Conditions: Type 1 Diabetes
Keywords: glycemic control insulin-resistant type 1 diabetes.
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
Primary objective

\- To determine whether oral ladarixin versus placebo adjunctive therapy improves glycemic control in overweight, insulin resistant (IR) adult subjects with type 1 diabetes (T1D).

Secondary objectives

* To ascertain the effect of ladarixin on glycemic variability as per CGM derived parameters.
* To determine the safety of oral ladarixin versus placebo adjunctive therapy in overweight, IR adult subjects with T1D.

Detailed description:
This study is a randomized, placebo-controlled, double-blinded, 2- parallel arm, phase II trial.

The planned number of patients to be enrolled was 86, across all genders, 21-65 years, inclusive, with established insulin-requiring T1D and IR, to be assigned (1:1) to receive either oral ladarixin 400 mg b.i.d. for 7 cycles (26 weeks) of 14 days on/14 days off (treatment group) or matched placebo (control group).

The planned duration of treatment was 7 cycles of 14 days with an interval of 14 days off (no IMP), for 26 weeks and a for total of 5 study visits.

Actually, only 24 patients were screened, 3 enrolled and 2 were randomized. The study was terminated early due to low recruitment rates; 2 patients completed the study, and therefore only their safety data are relevant to this study report.

No efficacy evaluation was conducted due to small numbers and early study termination. As a result, no conclusions can be made about the effectiveness of the treatment.

Only safety evaluations were conducted: no missing data on safety variables for the 2 randomized participants. At study termination, no TEAEs, ADRs, TESAEs, serious or severe ADRs had occurred, and therefore the safety profile of ladarixin had not changed.

Arms:
arm 1: Ladarixin was administered orally at the dose of 400 mg b.i.d. for 7 cycles of 14 days with an interval of 14 days off, for a total duration of 26 weeks. arm 2: Matching placebo was administered with the same treatment schedule of the IMP.

Interventions: intervention 1: Ladarixin intervention 2: Placebo
Intervention descriptions: intervention 1: The two daily oral doses of ladarixin (400 mg each dose) were administered at about a 12-hour interval (morning and evening; ideally between 6:30/11:30 and 18:30/23:30). At each administration, 2 capsules were swallowed with a glass of water, at least 2 hours apart from breakfast or dinner intervention 2: Placebo was administered with the same ladarixin schedule.

Protocol document:
Prot_000.pdf: 
Study LDX0122 
Ladarixin in insulin-resistant overweight T1D 
Page 1 of 71 
 
 
 
Protocol Version/Date: v3– Final 28Oct2022 
 
 
CLINICAL STUDY PROTOCOL 
Title:  
A phase II randomized, placebo-controlled, double-blinded, 2-parallel arm, clinical trial 
evaluating ladarixin 400 mg twice a day as adjunctive therapy to improve glycemic control 
in overweight insulin-resistant patients with type 1 diabetes. 
 
Short Title:  
A phase II randomized, placebo-controlled, double-blinded, 2-parallel arm, clinical trial 
evaluating ladarixin as adjunctive therapy to improve glycemic control in overweight 
insulin-resistant patients with type 1 diabetes 
 
Study Number: 
LDX0122 
 
Study Name:   
 
    CONSERVA 
 
 
IND / EudraCT number: 
147145 / 2022-000743-68 
 
 
Investigational Product: 
Ladarixin 
 
 
Phase of the study: 
Phase II 
 
  
Protocol Version – Date: 
version 3; Final 28 October 2022 
 
 
This protocol version results from revision of protocol version No. 1 
 
according to Amendment No. 1 (Final, 28 October 2022). For Italian Investigational sites, this 
protocol version results from revision of protocol version No. 2 (applicable to Italian sites only) 
 according to Italy-specific Amendment No. 2 (Final, 28 October 2022). 
 
 
 
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. 
 
 
 
CCI
CCI


Study LDX0122 
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Protocol Version/Date: v3– Final 28Oct2022 -
 
STUDY CONTACT INFORMATION 
 
 
SPONSOR 
Dompé farmaceutici s.p.a. [Dompé] 
 
Via Santa Lucia 6; 20122 Milan, Italy  
 
Medical Expert 
 
 
 
 
Clinical Operation Manager 
 
 
       
 
Development Director  
 
 
  
 
 
CONTRACT RESEARCH ORGANIZATIONS 
 
 
Clinical 
 
 
 
 
 
 
Biometrics 
 
 
 
 
 
 
 
PHARMACOVIGILANCE:  
CRO PhV: 
e-mail: 
  
 
  
 
Dompé PhV:
e-mail:
  
 
 
 
   
 
 
 
PRINCIPAL INVESTIGATORS AND STUDY STAFF 
 
 
Full list of investigational sites will be kept in the Trial Master File. Updated versions will be filed 
chronologically. Copies will be provided to the sites. 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
CCI
CCI


Study LDX0122 
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Protocol Version/Date: v3– Final 28Oct2022 - 
 
 
Table of Contents 
1. 
STUDY SYNOPSIS ...........................................................................................................8 
2. 
SCHEDULE OF EVALUATION ................................................................................... 14 
2.1. 
BACKGROUND INFORMATION .................................................................................. 15 
2.2 
RELEVANT NON-CLINICAL PHARMACOLOGY ...................................................... 15 
2.2.2. 
In vivo general studies ........................................................................................................ 15 
2.2.3. 
 Effects in models of type 1 diabetes ................................................................................. 16 
2.3. 
A SUMMARY OF TOXICOLOGY DATA ...................................................................... 17 
2.4. 
PHARMACOKINETICS AND PRODUCT METABOLISM .......................................... 19 
2.5. 
A SUMMARY OF CLINICAL DATA ............................................................................. 20 
2.5.1. 
Pharmacokinetics and product metabolism in humans ...................................................... 20 
2.5.2. 
Efficacy .............................................................................................................................. 20 
2.5.3. 
Safety ................................................................................................................................. 21 
2.6. 
DISEASE REVIEW AND STUDY RATIONALE ........................................................... 23 
2.6.1. 
Alternative treatments ........................................................................................................ 26 
2.6.2. 
Risk – benefit evaluation ................................................................................................... 26 
2.6.3. 
Description of the Investigational Products ....................................................................... 27 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ............................ 28 
3.1. 
STUDY OBJECTIVES ...................................................................................................... 28 
3.2. 
STUDY ADMINISTRATIVE STRUCTURES, STAFF AND RESPONSIBILITY ........ 28 
3.3. 
OVERALL STUDY DESIGN ........................................................................................... 28 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study ......... 29 
4. 
SELECTION OF STUDY POPULATION ................................................................... 30 
4.1. 
INCLUSION CRITERIA .................................................................................................. 30 
4.2. 
EXCLUSION CRITERIA ................................................................................................. 30 
4.3. 
ASSIGNMENT OF PATIENT NUMBER ........................................................................ 31 
5. 
STUDY MEDICATION .................................................................................................. 32 
5.1. 
PRESENTATION, PACKAGING AND LABELING, SUPPLY, AND STORAGE OF 
THE INVESTIGATIONAL MEDICINAL PRODUCT .................................................... 32 
5.1.1. 
Presentation of the Investigational Medicinal Product ...................................................... 32 
5.1.2. 
Manufacturing, Packaging and Labelling of IMP .............................................................. 32 
5.1.3. 
Supply, Storage and Handling of IMP ............................................................................... 32 
5.1.4. 
Blinding  and unblinding ................................................................................................... 33 
5.2. 
DOSE, ROUTE AND SCHEDUE OF IMP ADMINISTRATION ................................... 33 
5.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP ................................................................................ 33 
5.3.1. 
Criteria for schedule adjustment/dose-modification .......................................................... 33 
5.3.2. 
Criteria for discontinuation of the IMP .............................................................................. 33 
5.4. 
ACCOUNTABILITY OF THE IMP ................................................................................. 34 
5.4.1. 
Assessment of compliance ................................................................................................. 34 
5.5. 
PRIOR AND CONCOMITANT MEDICATION ............................................................. 35 
5.5.1. 
Reporting of prior and concomitant medication ................................................................ 35 
5.5.2. 
Prohibited medications ...................................................................................................... 35 
5.6. 
INSULIN TITRATION ..................................................................................................... 35 
6. 
STUDY PROCEDURE AND ASSESSMENT ............................................................... 36 


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6.1. 
STUDY VISITS AND STUDY EVENTS/PROCEDURES DETAILS ............................ 36 
6.1.1. 
Identification of potential subjects ..................................................................................... 36 
6.1.2. 
Visit schedule and events/procedures ................................................................................ 36 
6.2. 
GLUCOSE MONITORING DURING THE DURATION OF THE TRIAL .................... 38 
6.2.1. 
Glucose Monitoring ........................................................................................................... 38 
6.2.1. 
Assessment and management of hypoglycemia ................................................................ 38 
6.3. 
EARLY PATIENT WITHDRAWAL ................................................................................ 39 
6.3.1. 
Withdrawal criteria ............................................................................................................ 39 
6.3.2. 
Replacement procedures .................................................................................................... 39 
6.4. 
END OF STUDY ............................................................................................................... 39 
6.5. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION OR TERMINATION ... 39 
7. 
STUDY ENDPOINTS ...................................................................................................... 40 
7.1.  
EFFICACT ENDPOINTS ................................................................................................. 40 
7.2. 
SAFETY ENDPOINTS ..................................................................................................... 40 
8. 
ADVERSE EVENTS ....................................................................................................... 41 
8.1. 
DEFINITIONS ................................................................................................................... 41 
8.2. 
MONITORING FOR ADVERSE EVENTS ..................................................................... 42 
8.3. 
RECORDING OF ADVERSE EVENTS .......................................................................... 42 
8.3.1. 
Follow-up of patients with AEs ......................................................................................... 42 
8.3.2. 
Relationship of AEs to the Investigational Medicinal Product .......................................... 43 
8.3.3. 
Severity of adverse events ................................................................................................. 43 
8.4. 
SERIOUS ADVERSE EVENT REPORTING .................................................................. 44 
8.4.1. 
Reporting Procedure for the Investigator to Dompé/CRO ................................................. 44 
8.4.2. 
Conditions that should not be reported as serious adverse events ..................................... 44 
8.4.3. 
Adverse events exemption ................................................................................................. 44 
8.5. 
EXPOSURE TO IMP DURING PREGNANCY .............................................................. 46 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ....................... 46 
8.7. 
OVERDOSE ...................................................................................................................... 46 
9. 
STATISTICAL CONSIDERATIONS ........................................................................... 48 
9.1. 
SAMPLE SIZE .................................................................................................................. 48 
9.2. 
RANDOMIZATION ......................................................................................................... 48 
9.3. 
ANALYSIS POPULATION .............................................................................................. 48 
9.4. 
STATISTICAL METHODOLOGY .................................................................................. 48 
10. 
ETHICAL CONSIDERATIONS .................................................................................... 51 
10.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) / INSTITUTIONAL REVIEW 
BOARD (IRB) ................................................................................................................... 51 
10.2. 
ETHICAL CONDUCT OF THE STUDY ......................................................................... 51 
10.3. 
PATIENT INFORMATION AND CONSENT ................................................................. 51 
10.4. 
CONFIDENTIALITY ....................................................................................................... 52 
10.5. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION52 
11. 
DATA HANDLING AND RECORD-KEEPING ......................................................... 53 
11.1. 
CASE REPORT FORM (CRF) ......................................................................................... 53 
11.2. 
DIARY ............................................................................................................................... 53 
11.3. 
DATA MANAGEMENT .................................................................................................. 53 
11.4. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF, AND DURING THE 
STUDY .............................................................................................................................. 53 
11.5. 
ESSENTIAL DOCUMENT RETENTION ....................................................................... 54 
12. 
STUDY MANAGEMENT ............................................................................................... 55 


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12.1. 
REGULATORY BODY OF APPROVAL ........................................................................ 55 
12.2. 
MONITORING .................................................................................................................. 55 
12.3. 
ACCESS TO RECORD ..................................................................................................... 55 
12.4. 
AUDIT AND INSPECTION ............................................................................................. 55 
12.5. 
DATA MONITORING COMMITTEE ............................................................................. 55 
12.7. 
DISCONTINUATION OF THE STUDY ......................................................................... 56 
13. 
REFERENCES ................................................................................................................. 58 
14. 
APPENDICES .................................................................................................................. 68 
14.1. 
APPENDIX 1 - SPONSOR APPROVAL PAGE .............................................................. 68 
14.2. 
APPENDIX 2 - INVESTIGATOR’S SIGNATURE PAGE .............................................. 69 
14.3. 
APPENDIX 3 - PACKAGING AND LABELING DETAILS .......................................... 70 
14.4. 
METHODOLOGICAL DETAILS .................................................................................... 71 
14.4.1. 
Handling of samples for assays.......................................................................................... 71 
14.4.2. 
Calculation of eGFR .......................................................................................................... 71 
14.4.3. 
......................................................................................................... 71 
 
 
Table 1  Cumulative summary of Adverse Drug Reactions (number of events and frequency) in 
Phase I and Phase II studies with ladarixin ........................................................... 22 
Table 2: Composition for each ladarixin unit (capsule) ......................................................................... 32 
 
 
 
 


Study LDX0122 
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Protocol Version/Date: v3– Final 28Oct2022 - 
 
 
List of Abbreviations and Definitions of Terms 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
b.i.d. 
Bis in die 
BMI  
Body Mass Index 
BP 
Bullous pemphigoid 
ºC 
Degrees Celsius 
CGM 
Continuous Glucose Monitoring 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CXCL8 
CXC ligand 8 [formerly interleukin (IL)-8] 
CXCR1/2 
CXCL8 receptors 
CYP2C9 
Cytochrome P450 2C9 
DKA 
Diabetic Ketoacidosis 
DMC 
Data Monitoring Committee 
DPP-IV inhibitor 
Dipeptidyl peptidase-IV inhibitor 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate  
eGDR 
Estimated Glucose Disposal Rate 
FAS 
Full Analysis Set  
fMLP 
formyl-met-leu-phe 
GAD 
Glutamic Acid Decarboxylase 
GV 
Glycemic Variability 
HbA1c 
Glycated hemoglobin 
HIV 
Human Immunodeficiency Virus 
IA-2 
Islet Antigen-2 
IAA 
Insulin Auto Antibody 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization on Good Clinical Practice 
IEC 
Independent Ethics Committee 
IGV 
Impaired Glycemic Variability 
IMP 
Investigational Medicinal Product 
IR 
Insulin Resistance/Insulin Resistant 
IRB 
Institutional Review Board 
ISOC 
Insulin Standard of Care 
ITT 
Intention To Treat 
i.v. 
Intravenous 
LD50 
Lethal Dose50 


Study LDX0122 
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Protocol Version/Date: v3– Final 28Oct2022 - 
 
NET 
Neutrophil Extracellular Trap 
NGSP  
National Glycohemoglobin Standardization Program 
NOAEL 
No Observed Adverse Effect Level 
NOD 
Non-Obese Diabetic 
NOEL 
No Observed Effect Level 
PCP 
Primary Care Physician 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PMN 
Polymorphonuclear leukocyte 
p.o. 
per os (taken by mouth) 
QTcF 
Fridericia’s corrected QT interval 
SAE 
Serious Adverse Event 
SAF 
Safety population 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous 
SD 
Standard Deviation  
SGLT2 
Sodium-Glucose co-transporter-2  
SUSAR 
Suspected Unanticipated Serious Adverse Reaction 
TAR 
Time Above Range 
TBR 
Time Below Range 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TIR 
Time In Range 
t½ 
Elimination half life 
T1D 
Type 1 Diabetes 
T2D 
Type 2 Diabetes 
ULN 
Upper Limit of Normal 
ZnT8 
Zinc Transporter Isoform 8 
 


Study LDX0122 
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Protocol Version/Date: v3– Final 28Oct2022 - 
 
1. 
STUDY SYNOPSIS  
 
CLINICAL STUDY SYNOPSIS: 
Study Number  
LDX0122 
Title of Study  
A phase II randomized, placebo-controlled, double-blinded, 2-parallel 
arm, clinical trial evaluating ladarixin 400 mg twice a day as adjunctive 
therapy to improve glycemic control in overweight insulin-resistant 
patients with type 1 diabetes. 
Study Name 
CONSERVA 
IND – EudraCT N° 
147145 – 2022-000743-68 
Study Centers (Country)  
USA and Italy 
Development Phase  
II 
Objective  
Primary objective: To determine whether oral ladarixin versus placebo 
adjunctive therapy improves glycemic control in overweight, insulin-
resistant (IR) adult subjects with type 1 diabetes (T1D).  
Secondary objectives: To ascertain the effect of ladarixin on glycemic 
variability as per CGM derived parameters. To determine the safety of 
oral ladarixin versus placebo adjunctive therapy in overweight, IR adult 
subjects with T1D. 
Exploratory objectives (if site is able and deems appropriate to 
accommodate and conduct these objectives):
 
 
 
Study Design and Methodology  
This study will be a randomized, placebo-controlled, double-blinded, 2-
parallel arm, phase II trial. It will enroll up to 86 patients across all 
genders, 21-65 years, inclusive, with established insulin-requiring T1D 
and IR, assigned (1:1) to receive either oral ladarixin 400 mg b.i.d. for 7 
cycles (26 weeks) of 14 days on/14 days off (treatment group) or matched 
placebo (control group). Patients will be involved in the trial for 5 study 
visits, for a total of 28 weeks.  
Recruitment will be competitive among the study sites, until the planned 
number of patients is randomized. 
Number of Patients  
Up to 86 patients with established insulin-requiring T1D and with 
evidence of IR, aged 21-65 inclusive at the time of enrollment (patients 
consented and eligibility criteria confirmed) to target 76 evaluable 
patients. 
Diagnosis and Main Criteria for 
Inclusion/Exclusion  
Inclusion:  
1. clinical diagnosis of autoimmune T1D as documented by positive 
T1D-related autoantibodies [the presence of at least one or more of 
Insulin autoantibodies (IAA), Anti-GAD (GAD65), Anti-IA2 
(IA2), Zinc Transporter 8 (ZnT8)];  
2. age 21-65 years, inclusive, at the time of consent;  
3. T1D duration > 1 year;  
4. detectable fasting C-peptide as per the result of screening laboratory 
measurement; 
5. current insulin standard of care (ISOC), either established use of an 
insulin pump (closed loop system excluded) or a stable dose level 
and dose frequency for the last two months prior to screening, with 
no plans to switch the modality of insulin administration during the 
trial;  
CCI


Study LDX0122 
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6. routine use of a self-owned (if applicable) Continuous Glucose 
Monitoring (CGM) system that can record glucose concentrations 
continuously for at least 7 days; 
7. HbA1c value >7.5% as per the result of screening laboratory 
measurement;  
8. evidence of IR based on a total daily insulin dose >0.8 U/kg/day;  
9. subject is overweight or obese as per body mass index (BMI) of 
between 24-33 kg/m2, inclusive;  
10. ability to comply with all protocol procedures for the duration of the 
study, including scheduled follow-up visits and examinations, and 
willing to be contacted by clinical trial staff;  
11. provision of signed informed consent prior of any study-related 
procedure not part of standard medical care. 
 
Exclusion:  
1. use of a “closed loop system” for integrated glucose reading/insulin 
infusion; 
2. known or suspected hypersensitivity to the active pharmaceutical 
ingredient, non-steroidal anti-inflammatory drugs or any excipient 
of the investigational medicinal products (e.g. lactose and 
croscarmellose) as well as patients with congenital lactase 
deficiency, galactosaemia or glucose-galactose intolerance will 
have to be excluded; 
3. use of non-insulin medications for adjunctive blood glucose control 
(e.g: antidiabetic agents such as metformin, sulfonylureas, glinides, 
thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, 
SGLT-2 inhibitors or amylin) within one month of randomization 
as well as required in the participant’s standard of care;  
4. use of medications for weight reduction such as: Belviq 
(lorcaserin), Qsymia (Phentermine + topiramate), Orlistat (xenical) 
within one month of randomization as well as required in the 
participant’s standard of care;  
5. use of a medication such as stimulants, antidepressants and/or 
psychotropic agents that could affect weight gain or glycemic 
control of T1D;  
6. treatment with drugs metabolized by CYP2C9 with a narrow 
therapeutic index [i.e., phenytoin, warfarin, and high dose of 
amitriptyline (>50 mg/day)];  
7. use of angiotensin-converting enzyme inhibitors, interferons, 
quinidine antimalarial drugs, lithium, niacin;  
8. evidence of QTcF >470 msec and a history of significant 
cardiovascular disease/abnormality; 
9. any condition, including unstable diet and disordered eating 
behaviour, that in the judgment of the investigator will adversely 
affect patient’s safety or the completion of the protocol or 
otherwise confound study outcome;  
10. pregnancy: a) positive or missing pregnancy test (quantitative beta 
hCG) at screening; b) women of child-bearing potential and fertile 
men who do not agree to use effective contraceptive measures up 
to 2 months following trial discharge; lactating women; 
11. clinical diagnosis of celiac disease that is in poor control as defined 
by most recent tissue transglutaminase (tTG) that is in the abnormal 
range;  


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12. history of ≥1 Diabetic Ketoacidosis (DKA) events in the past 6 
months;  
13. hypoalbuminemia (serum albumin <3 g/dL); 
14. 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]; 
15. moderate to severe renal impairment calculated by estimated 
Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2 as 
determined 
using 
Chronic 
Kidney 
Disease 
Epidemiology 
Collaboration (CKD-EPI) creatinine equation;  
16. past (within 1 month prior to screening) or current administration 
of any immunosuppressive medications (including oral or 
systemically injected steroids) and use of any investigational 
agents, including any agents that impact the immune response;  
17. a condition already known which interferes with the ability to 
accurately determine glycated HbA1c; 
18. significant systemic infection during the 4 weeks before the 1st dose 
of study drug (e.g., infection requiring hospitalization, major surgery, 
or i.v. antibiotics to resolve; other infections, e.g., bronchitis, 
sinusitis, localized cellulitis, candidiasis, or urinary tract infections, 
must be assessed on a case-by-case basis by the investigator 
regarding whether they are serious enough to warrant exclusion). 
Test Product, Dosage and Mode 
of Administration  
The Investigational Medicinal Product (IMP) will be either ladarixin OR 
placebo capsules for oral administration. Ladarixin will be administered 
orally at the dose of 400 mg b.i.d. at about 12-hour interval (morning and 
evening). IMP will be dispensed as Patient Kits. 
Duration of Treatment  
The IMP will be administered for 7 cycles of 14 days on treatment with 
an interval of 14 days off treatment between cycles, for a total duration 
of 26 weeks. 
Reference product, Dosage and 
Mode of Administration  
Placebo will be administered with the same schedule as ladarixin. 
Study procedures 
Each patient will be involved in the study for a total of 5 visits, as detailed 
below.  
Subject identification phase (if needed as per site practice; pre-
screening): The study staff will identify potential study subjects (e.g. 
using electronic health records, diabetes or other relevant research study 
registries) and will reach out to them, via their primary healthcare 
manager/physician, offering information about the study and how to 
contact the study staff. Responsive individuals will be given 
comprehensive details about the study and then offered an informed 
consent form. The potential participants will have up to 7 days to decide 
if they are able and willing to participate. If they are, the study staff will 
arrange for the potential participant to come to Visit 1 for witnessed 
informed consent signing and then to undergo the screening procedures. 
Visit 1: Screening: The study physician or designee will present to 
discuss with the study subject the clinical trial and answer all questions. 
If the patient is able and willing to participate, after the informed consent 
has been obtained, study staff will assess past medical history to confirm 
T1D (e.g. results of past auto-antibody testing), will determine daily 
insulin requirement (U/kg/day - expressed as the average of the last 3 
days) and its stability, will measure body weight, height, waist and 
waist/hip circumference, will calculate 
 
 Body Mass Index (BMI), and will record the use of 
concomitant medication. Screening evaluation also include establishing 
the presence of IR as described (inclusion criteria, bullet 8)1-3. Blood 


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samples will be obtained to assess HbA1c, fasting C-peptide, standard 
safety laboratory tests, pregnancy in women with reproductive potential, 
T1D auto-antibody (excluding IAA) should past data not be available. 
Vital signs (blood pressure and heart rate) will be measured and an ECG 
performed. Patients must ensure the CGM sensor is correctly inserted and 
glucose monitored for at least the 7 days prior to the next visit. Potential 
study subjects must meet all inclusion and exclusion criteria prior to 
randomization. 
Visit 2: Randomization and start of IMP (Day 1): Within 2 weeks 
from the screening, the study subject will come to the site in the morning 
for visit 2. After at least 7 days of CGM data have been downloaded for 
measurement of glycemic variability outcomes and all inclusion/ 
exclusion criteria have been finally confirmed, eligible patients 
(enrolled patients) will be assigned a unique sequential randomization 
number and randomized 1:1 into either ladarixin or placebo, according 
to the randomization list. Vital signs will be measured, average 
(previous 3 days) daily insulin requirements (IU/kg/day) will be 
recorded, body weight, height, waist and waist/hip circumference will 
be assessed 
 and BMI calculated.  
 
 
 
 
IMP administration: The patients will begin administering the IMP, 
while on-site under medical supervision, ideally no later than 11:30 (1st 
dose of cycle 1). Treatment will proceed at home for the 1st and for 
additional 6 cycles of 14 days on/14 days off, for a total of 26 weeks. 
Visit 2b: (Week 4): An ECG will be performed and then the subject 
will undergo blood sampling for assessment of safety laboratory testing. 
Visit 3: (Week 11/12): Patient Kits (cycle 1 to 3) will be returned to 
verify treatment compliance. Medication use and Diary entries will be 
also ascertained. Vital signs will be measured followed by an ECG, and 
then the subject will undergo blood sampling for assessment of HbA1c, 
 
 
 average (previous 3 days) 
daily insulin requirements (IU/kg/day) will be recorded, body weight, 
height, waist and waist/hip circumference will be measured 
 
and BMI calculated. CGM data will be downloaded for measurement of 
glycemic variability in the previous 7 days. After IMP discontinuation 
criteria have been checked, Patient Kits (cycle 4 to 7) will be dispensed 
and the subject will be discharged from this visit. 
Visit 4; End of Study (Week 27/28): The study subject will come to 
the clinic for final assessment of vital signs, ECG, average (previous 3 
days) daily insulin requirements (IU/kg/day), body weight, height, waist 
and waist/hip circumference and for calculation of 
 BMI. 
Subjects will undergo blood sampling for assessment of HbA1c, safety 
laboratory testing, eGFR 
 
 CGM data will be downloaded for measurement of glycemic 
variability in the previous 7 days.  
At the end of the visit, upon the study physician’s order, the subject will 
be formally discharged from the study. 
Primary Efficacy Endpoint 
The proportion of responders at week 27/28 (visit 4), with responders 
defined as “patients with an HbA1c reduction from baseline of ≥0.50% 
(absolute difference) without episodes of severe hypoglycemia (level 3) 
Secondary Efficacy Endpoints  
- The proportion of responders at week 11/12 (visit 3) 
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- The mean difference from baseline in HbA1c assessed at week 11/12 
(visit 3) and 27/28 (visit 4) 
- Average (previous 3 days) daily insulin requirements (IU/kg/day) 
assessed at week 11/12 (visit 3) and 27/28 (visit 4) 
- Glycemic Variability by CGM (previous 7 days): time in range (TIR), 
time above range (TAR) time below range (TBR), standard deviation 
and coefficient of variation assessed at week 11/12 (visit 3) and 27/28 
(visit 4) 
Exploratory Endpoints  
- 
 
 
 
 
- 
 
- 
 
 
 
 
 
 
 
Safety Measures  
- Vital signs (blood pressure and heart rate) & Safety laboratory tests 
(hematology, clinical chemistry) assessed at screening, week 11/12 
(visit 3) and 27/28 (visit 4) 
- Incidence of Treatment Emergent Adverse Events (TEAEs) recorded 
from the beginning of study treatment to up to the end of study 
participation 
Statistical Methods 
This study is designed to be a randomized, placebo-controlled, double-
blinded, 2-parallel arm experiment in which subjects are randomized 
(1:1) to ladarixin or placebo. Sample size calculation was based on results 
obtained in the phase 2 trial with ladarixin in T1D onset. Considering the 
following assumptions: 
 
randomization ratio 1:1 (ladarixin: placebo), 
 
one-side type I error of 0.05, 
 
expected difference in favor of ladarixin in terms of responders: 
~22.5%, and 
 
power of 80% to detect the expected treatment effect 
a total of 76 evaluable patients are required; to account for a possible 10% 
of patients not evaluable for the primary variable after enrollment, up to 
86 patients will be enrolled.  
Summary statistics appropriate to the distribution of the primary variable 
will be calculated separately by treatment arm. A logistic regression 
model will be fit, adjusting for treatment, stratification factor, and other 
baseline characteristics.  
Summary statistics are defined for quantitative variables (number of 
observations, mean, standard deviation, median, minimum and 
maximum) and qualitative variables (number and percentage per 
category).  
The secondary 
 endpoints will be analyzed at each 
available time point by means of descriptive statistics and by appropriate 
inferential tests.  
TEAEs will be presented in terms of the number of TEAEs and incidence. 
Other safety parameters will be summarized by treatment at each 
available visit by means of descriptive statistics.  
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The Safety and the Full Analysis Set (FAS) population will consist of all 
patients who will be randomized and received at least one dose of the 
IMP. Safety population will be analyzed according to the actual treatment 
received; FAS population will be analyzed according to the Intention to 
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2.
SCHEDULE OF EVALUATION
The grid below summarizes the study schedule and the patient visits of the trial. For all measurements, the 
actual date and time of assessment, including date of sampling, will be recorded in the Source Document 
and/or eCRFs. Timeframe for each assessment is also shown in the grid below. 
ACTIVITY 
PRESCREENING* 
(Identify and 
reach out to 
potential 
participants and 
offer ICF) 
Screening 
Visit 1 
(Within week 
‐2)  
Treatment phase  
(week 1 to 26) 
End of study 
Visit 4 
(week 27/28) 
Randomization 
Visit 2 (Day 1) 
Visit 2b 
(week 4) 
Visit 3  
(week 11/12) 
Presentation of trial and ICF 
x
x
Informed Consent Form (ICF) 
signed  
x
Medical history and pre‐existing 
conditions 
x
Auto‐antibodies evaluation1 
x
Fasting C‐peptide 
x
Measurement of body weight, 
height, waist, and waist/hip 
circumference 
x
x
x
x
 BMI assessment 
x
x
x
x
Average (previous 3 days) Insulin 
requirement 
x
x
x
x
HbA1c 
x
x
x
x
CGM download for assessment of 
glycemic variability (previous 7 
days)2 
x
x
x
Vital signs 
x
x
x
x
Serum Pregnancy Test 
(blood/urine) 
x
x3
Safety laboratory tests 
(hematology, biochemistry) 
x
x
x
x
 
   
x
ECG (QTcF) 
x
x
x
x
eGFR 
x
x
x
Randomization 
x
IMP dispensation. 
x
x
Patient Diary delivery/check 
x
x
x
Treatment 
x-----------------------------x
Patient Phone call5  
x----------------------------------------------x
AE/SAE recording 
x---------------------------------------------------------------x
Prior and Concomitant Medication 
x---------------------------------------------------------------x
* Prescreening procedures can be performed during screening visit if applicable as per site practice
Legend:
1.
To include new testing should past data not be available;
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2. Secondary 
; 
3. Urine dipstick;  
4. 
 
