J Immunopathol Pharmacol 2005; 18:475-486. 
Citro A et al. CXCR2 inhibition improves islet transplantation outcome. Transplant Int 2011; abstract O-053 
page 15. 
Citro A et al. CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. J Clin Invest 2012a 
122:3647-3651. 
Citro A et al. CXCR2/1 inhibition modulates diabetes induced by multiple low doses of streptozotocin 
(MDL_STZ) injection in mouse. 2nd Joint AIDPIT and EPITA Winter Symposium. Igls/Innsbruck 2012b, 
Abstract book, abstract PP-18 
Clinical safety data management: Definitions and Standards for Expedited Reporting (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. 
Cugini D et al. Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to 
ischemia/reperfusion. Kidney Int 2005; 67:1753-1761. 
Dong M et al. Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for 
minimizing diabetes. Clin Endocrinol 2011; accepted article. 
Farley et al. Pancreatic resetion for ductal adenocarcinoma: total pancreatectomy versus partial pancreatectomy. 
Sem in Surg Onc 1995; 11:124-131. 
Garau A et al. Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia. Cytokine 2005; 
30:125-131. 
Garcea G et al. Total pancreatectomy with and without islet cell transplantation for chronic pancreatitis. Pancreas 
2009; 38:1-7. 
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Gorio A et al. Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes 
recovery of  function after traumatic lesion to the spinal cord. JPET 2007; 322:973-981. 
Greenbaum MD et al. Mixed-Meal tolerance test versus glucagon stimulation test for the assessment of β-cell 
function in therapeutic trials in type 1 diabetes. Diabetes Care 2008; 31:1966-1971. 
Gruessner RWG et al. Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. J 
Am Coll Surg 2004; 198:559-567. 
Hogle HH, Reemtsman K. Pancreatic autotransplantation following resection. Surgery 1978; 82:359-360. 
ICH Harmonised Tripartite Guideline for Good Clinical Practice (June 1996), as recommended for adoption to 
the three regulatory parties to ICH.  Approved on 17th July 1996 (CPMP/ICH/135/95). Approved by FDA on 9th 
May 1997 and effective 9th May 1997 (62 FR 25692). Accepted  and published by Health Canada, 1997. 
Linehan et al. Total pancreatectomy for chronic pancreatitis. Gut 1988; 29:358-365. 
Pollard et al. Long term outcome of islet autotransplantation following total pancreatectomy: the Leicester 
experience. Rev Diabetic Studies 2011; abstract O-016 page 100. 
Pollard et al. The cytokine response in the initial phase of islet auto- and allo-transplantation. Rev Diabetic 
Studies 2011; abstract P-227 page 182. 
Rafael E et al. Changes in liver enzymes after clinical islet transplantation. Transplantation 2003; 76:1280-1284. 
REP0101 - Clinical study ME0706; Dompé Internal Report (final). 
REP0102 - Clinical study ME0735; Dompé Internal Report (final). 
REP0103 - Clinical study ME0757; Dompé Internal Report (final). 
REP0203 - Clinical study ME0761; Dompé Internal Report (final). 
REP0104 - Dompé Internal Report (final). 
REP0204 - Dompé Internal Report (final). 
REP0110 - Dompé Study Protocol. 
Ryan EA et al. An assessment of β-cell function after islet transplantation. Diabetes Care 2005; 28:343-347. 
Sarr MG et al. Total pancreatectomy: an objective evaluation analysis of its use in pancreatic cancer. 
Hepatogastroenterology 1993; 40:418-421. 
Souza DG et al. Reparixin, a novel inhibitor of rat CXCR2 function, inhibits inflammatory responses that follow 
intestinal ischemia and reperfusion injury. Br J Pharmacol 2004; 143:132-142. 
Sutherland DER et al. Pancreatic islet cell transplantation. Surg Clin North Am 1978; 58:365-382. 
Sutherland et al. Total pancreatectomy and islet autotransplantationfor chronic pancreatitis. J Am Coll Surg       
2012; 214:409-424. 
Villa P et al. The Interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and 
reduces long-term inflammation in permanent and transient cerebral ischemia in rats. Mol Med 2007; 13:125-
133. 
 
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14.2. 
APPENDIX 2 - PACKAGING AND LABELING DETAILS 
The template of label specimens is provided below.   
 
 
Specimen label for the REPARIXIN Vial  
 
 
STUDY REP0112 
Sponsor Dompé s p.a.; Via Campo di Pile, L’Aquila – Italy 
 
Phone: + 39 346 8745908 
 
REPARIXIN 
 
  
INVESTIGATOR: 
 
CONTAINS: 
250 mL REPARIXIN (33 mg/mL) CONCENTRATE FOR SOLUTION FOR I.V. INFUSION 
 
BATCH No. 
EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C (86°F) 
 
 
 
DIRECTIONS: 
Transfer into an INFUSION BAG the content of the vial + 500 mL of 0.9% NaCl, according to 
procedures detailed in the “Instructions to the Pharmacy”.  
 
Caution: New Drug-Limited by Federal law to investigational use. 
 
 
 
 
Specimen label for the PLACEBO Vial  
 
 
STUDY REP0112 
Sponsor Dompé s p.a.; Via Campo di Pile, L’Aquila – Italy 
 
Phone: + 39 346 8745908 
 
PLACEBO 
 
  
INVESTIGATOR: 
 
CONTAINS: 
250 mL Physiologic salt solution (0.9% w/v sodium chloride) 
 
BATCH No. 
EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C (86°F) 
 
 
 
DIRECTIONS: 
Transfer into an INFUSION BAG the content of the vial + 500 mL of 0.9% NaCl, according to 
procedures detailed in the “Instructions to the Pharmacy”.  
 
Caution: New Drug-Limited by Federal law to investigational use. 
 
 
 
 
 
 
 
 
 
 
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Specimen label for Infusion Bag - “double tear off” label 
 
Each of the 2 sections of the double label will have identical information as per specimem below. 
 
STUDY REP0112 
Sponsor Dompé s p.a.; Via Campo di Pile, L’Aquila – Italy 
 
Phone: + 39 346 8745908 
PATIENT No. □□□□ 
    INFUSION BAG No. □ 
 
INVESTIGATOR: 
 
 
CONTAINS: 
750 mL OF REPARIXIN (11.00 mg/mL) or PLACEBO I.V. INJECTABLE DOSING SOLUTION  
 
PREPARED ON |__|__|/|__|__|/|__|__|__|__|     |__|__| : |__|__| 
 
 
     dd      /      mm    /           yyyy                         h       :      min 
 
DO NOT STORE AT >30°C (86°F) 
 
USE BY 
|__|__|/|__|__|/|__|__|__|__|     |__|__| : |__|__| 
 
 
     dd      /      mm    /           yyyy                         h       :      min 
 
 
 
DIRECTIONS:  
Administer as a continuous i.v. infusion into a (high flow) central vein, by an infusion pump. 
Infusion will start approximately 12 hours (6 to 18) before islet infusion. Pump rate will be 
adjusted according to patient body weight as per Appendix 3 of Study Protocol. 
 
Caution: New Drug-Limited by Federal law to investigational use. 
 
 
NOTE: 
Shadowed field are those to be completed by the pharmacist at the time of preparation. 
 
 
Patient No. 
Report the four digit number derived from the “IP Preparation 
Order Form” received from the Investigator. 
 
 
Infusion Bag No. 
Report the sequential bag number within the series for that 
patient. 
 
 
 
Preparation date/time 
Report the date and time when the preparation of the dosing 
solution has started. 
 
 
Use by date/time 
Calculate the use by date and time as date/time of preparation + 
maximum 72 hours (expiry date/time of the dosing solution), 
unless the site has more restrictive rules for reconstituted 
solutions (e.g. 24 hours). 
 
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14.4. 
APPENDIX 4 - STUDY FLOW CHART 
Test/Examination 
HOSPITAL STAY 
FOLLOW-UP 
 
Screening 
day  
-1 
day 0 
Tx day 
day 1 
day 2 
day 3 
day 4 
day 5 
day 6 
day 7 
Hospital 
discharge 
day 75+14 
post 
transplant 
day 365+14 
post 
transplant 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BP, HR, weight, height1 
X 
 
 
 
 
 
 
 
 
 
X1 
X1 
X1 
Safety laboratory tests 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Renal reserve/function2 & Total bilirubin 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Albumin and pre-albumin 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Concurrent sepsis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-operative portal hypertension 
X 
 
 
 
 
 
 
 
 
 
 
 
 
miR-375; Inflammatory chemokines/cytokines3 
XX3 
XXX3 
X3 
 
X3 
 
X3 
 
X3 
 
 
 
Study drug administration4 
 
X-----------------------------------------------------------------------------------X 
 
 
 
 
PK sampling4 
 
 
 
X 
 
X 
 
X 
X4 
 
 
 
ALT/AST 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
XDP, INR/PTT, CRP 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Average daily insulin; HbA1c 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Severe, Documented Symptomatic, 
Asymptomatic hypergycemia events 
 
 
 
 
 
 
 
 
 
 
 
X-----------------------------X 
MMTT5: Glucose, C-peptide, insulin 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
β-score – TEF calculation 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Steatorrhea6 and malnutrituion risk6 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse Events 
 
X-------------------------------------   Record all AEs up to each hospital discharge  Then, only SAEs   ------------------------------------X 
Concomitant Medication 
X-------Record all CMEDs up to each hospital discharge  Then, only drugs used for SAEs, oral hypoglycemic drugs and forbidden medications -------X 
1 = Measure only BP and HR at hospital discharge. Measure only weight at follow-up visits.  
2 = Assess Creatinine clearance on pre-transplant. Assess creatinine clearance AND urine output from day 1 to day 6 post-transplant. 
3 = Store a serum sample for centralized assay as detailed in Appendix 14.6.3. Take the 2 chemokines/cytokines pre-transplant samples 6 to 24 hours apart; obtain all basal samples before 
surgery and before the Investigational Product administration  is started. Take post-transplant samples @ 6, 12, 24, 72, 120 and 168hrs after islet infusion. 
4 = Start study drug infusion approximately 12 (6-18) hours before islet infusion. Obtain PK ideally in the morning (day 1, 3, 5 post-transplant). Obtain (if you are one of the 2 selected sites) a 
sample just prior to, and then 1, 3, 5, 6, 8, and 12 hours after the end of study drug administration.  
5= Mixed Meal Tolerance Test: measure glucose, C-peptide and insulin prior to (2 basal samples in the range between -20 to 0 prior to the meal) AND @ 15, 30, 60, 90, 120, 180 and 240 min 
after the meal, as detailed in Appendix 14.6.4. Store a blood sample for centralized assay of C-peptide and HbA1c as detailed in Appendix 14.6.3. 
6= Evaluate steatorrhea in the 4 weeks preceeding the follow-up visit. Evaluate malnutrition risk level as per pre-albumin value. 
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14.5. 
APPENDIX 5 - ACCEPTABLE TIME WINDOWS FOR ASSESSMENTS/ 
PROCEDURES 
 
Assessment/Procedure 
Window 
Investigational Product administration 
Start of Investigational Product infusion @ 
12hrs prior to islet transplant. 
 6-18hrs prior to start of islet infusion 
End of Infusion @ 7 days (168hrs). 
± 12hrs 
Follow-up visits 
Visit @ day 75 and 365after the transplant 
± 14 days 
Mixed Meal Tolerance Test 
Sampling @ 15, 30, 60, 90, 120, 180, 240 
mins after the meal 
± 5 mins (15 min and 30 min) or ± 10 mins 
(60 to 240 min) 
Chemokine/cytokines; miR-375 
Sampling @ 6, 12, 24, 72, 120 and 168hrs after 
islet infusion 
± 10 mins (6 to 24 hrs) or ± 30 mins (72 to 
168hrs) 
PK sampling 
 
Sampling on post-operative day 1, 3 and 5, 
ideally in the morning 
Between 5.30 a.m. and 12.30 p m. 
Sampling just prior to termination of 
Investigational Product administration 
Within 
6 
hrs 
before 
the 
end 
of 
Investigational Product administration 
Sampling @ 1, 3, 5, 6, 8, and 12 hrs after 
termination 
of 
Investigational 
Product 
administration 
± 10 mins 
 
 
 
 
 
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14.6. 
APPENDIX 6 - METHODOLOGICAL DETAILS 
14.6.1. 
Islet determination 
The following method will be used to quantify isolated and infused IEQ.   
After staining dithizone, islets will be counted by phase contrast microscope and grouped in classes 
according to their size (islet diameter; µm).  IEQ will be derived from the islet number in each class 
integrated by a conversion factor, as detailed in the table below, where “n” is the number of islet in each 
class.  
Class 
[islet diameter range (µm)] 
Conversion into IEQ  
[islets of 150 µm diameter] 
50-100 
n / 6 
101-150 
n / 1.5 
151-200 
n x 1.7 
201-250 
n x 3.5 
251-300 
n x 6.3 
301-350 
n x 10.4 
>350 
n x 15.8 
 
14.6.2. 
Calculation of creatinine clearance  
Renal function will be evaluated by creatinine clearance (CLcr), calculated by the following formula 
(Cockcroft-Gault, 1976): 
Male: CLcr = 
[140 - age (years)]  Weight (kg) 
 
Serum Creatinine (mmol / L)  815 
 
Female: CLcr = 
[140 - age (years)]  Weight (kg) 
 0.85 
Serum Creatinine (mmol / L)  815 
 
14.6.3. 
Handling of samples for centralized assays and assay methods 
Detailed instructions will be provided for preparation, storage and shipment of samples.  Tubes and labels 
for storage will be provided by the CRO appointed by Dompé, along with storage and shipment tracking 
forms.  
Samples will be shipped in appropriate package in dry ice (solid CO2) to maintain frozen conditions.  All 
samples will be shipped on an ongoing basis during the trial, according to logistics.  However, samples 
from the last patient visits will be shipped as soon as possible to ensure timely availability of results.   
Arrangements will be made with each centralized laboratory to provide appropriate procedures for receipt 
and analysis of the samples and, apart from PK analysis (see section “PK samples below”), back-
communication of the results to the sending site.  All steps will be tracked to ensure correct data reporting.  
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Once received from the centralized laboratory, each site will enter values pertaining to its patients in the 
corresponding CRF.  All samples will be destroyed after final study report has been issued or after the 
patient has withdrawn his/her consent. 
The centralized laboratory for the assay of C-Peptide, HbA1c and Inflammatory chemokines/cytokines will 
be: 
Northwest Lipid Metabolism and Diabetes Research Laboratories (Santica Marcovina, Ph.D., D.Sc.);  
University of Washington - 401 Queen Anne Ave North; Seattle, WA 98109 - US. Phone: +001 (206) 685 
3331; smm@u.washington.edu.  The laboratory is certified by CLIA and all the analyses are performed 
under strict quality control.  Also, the laboratory participates in the National Glycohemoglobin 
Standardization Program (NGSP) and the method is yearly certified at the level of Laboratory 1 
Certification to ensure that the HbA1c values are traceable to the DCCT values.  
 
The centralized laboratory for the assay of miR-375 will be: 
Diabetes Research Institute, β-cell Biology Unit (Lorenzo Piemonti, MD); IRCCS Ospedale San Raffaele; 
1st floor, Lot Q L33; Via Olgettina, 60; 20132 Milan, Italy.  
 
The centralized laboratory for the assay of PK samples will be: 
CDMO Department (Gaetano D’Anniballe BSc), Quality Control Laboratory; Dompé s.p.a. - Via Campo di 
Pile; 67100 L’Aquila - Italy. Phone: +39 0862 338361; e-mail: gaetano.danniballe@dompe.it 
 C-peptide  
Blood samples will be kept at room temperature for at least 30 min to allow clotting.  They will then be 
centrifuged at 700 × g within one hour from sampling.  Cell free serum samples for each time-point will be 
aliquoted (at least 2 x 0.5mL aliquots) and stored between -70°C and -80°C until shipment to the 
centralized laboratory.  Determination of C-peptide levels will be performed by a two site immuno-
enzymometeric assay using a Tosoh 2000 auto-analyzer (TOSOH, Biosciences, Inc., South San Francisco, 
CA).     
 HbA1c 
EDTA whole blood samples will be collected and at least 2 x 1 mL aliquots will be stored between -70°C 
and -80°C until shipment to the centralized laboratory.  Measurement of the relative proportion of 
hemoglobin subclasses and calculation of the HbA1c levels are performed by a dedicated analyzer 
(TOSOH, Biosciences, Inc) using non-porous ion exchange high performance chromatography to achieve 
rapid and precise separation of stable HbA1c from other hemoglobin fractions. 
 Inflammatory chemokines/cytokines  
Blood samples, obtained before (2 basal samples collected 6 to 24 hrs apart; both samples will be obtained 
before surgery and before Investigational Product administration is started) and 6, 12, 24, 72, 120 and 
168hrs after the end of islet infusion, will be immediately kept at 4°C, protected from the light and 
centrifuged within 2 hrs at 700 × g at 4°C.  Cell free serum will be aliquoted (4 x 100µL aliquots) and 
stored between -70°C and -80°C until shipment to the centralized laboratory and analysis.   
Starting from 25µL of thawed serum the following chemokines/cytokines will be determined by a multiplex 
technology that uses magnetic bead sets (BioRad BioPlex instrument using a Human Cytokine Panel; 
Millipore Inc., HCYTOMAG-60K): CXCL8, CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), IL-6, IL-10, 
INF-γ, TNF-α, and IL-1β.  Due to cross-reactivity with the Human Cytokine Panel (HCYTOMAG-60K), 
analysis of CXCL-9 (MIG) is performed on a BioRad BioPlex system using  MILLIPLEX MAP Human 
Cytokine/Chemokine Magnetic Bead Panel III (Millipore, Inc., HCYP3MAG-63K). 
 miR-375  
Blood samples, obtained before (one basal sample collected before surgery and before Investigational 
Product administration is started) and 6, 12, 24, 72, 120 and 168hrs after the end of islet infusion, will be 
immediately kept at 4°C, protected from the light and centrifuged within 2 hrs at 700 × g at 4°C.  Cell free 
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serum samples for each time-point will be aliquoted (at least 2 x 300µL aliquots) and stored between -70°C 
and -80°C until shipment to the centralized laboratory and analysis.   
Circulating miR-375 levels will be measured by droplet digital PCR (ddPCR); serum samples will be 
extracted with commercially available kits and the recovered miRNA fraction will be first reverse 
transcribed and then partitioned into approximately 20000 droplets using the droplet generator of the Bio-
Rad QX100 droplet digital PCR system.  After PCR amplification in a conventional thermal cycler, each 
individual droplet from each sample will be read and its fluorescent status assessed using the QX100 
droplet reader.  The output of the QX100 reader will be analyzed using the QuantaLife 1.3 software. 
 PK samples  
Blood samples will be taken into lithium heparin monovettes and centrifuged ideally within 15 minutes at 
2500 x g 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 4oC for not more than 24 hours before centrifugation.  Plasma will be aliquoted 
(2 x 1.5mL aliquots) and stored at a temperature in the range -20°C to -80°C into stopped tubes (glass or 
plastic), until shipment to the centralized analytical laboratory.  
Analaysis will be carried out within one year from sampling. i.e. before the study blind is broken. 
Therefore, all samples obtained during the conduct of the trial will be sent to the centralized laboratory and 
analyzed in order to maintain the study blind.  Appropriate procedures will be implemented by the 
centralized laboratory to guarantee the blinding; also, results will be released only after study blind has been 
broken. 
Analysis will be performed according to standardized and validated methods as per Good Laboratory 
Practices.  In particular, the following PK parameters will be determined: 
Cinitial 
Plasma concentration of reparixin and metabolites (DF 2243Y and ibuprofen) just prior to the 
end of infusion; 
Cmax 
Maximum plasma concentration of reparixin and metabolites; 
tmax 
Time of maximum plasma concentration reparixin and metabolites; 
λz 
Terminal phase rate constant of reparixin and metabolites; 
t½ 
Terminal half life of reparixin and metabolites; 
AUC0-t 
Area under the plasma concentration-time curve from time zero (Cinitial) to time t (time of last 
quantifiable plasma concentration) of reparixin and metabolites; 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero (Cinitial) to infinity of reparixin 
and metabolites 
Vz  
Volume of distribution of reparixin 
CL             Clearance of reparixin  
  
Data will be summarised in a separate report that will be integrated into the final study report.     
14.6.4. 
Mixed Meal Tolerance Test 
The MMTT will be performed on all patients possibly after an overnight fast, according to Greenbaum 
(2008).  The test will be initiated before 10 a m.  The Boost High Protein will be used for the MMTT.   
Patients will be given 6mL/kg of Boost preparation up to a maximum of 360mL, to be drunk within 5 min.  
Blood samples for glucose, C-peptide and insulin measurement will be withdrawn in basal condition (two 
samples in the range between -20 to 0 prior to the meal) and then @ 15, 30, 60, 90, 120, 180 and 240 min 
after the meal. 
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14.6.5. 
β-score calculation 
β-score will be calculated on a 0-8 scoring system (Ryan, 2005) which gives 0-2 points each for glucose, 
HbA1c, stimulated C-peptide and insulin requirement, as per the table below.   
 
