Clinical trial NCT02814838
Conditions: Diabetes Mellitus, Insulin-Dependent
Keywords: Diabetes mellitus Type 1 Beta cells function
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2016-08-01; Completion date: 2019-05-15
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial). The safety of ladarixin in the specific clinical setting will be also evaluated.

The study is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1 diabetes (T1D) were planned to be involved, randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off - treatment group) or placebo (control group).

Recruitment was competitive among the study sites, until the planned number of patients was enrolled. A total of 76 patients were actually recruited.

Detailed description:
T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing β-cells. The onset of the disease typically occurs before adulthood and seriously affects a person's quality of life.

T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels. However, even optimization of glucose control through the most recent technologies cannot adequately substitute for the finely tuned normal balance of the glucose levels. Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness and amputation. Additionally, hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring emergency care.

Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated to be associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, and overall reduction in morbidity and associated management costs. Therefore, pharmacological approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific interest.

Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of β-cell function and improvement of glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, none has been definitely approved for the "treatment" of diabetes onset. New strategies are being evaluated which combine agents targeting sequential arms of the immune and inflammatory response involved in β-cell disruption. In this regard, IL-8 appears to be an important mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose control.

As a result of these findings, the modulation or inhibition of IL8 activity is considered a valid target for the development of innovative treatments aimed to control the progression of T1D.

Results obtained with ladarixin in mouse models of T1D, and particularly reversal of "diabetes" in the NOD mice, clearly showed the ability of this CXCR1/2 inhibitor to protect β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects of ladarixin, coupled with the safety shown in phase 1 studies, provided a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supported the conduct of the present study.

Arms: arm 1: Ladarixin oral capsule arm 2: Placebo oral capsule
Interventions: intervention 1: Ladarixin intervention 2: Placebo
Intervention descriptions: intervention 1: Ladarixin oral capsule intervention 2: Placebo oral capsule

Protocol documents:
Prot_001.pdf: 
 
 
CLINICAL STUDY PROTOCOL – REVISION HISTORY 
 
 
Study Number: 
MEX0114 
 
EudraCT Number: 
2014-003968-20 
 
Investigational Product: 
Ladarixin 
 
Study Phase: 
2 
 
Title: 
A phase 2, multicentre, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of 400 mg twice a day oral ladarixin in patients with new-onset type 
1 diabetes.  
 
Protocol Version - 
Date 
Change 
Reason 
Version No. 1 –  
Final 5 March 2015 
--- 
--- 
Version No. 2 –  
Final 27 August 2015 
Contact information updated 
Logistics 
Study period updated in section 1 and 3.2 
To match current expectation 
NOAEL in rats and toxicological details 
updated in section 2.2 
To match the most recent (6 August 2015) 
“Risk Assessment of ladarixin” provided by 
Preclinic Expert  
Details of effective contraceptive methods 
added in section 5.2, bullet 14 
As per request from the IEC of the Italian 
coordinating site and Italian Competent 
Authority (to match Italian insurance 
coverage provisions) 
Insulin added as a non-reportable 
concomitant medication in section 6.5.1 
To make clear that insulin administration is 
not to be captured as a concomitant 
medication 
Typing errors corrected throughout the 
document 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this document contains privileged or confidential information that is the property of Dompé 
farmaceutici s.p.a. It is understood that the information will not be used, divulged, or published without 
prior written consent of Dompé farmaceutici, except to the extent such disclosure is required by applicable 
laws and regulations. 
Domp6 
Dompé farmaceutici s.p.a. (Dompé)
Version No.1
Protocol No. MEX0114
03 April 2020
17


CHANG~ APPROVAL SIGNATURES 
SPO:\'SOR: 
Medical Monitoring 
Signatu,e: 
/\J,,, \ rn 
Andrea Vergani, MD - vf~ical :soiateDirector 
Date: 
Development Director - Diabetes & Transplantation 
Signature: f1J;l-o {2/qJ1,,-.._ ' 
Date: 
Marcello Allegretti - Chief Scientific Officer 
------- - -- ----
Dompé farmaceutici s.p.a. (Dompé)
Version No.1
Protocol No. MEX0114
03 April 2020
18


Study MEX0114 
Ladarixin in Diabetes Onset 
Page 1 of  51 
Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
Study Number: 
MEX0114 
 
EudraCT Number: 
2014-003968-20 
 
Investigational Product: 
Ladarixin 
 
Study Phase: 
2 
 
 
 
 
Title: 
A phase 2, multicentre, randomized, double-blind, placebo-controlled study to 
assess the efficacy and safety of 400 mg twice a day oral ladarixin in patients with 
new-onset type 1 diabetes.  
 
 
 
 
Protocol Version - Date: 
Version No. 2 – Final 27 August 2015 
 
 
 
 
 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential 
information that is the property of Dompé farmaceutici s.p.a. It is understood that the information will 
not be used, divulged, or published without prior written consent of Dompé farmaceutici, except to the 
extent such disclosure is required by applicable laws and regulations. 
 
 


Study MEX0114 
Ladarixin in Diabetes Onset 
Page 2 of  51 
Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
CONTACT INFORMATION 
 
SPONSOR 
Dompé farmaceutici s.p.a. [Dompé] 
  
Via Santa Lucia 6; 20122 Milan, Italy 
  
 
Medical Monitoring 
Andrea Vergani, MD - Medical Associate Director 
  
Dompé Inc. - 540 Madison Ave, New York, NY 10022, US 
  
mobile US +1-617-331-9248; mobile IT +39-345-8531012 
  
e-mail: andrea.vergani@dompe.com  
 
Clinical Operation Management Olga Kastsiuchenka, PhD - Clinical Development Specialist 
 
Dompé farmaceutici s.p.a. 
 
Direct line: +39 02 58383210; Fax: +39 02 58383324 
 
e-mail: olga.kastsiuchenka@dompe.com 
 
Global Project Management 
Luisa Daffonchio, PhD - Clinical Development Manager 
 
Dompé farmaceutici s.p.a. 
 
Direct line: +39 02 58383246; Fax: +39 02 58383324 
 
 
e-mail: luisa.daffonchio@dompe.com   
 
 
CONTRACT RESEARCH 
QUINTILES S.p.A.  
ORGANIZATION (CRO) 
via Roma 108; 20060 Cassina De’ Pecchi (Milan), Italy 
 
 
Project Management 
Manuela Costa - Senior Project Manager  
 
 
Mobile +39 335 1295169; Telephone: +39 02 95794.1 
 
 
e-mail: manuela.costa@quintiles.com 
 
 
 
Pharmacovigilance 
QDUB - Quintiles Ireland Ltd. 
 
 
Eastpoint Business Park, Fairview, Dublin 3, Ireland 
  
Laura McConnell – Customer Delivery Specialist 
  
Direct line: +353 1 8195619 
  
e-mail: laura.mcconnel@quintiles.com 
  
SAE reporting mailbox:  QLS_ladarixin@quintiles.com 
  
A country specific SAE reporting fax number will be provided to 
each site. 
  
 
 
COORDINATING INVESTIGATOR 
 
Italy: 
Emanuele Bosi, MD 
 
U.O. Medicina Generale a Indirizzo Diabetologico e Endocrino Metabolico 
 
Ospedale San Raffaele S.r.l. - Via Olgettina 60, Milano, Italy 
 
OTHER COORDINATING INVESTIGATORS AND INVESTIGATIONAL SITES  
Full list of coordinating investigators and investigational sites will be kept in the Trial Master File. 
Updated versions, will be filed chronologically. Copies will be provided to the sites. 
 
CENTRALIZED LABORATORIES 
A list of centralized laboratories will be kept in the Trial Master File. Updated versions, will be filed 
chronologically.  




Study MEX0114 
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Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1. 
STUDY SYNOPSIS AND OVERALL DESIGN............................................................. 9 
2. 
BACKGROUND INFORMATION ............................................................................... 13 
2.1. 
RELEVANT NON-CLINICAL PHARMACOLOGY ...................................................... 13 
2.1.1. 
Mechanism of action and in vitro activity ......................................................................... 13 
2.1.2. 
In vivo general studies ....................................................................................................... 13 
2.1.3. 
Effects in models of type 1 diabetes .................................................................................. 13 
2.2. 
A SUMMARY OF TOXICOLOGY DATA ..................................................................... 14 
2.3. 
PHARMACOKINETICS AND PRODUCT METABOLISM .......................................... 15 
2.4. 
A SUMMARY OF CLINICAL DATA ............................................................................. 16 
2.4.1. 
Pharmacokinetics and product metabolism in humans ...................................................... 16 
2.4.2. 
Efficacy .............................................................................................................................. 16 
2.4.3. 
Safety ................................................................................................................................. 17 
2.5. 
DISEASE REVIEW AND STUDY RATIONALE ........................................................... 18 
2.5.1. 
Selection of dose and treatment schedule in the study ...................................................... 19 
2.5.2. 
Alternative treatments ........................................................................................................ 19 
2.5.3. 
Risk - benefit evaluation .................................................................................................... 20 
3. 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION....................................... 22 
3.1. 
STUDY DESIGN .............................................................................................................. 22 
3.2. 
STUDY TIME TABLE ..................................................................................................... 22 
3.3. 
END OF STUDY ............................................................................................................... 22 
4. 
OBJECTIVES AND ENDPOINTS ................................................................................ 23 
4.1. 
STUDY OBJECTIVES ..................................................................................................... 23 
4.2. 
STUDY ENDPOINTS ....................................................................................................... 23 
4.2.1. 
Efficacy endpoints ............................................................................................................. 23 
4.2.2. 
Exploratory endpoints ........................................................................................................ 23 
4.2.3. 
Safety endpoints ................................................................................................................ 23 
5. 
STUDY POPULATION .................................................................................................. 24 
5.1. 
INCLUSION CRITERIA .................................................................................................. 24 
5.2. 
EXCLUSION CRITERIA ................................................................................................. 24 
5.3. 
ASSIGNMENT OF PATIENT NUMBER ........................................................................ 25 
6. 
STUDY MEDICATION .................................................................................................. 26 
6.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................ 26 
6.1.1. 
Presentation of Investigational Medicinal Product ............................................................ 26 
6.1.2. 
Manufacturing, Packaging and Labelling of IMP ............................................................. 26 
6.1.3. 
Supply, Storage and Handling of IMP ............................................................................... 26 
6.1.4. 
Blinding ............................................................................................................................. 27 
6.2. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION ................................ 27 
6.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION/ 
DISCONTINUATION OF IMP ........................................................................................ 27 
6.3.1. 
Criteria for schedule adjustment or dose modification ...................................................... 27 


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CONFIDENTIAL 
6.3.2. 
Criteria for discontinuation of IMP ................................................................................... 27 
6.4. 
ACCOUNTABILITY OF THE IMP ................................................................................. 28 
6.4.1. 
Assessment of compliance ................................................................................................. 28 
6.5. 
CONCOMITANT MEDICATION ................................................................................... 28 
6.5.1. 
Reporting of prior and concomitant medications .............................................................. 28 
6.5.2. 
Restriction on allowed prior and concomitant medications ............................................... 29 
6.6. 
INSULIN TITRATION ..................................................................................................... 29 
7. 
STUDY PROCEDURE AND ASSESSMENTS ............................................................ 30 
7.1. 
ENROLMENT, SCREENING AND RANDOMIZATION .............................................. 30 
7.1.1. 
Enrolment and Intensive Diabetes Management ............................................................... 30 
7.1.2. 
Screening ........................................................................................................................... 30 
7.1.3. 
Randomization ................................................................................................................... 31 
7.2. 
PRE-DOSE ASSESSMENTS & DRUG ADMINISTRATION........................................ 31 
7.2.1. 
Pre-dose assessment - 1st treatment cycle .......................................................................... 31 
7.2.2. 
Pre-dose assessment - 2nd and 3rd treatment cycle ............................................................. 32 
7.2.3. 
IMP administration ............................................................................................................ 33 
7.3. 
FOLLOW-UP STUDY ASSESSMENTS ......................................................................... 33 
7.4. 
EARLY PATIENT WITHDRAWAL ............................................................................... 33 
7.4.1. 
Withdrawal criteria ............................................................................................................ 33 
7.4.2. 
Replacement policy ........................................................................................................... 34 
7.5. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION ...................................... 34 
8. 
ADVERSE EVENTS ....................................................................................................... 35 
8.1. 
DEFINITIONS .................................................................................................................. 35 
8.1.1. 
Definition of an Adverse Event ......................................................................................... 35 
8.1.2. 
Definition of an Adverse Drug Reaction ........................................................................... 35 
8.1.3. 
Definition of a Serious Adverse Event/Reaction ............................................................... 35 
8.2. 
RECORDING .................................................................................................................... 35 
8.2.1. 
Relationship of AEs to the Investigational Product ........................................................... 35 
8.2.2. 
Severity of AEs .................................................................................................................. 36 
8.3. 
SERIOUS ADVERSE EVENT REPORTING .................................................................. 36 
8.3.1. 
Reporting Procedure for Investigators to Dompé .............................................................. 36 
8.3.2. 
Reporting Procedure to IEC and to Regulatory Authorities .............................................. 37 
8.4. 
EMERGENCY PROCEDURES ....................................................................................... 37 
9. 
STATISTICAL ISSUES .................................................................................................. 38 
9.1. 
SAMPLE SIZE .................................................................................................................. 38 
9.2. 
RANDOMIZATION ......................................................................................................... 38 
9.3. 
ANALYSIS POPULATION ............................................................................................. 38 
9.4. 
STATISTICAL METHODOLOGY .................................................................................. 38 
9.4.1. 
Demographic and baseline characteristics ......................................................................... 39 
9.4.2. 
Analysis of efficacy variables ............................................................................................ 39 
9.4.3. 
Analysis of exploratory variables ...................................................................................... 39 
9.4.4. 
Analysis of safety variables ............................................................................................... 40 
9.4.5. 
Missing data ....................................................................................................................... 40 
10. 
ETHICAL CONSIDERATIONS ................................................................................... 41 
10.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) .............................................................. 41 


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Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
10.2. 
INFORMED CONSENT ................................................................................................... 41 
10.3. 
CONFIDENTIALITY ....................................................................................................... 42 
10.4. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND 
INDEMNIFICATION ....................................................................................................... 42 
11. 
DATA HANDLING AND RECORD KEEPING .......................................................... 43 
11.1. 
CASE REPORT FORMS .................................................................................................. 43 
11.2. 
DIARY CARD .................................................................................................................. 43 
11.3. 
DATA MANAGEMENT .................................................................................................. 43 
11.4. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING 
THE STUDY ..................................................................................................................... 43 
11.5. 
ESSENTIAL DOCUMENT RETENTION ....................................................................... 44 
12. 
STUDY MANAGEMENT ............................................................................................... 45 
12.1. 
REGULATORY BODY APPROVAL .............................................................................. 45 
12.2. 
STAFF INFORMATION & RESPONSIBILITIES .......................................................... 45 
12.3. 
MONITORING ................................................................................................................. 45 
12.3.1. 
Access to records ............................................................................................................... 45 
12.4. 
AUDIT AND INSPECTION ............................................................................................. 45 
12.5. 
PROTOCOL DEVIATIONS/AMENDMENTS ................................................................ 45 
12.6. 
DISCONTINUATION OF THE STUDY ......................................................................... 46 
12.7. 
PUBLICATIONS .............................................................................................................. 46 
13. 
REFERENCES ................................................................................................................ 47 
14. 
APPENDICES .................................................................................................................. 48 
14.1. 
APPENDIX 14.1 - PACKAGING AND LABELING DETAILS..................................... 48 
14.2. 
APPENDIX 14.2 – SAMPLE DIARY CARD [ENGLISH SPECIMEN] ......................... 49 
14.3. 
APPENDIX 14.3 – STUDY FLOW CHART ................................................................... 50 
14.4. 
APPENDIX 14.4 - METHODOLOGICAL DETAILS ..................................................... 51 
14.4.1. 
Handling of samples for centralized assay ........................................................................ 51 
14.4.2. 
Mixed Meal Tolerance Test ............................................................................................... 51 
 


Study MEX0114 
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CONFIDENTIAL 
List of Abbreviations and Definitions of Terms 
 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
b.i.d. 
Bis in die 
BP  
Bullous Pemphigoid 
 
 
ºC 
Degrees Celsius 
CLcr 
Calculated Creatinine Clearance (Cockcroft - Gault formula) 
Cmax 
Maximum Plasma Concentration 
CMED 
Concomitant Medication 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CXCL8 
CXC ligand 8 [formerly interleukin (IL)-8] 
CXCR1/2 
CXCL8 receptors 
dL 
Deciliter 
DPP-IV inhibitor 
Dipeptidyl peptidase-IV inhibitor 
fMLP 
formyl-met-leu-phe 
g 
Gram 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
i.v. 
Intravenous 
IU 
International Unit 
kg 
Kilogram 
L 
Litre 
LBBB 
Left Bundle Branch Block 
LD50 
Lethal Dose50 
miR-375 
MicroRNA-375 
mg 
Milligram 
mL 
Millilitre 
MLD-STZ 
Multiple Low Dose-Streptozotocin  
MMTT 
Mixed Meal Tolerance Test 
msec 
Millisecond 
ng 
Nanogram 
nmol 
Nanomole 
NOD 
Non-Obese Diabetic 
NOEL 
No Observable Effect Level 
PK 
Pharmacokinetics 


Study MEX0114 
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CONFIDENTIAL 
PMN 
Polymorphonuclear leukocyte 
p.o. 
per os (taken by mouth) 
QTc 
Corrected QT interval 
QTcF 
Fridericia's corrected QT interval 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
t½ 
Elimination half life 
Tmax 
Time to reach Maximum Plasma Concentration 
T1D 
Type 1 Diabetes 
ULN 
Upper Limit of Normal 
μg 
Microgram 
μmol 
Micromole 
 
 
 
 


Study MEX0114 
Ladarixin in Diabetes Onset 
Page 9 of  51 
Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
1. 
STUDY SYNOPSIS AND OVERALL DESIGN  
 
Study title 
A phase 2, multicentre, randomized, double-blind, placebo-controlled study to assess the efficacy and 
safety of 400 mg twice a day oral ladarixin in patients with new-onset type 1 diabetes.  
 
Study Number   MEX0114 
[EudraCT Number: 2014-003968-20] 
 
Study period 
Projected starting date (first-patient-in):  
December 2015 
 
Projected completion of patient accrual (last-patient-in): 
December 2016  
 
Projected study end date (last-patient-last-visit): 
December 2017 
 
Study design 
The study will be a phase 2, multicentre, double-blind study.  It will involve 72 patients with new-
onset type 1 diabetes (T1D), randomly (2:1) assigned to receive either ladarixin treatment (400 mg 
b.i.d. for 3 cycles of 14 days on/14 days off – treatment group) or placebo (control group).  The two 
groups will be balanced within each centre.  Recruitment will be competitive among the study sites, 
until the planned number of patients is enrolled. 
Sample size calculation has been based on the 2-hour area under the curve (AUC) of C-peptide 
response to a Mixed Meal Tolerance Test (MMTT) observed 12 months after randomization, as these 
are the only available data that best match the T1D population expected to be randomized in this trial 
(age, time from diagnosis, etc.) [Lachin, 2011].  On the other hand, the time frame for the primary 
endpoint (2-hour AUC of C-peptide response to the MMTT) has been set at week 13+1 in order to 
maximise the potential to observe an effect of ladarixin, considering the PK profile in humans as well 
as the reversibility of the pharmacological effect on CXCR1/2 receptors.  Such an approach is 
appropriate for a phase 2 proof of concept trial.  Follow-up is anyway extended up to 12 months. 
 
 
Objectives/endpoints 
The objective of this clinical trial is to investigate whether ladarixin has sufficient activity 
(preservation of -cell function and slow-down of the progression of T1D) to warrant its further 
development (proof of concept trial).  The safety of ladarixin in the specific clinical setting will be also 
evaluated.  
 
Efficacy endpoints will be: 
- 
2-hour area under the curve (AUC) of C-peptide response to a Mixed Meal Tolerance Test 
(MMTT) [Primary endpoint. Time frame: baseline, week 13+1].   
- 
2-hour AUC of C-peptide response to the MMTT [Time frame: baseline, weeks 26+2 and 52+2].   
- 
Average (previous 3 days) insulin requirements (IU/kg/day) [Time frame: baseline, weeks 13+1, 
26+2 and 52+2].  
- 
HbA1c levels [Time frame: baseline, weeks 13+1, 26+2 and 52+2].  
- 
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of C-peptide and 
glucose derived from the MMTT [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
- 
Cumulative severe hypoglycaemic events occurring from randomization [Time frame: weeks 
13+1, 26+2 and 52+2]. 
 
Exploratory endpoints will be: 
- 
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of glucagon 
derived from the MMTT [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
- 
Auto-antibodies (GAD, IA-2, IAA, ZnT8) [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
- 
MicroRNA-375 (miR-375) [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 


Study MEX0114 
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Page 10 of  51 
Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
- 
T-cell response ex vivo to major -cell antigens (pro-insulin, GAD65) - selected sites only 
[Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
 
Safety endpoints will be:  
- 
Vital signs (blood pressure and heart rate) [time frame: screening, end of 1st treatment cycle (i.e. 
pre-dose visit, 2nd cycle), week 13+1]. 
- 
Routine laboratory tests (haematology, clinical chemistry) [time frame: screening, end of 1st 
treatment cycle (i.e. pre-dose visit, 2nd cycle), weeks 13+1 (or withdrawal)]. 
- 
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [time frame: throughout 
the study].   
 
Number of patients  
Seventy-two (72) patients with new-onset T1D 
 
Inclusion/exclusion criteria 
Consented male and female patients aged 18-45 years, inclusive, with new-onset T1D (randomization 
within 100 days from 1st insulin administration).  Patients must be positive for at least one diabetes-
related auto-antibody (anti-GAD; IAA, if obtained within 10 days of the onset of insulin therapy; IA-2 
antibody; ZnT8); must require, or have required insulin (exclusion of patients taking twice daily pre-
mixed insulin or on insulin pump); must have peak stimulated (MMTT) C-peptide level >0.6ng/mL 
(0.2nmol/L). 
Patients will be excluded if they have any other chronic disease (including type 2 diabetes), apart from 
patients with autoimmune hypothyroidism requiring thyroid hormone replacement only; moderate to 
severe renal impairment (calculated creatinine clearance < 60 mL/min according to the Cockcroft-
Gault formula); hepatic dysfunction (increased ALT/AST > 3 x upper limit of normal and increased 
total bilirubin > 3 mg/dL [>51.3 μmol/L]); hypoalbuminemia (serum albumin < 3 g/dL); a QTcF > 470 
msec; complete Left Bundle Branch Block (LBBB); atrio-ventricular block (mobitz II 2nd degree or 
2:1 atrio-ventricular block); complete heart block; electronic pacemaker or implanted defibrillator; a 
history of significant cardiovascular disease; a known hypersensitivity to non-steroidal 
antiinflammatory drugs. Patients on treatment with phenytoin, warfarin, sulphanylurea hypoglycemics 
and high dose of amitriptyline (> 50 mg/day); with past (within 2 weeks prior to randomization) or 
current use of metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV 
inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. -blockers, 
angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, 
etc.) will also be excluded. Patients will be excluded as well in case of past (within 1 month prior to 
randomization) or current administration of any immunosuppressive medications (including oral, 
inhaled or systemically injected steroids)  and use of any investigational agents, including any agents 
that impact the immune response or the cytokine system. Also, pregnant or breast feeding women or 
patients unwilling to use effective contraceptive measures (females and males) will be excluded. 
 