 
 
  
 
 
5. Telephone calls at least every 30-45 days. 
Trial coordinators should contact participants prior to a clinic visit to review procedures as applicable. 
 
  
2.1. 
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 5-7. 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 
 
 Following promising results in mouse models of type 1 
diabetes (T1D), development in new onset T1D is ongoing7,8. 
Relevant pre-clinical, toxicological and clinical data are summarized further below (Section 2.2-2.4).  
Please also refer to the Investigator’s Brochure for detailed information. 
 
2.2 
RELEVANT NON-CLINICAL PHARMACOLOGY 
2.2.1. 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 receptor 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 CXCR29. 
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.  
Ladarixin (0.1 nM- 1 µM) results a potent inhibitor of IL-8-induced Neutrophil Extracellular Traps (NETs) 
release from isolated hPMN, with an IC50 of ≈ 1nM and an ICmax of 1 µM). Coherently with the selectivity 
data observed in the chemotaxis assay, ladarixin (1 µM) did not affect C5a, fMLP and PMA-induced NETs 
release. Ladarixin (1- 60 µg/mL) is also able to block IL-8-induced NETs formation in human whole blood 
in a concentration dependent manner with a complete inhibition at 60 µg/mL. Finally, the efficacy of ladarixin 
(1- 60 µg/mL) is evident on mCXCL1-mediated NET release in murine whole blood in a concentration 
dependent manner being the inhibition complete at 60 µg/mL.  
 
2.2.2. 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 rats10.  In addition, in an acute model of smoke exposure, ladarixin (3.75-15 mg/kg p.o.) reduces 
PMN infiltration by about 60%, whereas in the chronic exposure 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 edema formation (16% of inhibition), the cell 
infiltration (34% of inhibition on lymphocytes T and 32% of inhibition on PMNs) and the ear tissue levels 
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of keratinocyte chemokine (37%), VEGF-A (24%) and TNF- (44%) [See the Investigator’s Brochure  
Reference: A0811/E]. 
In a passive transfer mouse model of BP, 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 [See the Investigator’s Brochure 
Reference A0811/E].  
 
2.2.3.  Effects in models of type 1 diabetes 
Ladarixin was tested after oral administration (15mg/kg/day) in the Multiple Low Dose-Streptozotocin 
mouse 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, glycemic levels during the first 2 months remained constantly lower in the ladarixin treated 
group as compared with the vehicle group7,8. 
Ladarixin was also tested after oral administration (15 mg/kg/day for 14 days) in the non-obese diabetic 
(NOD) mouse model of autoimmune type 1 diabetes, starting treatment at 4, 8 and 12 weeks of age 
(“prevention” setting) 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 -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 blocked the progression of hyperglycemia while hyperglycemia 
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 glycaemia7,8. 
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-
lymphocytes7,8. 
 
2.2.4. Effects of Ladarixin on an in vitro adipocyte diabetic model 
The molecular mechanisms underlying the anti-diabetic effects of ladarixin were evaluated in differentiated 
adipocytes upon inflammatory and diabetic conditions. In high glucose (HG) conditions, the levels of 
expression of CXCR1 and CXCR2 are significantly increased, while ladarixin was able to counteract this 
effect, in particular at the highest concentrations tested, with the 10 µM concentration still significant. 
Moreover, to monitor glucose uptake, mature adipocytes 3T3-L1 were incubated with the fluorescent tracer 
2-NBDG and in HG condition and upon inflammatory stimuli the glucose uptake is significantly decreased, 
contrarily the treatment with ladarixin (both 10 µM and 50 µM concentrations tested) restored to control 
conditions (NG). Accordingly, in high glucose (HG) conditions, the levels of GLUT4 are significantly 
decreased, while ladarixin at the highest concentrations tested was able to revert the GLUT4 levels to those 
of control, however, also the 10µM concentration was significantly efficient in counteracting HG effects. 
Both HG and inflammatory conditions induced elevated lipolysis (high glycerol content) while ladarixin 
treatment (at both concentrations tested 10 and 50 µM) was able to reduce this effect.  
Furthermore, in these experimental conditions ladarixin demonstrated a significant effect on NFKB activation 
and cytokines release. Upon HG and inflammatory conditions, the levels of the cytokine mouse CXCL1/KC 
were strongly increased and ladarixin was able to significantly decrease CXCL1/KC levels and to reduce 
NFKB concentrations. On the other hand, the HG and inflammation-induced conditions determined lower 
levels of adiponectin compared to ladarixin-treated conditions, suggesting a restoration of the metabolic 


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activity mediated by ladarixin. In conclusion, this work reported the ability of CXCR2 inhibition through 
ladarixin treatment to exert a dual beneficial action in the cellular models tested (differentiated 3T3-L1 and 
primary human adipocytes derived from a non-obese patient), both preventing the harmful pro-inflammatory 
signal activated by adipose tissue in response to inflammation and high glucose (as observed in cytokine 
proteome array, NFKB and cytokines expressions) and restoring the adipocyte functional insulin-sensitivity 
(as observed in glucose transport analysis), potentially preventing insulin resistance mechanisms. On the light 
of the results obtained in this study, it is possible to postulate that ladarixin could be a potential treatment in 
insulin resistance conditions. [ CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 
Adipocytes by Inhibiting Inﬂammation and Improving Insulin Signaling Castelli V. et al. Cells 2021, 10, 
2324. https://doi.org/10.3390/cells10092324 ]. 
 
2.3. 
A SUMMARY OF TOXICOLOGY DATA 
Ladarixin was tested for toxicity in rodent and non-rodent animal species after single and/or repeated dose 
administrations.   
In the four-week studies performed in rats, the administration by gavage for 28 days up to the dose of 200 
mg/kg followed by a 2-weeks recovery period, did not cause relevant toxicity. There was no mortality. The 
immune system was not affected by the treatment with ladarixin. The liver and kidney weights increased in 
males in all dose groups and in females at 200 mg/kg. Hepatocellular hypertrophy was seen in the liver of all 
male treated groups and in females at 200 mg/kg that resolved after 2 weeks. The no-observed-adverse-effect-
level (NOAEL) was settled at 200 mg/kg/day.   
Treatment of rats with ladarixin orally for a 3 months’ period at dose levels of 35, 70 and 150 mg/kg did not 
induce mortality or toxicologically relevant changes in body weight and food consumption, ophthalmoscopic, 
hematology, and urinalysis parameters. Changes in biochemistry were only minimal and occurred mostly in 
males. They included increased activity of some liver enzymes (males at 150 mg/kg), dose-dependently 
decreased protein levels (males at all dose levels and females at 150 mg/kg in Week 8 only), and dose-
dependently decreased cholesterol and phospholipid concentrations (males from 70 mg/kg). Microscopic 
examination revealed treatment-related findings in the liver, thyroid gland and kidneys. In the liver, 
hepatocellular hypertrophy was noted in Week 8 in males at all treated groups and females at 150 mg/kg. 
Follicular cells hypertrophy of the thyroid gland was seen at 150 mg/kg and regarded secondary to the liver 
hypertrophy. In the kidneys hyaline droplet accumulation was present at increased incidence in males at 150 
mg/kg after 8 weeks of treatment only (interim sacrifice). This change is male rat sex-specific not relevant 
for humans. After the 4-week recovery period, full recovery or a clear trend to recovery was noted for all 
findings.  
In studies with up to 1 week administration in dogs by oral route, the dose of ladarixin had to be reduced 
from 500 to 150 mg/kg, due to poor tolerability and severe clinical signs, namely tremor, vomiting, 
uncoordinated movements. No macro or microscopic findings were present; organ weights were not affected. 
In the 4-week oral toxicity study in dogs, ladarixin was administered up to the dose of 120 mg/kg. No 
mortality occurred. Vomiting was seen at 120 mg/kg. An increase in the absolute and corrected-for-heart rate 
QT interval was observed at the doses of 60 and 120 mg/kg. Inflammatory changes were seen in the 
duodenum of two males treated with 120 mg/kg. After 2 weeks all values returned to normal. It was concluded 
that the no observed-effect-level (NOEL) is 30 mg/kg/day.  
In the 3-month study, the initial dose levels were 30, 60 and 120 mg/kg/day. However, due to test item-related 
moribundity of one high dose male and changes in body weight and food intake of a few other animals in the 
group, the highest dose level was lowered from 120 to 80 mg/kg/day from Day 24 onward. At 120/80 
mg/kg/day, one male and one female showed weight loss (up to -7%) and lower food intake during the first 
weeks of treatment and the clinical condition was reduced in Week 4. Food supplements were provided, 
which resulted in an improved clinical condition and normal body weight (gain) of these animals during the 
remainder of the treatment period after reduction of the dose level from 120 to 80 mg/kg/day. Prolongation 
of the QT and/or corrected QT intervals was observed in males and females treated at 120/80 mg/kg/day in 
Weeks 4, 8 and/or 13, generally more pronounced in females. In addition, higher heart rates were noted for 
males and (individual) females treated at 120/80 mg/kg/day in Weeks 4, 8 and/or 13. At the end of the 
Recovery period, only one male and one female at 120/80 mg/kg/day were still on study, and all 
electrocardiography parameters were returned to the normal limits.  For one female at 60 mg/kg/day, mixed 
cell inflammation of the brain parenchyma and meninges, with neuronal necrosis and gliosis was recorded at 
moderate degree. There were no correlating clinical signs or necropsy alterations noted for this animal. 


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Furthermore, no inflammation was recorded in the brain for any of the other dogs of the study; therefore, this 
change in a single dog at 60 mg/kg/day (mid dose) was regarded to be an incidental change, although rare 
and the origin of the lesions could not be determined. No test item-related changes were noted in any of the 
remaining parameters investigated in this study (i.e. ophthalmoscopy, coagulation parameters, urinalysis, 
macroscopic examination and organ weights). Based on the results of this study, the no-observed-adverse 
effect level (NOAEL) was considered to be 60 mg/kg/day after 13 weeks of dosing.  
Testing of ladarixin for mutagenic potential gave negative results for the in vitro chromosomal aberration 
test, for the Ames test and for the micronucleus assay test in vivo in bone marrow of rats.  
Phototoxicity potential of DF2156A was evaluated on Balb/c 3T3 cells. At dose levels of 100, 50.0, 25.0, 
12.5, 6.25, 3.13, 1.56 and 0.781 µg/mL, in the absence or presence of UVA light, neither reductions of the 
cell layer nor changes in cell morphology were observed after treatment with DF2156A at any concentration 
tested. No reduction in neutral red uptake was seen in any treatment condition. The IC50 values were not 
calculable, thus the Photo Irritation Factor (PIF) could not be determined. The Mean Photo Effect value 
(MPE) was 0.009. The score values obtained with DF2156A (i.e. PIF not calculable and MPE lower than 
0.1) are predictive of no phototoxicity   
A study of fertility and early embryonic development to implantation was performed 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 
in any dose levels and in males at 50 and 100 mg/kg/day. At the highest dose, effects were observed on 
spermatid counts, motility and morphology of spermatozoas. Changes were seen in the testes of some animals 
and consisted degeneration/atrophy of the seminipherous tubules. According to the results obtained in this 
study, the fertility effects are likely associated with a stress effect, even if a secondary effect of the test item 
in the affected animals cannot be excluded with certainty. The NOEL was 100 mg/kg/day for males and of 
200 mg/kg/day for females.  
In order to clarify the changes seen in the testes at 200 mg/kg/day, a specific study was designed in male 
Wistar and Sprague Dawley rats. Ladarixin was orally administered at the dose level of 200 mg/kg bw/day 
for a period of 6 weeks followed by a 4 weeks of treatment-free recovery period.  In both strains, the treatment 
with ladarixin caused a minimal increase in incidence of reduced size of testes and epididymides and a mean 
decrease of testes and epididymides weights. A mean decrease of sperm motility, of normal complete sperms 
and of the mean sperm count in the epididymides was observed. After the recovery period, the decrease of 
the motility was not seen in Wistar rats whereas it was observed in Sprague Dawley rats. The weight reduction 
of testes and epididymides and the sperm analyses correlated with microscopic changes in the testes 
(degeneration/atrophy) and epididymides (aspermia/oligospermia) of some treated animals of both strains. 
After 4 weeks of recovery period, none of the Wistar rats allocated to the recovery group presented any 
change in the testes or epididymides, while some of the Sprague-Dawley rats allocated to the recovery group 
had degeneration/atrophy of the testes and atrophy, oligospermia or cell debris in the epididymides. The 
incidence of the testicular changes was very likely associated to the stress induced by the treatment with the 
test item. In both strains, a decrease in body weight and body weight gain (associated to a decrease in food 
consumption) was observed particularly in the first 2 weeks of the treatment period. Ruffled fur and weakness 
were also present in some treated rats and a reduction of thymus weight was observed in treated Wistar rats. 
All these changes indicate a condition of stress and/or distress that caused the testicular changes. At the end 
of the recovery period, in the Wistar rat there were no changes in any of the parameters examined as well as 
no changes in the testes and epididymides; in Sprague Dawleys rats, testes and epididymides changes were 
present in some animals at the end of the recovery period.  
The prenatal developmental toxicity studies were conducted in Wistar Han rats and New Zealand White 
rabbits.  In rats no maternal toxicity and no developmental toxicity were observed up to the highest dose level 
tested (150 mg/kg/day). The NOAEL in rats was established as being at least 150 mg/kg/day for both the 
maternal and developmental toxicity. 
In rabbits, no maternal toxicity was observed up to the highest dose level tested (100 mg/kg/day). The 
NOAEL was established as being at least 100 mg/kg/day for both the maternal and developmental toxicity.   
Carcinogenicity studies have not been performed. 
According to the toxicology development program, a 6 and 9-month study in rats and dogs, respectively, 
have been recently completed to further support the chronic administration in humans. After oral treatment 
with DF 2156A for 6 months in rats at dose levels of 35, 70 and 150 mg/kg/day, no mortality or changes were 
observed in food consumption, ophthalmoscopy, hematology and coagulation parameters in both sexes, and 


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in clinical biochemistry and urinalysis in females. Only slight changes were observed in body weight in male 
and female and in clinical biochemistry parameters in males at ≥ 70 mg/kg/day and in urine parameters at 
150 mg/kg/day. Morphologic non-adverse alterations in liver, kidneys and thyroid gland were recorded for 
males at ≥ 35 mg/kg/day, and in females at the high dose of 150 mg/kg/day only. The higher exposure levels 
to DF 2156Y (acid form of DF 2156A) in males may explain that males were more affected than females. 
Following the 4-week treatment-free period, all changes observed in the animals recovered to normal values 
with the exception of brown pigment (likely lipofuscin) in the cytoplasm of tubular epithelium of kidneys of 
males and females, and hepatocellular pigments (likely lipofuscin) in liver of males at the dose level of 150 
mg/kg/day. 
In the 9-month study, dogs were treated orally with DF2156A at doses of 30, 60 and 100 mg/kg. No mortality 
occurred during the study period. The test item was clinically well tolerated up to the high dose of 
100 mg/kg/day, as all animals were in a good general condition until the end of study. ECG recordings in 
Weeks 13, 26 and 38 revealed a dose-related increase in (corrected) QT intervals in both males and females 
at 60 and 100 mg/kg/day at 2 to 4 hours after dosing, most prominently in Week 38. In addition, heart rates 
were increased in 100 mg/kg/day treated males and females at 2 and/or 4 hours post-dose in Weeks 13, 26 
and/or 38 (females were more affected than males). The QT prolongation and increased heart rates in females 
at 100 mg/kg/day were considered to be adverse, based on the maximum increase in QTcF interval of 25.5 
msec in Week 38 on a group mean basis, and based on the magnitude of change for heart rate. The No 
Observed Adverse Effect Level (NOAEL) for females was considered to be 60 mg/kg/day after 9 months of 
dosing. In males, the NOAEL was concluded to be at least 100 mg/kg/day. 
In conclusion, based on the toxicology testing performed through in vivo studies, the dose of 150 mg/kg 
appears to represent the NOAEL in rats for general toxicity while in dog, in the 9-month oral toxicity study, 
the NOAEL was established at 60 mg/kg (taking into consideration the lowest in this study). In rats, 150 
mg/kg is the NOAEL for developmental toxicity while in rabbits it was 100 mg/kg. 
 
2.4. 
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 ladarixin, this metabolite showed an accumulation ratio ranging between 1.4 and 2.4.  
After the daily oral administration of ladarixin 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 ladarixin. The dose 
proportionality for the main PK parameters was also seen for the two metabolites (DF 2108Y and DF 2227Y). 
After multiple doses, 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 ladarixin, DF 2108Y and DF 2227Y appeared to increase in a dose-
proportional manner. The clearance and the volume of distribution of ladarixin 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.   


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Co-administration of ladarixin 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. Thus, ladarixin can be classified 
as a moderate inhibitor of CYP2C9. 
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 at 400 mg b.i.d. administrations in humans confirmed the 
very high binding to plasma proteins (>99.99%).  
 
2.5. 
A SUMMARY OF CLINICAL DATA 
Clinical development includes 3 Phase I PK and tolerability studies with single 
 
and multiple 
 ascending dose oral 
administration.  The first multiple ascending dose study 
 also included the evaluation of potential 
interaction between ladarixin 200 mg and tolbutamide. A phase II efficacy and safety study was conducted 
with 150 mg twice a day (for 14 consecutive days) oral ladarixin in patients with moderately active Bullous 
Pemphigoid. A phase II efficacy and safety study
 has been completed in patients with new onset 
T1D.  
To date, a total of 195 subjects were involved in completed clinical trials, of whom 143 (89 healthy 
volunteers, 4 patients with Bullous Pemphigoid and 50 patients with T1D) were exposed to ladarixin. 
  
2.5.1. Pharmacokinetics and product metabolism in humans  
Three Phase I PK/safety/tolerability studies in healthy male volunteers were performed which included single 
 and multiple
 
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 detail in the most recent Investigator’s Brochure (IB). 
 
2.5.2. Efficacy 
A phase II, multicenter, single arm, pilot study was initiated to assess the safety and efficacy of ladarixin in 
patients with moderately active BP 
 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 I trial completed at the time of protocol implementation (treatment up to 200 mg twice 
a day). Four male patients aged 65-75 years, 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 were 
observed with the low dose tested in this trial and the study was prematurely discontinued due to lack of 
activity.   
A phase II, multicenter, randomized, double-blind, placebo-controlled study has recently been completed in 
patients with new onset T1D (first insulin within 100 days from randomization) 
 
. The trial involved 8 sites in Italy, Germany and Belgium. Seventy-six 
patients (31 females, 45 males) with mean age of about 27 years have been randomized (2:1) to receive either 
ladarixin (400 mg twice a day for 3 cycles of 14 days on/14 days off) or placebo. The primary endpoint was 
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the AUC of C-peptide measured during an MMTT performed on week 13 from randomization. Follow-up 
was extended up to one year. Out of 85 patients enrolled (consent signed), 76 were randomized, 50 to received 
ladarixin and 26 allocated to placebo; 48 patients in the ladarixin group and 25 in the placebo completed the 
trial (week 52 observation). The primary and secondary analyses were performed on the ITT population. The 
primary efficacy analysis of log (AUC [0-2 hrs]+1) of C-peptide response to MMTT showed no statistically 
significant difference (p=0.3303) between the ladarixin and placebo group at Week 13. Overall, there were 
no clinically relevant treatment effect differences between the treatment groups for other secondary 
endpoints, such as C-peptide at other time-points, insulin requirement, glucose levels and glucagon levels 
during the study. On the other hand, the proportion of patients with HbA1c <7% and absence of episodes of 
severe hypoglycemia was significantly higher at Week 26 (p=0.0248) in patients receiving ladarixin as 
compared with placebo (whole ITT population). 
A phase 3 multicenter, double-blind, placebo-controlled study with ladarixin is currently recruiting 
(ClinicalTrials.gov Id: NCT04628481) and aims to assess the efﬁcacy of ladarixin in patients with new-onset 
T1D. 
 
2.5.3. Safety  
A total of 89 male healthy subjects aged 18 to 52 years, 4 male BP patients aged 65-75 yeas, and 50 T1D 
patients aged 18-46 years 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, 150 mg twice a day up to a maximum of 14 days in BP patients, and 400 mg twice a day 
for 3 cycles of 14 days on-14 days off in T1D 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 I 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 I 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 Ladarixin 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. 
The phase II trial in new onset T1D further extended the experience with ladarixin. The frequency and profile 
of AEs/ADRs was similar in patients receiving ladarixin or placebo. A total of 37 patients (74.0%) in the 
ladarixin group and 22 patients (84.6%) in the placebo group experienced TEAEs during the study. The most 
common TEAEs presented by primary SOCs were infections and infestations (about 46% in both groups), 
followed by gastrointestinal disorders (about 35%) and nervous system disorders (34.0% ladarixin vs 26.9% 
placebo). The majority of the TEAEs reported in the study were considered mild in severity. A total of 3 
patients in the ladarixin group and 1 patient in the placebo group reported TESAEs. One patient in the 
ladarixin group reported 2 TESAEs (hyperglycemia and mental disorder); and 1 patient each in the ladarixin 
group reported TESAEs of gastrointestinal disorder and clavicle fracture, respectively. One patient in the 
placebo group reported TESAE of laceration. None of the SAEs were related to the study treatment. One 
patient in the ladarixin group was discontinued from the study treatment due to AEs of alanine 
aminotransferase increased and aspartate aminotransferase increased, and 1 patient in the placebo group was 
discontinued from the study treatment due to an AE of rash. Twenty patients (40.0%) in the ladarixin group 
had 52 ADRs and 8 patients (30.8%) in the placebo group had 17 ADRs during the study.  
Cumulative adverse drug reactions (ADRs), i.e. treatment-emergent AE judged at least possibly related to 
ladarixin, are presented in Table 1, below. 
 


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The system organ classes most frequently (>10%) affected by ADRs were:  
Gastrointestinal Disorders: (about 50%) including dyspepsia, dysphagia, abdominal pain, mouth ulceration, 
nausea. 
Nervous System Disorders: (about 30%) 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. 
 
2.6. 
DISEASE REVIEW AND STUDY RATIONALE 
T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing -
cells11. 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 years12,13. 
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, hypoglycemia unawareness is a serious consequence of recurrent hypoglycemia often requiring 
emergency care11.   
Many T1D patients develop insulin resistance (IR), exacerbated in part by pharmacologic insulin14-17 and 
overweight/obesity. IR is a significant risk for cardiovascular and renal disease14,16-23. While the mechanisms 
leading to T1D IR are not completely-understood, a chronic low-grade systemic inflammation similar to the 
one in metabolic syndrome and type 2 diabetes (T2D)24-31 has been implicated and may be responsible for IR 
independently of the underlying autoimmunity24-31, as illustrated in  Figure 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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In spite of breakthroughs in the design and action of modern insulin and insulin pharmacotherapy32-44, most 
people with T1D cannot achieve recommended HbA1c targets45-56. This is associated with significant risk 
for, and high incidence rates of long-term T1D complications (cardiovascular, neural, renal, and ophthalmic) 
resulting in earlier mortality, no matter how well insulin maintains their glucose control. This highlights the 
need for insulin adjunctive approaches to address the underlying metabolic imbalances beyond 
dysglycemia. One of the under-appreciated, but emerging complication in many T1D patients is IR14,16-23. 
It is associated with negative clinical outcomes14,15,17-20,22,23,51-53,55-69 and there are few if any interventions 
targeting IR15,57-59,61,65,66,68,69, despite an urgent clinical need34,40,43,54,70-78. The most common cause of death in 
adults with T1D is cardiovascular disease which correlates better with IR than with impaired glucose control 
disease14,16-23. Although IR is mainly observed in overweight and obese T1D patients14,15,17,20,58,79,80, recent 
evidence indicates that even lean patients can exhibit IR14,15,17,20,59-61,63,65,69,81,82.  
The following observations in T1D and T2D, underlying gaps in knowledge, and limitations of previous trials 
inform our hypothesis and the scientific premise: i) the IR-related exacerbation of a non-autoimmune 
systemic inflammation in T1D that further fuels IR in a vicious cycle60,64,83,84; ii) the role of N as potential 
“first responders” to the accumulation of advanced glycation end products (AGEs) consequent to impaired 
GV 18,21,85-111 as well as in response to hypertrophying adipose under weight gain conditions99,107,112,113; iii) 
the role of N in the impairment of insulin signaling in insulin-sensitive tissues further aggravating IR99,114; 
and iv) the marginal clinical outcomes of metformin as an adjunctive in IR59,61,65,66,79-81,115,116. In spite of its 
expected efficacy via improved insulin receptor signaling, metformin’s outcomes were predictable 
considering immunokine effects at the level of the insulin receptor and the downstream transducers. On the 
premise that N-driven inflammation exacerbates IR, we propose that ladarixin can short-circuit N 
margination into insulin-sensitive tissues that exhibit impaired GV-mediated accumulation of 
“danger/damage” signals (e.g. AGEs, microcirculation fluid shear stress damage). As a consequence, 
ladarixin suppression of local inflammation would mitigate immunokine-driven impairment of insulin 
signaling. An improvement in overall insulin sensitivity and better GV/glycemic control with the potential 
for decreased insulin requirements is therefore anticipated.   
Inflammation, “danger”, N, and IR: The chronic swings between hyper-/hypoglycemia in T1D facilitate a 
pro-inflammatory state associated with accumulation of microanatomical aberrations and lesions constituting 
“danger” signals for the immune system117-124. Impaired GV (IGV) outcomes can therefore trigger the 
activation of leukocytes of the innate arm of the immune system. One example is the oxidative stress in and 
around insulin-sensitive tissues, and the formation of AGEs. AGEs can potentially contribute to IR via 
numerous inflammatory pathways87,90,125-135. Reactive oxygen species (ROS) and oxidative stress are 
increased under hyperglycemia. Intermittent hyperglycemia exaggerates the production of ROS136-139. 
Oscillating glycemia in T2D impairs endothelial function via oxidative stress140,141 and AGE accumulation 
inside skeletal muscle and adipose activates pro-inflammatory signal pathways that abrogate insulin signaling 
and sensitivity142-145. AGEs activate the innate arm of the immune system, largely by binding RAGE, 
expressed mainly on N105,110,111,146.  
While the relevance of N in the onset and progression of T2D, especially under conditions of obesity is 
recognized, considerably less is known about their role in the onset and progression of IR under IGV. The 
Nto lymphocyte ratio (NLR) has been strongly associated as a risk marker of metabolic disorders where 
the immune system has been implicated147-150, especially in the studies by Shiny et al and Lorenzo et al in 
T2D151,152. In the former study, NLR increased with increasing severity of glucose intolerance and was found 
to be positively associated with IR. In the latter study, NLR was shown to be positively associated with the 
presence and severity of metabolic syndrome95. N account for ~90% of granulocytes and granulocytes 
comprise 60-79% of human blood leukocytes thus making N the largest fraction of leukocytes. 
Accumulating evidence implicates N in T2D and T1D (reviewed in94,96,101,109,153). Elevated N markers are 
present in the plasma of obese subjects154.  
Abnormal expansion of visceral adipose tissue is accompanied by influx of activated N early in the 
process107. Moreover, in vitro studies have shown that N physically bind adipocytes in a manner dependent 
on their activation state107. N produce a number of powerful proinflammatory molecules including a variety 
of proteinases like N elastase (NE). Genetic deletion of NE as well as its pharmacologic inhibition improved 
obesity-induced IR and suppressed inflammation in adipose tissue and liver in a T2D mouse model99,107. 
Intriguingly, NE can degrade IRS-1 protein and reduce insulin-induced Akt phosphorylation in adipocytes99. 
This mechanism may be involved in the N- and NE-dependent effect on IR in diet-induced obesity, as the 
levels of IRS-1 were higher in fat and liver of NE-deficient mice, as compared to NE-sufficient mice99. 