Components 
Score 2 
Score 1 
Score 0 
Fasting (or before breakfast) plasma glucose  
(mg/dL OR mmol/L) 
<99 
OR <5.5 
100 – 124 
OR 5.6-6.9 
>125 
OR >7.0 
HbA1c (%) 
<6.1 
6.2 – 6.9 
>7.0 
Daily 
average 
(previous 
week) 
insulin 
(IU/kg/day) 
--- 
0.01 – 0.24 
>0.25 
Stimulated C-peptide (ng/mL)1 
>0.9* 
0.3 – 0.89 
<0.3# 
1: C-peptide level in the blood sample taken 90 min after drinking the mixed meal. *: If fasting C-peptide is 
>0.9 ng/mL, then the stimulated C-peptide level is assumed to be >0.9 ng/mL. #: If stimulated C-peptide is 
<0. 3 ng/mL, then an overall score of 0 is awarded 
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SAP_000.pdf: 
16.1.9 
Documentation of Statistical Methods 
 
Statistical Analysis Plan 
Addendum to Statistical Analysis Plan 
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REP0112 
 
 
 
 
 
 
Statistical Analysis Plan  
Version date: 14 December 2017 
CONFIDENTIAL 
Page 1 of 30  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
REP0112 
 
 
A phase 2/3, multicenter, randomized, double-blind, placebo-controlled, parallel 
assignment study to assess the efficacy and safety of reparixin in pancreatic islet auto-
transplantation. 
 
 
 
 
                               DATE OF DOCUMENT:  14 December 2017 
 
 
Prepared for: 
 
 Dompé farmaceutici S.p.A 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
 
Version Number 
Author 
Final 2.0 
Lisa R. Reeves, 
INC Research / inVentiv Health Clinical 
 
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REP0112 
 
 
 
 
 
 
Statistical Analysis Plan  
Version date: 14 December 2017 
CONFIDENTIAL 
Page 3 of 30  
  
 
TABLE OF CONTENTS 
 
1 
Introduction 
5 
1.1 
General 
5 
1.2 
Changes From Protocol 
5 
1.3 
Changes From Previous Versions of SAP 
5 
2 
Study Objectives 
5 
3 
Study Design 
5 
3.1 
Overview 
5 
3.2 
Inclusion and Exclusion Criteria 
5 
3.3 
Sample Size Considerations 
7 
3.4 
Randomization 
8 
4 
Study Variables 
8 
4.1 
Primary Variable 
8 
4.2 
Secondary Variables 
9 
4.2.1 
Efficacy Variables 
9 
4.2.2 
Safety Variables 
9 
4.2.3 
Exploratory Variables 
10 
4.2.4 
Pharmacokinetic Variables 
11 
5 
Definitions and Derived Variables 
11 
6 
Analysis Populations 
12 
7 
Statistical Methods 
12 
7.1 
General Principles 
12 
7.2 
Missing Data 
13 
7.3 
Methods for Multiplicity Correction in Analyses 
13 
7.4 
Disposition, Baseline Data, Concomitant Medications, Drug Exposure 
14 
7.4.1 
Patient Disposition 
14 
7.4.2 
Protocol Deviations 
14 
7.4.3 
Demographic data 
14 
7.4.4 
Specific Clinical History 
14 
7.4.5 
Significant Medical History 
15 
7.4.6 
Concomitant Medications 
15 
7.4.7 
Investigational Product Exposure 
15 
7.5 
Efficacy Analyses 
16 
7.5.1 
Primary Variable 
16 
7.5.2 
Secondary Variables 
17 
7.6 
Safety Analyses 
19 
7.6.1 
Adverse Events 
19 
7.6.2 
Laboratory Data 
20 
7.6.3 
Vital Signs 
21 
7.6.4 
Steatorrhea Severity 
22 
7.6.5 
Malnutrition Risk Level 
22 
7.6.6 
Documented Hypoglycemic Episodes 
22 
7.6.7 
Diabetic Ketoacidosis-related Events 
22 
7.7 
Exploratory Analysis 
22 
7.7.1 
Inflammatory Chemokines/Cytokines 
22 
7.7.2 
MicroRNA-375 
23 
8 
Data Monitoring Committee 
23 
9 
Interim Analyses 
24 
10 
Tables, Figures, and Listings for Clinical Study Report 
25 
 
 
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REP0112 
 
 
 
 
 
 
Statistical Analysis Plan  
Version date: 14 December 2017 
CONFIDENTIAL 
Page 4 of 30  
  
 
GLOSSARY OF ABBREVIATIONS 
 
ADIR 
Average Daily Insulin Requirements 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
CLcr 
Calculated Creatinine Clearance (Cockcroft - Gault formula) 
CRF 
Case Report Form 
CRO 
Contract research organization 
CRP 
C-reactive Protein 
DMC 
Data Monitoring Committee 
HbA1c 
Glycated hemoglobin 
HR 
Heart Rate 
Kg 
Kilogram 
IAT 
Islet Auto-Transplantation 
IEQ 
Islet Equivalent 
INR 
International Normalized Ratio 
ITT 
Intent to Treat 
MMTT 
Mixed Meal Tolerance Test 
NSAID 
Non Steroidal Anti-inflammatory Drug 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PTT 
Partial Thromboplastin Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment emergent adverse event 
ULN 
Upper Limit of Normal 
XDP 
Fibrin Degradation Products 
 
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REP0112 
 
 
 
 
 
 
Statistical Analysis Plan  
Version date: 14 December 2017 
CONFIDENTIAL 
Page 5 of 30  
  
 
1 
INTRODUCTION 
 
1.1 
General  
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
analysis and reporting of data collected under Dompé farmaceutici S.p.A (Dompé) Protocol 
REP0112.   
The SAP will be finalized and approved by the sponsor in addition to the Project Manager and 
Statistician of the contract research organization appointed by Dompé  prior to database lock. 
 
1.2 
Changes From Protocol 
Not pertinent. 
 
1.3 
Changes From Previous Versions of SAP 
Not pertinent. 
2 
STUDY OBJECTIVES 
The objective of this clinical trial is to assess whether reparixin leads to improved transplant 
outcome as measured by the proportion of insulin-independent patients following islet 
auto-transplantation (IAT).  The safety of reparixin in the specific clinical setting will also be 
evaluated. 
3 
STUDY DESIGN 
 
3.1 
Overview 
 
The study will be a phase 2/3, multicenter, randomized, double-blind, placebo-controlled, parallel 
assignment pilot study. 
The goal of this study is to reach a total of 100 adult patients who are randomized and receive 
IAT after total or completion pancreatectomy.  Patients will be randomly (1:1) assigned to receive 
either reparixin [continuous intravenous infusion for 7 days (168 hours)], or matched placebo 
(control group), starting approximately 12 hours before islet infusion.  The two groups will be 
balanced within each centre.  All patients who are randomized and receive the investigational 
product (either reparixin or placebo) will be included in the intent to treat (ITT) analysis.  Patients 
will be in the ITT analysis whether or not they receive IAT, because exclusions cannot be made 
for events occurring after randomization that could be influenced by the randomized assignment. 
Recruitment will be competitive among the study sites, until 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 transplant rate among study sites.  Each centre will enroll patients 
as rapidly as possible, up to a maximum of 40 patients (as per the randomization list). 
Each patient will be involved in the study for at least a 7 day hospital stay during pancreatectomy 
followed by IAT, for all required measurements up to hospital discharge and for 2 post-transplant 
visits scheduled at Day 75 + 14 days and Day 365 + 14 days after the transplant. 
 
3.2 
Inclusion and Exclusion Criteria 
 
To be eligible for inclusion into this study, each patient must fulfill ALL of the following inclusion 
criteria: 
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Statistical Analysis Plan  
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1. 
Patients eligible for an IAT following total (or completion) pancreatectomy. 
2. 
Ages > 18 years. 
3. 
Patients willing and able to comply with the protocol procedures for the duration of the 
study, including scheduled follow-up visits and examinations. 
4. 
Patients who have given written informed consent, prior to any study-related procedure 
not part of normal medical care, with the understanding that consent may be withdrawn 
by the patient at any time without prejudice to their future medical care. 
Patients who meet any of the following exclusion criteria are NOT eligible for participation in the 
study: 
1. 
Recipients of a previous IAT (if completion pancreatectomy). 
2. 
Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic 
benign diseases other than chronic pancreatitis, including insulinomas, etc.  
3. 
Patients with inadequate renal reserve as per calculated creatinine clearance (CLcr) < 
60 mL/min according to the Cockcroft-Gault formula (1976). 
4. 
Patients 
with 
hepatic 
dysfunction 
as 
defined 
by 
increased 
alanine 
aminotransferase/aspartate aminotransferase (ALT/AST) > 3 x upper limit of normal 
(ULN) or increased total bilirubin above the upper limit at local laboratory.  Patients with 
Gilbert’s syndrome (elevated unconjugated bilirubin levels in the absence of any 
evidence of hepatic or biliary tract disease) are not excluded. 
5. 
Patients with a preoperative International Normalized Ratio (INR) > 1.5 or any known 
coagulopathy. 
6. 
Hypersensitivity to: 
 
a) 
ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID). 
 
b) 
more than one medication belonging to the class of sulfonamides, such as 
sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib; 
hypersensitivity to sulphanilamide antibiotics alone (e.g. sulfamethoxazole) does 
not qualify for exclusion. 
7. 
Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other 
signs of systemic sepsis syndrome). 
8. 
Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use 
of <5 mg prednisone daily or equivalent dose of hydrocortisone, for physiological 
replacement only) or with any immune modulators in the 4 weeks prior to enrolment. 
9. 
Patients with pre-existing diabetes or evidence of impaired β-cells function, based on 
pre-operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%, or requiring 
treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 
weeks prior to enrolment. 
10. Use of any investigational agent in the 4 weeks prior to enrolment, including any 
anti-cytokine/chemokine agents.  
11. Pregnant or breast-feeding women; unwillingness to use effective contraceptive 
measures (females and males). (NB: pregnancy should be avoided in patients or 
partners during the first month after completing the treatment with the investigational 
product; no other specific warnings are described, considering the treatment course of 
the investigational product, its pharmacokinetic (PK) profile, and the lack of significant 
adverse effects on mating performance and fertility in animal studies). 
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12. Patients with past or current history of alcohol abuse based on clinical history and/or 
past treatment for alcohol addiction. 
13. Patients with evidence of pre-operative portal hypertension as per clinical history and 
abdominal/liver imaging by ultrasound techniques. 
Sites will comply with any additional or more restrictive exclusion criteria locally accepted, as per 
centre practice. 
 
3.3 
Sample Size Considerations 
 
The primary efficacy endpoint of the clinical trial is the proportion of insulin-independent patients 
following IAT at Day 365 ± 14 days after the transplant. 
 
In the following considerations, statistical significance for this endpoint will be achieved if the 
Pearson Chi-square statistic yields a two sided p-value less than 0.05.  The corresponding false 
positive error rate is (one-sided) 0.025.  In addition, a 95% confidence interval for the difference 
of success (failure) rates between the reparixin and placebo groups will be provided based on the 
normal distribution approximation to the standardized difference in estimated success rates. 
 
Based on published data from a retrospective series (Sutherland, 2012), it appears that the 
likelihood of achieving insulin independence at 12 month follow-up in the placebo control arm 
depends upon the number of IEQ/kg, with patients categorized in three groups: 
 
• 
<2500 IEQ/kg: 13% insulin independence 
 
• 
2500-5000 IEQ/kg: 23% insulin independence 
 
• 
>5000 IEQ/kg: 55% insulin independence 
 
In their overall series, the yields were <2500 IEQ/kg in 36%, 2500-5000 IEQ/kg in 39% and 
>5000 IEQ/kg in 24% of patients.  In the more recent series of 217 patients receiving IAT from 
2006 to 2011, corresponding yields were <2500 IEQ/kg in 34%, 2500-5000 IEQ/kg in 42%, and 
>5000 IEQ/kg in 24%. 
 
Initial focus is placed on the cohort that is in the range 2500-5000 IEQ/kg, since these 
participants will be the largest fraction of enrollees.  It is anticipated that the percentage of such 
patients achieving insulin independence will be increased from 23% in the placebo control arm to 
55% in the reparixin arm.  Using standard statistical formulas based on the approximation of the 
binomial distribution by the normal distribution, the sample size of 44 patients per arm provides 
90% power to detect a 23% versus 55% true difference when using a Pearson Chi-square 
statistic having the traditional (one-sided) 2.5% false positive error rate.  Even accounting for the 
discreteness, the power should be in the 87% to 90% range.  Furthermore, with 44 patients per 
arm, statistical significance (i.e., one-sided p=0.025) will be obtained if the estimated difference is 
22.7% (10/44) versus 43.2% (19/44), which is an estimated 20.5% increase in percentage of 
patients achieving insulin independence.  Hence, with 44 patients per arm, statistical significance 
is achieved with an estimated effect size that is clinically meaningful. 
 
Even though the largest percentage of patients will be in the cohort receiving IEQ/kg in the range 
2500-5000 IEQ/kg, the trial will also enroll participants in two additional strata: <2500 IEQ/kg and 
>5000 IEQ/kg.  As noted above, we are presuming the middle strata would have an increase from 
23% to 55% in percentage of patients achieving insulin independence.  This is an odds ratio 
higher than 4.  If we have an odds ratio of approximately 4.3 to 4.5 in the other 2 strata and if 
approximately 1/2 of the patients would be from the 2500-5000 IEQ/kg stratum, then only a 
modest increase of about 12 additional patients beyond the 88 patient sample size would be 
needed to maintain the statistical power of the trial.  An increase in success rate from 13% to 
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40% in the <2500 IEQ/kg stratum would be an odds ratio of 4.4 and an increase in success rate 
from 55% to 84% in the >5000 IEQ/kg stratum would be an odds ratio of 4.3. 
 
Based on these considerations, it is planned to enroll 100 patients in this trial who receive IAT, 
with the expectation that there will be approximately 5 others who do not receive IAT.  Under 
such a plan, the trial would not be overpowered even if all participants were in the 2500-5000 
IEQ/kg stratum since statistical significance (i.e., one-sided p=0.025) would be obtained with 52 
patients per arm if the estimated difference is 23.1% (12/52) versus 42.3% (22/52), which is an 
estimated clinically significant 19.2% increase in percentage of patients achieving insulin 
independence. 
 
The sample size of 100 to 105 patients also provides high statistical power for the key secondary 
endpoint, C-peptide area under the curve (AUC) (mixed meal tolerance test [MMTT]) normalized 
by IEQ/kg.  Based on preliminary data reported from the ongoing pilot trial, Month 1 post 
transplant means and standard deviations for this endpoint are 1.92 ± 1.62 in the reparixin group 
and 0.44 ± 0.04 in the control group.  With 52 patients in each treatment group, the trial will have 
greater than 95% power to detect a difference in means of at least 1.48 (the difference between a 
treated mean of 1.92 and a control mean of 0.44) assuming that the common standard deviation 
is 1.37 and using an 0.0025 two-sided significance level. 
 
3.4 
Randomization 
Patients will be randomized in a 1:1 fashion to either reparixin or placebo. 
The randomization list will be generated with a computer procedure by the method of random 
permuted blocks in which treatment (in blocks of 4) will be balanced within centres.  A master 
randomization list will be generated, randomizing an excess of patients (a maximum of 40 for 
each site) to allow competitive recruitment within each centre. 
The randomization list will be prepared by an independent statistician and provided to Dompé in a 
sealed envelope to prevent unblinding. 
Similarly, individual treatment codes will be provided via a tamper-resistant system (either a 
sealed envelope or a scratch card).  Such a system will definitely allow recognition of whether the 
code has been broken and guarantees detection of any code misuse.  Individual treatment codes 
will be provided to: 
- 
the Pharmacist (or designee) within each participating site for investigational product 
preparation; 
- 
the Dompé Pharmacovigilance Department for safety procedures. 
The investigators can request to an independent facility (either by telephone or web based 
system) an individual code in the event of an emergency only, where knowledge of the blinded 
treatment for that patient could influence further patient care.  Any potential unauthorized code 
break and the reason behind it will be recorded. 
The randomization codes will also be accessible to an independent statistician (liaison between 
the contract research organization [CRO] database and Data Monitoring Committee [DMC] 
biostatistician) who will generate the reports for the DMC evaluation. 
The randomization code will be broken at study completion, i.e. when the last patient has 
completed his/her last follow-up visit (planned at 365 days after islet infusion), and once the 
database has been locked. 
4 
STUDY VARIABLES 
 
4.1 
Primary Variable 
 
The proportion of insulin-independent patients at Day 365 ± 14 days following IAT. 
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For the purpose of this protocol, insulin-independence is defined as freedom from the need to take 
exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: 
- 
a glycated hemoglobin (HbA1c) level <6.5%; 
- 
fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week 
(based on a minimum of one daily measurement; 
- 
a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past 
week (based on a minimum of one daily measurement); 
- 
a laboratory fasting glucose in the non-diabetic range (<126 mg/dL). 
   