Investigational Medicinal Product 
The investigational medicinal product (IMP) will be either ladarixin OR placebo hard gelatine 
capsules for oral administration.  Ladarixin will be administered orally at the dose of 400 mg twice a 
day at about 12 hour interval (morning and evening) for 3 cycles of 14 days on / 14 days off.  Placebo 
will be administered with the same schedule.   
Discontinuation criteria 
Administration of the investigational product will be discontinued in the case the QTcF becomes either 
> 500 msec or increases by > 60 msec from baseline measurement on two consecutive measurements 
(1 hour apart) or if the patient develops LBBB, or atrio-ventricular or heart block.  Similarly, 
administration of the investigational product will be discontinued in the case the patient develops renal 
(calculated CLcr < 60 mL/min) or hepatic (increased ALT/AST > 3 x ULN and increased total 
bilirubin > 3mg/dL [>51.3 mol/L]) dysfunction as well as hypoalbuminemia.  Lastly, administration 
of the investigational product will be immediately discontinued if the patient develops ketoacidosis or 
hypoglycaemic coma.  


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Cardiac, renal and hepatic function as well as albuminemia will be specifically monitored through 
ECG readings and laboratory tests obtained within 1 week before starting the 2nd and 3rd treatment 
cycle.  In addition, the IMP will be immediately discontinued in the event of any other possibly drug 
related occurrences that the Investigator believes might compromise patient’s safety.  Results of safety 
laboratory tests performed after the 1st treatment cycle will be also considered.     
 
Procedures 
Study period/visits are summarized in the study flow chart (see Appendix 14.3).   
 
Screening to Randomization  
Potential study patients with a recent clinical diagnosis of T1D will be identified from those referring 
to the site for diagnosis confirmation (auto-antibody testing) and/or disease management.  Screening, 
including confirmation of T1D diagnosis, will be performed in enrolled (consented) patients.  
From enrolment, patients will be admitted to an intensive diabetes management.  Patients will self-
monitor glucose levels at least 4 times a day and will take insulin as prescribed by the Investigator 
throughout the study participation. To ensure standardized glycaemic control in the treatment groups, 
the Investigator will provide guidance for insulin regimen adjustment, with insulin titrated up or down 
to target HbA1c levels of less than 7% and self-monitored (fingerstik): 
- 
pre-prandial blood glucose of 70-130 mg/dL 
- 
post-prandial blood glucose < 180 mg/dL 
- 
bed-time blood glucose of 110-150 mg/dL 
In order to optimize insulin titration, telephone calls (outside scheduled visits) will be scheduled on a 
regular basis to ensure timely evaluation of metabolic control and adjustment of insulin regimen.  
Patients will report their self-monitored glucose levels (logs, glucose meter, etc.) as per site standard 
diabetes management, but at least weekly up to week 13+1 and in the 2 weeks before each follow-up 
visit.    
Screening includes evaluation of past medical history and disease-specific clinical information, 
including date of first insulin administration, and blood sampling for measurement (centralized 
laboratory) of auto-antibody (anti-GAD; IAA, if obtained within 10 days of the onset of insulin 
therapy; IA-2 antibody; ZnT8) to confirm T1D diagnosis (time frame: from enrolment to 
randomization). 
The following baseline assessments (time frame: within 3 weeks before randomization – consider 
time for centralized assay of MMTT C-peptide) will be also performed during the screening period: 
• Measurement of blood pressure, heart rate, body weight, height; 
• Blood sampling(s) for measurement (local laboratories) of “Safety Laboratory Tests” i.e.: 
hematocrit, hemoglobin, red blood cells, platelets, white blood cells, differential white blood 
cells count, sodium, potassium, serum creatinine, serum albumin, blood urea nitrogen, total 
bilirubin, ALT, AST; 
• Evaluation of renal and hepatic function (to be derived from the safety laboratory test results).  
• Screening 12 lead ECG, performed using local equipment that allows automatic calculation of 
the QTcF. 
• Pregnancy test (urine dipstick or blood sample), if appropriate; 
• Baseline insulin requirement (IU/kg/day averaged over the previous 3 days);  
• Blood sampling for measurement (centralized laboratory) of baseline auto-antibody (anti-GAD; 
IAA; IA-2 antibody; ZnT8 – not to be repeated if “diagnostic” test is done within this 
timeframe), HbA1c and miR-375 (and T-cell response ex vivo at selected sites only).   
• Baseline MMTT.  Blood samples for measurement (centralized laboratory) of C-peptide, 
glucose and glucagon will be drawn pre-meal (2 basal samples in the range between -20 to 0) 
and 15, 30, 60, 90, 120, 180 min after the meal.    


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Patients fulfilling all the inclusion criteria and none of the exclusion criteria will be randomized, 
randomization day being defined as Study Day 0 with reference to day when IMP administration is 
started which is defined as Study Day 1. 
Treatment period and in-between visits 
Assessment to be done before the 1st dose in the 1st treatment cycle are part of the screening 
evaluation.  Thereafter, patients will refer to the site within 1 week before the expected date when the 
2nd or 3rd treatment cycle is due to start to confirm no condition that prevents their continuing 
participation into the study has arisen (as per discontinuation criteria above).  The amount of IMP for 
each treatment cycle will be dispensed only after compliance with criteria for drug administration has 
been confirmed.       
Follow-up visits 
After completion of study treatment, patients will attend the centre for study assessments on 3 follow-
up visits scheduled at weeks 13+1 (month 3), 26+2 (month 6) and 52+2 (month 12).  
At each visit, the following will be evaluated/measured. 
• Blood sampling for measurement (centralized laboratory) of auto-antibody (anti-GAD; IAA; 
IA-2 antibody; ZnT8), HbA1c and miR-375 (and T-cell response ex vivo at selected sites only); 
• MMTT.  Blood samples for measurement (centralized laboratory) of C-peptide, glucose and 
glucagon will be drawn pre-meal (2 basal samples in the range between -20 to 0 min) and 15, 
30, 60, 90, 120, 180 min after the meal; 
• Insulin requirement (IU/kg/day averaged over the previous 3 days); 
• Cumulative number of severe hypoglycaemia events in the interval from: randomization to 
week 13+1, week 13+1 to week 26+2, week 26+2 to week 52+2;  
• On week 13 ONLY: Measurement of blood pressure and heart rate; Blood sampling(s) for 
measurement (local laboratories) of “Safety Laboratory Tests” i.e.: hematocrit, hemoglobin, red 
blood cells, platelets, white blood cells, differential white blood cells count, sodium, potassium, 
serum creatinine, serum albumin, blood urea nitrogen, total bilirubin, ALT, AST. 
 
Statistics 
The Safety population will consist of all patients who received any study medication and will be based 
on the treatment actually received.  The Intent to Treat (ITT) population will consist of all patients 
who are randomized and receive the IMP (either ladarixin or placebo); it will be based on the 
treatment randomized, regardless of the treatment actually received.   
Appropriate descriptive statistics will be produced for all variables, according to the nature of the 
variable.   
Unless otherwise specified, the significance level used for statistical testing will be 0.05 and one-sided 
tests will be used.  
The primary variable [2-hour C-peptide AUC after the MMTT, log(x+1) transformed data, at week 
13+1 (primary efficacy endpoint)], will be analysed with Student t test for unpaired data using PROC 
TTEST within SAS®, including terms for treatment and centre.  The estimated treatment difference 
between ladarixin and placebo will be also presented together with the corresponding 95% confidence 
interval.   
The other secondary efficacy endpoints will be analysed using appropriate parametric and non-
parametric tests and appropriate 95% CI will be presented.   
Post-hoc analysis may be produced  to further allow comparison between ladarixin and placebo, 
according to the results obtained.    
 
 


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2. 
BACKGROUND INFORMATION 
Ladarixin (ladarixin) is a novel small molecule that inhibits the biological activity of the CXC ligand 8 
[CXCL8; formerly interleukin (IL)-8] through inhibition of the activation of CXCL8 receptors: 
CXCR1 and CXCR2.  This specific inhibitor stems from a program of drug design of molecules 
intended to modulate chemokine action. 
Original development plan of ladarixin was targeted to the dermatological area with a  phase II study 
in bullous pemphigoid (BP), a rare dermatological disease.  Following more recent promising results 
in mouse models of type 1 diabetes (T1D), development in new onset T1D is being implemented. 
Relevant pre-clinical, toxicological and clinical data are summarized below.  Please also refer to the 
Investigator’s Brochure for detailed information.      
2.1. 
RELEVANT NON-CLINICAL PHARMACOLOGY 
2.1.1. 
Mechanism of action and in vitro activity 
Ladarixin is a novel, potent and specific inhibitor of the biological activity of the chemokine CXCL8.  
In vitro chemotaxis experiments have shown that ladarixin, in the low nanomolar range, inhibits 
human polymorphonuclear leukocyte (PMN) migration induced by human CXCL8 receptors 
activation.  Chemotaxis of rodent PMN induced by mouse and rat counterparts of human CXCL8 is 
also inhibited, indicating that mice and rats are appropriate animal species for preclinical studies.  
Studies on the mechanism of action have shown that ladarixin is a non-competitive allosteric inhibitor 
of the CXCL8 receptors: CXCR1 and CXCR2 [Moriconi, 2007].  The selectivity of ladarixin on 
CXCR1 and CXCR2 is proven by its lack of efficacy against PMN migration induced by fMLP or C5a 
and against human monocyte chemotaxis induced by CCL2.  
2.1.2. 
In vivo general studies 
In vivo, ladarixin (4-16 mg/kg i.v.) prevents PMN infiltration (inhibition ranged from 38 to 80%) and 
tissue damage (inhibition ranged from 35 to 90%) in experimental models of ischemia/reperfusion 
injury of liver and brain in rats [Garau, 2006].  In addition, the effects of ladarixin were investigated 
in mouse models of acute and chronic smoke exposure.  In the acute model of smoke exposure, 
ladarixin (3.75-15 mg/kg p.o.) reduces PMN infiltration by about 60%, whereas in the chronic model 
the compound (7.5-15 mg/kg p.o.) completely prevents the development of pulmonary lesions. 
The antiflogistic activity of orally administered ladarixin was proven in the acute mouse model of 
cantharidin-induced ear inflammation where it reduced the ear oedema formation (16% of inhibition), 
the cell infiltration (34% of inhibition on lymphocytes T and 32% of inhibition on PMNs) and the ear 
tissue levels of keratinocyte chemokine (37%), VEGF-A (24%) and TNF- (44%) [A0811/E]. 
The efficacy of ladarixin in preventing PMN infiltration and tissue damage was also investigated in a 
passive transfer mouse model of BP.  In this model, ladarixin was either co-injected with anti-mouse 
BP180 IgG (therapeutic treatment) or injected before disease induction (preventive treatment).  
Ladarixin, administered both intradermally and intraperitoneally, dose-dependently reduces both the 
clinical disease score and PMN recruitment as shown by reduction in MPO levels.  At the highest dose 
tested (16.7 mg/kg), the clinical disease score and PMN migration were decreased by 90% and 60%, 
respectively [A0811/E].  
2.1.3. 
Effects in models of type 1 diabetes 
Ladarixin was tested after oral administration (15mg/kg/day) in the Multiple Low Dose-Streptozotocin 
(MLD-STZ) model of diabetes using different treatment schedules.  Results showed that ladarixin 
significantly affected the time to diabetes development with the 14 day administration starting from 
day -1 of fist STZ injection being the more efficient treatment schedule in prolonging the median 
diabetes free time.  When a 14 day treatment was started from day +5, ladarixin still maintained a 
good performance.  Even after diabetes development, glycaemic levels during the first 2 months 


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remained constantly lower in the ladarixin treated group as compared with the vehicle group [Citro, 
2012a]. 
Ladarixin was also tested after oral administration (15 mg/kg/day for 14 days) in Non-Obese Diabetic 
(NOD) mice, starting treatment at different ages to explore its effects in a “prevention” setting 
(animals treated at 4, 8 and 12 weeks of age) or at “onset of diabetes”(animals at about 16 weeks of 
age, after fasting hyperglycemia was developed).  In the “prevention” setting, the incidence of diabetes 
was reduced by ladarixin administration, regardless of the age when the treatment was started.  In 
particular, when ladarixin was administered in animals at 8 weeks of age, the incidence of diabetes 
was 47% and 11% in the vehicle and ladarixin treated group, respectively (p=0.029).  The ability of 
ladarixin to protect damage of -cells was confirmed in the “onset” setting.  Animals presenting two 
consecutive blood glucose readings above 250 mg/dL over 24 h were randomized to receive either 
ladarixin or vehicle with the same dosing schedule as used in the prevention setting.  Treatment with 
ladarixin at diabetes onset blocked the progression of hyperglycaemia while hyperglycaemia worsened 
in animals receiving vehicle.  Three animals treated with ladarixin at diabetes onset that subsequently 
developed diabetes (about 30 days from end of treatment) were re-treated with the test compound 
starting from day 35.  In 2 animals with “mild” diabetes (animals with glycaemia between 300 mg/dl 
and 450 mg/dl) out of the 3 animals re-treated, ladarixin apparently reverted increased glycaemia 
[Citro, 2012b].  In parallel, ladarixin  modifies leukocyte infiltration in the pancreas and the 
inflammatory process (insulitis) as well as affects the leukocyte subpopulations that express CXCR2, 
among which one subpopulation of B-lymphocytes [Citro, 2014]. 
2.2. 
A SUMMARY OF TOXICOLOGY DATA 
Ladarixin was tested for toxicity in rodent and non-rodent animal species after single or repeated 
administrations.  The repeated dose administration studies were conducted only by the oral route, 
according to the intended human administration route.  
The acute toxicity of DF 2156A, after single administration by i.v. route to rats resulted in a LD50 > 
500 mg/kg.  In dogs, an i.v. bolus (up to 400 mg/kg) caused mortality at 400 mg/kg and clinical signs 
of vomiting, salivation and tremor at the lower doses. 
The repeated dose administration to rats by i.v. boluses for 7 days up to the dose of 300 mg/kg did not 
cause mortality.  Liver weight was increased, resulting in hepatocytic hypertrophy.  Inflammatory and 
degenerative changes were seen at the injection site.  In studies with up to 7 day oral administration in 
rats (doses up to 600 mg/kg) there was no mortality.  Microscopically hepatocellular hypertrophy was 
present in all treated groups.  In studies with up to 1 week administration in dogs, the dose had to be 
reduced from 500 mg/kg to 150 mg/kg due to poor tolerability and severe clinical signs. 
In rats, the oral administration for 28 days up to the dose of 200 mg/kg did not cause relevant toxicity.  
The immune system was not affected by the treatment.  Hepatocellular hypertrophy was seen in the 
liver of all male treated groups and in females at the highest dose that resolved after 2 weeks of free 
dose.  
In the 4-week oral toxicity study in dogs the compound was well tolerated up to the doses of 120 
mg/kg and no mortality occurred.  Vomiting was seen at the highest dose.  An increase in the absolute 
and corrected-for-heart rate QT interval was observed at the middle (60 mg/kg) and highest (120 
mg/kg) doses.  After 2 week washout the QT values returned to normal. 
Testing for mutagenic potential (Ames test, in vitro chromosomal aberration test, in vivo micronucleus 
test in rats) gave negative results.  
The safety pharmacology of ladarixin was assessed on the renal function and on the central nervous 
system in male rats.  No relevant changes related to the administration of the compound were reported 
in doses (20, 50 and 150 mg/kg) far above those foreseen in humans. 
Cardiovascular safety studies were conducted in dogs by the oral route.  At the highest dose tested 
(100 mg/kg), ladarixin prolonged the QT corrected for heart rate at 1, 2 and 12 hours post-dosing 
when compared to pre-dosing values.  In vitro, ladarixin had no effect on the hERG potassium channel 


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when tested on hERG tail current at concentrations from 3 to 2000 μM.  Two metabolites of ladarixin 
(DF2108Y and DF2227Y) are formed in vivo in rats and dogs. They were tested in vitro on hERG tail 
current at doses up to 2000 µM.  A dose-related reduction of the tail current amplitudes was seen at 
concentrations higher than 100 µM (DF2108Y) or 500 µM (DF2227Y).  The IC50 was: 2247.35 µM 
(DF2108Y) and 1957.59 µM (DF2227Y), respectively.  
In conclusion based on the toxicology data, the No Observed Adverse Effect Level in rats is 200 
mg/kg and the No Observed Effect Level in dogs is 30 mg/kg. 
Fertility and early embryonic development to implantation was evaluated in male and female Han 
Wistar rats at the daily oral dose of 50, 100 and 200 mg/kg.  There were no treatment-related effects in 
females at any dose levels and in males at 50 and 100 mg/kg/day.  In males, at 200 mg/kg, body 
weight and mean body weight gain were minimally to slightly lower when compared with the controls. 
At the same dose level, fertility of males was minimally affected by the treatment and only few of 
them (4 out of 21) did not produce pregnancy in the females.  The minor fertility rate was associated to 
degenerative changes in the testes of few treated males at 200 mg/kg/day that, however, were 
considered related to the stress suffered from the animals in the first period of treatment and not to a 
direct toxic effect of the test item.  Sperm analysis in these few animals only also showed reduction in 
number, motility or shape. The NOEL was 100 mg/kg/day for males and of 200 mg/kg/day for 
females. The testicular changes in few animals were confirmed by an additional toxicity study in 
males only, using two rat species (Wistar and Sprague-Dawley) treated with 200 mg/kg/day over a 
period of 6 weeks. Also in this study the testicular changes were associated to the stress suffered in the 
first period of the treatment (a likely adaptation-stress to the high dose treatment).  In conclusion, 
findings observed in male rats should not be taken as indicating a potential hazard in humans and it 
should be disregarded in risk assessment for clinical trials of ladarixin. Based on these results and 
safety assessment, a NOAEL of 200 mg/kg/day can be settled in male rats as well. 
2.3. 
PHARMACOKINETICS AND PRODUCT METABOLISM  
The pharmacokinetics of DF2156Y was studied in rats and mice after single i.v. and oral 
administration and after multiple oral administrations in rats and dogs within the toxicity studies.  
DF2156Y is almost completely absorbed after oral administration in rats with an absolute 
bioavailability higher than 90%.  DF2156Y is slowly eliminated from plasma in all the three species 
tested (t½ ranging from 25 hours to 30 hours).  Gender differences in pharmacokinetic profile after 
oral administration (slightly lower exposure in females than in males) were observed in rats but not in 
dogs.  
A metabolite of DF2156Y named DF2108Y (R enantiomer) was identified, using a non-chiral 
analytical method, in both rats and dogs.  On the basis of the chiral analytical determination the S 
enantiomer (DF2227Y) was noted in the plasma of both rats and dogs.  The in vivo interconversion of 
DF2108Y into DF2227Y was about 90% in rats.  
In male and female rats DF2227Y was the major and long lasting circulating metabolite. After 
repeated daily oral administration of DF 2156A, this metabolite showed an accumulation ratio ranging 
between 1.4 and 2.4.  After the daily oral administration of DF 2156A at 200 mg/kg for 6 weeks, the 
parent compound and the metabolites showed comparable exposure in Wistar and Sprague Dawley 
rats either at day 1 or after repeated administrations.  
In humans, single oral doses of ladarixin (25 to 400 mg) provided quantifiable plasma concentration of 
DF2156Y within 1 hour, with peak concentration being reached between 1 and 3 hours.  After single 
doses, DF 2156A was excreted mainly as unmodified in human urine.  The presence of the two 
metabolites found in animal species (DF 2108Y and DF 2227Y) was confirmed in humans. Dose 
proportionality over the entire dose range investigated was observed as well as t½ (11-19 h) remained 
constant across the range of doses evaluated. Renal clearance accounted for approximately 60-80% of 
the total clearance of DF 2156Y.  The dose proportionality for the main PK parameters was also seen 
for the two metabolites (DF 2108Y and DF 2227Y). 


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After multiple dose, DF 2156Y reached the steady state around Day 5 and 6 following 50, 100, 200, 
300 and 400 mg b.i.d.  Systemic exposure to DF 2156Y, DF 2108Y and DF 2227Y appeared to 
increase in a dose-proportional manner.  The clearance and the volume of distribution of DF 2156Y 
appeared to be dose-independent on both Days 1 and 8 for all doses. Similarly, t½ (ranging from 11 to 
18 h) remained constant on Day 1 and on Day 8 across the range of doses evaluated.   
Co-administration of DF 2156Y increased the exposure and urinary excretion of tolbutamide while 
decreasing the exposure and the urinary excretion of tolbutamide metabolites. Plasma tolbutamide 
AUC values increased by about 2-fold and the AUCs of the metabolites decreased by about 2-fold.  
In vitro ladarixin appears to be a strong inhibitor of the enzyme CYP2C9 in humans (83%) and a 
moderate inhibitor in rats (51%).  No inhibition was observed in dogs.  No inhibition was detected in 
any species with regard to CYP2D6.  Also, no inhibition was shown for CYP 1A2, 2C19, and 2E1 
with respect to humans and dogs, but a moderate inhibition was shown in rats (about 50%).  As to 
CYP3A4, a slight inhibition was seen in all species which was higher than 20% only in rats (about 
28%).  In humans, co-administration of ladarixin (200 mg twice a day for 5 days) approximately 
doubled the exposure to tolbutamide (probe for CYP2C9 isoenzyme). 
Preliminary in-vitro protein binding studies showed that ladarixin is highly bound to plasma proteins; 
binding varies according to ladarixin concentrations and appears to be saturable: mice 97.7%, rats 
91.8-99.4%, dogs 80.4-99.5% and humans 93.0-99.9%.  Repeated administrations in humans 
confirmed the very high binding to plasma proteins (>99.99%).  
2.4. 
A SUMMARY OF CLINICAL DATA 
Clinical development includes 3 phase 1 PK and tolerability studies with single (25 to 400 mg – 
MEX0108) and multiple (50 to 400 mg twice a day up to 6 days, MEX0109, MEX0110) ascending 
dose oral administration.  The first multiple ascending dose study (MEX0109) also included the 
evaluation of potential interaction between ladarixin 200 mg and tolbutamide.  A phase 2 efficacy and 
safety study was also conducted with 150 mg twice a day (for 14 consecutive days) oral ladarixin in 
patients with moderately active BP.   
To date, a total of 119 male subjects were involved in clinical trials, of whom 93 (89 healthy 
volunteers and 4 patients with BP) were exposed to ladarixin.  
2.4.1. 
Pharmacokinetics and product metabolism in humans 
Three phase 1 PK/safety studies in healthy male volunteers were performed which included single (25 
to 400 mg – MEX0108) and multiple (50 to 400 mg twice a day up to 6 days, MEX0109, MEX0110) 
ascending dose oral administration.  An interaction evaluation for the 200 mg dose was also included 
in the first multiple ascending dose study.  Assay of ladarixin and its metabolite DF 2108Y and 
DF 2227Y was performed in samples collected at steady state conditions, on day 5 and 8 of 
treatment in 3 BP patients. PK results are discussed in Section 2.3. 
2.4.2. 
Efficacy 
A phase 2, multicentre, single arm, pilot study was initiated to assess the safety and efficacy of 
ladarixin in patients with moderately active BP [MEX0111].  The compound was given by the oral 
route at 150 mg twice a day (maximum of 14 days), a low dose that could be selected according to the 
phase 1 trial completed at the time of protocol implementation (treatment up to 200 mg twice a day).  
Four male patients aged between 65 to 75 with either newly diagnosed or relapsing BP of mild to 
moderate degree were enrolled at one Italian and three German sites.  Of the 4 patients enrolled, only 
one completed the 14-day treatment period.  The remaining 3 patients were withdrawn from the study 
(one patient due to treatment failure and the other 2 patients because admission to rescue therapy).  No 
disease remissions was observed with the low dose tested in this trial and the study was prematurely 
discontinued due to lack of activity.   