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Similar results were obtained in humans97,155 where an imbalance between NE and 1 antitrypsin (AAT) in 
obesity determines, to some degree, insulin sensitivity, systemic inflammation and energy expenditure97. In 
these studies, human obese subjects exhibited a decreased serum AAT level and increased NE concentration 
that correlated with BMI and leptin resistance 97. In this same study, NE accumulated in adipose throughout 
the development of obesity concurrent with increasing adipose inflammation97. These data suggest that 
inhibition of NE and/or the N activation that precedes its production may break a vicious cycle of obesity 
and IR-associated inflammation. N have also been implicated in the early stages of T1D in terms of their 
pancreatic accumulation156,157 where they activate type I cytokine production by plasmacytoid DC and trigger 
the subsequent activation of the adaptive immune response158.  
Treatment of T1D IR with adjunctive agents: It is increasingly challenging to treat obese, T1D individuals 
with insulin alone. As well known, intensive insulin therapy, based on multiple daily injections, is the gold 
standard treatment in T1D and rationale of intensive insulin therapy is to provide tight glucose control 
avoiding the higher risk of hypoglycemic events and weight gain. Furthermore, with the worldwide increase 
of obesity in childhood and adolescence insulin resistance is now occurring more frequently also in young 
patients with T1D. Consequently, the rising obesity in youth seems to induce a change of T1D phenotype, 
defining a hybrid form of diabetes, known as “double diabetes”.  On this basis, to improve glycemic control 
and peripheral insulin sensitivity, some insulin sensitizing drugs generally used in Type 2 Diabetes (T2D), 
such as metformin, are more frequently used as adjuvant treatment also in patients with DD. Despite the 
effect on glycemic control reducing body weight and daily IR in overweight or obese T1D patients, several 
limitations are related to metformin.  
Metformin is currently the most studied T1D adjunctive159 however outcomes were inconsistent59,61,65,115, as 
metformin faces compliance hurdles due to common AEs160. In fact, studies with metformin clearly showed 
that the drug may have many gastrointestinal side effects such as to reduce patients’ treatment adherence and 
consequently its own effectiveness. Other T2D agents have been tested as insulin adjunctive in T1D159,161-165. 
However, marginal efficacy outcomes15,161-163,166 and AEs162,163,166 including ketoacidosis challenge their 
wider use15,167-170.  
The data supporting a non-autoimmune inflammation, very likely driven by Nin the etiology of T1D IR 
are very compelling, justifying the adjunctive use of anti-N agents to improve insulin sensitivity. Anti-
inflammatory drugs that can target N include corticosteroids, macrolides, cAMP-elevating agents 
(including cyclooxygenases), 5-lipoxygenase inhibitors, leukotriene receptor antagonists, chemokine 
receptor antagonists, kinase inhibitors, activators of histone deacetylase-2, and antioxidants171-189. 
Corticosteroids are not specific to N and they induce glycogenolysis, raising blood glucose levels190,191. 
High dose antioxidant trials in T2D have been disappointing192. Other agents caused adverse events grades 
>2.  
Although T1D and T2D pathogenesis are significantly different, with the wide increase of childhood obesity, 
a great number of evidence supports the hypothesis that IR plays a crucial role also in T1D pathogenesis. 
Consequently, the therapeutic approach in these patients has considerably changed leading to a widespread 
use of insulin sensitizing drugs as adjuvant treatment of insulin therapy.  
In fact, in long standing T1D overweight or obese patients, the excess of white adipose tissue has been 
associated with low-grade chronic inflammation. Adipocytes are able to secrete adipokines such as TNF-α, 
IL-6, and IL-8, which due to their pro inflammatory properties, have been associated with enhanced activity 
of peripheral neutrophils, such as production of superoxide radicals and NET formation. 
For this reason, ladarixin as potent allosteric inhibitor of IL-8, could represent a first-in-kind adjunctive 
therapy in long standing T1D overweight or obese patients. 
Moreover, two preclinical studies were conducted with oral ladarixin (15 mg/kg/day for 28 days) in diet-
induced obese (DIO) or genetically prone (db-/-) mouse models. Results obtained in the first study showed 
that oral ladarixin significantly improved glucose tolerance and insulin sensitivity in the DIO mice, but not 
in the genetically obese mice. Improved insulin sensitivity was not paralleled by change in adipose tissue 
inflammation. In the second study, glucose homeostasis in DIO mice was slightly affected by ladarixin, as 
documented by a lower glucose excursion during the intraperitoneal glucose tolerance test, a lower fasting 
insulin (and associated improvement in HOMA-IR) and a relative reduction in hepatic glucose output through 
the gluconeogenesis pathway. The effect was greater in younger and less obese mice as compared to older 
and more obese animals. Evidence of reduced hepatic tissue inflammation was assessed by a lower MPO 


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activity, a decrease in IL-6 secretion and a decreased expression of multiple inflammatory/cytokine markers 
 
On this basis, this drug can address three pressure points in T1D IR: it can suppress i) IGV-associated 
activation and progression of a N -driven systemic inflammation; ii) N margination into insulin-sensitive 
tissues affected by IGV-driven microanatomic anomalies; and iii) the ability of activated N to orchestrate 
the progression of inflammation.  
Therefore, we hypothesized that the administration of ladarixin with its anti-inflammatory activity may have 
a potential therapeutic role in improving glycemic control in long standing T1D IR patients undergoing 
intensive insulin therapy Acting through an amelioration of insulin sensitivity, it can improve insulin 
resistance, endothelial dysfunction, decreasing the homocysteine and inflammatory mediators’ plasma levels, 
The purpose of this study is to evaluate the effect of ladarixin oral supplementation on glycemic control as 
assessed by HbA1c in overweight T1D patients undergoing intensive insulin therapy. Ladarixin is not the 
only N antagonist to impair N margination into areas of “danger”. Other than ladarixin and AZD50697,193-
205 (which have been discontinued), other anti-N agents7,193-205 do not have as extensive a 
developmental/clinical history as ladarixin. It is important to note that ladarixin and its infusion counterpart, 
reparixin, have demonstrated preclinical efficacy at the level of T1D pancreatic inflammation7, in the 
prolongation of islet allograft survival204,205. 
 
2.6.1. Alternative treatments 
There are no standard pharmacologic treatments, addressed to the prevention or treatment of IR in T1D other 
than adjustment of pharmacologic insulin dose and frequency. In fact, to achieve and maintain optimal 
glycemic control trough the standard insulin therapy, insulin doses are often increased causing a higher risk 
of hypoglycemic events, weight gain and poor glycemic control as well as exacerbating IR. 
Because of this, patients not willing to participate in the study will not be offered any specific alternative 
treatment other than insulin management in consultation with their existing endocrinologist/diabetes 
specialist.   
All patients, regardless of study participation, will receive the standard of optimal care for established, 
insulin-requiring, overweight T1D individuals in consultation with their existing endocrinologist/diabetes 
specialist. 
 
2.6.2. Risk – benefit evaluation 
2.6.2.1. 
Risk related to ladarixin 
Results from preclinical studies support the level of drug exposure planned in this study. 
Phase I and II clinical experience with doses as high as that planned in this study provides evidence of the 
safety of ladarixin. The safety was confirmed in the phase II trials; indeed, no safety concerns were raised 
either in elderly patients who were on several concomitant medications due to chronic disease, or in patients 
with new-onset T1D. No SUSAR or death occurred, and all the AEs encountered were mild to moderate in 
intensity. 
Any possible risk derived from the administration of ladarixin in the specific population involved in this 
study will be minimized by integrated monitoring which includes clinical observations, laboratory tests and 
ECG readings, scheduled at pre-planned intervals (see Section 5.3.2 and 6).  
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 4. and 5.5.2) will limit any possible risks 
derived from potential metabolic interactions.    
2.6.2.2. Peripheral blood collection  
Collection of peripheral blood for safety monitoring, HbA1c and C-peptide (up to 15 mL at visits 1, 2b, 3 
and 4) as well as HbA1c at visit 2 (up to 2 mL) might be at risk of minor pain, bruising, inflammation or 
excessive bleeding at the venipuncture site and faintness/lightheadedness. Also, multiple punctures might be 
required to identify the veins. Rare risks include hematoma, infection. In some patients, additional blood 
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samplings (up to 40 mL) will be required at visit 2, 3 and 4 for assessment of exploratory 
 parameters, if site is able and deems appropriate to accommodate and conduct 
these procedures. 
2.6.2.3. Continuous Glucose Monitoring (CGM) 
Continuous Glucose Monitoring (CGM) via sensor positioning is commonly used in patients with diabetes 
to monitor their glucose level. Patients with routine use of a self-owned (if applicable) CGM system will be 
enrolled. In the event that the CGM system is not owned by a patient, it will be provided by the Sponsor. 
Therefore, participation this trial will not add risk for the patient other than those already derived from 
patient’s standard of care. Specifically, patients can’t wear CGM (sensor, transmitter, receiver, or smart 
device) for magnetic resonance imaging (MRI), computed tomography (CT) scan, or high-frequency 
electrical heat (diathermy) treatment. Some skin care products, such as sunscreens and insect repellents, can 
make the plastic used in G6 crack.  
If the patient needs assistance with sensor placement/replacement, an ad-hoc visit should be performed. 
2.6.2.5. Potential benefit 
To the patient: Patients during ladarixin treatment period may possibly benefit with improved glycemic 
control and insulin sensitivity, but this is to be ascertained. 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 overall metabolic 
control in T1D long-standing IR patients. 
 
2.6.3. Description of the Investigational Products 
In this study the Investigational Medicinal Product (IMP) will be either ladarixin OR matched placebo. The 
proposed dose in this clinical study is 400 mg oral ladarixin twice a day for 7 cycles (26 weeks) of 14 days 
on - 14 days off. Placebo will be administered with the same schedule. 
The oral route has been selected based on the very good oral bioavailability of ladarixin, the long half-life 
and its good tolerability when given by this route.  
 
. The resulting average 
steady state plasma concentration of the ladarixin unbound fraction should ensure full inhibition of PMN 
migration, considering that the in vitro IC50 is in the range of 1 ng/mL. 
 
 In fact, in ladarixin-treated NOD mice with recent onset-diabetes 
the efficacy of the compound was clearly more pronounced within the 14 days after treatment interruption 
(in these animals, the average of non-fasting glycaemia was below 200 mg/dL) whereas blood glucose 
concentrations tended to progressively increase in 77% of remission NOD mice at later time after treatment 
discontinuation, suggesting that neutrophil recruitment as well the cross-talk with the other immune cells in 
the pancreas could restart after 14 days of ladarixin treatment discontinuation. This was further supported by 
the evidence that a second cycle of ladarixin treatment in NOD-mice with diabetes recurrence was able to 
reverse again diabetes in 67% of mice, thus supporting the concept that repeated cycles of treatment are 
necessary and appropriate for the management of the chronic condition.  
Furthermore, ladarixin prevented diabetes in a model of β-cell inflammatory injury induced by multiple low-
dose streptozotocin, and the treatment for 14 days starting 1 day before the induction of diabetes appeared 
the most efficient in prolonging the median diabetes-free time compared to regimens in which the treatment 
was only administered for 7 days and/or was started few days after the induction of diabetes by streptozotocin.  
The toxicity studies conducted to date, which include the 6 and 9-month study in rats and dogs, respectively, 
support the dose and the dose regimen proposed for this study.  
 
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3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN  
3.1. 
STUDY OBJECTIVES 
We propose a phase II randomized, placebo-controlled, double-blinded, 2-parallel arm, trial using the 
CXCR1/CXCR2 chemokine receptor antagonist ladarixin versus placebo as adjunctive therapy to insulin to 
first test whether it can improve glycemic control as assessed by HbA1c, in adult, insulin-requiring, 
overweight, IR T1D patients. Secondary study objectives include identifying the effect of ladarixin versus 
placebo on glycemic variability as per CGM derived parameters as well as to determine the safety in the 
population.  
The effect of ladarixin on
 
3.2. 
STUDY ADMINISTRATIVE STRUCTURES, STAFF AND RESPONSIBILITY 
This study will be performed at designated clinical spaces available for clinical studies, under the supervision 
and responsibility of the Principal Investigator (PI). The PI will be responsible for ensuring that the 
investigation is conducted according to the signed Investigator agreement, the protocol, GCP guidelines, 
institutional, federal, state and local regulations.  
The PI (and the Principal Physician should the PI not be an MD), each for his own role, will be responsible 
for the management of the study, which will consist of maintaining the study file and the patient records, 
corresponding with the Independent Review Board (IRB - specifically for US), reporting SAEs within 
required timelines, completing the electronic case report form (eCRF) and any other study document.  
The PI is responsible for supervising any individual or party to whom (s)he delegates trial related duties and 
functions conducted at the trial site. The PI/institution should ensure that any individual or party that performs 
trial related duties and functions is qualified to perform those trial related duties and functions and should 
implement procedures to ensure the integrity of the trial related duties and functions performed and any data 
generated. Similarly, it is the responsibility of the PI 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 PI 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 the delegation of authority/activity log 
for their performing each of the tasks delegated to them on the list. Where reference is made in this protocol 
to the PI, either the PI and/or one or more delegated members of his/her staff are meant, according to the list 
of delegated responsibility. 
 
3.3. 
OVERALL STUDY DESIGN 
The study is a randomized, placebo-controlled, double-blinded, 2-parallel arm, phase II trial.  
It will involve up to 86 adults, insulin-requiring, overweight, T1D patients with evidence of IR. After 
eligibility confirmation (enrollment), they will be randomly assigned to receive (1:1) either ladarixin (400 
mg b.i.d. for 7 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The 
two groups will be balanced within centers. 
Each patient will be involved in the study for up to 30 weeks. This period consists of 5 site visits for informed 
consent acquisition and screening, randomization, and 3 post-randomization study visits during a maximum 
of 28 weeks from the first IMP dose.  
Recruitment will be competitive among the study sites, until the planned number of patients is randomized. 
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. 
 


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3.3.1. Rationale for Selection of dose, control group and treatment schedule in the study  
The dose and dose regimen have been selected according to the rationale reported in Section 2.6.3. 
A double-blind, randomized study design is being adopted as the gold standard to minimize systematic bias 
and increase baseline comparability between treatment groups. The use of placebo control is critical to the 
study design for providing an accurate estimate of the IMP effect and does not prevent any standard treatment 
to be used.        
 
3.4. 
STUDY TIME-TABLE.  
Overall study timelines are reported below. 
Study period         Projected starting date (first-patient-in): Q2_2022 
 
Projected completion of patient accrual (last-patient-in): Q4_2022 
 
 
Projected study end date (last-patient-last-visit): Q3_2023 
 
 
 


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4. 
SELECTION OF STUDY POPULATION 
Number of patients: 86 adult patients with established insulin-requiring T1D and evidence of IR will be 
enrolled, provided that they fully meet all of the Inclusion Criteria and none of the Exclusion Criteria 
described in Sections 4.1. and 4.2. below. 
 
4.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria: 
1. 
clinical diagnosis of autoimmune T1D as documented by positive T1D-related autoantibodies [the 
presence of at least one or more of: Insulin autoantibodies (IAA), Anti-GAD (GAD65), Anti-IA2 
(IA2), Zinc Transporter 8 (ZnT8) must be documented from medical records or new laboratory 
measurement (not including IAA)];  
2. 
age 21-65 years at the time of consent;  
3. 
T1D duration > 1 year;  
4. 
detectable fasting C-peptide as per the result of screening laboratory measurement; 
5. 
current insulin standard of care (ISOC), either established use of an insulin pump (closed loop system 
excluded) or a stable dose level and dose frequency for the last two months prior to screening, with 
no plans to switch the modality of insulin administration during the trial;  
6. 
routine use of a self-owned (if applicable) CGM system that can record glucose concentrations 
continuously for at least 7 days; 
7. 
HbA1c >7.5% as per the result of screening laboratory measurement;  
8. 
evidence of IR based on a total daily insulin dose >0.8 U/kg/day;  
9. 
subject is overweight or obese with a BMI of between 24-33 kg/m2, inclusive;  
10. ability to comply with all protocol procedures for the duration of the study, including scheduled 
follow-up visits and examinations, and willing to be contacted by clinical trial staff;  
11. provision of written informed consent prior of any study-related procedure not part of standard 
medical care. 
 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study: 
1. 
use of a “closed loop system” for integrated glucose reading/insulin infusion; 
2. 
known or suspected hypersensitivity to non-steroidal anti-inflammatory drugs or any excipient of 
the investigational medicinal products (e.g. lactose and croscarmellose) as well as patients with 
congenital lactase deficiency, galactosaemia or glucose-galactose intolerance will have to be 
excluded; 
3. 
use of non-insulin medications for adjunctive blood glucose control (e.g: antidiabetic agents such as 
metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, 
SGLT-2 inhibitors or amylin) within one month of randomization as well as required in the 
participant’s standard of care;  
4. 
use of medications for weight reduction, such as: Belviq (lorcaserin), Qsymia (Phentermine + 
topiramate), Orlistat (xenical) within one month of randomization as well as required in the 
participant’s standard of care;  
5. 
use of a medication such as stimulants, antidepressants and/or psychotropic agents that could affect 
weight gain or glycemic control of T1D;  
6. 
treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index [i.e., phenytoin, 
warfarin, and high dose of amitriptyline (>50 mg/day)];  
7. 
use of angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, 
niacin;  
8. 
evidence of QTcF >470 msec and a history of significant cardiovascular disease/abnormality; 
9. 
any condition, including unstable diet and disordered eating behaviour, that in the judgment of the 
investigator will adversely affect patient’s safety or the completion of the protocol or otherwise 
confound study outcome;   
10. pregnancy: a) positive or missing pregnancy test (quantitative beta hCG) at screening; b) women of 
child-bearing potential and fertile men who do not agree to use effective contraceptive measures up 


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to 2 months following trial discharge [effective contraceptive measures include a 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)]; lactating women; 
11. clinical diagnosis of celiac disease that is in poor control as defined by most recent tissue 
transglutaminase (tTG) that is in the abnormal range;  
12. history of ≥1 Diabetic Ketoacidosis (DKA) event in the past 6 months;  
13. hypoalbuminemia defined as serum albumin < 3 g/dL; 
14. 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]; 
15. moderate to severe renal impairment calculated by estimated Glomerular Filtration Rate (eGFR) <60 
mL/min/1.73 m2 as determined using Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) creatinine equation;  
16. past (within 1 month prior to screening) or current administration of any immunosuppressive 
medications (including oral or systemically injected steroids) and use of any investigational agents, 
including any agents that impact the immune response;  
17. a condition already known which interferes with the ability to accurately determine glycated HbA1c. 
Examples include: genetic variants (e.g. HbS trait, HbC trait), elevated fetal hemoglobin (HbF) and 
chemically modified derivatives of hemoglobin (e.g. carbamylated Hb in patients with renal failure); 
any condition that shortens erythrocyte survival or decreases mean erythrocyte age (e.g., recovery 
from acute blood loss, hemolytic anemia); iron deficiency anemia, iron replacement therapy; 
18. significant systemic infection during the 4 weeks before the first dose of study drug (e.g., infection 
requiring hospitalization, major surgery, or i.v. antibiotics to resolve; other infections, e.g., 
bronchitis, sinusitis, localized cellulitis, candidiasis, or urinary tract infections, must be assessed on 
a case-by-case basis by the investigator regarding whether they are serious enough to warrant 
exclusion).  
 
4.3. 
ASSIGNMENT OF PATIENT NUMBER 
At the screening visit, each patient will be assigned a unique sequential Screening number. If the patient is 
randomized, the Randomization number will be assigned in a sequential manner as patients are found to be 
eligible and are randomized. This number will be used for identification throughout the study and will not be 
used for any other participant. 
If a patient is dropped from the study for any reason, the patient’s randomization number will not be 
reassigned. 


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5. 
STUDY MEDICATION 
5.1. 
PRESENTATION, PACKAGING AND LABELING, SUPPLY, AND STORAGE OF THE 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1.1. Presentation of the Investigational Medicinal Product  
In this study the Investigational Medicinal Product (IMP) will be either ladarixin OR matched placebo. 
It will be provided in the form of hard gelatin capsules for oral administration, with the following 
composition: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Batch release certificate will be provided together with the IMP.  
 
5.1.2. Manufacturing, Packaging and Labelling of IMP 
Capsules will be manufactured alternatively by 
 
 
 
 
The primary packaging, labelling and kitting of capsules in blisters to obtain the Patient Kit will be done 
alternatively by 
 
The study medication will be provided as 7 Patient Kits, each containing 56 capsules covering the treatment 
period of 14 days.  
All labels will be prepared to meet local regulatory requirements. Details of packaging and labelling are 
reported in Section 14.1. 
 
5.1.3. 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.  
PPD
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A temperature monitor will accompany the drug on shipment. Temperature range reached during shipment 
will be verified on receipt at site, 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 appointed CRO) and the use of the drug suspended until authorization 
for its continued use has been given by Dompé (or appointed CRO).   
The IMP must be stored at site 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 storage 
conditions should be immediately reported to Dompé (or appointed CRO) and the use of the drug suspended 
until authorization for its continued use has been given by Dompé (or appointed CRO).  
 
5.1.4. Blinding  and unblinding 
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. Any emergency unblinding must be notified to the CRO’s medical monitor.  
The sponsor’s personnel from the Pharmacovigilance Department of Dompé may break the treatment code 
for subjects who experience a Suspected Unexpected Serious Adverse Reaction (SUSAR), in order to 
determine if the individual case requires expedited regulatory reporting. 
With the exception of the above-mentioned episodes, the identity of the treatments will remain unknown to 
the subject, Investigator, site staff, CRO and Dompé’s personnel until the study completion and formal 
unmasking 
Study blind will be broken after database lock. 
 
5.2. 
DOSE, ROUTE AND SCHEDUE OF IMP ADMINISTRATION 
Ladarixin will be administered orally at the dose of 400 mg b.i.d. for 7 cycles of 14 days with an interval of 
14 days off, for a total duration of 26 weeks. The two daily doses will be administered at about a 12-hour 
interval (morning and evening; ideally between 6:30/11:30 and 18:30/23:30). At each administration, 2 
capsules will be swallowed with a glass of water, at least 2 hours apart from breakfast or dinner. Placebo will 
be administered with the same treatment schedule.  
 
5.3. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP 
5.3.1. Criteria for schedule adjustment/dose-modification  
No schedule adjustment and/or dose modification is foreseen, except for discontinuation of IMP as detailed 
below. 
 
5.3.2. Criteria for discontinuation of the 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 any significant cardiovascular disease/abnormality; 
 
The patient develops renal (calculated eGFR < 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 (serum 
albumin <3 g/dL); 


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 
Pregnancy occurs (subjects of child-bearing potential); 
 
The patient develops Diabetic Ketoacidosis (DKA) or hypoglycemic coma. 
Occurrence of any condition that qualify the patient to treatment discontinuation will be specifically 
monitored through ECG readings and safety laboratory tests obtained at week 4 (visit 2b) and 11/12 (visit 3) 
during treatment. Pregnancy (urine dipstick) will be also tested at week 11/12 (visit 3). 
In addition, the IMP will be immediately discontinued in the event of any other possibly drug related 
occurrences that the study physician believes might compromise patient’s safety.   
If the IMP administration is prematurely discontinued, the primary reason for discontinuation must be 
recorded in the eCRF. Patients who discontinue the treatment with the IMP will NOT be withdrawn from the 
study by default but will be asked to complete safety and efficacy observations as per the protocol, unless 
otherwise they withdraw their consent. 
 
5.4. 
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 center.   
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 or to the appointed CRO. A copy will be retained for the Investigator/Pharmacy file. 
The dispensing of the IMP will be carefully recorded on the eCRF and appropriate drug accountability forms 
and an accurate accounting will be available for verification by the CRA at each monitoring visit.       
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 in the 
Patient Diary and checked by the study staff during the next study visit. 
The CRA will review the drug accountability forms/eCRF 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 Patient Kit 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. 
 
5.4.1. Assessment of compliance 
Compliance with the study product dosing schedule will be verified by the delegated monitoring personnel 
of the study during on-site monitoring visits, as per records in the specific study eCRF and actual capsules in 
the Patient Kits returned by the patient.  
 


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5.5. 
PRIOR AND CONCOMITANT MEDICATION 
5.5.1. Reporting of prior and concomitant medication  
Administration of all prior (within 1 month before screening) and concomitant medications, apart from 
insulin and the agents listed below, will be reported in the appropriate section of the eCRF.   
All the details as per the eCRF fields (sequential number, drug name, indication, starting dose, start/stop date, 
route of administration) will be recorded. 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. 
 
5.5.2. Prohibited medications  
The following medications should not be used beginning from the start of the screening up to and including 
the end of study, unless otherwise specified:  
1) Non-insulin medications for adjunctive blood glucose control (e.g. antidiabetic agents such as 
metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, 
SGLT-2 inhibitors or amylin) within one month of randomization as well as required in the participant’s 
standard of care; 
2) Medications for weight reduction, such as: Belviq (lorcaserin), Qsymia (Phentermine + topiramate), 
Orlistat (xenical) within one month of randomization as well as required in the participant’s standard of 
care; 
3) Medication such as stimulants, antidepressants and/or psychotropic agents that could affect weight gain 
or glycemic control of T1D; 
4) Drugs metabolized by CYP2C9 with a narrow therapeutic index [i.e. drugs that may have their plasma 
concentration and effect altered by inhibition of CYP2C9 by ladarixin such as phenytoin, warfarin, and 
high dose of amitriptyline (>50 mg/day)]; 
5) Angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, lithium, niacin; 
6) Any immunosuppressive medications (including oral or systemically injected steroid), and any other 
investigational agents, including any agents that impact the immune response [off period before 
screening = 1 month]. Note that some oral, inhaled, nasal and topical corticosteroids are allowed, please 
speak with the study coordinator for more information.  
 
5.6. 
INSULIN TITRATION 
Patients will self-monitor blood glucose levels, as per their standard practice with self-owned (if applicable) 
CGM,and will take insulin as prescribed by the PI or their Primary Care Physician (PCP) and/or 
endocrinologist throughout the study participation. 
To ensure standardized glycemic control in the treatment groups, the PI/Study Physician, together with the 
patient’s PCP/endocrinologist will provide guidance for insulin regimen adjustment, with insulin titrated up 
or down to target HbA1c levels of less than 7% based on the following self- monitored glucose level: 
 pre-prandial blood glucose of 70-130 mg/dL 
In order to optimize insulin titration, telephone calls (outside scheduled visits) will be scheduled on a regular 
basis (at least every 30-45 days) to ensure timely evaluation of glucose levels and adjustment of insulin 
regimen.    
 


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6. 
STUDY PROCEDURE AND ASSESSMENT 
A schedule for the tests and evaluations to be conducted in this study is found in the flow chart in Section 2. 
Details are reported below.  
For all measurements, the actual date and time of assessment, including date of sampling, will be recorded 
in the Source Document and/or eCRFs. 
Each patient will be involved in the study for a total of 5 visits, as detailed below.  
 
6.1. 
STUDY VISITS AND STUDY EVENTS/PROCEDURES DETAILS 
6.1.1. Identification of potential subjects 
Potential subjects will be recruited after protocol approval by local Independent Ethics Committee 
(IEC)/IRBs. 
If needed as per site practice (pre-screening), the study staff will identify potential study subjects (e.g. using 
electronic health records, diabetes or other relevant research study registries) and will reach out to them, via 
their primary healthcare manager/physician, offering information about the study and how to contact the 
study staff. Responsive individuals will be given comprehensive details about the study and then offered an 
Informed Consent Form (ICF). The potential participants will have up to 7 days to decide if they are able and 
willing to participate. If they are, the study staff will arrange for the potential participant to come to Visit 1 
for witnessed informed consent signing and then to undergo the screening procedures. 
 
6.1.2. Visit schedule and events/procedures 
All subjects will follow the study procedures outlined below (see also grid in Section 2 above).   
Every effort should be made to adhere to the visit schedule. Visits should be scheduled at the designated 
time-point. If unavoidable, an unscheduled visit may be performed, but the schedule for subsequent visits 
must be maintained so that the total duration of the study period per patient is as close as possible to 30 
weeks. If a visit is scheduled at a time other than the protocol designated time, careful consideration must be 
given to the amount of study medication the subject has available. 
Patients should be counseled to fast (no food or drink except water and non-study medications as prescribed) 
for at least 8 hours prior to all study visits where blood will be collected. 
Each patient will be involved in the study for a screening visit, a randomization visit, the treatment period of 
26 weeks (14 days on /14 days off) with 3 follow-up visits to the clinical research site scheduled up to week 
28 after the 1st IMP dose.  
Visit schedule and events/procedures are detailed in the sections below. Visits 2b and 3 are scheduled during 
the 14 days off treatment, while visit 4 is set in the 2 weeks after treatment completion (last IMP dose in 
cycle 7).  
 