4.2 
Secondary Variables 
 
4.2.1 Efficacy Variables 
• Area under the curve (AUC) for serum C-peptide level during the first 4 hours of a MMTT, 
normalized by the number of IEQ/kg, at Day 75 ± 14 days and at Day 365 ± 14 days after IAT. 
• Average daily insulin requirement at Day 75 ± 14 days and at Day 365 ± 14 days after IAT.  
For the purpose of this protocol, daily insulin is reported as IU/kg and intake averaged over the 
previous week. 
• Time course of glucose derived from the MMTT at Day 75 ± 14 days and at Day 365 ± 14 
days after IAT.  For each MMTT, there are 2 basal samples taken separately between -20 to 0 
minutes before the meal followed by samples through 240 minutes after the meal. 
• Time course of C-peptide derived from the MMTT at Day 75 ± 14 days and at Day 365 ± 14 
days after IAT.  For each MMTT, there are 2 basal samples taken separately between -20 to 0 
minutes before the meal followed by samples through 240 minutes after the meal. 
• Time course of insulin derived from the MMTT at Day 75 ± 14 days and at Day 365 ± 14 days 
after IAT.  For each MMTT, there are 2 basal samples taken separately between -20 to 0 
minutes before the meal followed by samples through 240 minutes after the meal. 
• β-cell function as assessed by β-score at Day 75 ± 14 days and at Day 365 ± 14 days after 
IAT. 
• The proportion of patients with HbA1c ≤ 6.5% at Day 365 ± 14 days after IAT. 
• Cumulative number of severe hypoglycemic events from Day 75 ± 14 days to Day 365 ± 14 
days after IAT. 
For the purpose of this protocol, a severe hypoglycemic event is defined as an event with one of the 
following symptoms: “memory loss, confusion, uncontrollable behavior, irrationale behavior, unusual 
difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms”, in 
which the subject was unable to treat him/herself and which was associated with either a blood 
glucose level <54 mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon 
administration. 
• The proportion of patients with HbA1c ≤ 6.5% at Day 365 ± 14 days after IAT AND free of 
severe hypoglycemic events from Day 75 ± 14 days to Day 365 ± 14 days after IAT, inclusive.  
 
4.2.2 Safety Variables 
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
throughout the study up to Day 365 ± 14 days after IAT. 
• Standard laboratory tests including hematology (hematocrit, hemoglobin, red blood cells, 
platelets, white blood cells, differential white blood cells count), clinical chemistry (sodium, 
potassium, serum creatinine, blood urea nitrogen, total bilirubin, ALT, AST), and coagulation 
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(international normalized ratio [INR], partial thromboplastin time [PTT]) at pre-transplant 
hospital admission and post-transplant hospital discharge. 
• Vital signs, i.e. systolic and diastolic blood pressure (BP) and heart rate (HR) at pre-transplant 
hospital admission and post-transplant hospital discharge. 
• ALT, AST, INR, PTT, fibrin degradation products (XDPs), and C-reactive protein (CRP), all 
daily from Day 1 up to Day 7 after IAT; ALT and AST also on Day 75 ± 5 days after IAT. 
• Weight loss from pre-transplant value at Day 75 ± 14 days and Day 365 ± 14 days after IAT. 
• Serum level of albumin and pre-albumin, absolute and change from pre-transplant value, at 
Day 75 ± 14 days and Day 365 ± 14 days after IAT. 
• Proportion of patients falling into one of the following levels of steatorrhea severity at Day 75 ± 
14 days and Day 365 ± 14 days after IAT. 
For the purpose of this protocol, levels of steatorrhea severity (evaluated in the 4 weeks prior to Day 
75 ± 14 days and Day 365 ± 14 days), are defined as: 
- No steatorrhea; 
- Steatorrhea few times per week; 
- Steatorrhea daily; 
 
- Stool incontinence. 
• Proportion of patients falling into one of the following malnutrition risk levels according to 
pre-albumin level at Day 75 ± 14 days and Day 365 ± 14 days after IAT. 
For the purpose of this protocol, malnutrition risk levels are defined as (adapted from Bernstein, 
1995): 
- Poor prognosis = pre-albumin level <5.0 mg/dL 
- Significant risk = pre-albumin level 5.0 to 10.9 mg/dL 
- Increased risk = pre-albumin level 11.0 to 15.0 mg/dL 
- Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL 
• Cumulative number of episodes of documented hypoglycemia (documented symptomatic; 
asymptomatic) from Day 75 ± 14 days to Day 365 ± 14 days after IAT. 
For the purpose of this protocol, the following definition applies (Diabetes Care, 2005): 
- 
Documented symptomatic hypoglycemia = An event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration <70 mg/dL. 
- 
Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia, 
but with a measured plasma glucose concentration <70 mg/dL. 
• Cumulative number of diabetic ketoacidosis-related events from Day 75 ± 14 days to Day 365 
± 14 days after IAT. 
For the purpose of this protocol, a diabetic ketoacidosis event is defined as the presence of (Pediatrics, 
2004): 
- 
Hyperglycemia (blood glucose >200 mg/dL); 
- 
pH <7.3 or HCO3 <15; 
- 
Ketones positive in the serum or urine. 
 
4.2.3 Exploratory Variables 
• 
Time course of inflammatory chemokines/cytokines as assessed by serum level of CXCL8, 
CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10, INF-γ, TNF-α, 
and IL-1β at pre-infusion hospital admission (2 basal samples collected 6 to 24 hours apart 
with both samples obtained before surgery and before investigational product 
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administration is started) and 6, 12, 24, 72, 120, and 168 hours after the end of islet 
infusion. 
• 
Proportion of patients who are randomized but do not receive IAT. 
• 
Time course of serum microRNA-375 (miR-375) at pre-infusion hospital admission (sample 
will be obtained before surgery and before investigational product administration is started) 
and 6, 12, 24, 72, 120, and 168 hours after the end of islet infusion. 
 
4.2.4 Pharmacokinetic Variables 
• 
Plasma levels of reparixin (total and unbound) and relevant metabolites (DF2243Y and 
ibuprofen) at post-operative Days 1, 3, and 5 (steady state) in all patients; and just prior 
to, and then at 1, 3, 5, 6, 8, and 12 hours after termination of investigational product 
administration in a subset of at least 20-24 patients enrolled at Site 1 and Site 3. 
Pharmacokinetic summarization and analysis will not be done by the CRO which is conducting 
summarization and analysis of the primary, secondary, and exploratory variables described in this 
SAP.  Pharmacokinetic summarization and analysis will be described in a separate document and 
not discussed further in this SAP; pharmacokinetic data collected in the CRF will be listed. 
5 
DEFINITIONS AND DERIVED VARIABLES 
 
 
Study Day Relative to Date of First Date of Investigational Product Administration:  Day 1 will be 
defined as the first date on which infusion of investigational product is started.  Positive study 
days will be counted forward from Day 1.  Day -1 will be the date immediately preceding Day 1, 
and negative study days will be counted backward from Day -1. 
 
Study Day Relative to Date of Islet Auto-Transplantation:  Day 0 will be defined as the date on 
which islet are infused.  Positive study days will be counted forward from Day 0.  Day -1 will be 
the date immediately preceding Day 0, and negative study days will be counted backward from 
Day -1. 
 
Visit Windows:  For the per protocol population (see Section 6 of this SAP), data recorded at the 
Day 75 and Day 365 visits will be included in summarization and analysis only if the Day 75 and 
Day 365 visits fall within 14 days of the target study day relative to the date of IAT as indicated in 
the following table. 
 
 
Visit 
Target Study Day 
Relative to Date of IAT 
Acceptable Range of Study Days 
Relative to IAT 
Day 75 
75 
61 to 89 
Day 365 
365 
351 to 379 
 
 
Area Under the Curve (AUC) Normalized by the Number of IEQ/kg, C-peptide:  When C-peptide 
values are below the limit of detection (0.05 ng/mL), a value of 0.05 ng/mL will be assumed in the 
calculation of area under the curve.  Missing C-peptide values will be imputed via linear 
interpolation, and the average of the two basal samples (values, and mid-point of sample times) 
will be used as the first sample in the computation of the AUC.  Once these rules have been 
applied to the data, AUC for C-peptide will be computed using the trapezoidal rule, and 
normalized by dividing the computed AUC value by the total IEQ/kg infused during IAT as 
recorded on Page 12 of the CRF.  For ease of interpretation, the AUC value obtained will be 
divided by the total time the scale is assessed for reporting purposes.  Computation of AUC will 
be based on actual collection times, unless actual collection time is missing, in which case the 
scheduled collection time will be used. 
 
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Other definitions and derived variables are found within the applicable subsections of Section 7, 
Statistical Methods. 
6 
ANALYSIS POPULATIONS 
Five analysis populations will be identified and used in the summarization and analysis of data, 
namely all screened patients, all randomized patients, intent to treat, per protocol, and safety. 
 
• 
All Screened Patients:  This population will include all patients screened for participation 
in the trial. 
 
• 
All Randomized Patients:  This population will include all patients randomized to 
investigational product in the trial. 
 
• 
Intent to Treat:  This population will consist of all patients who are randomized and 
receive the investigational product (either reparixin or placebo).  Summarization and 
analysis of this population will be based on randomized treatment, regardless of 
treatment actually received.  Eligible patients will be included in this population whether or 
not they receive IAT, because exclusions cannot be made for events occurring after 
randomization that could be influenced by the randomized assignment. 
 
• 
Per Protocol:  This population will consist of all patients in the ITT population who meet all 
of the following criteria: 
 
− 
Received IAT 
 
− 
Completed 7 days of investigational product dosing 
 
− 
No major protocol violations, including violations of inclusion/exclusion criteria, 
errors in treatment assignment, use of prohibited medication, etc. 
 
− 
Visits occurring on Day 75 ± 14 days from IAT and Day 365 ± 14 days from IAT 
 
− 
Insulin-independence status recorded at Day 365 ± 14 days from IAT 
 
Further criteria for exclusion from the PP population may be identified during the data 
review meeting held prior to database lock. 
 
• 
Safety:  This population will consist of all randomized patients.  Summarization and 
analysis of this population will be based on treatment actually received. 
 
7 
STATISTICAL METHODS 
7.1 
General Principles 
The statistical package SAS® will be used to produce all summary tables, figures, and listings. 
In general, categorical data will be presented using counts and percentages, whilst continuous 
variables will be presented using the number of patients, mean, standard deviation, median, 
minimum, and maximum.  Denominators for calculation of percentages will be taken as the 
number of non-missing responses in the specified analysis population and treatment group 
unless otherwise stated, and percentages will be rounded to one decimal.  Minima and maxima 
will usually be reported to the same level of accuracy as the raw data; means, medians and 
standard deviations will be presented to one further decimal place; standard errors (if presented) 
will be presented to 2 decimal places more than the raw data.   
 
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All data recorded in the CRF will be listed. 
Unless otherwise specified, the significance level used for statistical testing will be 5% and 
two-sided tests will be used. 
 
7.2 
Missing Data 
All reasonable efforts will be made to reduce the rate of missing data, since any method used for 
imputation for missing observations would be based on untestable assumptions that likely would 
be invalid. 
Patients will be informed that they have the right at any time to withdraw from further participation 
in the study (withdrawal of consent), without prejudice to their medical care, and without being 
obliged to state their reasons.  However, the term withdrawal of consent should be used only 
when the patient no longer wishes to participate in the trial and no longer authorizes the 
investigators to make efforts to continue to obtain his/her outcome data. Ideally, if patients 
withdraw their consent, it should be done in writing. 
During the consent process, patients will be also educated about the scientific relevance of their 
continued participation as well as the deleterious effect that missing data will have on trial 
integrity.  
It is important to distinguish reasons for stopping randomized treatment (i.e., for non-adherence), 
from reasons to stop follow-up (i.e., for non-retention).  While there are many appropriate reasons 
to discontinue randomized treatment, the only reasons to discontinue follow-up would be death or 
withdrawal of consent. Patients who have discontinued the study treatment but have not 
withdrawn consent should be followed to ensure that primary and secondary outcome measures 
are assessed. 
Investigators will be trained about the importance of patient retention and full data capture.  Also, 
all reasonable attempts should be made by the investigators to emphasize continued patient’s 
participation for the full duration of the trial. If a patient fails to return to the center for a scheduled 
visit, all reasonable attempts should be made to contact the patient.  To minimize missing data, if 
a patient cannot refer to the site for a planned follow-up visit, the investigator will try to obtain any 
relevant information from the patients, including documents/lab results available from local 
medical care. 
Handling of missing data will be addressed for each summarization and analysis of data, as 
applicable, in sections of this SAP which describe summarization and analysis of data. 
Appropriate descriptive statistics will be produced to quantify the amount of missing data to allow 
comparison between the treatment groups. 
 
7.3 
Methods for Multiplicity Correction in Analyses  
If the primary analysis of the primary endpoint leads to rejection of the null hypothesis, the null 
hypotheses for the following secondary endpoints will be tested in a conditional sequential 
manner. The sequence in which these secondary endpoints will be tested is as follows: 
1. AUC for serum C-peptide level during the first 4 hours of a MMTT, normalized by the number 
of IEQ/kg, at Day 365 ± 14 days after IAT. 
2. Average daily insulin requirement at Day 365 ± 14 days after IAT.  
 
3. Time course of C-peptide derived from the MMTT at Day 365 ± 14 days after IAT. 
4. β-cell function as assessed by β-score at Day 365 ± 14 days after IAT. 
5. The proportion of patients with HbA1c ≤ 6.5% at Day 365 ± 14 days after IAT. 
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6. Cumulative number of severe hypoglycemic events from Day 75 ± 14 days to Day 365 ± 14 
days after IAT. 
7. The proportion of patients with HbA1c ≤ 6.5% at Day 365 ± 14 days after IAT AND free of 
severe hypoglycemic events from Day 75 ± 14 days to Day 365 ± 14 days after IAT, 
inclusive.  
A null hypothesis will be rejected if and only if the primary analysis of that endpoint and all 
primary analyses of preceding primary and secondary endpoints result in a rejection of the 
respective null hypotheses. This procedure protects the family-wise false positive error rate at the 
overall one-sided 0.025 level. 
7.4 
Disposition, Baseline Data, Concomitant Medications, Drug Exposure  
Summaries of disposition, baseline data, concomitant medications, and drug exposure will be 
produced using the screened, randomized, ITT, PP, and safety populations as noted in the 
following sections and will be presented by treatment group and overall. 
 
7.4.1 Patient Disposition 
The number of patients screened in total will be presented.  The number of patients randomized 
and number and percentage of randomized patients who did not receive IAT, who were treated, 
who were included and treated/included and not treated/excluded from the safety population (with 
reason for exclusion [not randomized] presented as a percentage of patients screened in total 
only), who were included/excluded from the ITT population (with reason for exclusion), who were 
included/excluded from the PP population (with reason for exclusion), who completed the study, 
and who withdrew early from the study (with primary reason for early withdrawal) will be 
presented by treatment group and in total.  The number and percentage of randomized patients 
who were included in the safety population will be summarized by treatment as received, or by 
treatment as randomized for those not treated.  Fisher’s exact test will be used to compare 
between treatment groups the proportion of randomized patients who did not receive IAT. 
Screening data recorded for patients who do not proceed to transplant with study drug 
administration will be listed separately. 
Patient disposition at each site will be presented by treatment group and in total, with the 
exception of there being no comparison between treatment groups of the proportion of 
randomized patients who did not receive IAT. 
7.4.2 Protocol Deviations 
 
Protocol deviations which exclude patients from the PP population (see Section 6 for definition) 
will be summarized by treatment group and in total.  The number and percentage of ITT patients 
with at least one protocol deviation and with each type of protocol deviation (by classification and 
sub-classification) will be presented. 
 
The summarization of protocol deviations will also be presented by site. 
 
7.4.3 Demographic data 
Demographic data will be presented for the ITT, PP, and safety populations.  Summary statistics 
for age in years, height in centimeters, and weight in kilograms at screening, and gender, race, 
and ethnic origin will be presented by treatment group and in total. 
 
7.4.4 Specific Clinical History 
 
Specific clinical history data will be presented for the safety population.  The number and 
percentage of safety patients with each type of pancreatectomy (total, completion), with each 
reason for pancreatectomy (chronic pancreatitis, recurrent acute pancreatitis), and with each 
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primary etiology of disease (hereditary or genetic disease, alcohol, sphincter of odi dysfunction, 
pancreas divisum, idiopathic or unknown, other) will be presented by treatment group and in total. 
 
The number and percentage of patients who had a completion pancreatectomy who had previous 
IAT and who had each type of prior partial resection (whipple (head) resection, distal 
pancreatectomy) will be presented by treatment group and in total. 
 
The summarization of specific clinical history will also be presented by site. 
 
Other non-chronic pancreatitis etiology (which are reasons for exclusion from the study) will be 
presented in a data listing. 
 
7.4.5 Significant Medical History 
Significant medical history will be summarized for the safety population. 
The number and percentage of patients reporting any significant medical history and any 
significant medical history which is ongoing at screening will be presented by treatment group and 
in total.  In addition, the number and percentage of patients reporting an item of significant 
medical history (any and ongoing at screening) within each of the following 15 body systems will 
also be presented by treatment group and in total:  general appearance;  head, ears, eyes, nose 
and throat; cardiovascular; pulmonary; gastrointestinal; liver; renal; genitourinary; endocrine; 
immune/allergy; psychiatric; central nervous system; dermatologic; musculoskeletal; and other.  
7.4.6 Concomitant Medications 
Concomitant medications will be summarized for the safety population. 
Concomitant medications will be those medications taken at or after the time of the start of 
investigational product.  Medications will be coded to standardized therapeutic classes and 
preferred terms using the WHO Drug Dictionary version as specified in the Data Management 
Plan associated with this protocol. 
The number and percentage of patients using at least one concomitant medication and using at 
least one concomitant medication within each therapeutic class and preferred term will be 
presented by treatment group and in total. 
7.4.7 Investigational Product Exposure 
Investigational product exposure will be summarized for the safety population. 
The number and percentage of patients who did not receive investigational product (in total only), 
received continuous investigational product infusion, who completed investigational product 
infusion (7 days), and who prematurely and permanently discontinued investigational product 
(and by reason for premature and permanent discontinuation of investigational product) will be 
summarized by treatment group and in total. 
Duration of investigational product infusion in hours, average rate of investigational product 
infusion in mL/hour, amount of investigational product infused in mL and in mg, and percentage of 
intended dose administered will be summarized descriptively by treatment group and in total.   
• 
Duration of investigational product infusion in hours will be computed as the last 
infusion end date/time minus the first infusion start date/time plus 1 second and minus 
the total interruption time in hours, divided by 3,600 seconds per hour. 
• 
Average rate of investigational product infusion to be summarized for a patient will be 
computed as the average of the infusion rates for all infusion bags which were started 
for the patient. 
• 
Amount of investigational product infused in mL will be estimated for a given patient 
for each infusion bag as infusion rate in mL/hour multiplied by duration of 
investigational product infusion per bag (according to definition of investigational 
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product infusion in hours but on a per bag basis), and will be estimated in total as the 
sum over all infusion bags of the amount of investigational product infused. 
• 
Amount of investigational product infused in mg will be estimated for a given patient 
for each infusion bag or over all infusion bags as the amount of investigational product 
infused in mL multiplied by 11.00 mg/mL (per Section 6.1.4 of the study protocol). 
• 
Percentage of intended dose administered will be computed as duration of 
investigational product infusion in hours divided by 168 hours, multiplied by 100, which 
is derived as follows. 
Actual dose administered will be equal to: 
(2.772 mg/kg) x (body weight in kg) x (duration of infusion in hours) 
Intended dose will be equal to: 
(2.772 mg/kg) x (body weight in kg) x (168 hours) 
The percentage of intended dose administered will be computed as: 
(actual dose administered) / (intended dose) x 100% 
= (duration of infusion in hours) / (168 hours) X 100% 
7.5 
Efficacy Analyses 
 
Summarization and analysis of efficacy parameters will be conducted for the ITT population 
(primary analysis) and PP population (secondary confirmatory analysis) by treatment group. 
 