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2.4.3. 
Safety 
A total of 89 male healthy subjects aged 18 to 52 years and 4 male BP patients aged 65-75 yeas were 
exposed to ladarixin in the clinical trials conducted to date.   Exposure included single (25 to 400 mg) 
as well as repeated (50 to 400 mg twice a day up to 6 days) oral administrations in healthy volunteers 
and 150 mg twice a day up to a maximum of 14 days  in BP patients.  In a subset of subjects, ladarixin 
(200 mg twice a day) was co-administered with tolbutamide.   
Overall, DF2156 was safe and well tolerated.  No deaths or Serious Adverse Events (SAEs) were 
reported from phase 1 trials, as well as no safety concerns were raised during co-administration of 
ladarixin with tolbutamide.  All the Adverse Events (AEs) were mild or moderate in intensity.   
Toxicology and safety pharmacology in animals pointed out the cardiovascular system (QT 
prolongation) as potential safety concern in humans.  Apparent isolated prolongations of the QTcF 
were observed at some time-points in phase 1 studies; core laboratory analysis of the ECG readings, 
including the review of changes in the QTcF intervals and of the pharmacokinetic-pharmacodynamic 
relationship, revealed no clinically significant effect of DF 2156A on cardiac repolarization. 
Safety was confirmed in elderly BP patients treated with several concomitant medications. Three out 
of 4 patients reported mild AEs which were all considered related to ladarixin with the exception of 
one AE in one patient (hypereosinophilia).   Two patients had a series of abnormal ECGs at baseline 
that continued throughout the study neither of which were considered clinically significant by the 
investigator, supporting the cardiosafety in elderly patients.  There were no other safety findings 
considered clinically significant by the investigator.  There were no deaths, SAEs, or discontinuations 
from the study due to AEs. 
Cumulative adverse drug reactions (ADRs), i.e. treatment-emergent AE judged at least possibly 
related to ladarixin, are presented in the Table below. 
 
Cumulative Adverse Drug Reactions - Number of events by Terms 
Study code ref./ System Organ Class (SOC) MedDRA Preferred Term 
(PT) 
Number of events 
Frequency 
Gastrointestinal disorders 
21 
52.50% 
MEX0109 - Part A 
MEX0110 
Abdominal pain 
2 
5.00% 
MEX0109 - Part A 
Diarrhoea 
1 
2.50% 
MEX0109 - Part A 
MEX0111 
Dry mouth 
2 
5.00% 
MEX0109 - Part A  
MEX0109 - Part C  
MEX0111 
Dyspepsia 
7 
17.50% 
MEX0109 - Part A 
Dysphagia 
2 
5.00% 
MEX0110 
Flatulence 
1 
2.50% 
MEX0108 
Mouth ulceration 
2 
5.00% 
MEX0108; MEX0110 
Nausea 
2 
5.00% 
MEX0109 - Part A 
Oral Pain 
1 
2.50% 
MEX0109 - Part A 
Vomiting 
1 
2.50% 
General disorders and administration site conditions 
1 
2.50% 
MEX0109 - Part A 
Feeling hot 
1 
2.50% 
Infections and infestations 
1 
2.50% 
MEX0108 
Oral herpes 
1 
2.50% 
Investigations 
1 
2.50% 
MEX0109 - Part A 
Liver function test abnormal 
1 
2.50% 
Musculoskeletal  and connective tissue disorders 
1 
2.50% 
MEX0109 - Part A 
Tendonitis 
1 
2.50% 
Nervous system disorders 
14 
35.00% 
MEX0108 
MEX0109 - Part A 
Dizziness 
2 
5.00%% 
MEX0108 
MEX0109 - Part A  
MEX0109 - Part C 
MEX0110; MEX0111 
Headache 
11 
27.50% 
MEX0109 - Part A 
Tremor 
1 
2.50% 
Respiratory, thoracic and mediastinal disorders 
1 
2.50% 
MEX0110 
Oropharyngeal discomfort 
1 
2.50% 


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Cumulative Adverse Drug Reactions - Number of events by Terms 
Study code ref./ System Organ Class (SOC) MedDRA Preferred Term 
(PT) 
Number of events 
Frequency 
TOTAL REPORTS 
40 
 
Subjects exposed to DF 2156A* with at least an ADR 
28 
 
*: figures include subjects exposed to DF 2156A plus tolbutamide (MEX0109 - Part C) and excluding placebo (8 events) 
Overall, 40 ADRs were reported in a total of 28 subjects out of 93 exposed to ladarixin. 
The most frequent (>10%) ADRs observed were:  
Gastrointestinal Disorders: (about 50%) including dyspepsia, dysphagia, abdominal pain, mouth 
ulceration, nausea. 
Nervous System Disorders: (about 35%) including headache, dizziness. 
Dyspepsia and dysphagia were both considered as definitely related to ladarixin because they occurred 
shortly after administration; also, dyspepsia consistently recurred on subsequent drug administration.  
All the ADRs resolved. 
2.5. 
DISEASE REVIEW AND STUDY RATIONALE 
T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing 
-cells.  The onset of the disease typically occurs before adulthood and seriously affects a person’s quality 
of life.  Incidence of T1D is rapidly increasing, with a predicted 70% increase in incidence over the next 
15 years in Europe [Atkinson, 2014; Waldron-Lynch, 2011]. 
T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels.  
However, even optimization of glucose control through the most recent technologies cannot adequately 
substitute for the finely tuned normal balance of the glucose levels. Pancreatic islet or whole pancreas 
transplantation still has limited success due to graft loss and immunosuppression derived side-effects.   
Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes 
results in secondary long-term complications and is one of the leading causes of end-stage renal disease, 
blindness and amputation.  Additionally, hypoglycaemia unawareness is a serious consequence of 
recurrent hypoglycaemia often requiring emergency care [Atkinson, 2014; Waldron-Lynch, 2011].   
Maintenance of residual -cell function (as measured by C-peptide response) was demonstrated to be 
associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, 
and overall reduction in morbidity and associated management costs.  Therefore, pharmacological 
approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic -
cells had attracted the clinical/scientific interest.  [Steffes, 2003; Barnard, 2010; Waldron-Lynch, 2011]. 
Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to 
phase III clinical trials.  Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are 
under clinical evaluation.  Unfortunately, even if safe preservation of -cell function and improvement of 
glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, 
none has been definitely approved for the “treatment” of diabetes onset [Ludvigson, 2008; MacroGenics, 
2010; Mastrandrea, 2009; Peskovitz, 2009; Waldron-Lynch, 2011; Raz, 2014].  
New strategies are being evaluated which combine agents targeting sequential arms of the immune and 
inflammatory response involved in -cell disruption.  In this regard, IL-8 appears to be an important 
mediator in the progression of type 1 diabetes.  Production and secretion of pro-inflammatory IL-8 has 
been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production 
of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients.  In parallel, circulating 
levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels 
of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose 
control [Aboelasrar, 2012; Erbağci, 2001; Glowacka, 2002; Diana, 2014; Van Sickle, 2009] 
As a result of these findings, the modulation or inhibition of CXCL8 activity is considered a valid 
target for the development of innovative treatments aimed to control the progression of T1D. 


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Results obtained with ladarixin in mouse models of T1D, and particularly reversal of “diabetes” in the 
NOD mice, clearly shows the ability of this CXC1/2 inhibitor to protect -cells and either prevent or 
delay the progression of hyperglycaemia.  The positive effects of ladarixin, coupled with the safety 
shown in phase 1 studies, provide a sound rationale for a clinical study aimed at evaluating the effect 
of ladarixin in patients with new onset diabetes and supports the conduct of the present study. 
2.5.1. 
Selection of dose and treatment schedule in the study 
The proposed dose in this clinical study is 400 mg oral ladarixin twice a day for 3 cycles of 2 weeks 
on - 2 weeks off.  
The oral route has been selected as the more appropriate for a 14 day continuous treatment.  The PK 
profile support this choice.  
The 400 mg dose has been selected to provide a drug exposure that would maximise the potential to 
observe a drug effect, while remaining within safety margins.  Indeed, this dose was already 
established to be safe in phase 1 clinical studies in adult male healthy subjects.  This dose will provide 
an average steady state plasma concentration of the ladarixin unbound fraction (about 100-150 ng/mL) 
that  should ensure full inhibition of PMN migration, considering that the in vitro IC50 is in the range 
of 1 ng/mL. 
The proposed treatment schedule (3 cycles of 14 days on - 14 days off) is intended to expose the 
patient to ladarixin for a period sufficient for such a molecule to establish a potential effect.  
According to International Conference on Harmonization (ICH) guidelines (guidance on non-clinical 
safety studies for the conduct of human clinical trials and marketing authorization for 
pharmaceuticals), the available repeated dose toxicity studies (4 weeks in rodents and dogs) support 
the conduct of phase 2 trials with a maximal exposure of 28 days.  This proposed treatment schedule 
appears to exceed the duration of administration in previous clinical studies and in total will involve 
drug exposure over a longer period than has previously been explored in man or animals.  However, 
each cycle of the proposed treatment can reasonably be regarded at this stage as a separate event that 
each is adequately supported by the available 28-day toxicity test results.  Indeed, the PK in animals 
and man suggests clearance of the drug and its metabolites from the body of humans within 2-3 days 
at the most.  Also, the pharmacodynamic studies in vitro and in vivo in animals and humans suggest 
reversibility of the effect on CXCR1/2 receptors within a short period after exposure to the drug has 
ceased. 
The good safety profile of ladarixin in animals and humans further supports the proposed treatment 
schedule for this study.     
2.5.2. 
Alternative treatments 
There are no standard pharmacologic treatments, addressed to the prevention or treatment of T1D 
other than insulin replacement.  Despite recent advances in the number of immunomodulatory agents 
available and clinical trials in T1D, including drugs targeted to the cytokine system, only a few 
approaches tested to date, such as DiaPep277 injections, have provided some evidence of successful 
control of disease progression.  No one drug has therefore reached either definite therapeutic 
placement or marketing authorization for this indication [Waldron-Lynch, 2011]. 
Because of this, patients not willing to participate in the study may either be offered to participate in 
another trial of experimental treatments or will not be offered any specific alternative treatment other 
than insulin management.   
All patients, regardless of study participation, will receive the standard of optimal care for a recent 
onset T1D individual. 


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2.5.3. 
Risk - benefit evaluation 
2.5.3.1. 
Risk related to the ladarixin 
Results from preclinical studies support the level of drug exposure planned in this study.   
Phase 1 clinical experience with doses as high as that planned in this study provides evidence of the 
safety of ladarixin.  No SAEs or death occurred and all the AEs encountered were mild to moderate in 
intensity.  The safety was confirmed in the phase 2 trial; indeed, no safety concerns were raised even 
in elderly patients who were on several concomitant medications due to chronic disease. 
Any possible risk derived from the administration of ladarixin in the specific population involved in 
this study will be minimized by integrated monitoring which include clinical observations, laboratory 
tests and ECG readings (see Section 7.2.2 for details).  
Ladarixin inhibits enzyme CYP2C9 and may affect plasma levels of those drugs that are metabolized 
by this system.  Restrictions of use and monitoring procedures (see Section 6.5.2 for details) will limit 
any possible risks derived from potential metabolic interactions.    
 
2.5.3.2. 
Blood sampling 
Participation in the study will require additional blood samplings other than the routine ones.  In 
particular: 
- a blood sample (about 10 mL) will be obtained at screening, at the end of 1st treatment cycle (i.e. 
pre-dose visit, 2nd cycle) and at the 13 week follow-up visit to evaluate standard haematology and 
clinical chemistry; 
- blood samples for  diagnostic auto-ab test (maximum 5 mL) and for baseline auto-ab, HbA1c, miR-
375, and MMTT c-peptide, glucose, glucagon (maximum 100 mL) will be taken during screening;  
- blood samples (about 5 mL) will be obtained before the 3rd treatment cycle is started to monitor 
renal (creatinine) and hepatic (ALT/AST, bilirubin) function, and albumin; 
- blood samples for auto-ab, HbA1c, miR-375 and MMTT c-peptide, glucose, glucagon (maximum 
100 mL) will be taken during each of the 3 follow-up visits;  
- T-cell response will require additional 10 mL of blood at the selected sites only. 
Blood sampling will occur through a peripheral vein and may cause faintness and/or swelling, pain, 
redness, bruising, or infection (infection rarely happens) at the site where the needle is inserted.  The 
volume of blood above is an amount that the body can safely replace. 
 
2.5.3.3. 
Mixed Meal Tolerance Test 
Participation in the study requires testing for -cell function through a Mixed Meal Tolerance Test 
(MMTT) to be performed in basal conditions (pre-dose) and then at follow up visits at weeks 13+1, 
26+2 and 52+2.  This is not a routine test in patients with new onset diabetes, but has become a standard 
for the purpose of research studies and is performed frequently by investigational sites.   
Apart from the risks due to blood samplings detailed above, the MMTT requires an overnight fast that 
may potentially increase the risk of a hypoglycaemic event.  However, detailed instruction for patient 
management provided by the Investigator will minimize the risk of metabolic unbalance. 
 
2.5.3.4. 
Potential benefit 
To the patients: 
One third of the patients will be assigned to the placebo arm and will therefore 
obtain no disease benefit.  The patients assigned to receive ladarixin may possibly 
benefit with control of disease progression, but this is to be ascertained.  


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All the patients will benefit of increased scrutiny and monitoring that comes with 
being part of a clinical trial. 
To society: 
This study may identify a useful medication that may help controlling the 
progression of T1D in patients with recent diagnosis. 
 


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3. 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION 
3.1. 
STUDY DESIGN 
The study will be a phase 2, multicentre, double-blind study.  It has been designed to investigate 
(proof of concept) whether ladarixin has sufficient activity (preservation of -cell function and slow-
down of the progression of T1D) to warrant its further development.      
It will involve 72 patients with new-onset T1D.  Patients will be randomly (2:1) assigned to receive 
either ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off - treatment group) or 
matched 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.  Competitive recruitment has been chosen to increase the speed of recruitment and to account 
for any difference among study sites in the rate and timing of patient referral.  Each site will recruit 
patients as rapidly as possible up to a maximum of 21 patients (as per randomization list).  
Each patient will be involved in the study for a screening period of up to 100 days followed by a post-
randomization period up to 52+2 weeks, as per details below: 
- 
a screening period including 2 or more visits during a period up to 100 days; this includes the 
time required to confirm the diagnosis; 
- 
a treatment period including 3 treatment cycles of 2 weeks each with 2 weeks interval between 
cycles and 2 corresponding pre-dose assessment visits; 
- 
3 follow-up visits scheduled at weeks 13+1 (month 3), 26+2 (month 6) and 52+2 (month 12).  
Sample size calculation has been based on the 2-hour area under the curve (AUC) of C-peptide 
response to a Mixed Meal Tolerance Test (MMTT) observed 12 months after randomization, as these 
are the only available data that best match the T1D population expected to be randomized in this trial 
(age, time from diagnosis, etc.) [Lachin, 2011].  On the other hand, the time frame for the primary 
endpoint (2-hour AUC of C-peptide response to the MMTT) has been set at week 13+1 in order to 
maximise the potential to observe an effect of ladarixin, considering the PK profile in humans as well 
as the reversibility of the pharmacological effect on CXCR1/2 receptors.  Such an approach is 
appropriate for a phase 2 proof of concept trial.  Follow-up is anyway extended up to 12 months.  
3.2. 
STUDY TIME TABLE 
Overall study timelines are reported below. 
Projected starting date (first-patient-in):  
December 2015 
Projected completion of patient accrual (last-patient-in): 
December  2016  
Projected study end date (last-patient-last-visit): 
December  2017 
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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4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
STUDY OBJECTIVES  
 
 
 
The objective of this clinical trial is to investigate whether ladarixin has sufficient activity 
(preservation of -cell function and slow of the progression of T1D) to warrant its further 
development.  The safety of ladarixin in the specific clinical setting will be also evaluated.  
4.2. 
STUDY ENDPOINTS 
4.2.1. 
Efficacy endpoints 
 
2-hour AUC of C-peptide response to the MMTT [Primary endpoint. Time frame: baseline, 
week 13+1].  
 2-hour AUC of C-peptide response to the MMTT [Time frame: baseline, weeks 26+2 and 52+2].   
 Average (previous 3 days) insulin requirement (IU/kg/day) [Time frame: baseline, weeks 13+1, 
26+2 and 52+2].  
 HbA1c levels [Time frame: baseline, weeks 13+1, 26+2 and 52+2].  
 Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of C-peptide and 
glucose derived from the MMTT [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
 Cumulative severe hypoglycaemic events occurring from randomization [Time frame: weeks 
13+1, 26+2 and 52+2]. 
For the purpose of this protocol, a severe hypoglycaemic event is defined as an event with one of the 
following symptoms: “memory loss, confusion, uncontrollable behaviour, irrational behaviour, 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 
<54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. 
4.2.2. 
Exploratory endpoints 
 
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of glucagon 
derived from the MMTT [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
 
Auto-antibodies (GAD, IA-2, IAA, ZnT8), [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
 
MicroRNA-375 (miR-375)  [Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
 
T-cell response ex vivo to major -cell antigens (pro-insulin, GAD65) - selected sites only 
[Time frame: baseline, weeks 13+1, 26+2 and 52+2]. 
4.2.3. 
Safety endpoints  
 
Vital signs (blood pressure and heart rate) [time frame: screening, end of 1st treatment cycle (i.e. 
pre-dose visit, 2nd cycle), week 13+1].  
 Routine laboratory tests (haematology, clinical chemistry) [time frame: screening, end of 1st 
treatment cycle (i.e. pre-dose visit, 2nd cycle), weeks 13+1 (or withdrawal)].   
 Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [time frame: throughout 
the study].  
 


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5. 
STUDY POPULATION 
Seventy-two (72) patients new-onset T1D will be included (randomized) in the study, selected from 
those referring to the clinical site for diabetes diagnosis and/or management. 
Each patient will be randomized provided that (s)he fully meets all of the study Inclusion Criteria and 
none of the 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 the following inclusion criteria.  
1. 
Male and female patients aged 18-45 years, inclusive; 
2. 
New-onset T1D (randomization within 100 days from 1st insulin administration);  
3. 
Positive for at least one diabetes-related auto-antibody (anti-GAD; IAA, if obtained within 10 
days of the onset of insulin therapy; IA-2 antibody; ZnT8); 
4. 
Require, or has required at some time, insulin, with the exclusion of patients taking twice daily 
pre-mixed insulin or on insulin pump; 
5. 
Residual -cell function as per peak stimulated (MMTT) C-peptide level >0.6ng/mL (0.2nmol/L); 
MMTT should not be performed within one week of resolution of a diabetic ketoacidosis event;  
6. 
Patient able to comply with all protocol procedures for the duration of the study, including 
scheduled follow-up visits and examinations; 
7. 
Patients who have given written informed consent prior of any study-related procedure not part of 
standard medical care; 
5.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study. 
1. 
Patients taking twice daily pre-mixed insulin or on insulin pump 
2. 
Any other chronic disease, including type 2 diabetes, apart from autoimmune hypothyroidism 
requiring thyroid hormone replacement only; patients with severe (myxedema) disease potentially 
requiring immunosuppressive therapy will be excluded;  
3. 
Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 60 mL/min 
according to the Cockcroft-Gault formula (Cockcroft-Gault, 1976); 
4. 
Hepatic dysfunction defined by increased ALT/AST > 3 x upper limit of normal (ULN) and 
increased total bilirubin > 3 mg/dL [>51.3 μmol/L]; 
5. 
Hypoalbuminemia defined as serum albumin < 3 g/dL; 
6. 
QTcF > 470 msec; 
7. 
Complete Left Bundle Branch Block (LBBB), atrio-ventricular block (mobitz II 2nd degree or 2:1 
atrio-ventricular block), complete heart block; 
8. 
Electronic pacemaker positioned or implanted defibrillator; 
9. 
History of significant cardiovascular disease;  
10. Known hypersensitivity to non-steroidal antiinflammatory drugs; 
11. Concomitant treatment with phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide, 
glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 
mg/day); 
12. Previous (within 2 weeks prior to randomization) and concomitant treatment with metformin, 
sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin, or 


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any medications known to influence glucose tolerance (e.g. -blockers, angiotensin-converting 
enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.); 
13. Past (within 1 month prior to randomization) or current administration of any immunosuppressive 
medications (including oral, inhaled or systemically injected steroids) and use of any 
investigational agents, including any agents that impact the immune response or the cytokine 
system; 
14. Pregnant or breast feeding women.  Unwillingness to use effective contraceptive measures up to 2 
months after the end of study drug administration (females and males).  Effective contraceptive 
measures include an hormonal birth control (e.g. oral pills, long term injections, vaginal ring, 
patch); the intrauterine device (IUD); a double barrier method (e.g. condom or diaphragm plus 
spermicide foam). 
5.3. 
ASSIGNMENT OF PATIENT NUMBER 
From enrolment (consent signature) to randomization patients will be identified by a Screening 
number will be assigned in a sequential manner within each site, as patients are enrolled (sign the 
consent).  It will consist of 4 digits, e.g. 0152, where first 2 digits represent site number (01 = site 1), 
last 2 digits, starting from 50, patient sequential enrolment number within the site (e.g. 50, 51, 52, 53, 
54, etc.).  
If randomized, the Randomization number will be assigned in a sequential manner within each site, as 
patients are found to be eligible and are randomized.  It will consist of 4 digits, e.g. 0102, where first 2 
digits represent site number (01 = site 1), last 2 digits, starting from 01, patient sequential 
randomization number within the site (e.g. 01, 02, 03, 04, etc.).  If a patient is dropped from the study 
for any reason, the patient’s randomization number will not be reassigned.  
 