Visit 1: Screening: The study physician or designee will present to/discuss with the study subject the clinical 
trial and answer all questions. If the patient is able and willing to participate, after the informed consent has 
been obtained, study staff will: 
- assess past medical history to confirm T1D (e.g. results of past auto-antibody testing),  
- determine daily insulin requirement (U/kg/day - expressed as the average of the last 3 days) and its 
stability,  
- measure body weight, height, waist and waist/hip circumference, 
- calculate 
 BMI,  
- record the use of concomitant medication, 
- establishing the presence of IR as described (inclusion criteria, bullet 8)1-3.  
Screening evaluation also include blood sampling for the assessment of: 
- HbA1c, 
- fasting C-peptide,  
- standard safety laboratory tests,  
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- pregnancy in subjects with reproductive potential; post-menopausal women, defined as no menses for 
12 months without an alternative medical cause, will not undergo pregnancy testing. 
- T1D auto-antibody (excluding IAA) should past data not be available.  
Vital signs (blood pressure and heart rate) will be measured and an ECG performed.  
Patients must ensure the CGM sensor is correctly inserted and glucose monitored for at least the 7 days prior 
to the next visit. Potential study subjects must meet all inclusion and exclusion criteria prior to randomization. 
The study subjects will be asked to continue regular glucose monitoring through the recording system as 
described in Section 5.6 to adjust their insulin intake according to T1D standard of care.  
After the screening visit, the sub-investigator/trial coordinator will reach out the subject in at least one 
occasion to ensure compliance with daily blood glucose measurement as described in Section 5.6 and 
familiarize with establishing and maintaining contact with the trial staff to report/discuss any possible AEs 
and/or other aspects of the trial protocol.  
Potential study subjects must meet all inclusion and exclusion criteria prior to randomization.  
 
Visit 2: Randomization and start of IMP (Day 1): Within 2 weeks from the screening, the study subject 
will come to the site in the morning for visit 2. After at least 7 days of CGM data have been downloaded for 
measurement of glycemic variability outcomes and all inclusion/exclusion criteria have been finally 
confirmed, eligible patients (enrolled patients) will be assigned a unique sequential randomization number 
and randomized 1:1 into either ladarixin or placebo, according to the randomization list. Dropouts after 
randomization will not be replaced. Vital signs will be measured, average (previous 3 days) daily insulin 
requirements (IU/kg/day) will be recorded, body weight, height, waist and waist/hip circumference will be 
assessed 
 and BMI calculated. Blood will be collected for the exploratory outcome measures 
 and for HbA1c assessment (up to 2 mL).  
At the end of the visit, Patient Kits for cycle 1 to 3 will be dispensed; it is the responsibility of the study 
physician to explain, and make sure that, patient fully understands any appropriate treatment related 
information. This includes, but is not limited to, treatment schedule, time of administration, time interval 
from meals, and recording of treatment administration in the Patient Diary.  
IMP administration: The patients will begin administering the IMP, while on-site under medical 
supervision, ideally no later than 11:30 (1st dose of cycle 1). Treatment will proceed at home for the 1st and 
for additional 6 cycles of 14 days on/14 days off, for a total of 26 weeks. 
 
Visit 2b: (Week 4): An ECG will be performed and then the subject will undergo blood sampling for 
assessment of safety laboratory testing. 
 
Visit 3: (Week 11/12): Patient Kits (cycle 1 to 3) and the Diary will be returned to and checked by the study 
staff to verify inventory and treatment compliance. Medication use will be also ascertained. Vital signs will 
be measured followed by an ECG, and then the subject will undergo blood sampling for assessment of 
HbA1c and safety laboratory testing and exploratory outcome measures 
 
; average (previous 3 days) daily insulin requirements (IU/kg/day) will be recorded, body weight, 
height, waist and waist/hip circumference will be measured and
CGM data will 
be downloaded for measurement of glycemic variability in the previous 7 days. After IMP discontinuation 
criteria have been checked, Patient Kits (cycle 4 to 7) will be dispensed and the subject will be discharged 
from this visit. 
 
Visit 4; End of Study (Week 27/28): The study subject will come to the clinic for final assessment of vital 
signs, ECG, average (previous 3 days) daily insulin requirements (IU/kg/day), body weight, height, waist 
and waist/hip circumference and for 
. Subjects will undergo blood sampling 
for assessment of HbA1c, safety laboratory testing, eGFR and exploratory outcome measures 
 CGM data will be downloaded for measurement of glycemic 
variability in the previous 7 days.  
At the end of the visit, upon the study physician’s order, the subject will be formally discharged from the 
study. 
REGULARLY-SCHEDULED PHONE CALLS: In-trial, the sub-investigator/study coordinator will 
proactively reach out to study subjects, at least every 30-45 days, for the entire study period from the time 
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of randomization visit onwards, to ensure compliance with treatment and importantly, ongoing identification 
of any AEs. It is the responsibility of the PI to adjust the frequency of such contacts, according to patient 
responsiveness and compliance with treatment. 
Unscheduled visits 
In addition to the scheduled visits, it is possible that subjects may need to complete an unscheduled visit if 
they experience an event that the PI or the Principal Physician believes to warrant follow-up. The unscheduled 
visit might include appropriate actions, such full physical examination and blood sample collection (less than 
30 mL) that the PI or the Principal Physician feels is required, based upon the event. 
 
6.2. 
GLUCOSE MONITORING DURING THE DURATION OF THE TRIAL 
6.2.1. Glucose Monitoring 
Glucose treatment decisions will be driven by protocol and controlled solely by the study staff.  
Glycemic management for participants will follow an established titration protocol based on CGM 
measurements as described in Section 5.6, aiming to pre-prandial blood glucose between 70 and 130 mg/dL 
and a glycated HbA1c levels of levels of less than 7% without symptomatic hypoglycemia.  
Blood glucose assessments will be performed for safety (to prevent hypoglycemia) according to ISOC 
recommendations. Pharmacologic insulin will be titrated based on results of these glucose measurements as 
is common in the course of usual care. Blood glucose measurements will also be performed for safety reasons 
by all participants in the presence of symptoms that suggest hypoglycemia, hyperglycemia, or during inter-
current illness likely to affect glucose control substantially. 
All participants will be followed until the end of their participation in this study. 
 
6.2.1. Assessment and management of hypoglycemia 
The site will review the symptoms and management of hypoglycemia with the subject. The site will counsel 
the subject to immediately check their glucose level if any symptoms occur that may be related to 
hypoglycemia (e.g., weakness, dizziness, shakiness, increased sweating, palpitations, or confusion), but also 
to avoid delay in treating these symptoms. Subjects should be instructed to contact the investigational site to 
report: any symptomatic episodes he/she believes may represent hypoglycemia, any episode of possible 
hypoglycemia resulting in symptoms, any episode of hypoglycemia for which assistance was required (i.e., 
severe hypoglycemia), any episode of self-monitored glucose of less than 70 mg/dL with or without 
symptoms. 
Each episode should be evaluated by the PI/Principal Physician according to ADA 2022 guidelines, as per the 
table below. 
 


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6.3. 
EARLY PATIENT WITHDRAWAL 
6.3.1. 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 center for a scheduled visit, attempts should be made to contact the patient to 
ensure that the reason for not returning is not an AE or 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 an AE or 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.  
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. 
In case of pregnancy, the patient will be withdrawn from the study, but she will be monitored for safety and 
pregnancy outcomes, unless she withdraws her consent. 
Any withdrawals must be fully documented in the eCRF. 
 
6.3.2. Replacement procedures 
There are no plans to replace discontinued subjects. 
 
6.4. 
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. 
 
6.5. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION OR TERMINATION 
After completion of Visit 4 (Study Discharge), or at study termination (for any other reason), patients will 
receive post-study care as prescribed by their PCP/endocrinologist and/or other non-study health care 
provider. No post-study or post study-termination treatment will be provided by the study team or Dompé. 
 
 
 
 


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7. 
STUDY ENDPOINTS 
7.1.  
EFFICACT ENDPOINTS 
Primary endpoint: The proportion of responders, with responders defined as “patients with an HbA1c 
reduction from baseline of ≥0.50% (absolute difference) without episodes of severe hypoglycemia (level 3) 
[timeframe: week 27/28 (visit 4)]. 
 
Secondary endpoints: 
The following secondary endpoints will be considered: 
- The proportion of responders [Timeframe: week 11/12 (visit 3)] 
- The mean difference from baseline in HbA1c [Timeframe: week 11/12 (visit 3) and 27/28 (visit 4)] 
- Average (previous 3 days) daily insulin requirements (IU/kg/day) [Timeframe: week 11/12 (visit 3) and 
27/28 (visit 4)] 
- Glycemic Variability by CGM (previous 7 days): time in range (TIR), time above range (TAR) time below 
range (TBR), standard deviation and coefficient of variation [Timeframe: week 11/12 (visit 3) and 27/28 
(visit 4)] 
 
Exploratory endpoints: 
The following exploratory endpoints will be considered: 
- 
 
 
- 
 
 
 
 
 
 
 
 
 
 
7.2. 
SAFETY ENDPOINTS 
- Vital signs (blood pressure and heart rate) [Timeframe: screening, week 11/12 (visit 3), 27/28 (visit 4)] 
- Laboratory tests [haematology (total WBC, neutrophils/lymphocytes/monocytes/basophils/eosinophils (% 
and absolute number), total RBC, MCV, hematocrit, platelet count) and clinical chemistry (sodium, 
potassium, serum creatinine, serum albumin, total bilirubin, ALT, AST)] [Timeframe: screening, week 
11/12 (visit 3) and 27/28 (visit 4)] 
- Incidence of Treatment Emergent Adverse Events (TEAEs), Adverse Drug Reaction (ADR) and Treatment 
Emergent Serious Adverse Events (TESAEs) [Timeframe: from the beginning of IMP administration up 
to the end of study participation].  
 
 
CCI
CCI


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8. 
ADVERSE EVENTS 
8.1. 
DEFINITIONS 
Adverse event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not 
related to the medicinal product.  
 
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. The definition covers also medication errors and uses outside what is foreseen in the 
protocol, including misuse and abuse of the product. For the purposes of IND safety reporting, “reasonable 
possibility” means there are facts (evidence) or arguments to suggest a causal relationship between the drug 
and the adverse event. 
 
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, 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency ward 
for observation and/or treatment (usually involving an overnight stay) that would not have been appropriate 
in the physician's office or an out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred, the event should be considered serious. 
 results in persistent or significant disability/incapacity, 
NOTE: This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained 
ankle, back pain) which may interfere or prevent everyday life functions, but do not constitute a substantial 
disruption. 
 is a congenital anomaly/birth defect 
 is medically significant or important medical condition, i.e. 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. 
NOTE: An important medical condition is an event that may not result in death, be life-threatening, or 
require hospitalization but may be considered a SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in patient 
hospitalization, or the development of drug dependency or drug abuse. 
Pre-planned hospitalization or hospitalization for routine treatment or monitoring of the studied indication, 
not associated with any deterioration in condition are not considered to be serious events. These events must 
be recorded in the AE section (except for hospitalization for study procedures) of the eCRF where a variable 
will be ticked to indicate that they are not SAEs.  
Death shall always be reported as SAE, and cause of death shall always be specified, when known. 


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Unexpected Adverse Events  
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure (Reference Safety 
Information section). An event is unexpected also when it is not listed at the specificity or severity that has 
been observed and listed in the Investigator Brochure. Events that are mentioned in the Investigator Brochure 
as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug but are 
not specifically mentioned as occurring with the particular drug under investigation are considered 
unexpected. The determination of expectedness shall be made on the basis of the IB Reference Safety 
Information (RSI) section. 
According to the Investigator Brochure (Reference to Safety Information, section 6.4), for the purpose of this 
study all ADRs are assumed to be unexpected.  
 
Suspected unexpected serious adverse reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an adverse reaction that is both 
unexpected (not consistent with the applicable product information) and also meets the definition of a Serious 
Adverse Reaction. 
 
8.2. 
MONITORING FOR ADVERSE EVENTS 
At each visit following study informed consent form signature, after the subject has had the opportunity to 
spontaneously mention any problem, the Investigator or appropriate designee should inquire about AEs by 
asking the standard questions:  
• “Have you had any health problems since your last study visit?”  
• “Have there been any changes in the medicines you take since your last study visit?”  
AEs should be reported for any clinically relevant change in concomitant condition(s) that is the result of an 
untoward (unfavorable and unintended) change in a subject’s medical health. Changes in any protocol-
specific systemic parameter evaluated during the study are to be reviewed by the Investigator. Any untoward 
(unfavorable and unintended) change in a protocol-specific parameter or questionnaire response that is 
clinically relevant is to be reported as an AE. These clinically relevant changes will be reported regardless of 
causality. 
 
8.3. 
RECORDING OF ADVERSE EVENTS 
All AEs (serious and non-serious) which occur from signature of the informed consent through patient 
participation in the study (last planned visit or early withdrawal date) will be collected and recorded in the 
eCRF. It is important that the AE dedicated section of the eCRF includes the duration of the AE 
(onset/resolution dates), the relationship to the drug, the severity, the outcome, the action(s) taken and 
relevant concomitant treatments dispensed. When possible, signs and symptoms indicating a common 
underlying pathology should be documented as one comprehensive event. 
All AEs should be followed-up to determine the outcome of the reaction. The Investigator should follow up 
the event until resolution or stabilization of the condition.  It is the Investigator's responsibility to assure that 
the subjects experiencing an AE receive definite treatment for any AE, if required.   
Medical conditions/diseases present before starting study treatment shall be documented in the medical 
history section of the eCRF; these conditions are considered AEs only if they increase either in frequency or 
severity once informed consent has been signed. 
 
8.3.1. Follow-up of patients with AEs 
The Investigator is responsible for adequate and safe medical care of subjects during the trial and for ensuring 
that appropriate medical care and relevant follow-up procedures are maintained after the trial. All AEs should 
be followed-up to determine outcome of the reaction. The Investigator should follow up the event until 


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resolution or stabilization of the condition. It is the Investigator's responsibility to assure that the subjects 
experiencing AEs receive definite treatment for any AE, if required. 
If subject was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to the Sponsor 
as soon as it becomes available. In addition, a letter from the Investigator that summarizes the events related 
to the case, as well as results of any relevant laboratory tests and redacted section of medical records may be 
provided to the Sponsor, if relevant for the SAE. In case of death, a copy of the autopsy report, if performed, 
should also be provided. 
The Investigator shall inform the Sponsor with an appropriate written communication, whenever he becomes 
aware of new available information regarding the SAE, once the condition is resolved or stabilized and when 
no more information about the event is expected. Follow-up SAE information should be processed as initial 
SAE notification (see Sections 8.4, 8.5). 
For pharmacovigilance purposes, all SAEs should be followed-up in order to clarify as completely as possible 
their nature and/or causality and until all queries have been resolved. All SAEs will be followed up until the 
events resolve or the events or sequelae stabilize, or it is unlikely that any additional information can be 
obtained after demonstration of due diligence with follow-up efforts (i.e. subject or Investigator is unable to 
provide additional information, or the subject is lost to follow up), unless subject has withdrawn his/her 
consent. 
 
8.3.2. Relationship of AEs to the Investigational Medicinal Product 
The Investigator will assess the causal relationship between the AE and the IMP (either ladarixin or placebo), 
according to the criteria in the Table below: 
Relationship of the AEs 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 the study drug 
will be considered as an ADR. 
 
8.3.3. Severity of adverse events 
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]) 
 


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8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. Reporting Procedure for the Investigator to Dompé/CRO 
The Principal Investigator must report all SAEs occurring during patient participation in the study, regardless 
of presumed causal relationship, to the appropriate Sponsor/CRO Pharmacovigilance contact 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” (See Page 2 of this Protocol).   
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 appropriate Pharmacovigilance or 
directly to the Dompé Global Pharmacovigilance, Safety and Surveillance Department, should the whole 
study have been ended.  Such “post-study cases” should be regarded for expedited reporting purposes as 
though they were study reports. Therefore, a causality assessment and determination of expectedness are 
needed for a decision on whether or not expedited reporting is required.  
Information on SAEs will be recorded on a specific 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. 
 
8.4.2. Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to be SAE and 
shall not be reported as such, but only need to be recorded in the eCRF: 
 
Hospitalizations planned before entry into the clinical study which is part of the normal treatment or 
monitoring of the studied indication and not associated with any deterioration in condition.  
 
Hospitalization for routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
 
Hospitalization for treatments, which was elective or pre-planned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen. 
 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of SAEs 
given above and not resulting in hospital admission.  
In addition, the following situation shall not be considered SAE:  
 
Abnormal laboratory values or test results that do not induce clinical signs and/or symptoms and do 
not require intervention/therapy, i.e. are clinically significant. 
 
8.4.3. Adverse events exemption 
Not applicable.  
 
8.4.4. Reporting Procedure to IEC and to Regulatory Authorities in the European Union 
Reporting of Suspected Unexpected Serious Adverse Reaction 
Investigator must report all serious adverse events to the sponsor immediately, within 24 hours.  


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Dompé Global Pharmacovigilance, Safety and Surveillance Department, with the support of the CRO as 
appropriate, shall report any SUSAR to the concerned IEC which approved the protocol and the Regulatory 
Authority (via the Eudravigilance Clinical Trial module) as soon as possible, and in no event later than: 
 
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. 
 
fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
Treatment will be unblinded by Dompé Global Pharmacovigilance, Safety and Surveillance department prior 
to regulatory submission of a potential SUSAR to Regulatory Authorities and IEC in the European Union. If 
the patient is on the active treatment, then Dompé Global Pharmacovigilance, Safety and Surveillance 
Department will report the case as a SUSAR. If the patient is revealed to have taken a placebo, then this 
would not require reporting as a SUSAR, unless there are concerns that there is a reaction to something in 
the placebo (such as an allergic reaction or a contaminant caused by a manufacturing issue).  
If the results of an investigation show that an AE not initially determined to be reportable is reclassified as 
reportable, Dompé shall notify such SUSAR in a written safety report as soon as possible, but in no event 
later than 7/15 calendar days after the determination is made. 
Copies of all correspondence relating to reporting of any SAEs to the IEC should be maintained in the 
Investigator’s Files. 
Periodical Reporting to EU Regulatory Authorities  
Dompé Global Pharmacovigilance, Safety and Surveillance Department will prepare and submit (via the 
CRO as applicable) to Investigators appropriate periodical safety updates as per applicable EU and local 
requirements and regulations. Dompé Global Pharmacovigilance, Safety and Surveillance Department shall 
also be responsible to prepare and submit annual safety reports (Development Safety Update Report – DSUR) 
to relevant Regulatory Authorities and to IECs. 
 
8.4.5. Reporting Procedure to IRB and to the FDA in the United States  
The Investigator must report all SAEs to the Sponsor/CRO immediately, within 24 hours (see Section 8.4.1).  
In addition to reporting the SAE to Dompé/CRO, the Investigator must also comply with the requirements 
related to the reporting of SAEs to the IRB which approved the study. As a minimum requirement, the 
Investigators must promptly report all SUSARs to their IRB.  
Reporting of Suspected Unexpected Serious Adverse Reaction 
In line with provisions set forth in 21CFR312, the Sponsor shall notify the Investigators and the FDA in an 
IND safety report of any SUSAR and of potential serious risks, from clinical trials or any other source, as 
soon as possible, but in no case later than:  
 
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. 
 
fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
The Investigators in turn shall notify their IRB: Investigators are required to promptly report “to the IRB all 
unanticipated problems involving risk to human subjects or others,” including AEs that should be considered 
unanticipated problems (21 CFR 312.66). 
The blind should ordinarily be broken for IND safety reports submitted to FDA and all participating 
investigators. Dompé Global Pharmacovigilance, Safety and Surveillance Department will unblind treatment 
prior to regulatory submission of a potential SUSAR to FDA and IRB and only cases referred to active 
treatment will be considered expeditable for regulatory reporting, in line with law requirements. In general, 
if the blind is broken and the subject was receiving placebo, the event should not be reported in an IND safety 
report because there is not a reasonable possibility that the drug caused the adverse event. 


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If the results of an investigation show that an AE not initially determined to be reportable is reclassified as 
reportable, Dompé Drug Safety Department shall notify such SUSAR in a written safety report as soon as 
possible, but in no event later than 7/15 calendar days after the determination is made. 
Copies of all correspondence relating to reporting of any SAEs to the IRB should be maintained in the 
Investigator’s Files. 
Potential serious risks arising from clinical trials or any other source, to be reported to FDA and to the 
Investigators, include: 
-  any SUSAR. Dompé must report an adverse event as a suspected adverse reaction only if there is evidence 
to suggest to the Sponsor a causal relationship between the drug and the adverse event. 
-  findings from other studies that suggest a significant risk in humans exposed to the drug. Such a finding 
would result in a safety-related change in the overall conduct of the clinical investigation. 
-  findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug 
-  increased rate of occurrence of serious suspected adverse reactions.  
Based on the specific Investigator’s site requirements, Dompé Global Pharmacovigilance, Safety and 
Surveillance Department will submit to IRBs and Investigators periodical safety updates, as per applicable 
local requirements and regulations.     
Dompé Global Pharmacovigilance, Safety and Surveillance Department shall also be responsible to prepare 
and submit annual safety reports (Development Safety Update Report - DSUR) to FDA and IRBs (Director 
of Clinical Trial Regulatory Affairs at AHN). 
 
8.5. 
EXPOSURE TO IMP DURING PREGNANCY 
Women of childbearing potential are defined as all women physiologically capable of becoming pregnant. 
Prior to enrolment in the clinical trial, female patients of childbearing potential and their partners must be 
advised of the importance of avoiding pregnancy during the entire course of the study treatment and for the 
2 months after the study discharge and of the potential risks associated with an unintentional pregnancy. 
During the trial (treatment period or follow up period), female patients are to be instructed to contact the 
Investigator immediately if they suspect they might be pregnant. In the same way, male patients who become 
aware that the partner might be pregnant, are to be instructed to contact the Investigator immediately. 
The Investigator must report every pregnancy on a pregnancy report form as soon as possible (within 24 
hours of learning of the pregnancy to the Pharmacovigilance Contacts specified in the section “Contact 
Information”, even if no AE has occurred, and follow it to term. If, however, the pregnancy is associated with 
an SAE (e g, if the mother is hospitalized for dehydration), in addition to the pregnancy report form, a separate 
SAE report form must be filed as described in Section 8.6, with the appropriate serious criterion indicated on 
the SAE report form. Miscarriage, stillbirth and any malformation/disease must be reported as a SAE. 
Any pregnancy leads to the immediate withdrawal of the study subject from the trial.  
 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and reasoned in 
the eCRF, and the patient must be followed up until the resolution of the AE or as instructed by the medical 
expert. 
 
8.7. 
OVERDOSE 
Accidental or intentional overdose, which may or may not result in serious adverse reactions, is to be reported 
to CRO Pharmacovigilance, Dompé Global Pharmacovigilance, Safety and Surveillance Department and to 
Dompé Medical Expert, following the same procedure for SAE, within 24 hours from the Investigator’s 
knowledge of its occurrence. This includes reports related to drug intake through different routes (e.g. 
ingestion) or with suicidal intentions and consequent drug overdose. 
An overdose of ladarixin is defined as the administration of 6 or more capsules on any given treatment day. 


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The Investigator shall provide in the SAE form information about symptoms, corrective treatment and 
outcome of overdose. The Medical Expert should be contacted to discuss corrective treatment, if necessary. 
 
8.8. 
EMERGENCY PROCEDURES AND UNMASKING OF STUDY TREATMENT 
The treatment allocation for each patient will be provided with a protected system to: 
- the Principal Investigator and study physicians for emergency procedures; 
- Dompé Pharmacovigilance for safety reporting. 
The treatment assignment information will be kept confidential and will not be disclosed to any other person 
than those ones involved in these emergency and safety procedures. 
Access to individual patient treatment information will be allowed only in the event of a medical emergency 
where the knowledge of patient treatment is required to provide the patient with appropriate care.  
Any code break and the reason behind it will be recorded (when it was opened, by whom and why) in the 
relevant section of the eCRF. Code break will be immediately communicated to Dompé, as appropriate.   
If the treatment code needs to be broken in the interest of patient safety for a medical emergency, the 
Investigator is allowed to break the treatment code for the specific patient, even before informing the Sponsor. 
The Investigator must always notify the Sponsor, so that the reason for any premature unmasking can be 
documented, by means of a communication to CRO and to Dompé Medical Expert.  
The Investigator will inform the Dompé representative (Dompé Medical Expert) if an emergency unmasking 
was performed without revealing the treatment identity, but only referring to the kit number involved in the 
unmasking in order to avoid a dissemination of unmasked information. 
Dompé Pharmacovigilance, Safety and Surveillance Department will unmask a patient treatment only for 
reported SAE potentially meeting criteria of a SUSAR, in order to fulfill expedited regulatory reporting 
requirements. The identity of the treatment will remain unknown to the patient, Investigator, site staff, CRO 
and Dompé’s Development personnel until the study is unmasked. Unblinding events will be recorded and 
reported in the clinical study report. 


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9. 
STATISTICAL CONSIDERATIONS 
This study is designed to be a randomized, placebo-controlled, double-blinded, 2-parallel arm, phase II trial 
in which subjects are randomized (1:1) to ladarixin or placebo.  
 
9.1. 
SAMPLE SIZE 
Sample size calculation was based on results obtained in the phase 2 trial with ladarixin in T1D onset. 
Considering the following assumptions: 
 
randomization ratio 1:1 (ladarixin:  placebo), 
 
one-side type I error of 0.05, 
 
expected difference in favor of ladarixin in terms of responders: ~22.5%, and 
 
power of 80% to detect the expected treatment effect 
a total of 76 evaluable patients are required; to account for a possible 10% of patients not evaluable for the 
primary variable after enrollment, up to 86 patients will be enrolled.  
 
9.2. 
RANDOMIZATION 
The randomization list will be generated with a computer procedure by a CRO independent statistician not 
involved in the conduct of the study and will be provided to Dompé in a sealed envelope to prevent 
unblinding. The facility responsible of IMP packaging/labelling will also receive appropriate randomization 
codes for the purpose of IMP preparation. 
Randomization will be stratified by site to ensure balanced assignment across treatment groups. A master 
randomization list will be generated, randomizing an excess of patients to allow competitive recruitment 
within each center.    
Access to individual patient treatment code will be allowed only in the event of a medical emergency where 
the knowledge of patient treatment is required to provide the patient with appropriate care. The investigator 
and Dompé Pharmacovigilance will have access to the randomization code for a specific patient in case of a 
medical emergency or for safety reasons. Unblinding events will be recorded and reported in the Clinical 
Study Report (CSR). The treatment assignment information will be kept confidential and will not be disclosed 
to any other. 
Once the study has been completed and the database has been locked, the treatment assignment information 
will be accessible to the study biostatistician(s) who will perform the statistical analyses and will generate 
reports.  
 
9.3. 
ANALYSIS POPULATION 
The following population will be defined: 
- The Safety (SAF) population will consist of all randomized patients who received at least one dose of 
the investigational product. Safety population will be analyzed according to the actual treatment 
received. The SAF population will be used to present results on safety data. 
- The Full Analysis Set (FAS) population will consist of all randomized patients who received at least one 
dose of the investigational product. FAS population will be analyzed according to the intention-to-treat 
(ITT) principle. The FAS population will be used for the primary analysis of the study and to present 
results on efficacy data. 
 
9.4. 
STATISTICAL METHODOLOGY 
Statistical analysis will be performed by the CRO appointed by Dompé. 
All patient data collected during the study will be listed by patient.  
Summary statistics appropriate to the distribution of the primary variable will be calculated separately by 
treatment arm.  


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For continuous data, number of observations, mean, standard deviation, median and range (minimum and 
maximum) will be presented. For qualitative data, frequency distributions and percentages per category will 
be presented. If appropriate, confidence intervals around the mean or the proportions will be presented.  
Unless otherwise specified, the significance level for statistical testing will be 0.05 and two-sided tests.  
The Statistical Analysis Plan (SAP) will be issued before database lock with more technical and detailed 
elaboration of the principal features of statistical analyses. Additional post-hoc analysis may be produced to 
further allow comparison between ladarixin and placebo, according to the results obtained.   
Any deviations from the original statistical plan (including unplanned analyses) will be clearly documented 
in the CSR.   
 
9.4.1. Demographic and baseline characteristics 
Demographic and baseline characteristics will be summarized for all patients in the FAS population, by 
treatment group. 
 
9.4.2. Analysis of efficacy variables 
9.4.2.1. Primary analysis   
The following null hypothesis is defined: the proportion of patients with an HbA1c reduction from baseline 
of ≥ 0.50% (absolute difference) without episodes of severe hypoglycemia (level 3) at week 27/28 (visit 4) 
in ladarixin group is lower or equal than control: 
H0: TLADARIXIN ≤ TCONTROL 
H1: TLADARIXIN > TCONTROL 
where TLADARIXIN and TCONTROL are the proportions of patients with an HbA1c reduction from baseline of 
≥0.50% without episodes of severe hypoglycemia for ladarixin and control groups, respectively. The null 
hypothesis H0 will be rejected, and superiority of ladarixin declared if primary analysis p-value will be lower 
than 0.05. 
Primary endpoint will be analyzed by means of a logistic regression model, adjusting for treatment, 
stratification factor and other baseline characteristics that will be defined in the SAP. A one-sided test will 
be used to test for differences between treatment groups.  
Summary statistics appropriate to the distribution of the primary variable will be calculated separately by 
treatment arm. 
 