7.5.1 Primary Variable 
The primary variable is the proportion of insulin-independent patients at Day 365 ± 14 days after 
IAT.  The number and percentage of patients who are insulin-independent at Day 365 ± 14 days 
after IAT will be presented by treatment group overall and by IEQ/kg (<2500 IEQ/kg, 2500-5000 
IEQ/kg, and >5000 IEQ/kg) infused at IAT. 
The percentage of patients who are insulin-independent at Day 365 ± 14 days after IAT will also 
be presented graphically as a bar chart overall and by IEQ/kg group.  Overall and within each 
IEQ/kg group there will be bars for reparixin and placebo. 
Primary Analysis 
The proportion of insulin-independent patients will be compared between treatment groups using 
the Cochran-Mantel-Haenszel test stratified by baseline IEQ/kg (<2500 IEQ/kg, 2500-5000 
IEQ/kg, and >5000 IEQ/kg). The hypothesis to be tested is: 
Null Hypothesis, H0:  preparixin ≤ pplacebo for all baseline IEQ/kg strata 
Alternantive Hypothesis, HA:  preparixin > pplacebo for at least one baseline IEQ/kg strata 
The significance level used for statistical testing will be 2.5% and a one-sided test will be used.  
The 95% confidence interval for treatment proportions and the one-sided 95% confidence interval 
for the difference in treatment proportion between reparixin and placebo will be produced. 
As a sensitivity analysis, the primary analysis will be repeated for the ITT population, dropping 
from the analysis any site with >20% of subjects not having data for the primary endpoint 
recorded; subjects will be considered to not have data recorded for the primary endpoint if they 
have discontinued the study prior to attending the Day 365 visit or if they have attended the Day 
365 visit but did not have the primary endpoint recorded.  The intent is to examine the sensitivity 
of the primary analysis to sites lacking a reasonable number of patients with data captured for the 
primary endpoint. 
The relevance of the treatment-by-site interaction will be investigated using a logistic regression 
model which will include the main effect of treatment and IEQ/kg infused at IAT (<2500 IEQ/kg, 
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2500-5000 IEQ/kg, and >5000 IEQ/kg) and site as covariates.  The analysis variable for treatment 
will be coded such that the reference treatment is placebo, the analysis variables for IEQ/kg 
infused at IAT will be coded such that the reference group is <2500 IEQ/kg, and the analysis 
variables for site will be coded such that the reference site is Site 1.  The treatment-by-site 
interaction will be examined, and if not significant at the 0.10 α-level, will be removed from the 
model.  The hypothesis to be examined is: 
Null Hypothesis, H0:  βtreatment ≤ 0 
Alternative Hypothesis, HA:  βtreatment > 0 
The treatment effect (βtreatment) will be declared significantly greater than 0 at the 0.025 α-level.  A 
model parameter estimate and the corresponding standard error, p-value, and odds ratio with a 
one-sided 95% confidence interval will be presented for the treatment effect. 
The logistic regression sensitivity analysis will also be performed for the ITT population, dropping 
from the analysis any site with >20% of subjects not having the primary endpoint recorded, using 
the same approach used for the sensitivity analysis of the primary endpoint. 
As further sensitivity analysis, the primary endpoint analysis and the corresponding logistic 
regression analysis will be repeated including Site 01 only, which is the largest site with the 
greatest number of patients receiving IAT, having possibly the best treatment balance, having a 
high rate of primary endpoint data capture, and also being the site with the highest experience in 
the field and thus transplanting patients under highly reproducible surgical and clinical conditions.  
When performing the logistic regression analysis, site will no longer be considered a covariate in 
the model.  The intent of these analyses is to examine the sensitivity of the primary analysis to 
the low enrollment/treatment balance, lesser experience level, and lower rates of retention which 
may be present at the other sites. 
For both the primary and sensitivity analyses, patients who die or who discontinue before the 
primary endpoint assessment at Day 365 ± 14 days after IAT, or those who reach the Day 365 
visit but have no primary endpoint assessment, will be treated as primary endpoint failures. 
7.5.2 Secondary Variables 
 
7.5.2.1 
Area Under the Curve for C-peptide During First 4 Hours of a Mixed Meal Tolerance 
Test 
C-peptide is to be collected at 9 time points (2 basal measurements and at 15, 30, 60, 90, 120, 
180, and 240 minutes) during the first 4 hours of a mixed meal tolerance test on both Days 75 
and 365 after IAT.  For both Days 75 and 365, the area under the curve normalized by IEQ/kg 
infused during IAT will be computed as described in Section 5 of this SAP.  AUC values at each 
day will be summarized descriptively by treatment group. 
Analysis will be performed in two steps.  First, the AUC normalized by IEQ/kg infused during IAT 
at each day will be compared between treatment groups using the t-test (two-sided tests at the 
5% level of significance).  
Second, the AUC normalized by IEQ/kg infused during IAT at the two days will be analyzed by a 
repeated measurements model using PROC MIXED within SAS®.  The model will include fixed 
effect terms for site, time (Days 75 and 365), and treatment.  Time will be specified as a repeated 
measurement.  In order to select an appropriate matrix for the observations within each patient, 3 
models will be fitted using the compound symmetry, Huynh-Feldt, and unstructured covariance 
structures.  The matrix for the final model will be selected using Akaike’s Information Criterion 
where the lowest value indicates the best fit.  Type III sums of squares from the mixed procedure 
within SAS® will be used to assess the significance of individual terms within the model using the 
selected matrix structure.  The importance of the treatment-by-site interaction will be investigated 
and if the term is not significant at the 0.10 α-level, it will be excluded from the model.  A 
logarithmic transformation of the data will be considered if found to be more suitable. 
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The adjusted least squares means and associated 95% confidence intervals will be estimated for 
each combination of day and treatment, and the adjusted least squares mean difference 
(reparixin minus placebo) and associated 95% confidence interval at each day will also be 
estimated.  The treatment effect within each day will be tested using a two-sided test at the 5% 
level.  The tests of the fixed effects in the model will also be presented. 
7.5.2.2 
Average Daily Insulin Requirements 
The average daily insulin requirement (ADIR) will be computed by site personnel using data from 
the patient diary card and reported on Pages 24 and 24.1 for Days 75 and 365, respectively.    
ADIR values at each day will be summarized descriptively by treatment group. 
ADIR will be analyzed in two steps as done for AUC of C-peptide. First, ADIR at each day will be 
compared between treatment groups using the t-test (two-sided tests at the 5% level of 
significance).  Second, ADIR at Day 75 and Day 365 will be analyzed as repeated measures with 
a single repeated measurements model using PROC MIXED within SAS®.  The model will include 
fixed effect terms for site, time (Days 75 and 365), and treatment.  Time will be specified as a 
repeated measurement.  In order to select an appropriate matrix for the observations within each 
patient, 3 models will be fitted using the compound symmetry, Huynh-Feldt, and unstructured 
covariance structures.  The matrix for the final model will be selected using Akaike’s Information 
Criterion where the lowest value indicates the best fit.  Type III sums of squares from the mixed 
procedure within SAS® will be used to assess the significance of individual terms within the model 
using the selected matrix structure.  The importance of the treatment-by-site interaction will be 
investigated and if the term is not significant at the 0.10 α-level, it will be excluded from the 
model.  A logarithmic transformation of the data will be considered if found to be more suitable. 
The adjusted least squares means and associated 95% confidence intervals will be estimated for 
each combination of day and treatment, and the adjusted least squares mean difference 
(reparixin minus placebo) and associated 95% confidence interval at each day will also be 
estimated.  The treatment effect within each day will be tested using a two-sided test at the 5% 
level.  The tests of the fixed effects in the model will also be presented. 
7.5.2.3 
Time Course of Glucose, C-peptide, and Insulin 
Glucose, C-peptide, and insulin are to be collected at 9 time points (2 basal measurements and at 
15, 30, 60, 90, 120, 180, and 240 minutes) during the first 4 hours of a mixed meal tolerance test 
on both Days 75 and 365 after IAT.   
The time course of each of these parameters at Days 75 and 365 will be analyzed separately with 
a repeated measurements model using PROC MIXED within SAS®.  Each repeated measures 
model will include fixed effect terms for site, time (the average of 2 basal measurements at time 0 
and at 15, 30, 60, 90, 120, 180, and 240 minutes), and treatment.  Time will be specified as a 
repeated measurement.  In order to select an appropriate matrix for the observations within each 
patient, 3 models will be fitted using the compound symmetry, Huynh-Feldt, and unstructured 
covariance structures.  The matrix for the final model will be selected using Akaike’s Information 
Criterion where the lowest value indicates the best fit.  Type III sums of squares from the mixed 
procedure within SAS® will be used to assess the significance of individual terms within the model 
using the selected matrix structure.  The importance of the treatment-by-site interaction will be 
investigated and if the term is not significant at the 0.10 α-level, it will be excluded from the 
model.  A logarithmic transformation of the data will be considered if found to be more suitable. 
Separately for each day (Day 75 and Day 365), parameter values at each time point will be 
summarized descriptively by treatment group.  The adjusted least squares means and associated 
95% confidence intervals will be estimated for each combination of time and treatment, and the 
adjusted least squares mean difference (reparixin minus placebo) and associated 95% 
confidence interval at each time will also be estimated.  The treatment effect within each time will 
be tested using a two-sided test at the 5% level.  Adjusted least squares means for each 
treatment and the treatment effect, associated 95% confidence intervals, and a two-sided p-value 
testing treatment effect over all time points at the 5% level will also be presented.  The tests of 
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the fixed effects in the model will also be presented.  The time course of adjusted least squares 
means for each parameter will be plotted over time. 
Separately for each day (Day 75 and Day 365), the peak (maximum) C-peptide and time to peak 
C-peptide value will be summarized descriptively.  The time to peak value in minutes will be 
computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the 
mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test CRF. 
7.5.2.4 
β-cell Function (β Score) 
The components of the β score and the total β score will be summarized descriptively at Day 75 ± 
14 days and Day 365 ± 14 days after IAT.  The Mann-Whitney U test will be used at each day 
(Days 75 and 365) in order to compare the distributions of the total β score of the two treatment 
groups.  Testing will be two-sided at the 0.05 level of significance. 
7.5.2.5 
Proportion of Patients With HbA1c <6.5% at Day 365 
HbA1c for Day 365 ± 14 days after IAT will be recorded on CRF Page 24.1 and this value will be 
used for summarization and analysis.  The number and percentage of patients with HbA1c <6.5% 
at Day 365 ± 14 days after IAT, the 95% confidence interval for the proportion, the treatment 
effect (reparixin percentage minus placebo percentage), and the 95% confidence interval for the 
treatment effect will be presented by treatment group.  The percentage of patients with HbA1c 
<6.5% at Day 365 ± 14 days after IAT will be compared between treatment groups using the 
Pearson chi-squared test (two-sided testing at the 0.05 level of significance).  If assumptions 
regarding expected cell counts are not met, Yate’s correction will be applied. 
7.5.2.6 
Cumulative Number of Severe Hypoglycemic Events From Day 75 to Day 365 After IAT 
The cumulative number of severe hypoglycemic events from the Day 75 to Day 365 visits (as 
recorded on CRF Page 24.1) will be summarized descriptively by treatment group. 
The effect of treatment on the rate of recurrent episodes of severe hypoglycaemia will be 
evaluated using an Andersen-Gill analysis with robust sandwich-type variance estimate.  From 
the model, the estimated hazard ratio (reparixin versus placebo), associated 95% confidence 
interval, and a two-sided p-value assessing the significance of the hazard ratio (at the 5% level) 
will be presented. 
7.5.2.7 
Proportion of Patients With HbA1c <6.5% at Day 365 and Free of Severe Hypoglycemic 
Events From Day 75 Through Day 365 
HbA1c for Day 365 ± 14 days after IAT and the number of severe hypoglycemic events from Day 
75 through Day 365 will be recorded on CRF Page 24.1, and these values will be used for 
summarization and analysis.  The number and percentage of patients with HbA1c <6.5% at Day 
365 ± 14 days after IAT and who are free of severe hypoglycemic events from Day 75 ± 14 days 
to Day 365 ± 14 days after IAT, the 95% confidence interval for the proportion, the treatment 
effect (reparixin percentage minus placebo percentage), and the 95% confidence interval for the 
treatment effect will be presented by treatment group.  The percentage of patients with HbA1c 
<6.5% at Day 365 ± 14 days after IAT and who are free of severe hypoglycemic events from Day 
75 ± 14 days to Day 365 ± 14 days after IAT will be compared between treatment groups using 
the Pearson chi-squared test (two-sided testing at the 0.05 level of significance).  If assumptions 
regarding expected cell counts are not met, Yate’s correction will be applied. 
 
7.6 
Safety Analyses 
The safety population will be used for the summarization and analysis of all safety data. 
7.6.1 Adverse Events 
All reported verbatim adverse event terms will be mapped to standard system organ classes and 
preferred terms using the MedDRA Dictionary as specified in the Data Management Plan for this 
protocol. 
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A treatment emergent adverse event (TEAE) is defined as any recorded adverse event which 
started on or after Day 1 of investigational product administration.  If the start date of an adverse 
event is incomplete or missing, the event will be assumed to be a TEAE, unless the incomplete 
start date (month and/or year) or the stop date (complete or incomplete) clearly indicates that the 
event started prior to dosing. 
The relationship of each adverse event to investigational product will be recorded as none, 
unlikely, possible, probable, or highly probable.  If a relation is missing for an adverse event, the 
relation of the event to investigational product will conservatively be assumed to be highly 
probable for summarization. 
The severity of each adverse event will be classified as mild, moderate, or severe.  If the severity 
of an adverse event is missing, the severity of the event will conservatively be assumed to be 
severe for summarization. 
Serious adverse events will be those events indicated as such on the CRF (a “Yes” response to 
“Serious”). 
An overview of TEAEs will summarize the number and percentage of patients and the number of 
events in the following categories:  any TEAE, any TEAE by relationship to investigational 
product, any TEAE by severity, any serious TEAE, any serious TEAE by relationship to 
investigational product, any serious TEAE by severity, any TEAE resulting in early withdrawal 
from study, and death.  For this overview, patients and events will be counted at each level of 
relationship to investigational product or severity at which an event is experienced (and not by 
worst relationship to investigational product and maximum severity). 
The number and percentage of patients reporting at least one event and the number of events 
reported within system organ class and preferred term will be summarized by treatment group 
and in total for the following type of adverse events:  TEAEs, TEAEs leading to discontinuation of 
the investigational product, TEAEs leading to early withdrawal from the study, serious TEAEs, 
serious TEAEs leading to discontinuation of the investigational product, and serious TEAEs 
leading to early withdrawal from the study.  Patients will be counted only once within each system 
organ class and preferred term for which they experience at least one event. 
A similar tabulation of these data, broken down further by relationship to investigational product, 
will be presented for TEAEs and serious TEAEs.  Patients with multiple events within a particular 
system organ class or preferred term will be counted only under the category of their most related 
event within that system organ class or preferred term.  Each category of relationship will be 
presented on a separate page or pages.  
A similar tabulation of these data, broken down further by severity, will also be presented for 
TEAEs and serious TEAEs.  Patients with multiple events within a particular system organ class 
or preferred term will be counted only under the category of their most severe event within that 
system organ class or preferred term.  Each category of severity will be presented on a separate 
page or pages. 
Listings will be presented by patient within treatment group for all adverse events, serious 
adverse events, adverse events leading to early withdrawal from the study, adverse events 
resulting in discontinuation of investigational product, and deaths.  
7.6.2 Laboratory Data 
 