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6. 
STUDY MEDICATION 
6.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT 
6.1.1. 
Presentation of Investigational Medicinal Product 
In this study the Investigational Medicinal Product (IMP) will be either ladarixin OR matched placebo. 
It will be provided as hard gelatine capsules for oral administration, with the following composition: 
Composition for each unit (capsule) 
 
NAME OF INGREDIENT 
FUNCTION OF 
INGREDIENT 
AMOUNT FOR 
CAPSULE 
(mg) 
REFERENCE  TO QUALITY  
STANDARDS 
 
 
ACTIVE PLACEBO 
 
Ladarixin 
Active ingredient 
200mg 
- 
Internal monograph 
Microcrystalline cellulose 
Filler 
up to 266.20 mg 
EP current edition 
Lactose monohydrate 
Filler 
up to 60 mg 
EP current edition 
Croscarmellose Sodium 
Disintegrant 
up to 14 mg 
EP current edition 
Hydroxypropyl cellulose 
Binder 
up to 6 mg 
EP current edition 
Citric acid monohydrate 
Stabilising agent 
up to 5.2 mg 
EP current edition 
Magnesium Stearate 
Lubricant 
up to 2 mg 
EP current edition 
 
Batch release certificate will be provided together with the IMP.  
6.1.2. 
Manufacturing, Packaging and Labelling of IMP 
Capsules will be manufactured and packaged in blisters by Patheon UK Limited, Abingdon, UK.     
The study medication will be provided as a Patient Kit, containing 3 Treatment Boxes (one box for 
each treatment cycle). Each Treatment Box will contain 56 capsules packaged in 7 
Aluminum/Aluminum blisters with 8 capsules in each blisters.   
All labels will be prepared to meet local regulatory requirements.  Details of packaging and labelling 
are reported in Appendix 14.1. 
6.1.3. 
Supply, Storage and Handling of IMP 
An appropriate number of packages will be initially sent to the site as soon as all essential documents 
and regulatory/ethics approvals have been obtained.  IMP re-supply will be planned on demand, 
according to enrolment rate.  
The IMP 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. 
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 IMP must be stored in a secure location, in a temperature controlled room.  Temperature records 
must be available for the CRA to review at monitoring visits; any deviations from the recommended 


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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 IMP will be dispensed only by the Pharmacist (or authorized designee).  The Investigator will 
ensure that study treatment is only administered by designated staff within the centre. 
6.1.4. 
Blinding 
Appearance, including packaging and labelling, of the IMP (capsules, packaging) will not allow to 
recognize actual treatment (either ladarixin or placebo). 
During the trial, blinding will be broken by the Investigator for emergency purposes only, where 
knowledge of the blinded treatment could influence further patient care.  In addition, safety reports 
will be unblinded, as per regulatory requirements. 
Study blind will be broken after database lock. 
6.2. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
Ladarixin will be administered orally at the dose of 400 mg twice a day for 3 cycles of 14 days on / 14 
days off.  Placebo will be administered with the same treatment schedule.  
The two daily doses will be administered at about 12 hour interval (morning and evening; ideally 
between 8.30/9.30 and 20.30/21.30).  At each administration, 2 capsules will be swallowed with a 
glass of water, at least 2 hours apart from breakfast or dinner.  
6.3. 
CRITERIA 
FOR 
SCHEDULE 
ADJUSTMENT/DOSE-MODIFICATION/ 
DISCONTINUATION OF IMP 
6.3.1. 
Criteria for schedule adjustment or dose modification 
No schedule adjustment and/or dose modification is foreseen, except for discontinuation of IMP as 
detailed below. 
6.3.2. 
Criteria for discontinuation of IMP 
The IMP will be discontinued in the case: 
 
QTcF is either > 500 msec or increases by > 60 msec from screening measurement on two 
consecutive ECG readings taken 1 hour apart;  
 
The patient develops LBBB, or atrio-ventricular or heart block; 
 
The patient develops any significant cardiovascular disease; 
 
The patient develops renal (calculated CLcr < 60 mL/min) or hepatic (increased ALT/AST > 3 x 
ULN and increased total bilirubin > 3mg/dL [>51.3 mol/L]) dysfunction as well as 
hypoalbuminemia; 
 
Pregnancy occurs (female patient). 
 
The patient develops ketoacidosis or hypoglycaemic coma. 
Cardiac, renal and hepatic safety will be specifically monitored through pre-planned ECG readings 
and laboratory tests obtained within one week before starting the 2nd and 3rd treatment cycles.   
In addition, the IMP will be immediately discontinued in the event of any other possibly drug related 
occurrences that the Investigator believes might compromise patient’s safety.  Results of safety 
laboratory tests performed after the 1st treatment cycle will be also considered.    
If the IMP administration is prematurely discontinued the primary reason for discontinuation must be 
recorded in the CRF.  Patients who discontinue the treatment with the IMP will not be withdrawn from 


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the study by default, but will be asked to complete safety and efficacy observations as per the protocol, 
unless otherwise they withdraw their consent. 
6.4. 
ACCOUNTABILITY OF THE IMP 
All supplies will be maintained under adequate security by the designated member of site staff, until 
they are dispensed to the patients.  The Investigator will ensure that study treatment is only dispensed 
by designated staff within the centre.   
When the IMP is received at the site, designated member of site staff will check for accurate delivery 
and acknowledge receipt by signing and dating the documentation provided by or on behalf of Dompé 
and returning it to Dompé.  A copy will be retained for the Investigator/Pharmacy file. 
The dispensing of the IMP will be carefully recorded on the CRF and appropriate drug accountability 
forms and an accurate accounting will be available for verification by the CRA at each monitoring 
visit.  Immediately before dispensing each Treatment Box, the removable label will be detached from 
the Treatment Box and attached to the relevant page of the CRF.     
Drug accountability records will include: 
1. the confirmation of receipt of the IMP at the trial site, 
2. the dispensing of the IMP to the patient, 
3. the receipt of IMP returned from the patient,  
4. the disposition of unused product(s), 
5. accounts of any IMP accidentally or deliberately destroyed, 
They should include dates, quantities, batch numbers, expiration dates (if applicable), and any unique 
code numbers assigned to the IMP and/or patients.  Investigators should maintain records which 
document adequately that: 
1. the patients were provided the doses specified by the protocol/amendment(s), 
2. the IMP provided was fully reconciled at the site. 
The administration of the IMP (date/time for each administration) will be recorded by the patient on a 
Diary Card (see Appendix 14.2) which will be returned to and checked by the Investigator during the 
next study visit. 
The CRA will review the drug accountability forms/CRF/Diary Cards and check all IMP (both unused 
and used) prior to making arrangements for their disposal. 
IMP which has been dispensed to a patient and returned unused will not be re-dispensed to a different 
patient.  Unused IMP (capsules) must remain in the blisters within the Treatment Box and must not be 
discarded or used for any purpose.  Any remaining test material at the end of the trial will be returned 
to Dompé or disposed of, as determined by Dompé. 
6.4.1. 
Assessment of compliance 
Compliance with the study product dosing schedule will be verified by a CRA during on-site 
monitoring visits, as per records in the CRF and Diary Card, versus accountability records.  
6.5. 
CONCOMITANT MEDICATION 
6.5.1. 
Reporting of prior and concomitant medications 
Administration of all prior (within 1 month before enrolment) and concomitant medications (CMEDs), 
apart from insulin and the agents listed below, will be reported in the appropriate section of the CRF.   


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All the details as per the CRF fields (sequential number, drug name, indication, starting dose, 
start/stop date, route of administration) will be recorded.  No change in dose will be tracked. 
The following agents do not need to be recorded: homeopathic medications; elective vitamins and 
minerals; osmotic laxatives and locally acting antacids; topical medication. 
6.5.2. 
Restriction on allowed prior and concomitant medications 
The following medications should not be used prior to enrolment and up to the end of study 
participation:  
Drugs that affect glucose homeostasis or its readout 
 Twice daily pre-mixed insulin or insulin pump; 
 Metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or 
amylin, or any medications known to influence glucose tolerance (e.g. -blockers, angiotensin-
converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc) [off 
period before randomization = 2 weeks]; 
 Any immunosuppressive medications, including oral, inhaled or systemically injected steroid,  and 
any other investigational agents, including any agents that impact the immune response or the 
cytokine system [off period before randomization = 1 month]. 
Drugs metabolized by CYP2C9 with a narrow therapeutic index (drugs that may have their plasma 
concentration and effect altered by inhibition of CYP2C9 by ladarixin). 
 Phenytoin, 
warfarin, 
sulphanylurea 
hypoglycemics 
(e.g. 
tolbutamide, 
glipizide, 
glibenclamide/glyburide, glimepiride, nateglinide) and high doses of amitriptyline (> 50 mg/day). 
 
The following medications can be used with the restrictions detailed below:  
 Non-steroidal antiinflammatory drugs (e.g. ibuprofen, flurbiprofen, indomethacin, piroxicam, 
naproxen, meloxicam, lornoxicam, celecoxib) can be used during treatment with ladarixin up to a 
maximum of 3 consecutive days, with a 3 days washout before re-treatment, if any (excluded 
patients with known hypersensitivity to non-steroidal antiinflammatory drugs). 
 Administration of low doses amitriptyline (< 50 mg/day) is allowed under clinical monitoring for 
possible side effect (e.g. sedation and anticholinergic symptoms).  In case a concern is raised, 
treatment with either amitriptyline or ladarixin should be immediately discontinued.  
 Any drug that is known to be a substrate for cytochrome CY2C9 should be considered for possible 
drug-drug interaction as per warnings/precautions reported in the Summary of Product 
Characteristics.  Any possible concern should be discussed with the sponsor Medical Expert prior 
to patient enrolment or concomitant administration with ladarixin.       
6.6. 
INSULIN TITRATION 
Patients will self-monitor glucose levels at least 4 times a day and will take insulin as prescribed by 
the Investigator throughout the study participation (see Section 7.1.1). 
To ensure standardized glycaemic control in the treatment groups, the Investigator will provide 
guidance for insulin regimen adjustment, with insulin titrated up or down to target HbA1c levels of 
less than 7% and self-monitored (fingerstik): 
- 
pre-prandial blood glucose of 70-130 mg/dL 
- 
post-prandial blood glucose < 180 mg/dL 
- 
bed-time blood glucose of 110-150 mg/dL 
In order to optimize insulin titration, telephone calls (outside scheduled visits) will be scheduled on a 
regular basis to ensure timely evaluation of glucose levels and adjustment of insulin regimen.    


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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 14.3. 
For all measurements, the actual date and time of assessment, including date of sampling, will be 
recorded in the CRF.  Where a time window is acceptable, this is clearly indicated in the following 
sections. 
7.1. 
ENROLMENT, SCREENING AND RANDOMIZATION 
7.1.1. 
Enrolment and Intensive Diabetes Management 
Potential study patients with a recent clinical diagnosis of T1D will be identified from those referring 
to the site for diagnosis confirmation (auto-antibody testing) and/or disease management.   
Enrolment is defined as signature of the Informed Consent Form (ICF) for study participation. 
From enrolment, patients will be admitted to an intensive diabetes management, according to current 
ADA recommendation [2014].  Patients will be instructed to self-monitor their glucose values at least 
4 times a day and to report (glucose meter/log) outcome to the diabetes management team.  Insulin 
intake will be adjusted to target HbA1c levels of less than 7% and self-monitored (fingerstik): 
- 
pre-prandial blood glucose of 70-130 mg/dL 
- 
post-prandial blood glucose < 180 mg/dL 
- 
bed-time blood glucose of 110-150 mg/dL 
Telephone calls (outside scheduled visits) will be scheduled on a regular basis to ensure optimization 
of metabolic control.  It is expected that patients are contacted at least every 2 to 3 weeks during study 
participation.  A telephone call will be anyway scheduled in the 2 weeks before a planned visits (as 
detailed in the sections below) to enable the Investigator to review glucose data and confirm/adjust 
insulin intake to be applied for at least 3 days before the visit. 
7.1.2. 
Screening 
Screening, including confirmation of T1D diagnosis, will be performed in enrolled patients. 
Screening includes the following assessments, and may be performed in one or more visits, as per 
details below:    
 time frame: from enrolment to randomization (clinical information) 
• Past medical history and disease-specific clinical information, including date of first insulin 
administration; 
• Blood sampling for measurement (centralized laboratory) of auto-antibody (anti-GAD; IAA, if 
obtained within 10 days of the onset of insulin therapy; IA-2 antibody; ZnT8) to confirm T1D 
diagnosis; Samples will be obtained and stored as detailed in Appendix 14.4.1. 
 
 time frame: within 3 weeks before randomization (baseline measurements - consider time for 
centralized assay of MMTT C-peptide – results available within 5 working days)  
• Measurement of blood pressure, heart rate, body weight, height; 
• Blood sampling(s) for measurement (local laboratories) of “Safety Laboratory Tests” i.e.: 
hematocrit, hemoglobin, red blood cells, platelets, white blood cells, differential white blood 
cells count, sodium, potassium, serum creatinine, serum albumin, blood urea nitrogen, total 
bilirubin, ALT, AST; 
• Evaluation of renal and hepatic function (to be derived from the safety laboratory test results).   
Renal function will be evaluated by CLcr, calculated according to the following formula [Cockcroft-


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Gault, 1976]: 
Male: CLcr = 
[140 - age (years)] x Weight (kg) 
 
Serum Creatinine (mol / L) x 0.815 
 
Female: CLcr = 
[140 - age (years)] x Weight (kg) 
x 0.85 
Serum Creatinine (mol / L) x 0.815 
Hepatic function will be evaluated by bilirubin and transaminases (ALT and AST). 
 
• Screening 12 lead ECG, performed using local equipment that allows automatic calculation of 
the QTcF. 
• Pregnancy test (urine dipstick or blood sample), if appropriate; 
• Baseline insulin requirement (IU/kg/day averaged over the previous 3days);  
• Blood sampling for measurement (centralized laboratory) of baseline auto-antibody (anti-GAD; 
IAA; IA-2 antibody; ZnT8 – not to be repeated if “diagnostic” test is done within this 
timeframe), HbA1c and miR-375 (and T-cell response ex vivo at selected sites only).  Sample 
handling is detailed in Appendix 14.4.1; 
• Baseline MMTT.  Blood samples for measurement (centralized laboratory) of C-peptide, 
glucose and glucagon will be drawn pre-meal (2 basal samples in the range between -20 to 0 
min) and 15, 30, 60, 90, 120, 180 min after the meal.  Procedures for MMTT and sample 
handling are detailed in Appendix 14.4.2 and Appendix 14.4.1, respectively.  MMTT should 
not be performed within one week of resolution of a diabetic ketoacidosis event;  
For the purpose of this protocol, a diabetic ketoacidosis event is defined as the presence of: 
  
hyperglycemia (blood glucose >200 mg/dL); 
  
pH <7.3 or HCO3 <15; 
  
ketones positive in the serum or urine.  
7.1.3. 
Randomization 
Compliance with inclusion/exclusion criteria will be finally verified vs demographic, laboratory test 
results and clinical information.   
Patients fulfilling all the inclusion criteria and none of the exclusion criteria will be randomized 
(randomization number assigned) by an Investigator (or designee), randomization to occur within 100 
days from the 1st insulin administration. 
Randomization is defined as Study Day 0 with reference to day when IMP administration is 
started which is defined as Study Day 1. 
Patients who do not meet the Inclusion Criteria or meet Exclusion Criteria will be considered 
screen failures (screen failure number assigned) and will not be allowed to be re-considered 
for inclusion into the study. 
7.2. 
PRE-DOSE ASSESSMENTS & DRUG ADMINISTRATION 
7.2.1. 
Pre-dose assessment - 1st treatment cycle 
Assessment to be done before the 1st dose are part of screening evaluation and reported in Section 
7.1.1 above.  On the day of randomization (Study Day 0), patient will be provided with the Treatment 
Box - Cycle No. 1 matching his/her randomization number, together with the Diary Card. 


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Before box delivery, the removable label on the Treatment Box (see Section 6.4) will be detached and 
attached to the relevant CRF page. 
It is the responsibility of the Investigator (or designee) to explain, and make sure patient fully 
understands any appropriate treatment related information.  This includes, but is not limited to 
treatment schedule, time of administration, time interval from meals, recording of administration in the 
Diary Card, etc.       
7.2.2. 
Pre-dose assessment - 2nd and 3rd treatment cycle 
Patient will refer to the site within 1 week before the expected date when the 2nd or 3rd treatment cycle 
is due to start.  The following will be evaluated:   
• General clinical evaluation to ensure patients has not developed concurrent clinical conditions, 
including pregnancy in female participants, which in the opinion of the Investigator may pose a 
safety risk for continuing participation in the study 
• Blood sampling(s) for measurement (local laboratories), of serum creatinine, serum albumin, 
total bilirubin, ALT, AST.  Renal and hepatic function will be evaluated as per details in Section 
7.1.1 above.   
• 12 lead ECG performed using local equipment that allows automatic calculation of the QTcF.  
If the QTcF is EITHER > 500 msec OR has increased by > 60 msec from baseline value, a 
second reading will be obtained 1 hour later. 
• Pregnancy test (urine dipstick or blood sample), if appropriate. 
• On pre-dose 2nd cycle ONLY: Measurement of blood pressure and heart rate; Blood 
sampling(s) will allow the measurement (local laboratories) of the whole set of “Safety 
Laboratory Tests” i.e.: hematocrit, hemoglobin, red blood cells, platelets, white blood cells, 
differential white blood cells count, sodium, potassium, serum creatinine, serum albumin, blood 
urea nitrogen, total bilirubin, ALT, AST. 
 
Laboratory results and ECG reading MUST be made available before the Treatment Box for the next 
treatment cycles is dispensed. 
As per discontinuation criteria (see Section 6.3.2), no IMP will be dispensed in the case: 
 
QTcF is either > 500 msec or increases by > 60 msec from screening measurement on two 
consecutive ECG readings taken 1 hour apart;  
 
The patient develops LBBB, or atrio-ventricular or heart block; 
 
The patient develops any significant cardiovascular disease; 
 
The patient develops renal (calculated CLcr < 60 mL/min) or hepatic (increased ALT/AST > 3 
x ULN and increased total bilirubin > 3mg/dL [>51.3 mol/L]) dysfunction as well as 
hypoalbuminemia; 
 
Pregnancy occurs (female patient). 
 
After having confirmed the patient has not developed a condition that prevents his/her continuing 
participation into the study, he/she will be provided with the Treatment Box - Cycle No. 2 or 
Treatment Box - Cycle No. 3 (as appropriate) matching his/her randomization number, together with 
the Diary Card. 
Before box delivery, the removable label on the Treatment Box (see Section 6.4) will be detached and 
attached to the relevant CRF page. 


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It is the responsibility of the Investigator (or designee) to check the Diary Card completed for the 
previous administration period to ensure correct intake of the IMP.  The Investigator will remind, and 
make sure patient still fully understands any appropriate treatment related information.     
7.2.3. 
IMP administration 
The day when the patient starts IMP administration  is defined as Study Day 1 (first day in Week 1). 
On each treatment cycle, the IMP will be administered at 12 hour interval (morning and evening; 
ideally in between 8.30/9.30 and 20.30/21.30).  At each administration, 2 capsules will be swallowed 
with a glass of water, at least 2 hours apart from breakfast or dinner.   
Administration of the IMP will continue for 14 consecutive days, unless there is any reason for drug 
discontinuation (see Section 6.3.2).  
The administration of the IMP (date/time for each administration, number of capsules) will be 
recorded by the patient on a Diary Card (see Appendix 14.2). 
Diary Card as well as the Treatment Box containing all the blisters, either unused or empty, will be 
returned to and checked by the Investigator during the next study visit. 
7.3. 
FOLLOW-UP STUDY ASSESSMENTS 
Patients will attend the centre for study assessments on 3 follow-up visits scheduled at weeks 13+1 
(month 3), 26+2 (month 6) and 52+2 (month 12).  
At each visit, the following will be evaluated/measured 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. 
• Blood sampling for measurement (centralized laboratory) of auto-antibody (anti-GAD; IAA; 
IA-2 antibody; ZnT8), HbA1c and miR-375 (and T-cell response ex vivo at selected sites only).  
Sample handling is detailed in Appendix 14.4.1; 
• MMTT.  Blood samples for measurement (centralized laboratory) of C-peptide, glucose and 
glucagon will be drawn pre-meal (2 basal samples in the range between -20 to 0 min) and 15, 
30, 60, 90, 120, 180 min after the meal.  Procedures for MMTT and sample handling are 
detailed in Appendix 14.4.2 and Appendix 14.4.1, respectively; 
• Insulin requirement (IU/kg/day averaged over the previous 3 days); 
• Cumulative number of severe hypoglycaemia events in the interval from: randomization to 
week 13+1, week 13+1 to week 26+2, week 26+2 too week 52+2;  
• On week 13 ONLY: Measurement of blood pressure and heart rate; Blood sampling(s) for 
measurement (local laboratories) of “Safety Laboratory Tests” i.e.: hematocrit, hemoglobin, red 
blood cells, platelets, white blood cells, differential white blood cells count, sodium, potassium, 
serum creatinine, serum albumin, blood urea nitrogen, total bilirubin, ALT, AST. 
7.4. 
EARLY PATIENT WITHDRAWAL 
7.4.1. 
Withdrawal criteria 
Patients will be informed that they have the right to withdraw from the study at any time (withdrawal 
of consent), without prejudice to their medical care, and are not obliged to state their reasons.   
If a patient fails to return to the centre for a scheduled visit, 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). 
Safety laboratory tests should be performed whenever possible at patient withdrawal.  


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Patients who discontinue the treatment with the IMP will not be withdrawn from the study, but will be 
asked to complete observations as per the protocol, unless otherwise they withdraw their 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 through the duration of the trial.       
Any withdrawals must be fully documented in the CRF. 
7.4.2. 
Replacement policy 
No patient who has been randomized and withdraws from the study for any reason will be replaced. 
7.5. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION 
After completion of the week 52 follow-up visit, patients will receive post-study care as prescribed by 
their health care provider.  No post-study treatment will be provided by Dompé.  


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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 unfavourable 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 [Detailed guidance on the 
collection, verification and presentation of adverse event/reaction reports arising from clinical trials 
on medicinal products for human use (‘CT-3’)].  
8.1.2. 
Definition of an Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) is defined as an adverse event which is reasonably likely to have 
been caused by the IMP. 
8.1.3. 
Definition of a Serious Adverse Event/Reaction 
A Serious Adverse Event (SAE)/Reaction 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. 
8.2. 
RECORDING 
AE data should be obtained through observation of the patient, from any information volunteered by 
the patient, or through patient questioning. 
All AEs (serious and non-serious) which occur from enrolment through patient participation in the 
study (last planned visit or early withdrawal date) will be reported and recorded in the CRF.  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). 
All AEs should be followed-up to determine 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.   
8.2.1. 
Relationship of AEs to the Investigational Product 
The Investigator will assess the causal relationship between the AE and the IMP (either ladarixin or 
placebo), according to the criteria in Table below: 


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Relationship of the Adverse Event to the IMP 
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 
Any AE reported in the study having a possible, probable or highly probable relationship to study drug 
will be considered as an ADR. 
8.2.2. 
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. 
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]) 
 
8.3. 
SERIOUS ADVERSE EVENT REPORTING 
8.3.1. 
Reporting Procedure for Investigators to Dompé 
The Investigator must report all SAEs occurring during patient participation in the study, regardless of 
presumed causal relationship, to the CRO Pharmacovigilance, by e-mail (preferred) or fax within 24 
hours of learning of the event.  Contact details for SAE reporting by the Investigator are provided in 
the section “Contact Information”.   
The Investigator should also report information on SAEs that continue after patient has completed 
his/her participation in the study (whether study completion or withdrawal), unless patient has 
withdrawn his/her consent. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not 
usually need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes 
aware of a SAE occurring to a patient after that patient has ended his/her participation in the study 
(whether study completion of withdrawal), the SAE should be reported by the Investigator to the the 
CRO Pharmacovigilance or directly to the Dompé Drug Safety department should the whole study 
have been ended.  Such “post-study cases” should be regarded for expedited reporting purposes as 


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though they were study reports.  Therefore, a causality assessment and determination of expectedness 
are needed for a decision on whether or not expedited reporting is required.  
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 e-mailed/faxed 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. 
CRO Pharmacovigilance will report to the Dompé Drug Safety any information received by the 
Investigators, by e-mail immediately and anyway within 24 hours of knowledge.  Copy of the SAE 
form received from the Investigator will be sent by the CRO to the Dompé Drug Safety immediately, 
and in no case later than 6 hours from knowledge, in case of fatal or life threatening events. 
8.3.2. 
Reporting Procedure to IEC and to Regulatory Authorities 
During the course of the clinical trial, Dompé shall report any serious unexpected* ADR, life-
threatening problems or deaths to the concerned IEC which approved the protocol and to the 
Competent Authorities 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; to be followed by any relevant information within eight days. 
(b) fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
* 
For the purpose of this study, all ADRs are assumed to be unexpected. 
 