9.4.2.2. Secondary analyses 
Analyses will be performed on all secondary 
 endpoints at each available time point by means 
of descriptive statistics and by appropriate inferential tests, depending on the nature of the variable and its 
distribution. Data transformation might be used in order to satisfy the assumption of normality requested by 
parametric statistical tests. In case such assumptions are not met, non-parametric counterpart tests will be 
used. Details will be provided in the SAP. 
The proportion of responders assessed at week 11/12 (visit 3) will be analyzed using the same strategy of the 
primary endpoint. 
 
9.4.2.3. Analysis of safety variables 
TEAEs, ADRs and TESAEs will be presented by treatment arms in terms of number of TEAEs and incidence 
by System Organ Class and Preferred Term using MedDRA. Analyses will be provided also by severity and 
relationship to the study drug.  
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Vital signs and safety laboratory tests will be presented using descriptive statistics at each available visit. 
Additionally, the frequency of subjects reporting an abnormal or abnormal clinically significant laboratory 
value will be presented for each laboratory parameter. 
 
9.4.3. Intermediate analyses for the DMC 
Safety data will be reviewed on an ongoing basis by a Data Monitoring Committee (DMC). Full details of 
the activities and responsibilities of the DMC are provided in the study DMC Charter (see additional details 
in Section 12.6). 
The DMC will give careful consideration to the appropriateness of trial continuation if there is emerging 
evidence that ladarixin is harmful. Since the DMC does not monitor primary endpoints for early efficacy 
termination, no Type I error adjustment is necessary. Anyhow, access to unblinded information on the 
primary analyses is allowed in order to balance patient safety risk against a possible gain in efficacy. 
 
9.4.4. Specification of subgroups for analysis 
Sub-group analyses of efficacy endpoints will be performed ad hoc (e.g. subgroup of patients defined by age, 
HbA1c value, BMI etc.), according to the results obtained in the whole population. Statistical details on 
subgroup analysis will be reported in the CSR. 
 
9.4.5. Missing data 
All reasonable efforts will be made to reduce the rate of missing data. 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. 
The number of subjects with missing data will be presented under the “Missing” category. Missing values 
will not 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. 
For the primary analysis, since patients who discontinue the IMP will not be withdrawn from the study but 
will be asked to complete safety and efficacy assessments as per the protocol, missing data due to intercurrent 
events will be addressed by using multiple imputation based on retrieved dropouts information. Retrieved 
dropout patients are defined as patients who discontinue study treatment and decide to remain in the study 
by following the schedule of assessments and continuing to adhere to protocol requirements. If not enough 
data were retrieved after study treatment discontinuation for assure the convergence of the MI-RD regression 
model (the final decision will be done at the time of the analysis and reported in the CSR), the same multiple 
imputation model will be fit using data from subjects of control group, washing-out the effect of treatment. 
This approach does not assume benefits for ladarixin in case of discontinuation and limits a post-
discontinuation clinical effect to that of placebo. Specific sensitivity analyses will be defined in the SAP to 
assess the robustness of results on primary endpoint versus assumptions used in the statistical model for the 
main estimator. 
 
 
 


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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) / INSTITUTIONAL REVIEW BOARD 
(IRB) 
It is the responsibility of the CRO appointed by Dompé or of the Study PI (US site) to obtain approval of the 
trial protocol/amendments from the appropriate IEC/IRB. 
Prior to the initiation of the study, the followings will be submitted to the IEC/IRB for approval: 
- 
the study protocol, 
- 
the ICF, 
- 
the current version of the Investigator’s Brochure, 
- 
Investigator’s current curriculum vitae (CV) as well as the current CVs of all key study personnel, 
- 
any other requested document(s). 
A copy of the IEC/IRB approval will be sent to Dompé along with relevant correspondence with the IEC/IRB, 
a roster of IEC/IRB members or the US Department of Health and Human Services (DHHS) general 
assurance number.   
The study will not be started until full written approval has been obtained from the appropriate IEC/IRB. The 
letter of approval should be dated, and should specify the type (e.g. protocol number) and the date of the 
documents which were reviewed and approved.   
The CRO appointed by Dompé or the PI will submit any future amendment to the protocol to the IEC/IRB 
which granted the original approval. Any amendment will be implemented only when full approval has been 
obtained from the appropriate IEC/IRB, except for those amendments which involve only logistical or 
administrative aspects of the study. 
The CRO appointed by Dompé or the PI will send to the IEC/IRB any updated Investigator’s Brochure. 
The CRO appointed by Dompé or the PI will also submit to the IEC/IRB which approved the protocol, at 
least annually, any required progress reports and study update, and will inform the IEC/IRB of the termination 
of the study. 
The CRO appointed by Dompé or the PI will report to the IEC/IRB any serious ADRs, life-threatening 
problems or deaths occurred in other clinical studies conducted with ladarixin.   
 
10.2. 
ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in compliance with the protocol and consistent with FDA and current Good 
Clinical Practices (GCP), adopting the principles of the Declaration of Helsinki, and all applicable regulatory 
requirements (ICH E6, 45CFR46, and FDA 21CFR sections 11, 50, 56, 312). 
Prior to study initiation, the protocol and the informed consent documents will be reviewed and approved by 
the IEC/IRB. Any amendments to the protocol or consent materials must also be approved before they are 
implemented. 
 
10.3. 
PATIENT INFORMATION AND 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 or delegate personnel according to site procedures, 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 has 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 
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The ICF will be signed and personally dated by both the patient and the Investigator or delegate personnel 
according to site procedures. 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) ICFs will be provided to the site once approved by the IEC/IRB. 
Any changes requested by the IEC/IRB must be approved by Dompé prior to the documents being used.   
 
10.4. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential. Only the minimum 
necessary information to complete this research trial will be shared with the Sponsor and always in a de-
identified manner compliant with HIPAA expectations. 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 USA data protection laws, HIPAA regulations, and 
European data protection Regulation (EU) No. 679/2016 of the European Parliament and of the European 
Council regarding the protection of natural person’s personal data and the free circulation of said data 
(hereinafter GDPR EU No. 679/2016) and according the standards of Good Clinical Practice (Law Decree 
211/2003).  
On the eCRF 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. 
 
The secondary use of personal data 
Personal Data will be processed for the purpose of conducting any further analysis to generate new scientific 
hypotheses that could be verified through new research. This further analysis of personal data (“the secondary 
use of personal data”) may deviate from this protocol and, for this reason, it may require a new clinical trial 
(and therefore a new legal basis for processing patient’s personal data). 
If the further analysis does not deviate from this protocol, there is no need to change the legal basis since the 
secondary use is considered to be compatible with the primary use. 
Analyses of subcategories of data, for example, may be conducted consistent with the primary use. 
The secondary use of data may be the subject of scientific and/or statistical publications. 
 
10.5. 
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 FORM (CRF) 
An electronic CRF (eCRF) will be used for this study. eCRF is 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. 
An eCRF is required and should be completed for each consented patient, regardless of actual enrollment. 
The Investigator will be responsible for the accuracy of the data entered in the eCRF. All entries must be 
written in ENGLISH. 
Source documents should be available to support all the data recorded in the eCRF; location of source 
documents will be specified and listed at the center Initiation Visit. 
The eCRF must be available for review to designated CRO/Dompé’s representatives at each scheduled 
monitoring/audit visit. 
 
11.2. 
DIARY 
A Diary (local language version) will be given to each patient randomized into the trial.   
The patient will report in the Diary IMP intake, i.e. the number of capsules assumed and the date/time of 
assumption as well as insulin requirement in the 3 days prior to visit 3 and 4. It is responsibility of the study 
team to explain to each patient how to enter the data in this logbook and to check the data inserted in this 
Diary to ensure correct intake of the IMP.  
The Patient Diary is the sole property of the Study Team and 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. 
 
11.3. 
DATA MANAGEMENT 
Data management will be performed by the CRO appointed by Dompé. 
The eCRF for all patients will constitute the study database, and the data will be verified for missing data, 
inconsistencies, and for any necessary medical clarifications. Queries arising from these checks will be sent 
by the appointed CRO to the Investigator for response and resolution. 
Once all data queries have been resolved, the study database will be declared to be “clean” and the study data 
will be locked ready for analysis.   
After the database lock has been achieved, PDF copies of the eCRFs will be archived at the center. All data 
collected in the context of this study will be stored and evaluated per regulatory requirements and any 
applicable guidance for electronic records. Data will be stored and evaluated in such a way as to guarantee 
patient confidentiality in accordance with the legal stipulations applying to confidentiality of data. Study 
records (e.g., copies of eCRF, regulatory documents) will be retained at the study center, along with adequate 
source documentation, according to FDA and ICH requirements. 
 
11.4. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF, AND DURING THE 
STUDY 
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. 
- 
Confidential disclosure agreement Form in accordance also with European data protection 
Regulation (EU) No. 679/2016 (GDPR) 
- 
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 


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external quality assessment or other validation).  Updates should be provided as soon as any reference 
value has changed. 
- 
A signed page of the most recently-IRB approved clinical protocol and any amendments. 
- 
IRB approval documentation, IRB-approved ICFs and study materials. Documentation of continuing 
IRB review and annual renewals. 
- 
A signed copy of the study Financial Agreement/Clinical Study Agreement with Dompé, including 
all study specific costs. 
- 
List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form).  
- 
FDA Form 1572 and financial disclosure form 3455 from all the persons listed on the 1572. If 
applicable, the PI will provide an updated financial disclosure agreement to the Sponsor 1 year after 
the completion of the study.  
 
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 eCRF, 
and Diary, 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, October 2013) and ICH Harmonised Tripartite Guideline for Good Clinical Practice 
(ICH-GCP) and any local regulations. 
 
12.1. 
REGULATORY BODY OF APPROVAL 
Dompé or the CRO or other consultant appointed by Dompé will obtain the necessary approval from the 
Competent Authorities, as needed, prior to initiation of the study. 
As to the US, since IND 147145 is in effect, Dompé will submit to the FDA this protocol as “new protocol”, 
according to 21 CFR Part 312.30. 
The study will not be started until written approval from the relevant Competent Authorities (or no objection 
within the timeframe set by the local regulation, as applicable) has been received by Dompé 
 
12.2. 
MONITORING 
Monitoring will be carried out by the monitor of the designated CRO.  
The purpose of the monitoring 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.  
It is expected that the PI 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 sponsor representative to ensure that any 
problems detected during the course of these monitoring visits are resolved. 
 
12.3. 
ACCESS TO RECORD 
The Investigator will allow designated Dompé representatives to have direct access to the source documents 
to verify the data reported in the eCRF. 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. The investigator/institution should maintain adequate and 
accurate source documents and trial records that include all pertinent observations on each of the site’s trial 
subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Changes to source data should be traceable, should not obscure the original entry, and should be explained if 
necessary via an audit trail.    
All study records must be available for audit by Dompé, its authorized representatives, and Regulatory 
Inspection by Regulatory Authority.  
      
12.4. 
AUDIT AND INSPECTION 
In addition to the IEC/IRB, audit activities will be performed by the Dompé Quality Assurance Unit or any 
other third party delegated by Dompé, as appropriate. 
 
12.5. 
DATA MONITORING COMMITTEE 
An independent DMC will be established and will be responsible for safeguarding the interests of trial 
participants, and for enhancing the integrity and credibility of the trial. The DMC will assess the safety of the 
interventions during the trial and will monitor the overall conduct of the clinical trial. The DMC will provide 
recommendations to Dompé about stopping or continuing the trial on safety basis. 
The DMC will operate independently of Dompé, and its members will not have connections to Dompé with 
the exception of the compensation to DMC members related to their activities.  


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The DMC will comprise three members. They will be a multidisciplinary group that will include: 
 Two diabetologists/endocrinologists with extensive experience in the diagnosis and management of 
patients with T1D, mainly at disease onset; 
 A Biostatistician with substantial experience in the DMC process. 
The DMC: 
 Will review unblinded data. To this purpose, an Independent Statistician will liaise with the CRO 
statistician and will have access to those components of the database necessary to generate the reports 
to the DMC. 
 Will be responsible for the ongoing (at least every 4 months) review of safety data throughout the trial.  
Primary among the safety data that will be reviewed are Serious AEs.  
 Will have also access to unblinded information on the primary analyses to enable the assessment of the 
acceptability of safety in the context of emerging evidence about efficacy. 
 Will be advisory to Dompé and make recommendations to Dompé regarding the continuation of the trial 
and potential modifications to the design and conduct of the trial. These recommendations will be made 
in a manner to maintain confidentiality of emerging information about efficacy and safety, unless access 
to certain data is needed to enable Dompé to make decisions about the DMC recommendations. Dompé 
will be responsible for promptly reviewing the DMC recommendations, to decide whether to continue 
or terminate the trial, and to determine whether amendments to the protocol or changes in the study 
conduct are required 
All details of the conduct and responsibilities of the DMC will comply with Guidance for Clinical Trial 
Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees and will be described 
in the ‘DMC Charter’ to be finalized during the set-up phase of the study and prior to the initiation of 
treatment. 
 
12.6. 
PROTOCOL AMENDMENTS 
Changes to the Protocol will be implemented only when written amendments have been signed by all 
individuals who signed the protocol.  
Any amendment will be sent to the IEC/IRB and/or Competent Authority/FDA, as appropriate.  No deviations 
from or changes to the protocol will be implemented without documented approval of an amendment from 
the IEC/IRB which granted the original approval, except where necessary to eliminate an immediate 
hazard(s) to trial patient, or when the change(s) involves only logistical or administrative aspects of the trial. 
The deviations from or changes to the protocol implemented to eliminate an immediate hazard to the trial 
patient and the proposed amendment, if appropriate, should be submitted to the IEC/ RB for review and 
approval as soon as possible.  
Any other deviation from the protocol that has not been approved by Dompé and the IEC/IRB could result 
in a discontinuation from the study at the center involved. 
Any written amendment will be sent to all recipients of the protocol. 
 
12.7. 
DISCONTINUATION OF THE STUDY 
Dompé reserves the right to stop the study at any time on the basis of new information regarding safety or 
efficacy, or if study progress is unsatisfactory, or for other valid administrative reasons. 
After such a decision is made, the Investigator must inform all relevant persons e.g. study staff, potential 
patients etc. within 2 weeks. All delivered study materials must be collected and all eCRF completed to the 
extent possible. 
Study discontinuation will be notified to Competent Authority/FDA within 15 days from decision. The 
Investigator will inform his IRB within the same timeframe. 
 


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12.8. 
 PUBLICATIONS 
Publications derived from this study will be planned and agreed with the participating Study 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 initial 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. The Sponsor reviews 
proposed manuscripts prior to submission within a reasonable period of time (30-90 business days in relation 
with the complexity of the work). 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. 
The Sponsor agrees that the study results (including negative and inconclusive as well as positive results) can 
be made publicly available by the Investigator publishing in peer reviewed journals; presenting results at 
scientific congresses; and posting information and results on internet-based public registers and databases. 
On an exceptional basis, the Sponsor may temporarily delay registration of certain data elements (e.g. 
compound, name, outcome, measures etc.) to seek necessary intellectual property protection. This is because 
early disclosure of such a data could, in some circumstances, prevents or negatively impacts patentability. 
 
 
 
 


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13. 
REFERENCES 
 
 
 
 
 
 
 
 
 
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2. 
Danielson KK, Drum ML, Estrada CL, Lipton RB. Racial and ethnic differences in an estimated 
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19. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell metabolism 
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162. Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK. Effect of sitagliptin 
on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover 
trial. Diabetic medicine : a journal of the British Diabetic Association 2011;28:1176-81. 
163. Hari Kumar KV, Shaikh A, Prusty P. Addition of exenatide or sitagliptin to insulin in new onset type 1 
diabetes: a randomized, open label study. Diabetes research and clinical practice 2013;100:e55-8. 
164. Biester T, Aschemeier B, Fath M, et al. Effects of dapagliflozin on insulin-requirement, glucose 
excretion and ss-hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 
diabetes. Diabetes, obesity & metabolism 2017;19:1635-9. 
165. Kim J, Kim SM, Nguyen HC, Redondo MJ. Therapeutics in pediatric diabetes: insulin and non-insulin 
approaches. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio 
Clementi, and Massimo Molteni. Pharmacological research 2012;65:1-4. 
166. Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in 
diabetes and beyond. Drugs in context 2015;4:212283. 
167. Bloomgarden ZT. Sodium-glucose cotransporter 2 inhibitors and diabetic ketoacidosis. Journal of 
diabetes 2016;8:175-6. 
168. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic Diabetic Ketoacidosis: A 
Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes care 
2015;38:1687-93. 
169. Pfutzner A, Klonoff D, Heinemann L, Ejskjaer N, Pickup J. Euglycemic ketosis in patients with type 2 
diabetes on SGLT2-inhibitor therapy-an emerging problem and solutions offered by diabetes 
technology. Endocrine 2017;56:212-6. 
170. Wang AY, Hou SK, Li SJ, Kao WF. Euglycemic diabetic ketoacidosis in type 2 diabetes with sodium 
glucose cotransporter 2 inhibitors. The American journal of emergency medicine 2017;35:379 e5- e6. 
171. Anderson R, Theron AJ, Gravett CM, Steel HC, Tintinger GR, Feldman C. Montelukast inhibits 
neutrophil pro-inflammatory activity by a cyclic AMP-dependent mechanism. British journal of 
pharmacology 2009;156:105-15. 
172. Barletta KE, Ley K, Mehrad B. Regulation of neutrophil function by adenosine. Arteriosclerosis, 
thrombosis, and vascular biology 2012;32:856-64. 
173. Barnes PJ. New molecular targets for the treatment of neutrophilic diseases. The Journal of allergy and 
clinical immunology 2007;119:1055-62; quiz 63-4. 
174. Barnes PJ. Glucocorticosteroids: current and future directions. British journal of pharmacology 
2011;163:29-43. 
175. Gaudreau R, Le Gouill C, Venne MH, Stankova J, Rola-Pleszczynski M. Threonine 308 within a 
putative casein kinase 2 site of the cytoplasmic tail of leukotriene B(4) receptor (BLT1) is crucial for 
ligand-induced, G-protein-coupled receptor-specific kinase 6-mediated desensitization. The Journal of 
biological chemistry 2002;277:31567-76. 
176. Gravett CM, Theron AJ, Steel HC, et al. Interactive inhibitory effects of formoterol and montelukast 
on activated human neutrophils. The European respiratory journal 2010;36:1417-24. 
177. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 
inhibitor roflumilast in vitro. The Journal of pharmacology and experimental therapeutics 
2001;297:267-79. 
178. Lazaar AL, Sweeney LE, MacDonald AJ, Alexis NE, Chen C, Tal-Singer R. SB-656933, a novel 
CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway 
inflammation in humans. British journal of clinical pharmacology 2011;72:282-93. 
179. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in 
chronic plaque psoriasis. The New England journal of medicine 2012;366:1190-9. 
180. Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe 
asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clinical and 
experimental allergy : journal of the British Society for Allergy and Clinical Immunology 
2012;42:1097-103. 
181. Ohnishi H, Miyahara N, Gelfand EW. The role of leukotriene B(4) in allergic diseases. Allergology 
international : official journal of the Japanese Society of Allergology 2008;57:291-8. 


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182. Sivertson KL, Seeds MC, Long DL, Peachman KK, Bass DA. The differential effect of 
dexamethasone on granulocyte apoptosis involves stabilization of Mcl-1L in neutrophils but not in 
eosinophils. Cellular immunology 2007;246:34-45. 
183. Stankova J, Turcotte S, Harris J, Rola-Pleszczynski M. Modulation of leukotriene B4 receptor-1 
expression by dexamethasone: potential mechanism for enhanced neutrophil survival. Journal of 
immunology 2002;168:3570-6. 
184. Steel HC, Theron AJ, Cockeran R, Anderson R, Feldman C. Pathogen- and host-directed anti-
inflammatory activities of macrolide antibiotics. Mediators of inflammation 2012;2012:584262. 
185. Steel HC, Theron AJ, Tintinger GR, Anderson R. Posaconazole attenuates leukotriene B4 release and 
uptake of calcium by chemoattractant-activated human neutrophils: a potential strategy to control 
neutrophil-mediated inflammation. The Journal of antimicrobial chemotherapy 2009;64:1008-12. 
186. Tannheimer SL, Sorensen EA, Haran AC, Mansfield CN, Wright CD, Salmon M. Additive anti-
inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human 
peripheral blood mononuclear cells. Pulmonary pharmacology & therapeutics 2012;25:178-84. 
187. Tintinger GR, Feldman C, Theron AJ, Anderson R. Montelukast: more than a cysteinyl leukotriene 
receptor antagonist? TheScientificWorldJournal 2010;10:2403-13. 
188. Tintinger GR, Steel HC, Theron AJ, Anderson R. Pharmacological control of neutrophil-mediated 
inflammation: strategies targeting calcium handling by activated polymorphonuclear leukocytes. Drug 
design, development and therapy 2009;2:95-104. 
189. Tsuchihashi Y, Oishi K, Yoshimine H, et al. Fourteen-member macrolides suppress interleukin-8 
production but do not promote apoptosis of activated neutrophils. Antimicrobial agents and 
chemotherapy 2002;46:1101-4. 
190. den Uyl D, van Raalte DH, Nurmohamed MT, et al. Metabolic effects of high-dose prednisolone 
treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation 
reduction. Arthritis and rheumatism 2012;64:639-46. 
191. Rafacho A, Ortsater H, Nadal A, Quesada I. Glucocorticoid treatment and endocrine pancreas 
function: implications for glucose homeostasis, insulin resistance and diabetes. The Journal of 
endocrinology 2014;223:R49-R62. 
192. Huang HY, Caballero B, Chang S, et al. The efficacy and safety of multivitamin and mineral 
supplement use to prevent cancer and chronic disease in adults: a systematic review for a National 
Institutes of Health state-of-the-science conference. Annals of internal medicine 2006;145:372-85. 
193. Sun L, Clavijo PE, Robbins Y, et al. Inhibiting myeloid-derived suppressor cell trafficking enhances T 
cell immunotherapy. JCI insight 2019;4. 
194. Roberts G, Chen S, Yates P, et al. Randomized, Double-Blind, Placebo-Controlled Study of the 
Safety, Tolerability, and Clinical Effect of Danirixin in Adults With Acute, Uncomplicated Influenza. 
Open forum infectious diseases 2019;6:ofz072. 
195. Madan A, Chen S, Yates P, et al. Efficacy and Safety of Danirixin (GSK1325756) Co-administered 
With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults 
Hospitalized With Influenza. Open forum infectious diseases 2019;6:ofz163. 
196. Iida T, Matsuzawa Y, Ogura H, et al. Evaluation of the Safety, Tolerability, Pharmacokinetics, and 
Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants. Clinical 
pharmacology in drug development 2019. 
197. Lazaar AL, Miller BE, Tabberer M, et al. Effect of the CXCR2 antagonist danirixin on symptoms and 
health status in COPD. The European respiratory journal 2018;52. 
198. Tavares LP, Garcia CC, Machado MG, et al. CXCR1/2 Antagonism Is Protective during Influenza and 
Post-Influenza Pneumococcal Infection. Frontiers in immunology 2017;8:1799. 
199. Busch-Petersen J, Carpenter DC, Burman M, et al. Danirixin: A Reversible and Selective Antagonist 
of the CXC Chemokine Receptor 2. The Journal of pharmacology and experimental therapeutics 
2017;362:338-46. 
200. Mozaffari S, Nikfar S, Abdollahi M. Inflammatory bowel disease therapies discontinued between 2009 
and 2014. Expert opinion on investigational drugs 2015;24:949-56. 
201. Russo RC, Guabiraba R, Garcia CC, et al. Role of the chemokine receptor CXCR2 in bleomycin-
induced pulmonary inflammation and fibrosis. American journal of respiratory cell and molecular 
biology 2009;40:410-21. 
202. Coelho FM, Pinho V, Amaral FA, et al. The chemokine receptors CXCR1/CXCR2 modulate antigen-
induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature. Arthritis and 
rheumatism 2008;58:2329-37. 


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203. Barsante MM, Cunha TM, Allegretti M, et al. Blockade of the chemokine receptor CXCR2 
ameliorates adjuvant-induced arthritis in rats. British journal of pharmacology 2008;153:992-1002. 
204. Pawlick RL, Wink J, Pepper AR, et al. Reparixin, a CXCR1/2 inhibitor in islet allotransplantation. 
Islets 2016;8:115-24. 
205. Citro A, Cantarelli E, Maffi P, et al. CXCR1/2 inhibition enhances pancreatic islet survival after 
transplantation. The Journal of clinical investigation 2012;122:3647-51. 
206. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Annals of internal medicine 2009;150:604-12. 
207. Ferreira-Hermosillo A, Ibarra-Salce R, Rodriguez-Malacara J, Molina-Ayala MA. Comparison of 
indirect markers of insulin resistance in adult patients with Double Diabetes. BMC endocrine disorders 
2020;20:87. 
208. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin 
secretion and resistance. The American journal of physiology 1979;237:E214-23. 
 
 
 
 


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14. 
APPENDICES 
14.1. 
APPENDIX 1 - SPONSOR APPROVAL PAGE 
 
 
A phase II randomized, placebo-controlled, double-blinded, 2-parallel arm, clinical trial evaluating 
ladarixin 400 mg twice a day as adjunctive therapy to improve glycemic control in overweight insulin-
resistant patients with type 1 diabetes. 
 
Medical Expert: _________________________________________  
Date: _____/______/______ 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Operation Manager: _________________________________  Date: _____/______/______ 
 
  
 
 
 
 
 
 
 
 
Development Director: _____________________________________  
Date: _____/______/______ 
 
  
 
 
 
 
 
 
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14.2. 
APPENDIX 2 - INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator’s Statement 
 
I have read study protocol LDX0122 (A phase II randomized, placebo-controlled, double-blinded, 2-parallel 
arm, clinical trial evaluating ladarixin 400 mg twice a day as adjunctive therapy to improve glycemic control 
in overweight insulin-resistant patients with type 1 diabetes) and agree to conduct the study as outlined in 
the protocol, and in accordance with the Declaration of Helsinki, ICH-GCP and any local regulations, being 
responsible for personally supervise the study conduct and ensure study staff complies with protocol 
requirement. 
 
 
 
  
 
 
 
 
Name of Principal Investigator and/or Principal Physician: ______________________________________ 
                                                                                                                       (block letters) 
 
Signature:  _______________________________  
Date: _____/______/______ 
 
 
 
 
 
 
 
 
 
 
 


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14.3. 
APPENDIX 3 - PACKAGING AND LABELING DETAILS 
A Patient Kit will be prepared for each patient, containing the treatment for 14 days, i.e. a total of 56 capsules.  
All items will have local language labels. Sample label content is summarized below and will be adjusted to 
meet local regulatory requirements.   
NOTE:  
Patient No. 
where XXX is the unique site number and ZZZ is patient randomization number 
Kit No.  
where XXX-ZZZ-YY is the unique Kit identifier for that patient 
 
Content of the Label for each Patient Kit 
STUDY CODE: LDX0122 
Sponsor Dompé farmaceutici s.p.a.; Via Santa Lucia 6, Milan – Italy -Phone: +39 02 583831 
INVESTIGATOR: 
PATIENT No. XXX-ZZZ  
 
KIT No. XXX-ZZZ-YY   
INVESTIGATIONAL PRODUCT: ladarixin (200 mg) or placebo oral capsules 
CONTAINS: 7 blisters of 8 capsules 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 on administration provided by the Investigator.  
Contact the Investigator should you have any questions 
For clinical trial use only 
CAUTION: New Drug-Limited by Federal (or United States) law to investigational 
use* 
Keep out of reach of children 
*For US labels only 
 
Content of the Label for the Blister  
STUDY CODE: LDX0122 
Sponsor Dompé farmaceutici s.p.a. 
KIT No. XXX-ZZZ-YY 
                                                              
INVESTIGATIONAL PRODUCT: ladarixin (200 mg) or placebo - 8 oral capsules  
coded BATCH No.  
 
 
 
 
 
DO NOT STORE AT >30°C  
DO NOT FREEZE 
DIRECTIONS: See directions in the label of the Patient Kit 
CAUTION: New Drug-Limited by Federal (or United States) law to investigational 
use* 
Keep out of reach of children 
* For US labels only  
 
 


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14.4. 
METHODOLOGICAL DETAILS 
14.4.1. Handling of samples for assays 
One or more laboratories will be involved for assay of HbA1c, safety laboratory tests, C-peptide, 
, and characterization by flow cytometry of 
 
The laboratory performing the assay of HbA1c should be certified by CLIA (or similar certification) and will 
perform the analyses under strict quality control.  
All steps will be tracked to ensure correct data reporting.   
All samples submitted to these labs will be destroyed after the CSR has been issued or after the patient has 
withdrawn his/her consent. 
 
14.4.2. Calculation of eGFR 
Renal function will be evaluated by estimated Glomerular Filtration Rate (eGFR), calculated by the following 
formula206:  
  
 
14.4.3. Calculation of
 
 
  
 

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Protocol Number: 
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STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: LDX0122 
A phase II randomized, placebo-controlled, double-blinded, 2 
parallel arm, clinical trial evaluating ladarixin 400 mg twice a 
day as adjunctive therapy to improve glycemic control in 
overweight insulin-resistant patients with type 1 diabetes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STATISTICAL ANALYSIS PLAN 
APPROVAL PAGE 
 
Document Information  
Protocol Number: 
LDX0122 
Version: 
final 1.0 
Document Date: 
27 Oct 2022 
Prepared for: 
Dompé 
Prepared by: 
 
 
The Statistical Analysis Plan has been completed and reviewed and the contents are approved for 
use for the analysis. 
 