7.6.2.1 
Safety Laboratory Parameters 
Safety laboratory parameters to be summarized include the following. 
• 
Hematology: hematocrit, hemoglobin, platelets, red blood cells, white blood cells, and 
differential white blood cells count (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
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• 
Clinical chemistry: sodium, potassium, blood urea nitrogen, serum creatinine, total 
bilirubin, ALT, AST. 
• 
Coagulation: activated partial thromboplastin time (aPTT) and international normalized 
ratio (INR). 
Samples for safety laboratory parameters are taken at screening and hospital discharge.  Each 
parameter will be summarized as the number and percentage of patients at each visit with out-of-
range results and with out-of-range clinically significant (as reported by the investigator on the 
laboratory CRFs) results by treatment group and in total. 
7.6.2.2 
Post-transplant Safety Laboratory Parameters 
Post-transplant safety laboratory parameters to be summarized include the following. 
• 
AST, ALT, INR, PTT, fibrin degradation products, and C-reactive protein. 
Samples for post-transplant safety laboratory parameters are taken at Days 1 through 7 
post-transplant and on Day 75 ± 14 days for AST and ALT.  Each parameter will be summarized 
descriptively at each applicable time point by treatment group and in total. 
Change from baseline (screening) at each applicable follow-up time point will be summarized for 
AST and ALT by treatment group and in total.  Change from baseline (screening) will be analyzed 
within a single repeated measurements model (for each of AST and ALT) using PROC MIXED 
within SAS®.  The model will include fixed effect terms for site, time (Days 1 through 7 and 75), 
and treatment; the treatment by time interaction; the treatment by study site interaction if 
significant at the 0.10 α-level; baseline value as a covariate; and a random effect for patient.  A 
compound symmetry covariance structure will be used to account for the multiple observations 
from the same patient. 
The adjusted least squares means and associated 95% confidence intervals will be estimated for 
each combination of day and treatment, and the adjusted least squares mean difference 
(reparixin minus placebo) and associated 95% confidence interval at each day will also be 
estimated.  The treatment effect within each day will be tested using a two-sided test at the 5% 
level.  The tests of the fixed effects in the model will also be presented. 
Observed values for all parameters will also be presented as box plots for each treatment group 
at each time point. 
7.6.2.3 
Albumin and Pre-albumin 
Serum levels of albumin and pre-albumin are collected pre-transplant and on Day 75 ± 14 days 
and Day 365 ± 14 days.  Each parameter will be summarized descriptively at each time point and 
change from pre-transplant to post-transplant time points (post-transplant value minus 
pre-transplant value) will be summarized descriptively by treatment group and in total.   
Observed values will also be presented as box plots for each treatment group at each time point 
7.6.3 Vital Signs 
Vital signs, including systolic and diastolic blood pressure and heart rate, are measured at 
pre-transplant hospital admission (screening) and post-transplant hospital discharge.  Each of 
these three parameters will be summarized descriptively at each time point and change from 
hospital admission to hospital discharge will be summarized descriptively by treatment group and 
in total. 
Weight is collected at screening, Day 75, and Day 365.  Observed values at each visit and 
change from screening to each follow-up visit will be summarized descriptively by treatment 
group and in total.  Change from baseline (screening) will be analyzed as repeated measures 
with a single repeated measurements model using PROC MIXED within SAS®.  The model will 
include fixed effect terms for site, time (Days 75 and 365), and treatment; the treatment by time 
interaction; the treatment by study site interaction if significant at the 0.10 α-level; baseline weight 
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as a covariate; and a random effect for patient.  An appropriate covariance structure will be 
selected.   
The adjusted least squares means and associated 95% confidence intervals will be estimated for 
each combination of day and treatment, and the adjusted least squares mean difference 
(reparixin minus placebo) and associated 95% confidence interval at each day will also be 
estimated.  The treatment effect within each day will be tested using a two-sided test at the 5% 
level.  The tests of the fixed effects in the model will also be presented. 
7.6.4 Steatorrhea Severity 
Summarization and analysis of steatorrhea severity will be performed separately at Day 75 and 
Day 365 after IAT by treatment group and in total.  The number and percentage of patients in 
each steatorrhea severity category and the associated 95% confidence interval for the proportion 
of patients in each category will be presented. 
7.6.5 Malnutrition Risk Level 
Summarization and analysis of malnutrition risk level will be performed separately at Day 75 and 
Day 365 after IAT by treatment group and in total.  The number and percentage of patients in 
each malnutrition risk level and the associated 95% confidence interval for the proportion of 
patients in each level will be presented. 
7.6.6 Documented Hypoglycemic Episodes 
The cumulative number of documented symptomatic hypoglycemic episodes and the cumulative 
number of asymptomatic hypoglycemia episodes occurring from Days 75 to 365 inclusive after 
IAT will be summarized descriptively by treatment group and in total.  The cumulative number of 
episodes for a patient will be the number of episodes recorded on CRF Page 27.1.  Treatment 
groups will be compared using a two-sided t-test or non-parametric Wilcoxon rank-sum test. 
7.6.7 Diabetic Ketoacidosis-related Events 
The cumulative number of diabetic ketoacidosis-related events occurring from Days 75 to 365 
inclusive after IAT will be summarized descriptively by treatment group and in total.  The 
cumulative number of diabetic ketoacidosis-related events for a patient will be the number of 
events recorded on CRF Page 27.1.  Treatment groups will be compared using a two-sided t-test 
or non-parametric Wilcoxon rank-sum test. 
7.7 
Exploratory Analysis 
The safety population will be used for the summarization and analysis of all exploratory data.  
Additional exploratory analyses beyond what is outlined below may be done. 
7.7.1 Inflammatory Chemokines/Cytokines 
Inflammatory chemokines/cytokines to be summarized include serum levels of CXCL8, CCL2 
(MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10, INF-γ, TNF-α, and IL-1β.  
Values are collected as 2 basal samples at pre-infusion hospital admission (6 to 24 hours apart) 
and at 6, 12, 24, 72, 120, and 168 hours after IAT. 
Observed values at each time point and baseline (the average of the two basal samples) and 
change from baseline (follow-up value minus baseline value) at each post-transplant time point 
will be summarized descriptively by treatment group and in total. 
Observed values will also be presented as box plots for each treatment group at each time point 
in order to graphically examine the time course of each parameter for each treatment group. 
The relationship between inflammatory chemokines/cytokines response (including AUC, peak 
level, and maximum change from baseline) and exposure to reparixin may be explored 
graphically, with inflammatory chemokines/cytokine response plotted against total reparixin dose 
(in mg/kg) received. 
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• 
Area under the curve will be computed as follows.  When parameter values are below the 
limit of detection, an appropriate value will be assumed in the calculation of area under the 
curve.  Missing parameter values will be imputed via linear interpolation, and the average of 
the two basal samples (values, and mid-point of the sample times) will be used as the first 
sample in the computation of the AUC.  Once these rules have been applied to the data, AUC 
for a parameter will be computed using the trapezoidal rule.  For ease of interpretation, the 
AUC value obtained will be divided by the total time the scale is assessed for reporting 
purposes.  Computation of AUC will be based on actual collection times, unless actual 
collection time is missing, in which case the scheduled collection time will be used. 
• 
Peak level for any given inflammatory chemokine/cytokine parameter will be the maximum 
post-baseline value, where the baseline value will be the average of the two basal values. 
• 
Maximum change from baseline for any given inflammatory chemokine/cytokine parameter 
will be the greatest change from baseline value, where change from baseline is computed as 
a post baseline value minus the baseline value and where baseline value is the average of 
the two basal values. 
7.7.2 MicroRNA-375 
MicroRNA-375 is collected pre-transplant and at 6, 12, 24, 72, 120, and 168 hours 
post-transplant. 
Observed values at each time point and change from pre-transplant (follow-up value minus 
pre-transplant value) at each post-transplant time point will be summarized descriptively by 
treatment group and in total. 
Observed values will also be presented as box plots for each treatment group at each time point 
in order to graphically examine the time course of MicroRNA-375 for each treatment group. 
8 
DATA MONITORING COMMITTEE 
Safety and efficacy data will be reviewed on an ongoing basis by an independent DMC.  Full 
details of the activities and responsibilities of the DMC are provided in the DMC Charter for the 
study. 
The DMC will assess the safety and efficacy of the interventions during the trial and will monitor 
the overall conduct of the clinical trial.  The DMC will provide recommendations to Dompé about 
stopping or continuing the trial.  To contribute to enhancing the integrity of the trial, the DMC may 
also formulate recommendations to Dompé relating to the selection/recruitment/retention of 
participants, their management, improving adherence to protocol-specified regimens and 
retention of participants, and the procedures for data management and quality control. 
The DMC: 
• Will review unblinded data. To this purpose, an independent statistician not affiliated with the 
conduct of the trial will liaise with the CRO statistician and will have access to those 
components of the database necessary to generate the reports for the DMC. 
• Will be responsible for the ongoing (at least every 4 months) review of safety data 
throughout the trial.  Primary among the safety data that will be reviewed are serious 
adverse events.  In particular, the DMC will monitor the number of deaths for both arms of 
the study to assess whether mortality is consistent with historical data.  The DMC also will 
give attention to post-surgical reoperation and clinically significant coagulation abnormalities 
(intra-abdominal as well as gastrointestinal hemorrhage have been reported to be the most 
common reasons for reoperation). 
• Will review efficacy data in an ongoing manner to enable the assessment of the acceptability 
of safety in the context of emerging evidence about efficacy, i.e. measures of metabolic 
control and graft function. 
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• Will be advisory to Dompé and make recommendations to Dompé regarding the continuation 
of the trial and potential modifications to the design and conduct of the trial.  These 
recommendations will be made in a manner to maintain confidentiality of emerging 
information about efficacy and safety, unless access to certain data is needed to enable 
Dompé to make decisions about the DMC recommendations.  Dompé will be responsible for 
promptly reviewing the DMC recommendations, to decide whether to continue or terminate 
the trial, and to determine whether amendments to the protocol or changes in the study 
conduct are required 
The independent statistician will use this SAP as a guideline for developing the outputs that are to 
be produced to facilitate DMC data review and deliberations. 
9 
INTERIM ANALYSES 
Primary endpoint data will not be available until each patient reaches one year post 
randomization.  Hence, it is expected that the majority of enrollment and treatment will be 
completed before meaningful evidence is available regarding treatment effect on the primary 
endpoint.  Thus, traditional group sequential methods would have more limited utility in this 
setting. 
The DMC will give careful consideration to the appropriateness of trial continuation if there is 
emerging evidence that reparixin is harmful.  One component of this assessment will be the rate 
of unexpected deaths.  Based on historical experiences from the published Minnesota series for 
1977-2011 that includes 356 adults, 217 underwent pancreatectomy and IAT from 2006-2011. 
There was 1 unexpected death within 12 months of transplant.  This translates to an estimated 
0.5% rate. 
The DMC will consider the following guidelines regarding early termination based on the 
occurrence of unexpected deaths.  Early termination will be considered if: 
• 
there are at least 2 unexpected deaths in the first 33 reparixin patients (an outcome with 
1.2% chance if the true event rate is 0.5%); 
• 
there are at least 3 unexpected deaths in reparixin patients at any time in the trial (an 
outcome with 0.2% chance in 50 reparixin patients if the true event rate is 0.5%).  
In making any recommendations about termination, the totality of data will be considered, 
including the number of unexpected deaths in the control group, and the available evidence about 
efficacy and the overall safety profile. 
The DMC will also give particular attention to clinically significant coagulation abnormalities, 
including but not limited to intra-abdominal or gastrointestinal hemorrhage.  Early termination 
would be considered if the rate of clinically significant post-surgical complications that require 
reoperation reliably exceeds the rate expected currently in standard practice settings.  Insights 
about that rate in standard practice settings will be provided by a literature review, and will include 
the publication for the Minnesota series, where intra-abdominal as well as gastrointestinal 
hemorrhage have been reported to be the most common reasons for reoperation (Sutherland, 
2012). 
The DMC will also consider early termination if the quality of conduct of the trial is such that the 
trial will not be able to provide a timely and reliable answer to the questions it was designed to 
address. 
 
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10 TABLES, FIGURES, AND LISTINGS FOR CLINICAL STUDY REPORT 
 
Section 14.1, Disposition, Baseline Characteristics, and Exposure Tables 
 
Table 14.1.1 
Patient Disposition 
Screened Patients 
Table 14.1.2 
Patient Disposition by Site 
Screened Patients 
Table 14.1.3 
Protocol Deviations 
Intent to Treat Population 
Table 14.1.4 
Protocol Deviations by Site 
Intent to Treat Population 
Table 14.1.5.1 
Demographics 
Safety Population 
Table 14.1.5.2 
Demographics 
Intent to Treat Population 
Table 14.1.5.3 
Demographics 
Per Protocol Population 
Table 14.1.6 
Specific Clinical History 
Safety Population 
Table 14.1.7 
Specific Clinical History by Site 
Safety Population 
Table 14.1.8 
Significant Medical History 
Safety Population 
Table 14.1.9 
Concomitant Medications 
Safety Population 
Table 14.1.10 
Investigational Product Exposure 
Safety Population 
 
 
Section 14.2, Efficacy Tables 
 
Table 14.2.1.1 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation 
Intent to Treat Population 
Table 14.2.1.1.A 
 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation 
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.1.1.B 
 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation 
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.1.2 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation 
Per Protocol Population 
Table 14.2.2.1 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis 
Intent to Treat Population 
Table 14.2.2.1.A 
 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis 
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.2.1.B 
 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis 
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.2.2 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis 
Per Protocol Population 
Table 14.2.3.1 
Area Under the Curve for C-peptide During First 4 
Hours of a Mixed Meal Tolerance Test 
Intent to Treat Population 
Table 14.2.3.2 
Area Under the Curve for C-peptide During First 4 
Hours of a Mixed Meal Tolerance Test 
Per Protocol Population 
Table 14.2.4.1 
Average Daily Insulin Requirements 
Intent to Treat Population 
Table 14.2.4.2 
Average Daily Insulin Requirements 
Per Protocol Population 
Table 14.2.5.1 
Time Course of Glucose (unit) at Day 75 
Intent to Treat Population 
Table 14.2.5.2 
Time Course of Glucose (unit) at Day 75 
Per Protocol Population 
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Table 14.2.6.1 
Time Course of Glucose (unit) at Day 365 
Intent to Treat Population 
Table 14.2.6.2 
Time Course of Glucose (unit) at Day 365 
Per Protocol Population 
Table 14.2.7.1 
Time Course of C-peptide (unit) at Day 75 
Intent to Treat Population 
Table 14.2.7.2 
Time Course of C-peptide (unit) at Day 75 
Per Protocol Population 
Table 14.2.8.1 
Peak C-peptide (unit) on Day 75 and Time to Peak 
Intent to Treat Population 
Table 14.2.8.2 
Peak C-peptide (unit) on Day 75 and Time to Peak 
Per Protocol Population 
Table 14.2.9.1 
Time Course of C-peptide (unit) at Day 365 
Intent to Treat Population 
Table 14.2.9.2 
Time Course of C-peptide (unit) at Day 365 
Per Protocol Population 
Table 14.2.10.1 
Peak C-peptide (unit) on Day 365 and Time to Peak 
Intent to Treat Population 
Table 14.2.10.2 
Peak C-peptide (unit) on Day 365 and Time to Peak 
Per Protocol Population 
Table 14.2.11.1 
Time Course of Insulin (unit) at Day 75 
Intent to Treat Population 
Table 14.2.11.2 
Time Course of Insulin (unit) at Day 75 
Per Protocol Population 
Table 14.2.12.1 
Time Course of Insulin (unit) at Day 365 
Intent to Treat Population 
Table 14.2.12.2 
Time Course of Insulin (unit) at Day 365 
Per Protocol Population 
Table 14.2.13.1 
β-score 
Intent to Treat Population 
Table 14.2.13.2 
β-score 
Per Protocol Population 
Table 14.2.14.1 
Proportion of Patients With HbA1c ≤6.5% at Day 365 
Intent to Treat Population 
Table 14.2.14.2 
Proportion of Patients With HbA1c ≤6.5% at Day 365 
Per Protocol Population 
Table 14.2.15.1 
Cumulative Number of Severe Hypoglycemic Events 
Intent to Treat Population 
Table 14.2.15.2 
Cumulative Number of Severe Hypoglycemic Events 
Per Protocol Population 
Table 14.2.16.1 
Proportion of Patients With HbA1c ≤6.5% at Day 365 
and Free of Severe Hypoglycemic Events From Day 
75 to 365 Inclusive 
Intent to Treat Population 
Table 14.2.16.2 
Proportion of Patients With HbA1c ≤6.5% at Day 365 
and Free of Severe Hypoglycemic Events From Day 
75 to 365 Inclusive 
Per Protocol Population 
 
 
Section 14.3, Safety Tables 
 
 
Table 14.3.1.1 
Overview of Treatment Emergent Adverse Events 
(TEAE) 
Safety Population 
Table 14.3.1.2 
Treatment Emergent Adverse Events (TEAE) 
Safety Population 
Table 14.3.1.3 
Treatment Emergent Adverse Events (TEAE) by Worst 
Relationship to Study Drug 
Safety Population 
Table 14.3.1.4 
Treatment Emergent Adverse Events (TEAE) by 
Maximum Severity 
Safety Population 
Table 14.3.1.5 
Treatment Emergent Adverse Events (TEAE) Leading 
to Discontinuation of Investigational Product 
Safety Population 
Table 14.3.1.6 
Treatment Emergent Adverse Events (TEAE) Leading 
to Early Withdrawal From the Study 
Safety Population 
Table 14.3.1.7 
Serious Treatment Emergent Adverse Events (TEAE) 
Safety Population 
Table 14.3.1.8 
Serious Treatment Emergent Adverse Events (TEAE) 
by Worst Relationship to Study Drug 
Safety Population 
Table 14.3.1.9 
Serious Treatment Emergent Adverse Events (TEAE) 
by Maximum Severity 
Safety Population 
Table 14.3.1.10 
Serious Treatment Emergent Adverse Events (TEAE) 
Leading to Discontinuation of Investigational Product 
Safety Population 
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Table 14.3.1.11 
Serious Treatment Emergent Adverse Events (TEAE) 
Leading to Early Withdrawal From the Study 
Safety Population 
Listing 14.3.2.1 
Listing of Deaths 
 
Listing 14.3.2.2 
Listing of Serious Adverse Events 
 
Listing 14.3.2.3 
Listing of Adverse Events Resulting in Discontinuation 
of Investigational Product 
 
Listing 14.3.2.4 
Listing of Adverse Events Leading to Early Withdrawal 
From the Study 
 
Table 14.3.4.1 
Hematology 
Safety Population 
Table 14.3.4.2 
Chemistry 
Safety Population 
Table 14.3.4.3 
Coagulation 
Safety Population 
Table 14.3.4.4 
Post-transplant Safety Endpoints, Excluding AST and 
ALT 
Safety Population 
Table 14.3.4.5 
Post-transplant Safety Endpoints, AST and ALT 
Safety Population 
Table 14.3.4.6 
Albumin and Pre-albumin 
Safety Population 
Table 14.3.5 
Vital Signs 
Safety Population 
Table 14.3.6 
Weight 
Safety Population 
Table 14.3.7 
Steatorrhea Severity 
Safety Population 
Table 14.3.8 
Malnutrition Risk Level 
Safety Population 
Table 14.3.9 
Cumulative Number of Documented Symptomatic 
Hypoglycemic Episodes From Days 75 to 365 
Following Islet Auto-transplantation 
Safety Population 
Table 14.3.10 
Cumulative Number of Asymptomatic Hypoglycemic 
Episodes From Days 75 to 365 Following Islet Auto-
transplantation 
Safety Population 
Table 14.3.11 
Cumulative Number of Diabetic Ketoacidosis-related 
Events From Days 75 to 365 Following Islet Auto-
transplantation 
Safety Population 
 
Section 14.3, Exploratory Tables 
 
Table 14.3.12 
Inflammatory Chemokines / Cytokines 
Safety Population 
Table 14.3.13 
miR-375 
Safety Population 
 
 
Section 14.4, Figures 
 
Figure 14.4.1.1 
Bar Chart of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation 
Intent to Treat Population 
Figure 14.4.1.2 
Bar Chart of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation 
Per Protocol Population 
Figure 14.4.2.1 
Time Course of Glucose (unit) at Day 75, Least 
Squares Means Over Time 
Intent to Treat Population 
Figure 14.4.2.2 
Time Course of Glucose (unit) at Day 75, Least 
Squares Means Over Time 
Per Protocol Population 
Figure 14.4.3.1 
Time Course of Glucose (unit) at Day 365, Least 
Squares Means Over Time 
Intent to Treat Population 
Figure 14.4.3.2 
Time Course of Glucose (unit) at Day 365, Least 
Squares Means Over Time 
Per Protocol Population 
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Figure 14.4.4.1 
Time Course of C-peptide (unit) at Day 75, Least 
Squares Means Over Time 
Intent to Treat Population 
Figure 14.4.4.2 
Time Course of C-peptide (unit) at Day 75, Least 
Squares Means Over Time 
Per Protocol Population 
Figure 14.4.5.1 
Time Course of C-peptide (unit) at Day 365, 
Least Squares Means Over Time 
Intent to Treat Population 
Figure 14.4.5.2 
Time Course of C-peptide (unit) at Day 365, 
Least Squares Means Over Time 
Per Protocol Population 
Figure 14.4.6.1 
Time Course of Insulin (unit) at Day 75, Least 
Squares Means Over Time 
Intent to Treat Population 
Figure 14.4.6.2 
Time Course of Insulin (unit) at Day 75, Least 
Squares Means Over Time 
Per Protocol Population 
Figure 14.4.7.1 
Time Course of Insulin (unit) at Day 365, Least 
Squares Means Over Time 
Intent to Treat Population 
Figure 14.4.7.2 
Time Course of Insulin (unit) at Day 365, Least 
Squares Means Over Time 
Per Protocol Population 
Figure 14.4.8 
Post-transplant Safety Endpoints, Excluding AST 
and ALT, Box Plots Over Time 
Safety Population 
Figure 14.4.9 
Post-transplant Safety Endpoints, AST and ALT, 
Box Plots Over Time 
Safety Population 
Figure 14.4.10 
Albumin and Pre-albumin, Box Plots Over Time 
Safety Population 
Figure 14.4.11 
Inflammatory Chemokines / Cytokines, Box Plots 
Over Time 
Safety Population 
Figure 14.4.12 
Inflammatory Chemokines / Cytokines, Area 
Under the Curve Versus Total Reparixin Dose 
Received 
Safety Population 
Figure 14.4.13 
Inflammatory Chemokines / Cytokines, Peak 
Level Versus Total Reparixin Dose Received 
Safety Population 
Figure 14.4.14 
Inflammatory Chemokines / Cytokines, Maximum 
Change From Baseline Versus Total Reparixin 
Dose Received 
Safety Population 
Figure 14.4.15 
miR-375, Box Plots Over Time 
Safety Population 
 