Dompé shall follow up safety information and shall report any relevant updated findings as soon as 
available. 
If the results of an investigation show that an adverse drug reaction not initially determined to be 
reportable is reclassified as reportable, Dompé 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. 
In addition, each IEC/Competent Authority and Investigator will receive appropriate periodic safety 
updates as per applicable European and local requirements and regulations.     
8.4. 
EMERGENCY PROCEDURES 
The treatment allocation for each patient will be provided in individual tamper-resistant decoding 
systems (sealed envelopes or scratch cards) to: 
- the Investigator for emergency procedures; 
- the Pharmacovigilance for safety procedures. 
Individual treatment codes 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 Investigators will open an individual envelope in the event of an emergency only, where 
knowledge of the blinded treatment could influence further patient care.  Any code break and the 
reason behind it will be recorded (when it was opened, by whom and why) in the relevant page of the 
CRF.  Code break will be immediately communicated to the CRO or Dompé, as appropriate.   
 


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9. 
STATISTICAL ISSUES 
9.1. 
SAMPLE SIZE 
There are no data available to estimate the effect size of ladarixin in T1D patients in this study.    
C-peptide decline over time have been measured in different populations of T1D patients (age, time 
from diagnosis, etc.) making it difficult to derive reliable data for sample size calculation in our trial. 
Only the paper of Lachin [2011] provide figures for the population of new onset T1D patients as close 
as possible to that planned to be recruited in this trial.  Authors also provide an algorithm for sample 
size calculation based on data transformed to account for homogeneous distribution. 
According to the log(x+1) transformed data [initially selected by TrialNet as the appropriate 
transformation for MMTT C-peptide AUC] and the sample size calculated on the data stratified by an 
adult population (> 18 years), 72 patients will provide 85% power to detect a 50% between-group 
difference in the 2-hour MMTT C-peptide AUC (2:1) at 0.05 significance level (one-sided test), 
assuming a 24% drop-out rate. 
9.2. 
RANDOMIZATION 
Patient will be randomized in a 2:1 fashion to either ladarixin or placebo.     
The randomization list will be generated with a computer procedure by the method of random 
permuted blocks in which treatment will be balanced within centres.  A master randomization list will 
be generated, randomizing an excess of patients (a maximum of 21 for each site) 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, the randomization list will be provided to the 
facility responsible for IMP packaging/labelling for the purpose of IMP preparation. 
Individual treatment codes will be provided as a tamper-resistant system (either a sealed envelope or a 
scratch card) to:  
- the Investigator for emergency procedures; 
- the Pharmacovigilance for safety procedures. 
Individual treatment codes 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 randomization code will be broken at study completion, i.e. when the last patient has completed 
his/her last follow-up visit, and once the database has been locked.  
9.3. 
ANALYSIS POPULATION 
The Safety population will consist of all patients who received any study medication and will be based 
on the treatment actually received.  The Safety population will be used to present the demographic and 
baseline data, and all safety data. 
The Intent to Treat (ITT) population will consist of all patients who are randomized and receive the 
IMP (either ladarixin or placebo); it will be based on the treatment randomized, regardless of the 
treatment actually received.  The ITT population will be used to present efficacy data.  
9.4. 
STATISTICAL METHODOLOGY 
All patient data collected on the CRF and on the Diary Card will be listed by patient and centre.  
Appropriate descriptive statistics will be produced, according to the variable.  For continuous data the 


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mean, standard deviation, standard error of the mean, median and range (minimum and maximum) and 
lower and upper 95% confidence limits (CI) will be presented.  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.  
When C-peptide values are below the limit of detection (0.2 ng/mL), a value of 0.2 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 last available basal sample (time and value) will be used as the first 
sample in the computation of the AUC.  Inferential statistics will be conducted on log(x+1) 
transformed data, according to Lachin [2011]. 
Unless otherwise specified, the significance level used for statistical testing will be 0.05 and one-sided 
tests will be used.  
Besides statistical analysis presented below, additional post-hoc analysis may be produced  to 
further allow comparison between ladarixin and placebo, according to the results obtained.  
They may include change from baseline in C-peptide AUC, peak stimulated C-peptide, time 
to peak, etc.   
A Statistical Analysis Plan will be issued describing details of all the statistical methods and analysis 
to be applied to trial results.  Any change in the planed analysis will be documented.  The data will be 
presented in the clinical study report.   
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. 
Analysis of efficacy variables 
The 2-hour C-peptide AUC after the MMTT at week 13+1 (primary efficacy endpoint), will be 
analysed with Student t test for unpaired data  using PROC TTEST within SAS®, including terms for 
treatment and centre.  The estimated treatment difference between ladarixin and placebo will be also 
presented together with the corresponding 95% confidence interval.  
Additional analysis will include the analysis of the AUC at the 3 time points with a single repeated 
measurements model using PROC MIXED within SAS®.  The adjusted least squares means will be 
estimated for each combination of time point and treatment.  The treatment effect within each time 
point will be compared using a two sided test at 0.05 level.  The tests of the fixed effects will be 
presented, together with the estimated least squares means and summary statistics of the raw AUC for 
each of the two treatments at each time point.  The estimated treatment difference between ladarixin 
and placebo at each time point will be presented together with the corresponding 95% confidence 
interval.  The confidence interval will be generated at a statistical level of 0.05.  
The mean in average daily insulin requirements and HbA1c value at the 3 time points will be analysed 
using a repeated measurements model using PROC MIXED within SAS®.   
The effect of treatment on the cumulative number of severe hypoglycaemic events 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. 
Analysis of exploratory variables 
Exploratory variables will be presented using appropriate descriptive statistics, by treatment group. 


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9.4.4. 
Analysis of safety variables 
AEs will be presented in terms of the number of AE, 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 routine laboratory tests will be assessed as being below the lower limit of the normal range, 
within the normal range or above the upper limit of the normal range.  The frequency of patients 
reporting an abnormal or abnormal clinically significant laboratory value at screening and follow-up 
will be presented for each laboratory variable. 
Vital signs will be presented using descriptive statistics. 
9.4.5. 
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.  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. 


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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) 
It is the responsibility of the CRO appointed by Dompé to obtain approval of the trial 
protocol/amendments from the appropriate IEC. 
Prior to the initiation of the study, the followings will be submitted to the IEC for approval: 
- 
the study protocol, 
- 
the ICF, 
- 
the current version of the Investigator’s Brochure, 
- 
Investigator’s current curriculum vitae, 
- 
Insurance certificate 
- 
any other requested document(s). 
A copy of the IEC approval will be sent to Dompé along with relevant correspondence with the IEC.  
The study will not be started until full written approval has been obtained from the appropriate IEC.  
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 CRO appointed by Dompé will submit any future amendment to the protocol to the IEC which 
granted the original approval.  Any amendment will be implemented only when full approval has been 
obtained from the appropriate IEC, except for those amendments which involve only logistical or 
administrative aspects of the study. 
The CRO appointed by Dompé will also submit to the IEC which approved the protocol any required 
progress reports and study update, and will inform the IEC of the termination of the study. 
Responsibility for safety reporting, including serious ADRs, life-threatening problems or deaths 
occurring at sites participating to this clinical trial and/or in other clinical studies conducted with 
ladarixin, remains within Dompé.   
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 ICF.  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.  Similarly, patients will be informed 
that safety data might have to be collected after their participation in the study have been completed.  
If the patient is willing to participate in the study, (s)he will be requested to give written informed 
consent after being given sufficient time to consider his/her participation and the opportunity to ask for 
further details. 
The ICF will be signed and personally dated by both the patient and the Investigator.  A copy of the 
signed form will be provided to the patient, and the original signed ICF will be retained and filed in 
the Investigator Site File.  Patient consent will be documented in the hospital records.  
Individual (i.e. site specific; local language) ICF will be provided to the site once approved by the 
IEC.  Any changes requested by the IEC must be approved by Dompé prior to the documents being 
used.   
 
 


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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 ICF.  
Patient’s data collected during (or after completion of ) the study will be handled in accordance with 
applicable data protection laws and regulations.  
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 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 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 ICF. 
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 
CRFs will be supplied as 3-pages/ No-Carbon Required binder.  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 patient enrolled.  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; 
location of source documents, 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. 
The CRF must be available for review/collection to designated Dompé’s representatives at each 
scheduled monitoring/audit visit.  
11.2. 
DIARY CARD 
Diary Cards will be supplied as a single-page document.  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 Diary Card (local language version) will be provided to each patient randomized into the trial.  A 
sample English specimen is provided in Appendix 14.2.   
The patient will report in the Diary Card the details (date, time, number of capsules) of each 
administration of the IMP.  It is responsibility of the Investigator to explain to each patient how to 
enter the data in the Diary Card and to check the Diary Card returned to ensure correct completion as 
well as correct intake of the IMP.    
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 
data-base, 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 data-base 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 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 documents will be 
required from the Investigator prior to the initiation visit (and during the course of the study in case of 
any update): 
- 
Current, signed and dated Curriculum Vitae of Principal Investigator and any 
Sub-Investigators/co-workers.  Updates should be provided at least 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 copy of the study Financial Agreement/Clinical Study Agreement with Dompé (or 
designee), including all study specific costs. 
- 
List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form).  
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, but are not limited to: 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 (or designee) 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 (64th WMA 
General Assembly, Fortaleza, October2013) and ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (ICH-GCP) and any local regulations. 
12.1. 
REGULATORY BODY APPROVAL 
The CRO appointed by Dompé will obtain the necessary approval from the Competent Authorities 
prior to initiation of the study.  
The study will not be started until full written approval from the relevant Competent Authorities has 
been received by Dompé.  
12.2. 
STAFF INFORMATION & RESPONSIBILITIES 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are fully 
informed of all relevant aspects of the study, including detailed knowledge of and training in all 
procedures to be followed. 
The Investigator will maintain a list of delegated responsibility 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 CRO appointed by Dompé.  
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.  
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. 
12.3.1. 
Access to records 
The Investigator will allow designated Dompé representatives, including staff from the appointed 
CRO, and regulatory/ethics 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.       
12.4. 
AUDIT AND INSPECTION 
Audit activities will be performed by the Dompé Quality Assurance Unit or any other third party 
delegated by Dompé or by the CRO, as appropriate. 
12.5. 
PROTOCOL DEVIATIONS/AMENDMENTS 
Changes to the Protocol will be implemented only when written amendments have been signed by all 
individuals who signed the protocol.  


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Any amendment will be sent to the IEC and Competent Authority as appropriate.  No deviations from 
or changes to the protocol will be implemented without documented approval of an amendment from 
the IEC which granted the original approval, except where necessary to eliminate an immediate 
hazard(s) to trial patient, or when the change(s) involves only logistical or administrative aspects of 
the trial.  The 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 IEC 
for review and approval as soon as possible.  
Any other deviation from the protocol that has not been approved by Dompé and the IEC could result 
in a discontinuation from the study at the centre involved. 
Any written amendment will be sent to all recipients of the protocol. 
12.6. 
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/Diary Cards completed to the extent possible. 
Study discontinuation will be notified to Competent Authorities within 15 days from decision. 
12.7. 
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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CONFIDENTIAL 
13. 
REFERENCES 
A0811/E. Dompé Internal Report 
Aboelasrar MA et al. insulin-like growth factor-1 cytokines cross-talk in type 1 diabetes mellitus: relationship to 
microvascular complication and bone mineral density. Cytokine 2012; 59:86-93. 
American Diabetes Association. Standards for medical care in diabetes – 2014. Diabetes Care 2014; 37(1):S14-
S80. 
Atkinson MA et al. Type 1 diabetes. The Lancet 2014, 383:69-82. 
Barnard K et al. Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. BMC 
Pediatr 2010; 10:50. 
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 2012a, Abstract book, 
abstract PP-18. 
Citro A et al. CXCR2/1 inhibition prevents and reverts diabetes in NOD mouse. 2nd Joint AIDPIT and EPITA 
Winter Symposium. Igls/Innsbruck 2012b, Abstract book, abstract OP-27. 
Citro A et al., CXCR1/2 inhibition blocks and reverts type 1 diabetes in mice. Diabetes 2014, in press. 
Cockcroft and Gault MH, Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1):31-41. Diana J and Lehuen A. Macrophages and 
-cells are responsible for CXR2-mediated neutrophil infiltration of 
the pancreas during autoimmune diabetes. EMBO Mod Med 2014, 26:1090-1104.  
Erbağci AB et al. Mediators of inflammation in children with type 1 diabetes mellitus: cytokines in type 1 diabetic 
children. Clin Biochem 2001; 34:645-650. 
Garau A et al. Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in 
a model of transient cerebral ischemia in the rat. Eur Cytokine Netw 2006; 17(1):35-41. 
Glowacka E et al. The effect of LPS on neutrophils from patients with high risk of type 1 diabetes mellitus in 
relation to IL-8, IL-10 and IL-12 production and apoptosis in vitro. Scand J Immunol 2002; 55:210-217. 
Greenbaum MD et al. Mixed-Meal tolerance test versus glucagon stimulation test for the assessment of 
-cell 
function in therapeutic trials in type 1 diabetes. Diabetes Care 2008; 31:1966-1971 
Lachin JM et al., Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed 
type 1 diabetes. PLoS ONE 2011; 6:e26471. 
Ludvigsson et al. GAD treatment and Insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008, 
359:1909-1920. 
MEX0108: Dompé Internal Report 
MEX0109: Dompé Internal Report 
MEX0110: Dompé Internal Report 
MacroGenics. Press Release. MacroGenics and Lilly announce pivotal clinical trial of teplizumab did not meet 
primary efficacy endpoint. MacroGenics [online], http://macrogenics.com/press_release-284.html (2010). 
Mastrandrea L et al. Etanercept treatment in children with new-onset type 1 diabetes. Diabetes Care 2009; 
32:1244-1249. 
Moriconi A et al. Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem 
2007; 50:3984-4002. 
Peskovitz MD et al. Rituximab, b-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 
2009; 361:2143-2152. 
Raz I et al. Treatment of recent-onset type 1 diabetic patients with DiaPep277: results of a double-blind, placebo-
controlled, randomized phase 3 trial. Diabetes Care 2014; 37:1392-1400. 
Steffes MW et al. -cell function and the development of diabetes-related complications in the diabetes control 
and complication trial. Diabetes Care 2003; 26:832-836. 
Van Sickle BJ et al. Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic 
control in adolescents with type 1 diabetes mellitus. Cytokine 2009; 48:290-4. 
Waldron-Lynch F, Herold KC. Immunomodulatory therapy to preserve pancreatic -cell function in type 1 
diabetes. Nature Reviews 2011; 10:439-452. 


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14. 
APPENDICES 
14.1. 
APPENDIX 14.1 - PACKAGING AND LABELING DETAILS 
A Patient Kit will be prepared for each patient, containing 3 Treatment Boxes, one for each treatment 
cycles.  Each Treatment Box will contain 7 blisters of 8 pockets each, for a total of 56 capsules 
(amount needed for each treatment cycle). 
All items will have local language labels.  The template of the English label is provided below.  Label 
content will be adjusted to meet local regulatory requirements.  Only the label of the “Treatment Box” 
will be a “double - tear off” label.   
NOTE: Patient No. XXYY where 
XX = Study site; YY = Patient sequential number at the site 
 
Treatment cycle No. Z where 
“Z” can be either 1, or 2, or 3 
 
Specimen Label for each Patient Kit  
STUDY MEX0114 
Sponsor Dompé farmaceutici s.p.a.; Via San Martino 12, Milan – Italy 
 
INVESTIGATOR: (name) 
 
PATIENT No. XXYY 
 
  
INVESTIGATIONAL PRODUCT: ladarixin (200 mg) or placebo oral capsules 
 
CONTAINS: 3 TREATMENT BOXES, ONCE FOR EACH TREATMENT CYCLE; TOTAL 168 CAPSULES (IN 21 
BLISTERS) 
 
coded BATCH No. 
coded EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C 
 
 
DO NOT FREEZE 
 
 
 
 
 
 
 
 
 
 
 
DIRECTIONS: Dispense the Treatment Box, corresponding to the cycle, just before the planned start of 
that treatment cycle. For any questions, please contact (to be identified in the final label) 
For clinical trial use only. Box not to be dispensed to the patient. 
 
Specimen Label for each Treatment Box [double - tear off label] 
STUDY MEX0114 
Sponsor Dompé farmaceutici s.p.a.; Via San Martino 12, Milan – Italy 
 
INVESTIGATOR: (name) 
 
PATIENT No. XXYY  
TREATMENT BOX – CYCLE No. Z 
 
  
INVESTIGATIONAL PRODUCT: ladarixin (200 mg) or placebo oral capsules 
 
CONTAINS: 7 BLISTER WITH 8 POCKETS EACH; TOTAL 56 CAPSULES 
 
coded BATCH No. 
coded EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C 
 
 
DO NOT FREEZE 
 
 
 
 
 
 
 
 
 
 
 
DIRECTIONS: Take the drug twice a day (2 capsules in the morning and 2 in the evening) for 14 
consecutive days. See additional instructions in the Diary Card.  
 
Contact the Investigator (see Diary Card) should you have any questions. 
 
For clinical trial use only. Keep out of reach of children. 
 
Specimen Label for each blister 
STUDY MEX0114 
Sponsor Dompé farmaceutici s.p.a. 
 
 
INVESTIGATOR: (name) 
 
coded BATCH No. 
coded EXPIRY DATE mm/yyyy 
 
PATIENT No. XXYY  
Cycle No.  
 
For clinical trial use only. Keep out of reach of children. 


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14.2. 
APPENDIX 14.2 – SAMPLE DIARY CARD [English specimen] 
 
Clinical Trial MEX0114 - Sponsor: Dompé farmaceutici s.p.a. 
DIARY CARD 
 
PATIENT No. □□□□ TREATMENT CYCLE No. □  
INVESTIGATOR NAME and CONTACT DETAILS: ____________________________ 
The study doctor has provided you with a Treatment Box containing the study drug for the treatment cycle reported above.  
Each day, you are requested to take 2 capsules in the morning and 2 capsules in the evening.  Please swallow the 2 capsules with a glass of water, 2 hours apart from 
breakfast or dinner, ideally in the period 8.30/9.30 and 20.30/21.30, respectively.  Any time you take the study drug, please report below the number of capsules taken, and 
the date and time when you take the capsules.  Please enter the information with indelible ink. 
Please, DO NOT DISCARD any of the blisters provided.  All the blisters, either unused or empty MUST remain in the Treatment Box. Return the Treatment Box to the 
study doctor during the next study visit, together with this Diary Card. 
Day 
Date 
day/month/year 
 
Time 
24 hour clock, 
e.g. 18.30 
No. of 
capsules 
 
Day 
Date 
day/month/year 
 
Time 
24 hour clock, 
e.g. 18.30 
No. of 
capsules 
Day 1 
 
Morning  
 
 
Day 8 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Day 2 
 
Morning  
 
 
Day 9 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Day 3 
 
Morning  
 
 
Day 10 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Day 4 
 
Morning  
 
 
Day 11 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Day 5 
 
Morning  
 
 
Day 12 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Day 6 
 
Morning  
 
 
Day 13 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Day 7 
 
Morning  
 
 
Day 14 
 
Morning  
 
 
Evening 
 
 
Evening 
 
 
Investigator’s signature (for review): ______________________________________________ 
 
 
date: ______________________ 


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14.3. 
APPENDIX 14.3 – STUDY FLOW CHART  
 
1st INSULIN ADMINISTRATION 
100 days 
RANDOMIZATION –  STUDY DAY 0 [1st cycle IMP dispensed] 
 
 
 
 
 
 
 
 
 
 
 
ENROLLMENT (consent signed) 
VISIT 
SCREENING 
(one or more visits) 
 
Pre-dose visit  
(2nd cycle) 
 
Pre-dose visit 
(3rd cycle) 
 
 
FU visit 
3months 
 
FU visit 
6months 
 
FU visit 
12months 
Week 
From 
enrolment 
- 3 to 0 
1-2 
4 
5-6 
8 
9-10 
11 
12 
13+1 
24 
25 
26+2 
50 
51 
52+2 
ASSESSMENTS 
Past medical 
history and 
disease-
specific 
information 
BP/HR,  
Weight, Height 
Safety lab test 
(hematology & 
biochemistry) 
12 lead ECG 
Pregnancy 
Treatment cycle No.1 (start on Study Day 1)   
BP/HR 
Safety lab test 
(hematology & 
biochemistry) 
12 lead ECG 
(repeat 1 hour 
apart if QTcF is 
EITHER > 500 
msec OR has 
increased by > 
60 msec from 
screening value) 
Pregnancy 
Treatment cycle No. 2 
serum creatinine 
and  albumin,  
total bilirubin, 
ALT/AST,  
12 lead ECG 
(repeat 1 hour 
apart if QTcF is 
EITHER > 500 
msec OR has 
increased by > 
60 msec from 
screening value) 
Pregnancy 
Treatment cycle No. 3 
Pre-visit phone call 
Insulin 
(IU/kg/day) 
Severe 
hypoglycaemia 
HbA1c,   
Auto-Ab and 
miR-375 
Pre-visit phone call 
Insulin 
(IU/kg/day)  
Severe 
hypoglycaemia 
HbA1c,   
Auto-Ab and 
miR-375 
Pre-visit phone call 
Insulin 
(IU/kg/day) 
 Severe 
hypoglycaemia 
HbA1c,   
Auto-Ab and 
miR-375 
Auto-Ab 
to confirm 
diagnosis 
Baseline Insulin 
(IU/kg/day) 
Baseline$ HbA1c, 
Auto-Ab and 
miR-375 
MMTT 
C-peptide 
glucose 
glucagon 
MMTT 
C-peptide 
glucose 
glucagon 
MMTT 
C-peptide 
glucose 
glucagon 
 
Baseline MMTT# 
C-peptide, 
glucose, glucagon 
2nd cycle IMP 
dispensed if no 
contraindication 
has arisen (see 
discontinuation 
criteria below*) 
3rd cycle IMP 
dispensed if no 
contraindication 
has arisen (see 
discontinuation 
criteria below*) 
BP/HR 
Safety lab test 
(hematology & 
biochemistry) 
 
 
 
 
 
 
T-cell response 
ex vivo §  
 
 
 
 
 
 
 
T-cell response 
ex vivo § 
 
T-cell response 
ex vivo § 
 
T-cell response 
ex vivo § 
Assay of green entries will be done at a centralized laboratory. Auto-Antibodies (Auto-Ab) include anti-GAD; IAA; IA-2 antibody; ZnT8. [$ Baseline Auto-Ab test will not be repeated if test to confirm 
diagnosis is done within the -3 to 0 week timeframe].  
 
 
 
 
# = Baseline MMTT should be planned to ensure the sample is sent to the centralized laboratory and C-peptide result is available (consider 5 working days) in time for randomization.  
§ = T-cell to be collected at selected sites only. 
* = As per Treatment discontinuation criteria, no IMP will be dispensed in the case:  QTcF is either > 500 msec or increases by > 60 msec from screening measurement on two consecutive ECG readings taken 1 
hour apart; Patient develops LBBB, or atrio-ventricular or heart block; or any significant cardiovascular disease; Patient develops renal (calculated CLcr < 60 mL/min) or hepatic (increased ALT/AST > 3 x ULN 
and increased total bilirubin > 3mg/dL [>51.3 mol/L]) dysfunction as well as hypoalbuminemia; Female patient has become pregnant.  
Randomization = Study Day 0 with reference to Study Day 1 = first day when the IMP administration is started.  