Lead Statistician details: 
Name: 
 
Job Role: 
Principal Biostatistician 
Company: 
 
Signature: 
 
Date of signature: 
 
 
 
Sponsor Approver details: 
Name: 
 
Job Role: 
 Data Management and Statistics 
Company: 
Dompé 
Signature: 
 
Date of signature: 
 
 
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Contents 
STATISTICAL ANALYSIS PLAN .................................................................................................... 2 
APPROVAL PAGE ............................................................................................................................. 2 
Abbreviations ...................................................................................................................................... 7 
Revision History .................................................................................................................................. 8 
1. 
Introduction ................................................................................................................................. 9 
2. 
Study Objectives .......................................................................................................................... 9 
3. 
Study Design ............................................................................................................................... 9 
3.1 
General design and plan ........................................................................................................ 9 
3.2 
Study day ............................................................................................................................ 10 
3.3 
Visit Schedule and Visit Windows ..................................................................................... 10 
3.4 
Sample size justification ..................................................................................................... 12 
3.5 
Randomization and blinding ............................................................................................... 12 
3.5.1 
Randomization .............................................................................................................12 
3.5.2 
Unblinding ...................................................................................................................13 
3.6 
Efficacy endpoints .............................................................................................................. 13 
3.6.1 
Primary endpoint .........................................................................................................13 
3.6.2 
Secondary efficacy endpoints ......................................................................................13 
3.6.3 
Exploratory efficacy endpoints ....................................................................................13 
3.7 
Safety endpoints .................................................................................................................. 14 
4. 
Statistical Analysis .................................................................................................................... 14 
4.1 
General ................................................................................................................................ 14 
4.2 
Analysis sets ....................................................................................................................... 15 
4.2.1 
Screened set .................................................................................................................15 
4.2.2 
Enrolled set (ENR) ......................................................................................................15 
4.2.3 
Randomized set (RND) ...............................................................................................15 
4.2.4 
Full analysis set (FAS) ................................................................................................15 
4.2.5 
Safety set (SAF) ..........................................................................................................15 
4.2.6 
Per Protocol set (PP) ....................................................................................................15 
4.3 
Usage of analysis sets ......................................................................................................... 15 
4.4 
Estimands ............................................................................................................................ 16 
4.4.1 
Primary estimand .........................................................................................................16 
4.4.2 
Secondary estimands ...................................................................................................16 
4.5 
Sub-group analyses ............................................................................................................. 18 
4.6 
Interim analyses .................................................................................................................. 18 
4.7 
Handling of missing and incomplete data ........................................................................... 18 
4.8 
Changes in the planned analysis ......................................................................................... 19 
4.9 
Data Review Meeting ......................................................................................................... 19 
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4.10 
Software .............................................................................................................................. 19 
5. 
Evaluation of Demographic and Baseline Characteristics ........................................................ 19 
5.1 
Subject enrolment and disposition ...................................................................................... 19 
5.2 
Protocol violations .............................................................................................................. 20 
5.3 
Permanent treatment discontinuation criteria ..................................................................... 20 
5.4 
Patient phone calls .............................................................................................................. 20 
5.5 
Study discontinuations ........................................................................................................ 20 
5.6 
Demographics and baseline characteristics ........................................................................ 21 
5.7 
Medical and surgical history ............................................................................................... 21 
5.8 
Prior and concomitant medications ..................................................................................... 22 
5.9 
Other baseline characteristics ............................................................................................. 22 
5.9.1 
Auto-Antibodies ..........................................................................................................22 
5.9.2 
T1D diagnosis ..............................................................................................................23 
5.9.3 
Fasting C-Peptide ........................................................................................................23 
5.9.4 
Glycemic control parameter HbA1c result ..................................................................23 
5.9.5 
Daily insulin requirement ............................................................................................23 
5.9.6 
Routine use of a self-owned CGM system ..................................................................23 
6. 
Evaluation of Treatment Compliance and Exposure ................................................................. 23 
6.1 
Compliance to IMP ............................................................................................................. 23 
6.2 
Exposure to study drug ....................................................................................................... 24 
7. 
Evaluation of Efficacy ............................................................................................................... 24 
7.1 
Analysis of primary endpoint ............................................................................................. 24 
7.1.1 
Analysis details ............................................................................................................24 
7.1.2 
Sensitivity analyses .....................................................................................................25 
7.1.3 
Supportive analyses .....................................................................................................26 
7.2 
Analysis of secondary efficacy endpoints........................................................................... 27 
7.2.1 
Proportion of responders at week 11/12 ......................................................................27 
7.2.2 
Mean difference from baseline in HbA1c ...................................................................27 
7.2.3 
Average (previous 3 days) daily insulin requirement ..................................................28 
7.2.4 
Glycemic Variability by CGM (previous 7 days): ......................................................29 
7.3 
Analysis of exploratory efficacy endpoints ........................................................................ 29 
7.3.1 
 .......................................29 
7.3.2 
 ..................................................29 
7.3.3 
 ..............................................................29 
7.3.4 
 ...29 
7.3.5 
 .............................................................30 
8. 
Evaluation of Safety .................................................................................................................. 30 
8.1 
Adverse events .................................................................................................................... 30 
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8.2 
Clinical laboratory evaluation ............................................................................................. 31 
8.3 
Vital signs, Estimated Glucose Disposal Rate and BMI .................................................... 32 
8.4 
ECGs ................................................................................................................................... 32 
8.5 
Pregnancy test over the study ............................................................................................. 33 
9. 
Derivations and date conventions .............................................................................................. 34 
9.1 
Variable derivation ............................................................................................................. 34 
9.2 
CGM value derivation ........................................................................................................ 36 
9.3 
Partial date conventions ...................................................................................................... 37 
10. Tables, Figures and Listings ...................................................................................................... 40 
10.1 
Output conventions ............................................................................................................. 40 
10.2 
Format requirements: .......................................................................................................... 40 
10.3 
Table Conventions .............................................................................................................. 40 
10.4 
Listing Conventions ............................................................................................................ 41 
11. Reference ................................................................................................................................... 41 
12. Appendices ................................................................................................................................ 42 
12.1 
R code for CGM ................................................................................................................. 42 
12.2 
List of TFLs ........................................................................................................................ 55 
12.2.1 Tables ..........................................................................................................................55 
12.2.2 Listings ........................................................................................................................60 
12.2.3 Figures .........................................................................................................................62 
 
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Index of Tables 
 
Table 1: Study Flow Chart ................................................................................................................11 
Table 2: Scheduled Visit Window and Mapping of Assessments for Analysis ................................12 
Table 3: Usage of analysis set ...........................................................................................................15 
Table 4: Variable derivation rules .....................................................................................................34 
Table 5: Variable in cgmanalysis ......................................................................................................37 
Table 6: Algorithm for Treatment Emergence of Adverse Events ....................................................37 
Table 7: Algorithm for Prior/Concomitant medications....................................................................39 
 
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Abbreviations 
ADR 
AE  
Adverse Drug Reaction 
Adverse Event  
ATC  
AUC 
BDRM 
BMI 
CGM 
Anatomical Therapeutic Chemical  
Area Under the Curve 
Blinded Data Review Meeting 
Body Mass Index 
Continuous Glucose Monitoring 
CI  
Confidence Interval  
CRF 
CS 
CSR 
Case Report Form 
Clinically Significant 
Clinical Study Report 
DMC 
Data Monitoring Committee 
ECG 
eGDR 
ENR 
Electrocardiogram 
Estimated Glucose Disposal Rate 
Enrolled set 
FAS 
HbA1c 
ICF 
IMP 
IR 
Full Analysis Set 
Glycated hemoglobin 
Informed Consent Form 
Investigational Medicinal Product 
Insulin Resistant 
ITT  
Intent to Treat  
MAGE 
Mean Amplitude Glycemic Excursion 
MAR 
Missing at Random 
MedDRA  
MI 
MI-RD 
MODD 
MMRM 
NCS 
PP 
Medical Dictionary for Regulatory Activities 
Multiple Imputation  
Multiple Imputation using Retrieved Dropouts 
Mean Of the Daily Differences 
Mixed Model for Repeated Measurements 
Not Clinically Significant 
Per Protocol 
PT 
QTcF 
RND 
Preferred Term 
corrected QT interval by Fredericia 
Randomized Set 
SAE(s)  
SAF 
Serious Adverse Event(s)  
Safety Analysis Set 
SAP 
SAS 
SD 
SE 
Statistical Analysis Plan 
Statistical Analysis Systems 
Standard Deviation 
Standard Error 
SOC  
T1D 
TAR 
TBR 
System Organ Class  
Type 1 Diabetes 
Time Above Range 
Time Below Range 
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TEAE 
TESAE 
TIR 
Treatment Emergent Adverse Event 
Treatment Emergent Serious Adverse Event 
Time In Range 
 
Revision History 
Document Version 
Changes Made 
Document Date 
Final 1.0 
Final version 1.0, first release.  
27 OCTOBER 2022 
 
 
 
 
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1.  Introduction 
This document outlines the statistical methods to be implemented in the analysis of the data of 
LDX0122 Clinical Trial. The purpose of this plan is to provide general guidelines from which the 
analysis will proceed, containing a more technical and detailed elaboration of the principal features 
of the analysis described in the protocol. Any changes to the protocol or Case Report Form (CRF) 
may necessitate updates to the Statistical Analysis Plan (SAP). In case of deviations from this updated 
SAP, explanations will be provided in the clinical study report. 
This SAP is based on study protocol Version No. 1 final – 
, Version No.2 final – 
 
 (applicable to the Italian investigational sites only) and eCRF Version No. 3 – 
 
.  
2.  Study Objectives 
The primary objective of this trial is to determine whether oral ladarixin versus placebo adjunctive 
therapy improves glycemic control in overweight, insulin resistant (IR) adult subjects with type 1 
diabetes (T1D). 
 
The secondary objectives are: 
• to ascertain the effect of ladarixin on glycemic variability as per Continuous Glucose 
Monitoring (CGM) derived parameters  
• to determine the safety of oral ladarixin versus placebo adjunctive therapy in overweight, IR 
adult subjects with T1D. 
 
Exploratory objectives (if site is able and deems appropriate to accommodate and conduct these 
objectives) are:  
• 
 
  
 
 
 
 
3.  Study Design 
3.1 
General design and plan  
This study will be a randomized, placebo-controlled, double-blinded, 2-parallel arm, phase II trial. It 
will enroll up to 86 patients across all genders, 21-65 years, inclusive, with established insulin -
requiring T1D and IR, randomly assigned to receive (1:1) either oral ladarixin 400 mg b.i.d. for 7 
cycles of 14 days on/14 days off (treatment group) or matched placebo (control group).  
Each patient will be involved in the study for up to 30 weeks. This period consists of 4 site visits for 
informed consent acquisition and screening, randomization, and 2 post-randomization study visits 
during a maximum of 28 weeks from the first Investigational Medical product (IMP) dose. 
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Recruitment will be competitive among the study sites, until the planned number of patients is 
randomized. 
3.2 
Study day 
The study day describes the day of the event or assessment date, relative to the reference start date 
which is the date of Randomization (Day 1 – Baseline). 
The study day is defined as: 
• The date of the event (visit date, onset date of an event, assessment date, etc.) – reference start 
date + 1 if event is on or after the reference start date. 
• The date of the event (visit date, onset date of an event, assessment date, etc.) – reference start 
date if event precedes the reference start date. 
 
There is no ‘Day 0’. 
3.3 
Visit Schedule and Visit Windows 
Please refer to Table 1: Study Flow Chart Study Flow Chart for full details on the schedule of suggested 
assessments. 
 
For all measurements, the actual date and time of assessment, including date of sampling, will be 
recorded in the eCRF. 
 
 
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits for all parameters. Listed below are the visit windows and the 
target days for each visit. The reference day is Study Day 1, as defined in Section 3.2. If a subject 
has two or more actual visits in a visit window, the visit closest to the target day will be used as the 
protocol visit for that visit window. The additional unscheduled visit(s) will not be used in the 
summaries or analyses by visit,  but they are used for determination of clinically important 
endpoints as described in this document. If two actual visits are equidistant from the target day 
within a visit window, the later visit is used. If more than one value falls on the same day then the 
worst value will always be used (higher or lower value, depending on the parameter). 
All assessments corresponding to both scheduled and unscheduled visits will be included in subject 
listings. 
 
In Table 2 there are the visit windows and the target study days for each visit defined in the protocol; 
lower and upper limits associated to each visit are enlarged to cover all possible days from 
randomization to allow for mapping all assessments to the visits. 
Unless otherwise specified, time points considered for analyses will be baseline, Week 4 (for Italian 
subjects only), Week 11/12 and Week 27/28.  
 
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Table 1: Study Flow Chart 
Activity 
 
 
PRESCREENING* 
(Identify and reach 
out to potential 
participants and 
offer ICF) 
Screening 
Visit 1 
(Within 
week -2) 
 
Treatment phase 
(week 1 to 26) 
 
 
End 
of 
study 
Visit 4 
(week 
27/28) 
Randomization 
Visit 2 (Day 1) 
Visit 
2b 
(week 
4) ** 
 
Visit 3 
(week 
11/12) 
PRESCREENING* 
(Identify and reach out to 
Potential participants and 
offer ICF) 
x 
x 
 
 
 
 
Informed Consent Form 
(ICF) signed 
 
x 
 
 
 
 
Medical history and pre-
existing conditions 
 
x 
 
 
 
 
Auto-antibodies evaluation1 
 
x 
 
 
 
 
Fasting C-peptide 
 
x 
 
 
 
 
Measurement of body 
weight, height, waist, and 
waist/hip circumference 
 
x 
x 
 
x 
x 
eGDR and BMI assessment 
 
x 
x 
 
x 
x 
Average (previous 3 days) 
Insulin requirement 
 
x 
x 
 
x 
x 
HbA1c 
 
x 
x 
 
x 
x 
CGM download for 
assessment of glycemic 
variability (previous 7 days)2 
 
 
x 
 
x 
x 
Vital signs 
 
x 
x 
 
x 
x 
Serum Pregnancy Test 
(blood/urine) 
 
x 
 
 
x3 
 
Safety laboratory tests 
(hematology, biochemistry) 
 
x 
 
x 
x 
x 
 
 
 
 
 
 
 
 
ECG (QTcF) 
 
x 
 
x 
x 
x** 
eGFR 
 
x 
 
 
x 
x** 
Randomization 
 
 
x 
 
 
 
IMP dispensation 
 
 
x 
 
x 
 
Patient Diary delivery/check 
 
 
x 
 
x 
x 
Treatment 
 
 
      x------------------         x 
 
Patient Phone call5 
 
 
       x------------------------------x 
 
AE/SAE recording 
 
 
      x-----------------------------------------x 
Prior and Concomitant 
Medication 
 
 
      x----------------------------------------x 
* Prescreening procedures can be performed during screening visit if applicable as per site practice 
1. To include new testing should past data not be available. 
2. Secondary 
. 
3. Urine dipstick. 
 
 
 
5. Telephone calls at least every 30-45 days. 
** For Italian subjects only 
 
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Table 2: Scheduled Visit Window and Mapping of Assessments for Analysis 
Scheduled 
Visit Number 
Scheduled 
Time point 
Label on 
output 
Target 
Study 
Day* 
Time Interval 
Lower Limit 
(Day*) 
Time Interval 
Upper Limit 
(Day*) 
Baseline / Visit 2 
Day 1 
Baseline 
1 
−14 
1 
Visit 2b** 
Week 4 
Week 4 
29 
15 
43 
Visit 3 
Week 11/12 
Week 11/12 
81 
64 
99 
Visit 4 
Week 27/28 
Week 27/28 
193 
176 
211 
*Relative to Study Day 1 
**For Italian subjects only 
 
 
3.4 
Sample size justification 
Sample size calculation was based on results obtained in the phase 2 trial with ladarixin in T1D onset. 
Considering the following assumptions: 
• randomization ratio 1:1 (ladarixin: placebo), 
• one-side type I error of 0.05 
• expected difference in favor of ladarixin in terms of responders: ~22.5% 
• power of 80% to detect the expected treatment effect 
a total of 76 evaluable patients are required; to account for a possible 10% of patients not evaluable 
for the primary variable (section 3.6.1) after enrollment, up to 86 patients will be enrolled. 
3.5 
Randomization and blinding 
3.5.1 Randomization 
A CRO independent statistician not involved in the conduct of the study will generate with a 
computer procedure the randomization list that will be provided to Dompé in a sealed envelope to 
prevent unblinding. 
The facility responsible of IMP packaging/labelling will also receive appropriate randomization 
codes for the purpose of IMP preparation. 
Randomization will be stratified by site to ensure balanced assignment across treatment groups.  
A master randomization list will be generated, randomizing an excess of patients to allow competitive 
recruitment within each center. 
The treatment assignment information will be kept confidential and will not be disclosed to any other 
person. The investigator and Dompé Pharmacovigilance will have access to the randomization code 
for a specific patient in case of a medical emergency or for safety reasons.  
The randomization codes will be accessible to the independent statistician(s) who will generate the 
reports for the Data Monitoring Committee (DMC) evaluation. 
Once the study has been completed and the database has been locked, the treatment assignment 
information will be accessible to the study biostatistician(s) who will perform the statistical analyses 
and will generate reports. 
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3.5.2 Unblinding 
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. 
Only in case of a medical emergency for which the knowledge of patient is required to provide the 
patient with appropriate care, access to individual patient treatment code will be allowed. 
Unblinding events will be recorded and reported in the Clinical Study Report (CSR). 
Study blind will be broken after database lock. 
  
3.6 
Efficacy endpoints 
3.6.1 Primary endpoint  
• The proportion of responders, defined as “proportion of patients with an HbA1c reduction 
from baseline of ≥0.50% (absolute difference) without episodes of severe hypoglycemia 
[timeframe: week 27/28 (visit 4)]. 
3.6.2 Secondary efficacy endpoints 
The following secondary endpoints will be considered: 
1. The proportion of responders [Timeframe: week 11/12 (visit 3)] 
2. The mean difference from baseline in HbA1c [Timeframe: week 11/12 (visit 3) and 27/28 
(visit 4)] 
3. Average (previous 3 days) daily insulin requirements (IU/kg/day) [Timeframe: week 11/12 
(visit 3) and 27/28 (visit 4)] 
4. Glycemic Variability by CGM (previous 7 days before the visit): time in range (TIR), time 
above range (TAR) time below range (TBR), standard deviation and coefficient of variation 
[Timeframe: week 11/12 (visit 3) and 27/28 (visit 4)] 
3.6.3 Exploratory efficacy endpoints 
The following exploratory endpoints will be considered: 
• 
 
 
 
• 
 [Timeframe: 
 
• 
 
 
 
 
 
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• 
 
 
 
 
 
 
3.7 
Safety endpoints 
• Vital signs (blood pressure and heart rate) [Timeframe: baseline, week 11/12 (visit 3), 27/28 
(visit 4)] 
• Laboratory tests [haematology (total WBC, neutrophils / lymphocytes / monocytes / 
basophils / eosinophils (% and absolute number), total RBC, MCV, hematocrit, platelet 
count) and clinical chemistry (sodium, potassium, serum creatinine, serum albumin, total 
bilirubin, ALT, AST)] [Timeframe: baseline, week 11/12 (visit 3) and 27/28 (visit 4)] 
• Incidence of Treatment Emergent Adverse Events (TEAEs), Adverse Drug Reaction (ADR) 
and Treatment Emergent Serious Adverse Events (TESAEs) [Timeframe: from the beginning 
of IMP administration up to the end of study participation]. 
4.  Statistical Analysis 
4.1 
General 
Appropriate summary statistics will be produced separately by treatment arms according to the 
nature of the variable. 
• For continuous data, number of observations, mean, standard deviation, median, first (Q1) 
and third (Q3) quartiles, and range (minimum and maximum) will be presented.  
• For qualitative data, frequency distributions and percentages per category will be presented. 
If appropriate, confidence intervals around the mean or the proportions will be presented. 
 
For primary analysis, the threshold for claiming statistical significance will be 0.05 one-sided. For 
secondary, exploratory and other analysis, unless otherwise specified, hypothesis testing will be 
carried out at the alpha = 0.05 level (two-sided) when comparing treatments. 
In case data transformation is needed to meet normality assumptions, data will be presented both in 
the original and transformed scales and a specific focus will be added in CSR for interpreting the fact 
that the comparison between treatments is based on a transformed scale. Similarly, in case of use of 
non-parametric tests, it will be clarified which parameters are compared allowing for a fair and 
correct interpretation. 
 
Additional post-hoc analysis may be produced to further allow comparison between ladarixin and 
placebo, according to the results obtained. 
Any deviations from the original statistical plan (including unplanned analyses) will be clearly 
documented in the CSR. 
 
All patient data collected and derived in the study will be listed by patient. 
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4.2 
Analysis sets 
4.2.1 Screened set 
The Screened set will consist of all patients with signed written informed consent and have a subject 
identification number. 
4.2.2 Enrolled set (ENR) 
The ENR set will consist of all patients with signed written informed consent and fulfillment of 
eligibility criteria (i.e., not reported as screening failure). 
4.2.3 Randomized set (RND) 
The RND set will consist of all patients in the ENR set who are randomized to the study, regardless 
of whether they receive the IMP or not. 
4.2.4 Full analysis set (FAS) 
The FAS population will consist of all randomized patients who received at least one dose of the 
investigational product. FAS population will be analyzed according to the intention-to-treat (ITT) 
principle, i.e., by treatment allocation. The FAS population will be used to analyze results on efficacy 
data. 
4.2.5 Safety set (SAF) 
The SAF population will consist of all randomized patients who received at least one dose of the 
investigational product. Safety population will be analyzed according to the actual treatment 
received. The SAF population will be used to present results on safety data. 
4.2.6 Per Protocol set (PP) 
The PP set will consist of all patients in the FAS population who do not have Major Protocol 
Deviations. The PP population will be used for sensitivity supplemental analyses. 
4.3 
Usage of analysis sets 
The usage of the analysis sets (see previous section) for the creation of tables and figures are 
illustrated in Table 3. Unless otherwise specified, all listings will be done for RND set. All listings 
will have planned and actual treatment names included, as well as the flag(s) of the analysis set(s) 
used to analyses the information of the listing (according to the Table 3).  
Table 3: Usage of analysis set 
Analysis 
SCR 
ENR 
RND 
FAS 
SAF 
PP 
Subject enrolment and disposition 
X 
 
 
 
 
 
Protocol violations 
 
 
X 
 
 
 
Study discontinuations 
 
 
X 
 
 
 
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Analysis 
SCR 
ENR 
RND 
FAS 
SAF 
PP 
Demographics and baseline characteristics 
 
 
 
X 
 
 
Medical or surgical history and/or Concomitant 
Diseases 
 
 
 
X 
 
 
Prior and concomitant medications 
 
 
 
X 
 
 
Other baseline characteristics 
 
 
 
X 
 
 
Compliance to IMP 
 
 
 
 
X 
 
Exposure to IMP 
 
 
 
 
X 
 
Analysis of primary efficacy endpoints 
 
 
 
X 
 
 
Sensitivity analysis 
 
 
 
X 
 
X 
Analysis of secondary efficacy endpoints 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Adverse events 
 
 
 
 
X 
 
Clinical laboratory evaluation 
 
 
 
 
X 
 
Vital signs, 
 and BMI 
 
 
 
X 
X 
 
ECGs 
 
 
 
 
X 
 
Pregnancy test over the study 
 
 
 
 
X 
 
Permanent treatment discontinuation criteria 
 
 
 
 
X 
 
Patient phone calls 
 
 
 
 
X 
 
4.4 
Estimands 
4.4.1 Primary estimand 
The primary estimand is defined by the following:  
• Population: Subjects in the Full Analysis Set population. 
• Variable: HbA1c reduction from baseline of ≥0.50% (absolute difference) without episodes 
of severe hypoglycemia [timeframe: week 27/28 (visit 4)]. 
• Intercurrent event: In case of death before week 27/28 (Visit 4) a “composite strategy” will 
be used: the subject will be considered not reduced. Instead, the occurrence of other 
intercurrent events is irrelevant (the treatment policy will be used): all observed values will 
be used regardless of occurrence of these intercurrent events. 
• Population-level summary: Proportion of Patients with an HbA1c reduction from baseline of 
≥0.50% (absolute difference) without episodes of severe hypoglycemia [timeframe: week 
27/28 (visit 4)]. 
 
4.4.2 Secondary estimands 
Secondary endpoint #1 (section 3.6.2) will be analyzed according to the following estimand: 
• Population: Subjects in the Full Analysis Set population. 
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• Variable: HbA1c reduction from baseline of ≥0.50% (absolute difference) without episodes 
of severe hypoglycemia [timeframe: week 11/12 (visit 3)]. 
• Intercurrent event: In case of death before week 11/12 (Visit 3), a “composite strategy” will 
be used: the subject will be considered not reduced Instead, the occurrence of other 
intercurrent events is irrelevant (the treatment policy will be used): all observed values will 
be used regardless of occurrence of these intercurrent. 
• Population-level summary: Treatment difference in the proportion of Patients with an HbA1c 
reduction from baseline of ≥0.50% (absolute difference) without episodes of severe 
hypoglycemia [timeframe: week 11/12 (visit 3)]. 
 
Secondary endpoint #2 (section 3.6.2) will be analyzed according to the following estimand: 
• Population: Subjects in the Full Analysis Set population. 
• Variable: Difference from baseline in HbA1c [Timeframe: week 11/12 (visit 3) and week 
27/28 (visit 4)]. 
• Intercurrent event: In case of death before week 11/12 (Visit 3), a “composite strategy” will 
be used: the 95th percentile change from baseline distribution within treatment and visit will 
be imputed to this secondary endpoint (95th worst value percentile). Instead, the occurrence 
of other intercurrent events is irrelevant (the treatment policy will be used): all observed 
values will be used regardless of occurrence of these intercurrent events. The same is applied 
for the other timeframe: week 27/28 (visit 4). 
• Population-level summary: Treatment difference in the mean difference from baseline in 
HbA1c [Timeframe: week 11/12 (visit 3) and week 27/28 (visit 4)]. 
 
Secondary endpoint #3 (section 3.6.2) will be analyzed according to the following estimand: 
• Population: Subjects in the Full Analysis Set population. 
• Variable: Average (previous 3 days) daily insulin requirements (IU/kg/day) [Timeframe: 
week 11/12 (visit 3) and 27/28 (visit 4)]. 
• Intercurrent event: the occurrence of intercurrent events is irrelevant, the treatment policy will 
be used.  
• Population-level summary: Treatment difference in the average (previous 3 days) daily  
      insulin requirements (IU/kg/day) [Timeframe: week 11/12 (visit 3) and 27/28 (visit 4)]. 
 
Secondary endpoint #4 (section 3.6.2) will be analyzed according to the following estimand: 
• Population: Subjects in the Full Analysis Set population. 
• Variable: Glycemic Variability by CGM (previous 7 days before the visit): time in range 
(TIR), time above range (TAR), time below range (TBR) [Timeframe: week 11/12 (visit 3) 
and 27/28 (visit 4)]. 
• Intercurrent event: In case of death before week 11/12 (Visit 3), a “composite strategy” will 
be used: the 95th percentile of variable distribution within treatment and visit  will be imputed 
to this secondary endpoint (95th worst value percentile). Instead, the occurrence of other 
intercurrent events is irrelevant (the treatment policy will be used): all observed values will 
be used regardless of occurrence of these intercurrent events. The same is applied for the 
other timeframe: week 27/28 (visit 4). 
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• Population-level summary: Treatment difference in the variability by CGM (previous 7 days 
      before the visit): time in range (TIR), time above range (TAR) time below range (TBR)  
     [Timeframe: week 11/12 (visit 3) and 27/28 (visit 4)] 
4.5 
Sub-group analyses 
Subgroup analyses will be performed on the following subgroups of baseline characteristics: 
• Age class (≤Median, >Median of the FAS), 
• Sex, 
• Race, 
• Ethnicity, 
Within each subgroup level, descriptive in nature analyses will be performed on: 
• The proportion of responders 
• The mean difference from baseline in HbA1c  
• Average (previous 3 days) daily insulin requirements (IU/kg/day)  
• Glycemic Variability by CGM (previous 7 days before the visit): time in range (TIR), time 
above range (TAR) time below range (TBR), standard deviation and coefficient of variation  
at each available timepoints by means of descriptive statistics.  
 
In case of continuous measures, analyses will be provided for baseline visit, each post-baseline visit, 
and their change from baseline.  
In case of categorical variables, the means of a Chi-square test or, if more appropriate, a Fisher’s 
Exact  be provided in addition to summary description. 
 