 
Section 16.2, Listings 
 
 
Listing 16.2.1.1 
Screen Failure and Randomization 
Listing 16.2.1.2 
Disposition – End of Study 
Listing 16.2.2.1 
Inclusion and Exclusion Criteria 
Listing 16.2.2.2 
Protocol Deviations 
Listing 16.2.3 
Patient Evaluability 
Listing 16.2.4.1 
Informed Consent, Demography, and Childbearing Potential 
Listing 16.2.4.2 
Specific Clinical History 
Listing 16.2.4.3 
Significant Medical History 
Listing 16.2.4.4 
Renal Reserve at Screening 
Listing 16.2.4.5 
Concurrent Sepsis at Screening 
Listing 16.2.4.6 
Portal Hypertension (Pre-operative) at Screening 
Listing 16.2.4.7 
Hospital Admission and Surgery Details 
Listing 16.2.4.8 
Islet Information and Pre-transplant Laboratory Draws 
Listing 16.2.4.9 
Transplant Details 
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Listing 16.2.4.10 
Post-transplant Glycemic Control 
Listing 16.2.4.11 
Hospital Discharge 
Listing 16.2.4.12 
Prior and Concomitant Medications 
Listing 16.2.5.1 
Investigational Product Administration 
Listing 16.2.5.2 
Investigational Product (IP) Administration Failure and Termination of Drug 
Infusion 
Listing 16.2.6.1 
Follow-up Visits, Part 1 
Listing 16.2.6.2 
Follow-up Visits, Part 2 
Listing 16.2.6.3.1 
Mixed Meal Tolerance Test 
Listing 16.2.6.3.2 
Mixed Meal Tolerance Test, C-peptide Area Under the Curve (AUC) 
Listing 16.2.6.4 
Patient Diary Card 
Listing 16.2.6.5 
β-cell Function 
Listing 16.2.6.6 
Hypoglycemic Episodes 
Listing 16.2.7.1 
Adverse Events 
Listing 16.2.7.2 
Death Report 
Listing 16.2.8.1.1 
Laboratory Results, Hematology – Hematocrit 
Listing 16.2.8.1.2 
Laboratory Results, Hematology – Hemoglobin 
Listing 16.2.8.1.3 
Laboratory Results, Hematology – Platelet Count 
Listing 16.2.8.1.4 
Laboratory Results, Hematology – Red Blood Cells 
Listing 16.2.8.1.5 
Laboratory Results, Hematology – White Blood Cells 
Listing 16.2.8.1.6 
Laboratory Results, Hematology – Differential White Blood Cell Count 
Listing 16.2.8.1.7 
Laboratory Results, Hematology – Neutrophils 
Listing 16.2.8.1.8 
Laboratory Results, Hematology – Lymphocytes 
Listing 16.2.8.1.9 
Laboratory Results, Hematology – Monocytes 
Listing 16.2.8.1.10 
Laboratory Results, Hematology – Eosinophils 
Listing 16.2.8.1.11 
Laboratory Results, Hematology – Basophils 
Listing 16.2.8.2.1 
Laboratory Results, Chemistry and Coagulation – Sodium 
Listing 16.2.8.2.2 
Laboratory Results, Chemistry and Coagulation – Potassium 
Listing 16.2.8.2.3 
Laboratory Results, Chemistry and Coagulation – Blood Urea Nitrogen 
Listing 16.2.8.2.4 
Laboratory Results, Chemistry and Coagulation – Serum Creatinine 
Listing 16.2.8.2.5 
Laboratory Results, Chemistry and Coagulation – Total Bilirubin 
Listing 16.2.8.2.6 
Laboratory Results, Chemistry and Coagulation – Alanine 
Aminotransferase 
Listing 16.2.8.2.7 
Laboratory Results, Chemistry and Coagulation – Aspartate 
Aminotransferase 
Listing 16.2.8.2.8 
Laboratory Results, Chemistry and Coagulation – Albumin 
Listing 16.2.8.2.9 
Laboratory Results, Chemistry and Coagulation – Pre-albumin 
Listing 16.2.8.2.10 
Laboratory Results, Chemistry and Coagulation – Activated Partial 
Thromboplastin Time 
Listing 16.2.8.2.11 
Laboratory Results, Chemistry and Coagulation – International Normalized 
Ratio 
Listing 16.2.8.3 
Post-transplant Assessments – Safety Endpoints 
Listing 16.2.8.4 
Post-transplant Assessments – Renal Function and Total Bilirubin 
Listing 16.2.9 
Vital Signs 
Listing 16.2.10 
Post-transplant Follow-up Visits – Safety Endpoints 
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Listing 16.2.11 
Diabetic Ketoacidosis Episodes 
Listing 16.2.12 
Post-transplant Sampling Storage for Centralized Assay 
Listing 16.2.13 
Inflammatory Chemokines/Cytokines 
Listing 16.2.14 
Inflammatory Chemokines/Cytokines, Response Measures 
Listing 16.2.15 
miR-375 
Listing 16.2.16 
Pharmacokinetic Sampling – Blood 
 
 
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Addendum to Statistical Analysis Plan  
Version date: 13 June 2018 
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Addendum to Statistical Analysis Plan 
 
REP0112 
 
 
A phase 2/3, multicenter, randomized, double-blind, placebo-controlled, parallel 
assignment study to assess the efficacy and safety of reparixin in pancreatic islet auto-
transplantation. 
 
 
 
 
                               DATE OF DOCUMENT:  13 June 2018 
 
 
Prepared for: 
 
 Dompé farmaceutici S.p.A 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
 
Version Number 
Author 
Final 1.0 
Lisa R. Reeves, Jed Henke 
Syneos Health 
 
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Addendum to Statistical Analysis Plan  
Version date: 13 June 2018 
CONFIDENTIAL 
Page 3 of 11  
  
 
TABLE OF CONTENTS 
 
1 
Introduction 
5 
2 
Definitions and Derived Variables 
5 
3 
Statistical Methods 
5 
3.1 
Methods for Multiplicity Correction in Analyses 
5 
3.2 
Efficacy Analyses 
5 
3.2.1 
Primary Variable 
5 
3.2.2 
Secondary Variables 
6 
3.3 
Exploratory Analysis 
7 
3.3.1 
Inflammatory Chemokines/Cytokines 
7 
3.3.2 
MicroRNA-375 
7 
4 
Tables, Figures, and Listings for Clinical Study Report 
8 
 
 
 
 
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Addendum to Statistical Analysis Plan  
Version date: 13 June 2018 
CONFIDENTIAL 
Page 4 of 11  
  
 
GLOSSARY OF ABBREVIATIONS 
 
ADIR 
Average Daily Insulin Requirements 
AUC 
Area Under the Curve 
HbA1c 
Glycated hemoglobin 
Kg 
Kilogram 
IAT 
Islet Auto-Transplantation 
IEQ 
Islet Equivalent 
ITT 
Intent to Treat 
MMTT 
Mixed Meal Tolerance Test 
PP 
Per Protocol 
SAP 
Statistical Analysis Plan 
 
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Addendum to Statistical Analysis Plan  
Version date: 13 June 2018 
CONFIDENTIAL 
Page 5 of 11  
  
 
1 
INTRODUCTION 
This addendum to the statistical analysis plan (SAP) for Dompé farmaceutici S.p.A (Dompé) 
Protocol REP0112 describes the statistical methods to be used for analysis and reporting which 
are to be performed in addition to those described in the SAP.   
The addendum to the SAP will be finalized and approved by the sponsor in addition to the 
statistician of the contract research organization appointed by Dompé prior to database lock. 
2 
DEFINITIONS AND DERIVED VARIABLES 
 
 
Area Under the Curve (AUC), C-peptide:  When C-peptide values are below the limit of detection 
(0.05 ng/mL), a value equal to the limit of detection will be assumed in the calculation of area 
under the curve.  Missing C-peptide values will be imputed via linear interpolation, and the 
average of the two basal samples (values, and mid-point of sample times) will be used as the first 
sample in the computation of the AUC.  Once these rules have been applied to the data, AUC for 
C-peptide will be computed using the trapezoidal rule.  For ease of interpretation, the AUC value 
obtained will be divided by the total time the scale is assessed for reporting purposes.  
Computation of AUC will be based on actual collection times, unless actual collection time is 
missing, in which case the scheduled collection time will be used. 
 
AUC0-72H, miR-375:  Missing miR-375 values will be imputed via linear interpolation.  Once these 
rules have been applied to the data, AUC0-72H for miR-375 will be computed using the trapezoidal 
rule.  Computation of AUC0-72H will be based on actual collection times, unless actual collection 
time is missing, in which case the scheduled collection time will be used. 
 
Other definitions and derived variables are found within the applicable subsections of Section 3, 
Statistical Methods. 
3 
STATISTICAL METHODS 
3.1 
Methods for Multiplicity Correction in Analyses  
All efficacy endpoints planned in this addendum are exploratory in nature and will be tested 
without a multiplicity correction being applied.  In addition, all efficacy endpoints planned in the 
SAP will also be interpreted without the planned conditional sequential multiplicity correction 
being applied. 
3.2 
Efficacy Analyses 
Summarization and analysis of efficacy parameters will be conducted for the ITT population 
(primary analysis) and PP population (secondary confirmatory analysis) by treatment group. 
3.2.1 Primary Variable 
The primary variable is the proportion of insulin-independent patients at Day 365 ± 14 days after 
IAT.  In addition to the insulin-independence defined in the protocol, patients will be defined as 
being insulin-independent if the following criteria are satisfied: 
• 
freedom from the need to take exogenous insulin for 14 or more consecutive days;  
• 
a glycated hemoglobin (HbA1c) level ≤ 6.5%; 
 •
a laboratory fasting glucose in the non-diabetic range (<126 mg/dL); 
• 
a 90 minute blood glucose not exceeding 180 mg/dL from the MMTT. This measure is 
proposed as an alternative to finger-stick 2-hour post-prandial glucose on patient diary. 
The same analyses defined in Section 7.5.1 of the SAP version 2.0 will be performed using the 
above insulin-independent definition. 
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Addendum to Statistical Analysis Plan  
Version date: 13 June 2018 
CONFIDENTIAL 
Page 6 of 11  
  
 
In addition to the protocol and alternative insulin-independent definitions, the same analyses 
defined in Section 7.5.1 of the SAP version 2.0 will be run considering that Patient 0106 with 
sporadic and very low doses of insulin might be associated to “off insulin” criterion (freedom from 
the need to take exogenous insulin).  
3.2.2 Secondary Variables 
 
3.2.2.1 
Area Under the Curve for C-peptide During First 4 Hours of a Mixed Meal Tolerance 
Test 
C-peptide is to be collected at 9 time points (2 basal measurements and at 15, 30, 60, 90, 120, 
180, and 240 minutes) during the first 4 hours of a mixed meal tolerance test on both Days 75 
and 365 after IAT.  For both Days 75 and 365, the AUC will be computed as described in Section 
2.  AUC values at each day will be summarized descriptively by treatment group, and analyzed as 
described in section 7.5.2.1 of the SAP version 2.0. 
Change (absolute and percentage) in AUC values from Day 75 to Day 365 (∆75-365) will be 
summarized descriptively by treatment group, and analyzed using a t-test to compare treatment 
groups (two-sided tests at the 5% level of significance) and using a general linear model which 
includes change in AUC as the response; treatment group and study site as fixed main effects; 
and the treatment by study site interaction if significant at the 0.10 α-level.  Least squares means, 
standard errors, and associated 95% confidence intervals will be presented for each treatment 
group, along with the least square mean difference (reparixin minus placebo), standard error, 
associated 95% confidence interval, and p-value (two sided at the 5% level of significance).  Data 
transformations will be considered,  if appropriate. 
Data will be plotted as a regression curve for AUC0-240 versus IEQ/kg on days 75 and 365 after 
IAT by treatment group. The slope and intercept of the regression line and R2 will be calculated 
and displayed on the figure. The p-value testing the slope for difference from zero will also be 
displayed. In addition, regression curve AUC0-240 versus IEQ/kg will be plotted and analyzed only 
for patients receiving IEQ/kg ≤5000. 
3.2.2.2 
Average Daily Insulin Requirements 
The average daily insulin requirement (ADIR) will be computed by site personnel using data from 
either the patient diary card or other appropriate source documents/information and reported on 
Pages 24 and 24.1 for Days 75 and 365, respectively.     
In addition to the analyses described in Section 7.5.2.2 of SAP version 2.0, ADIR at Day 75 and 
Day 365 will be analyzed as repeated measures with a single repeated measurements model, as 
specified in the SAP, but also including IEQ/kg infused at IAT (<2500 IEQ/kg, 2500-5000 IEQ/kg, 
and >5000 IEQ/kg) as a fixed effect term. The importance of the treatment-by- IEQ/kg infused at 
IAT interaction will be investigated and if the term is not significant at the 0.10 α-level, it will be 
excluded from the model.  If the addition of the IEQ/kg infused at IAT factors into the model cause 
the data to be too sparse for the model to converge, the repeated measures analysis will not be 
performed.  
Summary statistics for ADIR at Day 75 and Day 365 will be provided for each IEQ/kg infused at 
IAT category (<2500 IEQ/kg, 2500-5000 IEQ/kg, and >5000 IEQ/kg) and treatment group.  ADIR 
at Day 75 and Day 365 will be compared across treatment groups within each IEQ/kg infused at 
IAT category using a t-test. 
3.2.2.3 
Proportion of Patients With HbA1c <6.5% at Day 365 
The percentage of patients with HbA1c <6.5% at Day 365 ± 14 days after IAT, as specified in 
Section 7.5.2.5 of SAP version 2.0, will also be compared between treatment groups using the 
Cochran-Mantel-Haenszel test stratified by baseline IEQ/kg (<2500 IEQ/kg, 2500-5000 IEQ/kg, 
and >5000 IEQ/kg). The hypothesis to be tested is: 
Null Hypothesis, H0:  preparixin ≤ pplacebo for all baseline IEQ/kg strata 
Alternative Hypothesis, HA:  preparixin > pplacebo for at least one baseline IEQ/kg strata 
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CONFIDENTIAL 
Page 7 of 11  
  
 
The significance level used for statistical testing will be 2.5% and a one-sided test will be used.  
The 95% confidence interval for treatment proportions and the one-sided 95% confidence interval 
for the difference in treatment proportion between reparixin and placebo will be produced. 
3.2.2.4 
Proportion of Patients With HbA1c <7% at Day 365 and Free of Severe Hypoglycemic 
Events From Day 75 Through Day 365 
The same analyses described in Section 7.5.2.7 of SAP version 2.0 will be used to analyze the 
proportion of patients with HbA1c <7% at Day 365 and free of severe hypoglycemic events from 
Day 75 through Day 365. 
3.3 
Exploratory Analysis 
The safety population will be used for the summarization and analysis of all exploratory data.   
3.3.1 Inflammatory Chemokines/Cytokines 
Inflammatory chemokines/cytokines to be summarized include serum levels of CXCL8, CCL2 
(MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10, INF-γ, TNF-α, and IL-1β.  
Values are collected as 2 basal samples at pre-infusion hospital admission (6 to 24 hours apart) 
and at 6, 12, 24, 72, 120, and 168 hours after IAT. Mean values for each inflammatory 
chemokine/cytokine will be plotted for each sample time point by treatment group. 
AUC0-72H will be computed as defined in Section 7.7.1 of SAP version 2.0. AUC0-72H for CCL2, IL-6 
and IL-10 will be plotted versus IEQ as a regression curve for each treatment group.  The slope 
and intercept of the regression line and R2 will be calculated and displayed on the figure. The p-
value testing the slope for difference from zero will also be displayed. 
3.3.2 MicroRNA-375 
MicroRNA-375 (miR-375) is collected pre-transplant and at 6, 12, 24, 72, 120, and 168 hours 
post-transplant. Mean miR-375 values will be plotted for each sample time point by treatment 
group.  AUC0-72H for miR-375 will be calculated as specified in section 2 and plotted versus IEQ 
as a regression curve for each treatment group.  The slope and intercept of the regression line 
and R2 will be calculated and displayed on the figure. The p-value testing the slope for difference 
from zero will also be displayed. 
 