Study MEX0114 
Ladarixin in Diabetes Onset 
Page 51 of  51 
Version No. 2 – Final 27 August 2015 
 
 
 
 
CONFIDENTIAL 
14.4. 
APPENDIX 14.4 - METHODOLOGICAL DETAILS 
14.4.1. 
Handling of samples for centralized assay 
A study-specific Laboratory Manual will be issued to all sites, reporting detailed instructions for blood 
sampling, and preparation, storage and shipment of samples.   
The protocol requires that either cell-free serum (blood allowed to clot and centrifuged) or EDTA 
whole blood samples are stored between -70°C and -80°C until shipment to the centralized laboratory. A 
refrigerated centrifuge will also be required.  
Samples will be shipped from the site to the centralized laboratory 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.   
Handling of samples on receipt at the centralized laboratory and assay methods will be described 
in detail in the Laboratory Manual.  Similarly, arrangements will be made for back-communication of 
the results to the sending site.  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. 
Tubes and labels for blood withdrawal and sample storage will be provided by the CRO appointed by 
Dompé, along with storage and shipment tracking forms.  The appointed CRO will also coordinate 
shipment to the centralized laboratory.   
All steps will be tracked to ensure correct data reporting.   
Any laboratory involved in centralized assay will be listed in the Laboratory Manual, along with relevant 
contact details. 
 
14.4.2. 
Mixed Meal Tolerance Test 
The MMTT will be performed after an overnight fast, according to Greenbaum (2008) at baseline (within 1 
week prior of randomization) and at each follow-up visit on weeks 13+1, 26+2 and 52+2. Screening MMTT 
should not be performed within one week of resolution of a diabetic ketoacidosis event, defined as the 
presence of  
hyperglycemia (blood glucose >200 mg/dL); pH <7.3 or HCO3 <15;  
ketones 
positive 
in the serum or urine. 
Prior to the test, patients will withhold long-acting insulin on the morning of the test.  Rapid-acting and 
short-acting insulin will be allowed up to 6hrs and 2 hrs, respectively, before the test.  Test will be re-
scheduled if the patient has a capillary glucose value of >200mg/dL or <70mg/dL.  
The test will be initiated before 10 a.m.  After 2 pre-meal basal samples have been drawn between -20 to 0 
min (basal 1 and basal 2), patients will be given 6mL/kg of Boost® High Protein Nutritional Drink (Nestlé 
Nutrition) up to a maximum of 360mL, to be drunk within 5 min.  Post-meal samples will be drawn at 
15+5, 30+5, 60+10, 90+10, 120+15, 180+15 min after the meal.     
 
 
 

SAP_000.pdf: 
Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
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Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
Statistical Analysis Plan
Dompé farmaceutici S.p.A.
Study Number: MEX0114
EudraCT Number: 2014-003968-20
Test Product: Ladarixin
A phase 2, multicentre, randomized, double-blind, placebo-controlled study
to assess the efficacy and safety of 400 mg twice a day oral ladarixin in
patients with new-onset type 1 diabetes.
Author: Claudio Iannacone
Version Number and Date: Final Version 4.4, 17SEP2019
STATEMENT OF CONFIDENTIALITY
Information in this statistical analysis plan and accompanying documents contains privileged or
confidential information that is the property of Dompé farmaceutici s.p.a. It is understood that the
information will not be used, divulged, or published without prior written consent of Dompé farmaceutici,
except to the extent such disclosure is required by applicable laws and regulations.






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Author:
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Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
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reproduction is strictly prohibited.
Modification History
Unique
Identifier
for
this Version
Date
of
the
Document
Version
Author
Significant Changes from Previous Authorized
Version
Version 1.0
18OCT2016
Claudio Iannacone
N/A – first version
Version 1.1
17JUL2017
Claudio Iannacone
Previous version not yet approved.
No significant changes in the document. Minor
changes to the body text.
Version 1.2
02AUG2017
Claudio Iannacone
Previous version not yet approved.
No significant changes in the document. Minor
changes to the body text.
Version 1.3
08SEP2017
Claudio Iannacone
Previous version not yet approved.
No significant changes in the document. Minor
changes to the body text.
Version 1.4
18SEP2017
Claudio Iannacone
Previous version not yet approved.
No significant changes in the document. Minor
changes to the body text.
Version 1.5
27SEP2017
Claudio Iannacone
Previous version not yet approved.
No significant changes in the document. Minor
changes to the body text.
Version 1.6
04OCT2017
Claudio Iannacone
Previous version not yet approved.
No significant changes in the document. Minor
changes to the body text.
Version 2.0
06OCT2017
Claudio Iannacone
Version approved by Dompé farmaceutici on
09OCT2017.
Version 3.0
07JUN2019
Claudio Iannacone
Significant changes vs version 2.0:

Added two new efficacy endpoints
(Proportion of patients maintaining a
residual β-cell function) at weeks 13, 
26, and 52 and C-peptide AUC above
fasting value at weeks 13, 26, and 52);

Subgroups
analyses
on
efficacy
endpoints according to age class and
fasting C-peptide on screening;

Added new major deviations criteria
for
exclusion
from
Per-protocol
analysis set.
Version 4.0
26JUN2019
Claudio Iannacone
Version 3.0 not yet approved.
Significant changes vs version 3.0:
-
C-peptide AUC above fasting value
calculated also at Baseline;


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Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
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reproduction is strictly prohibited.
Unique
Identifier
for
this Version
Date
of
the
Document
Version
Author
Significant Changes from Previous Authorized
Version

BUN values will not be analyzed or
listed in the statistical analysis.
Version 4.1
02JUL2019
Claudio Iannacone
Version 4.0 not yet approved. Used for revision
and comments
Significant changes vs version 4.0:
-
Added
as
secondary
efficacy
endpoints
“Percent
change
from
baseline of 2-hour AUC of C-peptide
response
to
the
MMTT”
and
“Proportion of patients with HbA1c <
7% and absence of episodes of severe
hypoglycaemia
from
the
previous
visit”;
-
Cmax and Tmax of C-peptide analyzed
over the study by means of a mixed
linear model;
-
Descriptive analysis of demographics
and
other
baseline
characteristics
performed on the ITT population;
Version 4.2
03SEP2019
Claudio Iannacone
Version 4.1 not yet approved. Used for revision
and comments.
Significant changes vs version 4.1:
-
Changed
the
approach
used
to
address missing values in C-peptide
values in MMTT;
-
Added an explorative analysis on AUC
C-peptide stratified by the number of
positivity
in
auto-antibodies
at
Screening visit;
-
Change the rule to define Prior and
Concomitant Medications;
-
Classification of protocol deviations in
minor and major categories removed;
Version 4.3
06SEP2019
Claudio Iannacone
Version 4.2 not yet approved. Used for revision
and comments.
No significant changes made vs version 4.2.
Added in the document more details regarding
the derivation and the statistical analysis of the
variables.
Version 4.4
17SEP2019
Claudio Iannacone
Version 4.3 not yet approved. Used for revision
and comments.
No significant changes made vs version 4.3.


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Unique
Identifier
for
this Version
Date
of
the
Document
Version
Author
Significant Changes from Previous Authorized
Version
-
Added more details for the calculation
of exposure to study medication
-
Added a summary table for the major
protocol deviations
-
Added the analysis of the exploratory
endpoint “Proportion of responders at
week 52” (for definition see paragraph
16.3.1)


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Final Version 4.4
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Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
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reproduction is strictly prohibited.
Table of Contents
1.
List of Abbreviations .............................................................................................................................11
2.
Introduction..........................................................................................................................................13
3.
Study Objectives and Endpoints............................................................................................................13
3.1.
Study Objectives ...................................................................................................................................13
3.2.
Study Endpoints....................................................................................................................................13
3.2.1.
Efficacy Endpoints.................................................................................................................................13
3.2.2.
Exploratory Endpoints...........................................................................................................................14
3.2.3.
Safety Endpoints...................................................................................................................................14
4.
Study Design .........................................................................................................................................14
4.1.
General Description ..............................................................................................................................14
4.1.1.
Description of the study........................................................................................................................14
4.1.2.
Sample size ...........................................................................................................................................14
4.1.3.
Description of treatments.....................................................................................................................14
4.1.4.
Description of the study flow................................................................................................................15
4.2.
Schedule of Events................................................................................................................................15
4.3.
Changes to Analysis from Protocol........................................................................................................16
5.
Planned Analyses..................................................................................................................................17
5.1.
Data Monitoring Committee (DMC) ......................................................................................................18
5.2.
Interim Analysis ....................................................................................................................................18
5.3.
Final Analysis ........................................................................................................................................18
6.
Analysis Sets .........................................................................................................................................18
6.1.
All Subjects Enrolled Set [ENR]..............................................................................................................18


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reproduction is strictly prohibited.
6.2.
Randomized Analysis Set [RND]............................................................................................................18
6.3.
Safety Analysis Set [SAF].......................................................................................................................19
6.4.
Intent to Treat Set [ITT].........................................................................................................................19
6.5.
Protocol Deviations...............................................................................................................................19
7.
General Considerations.........................................................................................................................19
7.1.
Reference Start Date and Study Day .....................................................................................................19
7.2.
Study Baseline ......................................................................................................................................20
7.3.
Retests, Unscheduled Visits and Early Termination Data ......................................................................20
7.4.
Windowing Conventions.......................................................................................................................20
7.5.
Statistical Tests .....................................................................................................................................20
7.6.
Common Calculations ...........................................................................................................................20
7.7.
Software Version ..................................................................................................................................21
8.
Statistical Considerations......................................................................................................................21
8.1.
Adjustments for Covariates and Factors to be Included in Analyses......................................................21
8.2.
Multicentre Studies...............................................................................................................................21
8.3.
Missing data..........................................................................................................................................22
8.4.
Multiple Comparisons/ Multiplicity ......................................................................................................22
8.5.
Active-Control Studies Intended to Show Non-inferiority or Equivalence .............................................22
8.6.
Examination of Subgroups ....................................................................................................................22
9.
Output Presentations............................................................................................................................22
10.
Disposition, Withdrawals and Protocol Deviations ...............................................................................23
11.
Demographic and other Baseline Characteristics ..................................................................................23
11.1.
Derivations ...........................................................................................................................................24
12.
Significant Medical History....................................................................................................................24
13.
Medications..........................................................................................................................................24
14.
Study Medication Exposure ..................................................................................................................25


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reproduction is strictly prohibited.
14.1.
Derivations ...........................................................................................................................................25
15.
Study Medication Compliance ..............................................................................................................25
15.1.
Derivations ...........................................................................................................................................25
16.
Analysis of Efficacy and Safety Variables...............................................................................................25
16.1.
Primary Efficacy Analysis.......................................................................................................................26
16.1.1.
Primary Efficacy Variable ......................................................................................................................26
16.1.2.
Primary Analysis of Primary Efficacy Variable .......................................................................................26
16.2.
Secondary Efficacy Analyses..................................................................................................................26
16.2.1.
Secondary Efficacy Variables.................................................................................................................26
16.2.2.
Analysis of Secondary Efficacy Variables...............................................................................................27
16.3.
Exploratory and Post-Hoc Analyses.......................................................................................................28
16.3.1.
Exploratory Variables............................................................................................................................28
16.3.2.
Analysis of Exploratory Variables..........................................................................................................28
16.3.3.
Post-Hoc and Subgroups Analyses.........................................................................................................28
16.4.
Safety Analyses.....................................................................................................................................29
16.4.1.
Safety Variables ....................................................................................................................................29
16.4.2.
Analysis of Safety Variables ..................................................................................................................29
16.4.3.
Adverse Events .....................................................................................................................................29
16.4.4.
Safety Laboratory Evaluations...............................................................................................................30
16.4.4.1. Conversion of Laboratory Values Units .................................................................................................30
16.4.5.
Vital Signs Analysis................................................................................................................................31
16.5.
ECG Evaluations ....................................................................................................................................32
16.6.
Pregnancy Test over the study ..............................................................................................................32
16.7.
Permanent treatment discontinuation criteria .....................................................................................32
16.8.
Pre-visit Phone Calls..............................................................................................................................33
17.
Analysis of pharmacokinetic data .........................................................................................................33


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reproduction is strictly prohibited.
18.
Table Shells and Specifications..............................................................................................................33
18.1.
Table Specifications ..............................................................................................................................33
18.2.
Line Listings Specifications ....................................................................................................................34
APPENDIX 1.
Programming Conventions for Outputs .....................................................................................35
APPENDIX 2.
Partial Date Conventions...........................................................................................................36


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reproduction is strictly prohibited.
1. LIST OF ABBREVIATIONS
AE
Adverse Event
ADA
American Diabetes Association
ADaM
Analysis Data Model
ADR
Adverse Drug Reaction
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
BUN
Blood Urea Nitrogen
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CLcr
Calculated Creatinine Clearance (Cockcroft - Gault formula)
Cmax
Maximum Plasma Concentration
CRF
Case Report Form
CS
Clinically Significant
DBP
Diastolic Blood Pressure
dL
Deciliter
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ENR
Enrolled Analysis Set
g
Gram
HbA1c
Glycated Haemoglobin
HR
Heart Rate
ICF
Informed Consent Form
IMP
Investigational Medicinal Product
ITT
Intent to Treat Analysis Set
i.v.
Intravenous
IU
International Unit
kg
Kilogram
L
Litre
LLN
Lower Limit of Normal
MCR
Mediolanum Cardio Research
MedDRA
Medical dictionary for drug regulatory activities
mg
Milligram
miR-375
MicroRNA-375
mL
Millilitre
MMTT
Mixed Meal Tolerance Test


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reproduction is strictly prohibited.
msec
Millisecond
NCS
Not Clinically Significant
ng
Nanogram
nmol
Nanomole
PT
Preferred Term
QTc
Corrected QT interval
QTcF
Fridericia's corrected QT interval
RND
Randomized Analysis Set
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical analysis plan
SAS
The Statistical Analysis System (software)
SBP
Systolic Blood Pressure
SDTM
Study Data Tabulation Model
SEM
Standard Error of the Mean
s.c.
Subcutaneous
SD
Standard Deviation
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
TESAE
Treatment Emergent Serious Adverse Event
Tmax
Time to reach Maximum Plasma Concentration
T1D
Type 1 Diabetes
ULN
Upper Limit of Normal
μg 
Microgram
μmol 
Micromole
WHO-DD
World Health Organization Drug Dictionary
WHO-DRL
World Health Organization Drug Reference List


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Final Version 4.4
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[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
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reproduction is strictly prohibited.
2. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and analysis of efficacy,
exploratory and safety data for Protocol MEX0114. It describes the data to be summarized and analyzed, including
specifics of the statistical analyses to be performed.
This statistical analysis plan (SAP) is based on study protocol version 2, dated 27th August 2015. This SAP takes as
well into account:
-
Amendment No.1 version 1, dated 7th March 2016, applicable to the belgian investigational sites only
-
Amendment No.2 version 1, dated 20th July 2016, applicable to the german investigational sites only
3. STUDY OBJECTIVES AND ENDPOINTS
3.1. STUDY OBJECTIVES
The objective of this clinical trial is to investigate whether Ladarixin has sufficient activity (preservation of β-cell 
function and slowdown of the progression of type 1 diabetes) to warrant its further development. The safety of
Ladarixin in the specific clinical setting will be also evaluated.
3.2. STUDY ENDPOINTS
3.2.1. EFFICACY ENDPOINTS
-
2-hour AUC of C-peptide response to the MMTT [Primary endpoint. Time point: week 13±1].
-
2-hour AUC of C-peptide response to the MMTT [Time points: baseline, weeks 26±2 and 52±2].
-
Percent change from baseline of 2-hour AUC of C-peptide response to the MMTT [Time points: weeks
13±1, 26±2 and 52±2].
-
Average (previous 3 days) insulin requirement (IU/kg/day) [Time points: baseline, weeks 13±1, 26±2
and 52+2]. For the patients reporting “off insulin” response in the CRF the daily insulin requirement
value will be conventionally set to zero in the statistical analysis.
-
HbA1c levels [Time points: baseline, weeks 13±1, 26±2 and 52±2].
-
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of C-peptide and
glucose derived from the MMTT [Time points: baseline, weeks 13±1, 26±2 and 52±2].
-
Cumulative severe hypoglycemic events occurring from randomization [Time points: weeks 13±1, 26±2
and 52±2].
-
Proportion of patients maintaining a residual β-cell function [Time points: baseline, weeks 13±1, 26±2 
and 52±2].
-
Proportion of patients with HbA1c < 7% and absence of episodes of severe hypoglycemia from the
previous visit [Time points: weeks 13±1, 26±2 and 52+2].
-
C-peptide AUC (15-120 min) above fasting value [Time points: baseline, weeks 13±1, 26±2 and 52±2].


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reproduction is strictly prohibited.
3.2.2. EXPLORATORY ENDPOINTS
-
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of glucagon derived
from the MMTT [Time points: baseline, weeks 13±1, 26±2 and 52±2].
-
Auto-antibodies (GAD, IA-2, IAA, ZnT8), [Time points: baseline, weeks 13±1, 26±2 and 52±2].
-
MicroRNA-375 (miR-375) [Time points: baseline, weeks 13±1, 26±2 and 52±2].
-
T-cell response ex vivo to major β-cell antigens (pro-insulin, GAD65) - selected sites only [Time points: 
baseline, weeks 13±1, 26±2 and 52±2].
-
2-hour AUC of C-peptide response to the MMTT stratified by the number of positivity in auto-
antibodies (1, 2, 3, and 4) at Screening visit.
3.2.3. SAFETY ENDPOINTS
Vital signs (blood pressure and heart rate) [time points: Screening, end of 1st treatment cycle (i.e. pre-dose visit, 2nd
cycle), week 13+1].
Routine laboratory tests (hematology, clinical chemistry) [time points: Screening, end of 1st treatment cycle (i.e.
pre-dose visit, 2nd cycle), weeks 13±1 (or withdrawal)].
Incidence of Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
[time frame: throughout the study].
4. STUDY DESIGN
4.1. GENERAL DESCRIPTION
4.1.1. DESCRIPTION OF THE STUDY
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled study carried out in patients with new-
onset type 1 diabetes (T1D) to investigate whether Ladarixin has sufficient activity (preservation of β-cell function 
and slow-down of the progression of T1D) to warrant its further development.
4.1.2. SAMPLE SIZE
Seventy-two (72) patients with new-onset T1D will be randomized, after consenting in written for the study and
after having undergone clinical investigations for compliance with the selection criteria and approval by the
Investigator.
According to the log(x+1) transformed data [initially selected by TrialNet as the appropriate transformation for
MMTT C-peptide AUC] and the sample size calculated on the data stratified by an adult population (> 18 years), 72
patients will provide 85% power to detect a 50% between-group difference in the 2-hour MMTT C-peptide AUC (2:1)
at 0.05 significance level (one-sided test), assuming a 24% drop-out rate.
4.1.3. DESCRIPTION OF TREATMENTS
Patients will be randomized with a 2:1 ratio to either Ladarixin or placebo. The Investigational Medicinal Product


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reproduction is strictly prohibited.
(IMP) will be provided as hard gelatin capsules for oral administration. Ladarixin will be administered orally at the
dose of 400 mg twice a day for 3 cycles of 14 days on / 14 days off. Placebo will be administered with the same
treatment schedule.
The two daily doses will be administered at about 12 hours’ interval (morning and evening; ideally between
8.30/9.30 and 20.30/21.30). At each administration, 2 capsules will be swallowed with a glass of water, at least 2
hours apart from breakfast or dinner.
4.1.4. DESCRIPTION OF THE STUDY FLOW
Each patient will be involved in the study for a screening period up to 100 days followed by a post-randomization
period up to 52±2 weeks.
The study consists of the following periods:
1)
Screening period, including 2 or more visits during a period up to 100 days; this includes the time required
to confirm the diagnosis.
Potential study patients with a recent clinical diagnosis of T1D will be identified from those referring to the site for
diagnosis confirmation (auto-antibody testing) and/or disease management.
Enrolment is defined as signature of the Informed Consent Form (ICF) for study participation. From enrolment,
patients will be admitted to an intensive diabetes management, according to current ADA recommendation. Patients
will self-monitor glucose levels at least 4 times a day and will take insulin as prescribed by the Investigator
throughout the study participation. To ensure standardized glycemic control in the treatment groups, the
Investigator will provide guidance for insulin regimen adjustment.
Compliance with inclusion/exclusion criteria will be finally verified vs demographic, laboratory test results and
clinical information (baseline assessments to be completed within 3 weeks before randomization).
2)
Randomization: Patients fulfilling all the inclusion criteria and none of the exclusion criteria will be
randomized, randomization to occur within 100 days from the 1st insulin administration. Randomization is
defined as Study Day 0 with reference to day when IMP administration is started, which is defined as Study
Day 1.
3)
Treatment period, including 3 treatment cycles of 2 weeks each with 2 weeks’ interval between cycles and
2 corresponding pre-dose assessment visits.
Assessments to be done before the 1st dose in the 1st treatment cycle are part of the screening evaluation.
Thereafter, patients will refer to the site within 1 week (“pre-dose visits”) before the expected date when the 2nd or
3rd treatment cycle is due to start to confirm no condition that prevents their continuing participation into the study
has arisen. The amount of IMP for each treatment cycle will be dispensed only after compliance with criteria for drug
administration has been confirmed.
4)
Follow-up period: 3 follow-up visits scheduled at weeks 13±1 (month 3), 26±2 (month 6) and 52±2 (month
12).
4.2. SCHEDULE OF EVENTS
Schedule of events can be found in Section 14.3 of the study protocol; additional events for the Belgian and German
investigational sites can be found in Section 14.3 of Amendment No.1 (for Belgian investigational sites) and of
Amendment No.2 (for German investigational sites).


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Effective Date: 01Apr2016
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reproduction is strictly prohibited.
4.3. CHANGES TO ANALYSIS FROM PROTOCOL
1)
Primary analysis of primary efficacy variable has been modified in order to be consistent with the definition
of the primary endpoint.
In the study protocol the following analysis was proposed:
“The 2-hour C-peptide AUC after the MMTT at week 13±1 will be analyzed with Student t-test for unpaired data
using PROC TTEST within SAS®, including terms for treatment and Centre. The estimated treatment difference
between Ladarixin and placebo will be also presented together with the corresponding 95% confidence interval.”
In the present SAP the primary analysis has been modified as follows:
“The 2-hour C-peptide AUC after the MMTT (log(x+1) transformed data) at week 13±1 will be analyzed with Student
t-test for unpaired data using PROC TTEST within SAS®, including terms for treatment. The estimated treatment
difference between Ladarixin and placebo will be also presented together with the corresponding 95% confidence
interval.”.
2)
The analysis corresponding to the 2-hour AUC C-peptide (log(x+1) transformed data) secondary efficacy
endpoint has been reformulated as “The comparisons between groups on 2-hour AUC of C-peptide efficacy
endpoint will be carried-out using a mixed linear model with 2-hour AUC of C-peptide as dependent
variable, treatment group, visit, treatment by visit interaction as fixed factors of the model and patient as
random effect. An unstructured covariance matrix for each patient is considered and the Kenward-Roger
adjustment is used for the degrees of freedom”. In the study protocol the following was stated: “Analysis
of the 2-hour AUC of C-peptide at the 3 time points (baseline, weeks 26±2 and 52±2) will be performed
through a single repeated measurements model using PROC MIXED within SAS®. The adjusted least square
means will be estimated for each combination of time point and treatment. The treatment effect within
each time point will be compared using a two-sided test at 0.05 level. The tests of the fixed effects will be
presented, together with the estimated least squares means and summary statistics of the AUC for each of
the two treatments at each time point. The estimated treatment difference between Ladarixin and placebo
at each time point will be presented together with the corresponding 95% confidence interval. The
confidence interval will be generated at a statistical level of 0.05”.
3)
The analysis corresponding to the average insulin requirement secondary efficacy endpoint has been
reformulated as “The comparisons between groups on insulin requirement secondary efficacy endpoints
will be carried-out using a mixed linear model with average daily insulin requirement as dependent variable,
treatment group, visit, treatment by visit interaction as fixed factors of the model and patient as random
effect. An unstructured covariance matrix for each patient is considered and the Kenward-Roger
adjustment is used for the degrees of freedom.” In the study protocol, the following was stated: “The mean
in average daily insulin requirement at the 4 time points (baseline, weeks 13±1, 26±2 and 52±2) will be
analysed using a repeated measurements model using PROC MIXED within SAS®.”
4)
The analysis corresponding to the HbA1c secondary efficacy endpoint has been reformulated as “The
comparisons between groups on HbA1c secondary efficacy endpoint will be carried-out using a mixed linear
model with HbA1c value as dependent variable, while treatment group, visit, treatment by visit interaction
as fixed factors of the model and patient as random effect. An unstructured covariance matrix for each
patient is considered and the Kenward-Roger adjustment is used for the degrees of freedom.” In the study
protocol, the following was stated: “The mean in HbA1c value at the 4 time points (baseline, weeks 13±1,
26±2 and 52±2) will be analysed using a repeated measurements model using PROC MIXED within SAS®.”
5)
In the study protocol, the default summary statistics for quantitative variables were the number of
observations (n), mean, standard deviation (SD), standard error of the mean, median, minimum (min) and
maximum (max), lower and upper 95% confidence limits for those patients with data.
This was modified as follows:
“The default summary statistics for quantitative variables will be the number of observations (n), mean, standard
deviation (SD), median, minimum (min) and maximum (max) for those patients with data. For quantitative efficacy


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MEX0114_SAP_v4_4 Final Methods.docx
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Version Number:
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Effective Date: 01Apr2016
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reproduction is strictly prohibited.
variables, standard error of the mean and lower and upper 95% confidence limits (CI) will be also presented.”
6)
The analyses of new efficacy endpoints have been planned:

Proportion of patients maintaining a residual β-cell function [Time points: weeks 13±1, 26±2 and 
52±2].