Additional sub-group analyses will be performed ad hoc according to the results obtained in the 
whole population. Statistical details on subgroup analysis will be reported in the CSR. 
4.6 
Interim analyses 
No formal Interim analysis is planned for the study. 
4.7 
Handling of missing and incomplete data 
The number of patients with missing data will be presented under the “Missing” category, if present. 
Missing values will not be included in the denominator count when computing percentages. 
Similarly, only the non-missing values will be evaluated for computing summary statistics for 
continuous endpoint. Any exception will be clarified as a note. 
Since patients who discontinue the treatment with the IMP will not be withdrawn from the study but 
will be asked to complete safety and efficacy assessments as per the protocol, for the primary 
analyses missing data will be addressed by modeling patients with missing data after retrieved 
dropouts (see section 7.1.1). This approach is based on the assumption that missing data would have 
been like retrieved dropouts if they were assessed. If the MI-RD regression model doesn’t converge 
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due to not enough retrieved dropouts, for assuring the convergence of the MI-RD regression model, 
the same multiple imputation model will be fitted using data from subjects of control group, washing-
out the effect of treatment. This approach does not assume benefits for ladarixin in case of 
discontinuation and limits a post discontinuation clinical effect to that of placebo. When death 
prevents the collection of the endpoint and, in the variable derivation is included the “composite 
strategy” method to handle death, the MI will be done on data still missing after having considered 
the death. 
4.8 
Changes in the planned analysis 
Analysis on exploratory endpoint 
 
 will be done for all subjects although this endpoint is only 
mentioned in protocol 
 – 
 (applicable to the Italian investigational 
sites only). 
4.9 
Data Review Meeting 
A Blinded Data Review Meeting (BDRM) will be held before the DB lock and the unblinding of the 
data. Any other details will be provided in the BDRM Report.  
4.10 Software 
All statistical analyses and data processing will be performed using Statistical Analysis Systems 
(SAS®) Software (release 9.4) on a Windows 10 operating system. CGM data at patient level will 
be processed using cgmanalysis package 2 in R version 3.6.1 (or later) before performing statistical 
analysis. 
 
5.  Evaluation of Demographic and Baseline Characteristics 
5.1 
Subject enrolment and disposition 
All presentations for subject disposition will be by treatment group, and overall. The table will be 
presented by country and site as well. 
For describing the subject disposition, the following populations will be summarized:  
• Subjects screened overall (N).  
• Subjects with ongoing screening (N), not applicable for CSR. 
• Subjects enrolled overall (N, 100%)  
• Subjects enrolled but not randomized and reasons for non-allocation overall (N, %); 
percentage denominator will be the number of enrolled subjects. 
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• Subjects randomized by treatment group and overall (N, %); the percentage denominator will 
be the number of randomized subjects within each arm.  
• Subjects randomized but not treated by treatment group, and overall (N, %); the percentage 
denominator will be the number of randomized subjects within each arm and overall. 
• Subjects in each analysis set (FAS, SAF, PP) and reasons for exclusion by treatment group 
and overall (N, %); the percentage denominator will be the number of randomized subjects 
within each arm and overall. 
• Number of subjects who completed each planned visit.  
 
Listings will be provided based on ENR set. 
5.2 
Protocol violations 
All the protocol deviations will be discussed case by case before unblinding of the treatment code 
with the clinical team during the BDRM and described in the BDRM Report. Any deviation from 
these protocol procedures will be reported in the study-specific Protocol Deviation form. 
 
Number of occurrences and of subjects with at least one major and minor protocol violations will be 
summarized for each treatment and overall. Major and minor protocol deviations will be tabulated 
separately. 
5.3 
Permanent treatment discontinuation criteria 
A summary table showing at each available timepoint (Section 3.3) the number and percentages of 
subjects who discontinued the study treatment along with the discontinuation criteria will be 
produced by treatment group. The number of patients still under treatment of discontinuing at the 
specific visit will be used as denominator for percentages. 
 
5.4 
Patient phone calls 
A summary table showing at each available timepoint (Section 3.3) the number and percentages of 
subjects who were contacted by phone call and who needed/not needed an adjustment in the insulin 
regimen will be produced by treatment group. The number of all patients (including subjects that 
have discontinued IMP but still in the study) at the specific visit will be used as denominator for 
percentages. 
5.5 
Study discontinuations 
The following information will be summarized for the randomized patients by treatment and overall: 
• Trial completers; 
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• Trial ongoing (not applicable for the CSR); 
• Subjects who discontinued the IMP” 
o Subjects who discontinued the IMP but complete the study 
o Subjects who discontinued the IMP and discontinued the trial prematurely 
• Subjects who completed the IMP 
• Subjects who are ongoing in the IMP (not applicable for the CSR); 
• Subjects who discontinued the trial prematurely (and reason); 
• Broken randomization code (and reason). 
If more than 30% of randomized subjects discontinue the study prematurely, the distribution of the 
time from randomization to discontinuation (time to discontinuation, Section 9.1) will be 
summarized using time-to-event method (Kaplan-Meier estimates and plots will be provided with 
95% confidence interval bounds calculated per Greenwood3 method, the respective number of patients 
at risk, and the log-rank test p-value). Subjects who have not prematurely discontinued the trial will 
be censored at study termination or cut-off date. 
5.6 
Demographics and baseline characteristics 
The baseline demographic characteristics will be summarized by treatment and overall, by means of 
descriptive statistics. 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: 
• Demography 
o Geographic region of the site 
o Age (years) 
o Sex (Male, Female) 
o If female, potential childbearing (Yes, No) 
o Race (White/Caucasian, Black or African American, Asian, Other) 
o Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• Pregnancy test result (Positive or Negative), if appropriate 
• BMI (BMI≤25kg/m2 vs 25kg/m2<BMI≤30kg/m2 vs BMI>30kg/m2) 
5.7 
Medical and surgical history 
A disease is defined: 
•  medical/surgical history if it is ended before screening visit. 
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• concomitant disease if it is ongoing at screening visit. 
Medical history and concomitant diseases will be coded using Medical Dictionary for regulatory 
activities (MedDRA) dictionary and frequency distributions and percentages will be summarized by 
treatment, by System Organ Class (SOC), and Preferred Term (PT). 
Medical history and concomitant diseases will be analyzed separately. Frequency distributions and 
percentages by treatment will be given for both SOC and PT by subject. Subjects experiencing more 
than one past/concomitant disease event will be counted only once within each SOC and PT. 
 
5.8 
Prior and concomitant medications 
Medications will be coded using World Health Organization Drug Dictionary (WHO DD). 
Based on the start/end medication date(s) reported in the eCRF (see Table 7 for derivation rules), a 
medication will be defined as follows: 
 
• Prior medications are those which stop prior to the date of informed consent.  
• Concomitant medications are those which: 
o start prior to, on or after the date of informed consent and start no later than date of 
study completion or discontinuation or cut-off date, and 
o end on or after the date of informed consent or are ongoing at the study completion or 
discontinuation or cut-off date. 
In case of missing or incomplete dates/times not directly allowing allocation to any of the two 
categories of medications, a worst-case allocation will be done according to the available parts of the 
start and the end dates. The medication will be allocated to the first category allowed by the available 
data, according to the following order: 
• concomitant medication 
• prior medication. 
Prior and concomitant medications will be summarized separately. Frequency distributions and 
percentages by treatment will be given by Anatomical Main Group (1st level of the Anatomical 
Therapeutic Chemical (ATC) classification), Chemical Subgroup (4th level of the ATC classification) 
and Preferred Name.  
Subjects experiencing more than one medication classified in the same category (prior medications 
or concomitant medications) within the same anatomical main group, chemical subgroup and 
preferred name will be counted only once. 
5.9 
Other baseline characteristics 
5.9.1 Auto-Antibodies 
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Auto-antibodies (anti-GAD; Insulin autoantibodies (IAA); anti-IA2; Zinc Transporter 8 (ZnT8)) 
results to confirm T1D diagnosis will be descriptively summarized. The distribution of patients by 
the number of positive antibodies (0, 1, 2, 3, 4) will be reported. 
5.9.2 T1D diagnosis 
The following parameters will be descriptively summarized by treatment: 
• Diagnosis of T1D confirmed (Yes, No) 
• Time from T1D diagnosis to inform consent (days), Section 9.1. 
5.9.3 Fasting C-Peptide 
Summary statistics by treatment of fasting C-Peptide value (nmol/L) at baseline will be provided. 
5.9.4 Glycemic control parameter HbA1c result 
Summary statistics by treatment of HbA1c (%) at baseline will be provided. 
 
5.9.5 Daily insulin requirement 
Summary statistics by treatment of Daily insulin requirement (U/kg/day – expressed as the average of 
the last 3 days)  at baseline will be provided. 
 
5.9.6 Routine use of a self-owned CGM system 
The following parameters will be descriptively summarized by treatment: 
• Device positioned (Yes, No) 
• CGM data recorded for at least 7 days (Yes, No) 
 
6.  Evaluation of Treatment Compliance and Exposure 
6.1 
Compliance to IMP 
Descriptive analysis of the following parameters will be presented by treatment group for each cycle 
and during the entire treatment period: 
• from IMP dispensation form  
o number of capsules dispensed (given by the number of dispensed kits considering that 
each kit contains 56 capsules) 
• from IMP accountability form 
o number of returned blisters 
o number of capsules taken 
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o number of returned unused capsules 
o compliance to the study treatment (Yes, No) 
On a per patient basis, the evaluation of the compliance during the overall treatment period will be 
done using the following formula: 
 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%)
= 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 
×  100 
 
where “total number of capsules taken during the treatment period” is the sum of number of capsules 
taken at each cycle (CRF IMP ACCOUNTABILITY form), while the “total number of capsules 
dispensed during the treatment period” is given by the number of dispensed kits (CRF IMP 
DISPENSATION form) considering that each kit contains 56 capsules. For DMC analysis, for 
subjects ongoing in IMP, the last dispensed kit will not be counted because the number of capsules 
returned will be known only in the next visit.  
Compliance will be summarized by treatment by means of summary statistics.  In addition, 
compliance to IMP will also be presented for the following categories: <80%, ≥80%. 
6.2 
Exposure to study drug 
The extent of exposure to IMP in weeks will be summarized overall with descriptive statistics by 
treatment group. The extent of exposure (weeks) will be calculated using the formula: 
Extent of exposure (weeks) = (Date of last IMP intake – Date of first IMP intake +1)/7. 
7.  Evaluation of Efficacy 
7.1 
Analysis of primary endpoint 
The following null hypothesis is defined: the proportion of patients with an HbA1c reduction from 
baseline of ≥ 0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 
(visit 4) in ladarixin group is lower or equal than control: 
H0: TLADARIXIN ≤ TCONTROL 
H1: TLADARIXIN > TCONTROL 
where TLADARIXIN and TCONTROL are the proportions of patients with an HbA1c reduction from 
baseline of ≥ 0.50% without episodes of severe hypoglycemia for ladarixin and control groups, 
respectively. The null hypothesis H0 will be rejected, and superiority of ladarixin declared if primary 
analysis p-value will be lower than 0.05 one sided. 
 
7.1.1 Analysis details 
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Primary endpoint will be analyzed by means of a logistic regression model, adjusting by predefined 
factors (treatment, HbA1c baseline value, gender, age class, BMI and country as fixed effect). A one-
sided test will be used to test for differences between treatment groups. 
Summary statistics of the primary variable will be calculated separately by treatment arm. 
 
Primary endpoint at week 27/28 will be analyzed by means of Multiple Imputation using retrieve 
dropouts (MI-RD). Retrieved dropout patients are defined as patients who discontinue study 
treatment and decide to remain in the study by following the schedule of assessments and continuing 
to adhere to protocol requirements. Consequently, MI will be performed based on the subjects’ 
allocated treatment arm and observed values as covariates in a MI regression model using data from 
retrieved dropout patients that have the primary endpoint assessment done. Only data up to 27/28 
week will be used to impute primary endpoint missing data. 
For the imputation of missing data, a logistic regression model will be created by including treatment, 
gender, HbA1c baseline value, age class, BMI and Country (for convenience we will refer to this 
method as “MI regression model”). One thousand data sets will be generated. The random seed 
number will be 465789. MI will be implemented in the following steps:  
1. Missing primary endpoint data will be imputed using the specified MI regression model. 
According to MI-RD approach, only non-missing values from retrieve dropouts will be used 
to inform the MI regression model. A total of 1000 datasets will be created. These datasets 
will be utilized in Step #2. 
2. Each of the 1000 datasets with observed and imputed data will be analyzed using the logistic 
regression model. Rubin’s rule will be used for combining results to draw inference.  
If there are not enough retrieved dropouts for convergence of the MI regression model, a reference-
based MI approach will be adopted to consider a Missing Not at Random (MNAR) mechanism for 
missing data: imputation of values in the ladarixin arm (above step #1) will be done using the non-
missing values from the control group (this approach will be referred as “Copy Reference”). This 
approach does not assume benefits for ladarixin in case of discontinuation and limits a post-
discontinuation clinical effect to that of placebo. If the MI-RD model does not converge, then the 
Copy reference will be used as primary analysis and reported in the CSR. If the MI-RD strategy will 
be performed, then the Copy-Reference method will be computed as sensitivity analysis (section 
7.1.2.3). 
Whether for MI-RD or Copy-Reference approach, the adjusted estimated treatment odds ratio 
between ladarixin and placebo at week 27/28 will be displayed together with the corresponding two-
sided 95% confidence intervals and p-value. This p-value will be compared to the threshold 0.05 to 
demonstrate the superiority of ladarixin. In addition to odds ratio, the absolute risk difference and its 
95% confidence interval will be provided. 
7.1.2 Sensitivity analyses 
Sensitivity analyses are defined to assess the robustness of results on primary endpoint versus 
assumptions used in the statistical model for the main estimator. 
 
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7.1.2.1 Missing at Random assumption 
The comparison between treatment and control will be performed by means of MI under Missing at 
Random (MAR) assumption instead of MNAR. MI will be implemented in the following steps. The 
random seed number will be 465789.  
• Missing primary endpoint data will be imputed using the MI regression model (section 7.1). 
According to MAR approach, all patients with non-missing values will be used to inform the 
MI regression model. A total of 1000 datasets will be created. These datasets will be utilized 
in Step #2.  
• Each of the 1000 datasets with observed and imputed data will be analyzed using the logistic 
regression model. Rubin’s rule will be used for combining results to draw inference.  
The adjusted estimated treatment odds ratio between ladarixin and placebo at week 27/28 will be 
displayed together with the corresponding two-sided 95% confidence intervals and p-value. In 
addition to odds ratio, the absolute risk difference and its 95% confidence interval will be provided. 
7.1.2.2 Tipping point  
If superiority of ladarixin is shown, tipping point analysis will assess how departures from MI under 
MNAR assumptions must be to overturn conclusions from the primary superiority analysis. Tipping 
point will be based on iterative application of MI. In the first iteration, MI-RD method or Copy 
Reference is assumed as described in section 7.1. In successive iterations, the imputed values for the 
ladarixin arm are shifted by a constant to represent a worse effect in each iteration. This can be 
achieved by using the N completed datasets obtained under MI-RD (or Copy Reference) and shift 
the imputed values. The tipping point is the shift at which the p-value becomes non-significant. 
Outline of tipping point: 
• Use MI-RD (or Copy Reference) to impute missing values. 
• Assuming that the tipping point is between 0 and 20, the following actions will be performed 
for Δ = 0, 0.5, 1, 1.5, etc., 20: 
o Add Δ to the imputed values at the ladarixin arm 
o Analyze the completed data sets using the same method outlined in section 7.1 
• the plot of all p-values for Δ will be created 
• based on the plot, the approximate value of the tipping point Tpapprox. is identified considering 
a threshold for the p-values of 0.05. 
• after identification of Tpapprox., finest research of the tipping point will be performed in the 
range Tpapprox. ± 1 by incrementing Δ of 0.01 and following the usual steps: 
o Add Δ to the imputed values at the ladarixin arm 
o Analyze the completed data sets using the same method outlined in section 7.1. 
• The tipping point is the smallest Δ at which p-value ≥ 0.05. 
7.1.2.3 Copy reference 
In case the Copy-Reference approach will not be used for the primary analysis (instead of MI-RD), 
it will we performed for sensitivity purposes. See details in 7.1.1.  
 
7.1.3 Supportive analyses 
Per Protocol Set; this analysis will assess the robustness of  results to protocol deviations. 
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7.1.3.1 Complete cases 
The analysis of primary endpoint will be performed by fitting the logistic regression model described 
in section 7.1.1 on complete cases only i.e., without considering patients with missing primary 
endpoint, without implementing the MI and without use the “composite strategy”. 
7.2 
Analysis of secondary efficacy endpoints 
Analyses on secondary endpoints (section 3.6.2) will be performed at each available timepoint by 
means of descriptive statistics (section 4.1). In case of continuous measures, analyses will be 
provided for: 
• baseline visit,  
• each post-baseline visit, and  
• the change from baseline measurements to each visit.  
The following results will be displayed graphically: 
• The proportion at each timepoint by treatment of patients with HbA1c reduction from 
baseline of ≥0.50% (absolute difference) without episodes of severe hypoglycemia; 
• Boxplots at each timepoint by treatment of the HbA1c and its change from baseline; 
• Waterfall plot by treatment of the proportion of patients with an HbA1c reduction from 
baseline of ≥ 0.50% (absolute difference) without episodes of severe hypoglycemia at week 
27/28 (visit 4) – complete cases; 
• Boxplots at each timepoint by treatment of the Time in range (TIR), time above range (TAR) 
and time below range (TBR) and its change from baseline; 
• Boxplots at each timepoint by treatment of the daily insulin requirement (IU/kg/day);  
In each graph, where possible, significant p-values from the below analyses (sections 7.2.1 – 7.2.4) 
will be reported in the plot area, in correspondence of the associated timepoint. 
7.2.1 Proportion of responders at week 11/12 
The proportion of responders at week 11/12 (visit 3) will be analyzed with the same MI approach 
and the same logistic regression model described in section 7.1 for the primary efficacy endpoint. 
 
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of 
responders during treatment will be calculated for Week 11/12. 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. 
Severe hypoglycemic events will be listed. 
7.2.2 Mean difference from baseline in HbA1c 
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Mean difference in HbA1c from baseline [Timeframe: week 11/12 (visit 3) and 27/28 (visit 4)] will 
be analyzed by means of an ANOVA adjusting by pre-defined factors (treatment, HbA1c baseline 
value, gender, age class, BMI and Country as fixed effect) and a one-sided test will be used to test 
for differences between treatment groups. If assumption of normality is not confirmed (by a visual 
inspection of distribution) a log-transformation will be used. Before the log-transformation, the 
minimum change+0.001 will be computed and added to the original scale values. In this case negative 
and zero values will be avoided. 
For the imputation of missing data, a MI regression model will be created by including treatment, 
HbA1c baseline value, gender ,age class, BMI and Country as covariates. One thousand data sets 
will be generated. MI will be implemented in the following steps. The random seed number will be 
476534:  
1. Missing HbA1c data will be imputed using the specified MI regression model. According to 
MI-RD approach, only non-missing values from retrieve dropouts will be used to inform the 
MI regression model. A total of 1000 datasets will be created. These datasets will be utilized 
in Step #2. 
2. Each of the 1000 datasets with observed and imputed data will be analyzed using the ANOVA 
model. Rubin’s rule will be used for combining results to draw inference.  
 
If there are not enough retrieved dropouts for convergence of MI regression model, the Copy 
Reference approach will be used. The final decision on the use of the MI-RD vs Copy-Reference will 
be done at the time of the analysis and reported in the CSR. 
Whether for MI-RD or Copy-Reference approach, the adjusted estimated treatment differences 
between ladarixin and placebo will be displayed together with the corresponding two-sided 95% 
confidence intervals and p-value.  
 
7.2.3 Average (previous 3 days) daily insulin requirement 
Average (previous 3 days) daily insulin requirement analysis at week 11/12 (visit 3) and 27/28 (visit 
4) will be carried out using a mixed model for repeated measurements (MMRM) with treatment 
group, visit, treatment by visit interaction, age class, gender, BMI and County 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 case where the model 
does not converge, different covariance structures will be used, following the below order: 
1. a heterogeneous Toeplitz covariance structure, or 
2. a Toeplitz covariance structure, or 
3. A compound symmetry structure (CS). 
The adjusted estimated treatment differences between ladarixin and placebo at each timepoint will 
be displayed together with the corresponding 95% confidence intervals and p-values. The tests of the 
fixed effects (treatment, age class, gender, BMI and Country) will be presented, together with the 
estimated least squares means with the corresponding 95% confidence interval. 
Assumption of normal distribution of this endpoint will be assessed by visual inspection. If required, 
a log transformation will be applied and specified in the notes. 
 
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7.2.4 Glycemic Variability by CGM (previous 7 days): 
Time in range (TIR), time above range (TAR) and time below range (TBR) will be analyzed using 
the MI-RD modeling or, if not feasible, the model based on placebo completers (Copy Reference), 
as detailed in Section 7.2.2. The adjusted estimated treatment differences between ladarixin and 
placebo at each timepoint will be displayed together with the corresponding 95% confidence intervals 
and p-values. The tests of the fixed effects (treatment, baseline value of the variable, age class, 
gender, CGM device,BMI and County) will be presented, together with the estimated least squares 
means with the corresponding 95% confidence interval. 
 
Assumption of normal distribution of Glycemic Variability by CGM will be assessed by visual 
inspection. If required, a log transformation will be applied and specified in the notes. 
7.3 
Analysis of exploratory efficacy endpoints 
7.3.1 
 
 
 
 
 
 
 
7.3.2 
 
 will be 
performed by means of two-sample t-test or, if assumptions of normality are not confirmed (by visual 
inspection), two-sample Mann–Whitney U test. 
 
7.3.3 
 
 
 
 
 
 
 
 
 
 
 
 
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8.  Evaluation of Safety 
8.1 
Adverse events 
Adverse Events (AEs) started before administration of study treatment will be considered as pre-
treatment. Any AE which starts at or after the first administration of study treatment will be 
considered a Treatment Emergent Adverse Event (TEAE). Pre-treatment AEs and TEAEs will be 
presented separately. Pre-treatment AEs will be presented in the listings only. In case of missing or 
incomplete dates not allowing a direct allocation to any of the two categories of AEs, a worst-case 
allocation will be done according to the available parts of the onset and the end dates. The AE will 
be allocated to the first category allowed by the available data, according to the following order: 
• TEAE (defined in Section 9.3); 
• Pre-treatment AE (Not TEAE, with start date< IMP start date). 
In case a pre-treatment AE change severity (became worst) occurs on or after treatment start date, 
then the date of change in severity will be considered as start date of a treatment-emergent AE. 
 
In case of TEAE, the event can be classified as (Section 9.3): 
• On Treatment Period, or 
• On Follow-up period 
according to the available parts of the onset and the end dates. 
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. In addition, each AE will be graded according to 
severity definitions as “Mild”, “Moderate” or “Severe”. 
TEAEs will be reported on a per-patient basis, i.e. 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 IMP or missing relationships will be defined as “Adverse Drug 
Reaction” (ADR). 
The following tables and listings will be presented by treatment group: 
• An overview of TEAEs including the number of patients who exhibited at least one TEAE, 
at least one severe TEAE, at least one TESAE, at least one non-serious TEAE, at least one 
ADR, at least one serious ADR, at least one hypoglycemic episode, number of TEAEs, 
number of non-serious TEAEs, number of TESAEs, number of ADRs, number of serious 
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ADRs, number of deaths, number of patients who discontinued IMP due to a TEAE, number 
of hypoglycemic episodes; 
• Summary of TEAEs by primary System Organ Class and Preferred Term and by study period 
(on treatment/follow-up and overall); 
• Summary of TEAEs by primary System Organ Class, Preferred Term and Severity; 
• Summary of Serious TEAEs by Primary System Organ Class and Preferred Term and by 
study period (on treatment/follow-up and overall); 
• Summary of ADRs by Primary System Organ Class and Preferred Term and by study period 
(on treatment/follow-up and overall); 
• Summary of ADRs by Primary System Organ Class and Preferred Term and Severity; 
• Summary of TEAEs leading to IMP Discontinuation by Primary System Organ Class and 
Preferred Term and by study period (on treatment/follow-up and overall); 
• Summary of TEAEs leading to Death by Primary System Organ Class and Preferred Term 
and by study period (on treatment/follow-up and overall); 
• Summary of Hypoglycemic Episodes by ADA Criteria by study period (on treatment/follow-
up and overall); 
• Listing of all Aes by Patient; 
• Listing of SAEs by Patient; 
• Listing of ADR by Patient; 
• Listing of Deaths. 
In addition, time-to-event methods will be used to summarize the time to onset of hypoglycemic 
episodes from first dose of treatment. Kaplan-Meier estimates and plots will be provided with:  
• the 95% confidence interval bounds calculated per the method proposed by Greenwood3;  
• the respective number of patients at risk and Kaplan-Meier estimates at different time points; 
• the median and its 95% confidence interval; 
• the log-rank test p-value.  
Subjects ongoing and who are free from event at the analysis cut-off date will be censored at that 
date. A table footnote will clarify the analysis cut-off date. Subjects who have discontinued the study 
without an event will be censored at the date of discontinuation. 
 
8.2 
Clinical laboratory evaluation 
Analysis of clinical laboratories data will be performed by treatment for Hematology and 
Biochemistry tests. In case of different units of measure considered for the same laboratory 
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parameter, all values will be converted into Standard International (SI) units (if applicable) or to the 
same unit. 
The following summaries will be provided: 
• A summary table showing for all laboratory tests the values and changes from baseline to 
each subsequent visit; 
• A summary table showing for all laboratory tests the frequency of patients reporting an 
abnormal (clinically or not clinically significant) laboratory value at baseline , at subsequent 
visits and at least one at any visit 
• Shift tables presenting the number and the percentage of patients in each bivariate category 
(baseline versus each post-baseline visit) with regards to investigator’s interpretation.  
The following graphical representations will be provided for all laboratory parameters: 
• Spaghetti plot of individuals’ observed data and change from baseline (with x-axis marked 
by days relative to start of actual treatment); 
 
8.3 
Vital signs, Estimated Glucose Disposal Rate and BMI 
Summary statistics by treatment will be provided along with summary of the change from baseline 
at each timepoint for: 
• Vital signs: 
o Systolic Blood Pressure (mmHg), 
o Diastolic Blood Pressure (mmHg), and  
o Heart Rate (bpm)); 
•  
 BMI evaluations: 
o Weight (Kg) and Height (cm),  
o BMI (Kg/m2) – derived from CRF,  
o Waist circumference (cm) and Waist-to-Hip Ratio,  
o Hypertension status (Yes, No) 
The following graphical representations will be provided for all quantitative vital signs: 
• Spaghetti plot of individuals’ observed data and change from baseline (with x-axis marked 
by days relative to start of actual treatment); 
 
8.4 
ECGs 
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Summary statistics by treatment of QTcF Interval (msec) and ECG interpretation (Normal, Abnormal 
NCS, Abnormal CS, No Result) will be provided along with summary of the change/shift from 
baseline at each timepoint.  
In case of repetition of ECG evaluation (according to protocol), the repeated QTcF value will be 
considered as the only evaluation value for that visit. 
8.5 
Pregnancy test over the study 
A summary table showing test results (Negative/Positive) over the study will be produced by 
treatment group, where applicable. 
 
 
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9.  Derivations and date conventions 
9.1 
Variable derivation 
Table 4: Variable derivation rules 
Parameter 
Calculation 
Screened 
A patient is considered screened if (s)he has “Date of written informed 
consent signature from patient (dd-MMM-yyyy)” filled.  
Enrolled 
A patient is considered enrolled if (s)he has signed written informed 
consent and fulfillment of eligibility criteria (i.e., not reported as 
screening failure). 
Timepoint 
Defined in Section 3.3 
IMP start date 
Start of treatment refers to the date of the first IMP administration. 
End of treatment 
End of treatment (EOT) refers to the date of the last IMP administration. 
Baseline 
 
Baseline is defined as the last visit prior to and including date of the 
randomization visit (Day 1). Unless otherwise specified, baseline values 
are defined as the measurements taken during this visit. In case of 
multiple measurements during baseline visit, the last assessment before 
start of treatment will be considered as baseline evaluation. 
 
Visit completion 
If the visit is available (present in the source datasets) the visit is 
completed 
Trial completers 
A patient is considered completer if the tick box “Did the patient 
complete the study?” is ticked “Yes” in the “STUDY TERMINATION” 
page. 
If box is not ticked, the subject is considered ongoing in the trial (not 
applicable for the CSR). 
Subject discontinued 
A patient is considered completer if the tick box “Did the patient 
complete the study treatment?” is ticked “No” in the “END OF 
TREATMENT” page. 
If box is not ticked, the subject is considered ongoing in the IMP (not 
applicable for the CSR). 
Patient with concomitant 
disease 
A patient is considered with concomitant disease if CRF term “Has the 
patient experienced any relevant  past and/or concomitant diseases or 
past surgeries?” = YES and at least a medical history term has 
“Ongoing” flagged. 
Otherwise the patient is considered as with no concomitant disease. 
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Parameter 
Calculation 
Prior Medical and surgery 
history 
A patient is considered having a prior medical/surgery history if CRF 
term “Has the patient experienced any relevant past and/or concomitant 
diseases or past surgeries?” = YES and no medical history term has 
“Ongoing” flagged. 
Otherwise the patient is considered having no prior medical and surgery 
history 
Treatment period 
Starts from randomization [timeframe: Day 1 (visit 2)] and ends on the 
day of the last dose of study treatment. 
Change from baseline 
Each change from baseline will be defined as difference between the 
value (minuend) at each post-baseline assessment and the baseline value 
(subtrahend). 
Severe hypoglycemia 
An adverse event is considered as “severe hypoglycemia” if the 
assessment has 
• 
Ticked “yes” in the “SELF REPORTED HYPOGLYCEMIA” 
page 
And 
• 
Has ticked “Level 3” in the “ADVERSE EVENTS” eCRF form. 
Time from T1D diagnosis to 
inform consent 
 
Time from T1D diagnosis to IC (days) = Date of IC signature – Date of 
T1D diagnosis +1. 
Missing/partial dates will not be imputed. Anyway, since these dates are 
crucial for enrolment, their complete presence in the final database is 
expected. 
Time to discontinuation 
Time to discontinuation (days)= Date of discontinuation - date of 
randomization+1 
Missing/partial dates will not be imputed. Anyway, since these dates are 
crucial for enrolment, their complete presence in the final database is 
expected. 
Extent of exposure 
 
Extent of exposure (days) = Date of last IMP intake – Date of first IMP 
intake +1. 
 