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Addendum to Statistical Analysis Plan  
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4 
TABLES, FIGURES, AND LISTINGS FOR CLINICAL STUDY REPORT 
 
Section 14.2, Efficacy Tables 
 
Table 14.2.1.1.1 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation, With 
Patient 0106 Included  as Insulin Independent  
Intent to Treat Population 
Table 14.2.1.1.1.A 
 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation, With 
Patient 0106 Included as Insulin Independent  
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.1.1.1.B 
 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation, With 
Patient 0106 Included as Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.1.2.1 
Proportion of Insulin-independent Patients at Day 
365 Following Islet Auto-Transplantation, With 
Patient 0106 Included as Insulin Independent 
Per Protocol Population 
Table 14.2.2.1.1 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis, With Patient 
0106 Included as Insulin Independent 
Intent to Treat Population 
Table 14.2.2.1.1.A 
 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis, With Patient 
0106 Included as Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.2.1.1.B 
 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis, With Patient 
0106 Included as Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.2.2.1 
Analysis of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, Sensitivity Analysis, With Patient 
0106 Included as Insulin Independent 
Per Protocol Population 
 
 
 
Table 14.2.1.1.2 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation  
Intent to Treat Population 
Table 14.2.1.1.2.A 
 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation  
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.1.1.2.B 
 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation  
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.1.2.2 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation  
Per Protocol Population 
Table 14.2.2.1.2 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis  
Intent to Treat Population 
Table 14.2.2.1.2.A 
 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis  
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.2.1.2.B 
 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis  
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
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Page 9 of 11  
  
 
Table 14.2.2.2.2 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis  
Per Protocol Population 
 
 
 
Table 14.2.1.1.3 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation, With Patient 0106 Included as 
Insulin Independent 
Intent to Treat Population 
Table 14.2.1.1.3.A 
 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation, With Patient 0106 Included as 
Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.1.1.3.B 
 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation, With Patient 0106 Included as 
Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.1.2.3 
Proportion of Insulin-independent (Alternate 
Definition) Patients at Day 365 Following Islet Auto-
Transplantation, With Patient 0106 Included as 
Insulin Independent 
Per Protocol Population 
Table 14.2.2.1.3 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis, With 
Patient 0106 Included as Insulin Independent 
Intent to Treat Population 
Table 14.2.2.1.3.A 
 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis, With 
Patient 0106 Included as Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis 
Table 14.2.2.1.3.B 
 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis, With 
Patient 0106 Included as Insulin Independent 
Intent to Treat Population 
Sensitivity Analysis, Site 
01 Only 
Table 14.2.2.2.3 
Analysis of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, Sensitivity Analysis, With 
Patient 0106 Included as Insulin Independent 
Per Protocol Population 
 
 
 
Table 14.2.3.1.1 
Area Under the Curve for C-peptide (Alternate 
Computation) During First 4 Hours of a Mixed Meal 
Tolerance Test 
Intent to Treat Population 
Table 14.2.3.2.1 
Area Under the Curve for C-peptide (Alternate 
Computation) During First 4 Hours of a Mixed Meal 
Tolerance Test 
Per Protocol Population 
Table 14.2.3.3.1 
Change in Area Under the Curve for C-peptide 
(Alternate Computation) During First 4 Hours of a 
Mixed Meal Tolerance Test 
Intent to Treat Population 
Table 14.2.3.3.2 
Change in Area Under the Curve for C-peptide 
(Alternate Computation) During First 4 Hours of a 
Mixed Meal Tolerance Test 
Per Protocol Population 
 
 
 
Table 14.2.4.1.1 
Average Daily Insulin Requirements, Stratified by 
IEQ/kg 
Intent to Treat Population 
Table 14.2.4.2.1 
Average Daily Insulin Requirements, Stratified by 
IEQ/kg 
Per Protocol Population 
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Table 14.2.14.1.1 
Proportion of Patients With HbA1c ≤6.5% at Day 
365, Stratified by IEQ/kg 
Intent to Treat Population 
Table 14.2.14.2.1 
Proportion of Patients With HbA1c ≤6.5% at Day 
365, Stratified by IEQ/kg 
Per Protocol Population 
 
 
 
Table 14.2.16.1.1 
Proportion of Patients With HbA1c ≤7.0% at Day 365 
and Free of Severe Hypoglycemic Events From Day 
75 to 365  
Intent to Treat Population 
Table 14.2.16.2.1 
Proportion of Patients With HbA1c ≤7.0% at Day 365 
and Free of Severe Hypoglycemic Events From Day 
75 to 365  
Per Protocol Population 
 
 
 
 
Section 14.4, Figures 
 
Figure 14.4.1.1.1 
Bar Chart of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, With Patient 0106 Included as 
Insulin Independent 
Intent to Treat Population 
Figure 14.4.1.2.1 
Bar Chart of Proportion of Insulin-independent 
Patients at Day 365 Following Islet Auto-
Transplantation, With Patient 0106 Included as 
Insulin Independent 
Per Protocol Population 
 
 
 
Figure 14.4.1.1.2 
Bar Chart of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation  
Intent to Treat Population 
Figure 14.4.1.2.2 
Bar Chart of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation  
Per Protocol Population 
 
 
 
Figure 14.4.1.1.3 
Bar Chart of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, With Patient 0106 
Included as Insulin Independent 
Intent to Treat Population 
Figure 14.4.1.2.3 
Bar Chart of Proportion of Insulin-independent 
(Alternate Definition) Patients at Day 365 Following 
Islet Auto-Transplantation, With Patient 0106 
Included as Insulin Independent 
Per Protocol Population 
 
 
 
Figure 14.4.4.3 
Area Under the Curve for C-peptide at Day 75 During 
First 4 Hours of a Mixed Meal Tolerance Test and 
Not Corrected for IEQ/kg Versus IEQ/kg 
Intent to Treat Population 
Figure 14.4.4.4 
Area Under the Curve for C-peptide at Day 75 During 
First 4 Hours of a Mixed Meal Tolerance Test and 
Not Corrected for IEQ/kg Versus IEQ/kg 
Per Protocol Population 
Figure 14.4.4.5 
Area Under the Curve for C-peptide at Day 75 During 
First 4 Hours of a Mixed Meal Tolerance Test and 
Not Corrected for IEQ/kg Versus IEQ/kg – Only 
Patients Receiving IEQ/kg ≤5000 
Intent to Treat Population 
Figure 14.4.4.6 
Area Under the Curve for C-peptide at Day 75 During Per Protocol Population 
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First 4 Hours of a Mixed Meal Tolerance Test and 
Not Corrected for IEQ/kg Versus IEQ/kg – Only 
Patients Receiving IEQ/kg ≤5000 
Figure 14.4.5.3 
Area Under the Curve for C-peptide at Day 365 
During First 4 Hours of a Mixed Meal Tolerance Test 
and Not Corrected for IEQ/kg Versus IEQ/kg 
Intent to Treat Population 
Figure 14.4.5.4 
Area Under the Curve for C-peptide at Day 365 
During First 4 Hours of a Mixed Meal Tolerance Test 
and Not Corrected for IEQ/kg Versus IEQ/kg 
Per Protocol Population 
Figure 14.4.5.5 
Area Under the Curve for C-peptide at Day 365 
During First 4 Hours of a Mixed Meal Tolerance Test 
and Not Corrected for IEQ/kg Versus IEQ/kg – Only 
Patients Receiving IEQ/kg ≤5000 
Intent to Treat Population 
Figure 14.4.5.6 
Area Under the Curve for C-peptide at Day 365 
During First 4 Hours of a Mixed Meal Tolerance Test 
and Not Corrected for IEQ/kg Versus IEQ/kg – Only 
Patients Receiving IEQ/kg ≤5000 
Per Protocol Population 
 
 
 
Figure 14.4.11.1 
Inflammatory Chemokines / Cytokines, Plots of Mean 
Values Over Time 
Safety Population 
Figure 14.4.12.1 
Area Under the Curve for CCL2, IL-6 and IL-10 
During 72 Hours Following Transplant Versus IEQ, 
[Parameter Name] 
Safety Population 
 
 
 
Figure 14.4.15.1 
mIR-375, Plots of Mean Values over Time 
Safety Population 
Figure 14.4.15.2 
Area Under the Curve for miR-375 During 72 Hours 
Following Transplant Versus IEQ 
Safety Population 
 
 
Section 16.2, Listings 
 
Listing 16.2.6.1.1 
Insulin Independence, Alternative Definition 
 
 
Listing 16.2.6.3.3 
Mixed Meal Tolerance Test, C-peptide Area Under the Curve (AUC), Alternative 
Computation 
 
 
Listing 16.2.15.1 
miR-375, Area Under the Curve (AUC) 
 
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Table 14.2.1.X Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation (IAT) – [Analysis Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
Reparixin Minus Placebo 
 
n 
% 
95% CI 
n 
% 
95% CI 
p-value 
Estimate 
95% CI 
 
 
 
 
 
 
 
 
 
 
Insulin-independent at Day 365 
Following Islet  
Auto-Transplantation [n (%)] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Overall 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
0.XXX 
XXX.X 
(XXX.X, --) 
 
 
 
 
 
 
 
 
 
 
     <2500 IEQ/kg Infused at IAT 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     2500-5000 IEQ/kg Infused at IAT 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     >5000 IEQ/kg Infused at IAT 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference:  16.2.4.9, 16.2.6.1 
Notes:  p-value comparing proportion of insulin-independent patients at Day 365 following IAT between treatment groups using a Cochran-Mantel-Haenszel test 
controlling for IEQ/kg at baseline. 
 
The following tables will be created from the above shell: 
 
Table 14.2.1.1.1 Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included as Insulin 
Independent – Intent to Treat Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
Table 14.2.1.1.2 Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation – Intent to Treat Population 
 
Table 14.2.1.1.3 Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included 
as Insulin Independent – Intent to Treat Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
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Table 14.2.1.1.1.A 
Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included as Insulin 
Independent – Intent to Treat Population Sensitivity Analysis 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis excludes any site with >20% of subjects not having data for the primary endpoint recorded; subjects were 
considered to not have data recorded for the primary endpoint if they discontinued the study prior to attending the Day 365 visit or if they attended the 
Day 365 visit but did not have the primary endpoint recorded.  Specific sites excluded were Sites XX, YY, and ZZ.” 
 
Table 14.2.1.1.2.A 
Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation – Intent to Treat 
Population Sensitivity Analysis 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ This sensitivity analysis excludes any site with >20% of subjects not having data for 
the primary endpoint recorded; subjects were considered to not have data recorded for the primary endpoint if they discontinued the study prior to 
attending the Day 365 visit or if they attended the Day 365 visit but did not have the primary endpoint recorded.  Specific sites excluded were Sites XX, 
YY, and ZZ.” 
 
Table 14.2.1.1.3.A 
Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 
Included as Insulin Independent – Intent to Treat Population Sensitivity Analysis 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis excludes any site with >20% of subjects not having data for the primary endpoint recorded; subjects were 
considered to not have data recorded for the primary endpoint if they discontinued the study prior to attending the Day 365 visit or if they attended the 
Day 365 visit but did not have the primary endpoint recorded.  Specific sites excluded were Sites XX, YY, and ZZ.” 
 
Table 14.2.1.1.1.B 
Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included as Insulin 
Independent – Intent to Treat Population Sensitivity Analysis, Site 01 Only 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis includes only Site 01.” 
 
Table 14.2.1.1.2.B 
Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation – Intent to Treat 
Population Sensitivity Analysis, Site 01 Only 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ This sensitivity analysis includes only Site 01.” 
 
Table 14.2.1.1.3.B 
Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 
Included as Insulin Independent – Intent to Treat Population Sensitivity Analysis, Site 01 Only 
 
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• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis includes only Site 01.” 
 
 
Table 14.2.1.2.1 Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included as Insulin 
Independent – Per Protocol Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
Table 14.2.1.2.2 Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation – Per Protocol Population 
 
Table 14.2.1.2.3 Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included 
as Insulin Independent – Per Protocol Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
 
 
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Table 14.2.2.X Analysis of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity Analysis – [Analysis 
Population] 
 
 
Model Variable 
Estimate 
of Beta 
Standard Error 
of Beta 
 
p-value 
 
Odds Ratio 
95% Confidence Interval 
for Odds Ratio 
 
 
 
 
 
 
Reparixin 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
2,500 to 5,000 IEQ/kg Infused at IAT 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
>5,000 IEQ/kg Infused at IAT 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
Study Site 2 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
Study Site 3 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
Study Site 4 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
Study Site 5 
X.XXX 
X.XXX 
0.XXX 
X.XXX 
(X.XXX, --) 
 
 
 
 
 
 
Reference:  16.2.4.9, 16.2.6.1 
Notes:  Treatment groups compared using a logistic regression model with the main effect of treatment and IEQ/kg 
infused at IAT and study site as covariates.  Odds of achieving insulin-independence at Day 365 following islet auto-
transplantation are presented for reparixin relative to placebo; for patients with 2,500 to 5,000 IEQ/kg infused at IAT 
relative to patients with <2,500 IEQ/kg infused at IAT; for patients with >5,000 IEQ/kg infused at IAT relative to 
patients with <2,500 IEQ/kg infused at IAT; and for each study site versus Study Site 1. 
 
The following tables will be created from the above shell: 
 
Table 14.2.2.1.1 Analysis of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity Analysis, With Patient 
0106 Included as Insulin Independent – Intent to Treat Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
Table 14.2.2.1.2 Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity 
Analysis – Intent to Treat Population 
 
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Table 14.2.2.1.3 Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity 
Analysis, With Patient 0106 Included as Insulin Independent – Intent to Treat Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
Table 14.2.2.1.1.A 
Analysis of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity Analysis, With 
Patient 0106 Included as Insulin Independent – Intent to Treat Population Sensitivity Analysis 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis excludes any site with >20% of subjects not having data for the primary endpoint recorded; subjects were 
considered to not have data recorded for the primary endpoint if they discontinued the study prior to attending the Day 365 visit or if they attended the 
Day 365 visit but did not have the primary endpoint recorded.  Specific sites excluded were Sites XX, YY, and ZZ.” 
 
Table 14.2.2.1.2.A 
Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, 
Sensitivity Analysis – Intent to Treat Population Sensitivity Analysis 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ This sensitivity analysis excludes any site with >20% of subjects not having data for 
the primary endpoint recorded; subjects were considered to not have data recorded for the primary endpoint if they discontinued the study prior to 
attending the Day 365 visit or if they attended the Day 365 visit but did not have the primary endpoint recorded.  Specific sites excluded were Sites XX, 
YY, and ZZ.” 
 
Table 14.2.2.1.3.A 
Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, 
Sensitivity Analysis, With Patient 0106 Included as Insulin Independent – Intent to Treat Population Sensitivity Analysis 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis excludes any site with >20% of subjects not having data for the primary endpoint recorded; subjects were 
considered to not have data recorded for the primary endpoint if they discontinued the study prior to attending the Day 365 visit or if they attended the 
Day 365 visit but did not have the primary endpoint recorded.  Specific sites excluded were Sites XX, YY, and ZZ.” 
 
Table 14.2.2.1.1.B 
Analysis of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity Analysis, With 
Patient 0106 Included as Insulin Independent – Intent to Treat Population Sensitivity Analysis, Site 01 Only 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis includes only Site 01.” 
 
• 
The model notes in the table should read as follows:  Treatment groups compared using a logistic regression model with the main effect of treatment and 
IEQ/kg infused at IAT as a covariate.  Odds of achieving insulin-independence at Day 365 following islet auto-transplantation are presented for 
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reparixin relative to placebo; for patients with 2,500 to 5,000 IEQ/kg infused at IAT relative to patients with <2,500 IEQ/kg infused at IAT; and for 
patients with >5,000 IEQ/kg infused at IAT relative to patients with <2,500 IEQ/kg infused at IAT. 
 
• 
The “ Study Site X” rows will not appear in the table. 
 
Table 14.2.2.1.2.B 
Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, 
Sensitivity Analysis – Intent to Treat Population Sensitivity Analysis, Site 01 Only 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ This sensitivity analysis includes only Site 01.” 
 
• 
The model notes in the table should read as follows:  Treatment groups compared using a logistic regression model with the main effect of treatment and 
IEQ/kg infused at IAT as a covariate.  Odds of achieving insulin-independence at Day 365 following islet auto-transplantation are presented for 
reparixin relative to placebo; for patients with 2,500 to 5,000 IEQ/kg infused at IAT relative to patients with <2,500 IEQ/kg infused at IAT; and for 
patients with >5,000 IEQ/kg infused at IAT relative to patients with <2,500 IEQ/kg infused at IAT. 
 
• 
The “ Study Site X” rows will not appear in the table. 
 
Table 14.2.2.1.3.B 
Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, 
Sensitivity Analysis, With Patient 0106 Included as Insulin Independent – Intent to Treat Population Sensitivity Analysis, Site 01 Only 
 
• 
The “ Notes” on this table will begin with the following sentences:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically. This sensitivity analysis includes only Site 01.” 
 
• 
The model notes in the table should read as follows:  Treatment groups compared using a logistic regression model with the main effect of treatment and 
IEQ/kg infused at IAT as a covariate.  Odds of achieving insulin-independence at Day 365 following islet auto-transplantation are presented for 
reparixin relative to placebo; for patients with 2,500 to 5,000 IEQ/kg infused at IAT relative to patients with <2,500 IEQ/kg infused at IAT; and for 
patients with >5,000 IEQ/kg infused at IAT relative to patients with <2,500 IEQ/kg infused at IAT. 
 
• 
The “ Study Site X” rows will not appear in the table. 
 
 
Table 14.2.2.2.1 Analysis of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity Analysis, With Patient 
0106 Included as Insulin Independent – Per Protocol Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
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Table 14.2.2.2.2 Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity 
Analysis – Per Protocol Population 
 
Table 14.2.2.2.3 Analysis of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, Sensitivity 
Analysis, With Patient 0106 Included as Insulin Independent – Per Protocol Population 
 
• 
The “ Notes” on this table will begin with the following sentence:  “ Patient 0106 is considered off-insulin because of low doses of insulin administered 
sporadically.” 
 
 
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Table 14.2.3.X Area Under the Curve for C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – [Analysis Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
 
AUC at Day 75 [unit to be determined] 
 
 
     N 
XX 
XX 
     Mean 
XXX.XX 
XXX.XX 
     SD 
XXX.XXX 
XXX.XXX 
     Median 
XXX.XX 
XXX.XX 
     Min 
XXX.X 
XXX.X 
     Max 
XXX.X 
XXX.X 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
XXX.XX (XX.XX) 
XXX.XX (XX.XX) 
     95% CI for LS Mean 
(XXX.XX, XXX.XX) 
(XXX.XX, XXX.XX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
XXX.XX (XX.XX) 
 
     95% CI for LS Mean Difference 
(XXX.XX, XXX.XX) 
 
     p-value 
0.XXX 
 
 
 
 
Reference:  16.2.6.3.2 
Note:  AUC = Area Under the Curve, LS = Least Squares, SE = Standard Error, CI = Confidence Interval.  Least squares means, standard errors, 
and confidence intervals come from a mixed repeated measures model which includes AUC as the response; treatment group, time, and study site 
as fixed main effects; the treatment by time interaction; the treatment by study site interaction if significant at the 0.10 α-level; patient as a random 
effect; and uses a [to be specified] covariance structure. 
 
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Table 14.2.3.X Area Under the Curve for Serum C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – [Analysis 
Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
 
AUC at Day 365 [unit to be determined] 
 
 
     N 
XX 
XX 
     Mean 
XXX.XX 
XXX.XX 
     SD 
XXX.XXX 
XXX.XXX 
     Median 
XXX.XX 
XXX.XX 
     Min 
XXX.X 
XXX.X 
     Max 
XXX.X 
XXX.X 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
XXX.XX (XX.XX) 
XXX.XX (XX.XX) 
     95% CI for LS Mean 
(XXX.XX, XXX.XX) 
(XXX.XX, XXX.XX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
XXX.XX (XX.XX) 
 
     95% CI for LS Mean Difference 
(XXX.XX, XXX.XX) 
 
     p-value 
0.XXX 
 
 
 
 
Final Model p-values 
 
 
     Treatment 
0.XXX 
 
     Time 
0.XXX 
 
     Study Site 
0.XXX 
 
     Treatment by Time Interaction 
0.XXX 
 
     Treatment by Study Site Interaction 
0.XXX 
 
     [only included in final model and displayed if significant at the 0.10 α-level] 
 
 
 
 
 
Reference:  16.2.6.3.2 
Note:  AUC = Area Under the Curve, LS = Least Squares, SE = Standard Error, CI = Confidence Interval.  Least squares means, standard errors, 
and confidence intervals come from a mixed repeated measures model which includes AUC as the response; treatment group, time, and study site 
as fixed main effects; the treatment by time interaction; the treatment by study site interaction if significant at the 0.10 α-level; patient as a random 
effect; and uses a [to be specified] covariance structure. 
 