C-peptide AUC (15-120 min) above fasting value [Time points: baseline, weeks 13±1, 26±2 and
52±2].

Percent change from baseline of 2-hour AUC of C-peptide response to the MMTT [Time points:
weeks 13±1, 26±2 and 52±2].

Proportion of patients with HbA1c < 7% and absence of episodes of severe hypoglycemia from the
previous visit [Time points: weeks 13±1, 26±2 and 52+2].

Proportion of responders at week 52, defined as patients with percent decrease from baseline in
2-hour AUC of C-peptide above the median percent decrease from baseline to Week 52.
7)
Planned subgroups descriptive analyses on the efficacy endpoints according to age class at Screening (≤ 25 
and > 25 years) and to fasting C-peptide (Pre-MMTT) (≤ median value and > median value) at Screening 
visit.
8)
A subgroup analysis on 2-hour AUC of C-peptide response to the MMTT stratified by the number of
positivity in auto-antibodies (1, 2, 3, and 4) at Screening visit has been planned.
9)
The approach to deal missing C-peptide values has been changed: the sentence “missing C-peptide values
will be imputed via linear interpolation” of the study protocol has been changed in “Missing C-peptide
values will be imputed with the average of the C-peptide value that precedes and follows the missing value.
Missing data in C-peptide at 180 minutes (final) will be replaced by the last non-missing value.”.
10) In the study protocol was stated “When C-peptide values are below the limit of detection (0.2 ng/mL), a
value of 0.2 ng/mL will be assumed in the calculation of area under the curve.” This rule to address the C-
peptide values below 0.2 ng/mL will not be applied. C-peptide values will analysed as reported in the CRF.
5. PLANNED ANALYSES
The following analyses will be performed for this study:
1.
No analyses for Data Monitoring Committee (DMC) meeting or Interim Data Analysis are scheduled;
2.
Interim transfer of clinical data listings: four interim transfers are expected during the study, upon request
of the Sponsor;
3.
Only the Final Analysis will be performed for this study.
Statistical analysis will be performed by SPARC Consulting, Milan, Italy on behalf of IQVIA RDS Italy, Milan, Italy on
study data provided by Mediolanum Cardio Research (MCR), Milan, Italy.
SAS source (raw) data will be transferred as SAS datasets, together with laboratory reference range, and any support
datasets. Transfer will occur via secured (encrypted, password-protected e-mail).
The statistical analysis will be based on analysis datasets according to the CDISC format.
Production SAS programmers will create SDTM datasets from the Source (Raw) datasets as per the mapping
instructions given in the SDTM mapping specifications. Simultaneously, the Validation (QC) SAS programmer will
create the same SDTM datasets independently and will do a comparison with production datasets to validate them.
Similarly, ADaM datasets will be created from SDTM datasets as per ADaM specifications using double programming
approach for production and QC.
Validated draft SDTM and ADaM datasets will be sent to the Study Lead Biostatistician for review and approval.
When the final source data transfer is made available (after database lock), the production and validation programs
will be re-run to create the final SDTM and ADaM datasets deliverable to be used for the final statistical analysis.


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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
The statistical SAS output generated after running SAS programs will be copied in a Word file and paginated as
specified in the Paragraph 18 of this document.
Tables, Listings and Figures will be presented according to TFL Shells Version 4.4 (Dated 17SEP2019).
5.1. DATA MONITORING COMMITTEE (DMC)
There will be no statistical analyses for DMC for this study.
5.2. INTERIM ANALYSIS
There will be no Interim Analysis for this study.
5.3. FINAL ANALYSIS
All final, planned analyses identified in this SAP will be performed by SPARC Consulting, Milan, Italy on behalf of
IQVIA RDS Italy, Milan, Italy following Sponsor Authorization of this Statistical Analysis Plan, Database Lock, Sponsor
Authorization of Analysis Sets and Unblinding of Study Treatment.
The default summary statistics for quantitative variables will be the number of observations (n), mean, standard
deviation (SD), median, minimum (min) and maximum (max) for those patients with data. For quantitative efficacy
variables, standard error of the mean (SEM) and lower and upper 95% confidence limits (CI) for mean will be also
presented.
For qualitative variables, the number (n) and percentage (%) of patients with non-missing data per category will be
the default summary presentation, and where appropriate and present, the number of missing values as a “Missing”
category. If appropriate, 95% confidence intervals around the proportions will be presented using the Clopper-
Pearson’s formula.
6. ANALYSIS SETS
Agreement and authorization of patients included/excluded from each analysis set will be performed on a case-by-
case basis before the database lock. A blind data review meeting will be held before database lock and before
opening randomization codes, in order to assign the patients to each of the analysis sets according to the specified
definitions. Patient’s exclusion from each of the analysis sets will be documented and justified in a Blind Data Review
Report.
6.1. ALL SUBJECTS ENROLLED SET [ENR]
The enrolled (ENR) set will contain all patients who provided informed consent for this study.
6.2. RANDOMIZED ANALYSIS SET [RND]
The Randomized Analysis (RND) set will contain all patients in the ENR set who were randomized to the study,
regardless of whether they received study medication or not.


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reproduction is strictly prohibited.
6.3. SAFETY ANALYSIS SET [SAF]
The Safety Analysis (SAF) set will contain all patients in the RND set who received any study medication and will be
based on the treatment actually received.
6.4. INTENT TO TREAT SET [ITT]
The Intent to Treat (ITT) set will contain all patients who were randomized and received at least one dose of study
medication (either Ladarixin or placebo). It will be based on the treatment randomized, regardless of the treatment
actually received. The ITT set will be used to present efficacy data.
6.5. PROTOCOL DEVIATIONS
All the protocol deviations will be discussed case by case by the clinical team during the review of the data before
the lock of the study database and described in the Blind Data Review Report.
However, the following protocol deviations are anticipated to be considered as major:

Inclusion and exclusion criteria not respected;

Received treatment other than they were randomized to;

Missing information on IMP administration that does not allow calculation of IMP exposure/compliance;

Overall study treatment compliance < 80%;

Incorrect Boost dose at one or more MMTT visits;

Missing data for the primary endpoint (AUC C-peptide from MMTT at week 13);

Primary endpoint (AUC C-peptide from MMTT) at week 13 assessed out-of-window visit (± 1 week);

Use of prohibited concomitant medications prior to enrolment and up to the end of the study participation
(Concomitant treatment with phenytoin, warfarin, sulphanylurea hypoglycemics (e.g. tolbutamide,
glipizide, glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (> 50 mg/day),
concomitant treatment with metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide,
DPP-IV inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. β-blockers, 
angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin, etc.),
current administration of any immunosuppressive medications (including oral, inhaled or systemically
injected steroids) and use of any investigational agents, including any agents that impact the immune
response or the cytokine system);

Concurrent illnesses/TEAEs that may impact the glycemic control or trial read-out, to be defined case by
case.
7. GENERAL CONSIDERATIONS
7.1. REFERENCE START DATE AND STUDY DAY
Randomization is defined as Study Day 0 with reference to day when IMP administration is started, which is defined
as Study Day 1.
In general, reference start date is defined as the day of the first dose of study medication (Study Day 1: first day in


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reproduction is strictly prohibited.
Week 1), and will appear in every listing where an assessment date or event date appears. However, different
reference start date could be used in the statistical analysis according to the objective of the analysis. In such case,
notes defining the reference start date will be added in the statistical tables and line listings.
Study Day will be calculated from the reference start date, and will be used to show start / stop day of assessments
and events.

If the date of the event is on or after the reference start date then:
Study Day = (date of event – reference start date) + 1

If the date of the event is prior to the reference start date then:
Study Day = (date of event – reference start date)
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and
Study Day and any corresponding duration will be presented based on the imputations specified in Appendix 2
(Partial Date Conventions).
7.2. STUDY BASELINE
Unless otherwise specified, study baseline is defined as the last non-missing measurement taken prior to IMP
administration (including unscheduled assessments). In the analysis of MMTT variables (Glucose, C-peptide and
Glucagon) (reported and calculated parameters) the Basal of those variables is defined as the average of the two
basal values (Basal #1 and Basal #2 (pre-meal values)). If one of the two basal values is missing the non-missing basal
value will be considered as Basal in the analysis of MMTT variables.
7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA
No unscheduled visits have been foreseen in the study.
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements
will not be included in by-visit summaries.
Listings will include scheduled, unscheduled and early discontinuation data.
7.4. WINDOWING CONVENTIONS
Actual dates of visits will be used for calculations of time intervals. No visit windowing will be performed for this
study. Out-of-window visits will not be reallocated to the nearest timepoint.
7.5. STATISTICAL TESTS
All statistical tests will be performed one sided with α=0.05 and 95% confidence intervals will be employed, unless 
otherwise specified in the description of the analyses.
7.6. COMMON CALCULATIONS
For some quantitative measurements, change from baseline will be calculated as:

Absolute: Value at Visit X – Baseline Value


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
Relative: ((Value at Visit X – Baseline Value)/Baseline Value) *100
7.7. SOFTWARE VERSION
All statistical analyses will be conducted using The SAS System version 9.4 under Windows 10 PRO operating system.
8. STATISTICAL CONSIDERATIONS
8.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES
In the analysis of secondary efficacy variables 2-hour AUC of C-peptide response to the MMTT, average (previous 3
days) insulin requirement (IU/kg/day), HbA1c levels, and C-peptide AUC (15-120) above fasting value the following
fixed factors will be considered in the mixed linear model:

Treatment group

Visit

Treatment by visit interaction
In the analysis of percent change from baseline in 2-hour AUC of C-peptide response to the MMTT the baseline value
of 2-hour AUC of C-peptide will be considered as a covariate of the mixed linear model. Moreover, treatment group,
visit and the treatment by visit interaction will be the fixed effects of the mixed linear model.
In the analysis of actual values of the efficacy endpoints C-peptide, Glucose and Glucagon over the study the
following fixed factors will be considered in the mixed linear model:

Treatment group

Visit

Time

Treatment by visit interaction

Treatment by time interaction

Treatment by visit and by time interaction
In the analysis of 2-hour AUC C-peptide according to the number of positivity in auto-antibodies counted at Screening
visit the following fixed factors will be considered in the mixed linear model:

Treatment group

Visit

Treatment by visit interaction

Number of positivity

Treatment by number of positivity interaction
8.2. MULTICENTRE STUDIES
This study will be conducted by multiple investigators at multiple centers. Site-related differences will not be
evaluated and presented in the statistical output as the study does not foresee a randomization stratified by Centre.


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Document:
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Author:
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Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
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reproduction is strictly prohibited.
8.3. MISSING DATA
If the actual time for Mixed Meal Tolerance Test is not recorded, the scheduled time will be used.
Missing C-peptide values will be imputed with the average of the C-peptide value that precedes and follows the
missing value. Missing data in C-peptide at 180 minutes (final) will be replaced by the last non-missing value.
The last available basal sample time will be used as the first sample time in the computation of the AUC, and the
average of the basal sample values (Basal #1 and Basal #2) will be used as the first sample value in the computation
of the AUC.
Other missing data will not be replaced.
The number of patients with missing data will be presented under the “unknown” category. Missing values will be
included in the denominator count when computing percentages.
When continuous data will be summarized, only the non-missing values will be evaluated for computing summary
statistics.
8.4. MULTIPLE COMPARISONS/ MULTIPLICITY
No alpha adjustment for multiple comparisons will be introduced, because only the comparison between Ladarixin
and placebo group on the primary efficacy endpoint will be considered as confirmatory.
8.5. ACTIVE-CONTROL STUDIES INTENDED TO SHOW NON-INFERIORITY OR
EQUIVALENCE
Not applicable for this study.
8.6. EXAMINATION OF SUBGROUPS
Subgroup descriptive analyses will be performed on the efficacy endpoints (listed in paragraph 3.2.1) according to
age class at Screening (≤ 25 and > 25 years). to fasting C-peptide (Pre-MMTT) (≤ median value and > median value) 
at Screening visit and to number (1 to 4) of positive auto-Ab at Screening/diagnosis . Statistical comparisons between
the two treatment groups will be performed only if the number of patients (n) of the two treatment groups is quite
balanced within each stratum and with n ≥ 10 per treatment group in each stratum. Such statistical comparisons will 
be performed using non-parametric statistical tests.
9. OUTPUT PRESENTATIONS
Appendix 1 shows conventions for presentation of data in outputs.
The templates provided with this SAP describe the presentations shell for this study and therefore the format and
content of the summary tables, figures and listings to be provided.
The reference analysis set of each table and line listing is reported in the corresponding table and line listing.


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Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
10.
DISPOSITION, WITHDRAWALS AND PROTOCOL DEVIATIONS
The number of patients enrolled, a summary of analysis populations, a summary of reasons for exclusion from
analysis populations, a summary of reasons for premature withdrawal of patients from the study, and an individual
data listing of the patients who prematurely interrupted the treatment/study will be presented.
Furthermore, a summary and an individual data listing of protocol deviations and major protocol deviations will be
produced.
11.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Summary demographic data and other baseline characteristics will be tabulated for the ITT population.
No statistical testing will be carried out for demographic or other baseline characteristics.
The following demographic and baseline characteristics will be reported for this study:

Demographic variables:
o
Age (years)
o
Gender (Male, Female)
o
Race (White/Caucasian, Asian, Black or African American, Other)

Pregnancy test result (Positive or Negative), if appropriate

Disease-specific information:
o
Auto-antibodies results to confirm T1D diagnosis: quantitative (IAA (U/mL), GAD (IU/mL), IA-2
(U/mL), ZnT8 (U/mL)) and qualitative, i.e. positive or negative. Quantitative results at Screening
visit can be considered as “Baseline values” if sample is taken within 3 weeks prior of
randomization. In case of missing values then auto-antibodies non-missing values reported at CRF
page 7 will be considered as “Baseline values”.
o
Baseline Auto-antibodies quantitative results (IAA (U/mL), GAD (IU/mL), IA-2 (U/mL), ZnT8 (U/mL)),
o
Baseline insulin (IU/kg/day) and HbA1c (%) results

Vital Signs:
o
Height (cm)
o
Weight (Kg)
o
Systolic Blood Pressure (mmHg)
o
Diastolic Blood Pressure (mmHg)
o
Heart Rate (bpm)

Baseline 12-Lead ECG:
o
ECG Result (Normal, Abnormal not clinically significant, Abnormal clinically significant)
o
QT corrected for HR with Fridericia’s formula (QTcF) (msec)

Baseline Mixed Meal Tolerance Test: glucose, C-peptide and glucagon (time course 0-180 min, i.e. levels at
the following timepoints: Basal 1, Basal 2, 15 min, 30 min, 60 min, 90 min, 120 min, 180 min). Cmax
(Maximum Plasma Concentration) and Tmax (Time to reach Maximum Plasma Concentration) of the MMTT
will be provided. Individual plots will be presented. Based on the observed trends, additional analyses might
be performed. Cmax and Tmax will be calculated up to 180 minutes after mixed meal administration (time
interval ranging from 15 min. to 180 min.).
Furthermore, the 2-hour AUC of C-peptide response calculation 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. Missing C-peptide values will be imputed with the average of the C-
peptide value that precedes and follows the missing value. Missing data in C-peptide at 180 minutes (final)
will be replaced by the last non-missing value, and the last available basal sample (time and value) will be
used as the first sample in the computation of the AUC.


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.

Baseline MicroRNA-375 expression level (Copies/mL)

T-cells response (T-cell proliferation (CD4) and rate of precursor (CD8)).

Renal Reserve: Creatinine Clearance (CLcr) (mL/min) – calculated in the CRF. The formula that will be used
to verify the calculation is reported in section 11.1.

Time since first insulin injection (days) – calculated as specified in section 11.1.
Default frequency tabulations will be provided for categorical variables and descriptive summary statistics will be
provided for continuous parameters.
11.1. DERIVATIONS
The following variables will be derived:

“Basal” Mixed Meal Tolerance Test measurement = (Basal 1 measurement + Basal 2 measurement) / 2

CLcr (mL/min):
o
MALE patients = [[140 – age (years)] x Weight (kg)] / [Serum Creatinine (µmol/L) x 0.815]
o
FEMALE patients = [[140 – age (years)] x Weight (kg)] / [Serum Creatinine (µmol/L) x 0.815] x 0.85

Time since first insulin injection (days) = Date of randomization – Date of first insulin injection +1
12. SIGNIFICANT MEDICAL HISTORY
Significant medical history information will be tabulated for the ITT population.
All verbatim terms will be assigned to a Preferred Term (PT) and will be classified by primary System Organ Class
(SOC) according to MedDRA dictionary version 19.1 or higher.
Medical conditions which are not ongoing at Screening will be considered as previous diseases while those reported
as “ongoing” in CRF will be considered as concomitant diseases.
Previous and concomitant diseases will be analyzed separately with frequency tables reporting the number of
patients who exhibited at least one disease and showing diseases by primary System Organ Class and Preferred term.
13. MEDICATIONS
Medications will be tabulated for the ITT population and coded using WHO-DRL dictionary version 2016 or higher.
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define a
medication as prior or concomitant, the medication will be classified by the worst case; i.e. concomitant.
Prior medications are those which stopped prior to the date of informed consent.
Concomitant medications are those which:

started prior to, on or after the date of informed consent and started no later than date of end study,

AND ended on or after the date of informed consent or were ongoing at the end of the study.
The classification of medications into prior or concomitant medications as above was done for statistical purposes.
The following tables will be presented:

A frequency tables of prior medications by primary therapeutic subgroup (3rd level ATC level subgroup) and
generic name.

A frequency tables of concomitant medications by primary therapeutic subgroup (3rd level ATC level
subgroup) and generic name.


Dompé farmaceutici S.p.A - Protocol MEX0114
Page 25 of 37
Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
14. STUDY MEDICATION EXPOSURE
Exposure to study medication (total duration of exposure and during each treatment cycle) in days will be
summarized with descriptive statistics for the SAF by treatment group.
The date of first study medication administration will be taken from the “Diary Card” form (Treatment Cycle No.1,
Day 1).
In case of treatment discontinuation, the date of last study medication will be taken from the last available “Diary
Card” form.
In case of 3-cycle treatment completion, the date of last study medication will be taken from the “Diary Card” Form
taking the date of Treatment Cycle No. 3 Day 14.
14.1. DERIVATIONS

Duration of exposure (days) for each treatment cycle = (date of last IMP dose intake – date of first IMP dose
intake) +1

Total duration of exposure (days) = sum of the duration of exposure of each treatment cycle.
15. STUDY MEDICATION COMPLIANCE
Data will be summarized by treatment group for SAF population with descriptive statistics.
Descriptive analyses will be presented separately by treatment group for the total number of capsules dispensed,
returned and taken, the dose administered (by treatment cycle and overall) as well as the overall compliance to
study medication and the compliance by treatment cycle.
Compliance will be calculated from the derived variable “calculated number of capsules taken”.
15.1. DERIVATIONS

Overall study medication compliance = Calculated number of capsules taken / 168 capsules (theoretical no.
of capsules to be taken over the study).

Study medication compliance by cycle = Calculated number of capsules taken in each cycle / 56 capsules
(theoretical no. of capsules to be taken in each treatment cycle).

Overall dose of ladarixin administered (mg) = Calculated number of capsules taken * 200 mg

Dose of ladarixin administered by cycle (mg) = Calculated number of capsules taken in each cycle * 200 mg
16. ANALYSIS OF EFFICACY AND SAFETY VARIABLES
All the efficacy analyses will be performed for the ITT set.
All the AUC analyses (2-hour and 15-120) 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.
C-peptide AUC values will be transformed to the log(x+1) [selected by TrialNet as the appropriate transformation for
MMTT C-peptide AUC].
C-peptide 2-hour AUC values will be calculated from 0-120 C-peptide values of the MMTT. C-peptide (15-120) above
fasting AUC will be calculated on the changes from Basal in C-peptide values of the MMTT. Basal value is the average


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
of Basal #1 and Basal #2 C-peptide values in MMTT. The last non-missing time of Basal #1 and Basal #2 values will be
used to calculate the time differences in the AUC.
16.1. PRIMARY EFFICACY ANALYSIS
16.1.1. PRIMARY EFFICACY VARIABLE
The primary variable is the 2-hour C-peptide AUC after the MMTT [Time point: week 13±1].
16.1.2. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE
The 2-hour C-peptide AUC after the MMTT at week 13 ± 1 will be transformed as log(x+1) values; transformed AUC
will be analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and
placebo groups. The estimated treatment difference between Ladarixin and placebo will be also presented together
with the corresponding 95% confidence interval.
16.2. SECONDARY EFFICACY ANALYSES
16.2.1. SECONDARY EFFICACY VARIABLES
The secondary efficacy variables are:
1.
2-hour AUC of C-peptide response to the MMTT [Time points: baseline, weeks 13±1, 26±2 and 52±2].
2.
Percent change from baseline of 2-hour AUC of C-peptide response to the MMTT [Time points: weeks 13±1,
26±2 and 52±2].
3.
Average (previous 3 days) insulin requirement (IU/kg/day) [Time points: baseline, weeks 13±1, 26±2 and
52±2].
For the patients reporting “off insulin” response in the CRF the daily insulin requirement value will be
conventionally set to zero in the statistical analysis.
4.
HbA1c levels [Time points: baseline, weeks 13±1, 26±2 and 52±2].
5.
Number of severe hypoglycemic events occurring from randomization [Time points: weeks 13±1, 26±2 and
52±2].
A severe hypoglycemic event is defined as an event with one of the following symptoms: “Memory loss,
confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure,
seizure, loss of consciousness, or visual symptoms”, in which the patient 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.
6.
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of C-peptide and glucose
derived from the MMTT [Time points: baseline, weeks 13±1, 26±2 and 52±2].
7.
Proportion of patients maintaining a residual β-cell function [Time points: baseline, weeks 13±1, 26±2 and 
52±2].
Maintenance of a residual β-cell function is defined as at least one MMTT C-peptide value > 0.2 nmol/L. 
8.
Proportion of patients with HbA1c < 7% and absence of episodes of severe hypoglycemia from the previous
visit [Time points: weeks 13±1, 26±2 and 52+2].
9.
C-peptide AUC (15-120 minutes) above fasting value [Time points: baseline, weeks 13±1, 26±2 and 52±2].


Dompé farmaceutici S.p.A - Protocol MEX0114
Page 27 of 37
Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
16.2.2. ANALYSIS OF SECONDARY EFFICACY VARIABLES
The following analyses of secondary efficacy variables will be performed:
1.
The comparisons between groups on 2-hour AUC C-peptide efficacy endpoint will be carried-out using a
mixed linear model where the log(x+1) transformed 2-hour AUC C-peptide will be the dependent variable,
while treatment group, visit, treatment by visit interaction will be the fixed factors of the model and patient
will be the random effect. An unstructured covariance matrix for each patient is considered and the
Kenward-Roger adjustment is used for the degrees of freedom.
2.
The comparisons between groups on the percent change from baseline of 2-hour AUC C-peptide will be
carried-out using a mixed linear model with percent change from baseline of 2-hour AUC C-peptide as
dependent variable, treatment group, visit, treatment by visit interaction as fixed factors of the model and
patient as random effect. The baseline value of 2-hour AUC C-peptide will be considered as a covariate of
the model. An unstructured covariance matrix for each patient is considered and the Kenward-Roger
adjustment is used for the degrees of freedom.
3.
The comparisons between groups on insulin requirement secondary efficacy endpoint will be carried-out
using a mixed linear model with average daily insulin requirement as dependent variable, treatment group,
visit, treatment by visit interaction as fixed factors of the model and patient as random effect. An
unstructured covariance matrix for each patient is considered and the Kenward-Roger adjustment is used
for the degrees of freedom.
4.
The comparisons between groups on HbA1c secondary efficacy endpoint will be carried-out using a mixed
linear model with HbA1c value as dependent variable, treatment group, visit, treatment by visit interaction
as fixed factors of the model and patient as random effect. An unstructured covariance matrix for each
patient is considered and the Kenward-Roger adjustment is used for the degrees of freedom.
5.
The effect of treatment on the cumulative number of severe hypoglycemic events will be evaluated by
means of a Cox proportional hazards model with sandwich variance estimate. The Andersen-Gill intensity
model with model-based variance will be utilized.
6.
The comparisons between groups on the C-peptide and glucose in terms of basal to 180 min time course
will be carried-out using a mixed linear model with C-peptide and glucose derived from the MMTT as
dependent variables, treatment group, visit, time, treatment by visit interaction, time by visit interaction
and treatment by time by visit interaction as fixed factors of the model and patient as random effect. An
unstructured covariance matrix for each patient is considered and the Kenward-Roger adjustment is used
for the degrees of freedom. Furthermore, default summary statistics of Cmax and Tmax of the MMTT at
each visit will be provided. Cmax and Tmax will be calculated up to 180 minutes after mixed meal
administration (time interval ranging from 15 min. to 180 min.). Individual plots will be presented. Based on
the observed trends, additional analyses might be performed.
7.
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients
maintaining a residual β-cell function at the single time points will be calculated. The comparison between 
the two study treatment arms will be performed by means of a Chi-square test or, if more appropriate, a
Fisher’s Exact test at each time point.
8.
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients with
HbA1c < 7% and absence of episodes of severe hypoglycemia from the previous visit will be calculated for
each time point. The comparison between the two study treatment arms will be performed by means of a
Chi-square test or, if more appropriate, a Fisher’s Exact test at each time point.
9.
The comparisons between groups on C-peptide AUC (15-120) above fasting value will be carried-out using
a mixed linear model where the log(x+1) transformed C-peptide AUC above fasting value will be the
dependent variable, while treatment group, visit, treatment by visit interaction will be the fixed factors of
the model and patient will be the random effect. An unstructured covariance matrix for each patient is
considered and the Kenward-Roger adjustment is used for the degrees of freedom.


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
16.3. EXPLORATORY AND POST-HOC ANALYSES
16.3.1. EXPLORATORY VARIABLES
The exploratory variables are:
1.
Basal (2 basal samples in the range between -20 to 0 min) to 180 min time course of glucagon derived from
the MMTT [Time frame: baseline, weeks 13±1, 26±2 and 52±2].
2.
Auto-antibodies (GAD, IA-2, IAA, ZnT8), [Time frame: baseline, weeks 13±1, 26±2 and 52±2].
3.
MicroRNA-375 expression level (miR-375) [Time frame: baseline, weeks 13±1, 26±2 and 52±2].
4.
T-cell response ex vivo to major β-cell antigens (e.g. pro-insulin, GAD65) - selected sites only [Time frame: 
baseline, weeks 13±1, 26±2 and 52±2].
5.
2-hour AUC of C-peptide response to the MMTT stratified by the number of positivity in auto-antibodies (1,
2, 3, and 4) at Screening visit.
6.
Proportion of responders at week 52, defined as patients with percent decrease from baseline in 2-hour
AUC of C-peptide above the median percent decrease from baseline to Week 52.
16.3.2. ANALYSIS OF EXPLORATORY VARIABLES
Data will be summarized for all patients in the ITT population, by treatment group.
For the endpoint #1, the comparisons between groups on glucagon in terms of basal to 180 min time course will be
carried-out using a mixed linear model with glucagon derived from the MMTT as dependent variables, treatment
group, visit, time, treatment by visit interaction, time by visit interaction and treatment by time by visit interaction
as fixed factors of the model and patient as random effect. An unstructured covariance matrix for each patient is
considered and the Kenward-Roger adjustment is used for the degrees of freedom. Furthermore, default summary
statistics of Cmax and Tmax of the MMTT at each visit will be provided. Cmax and Tmax will be calculated up to 180
minutes after mixed meal administration (time interval ranging from 15 min. to 180 min.).
For the endpoints from #2 to #4 default summary statistics of the values over time and the changes from baseline
will be provided.
For the endpoint #5, the comparisons between groups will be carried-out using a mixed linear model with 2-hour
AUC of C-peptide response to the MMTT as dependent variable, treatment group, visit, number of positivity in auto-
antibodies at Screening visit, treatment by visit interaction, treatment by number of positivity interaction as fixed
factors of the model and patient as random effect. An unstructured covariance matrix for each patient is considered
and the Kenward-Roger adjustment is used for the degrees of freedom.
Analysis of endpoint #6 will be performed calculating the number and proportion along the 95% confidence interval
(Clopper-Pearson’s formula) of patients responder. The comparison between the two study treatment arms will be
performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test.
16.3.3. POST-HOC AND SUBGROUPS ANALYSES
Post-hoc and subgroups analyses aiming to compare the two treatment groups might be considered for all the
efficacy endpoints. Such analyses might include, but may not be limited to, calculation of additional endpoints (e.g.,
Igls score and/or beta2 score), subgroup analysis of efficacy variables by time from first insulin dose to
randomization, i.e. ≤6 weeks and ≤10 weeks). Descriptive and appropriate inferential statistical tests will be used. 
The reason to perform such post-hoc and subgroups analyses will be presented and justified in an appropriate
document before to perform the analysis.


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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
16.4. SAFETY ANALYSES
16.4.1. SAFETY VARIABLES
The safety analyses will include the following variables:
1.
Vital signs (SBP, DBP and heart rate)
2.
Routine laboratory tests (hematology, clinical chemistry)
3.
Incidence of Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events
(TESAEs)
16.4.2. ANALYSIS OF SAFETY VARIABLES
Data will be summarized for SAF set with descriptive statistics, by treatment group.
Default summary statistics of vital signs and results for routine laboratory tests over time and the changes from
baseline will be provided. Vital signs (SBP, DBP and heart rate) will be recorded at baseline, at pre-dose visit of 2nd
cycle and at week 13±1 follow-up visit. Routine laboratory tests will be performed at baseline, pre-dose visit of 2nd
cycle and at week 13 ±1 follow-up visit only.
Moreover, results for routine laboratory tests will be assessed as being below the lower limit of the normal range,
within the normal range or above the upper limit of the normal range and will be summarized with a frequency table
for each visit.
The frequency of patients reporting an abnormal (not clinically significant or clinically significant) laboratory value
at Screening and at subsequent visits will be presented for each laboratory variable.
TEAEs will be presented in terms of the number of TEAEs, the incidence, severity and relationship to the study drug,
overall and by System Organ Class and Preferred Term. TESAEs will be presented in the same way.
16.4.3. ADVERSE EVENTS
All AEs will be assigned to a Preferred Term (PT) and will be classified by primary System Organ Class (SOC) according
to the MedDRA thesaurus version 19.1 or higher.
Any AE which started at or after the first administration of study treatment will be considered a Treatment Emergent
Adverse Event (TEAE).
Each AE will be graded according to severity definitions as “Mild”, “Moderate” or “Severe”.
Summary of TEAEs will be presented for the SAF set by treatment group.
If the start date is missing for an AE, the AE will be considered to be treatment emergent (See Appendix 2 for more
details about how to handle with partial or missing start/stop dates).
TEAEs will be reported on a per-patient basis. This means that even if a patient reported the same event repeatedly
(i.e. events mapped to the preferred term) the event will be counted only once.
For summaries, the drug-event relationship will be assessed as “None”, “Unlikely”, “Possible” “Probable” or “Highly
probable”. Any TEAE reported in the study having a possible, probable or highly probable relationship to study drug
will be defined as “Adverse Drug Reaction” (ADR).
The following tables and listings will be presented:
1) An overview of TEAEs including the number of patients who exhibited at least one TEAE, at least one serious TEAE,
at least one non-serious TEAE, at least one ADR, at least one serious ADR, number of TEAEs, number of non-serious


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
TEAEs, number of TESAEs, number of ADRs, number of serious ADRs, number of deaths, number of patients who
discontinued study drug due to a TEAE;
2) Summary of TEAEs by primary System Organ Class and Preferred Term;
3) Summary of TEAEs by primary System Organ Class, Preferred Term and Severity;
4) Summary of Serious TEAEs by Primary System Organ Class and Preferred Term;
5) Summary of ADRs by Primary System Organ Class and Preferred Term;
6) Summary of TEAEs leading to Study Drug Discontinuation by Primary System Organ Class and Preferred Term;
7) Summary of TEAEs leading to Death by Primary System Organ Class and Preferred Term;
8) Line Listing of all AEs by Patient;
9) Line Listing of SAEs by Patient;
10) Line Listing of Adverse Drug Reactions by Patient;
12) Line Listing of Deaths;
16.4.4. SAFETY LABORATORY EVALUATIONS
Results from the local laboratories will be included in the reporting of this study for Hematology and Blood
Chemistry. Data will be summarized for the SAF set.
Presentations will use SI Units.
The following summaries will be provided for Hematology and Blood Chemistry laboratory data:
1)
A summary table showing for all laboratory tests the values and changes from baseline to each subsequent
visit by treatment group;
2)
A summary table showing for all laboratory tests the frequency of patients reporting an out-of-range (below
LLN or above ULN) laboratory value at Screening and at subsequent visits by treatment group.
3)
A summary table showing for all laboratory tests the frequency of patients reporting an abnormal (clinically
or not clinically significant) laboratory value at Screening and at subsequent visits by treatment group.
A listing showing values, the reference ranges and the clinical significance according to investigators’ opinion will be
produced. Laboratory data will be presented by-patient and within-patient by laboratory test and visit.
16.4.4.1.
Conversion of Laboratory Values Units
To convert from the conventional unit to the SI unit, multiply by the conversion factor:
Parameter
Conventional
Unit
Conversion
Factor
SI Unit
Hematology
Hemoglobin
g/dL
10
g/L
Hematocrit
%
0.01
Proportion of 1.0
RBC count
x 106/µL
x 106/mm3
0.1
1
x 1012/L
WBC count
x 103/µL
x 103/mm3
1
1
x 109/L
Neutrophils
x 103/µL
1
x 109/L


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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
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Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
Parameter
Conventional
Unit
Conversion
Factor
SI Unit
x 103/mm3
%
1
x WBC/100
Lymphocytes
x 103/µL
x 103/mm3
%
1
1
x WBC/100
x 109/L
Monocytes
x 103/µL
x 103/mm3
%
1
1
x WBC/100
x 109/L
Basophils
x 103/µL
x 103/mm3
%
1
1
x WBC/100
x 109/L
Eosinophils
x 103/µL
x 103/mm3
%
1
1
x WBC/100
x 109/L
Platelets
x 103/µL
x 103/mm3
1
1
x 109/L
Blood chemistry
Total Bilirubin
mg/dL
g/dL
g/L
17.104
17104
171.04
µmol/L
Aspartate aminotransferase (AST)
units/L
1
U/L
Alanine aminotransferase (ALT)
units/L
1
U/L
Serum Albumin
g/dL
%
10
1
g/L
%
Urea
mg/dL
0.357
mmol/L
Sodium
mEq/L
1.0
mmol/L
Potassium
mEq/L
1.0
mmol/L
Serum Creatinine
mg/dL
88.4
µmol/L
16.4.5. VITAL SIGNS ANALYSIS
Data will be summarized for the SAF Set.
The following vital sign measurements will be reported for this study as part of safety endpoints:
1.
Systolic Blood Pressure (mmHg) – at Screening, pre-dose visit of 2nd cycle, Follow-up visit week 13
2.
Diastolic Blood Pressure (mmHg) – at Screening, pre-dose visit of 2nd cycle, Follow-up visit week 13
3.
Heart Rate (bpm) – at Screening, pre-dose visit of 2nd cycle, Follow-up visit week 13


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
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Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
Vital sign measurements performed at Day 3 to 5 of 1st treatment cycle for German investigational sites only will
also be reported, even if they are not protocol-defined safety endpoints.
For SBP, DBP and heart rate, the change from Screening to each subsequent visit after Screening will be calculated
as follows: Absolute Change (unit) = (Absolute Value at Visit X – Baseline Value).
Default summary statistics for SBP, DBP and heart rate at each visit and changes form baseline to each visit will be
produced by treatment group.
16.5. ECG EVALUATIONS
Data will be summarized for the SAF set.
ECG will be performed at Screening, at pre-dose visit of 2nd cycle and at pre-dose visit of 3rd cycle.
For German investigational sites only: an ECG will be performed at Day 3 to 5 of 1st treatment cycle.
If QTcF value at subsequent visit after Screening is either > 500 msec or has increased by > 60 msec from screening
value, the ECG evaluation will be repeated and the repeated QTcF value will be considered as the only evaluation
value for that visit.
A summary table showing for QTcF the values and changes from baseline to each subsequent evaluation will be
produced by treatment group.
A summary table showing the Investigator’s judgement on ECG evaluation (Normal/Abnormal NCS/Abnormal CS)
will be produced at Screening and at subsequent visits by treatment group.
16.6. PREGNANCY TEST OVER THE STUDY
Data will be summarized for the SAF set.
Pregnancy tests will be performed at Screening, at pre-dose visit of 2nd cycle and at pre-dose visit of 3rd cycle.
For Belgian investigational sites only: a pregnancy test will be performed at Follow-up Visit at 3 months.
A summary table showing test results (Negative/Positive) over the study will be produced by treatment group.
16.7. PERMANENT TREATMENT DISCONTINUATION CRITERIA
Data will be summarized for the Safety Analysis Set (SAF).
The following measurements will be reported:

IMP treatment completed (Yes/No)

If No: total number of capsules administered

If No: reason for permanent discontinuation of IMP:
o
QTcF > 500 msec or increased by 60 msec from Screening measurement on two consecutive ECG
reading (1 hour apart)
o
Complete Left Bundle Branch Block (LBBB), atrio-ventricular block, complete heart block
o
Significant cardiovascular disease
o
Renal Dysfunction
o
Hepatic Dysfunction


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
o
Hypoalbuminemia
o
Pregnancy
o
Other AE
o
Other
The following listings of discontinuation criteria will be presented:
-
Laboratory test results: Serum Creatinine, Serum Albumin, Total Bilirubin, ALT, AST (Screening, Pre-dose
visit 2nd and 3rd cycle, for German Investigational sites only also Day 3-5 of 1st cycle).
-
Creatinine Clearance (Screening, Pre-dose visit 2nd and 3rd cycle, for German Investigational sites only also
Day 3-5 of 1st cycle).
16.8. PRE-VISIT PHONE CALLS
Pre-visit phone calls will be performed at Week 11/12, at Week 24/25 and at Week 50/51.
Listings will be presented and will include: Date of call, glucose data checked (Yes/No), Insulin intake (Confirmed
/Adjusted).
17. ANALYSIS OF PHARMACOKINETIC DATA
Not applicable for this study.
18. TABLE SHELLS AND SPECIFICATIONS
18.1. TABLE SPECIFICATIONS
Tables will be provided as defined by the table shells.
Similar tables based on different populations will have the same number, except for the last digit.
All output will be generated by SAS and exported into a Microsoft Word document in RTF format. All output will be
in landscape orientation. Left and right margins will be 2 cm from the side; the top and bottom margins will be 2.5
cm. Font size will be Courier New 7 pt.
The header containing the sponsor name (Dompé farmaceutici S.p.A) and protocol number will appear on the top
left corner of each page of the output. The page number, in the format of “Page x of y”, will appear on the top right
corner of the output, where y = last page of corresponding output.
Column headers in tables include the total possible numbers to be included in summaries for that table, designated
as “(N=XX)”.
The SAS program name, and the date of the creation of the output (run date) will appear on the bottom left corner
as follows:
Source: [program name].sas, Run on ddmmmyyyy
Table Format Specification:
Maximum and minimum values will be reported with the same number of decimal places as collected. Means and
medians will be reported to one additional decimal place. Standard deviations and standard errors will be reported
to two decimal places more than the collected data. Percentages will be reported with one decimal place.


Dompé farmaceutici S.p.A - Protocol MEX0114
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Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
Data in the tables are formatted as follows:

Text fields in the body of the tables and listings will be left-justified.

When no data are available for a table, an empty page with the title will be produced with suitable
text. Example: THERE WERE NO SERIOUS ADVERSE EVENTS.
18.2. LINE LISTINGS SPECIFICATIONS
Individual line listings will be provided as defined by the listing shells.
All output will be generated by SAS and exported into a Microsoft Word document in RTF format. All output will be
in landscape orientation. Left and right margins will be 2 cm from the side; the top and bottom margins will be 2.5
cm. Font size will be Courier New 7 pt.
The header containing the sponsor name (Dompé farmaceutici S.p.A) and protocol number will appear on the top
left corner of each page of the output. The page number, in the format of “Page x of y”, will appear on the top right
corner of the output, where y = last page of corresponding output.
The SAS program name, and the date of the creation of the output (run date), the reference to CRF page or diary
card will appear on the bottom left corner as follows:
CRF source: Form “<Form Name>”, Section “<Section Name>”, Page <nn>.
Source: [program name].sas, Run on ddmmmyyyy.


Dompé farmaceutici S.p.A - Protocol MEX0114
Page 35 of 37
Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS
Quintiles Output Conventions:
Outputs will be presented according to the standard Quintiles’ (now IQVIA) layout of tables and line listings.
Dates & Times:
Depending on data available, dates and times will take the form ddmmmyyyy hh:mm:ss (i.e. 01JAN2017 10:20:15)
Spelling Format:
English US.
Listings:
All listings will be ordered by the following (unless otherwise indicated in the template):

Randomized treatment group (or treatment received if it’s a safety output) with active IMP first and
then placebo

Randomization number

Date (where applicable)

For listings where non-randomized patients are included, these will appear in a category after the
randomized treatment groups labelled ‘Not Randomized’.
In all listings missing data will be reported, according to the variable type, as follows:
-
Character variables and dates will be presented as empty fields
-
Numerical variables will be presented with a “-“


Dompé farmaceutici S.p.A - Protocol MEX0114
Page 36 of 37
Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
APPENDIX 2. PARTIAL DATE CONVENTIONS
Algorithm for Treatment Emergence of Adverse Events:
START DATE
STOP DATE
ACTION
Known
Known
If start date < study med start date, then not TEAE
If start date >= study med start date, then TEAE
Partial
If start date < study med start date, then not TEAE
If start date >= study med start date, then TEAE
Missing
If start date < study med start date, then not TEAE
If start date >= study med start date, then TEAE
Partial,
but
known
components show that it
cannot be on or after study
med start date
Known
Not TEAE
Partial
Not TEAE
Missing
Not TEAE
Partial, could be on or after
study med start date
Known
If stop date < study med start date, then not TEAE
If stop date >= study med start date, then TEAE
Partial
Impute stop date as latest possible date (i.e. last day of
month if day unknown or 31st December if day and month
are unknown), then:
If stop date < study med start date, then not TEAE
If stop date >= study med start date, then TEAE
Missing
Assumed TEAE
Missing
Known
If stop date < study med start date, then not TEAE
If stop date >= study med start date, then TEAE
Partial
Impute stop date as latest possible date (i.e. last day of
month if day unknown or 31st December if day and month
are unknown), then:
If stop date < study med start date, then not TEAE
If stop date >= study med start date, then TEAE
Missing
Assumed TEAE


Dompé farmaceutici S.p.A - Protocol MEX0114
Page 37 of 37
Document:
MEX0114_SAP_v4_4 Final Methods.docx
Author:
Claudio Iannacone
Version Number:
Final Version 4.4
Version Date:
[17SEP2019]
Template No: CS_TP_BS016 – Revision 4
Reference: CS_WI_BS005
Effective Date: 01Apr2016
Copyright © 2009, 2010, 2012, 2016 Quintiles Transnational Corp. All rights reserved.
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or
reproduction is strictly prohibited.
Algorithm for Prior / Concomitant Medications:
START DATE
STOP DATE
ACTION
Known
Known
If stop date < date of informed consent, assign as prior
If stop date >= date of informed consent and start date <= end of treatment,
assign as concomitant
If stop date >= date of informed consent and start date > end of treatment,
assign as post study
Partial
Impute stop date as latest possible date (i.e. last day of month if day unknown
or 31st December if day and month are unknown), then:
If stop date < date of informed consent, assign as prior
If stop date >= date of informed consent and start date <= end of treatment,
assign as concomitant
If stop date >= date of informed consent and start date > end of treatment,
assign as post treatment
Missing
If stop date is missing could never be assumed a prior medication
If start date <= end of treatment, assign as concomitant
If start date > end of treatment, assign as post treatment
Partial
Known
Impute start date as earliest possible date (i.e. first day of month if day
unknown or 1st January if day and month are unknown), then:
If stop date < date of informed consent, assign as prior
If stop date >= date of informed consent and start date <= end of treatment,
assign as concomitant
If stop date >= date of informed consent date and start date > end of
treatment, assign as post treatment
Partial
Impute start date as earliest possible date (i.e. first day of month if day
unknown or 1st January if day and month are unknown) and impute stop date
as latest possible date (i.e. last day of month if day unknown or 31st December
if day and month are unknown), then:
If stop date < date of informed consent, assign as prior
If stop date >= date of informed consent and start date <= end of treatment,
assign as concomitant
If stop date >= date of informed consent and start date > end of treatment,
assign as post treatment
Missing
Impute start date as earliest possible date (i.e. first day of month if day
unknown or 1st January if day and month are unknown), then:
If stop date is missing could never be assumed a prior medication
If start date <= end of treatment, assign as concomitant
If start date > end of treatment, assign as post treatment
Missing
Known
If stop date < date of informed consent, assign as prior
If stop date >= date of informed consent, assign as concomitant
Cannot be assigned as ‘post treatment’
Partial
Impute stop date as latest possible date (i.e. last day of month if day unknown
or 31st December if day and month are unknown), then:
If stop date < date of informed consent, assign as prior
If stop date >= date of informed consent, assign as concomitant
Cannot be assigned as ‘post treatment’
Missing
Assign as concomitant