The following tables will be created from the above shell: 
 
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Table 14.2.3.1.1 Area Under the Curve for C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – Intent to Treat 
Population 
Table 14.2.3.2.1 Area Under the Curve for C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – Per Protocol Population 
 
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Table 14.2.3.3.X    Change in Area Under the Curve for C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – [Analysis 
Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
 
Change in AUC (Day 365 – Day 75) [unit to be determined] 
 
 
     N 
XX 
XX 
     Mean 
XXX.XX 
XXX.XX 
     SD 
XXX.XXX 
XXX.XXX 
     Median 
XXX.XX 
XXX.XX 
     Min 
XXX.X 
XXX.X 
     Max 
XXX.X 
XXX.X 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
XXX.XX (XX.XX) 
XXX.XX (XX.XX) 
     95% CI for LS Mean 
(XXX.XX, XXX.XX) 
(XXX.XX, XXX.XX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
XXX.XX (XX.XX) 
 
     95% CI for LS Mean Difference 
(XXX.XX, XXX.XX) 
 
     p-value 
0.XXX 
 
 
 
 
Final Model p-values 
 
 
     Treatment 
0.XXX 
 
     Study Site 
0.XXX 
 
     Treatment by Study Site Interaction 
0.XXX 
 
     [only included in final model and displayed if significant at the 0.10 α-level] 
 
 
 
 
 
Page will be repeated for Percent Change in AUC (Day 365 – Day 75) 
 
 
 
 
 
Reference:  16.2.6.3.2 
Note:  AUC = Area Under the Curve, LS = Least Squares, SE = Standard Error, CI = Confidence Interval.  Least squares means, standard errors, 
and confidence intervals come from a general linear model which includes change in AUC as the response; treatment group and study site as fixed 
main effects; and the treatment by study site interaction if significant at the 0.10 α-level. 
 
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Table 14.2.3.3.1 Change in Area Under the Curve for C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – Intent to Treat 
Population 
 
Table 14.2.3.3.2 Change in Area Under the Curve for C-peptide (Alternate Computation) During First 4 Hours of a Mixed Meal Tolerance Test – Per Protocol 
Population 
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Table 14.2.4.X Average Daily Insulin Requirements, Stratified by IEQ/kg – [Analysis Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
 
Average Daily Insulin Requirement  at Day 75 (IU/kg/day) 
 
 
 
 
 
 <2500 IEQ/kg Infused at IAT 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
 2500-5000 IEQ/kg Infused at IAT 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
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 >5000 IEQ/kg Infused at IAT 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
 Overall 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
Reference:  16.2.6.1, 16.2.6.4 
Note:  LS = Least Squares, SE = Standard Error, CI = Confidence Interval.  Least squares means, standard errors, and confidence intervals 
come from a mixed repeated measures model which includes average daily insulin requirement (IU/kg/day) as the response; treatment group, 
time, IEQ/kg infused at IAT, and study site as fixed main effects; the treatment by time interaction; the treatment by study site interaction and 
treatment by IEQ/kg infused at IAT interaction if significant at the 0.10 α-level; patient as a random effect; and uses a [to be specified] 
covariance structure. 
 
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Table 14.2.4.X Average Daily Insulin Requirements, Stratified by IEQ/kg – [Analysis Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
 
Average Daily Insulin Requirement at Day 365 (IU/kg/day) 
 
 
 
 
 
 <2500 IEQ/kg Infused at IAT 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
 2500-5000 IEQ/kg Infused at IAT 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
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 >5000 IEQ/kg Infused at IAT 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
 Overall 
 
 
     N 
XX 
XX 
     Mean 
X.XXX 
X.XXX 
     SD 
X.XXXX 
X.XXXX 
     Median 
X.XXX 
X.XXX 
     Min 
X.XX 
X.XX 
     Max 
X.XX 
X.XX 
     p-value Comparing Treatments Using t-test 
0.XXX 
 
 
 
 
     LS Mean (SE) 
X.XXX (X.XXXX) 
X.XXX (X.XXXX) 
     95% CI for LS Mean 
(X.XXX, X.XXX) 
(X.XXX, X.XXX) 
 
 
 
     LS Mean Difference, Reparixin – Placebo (SE) 
X.XXX (X.XXXX) 
 
     95% CI for LS Mean Difference 
(X.XXX, X.XXX) 
 
     p-value 
0.XXX 
 
 
 
 
Final Model p-values 
 
 
     Treatment 
0.XXX 
 
     Time 
0.XXX 
 
     Study Site 
0.XXX 
 
     IEQ/kg Infused at IAT 
0.XXX 
 
     Treatment by Time Interaction 
0.XXX 
 
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     Treatment by Study Site Interaction 
     [only included in final model and displayed if significant at the 0.10 α-level] 
0.XXX 
 
     Treatment by IEQ/kg Infused at IAT Interaction 
0.XXX 
 
     [only included in final model and displayed if significant at the 0.10 α-level] 
 
 
 
 
 
Reference:  16.2.6.1, 16.2.6.4 
Note:  LS = Least Squares, SE = Standard Error, CI = Confidence Interval.  Least squares means, standard errors, and confidence intervals 
come from a mixed repeated measures model which includes average daily insulin requirement (IU/kg/day) as the response; treatment group, 
time, IEQ/kg infused at IAT, and study site as fixed main effects; the treatment by time interaction; the treatment by study site interaction and 
treatment by IEQ/kg infused at IAT interaction if significant at the 0.10 α-level; patient as a random effect; and uses a [to be specified] 
covariance structure. 
 
The following tables will be created from the above shell: 
 
Table 14.2.4.1.1 Average Daily Insulin Requirements, Stratified by IEQ/kg – Intent to Treat Population 
Table 14.2.4.2.1 Average Daily Insulin Requirements, Stratified by IEQ/kg – Per Protocol Population 
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Table 14.2.14.X Proportion of Patients With HbA1c ≤6.5% at Day 365, Stratified by IEQ/kg – [Analysis Population] 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
Reparixin Minus Placebo 
 
n 
% 
95% CI 
n 
% 
95% CI 
p-value 
Estimate 
95% CI 
 
 
 
 
 
 
 
 
 
 
HbA1c ≤6.5% at Day 365 [n (%)] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Overall 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
0.XXX 
XXX.X 
(XXX.X, --) 
 
 
 
 
 
 
 
 
 
 
     <2500 IEQ/kg Infused at IAT 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     2500-5000 IEQ/kg Infused at IAT 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     >5000 IEQ/kg Infused at IAT 
XX 
XXX.X 
(XXX.X, XXX.X) 
XX 
XXX.X 
(XXX.X, XXX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference:  16.2.6.2 
Notes:  p-value comparing proportion of patients with HbA1c ≤6.5% at Day 365 between treatment groups using a Cochran-Mantel-Haenszel test controlling for 
IEQ/kg at baseline. 
 
 
The following tables will be created using the above shell: 
 
Table 14.2.14.1.1Proportion of Patients With HbA1c ≤6.5% at Day 365, Stratified by IEQ/kg – Intent to Treat Population 
Table 14.2.14.2.1Proportion of Patients With HbA1c ≤6.5% at Day 365, Stratified by IEQ/kg – Per Protocol Population 
 
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Table 14.2.16.X Proportion of Patients With HbA1c ≤7.0% at Day 365 and Free of Severe Hypoglycemic Events From Day 75 to 365 Inclusive – [Analysis 
Population] 
 
 
 
Reparixin 
(N = XX) 
Placebo 
(N = XX) 
 
 
 
HbA1c ≤7.0% at Day 365 and Free of Severe Hypoglycemic Events From Day 75 to 365 Inclusive [n (%)] 
 
 
     n (%) of Patients 
XX (XXX.X) 
XX (XXX.X) 
     95% Confidence Interval for Proportion 
(XXX.X, XXX.X) 
(XXX.X, XXX.X) 
     Treatment Effect (Reparixin minus Placebo) 
XXX.X 
 
     95% Confidence Interval for Treatment Effect 
(XXX.X, XXX.X) 
 
     p-value 
0.XXX 
 
 
 
 
Reference:  16.2.6.1, 16.2.6.2, 16.2.6.6 
Note:  p-value comparing treatment groups using the Pearson chi-squared test. 
 
The following tables will be created from the above shell: 
 
Table 14.2.16.1.1Proportion of Patients With HbA1c ≤7.0% at Day 365 and Free of Severe Hypoglycemic Events From Day 75 to 365 Inclusive – Intent to Treat 
Population 
Table 14.2.16.2.1Proportion of Patients With HbA1c ≤7.0% at Day 365 and Free of Severe Hypoglycemic Events From Day 75 to 365 Inclusive – Per Protocol 
Population 
 
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Figure 14.4.1.X Bar Chart of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation 
 
Figure Type:  Bar Chart 
 
X-axis:  Overall and IEQ/kg Infused at IAT (<2500 IEQ/kg, 2500-5000 IEQ/kg, >5000 IEQ/kg).  Overall and within each IEQ/kg group there will be a bar chart 
with bars for reparixin and placebo appearing with different color fill and an accompanying legend. 
 
Y-axis:  Percentage of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation 
 
The following figures will be created from the above details: 
 
Figure 14.4.1.1.1 Bar Chart of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included as 
Insulin Independent – Intent to Treat Population 
Reference:  14.2.1.1.1, 16.2.4.9, 16.2.6.1 
 
Figure 14.4.1.1.2 Bar Chart of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation – Intent to 
Treat Population 
Reference:  14.2.1.1.2, 16.2.4.9, 16.2.6.1 
 
Figure 14.4.1.1.3 Bar Chart of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, With Patient 
0106 Included as Insulin Independent – Intent to Treat Population 
Reference:  14.2.1.1.3, 16.2.4.9, 16.2.6.1 
 
Figure 14.4.1.2.1 Bar Chart of Proportion of Insulin-independent Patients at Day 365 Following Islet Auto-Transplantation, With Patient 0106 Included as 
Insulin Independent – Per Protocol Population 
Reference:  14.2.1.2.1, 16.2.4.9, 16.2.6.1 
 
Figure 14.4.1.2.2 Bar Chart of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation – Per Protocol 
Population 
Reference:  14.2.1.2.2, 16.2.4.9, 16.2.6.1 
 
Figure 14.4.1.2.3 Bar Chart of Proportion of Insulin-independent (Alternate Definition) Patients at Day 365 Following Islet Auto-Transplantation, With Patient 
0106 Included as Insulin Independent – Per Protocol Population 
Reference:  14.2.1.2.3, 16.2.4.9, 16.2.6.1 
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Figure 14.4.X.X Area Under the Curve for C-peptide at Day 75 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – [Analysis Population] 
 
X-axis:  IEQ/kg 
 
Y-axis:  Area Under the Curve (unit to be determined) 
 
Data will be plotted as a regression curve for AUC versus IEQ/kg on days 75 and 365 after IAT by treatment group. The slope and intercept of the regression line 
and R2 will be calculated and displayed on the figure. The p-value testing the slope for difference from zero will also be displayed. 
 
The following figures will be created from the above details: 
 
Figure 14.4.4.3 Area Under the Curve for C-peptide at Day 75 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Intent to Treat Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.4.4 Area Under the Curve for C-peptide at Day 75 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Per Protocol Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.4.5 Area Under the Curve for C-peptide at Day 75 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Only Patients Receiving IEQ/kg ≤5000 – Intent to Treat Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.4.6 Area Under the Curve for C-peptide at Day 75 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Only Patients Receiving IEQ/kg ≤5000 – Per Protocol Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.5.3 Area Under the Curve for C-peptide at Day 365 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Intent to Treat Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.5.4 Area Under the Curve for C-peptide at Day 365 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Per Protocol Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.5.5 Area Under the Curve for C-peptide at Day 365 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Only Patients Receiving IEQ/kg ≤5000 – Intent to Treat Population 
Reference:  16.2.6.3.2 
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Dompé farmaceutici S.p.A 
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Figure 14.4.5.6 Area Under the Curve for C-peptide at Day 365 During First 4 Hours of a Mixed Meal Tolerance Test and Not Corrected for IEQ/kg Versus 
IEQ/kg – Only Patients Receiving IEQ/kg ≤5000 – Per Protocol Population 
Reference:  16.2.6.3.2 
 
Figure 14.4.12.1 Area Under the Curve for CCL2, IL-6 and IL-10 During 72 Hours Following Transplant Versus IEQ, [Parameter Name] – Safety Population 
Reference:  16.2.14 
 
Programming note, this figure is versus IEQ, not IEQ/kg. 
 
Figure 14.4.15.2 Area Under the Curve for miR-375 During 72 Hours Following Transplant Versus IEQ – Safety Population 
Reference:  16.2.15 
 
Programming note, this figure is versus IEQ, not IEQ/kg. 
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Dompé farmaceutici S.p.A 
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Figure 14.4.11.1 Inflammatory Chemokines / Cytokines, Plots of Mean Values Over Time – Safety Population 
 
X-axis:  Time Point (Basal, 6 Hours Post, 12 Hours Post, 24 Hours Post, 72 Hours Post, 120 Hours Post, and 168 Hours Post) 
 
Y-axis:  Parameter (unit), mean ± standard error 
 
Reference:  14.3.12, 16.2.13 
 
Notes:  Plots for mean values ± standard error bars will be presented for each treatment group at each time point (where “ Basal” is the single baseline which is 
the average of the two basal values).  Each treatment group will be in a different color with an accompanying legend.  Separate pages will be created for CXCL8 
(pg/mL), CCL2 (MCP-1) (pg/mL), CCL3 (pg/mL), CCL4 (pg/mL), CXCL10 (IP-10) (pg/mL), CXCL9 (MIG) (pg/mL), IL-6 (pg/mL), IL-10 (pg/mL), INF-γ 
(pg/mL), TNF-α (pg/mL), and IL- 1β (pg/mL). 
 
 
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Dompé farmaceutici S.p.A 
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Figure 14.4.15.1 miR-375, Plots of Mean Values Over Time – Safety Population 
 
X-axis:  Time Point (Pre-transplant 1, 6 Hours Post, 12 Hours Post, 24 Hours Post, 72 Hours Post, 120 Hours Post, and 168 Hours Post) 
 
Y-axis:  miR-375 (copies/mL), mean ± standard error 
 
Reference:  14.3.13, 16.2.15 
 
Notes:  Plots for mean values ± standard error will be presented for each treatment group at each time point.  Each treatment group will be in a different color 
with an accompanying legend. 
 
 
 
  
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Listing 16.2.6.1.1 Insulin Independence, Alternative Definition 
 
Treatment: Reparixin or Placebo 
Patient 
Number 
 
Visit 
 
Date (Day) of Visit 
 
Insulin Ind, Alternative Definition 
 
 
 
 
XXXX 
Day 365 
DDMMMYYYY (XXX) 
Yes 
 
 
 
 
 
 
 
 
XXXX 
Day 365 
DDMMMYYYY (XXX) 
Yes 
 
 
 
 
 
 
 
 
XXXX 
Day 365 
DDMMMYYYY (XXX) 
Yes 
 
 
 
 
 
 
 
 
 
. 
 
 
 
. 
 
 
 
. 
 
 
 
 
 
 
Reference:  CRF Page 24 and 24.1 and listings 16.2.6.2, 16.2.6.3.1 and 16.2.6.4. 
Notes:  Ind = Independent. Alternative definition: freedom from the need to take exogenous insulin for 14 or more consecutive days; a glycated hemoglobin 
(HbA1c) level ≤ 6.5%; a laboratory fasting glucose in the non-diabetic range (<126 mg/dL); and a 90 minute blood glucose not exceeding 180 mg/dL from the 
MMTT. This measure is proposed as an alternative to finger-stick 2-hour post-prandial glucose on patient diary. 
 
 
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Listing 16.2.6.3.3Mixed Meal Tolerance Test, C-peptide Area Under the Curve (AUC), Alternative Computation 
 
Treatment: Reparixin or Placebo 
Patient 
Number 
IEQ/kg Infused 
During IAT 
 
Visit 
Mixed Meal 
Administration Date (Day) 
End 
Time 
Time 
Point 
Sample 
Time 
C-peptide 
(ng/mL) 
Area Under the Curve 
(unit) 
 
 
 
 
 
 
 
 
 
XXXX 
XXXXX 
Day XXX 
DDMMMYYYY (XXX) 
HH:MM 
Basal 1 
HH:MM 
X.XX 
XXX.X 
 
 
 
 
 
Basal 2 
HH:MM 
X.XX 
 
 
 
 
 
 
Basal 
HH:MM 
X.XX 
 
 
 
 
 
 
15 min 
HH:MM 
X.XX 
 
 
 
 
 
 
30 min 
HH:MM 
X.XX 
 
 
 
 
 
 
60 min 
HH:MM ** X.XX ** 
 
 
 
 
 
 
90 min 
HH:MM 
X.XX 
 
 
 
 
 
 
120 min HH:MM ** X.XX 
 
 
 
 
 
 
180 min HH:MM 
X.XX 
 
 
 
 
 
 
240 min HH:MM 
X.XX 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference:  CRF Pages 12, 25, and 25.1.  
Notes:  All times are on a 24-hour clock.  IAT = Islet Auto-transplantation.  For C-peptide values below the limit of detection (0.05ng/mL), a 
value of 0.05 ng/mL is assumed in the calculation of AUC.  Missing C-peptide values are imputed via linear interpolation, and the average of the 
two basal samples (values, and mid-point of sample times) is used as the first sample in the computation of the AUC.  AUC is computed using 
the trapezoidal rule.  For ease of interpretation, the AUC value is also divided by the total time the scale is assessed.  Computation of AUC is 
based on actual collection times, unless actual collection time is missing, in which case the scheduled collection time will be used.  ** = Imputed 
value. 
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Listing 16.2.15.1 miR-375, Area Under the Curve (AUC) 
 
Treatment: Reparixin or Placebo 
 
Patient 
Number 
Sample 
Date (Day) 
Time 
 
miR-375 
(serum copies/mL) 
 
Area Under the Curve 
(unit) 
 
 
 
 
XXXX 
Pre-transplant 1 
DDMMMYYYY (XXX) 
HH:MM 
XXXXXX 
XXXXXX 
 
 
 
 
 
Pre-transplant 2 
DDMMMYYYY (XXX) 
HH:MM 
XXXXXX 
 
 
 
 
 
 
6 Hours Post-transplant 
DDMMMYYYY (XXX) 
HH:MM 
XXXXXX ** 
 
 
 
 
 
 
. 
 
 
 
. 
 
 
 
. 
 
 
 
 
 
 
Reference:  CRF Page 402. 
Notes:  All times are on a 24-hour clock.  Missing miR-375 values are imputed via linear interpolation.  Once these 
rules have been applied to the data, AUC0-72H for miR-375 will be computed using the trapezoidal rule.  Computation 
of AUC0-72H will be based on actual collection times, unless actual collection time is missing, in which case the 
scheduled collection time will be used. ** = Imputed value. 
 
 
 
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