CGM parameters 
See section 12.1. 
Identification of 
hypoglycemic episodes 
CRF – SELF REPORTED HYPOGLYCEMIA form: Did the patient 
experience any hypoglycemic episodes? 
Time to hypoglycemic 
episode from first IMP 
intake 
Time to hypoglycemic episode = Date of onset of hypoglycemic episode 
(CRF - ADVERSE EVENTS form) - Date of first IMP intake +1. 
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Parameter 
Calculation 
Time from randomization to 
study discontinuation 
Time from randomization to study discontinuation (days) = Date of study 
discontinuation - Date of randomization +1. 
Responder definition: 
patients with an HbA1c 
reduction from baseline of 
>= 0.50% (absolute 
difference) without episodes 
of severe hypoglycemia 
[timeframe: Week xx (Visit 
xx)] 
A patient is considered as responder at Week XX (Visit XX) 
- if  reduction of HbA1c from baseline of >=0.50% (absolute difference) 
at Week XX (Visit XX), 
AND 
- no episodes of severe hypoglycemia by Week XX (Visit XX) 
 
Average (previous 3 days) 
insulin requirements 
(IU/kg/day) 
CRF - DAILY INSULIN REQUIREMENT EVALUATION form: 
Average Insulin requirement (IU/kg/day) 
Conversion of Time Intervals  
 
If a time interval was calculated in minutes, hours or days and needs to 
be converted into months or years the following conversion factors will 
be used:  
• 
1 month = 30.4375 days  
• 
1 year = 365.25 days  
Cut-off Date 
For DMC only. 
The database snapshot date is the date of the raw data extraction to create 
the Study Data Tabulation Model (SDTM) datasets. The SDTM 
production date may be later. 
The cutoff date is used to exclude all subjects screened after that date, as 
well as all the assessments carried out after that date. For adverse events, 
the onset date is compared to the cutoff date. The events with onset date 
after the cutoff date are excluded from the analyses. 
In case of purpose of the analyses is the CSR, cut-off date will be not 
applied. 
 
9.2 
CGM value derivation 
Different Continuous Glucose Monitoring System may be used to perform CGM during the study. Each of 
them uses proprietary algorithms to create fully customable reports and summary measures for patients and 
clinicians. These reports will not be used during the trail given the fully customizable features. Instead, in 
order to standardize the summary statistics from each patient, the cgmanalysis package2 written entirely in the 
statistical programming language R (R Foundation for Statistical Computing, Vienna, Austria) will be used. 
Gaps in glucose data shorter or equal than 30 minutes will be imputed using linear interpolation. The 
cgmanalysis package2 cleandata function will be used. 
After filling eventual gaps in the glucose data, the following requirements should be met for a visit in order to 
be considered eligible for analysis: 
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• 
a total of at least 7 days of valid CGM recordings will be required for a visit to be used for analysis: 
o cgmanalysis: num_days_good_data >= 7; 
• 
the number of sensor readings as a percentage of the number of potential readings (given time worn) 
has to be greater than 80%: 
o cgmanalysis: percent_cgm_wear > 80%.  
The cgmanalysis package2cgmvariables function will be used for the CGM parameters (sections 3.6.2 and 
3.6.3). The package has been modified in order to perform additional simultaneous analyses (see Appendix 
XX for the entire R code). Table 5 reports the correspondence between required endpoint and cgmvariables 
outcomes.  
For the calculation of 2h PPG, the raw data from Dexcom G6 System have to be filtered in order to keep only 
observations ≤ 120 minutes from meals, where the exact time of meals (breakfast, lunch and dinner) are taken 
from eDiary. If time of meal is missing, the adjacent CGM observations will not be considered. 
 
Table 5: Variable in cgmanalysis 
Endpoint 
Variable in cgmanalysis 
TIR 
percent_time_70_180 
TAR 
percent_time_over_180 
TBR 
percent_time_under_70 
*raw data must be filtered with observations ≤ 180 minutes from meals (eDiary) 
 
9.3 
Partial date conventions 
Table 6: Algorithm for Treatment Emergence of Adverse Events 
AE START DATE^ 
AE STOP 
DATE 
RULE for TEAE definition 
RULE for 
“Treatment”/”Follow-up” study 
period definition for TEAE 
summaries 
Known 
Known, 
Partial or 
Missing 
If AE start date < IMP start 
date, then not TEAE 
If AE start date >= IMP start 
date, then TEAE 
If End of treatment is not missing, 
AE start date > End of Treatment 
then 
“Follow-up”, 
otherwise 
“Treatment” period. 
 
 
 
 
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AE START DATE^ 
AE STOP 
DATE 
RULE for TEAE definition 
RULE for 
“Treatment”/”Follow-up” study 
period definition for TEAE 
summaries 
Partial, but known 
components show 
that it cannot be on 
or after IMP start 
date 
Known, 
Partial or 
Missing 
Not TEAE 
Not Applicable 
 
 
 
 
Partial, could be on 
or after IMP start 
date 
Known 
If AE stop date < IMP start 
date, then not TEAE 
If AE stop date >= IMP start 
date, then TEAE 
If TEAE, then Treatment study 
period for TEAE occurrence. 
 
 
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 AE stop date < IMP start 
date, then not TEAE 
If AE stop date >= IMP start 
date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
 
Missing 
Known 
If AE stop date < IMP start 
date, then not TEAE 
If AE stop date >= IMP start 
date, then TEAE 
If TEAE, then Treatment study 
period for TEAE occurrence. 
 
 
Partial 
Impute AE 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 AE stop date < IMP start 
date, then not TEAE 
If AE stop date >= IMP start 
date, then TEAE 
 
Missing 
Assumed TEAE 
NOTE: * Assignment to “Treatment” or “Follow-up”study period is applicable only for TEAEs. 
^For start date the cut-off date rule is used (Section 9.1)  
 
 
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Table 7: Algorithm for Prior/Concomitant medications 
MEDICATION START 
DATE 
MEDICATION 
STOP DATE 
RULE for prior or concomitant categorization 
Known 
Known 
If medication stop date < date of informed consent, assign as 
prior  
If medication stop date >= date of informed consent, assign as 
concomitant  
 
Partial 
Impute medication 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 medication stop date < date of informed consent, assign as 
prior 
If medication stop date >= date of informed consent, assign as 
concomitant 
 
Missing 
Assign as concomitant 
 
 
 
 
Partial or Missing 
Known 
If medication stop date < date of informed consent, assign as 
prior 
If medication stop date >= date of informed consent, assign as 
concomitant 
 
Partial 
Impute medication 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 medication stop date < date of informed consent, assign as 
prior 
If medication stop date >= date of informed consent, assign as 
concomitant 
 
Missing 
Assign as concomitant 
 
 
 
 
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10.  
Tables, Figures and Listings 
10.1 Output conventions 
• Each Table, Listing and Figure (TLF) should be numbered, following the ICH E3 Guideline. 
• All titles have to be sufficiently explanatory, i.e. the content of the outputs should be clear 
even when consulted independently from the SAP. 
• For numeric variables, units will be presented enclosed in square brackets ([ ])., when 
appropriate. 
• Each table and each figure should provide reference to the listing where the data on which 
the table/figure is based are shown. 
• Listings should include raw data, i.e. data collected in CRF or other data collection tool, as 
well as derived data, i.e. data of variables that have been generated for statistical analysis. 
The derived data must be clearly identified. 
• Every TLF should report the following information on the upper side of the output: 
o Left aligned: 
▪ Protocol number 
o Centered aligned: 
▪ “Confidential” 
o Right aligned: 
▪ Dompé Farmaceutici SpA 
▪ Draft/Final Run <date> 
• Every TLF should report the following information on the bottom side of the output: 
o Left aligned: 
▪ the name of the SAS program which will generate the output 
o Centered aligned: 
▪ Draft/Final Version - Date <date> 
o Right aligned: 
▪ “Page n of N”, where n is the page number and N is the total number of pages 
of the document. 
10.2 Format requirements: 
• All TLFs will be produced in landscape format on A4 paper size, unless otherwise specified.  
• The titles are centered. The analysis sets are identified on the line following the title.  
• it is preferable to use “Courier New” with minimal font size of 8, which is the smallest 
acceptable point size for the Regulatory Authorities. 
• Output files will be delivered in Rich Text Format (RTF) that can be manipulated in Word. 
10.3 Table Conventions 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table even in case of frequency equal to 0.  
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• If the categories are not ordered (e.g., Medical History), then only those categories for which 
there is at least 1 subject represented in 1 or more groups are included. 
• Unless otherwise specified, the estimated mean and median for a set of values are printed out 
to 1 more significant digit than the original values, and SDs. 
• Missing descriptive statistics or p-values which cannot be estimated are reported as “-”. 
10.4 Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups, subject number, and 
visit. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of 
dates are represented on subject listings as dashes (--JUL2000). 
• In case listings will not fit the page, it will be splitted in two different parts. 
11.  
Reference 
1. Study protocol, A phase II randomized, placebo-controlled, double-blinded, 2-parallel arm, 
clinical trial evaluating ladarixin 400 mg twice a day as adjunctive therapy to improve glycemic 
control in overweight insulin-resistant patients with type 1 diabetes., Protocol Version - Date: 
Version No. 1 final – 
. 
2. Vigers T, Chan CL, Snell-Bergeon J, Bjornstad P, Zeitler PS, Forlenza G, et al. (2019) Cgmanalysis: 
An R package for descriptive analysis of continuous glucose monitor data. PLoS ONE 14 (10): 
e0216851. https://doi.org/10.1371/journal.pone.0216851 
3. Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New 
York: John Wiley & Sons. 
4. P. K. Andersen.   R. D. Gill.    "Cox's Regression Model for Counting Processes: A Large Sample 
Study."   Ann. Statist.   10   (4)   1100 - 1120,   December, 1982.    
 
 
 
 
 
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12.  
Appendices  
12.1 R code for CGM 
R code 
Notes 
 
Cgmvariables_mod <- function(inputdirectory, 
                         outputdirectory = tempdir(), 
                         outputname = "Dexcom", 
                         customintervals = list(c(,)), 
                         aboveexcursionlength = 35, 
                         belowexcursionlength = 10, 
                         magedef = "1sd", 
                         daystart = 0, 
                         dayend = 24, 
                         id_filename = F, 
                         format = "rows", 
                         printname = F) { 
   
  # Read in data, create results dataframe. The dataframe has one column for each  
  # file in the input directory, and is desgined to be uploaded to REDCap.  
  files <- base::list.files(path = inputdirectory,full.names = TRUE) 
  cgmupload <-  
    base::as.data.frame(base::matrix(nrow = 0,ncol = base::length(files))) 
  base::colnames(cgmupload) <- base::rep("Record",base::length(files)) 
  # Define the order in which lubridate parses dates.   
  dateparseorder <- c("mdy HM","mdy HMS","mdY HM","mdY HMS","dmy 
HM","dmy HMS", 
                      "dmY HM","dmY HMS","Ymd HM","Ymd HMS","ymd HM","ymd 
HMS", 
                      "Ydm HM","Ydm HMS","ydm HM","ydm HMS") 
  allhours <- 0:23 
  # Iterate through the input directory and calculate CGM variables for each file. 
  # The cgmvariables() function only works on CSV files that have been cleaned by  
  # cleandata(), or that have been manually edited and fit the format of 
  # cleandata() output.  
  for (f in 1:base::length(files)) {     
    # Basic variables 
    table <- utils::read.csv(files[f],stringsAsFactors = FALSE,na.strings = c("NA","")) 
    # Remove duplicates 
    if(id_filename == F) { 
      table$subjectid <- table$subjectid[1] 
    } else { 
      table$subjectid[1] <- sub("*.csv","",basename(files[f])) 
    } 
    table <- unique(table) 
    # Print name 
    if(printname == T) { 
      print(basename(files[f])) 
    } 
    # Column names to lower case 
    colnames(table) = tolower(colnames(table)) 
    cgmupload["subject_id",f] <- table$subjectid[1] 
    # Format columns.     
 
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R code 
Notes 
    table$timestamp <-  
      base::as.POSIXct(lubridate::parse_date_time(table$timestamp, 
                                                  dateparseorder,tz = "UTC")) 
    table$sensorglucose <- suppressWarnings(base::as.numeric(table$
 
    interval <- pracma::Mode(base::diff(base::as.numeric(table$timestamp))) 
    interval <- base::abs(interval) 
    cgmupload["date_cgm_placement", f] <-  
      base::as.character(min(table$timestamp,na.rm = T)) 
     
    totaltime <-  
      base::as.numeric(base::difftime(base::max(table$timestamp, na.rm = T), 
                                      base::min(table$timestamp,na.rm = T), 
                                      units = "secs")) 
    cgmupload["percent_cgm_wear",f] <-  
      
 
    
  
      
 
     
    table <- table[!is.na(table$timestamp) & !is.na(table$
 
     
    cgmupload["total_sensor_readings",f] <-  
      base::as.numeric(base::length(base::which(!is.na(table$
 
    cgmupload["average_sensor",f] <-  
      base::mean(table$
[base::which(!is.na(table$
,na.rm = 
T) 
    cgmupload["estimated_a1c",f] <-  
      
 
        
 
    
 
 
      base::which(!is.na(table$
 digits = 1) 
    cgmupload["q1_sensor",f] <-  
      base::as.numeric(base::summary(table$
 
        base::which(!is.na(table$
[2]) 
    cgmupload["median_sensor",f] <-  
      base::as.numeric(base::summary(table$
 
        base::which(!is.na(table$
[3]) 
    cgmupload["q3_sensor",f] <-  
      base::as.numeric(base::summary(table$
 
        base::which(!is.na(table$
[5]) 
    cgmupload["standard_deviation",f] <-  
      stats::sd(table$
[base::which(!is.na(table$
 
    cgmupload["cv",f] <-  
      (stats::sd(table$
[base::which(!is.na(table$
 
      base::mean(table$
[base::which(!is.na(table$
 
    cgmupload["min_sensor",f] <-  
      base::min(table$
[base::which(!is.na(table$
 
    cgmupload["max_sensor",f] <-  
      base::max(table$
[base::which(!is.na(table$
 
     
    # 
 
    
 <-  
      base::as.numeric(table$
[base::which(!is.na( 
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R code 
Notes 
        table$sensorglucose))],length = 1) 
    
 
    
 
    
 
    
  
      base::
 
     
    cgmupload[
,f] <-  
      base::length(base::which(
 >  
                                 ((aboveexcursionlength * 60)/interval))) 
    cgmupload["
",f] <- base::sum(
) * (interval/
 
    cgmupload["p
",f] <-  
      ((base::sum(BGover120) * (interval/
 
         (base::length(table$
 * (interval/
 * 100 
     
    # Over 
 
    
 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    
 
    
 
    
 
    
  
      base::as.
 
     
    cgmupload["excursions_
",f] <-  
      base::length(base::
0 >  
                                 ((aboveexcursionlength * 
/interval))) 
    cgmupload[
] <- base::sum(
) * (interval/
 
    cgmupload["percent_time_over_140",f] <-  
      ((base::sum
) * (interval/
 
         (base::length(table$
 * (interval/
 * 100 
     
    # Over 
 
    
 <-  
      base::as.numeric(table$
[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    
 
    
 
    
 
    
-  
      base::as.
 
     
    cgmupload["excursions_
_
,f] <-  
      base::length(base::
>  
                                 ((aboveexcursionlength * 
/interval))) 
    cgmupload["
",f] <- base::sum(
 * (interval/
 
    cgmupload[
",f] <-  
      ((base::sum(
) * (interval/
 
         (base::length(table$sensorglucose) * (interval/
 * 100 
     
    # Over 
 
    
 <-  
      base::as.numeric(table$
[base::which(!is.na( 
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R code 
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        table$sensorglucose))],length = 1) 
    
 
    
 
    
 
    
  
      base::as.
(
 
     
    cgmupload["excursions_
,f] <-  
      base::length(base::
 >  
                                 ((aboveexcursionlength * 
/interval))) 
    cgmupload["
",f] <- base::sum(
) * (
/60) 
    cgmupload["
",f] <-  
      ((base::sum
) * (interval/
 
         (base::length(table$sensorglucose) * (interval/
 * 100 
     
    cgmupload["
",f] <-  
      as.numeric(cgmupload["e
",f])/ 
      as.numeric(cgmupload["num_days_good_data",f]) 
    cgmupload["avg_
] <-  
      as.numeric(cgmupload[
",f])/ 
      as.numeric(cgmupload["num_days_good_data",f]) 
     
    # 
 
    
 <-  
      base::as.numeric(table$
[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    
 
    
 
    
 
    
 <-  
      base::
 
     
    cgmupload["
",f] <-  
      base::length(base::which(
0 >  
                                 ((aboveexcursionlength * 
/interval))) 
    cgmupload["
0",f] <- base::sum(
) * (interval/
 
    cgmupload["
0",f] <-  
      ((base::sum(
) * (interval/
 
         (base::length(table$sensorglucose) * (interval/
 * 100 
     
    # 
 
    
4 <-  
      base::as.numeric(table$
[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    
 
    
 
    
 
    
  
      base::as.numeric(BG54.rle$lengths[base::which(BG54.rle$values == 1)]) 
     
    cgmupload["e
] <-  
      base::length(base::which(
 >  
                                 ((belowexcursionlength * 
/interval))) 
    cgmupload["
",f] <- base::sum(
) * (interval/6 ) 
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Statistical Analysis Plan Template 
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Protocol Number: 
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Version: Final 1.0 
 
 
 
 
R code 
Notes 
    cgmupload[
",f] <-  
      ((base::sum(
) * (interval
))/ 
         (base::length(table$
 * (interval/
 * 100 
     
    # 
 
    
 <-  
      base::as.numeric(table$
[base::which(!is.na( 
        table$
,length = 1) 
    
 
    
 
    
 
    
  
      base::as.numeric(BG60.rle$lengths[base::which(BG60.rle$values == 1)]) 
     
    cgmupload["
,f] <-  
      base::length(base::which
 >  
                                 ((belowexcursionlength * 
/interval))) 
    cgmupload["
",f] <- base::sum
 * (interval/
 
    cgmupload["percent_time_under_
,f] <-  
      ((base::sum(BGunder60) * (interval/
 
         (base::length(table$
 * (interval
))) * 100 
     
    # 
 
    
 <-  
      base::as.numeric(table$
[base::which(!is.na(table$
 
                       length = 1) 
    
 
    
 
    
 
    
  
      base::
 
     
    cgmupload[
 <-  
      base::length(base::which(
  
                                 ((belowexcursionlength * 
/interval))) 
    
 
    
  
      
 
         
 
     
    # Time in range. 
    BGinrange <-  
      base::as.numeric(table$
[base::which(!is.na(table$
 
                       length = 1) 
    
 
    
 
    
  
      
 
         
 
     
    # 
 
    
 
      
 
      
 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
47 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
      
 
        
 
        
- 
base::as.numeric(table$
[base::which(!is.na(table$
 
                                      length = 1) 
        
 
        
 
        
 
        
 
        
  
          
 
             
 
        # Below 
        BGunder <-  
          base::as.numeric(table$
[base::which(!is.na(table$
 
                           length = 1) 
        
 
        
 
        
 
        
  
          
 
         
        
  
          
  
                                     
 
        
 
 
        
  
          
 
             
 100 
        # Above 
        BGover <-  
          base::as.numeric(table$
[base::which(!is.na( 
            table$
,length = 1) 
        
 
        
 
        
 
        
<-  
          base::as.
 
         
        cgmupload[paste0(
]),f] <-  
          base::length(base::which(excursionsover >  
                                     
))) 
        
 
(interval/60) 
        cgmupload[paste0("percent_time_over_",highs[r]),f] <-  
          ((base::sum(BGover) * (
)/ 
             (base::length(table$
 * 
 
      } 
    } 
    # Find daytime AUC. 
    if ("wake" %in% colnames(table)) { 
      daytime_indexes <-  
        base::which(table$wake == 1) 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
48 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
    } else { 
      daytime_indexes <-  
        base::which(base::as.numeric(base::format(table$timestamp,"%H")) %in%  
                      daystart:dayend) 
    } 
    daytime_sensor <- table$
[daytime_indexes] 
    xaxis <-  
      base::seq(from = 0, length.out = base::length(daytime_sensor),by =  
                  (interval / 60)) 
     
    # Remove NAs if they are present. 
    xaxis[base::which(is.na(daytime_sensor))] <- NA 
    xaxis <- xaxis[!is.na(xaxis)] 
    daytime_sensor <- daytime_sensor[!is.na(daytime_sensor)] 
    aucs <- pracma::cumtrapz(xaxis,daytime_sensor) 
    cgmupload["daytime_auc",f] <- aucs[base::length(daytime_sensor)] 
     
    # TIR variables for daytime 
    BGinrange <- ifelse(
) 
    c
<- base::sum(BGinrange,na.rm = T) * 
(interval/
 
    cgmupload[
] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    BGinrange <- ifelse(
) 
    cgmupload["
 <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
    cgmupload["p
 <-  
      (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    BGinrange <- ifelse(
) 
    cgmupload[
] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["
] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    BGinrange <- ifelse(
) 
    cgmupload["
f] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
    cgmupload["
 <-  
      (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    BGinrange <- ifelse(
) 
    cgmupload["
] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
    cgmupload["
] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    BGinrange <- ifelse(
) 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
49 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
    cgmupload["
] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
    cgmupload["
] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    BGinrange <- ifelse(
) 
    cgmupload["
<- base::sum(BGinrange,na.rm = T) * 
(interval/
 
    cgmupload["percent_time_over_250_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(daytime_sensor) * 
(interval/
 * 100 
     
    # 
 
    
  
      
 
    
 
    
 
    
 
     
    # Nighttime AUC. 
    if ("wake" %in% colnames(table)) { 
      nighttime_indexes <- base::which(table$wake == 0) 
    } else { 
      nighttime_indexes <-  
        base::which(base::as.numeric(base::format(table$timestamp,"%H")) %in%  
                      allhours[base::which(!(0:23 %in% daystart:dayend))]) 
    } 
    if (length(nighttime_indexes) > 0) { 
      nighttime_sensor <- table$sensorglucose[nighttime_indexes] 
      xaxis <-  
        base::seq(from = 0, length.out = base::length(nighttime_indexes),by =  
                    (interval / 
 
       
      # Day/night ratio. 
      cgmupload["day_night_sensor_ratio",f] <-  
        base::round(base::length(daytime_sensor)/base::length(nighttime_sensor),1) 
       
      # Remove NAs if they are present. 
      xaxis[base::which(is.na(nighttime_sensor))] <- NA 
      xaxis <- xaxis[!is.na(xaxis)] 
      nighttime_sensor <- nighttime_sensor[!is.na(nighttime_sensor)] 
      aucs <- pracma::cumtrapz(xaxis,nighttime_sensor) 
      cgmupload["nighttime_auc",f] <- aucs[base::length(nighttime_sensor)] 
       
      # TIR variables for nighttime 
      BGinrange <- ifelse(
 
      cgmupload["
] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload["
] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(nighttime_sensor) 
* (interval/
 * 100 
       
      BGinrange <- 
 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
50 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
      cgmupload[
 <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload[
] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(nighttime_sensor) 
* (interval/
 * 100 
       
      BGinrange <- 
) 
      cgmupload["
 <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload["p
 <-  
        (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(nighttime_sensor) 
* (interval/
 * 100 
       
      BGinrange <- 
) 
      cgmupload[
] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload["
] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(nighttime_sensor) 
* (interval/
 * 100 
       
      BGinrange <- ifelse(nighttime_sensor > 180, 1,0) 
      cgmupload[
f] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload["
<-  
        (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(nighttime_sensor) 
* (interval/
 * 100 
       
      BGinrange <-
) 
      cgmupload[
<- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload["p
 <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) 
* (interval/
 * 100 
       
      BGinrange <- ifelse(
) 
      cgmupload[
] <- base::sum(BGinrange,na.rm = T) * 
(interval/
 
      cgmupload["
] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/
(base::length(nighttime_sensor) 
* (
/60)) * 100     
       
      # Other nighttime sensor glucose variables. 
      cgmupload["nighttime_avg_sens_glucose",f] <-  
        base::mean(stats::na.omit(nighttime_sensor)) 
      cgmupload["nighttime_min_sens_glucose",f] <- base::min(nighttime_sensor) 
      cgmupload["nighttime_max_sens_glucose",f] <- base::max(nighttime_sensor) 
      cgmupload["nighttime_sd",f] <- stats::sd(nighttime_sensor) 
    } 
     
    # Total AUC. 
    sensorBG <- base::as.numeric(table$
,length = 1) 
    xaxis <-  
      
  
                  
 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
51 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
     
    # Remove NAs if they are present. 
    xaxis[base::which(is.na(sensorBG))] <- NA 
    xaxis <- xaxis[!is.na(xaxis)] 
    sensorBG <- sensorBG[!is.na(sensorBG)] 
    aucs <- pracma::cumtrapz(xaxis,sensorBG) 
    cgmupload["total_auc",f] <- aucs[base::length(sensorBG)] 
     
    cgmupload["average_auc_per_day",f] <- 
      base::as.numeric(cgmupload["total_auc",f]) / 
      base::as.numeric(cgmupload["num_days_good_data",f]) 
     
    # 
 
    
 
    
 
    
 
    
  
      
  
                  
 
     
    # Calculate cumulative AUC, and subtract rectangle where length = 
 
    
 
    
 
      
 
      
  
        
 
      
 
    
 
      
 
     
    
 
      
 
      
 
 
    # 
 
    
 
    
 
    
 
    
  
      
  
                  
 
     
    # Calculate cumulative 
 and subtract recatangle where length = 
 
    
. 
    if (base::length(
 { 
      aucs <- pracma::cumtrapz(xaxis,sensorlower70) 
      aucs <-  
        -(aucs[base::length
)]) + (xaxis[base::length(xaxis)] * 
 
       
      cgmupload["
] <- aucs 
    } else { 
      cgmupload["
 
    } 
    cgmupload["
 
This section has been 
modified in order to 
calculate the AUC 
between 70 (upper limit) 
and the glucose curve 
(lower limit). 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
52 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
      base::as.numeric(cgmupload["
/ 
      base::as.numeric(cgmupload["n
    
     
    cgmupload["interval (sec)",f] <- interval 
     
    # Calculate 
 
    # Smooth data using an exponentially weighted moving average, calculate SD of  
    # unsmoothed data.   
    table$smoothed <-  
      base::as.numeric(zoo::rollapply(zoo::zoo(
  
                                      
  
                                        
 
    table$smoothed[1:4] <- base::mean(stats::na.omit(table$
[
)) 
    table$smoothed[(base::length(table$smoothed)
): 
                     base::length(table$smoothed)] <-  
      base::mean(table$sensorglucose[(base::length
-
 
                                       base::length(table$
 
     
    sd <- stats::sd(table$
 
    # Identify turning points, peaks, and nadirs. 
    tpoints <- pastecs::turnpoints(table$smoothed) 
    peaks <- base::which(tpoints[["peaks"]] == TRUE) 
    pits <- base::which(tpoints[["pits"]] == TRUE) 
    # 
      
    
  
    
 
    if (tpoints[["firstispeak"]] == TRUE && base::length(peaks) !=  
        base::length(pits)) { 
      peaks <- peaks[2:base::length(peaks)] 
    } else if (tpoints[["firstispeak"]] == FALSE &&  
               base::length(peaks) != base::length(pits)) { 
      pits <- pits[1:(base::length(pits)-1)] 
    } 
    differences <- table$sensorglucose[peaks] - table$sensorglucose[pits] 
     
    #
  
    
 
    if (magedef == "1sd") { 
      cgmupload["r_mage",f] <-  
        base::mean(stats::na.omit(differences[base::which(differences > sd)])) 
    } else if (
") { 
      cgmupload["r_mage",f] <-  
        base::mean(stats::na.omit(differences[base::which(differences >  
                                                            (sd * 1.5))])) 
    } else if ( magedef == "2sd") { 
      cgmupload[
<-  
        base::mean(stats::na.omit(differences[base::which(differences >  
                                                            (sd * 2))])) 
    } else { 
      cgmupload["
<-  
        base::mean(stats::na.omit(differences[base::which(differences >  
                                                            
 
    } 
     
 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
53 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
    
 
    cgmupload["j_index",f] <-  
      0.001 * (base::mean(table$
 na.rm = T) +  
                 stats::sd(table$
 na.rm = T))^2 
  
    
. 
    
 
    
 
    
  
      
  
                                      
 
    
 
    
 
    
    
    
 
      
  
        
 
          
 
    } 
    # Average the averages. 
    cgmupload["modd",f] <-  
      base::mean(stats::na.omit(moddtable$mean_differences)) 
     
    # 
 
    
 
    
 
    
 
    table$gluctransform <- y * ((base::log(t
^a)-b) 
    table$rBG <- 10 * (table$gluctransform^2) 
    rl <- table$rBG[base::which(
 
    rh <- table$rBG[base::
 
    
 
    
 
  } 
   
  # Write file. 
  cgmupload <-  
    base::cbind("Variable / Field Name" = rownames(cgmupload),cgmupload) 
  if (format == "rows") { 
    cgmupload <- base::as.data.frame(base::t(cgmupload)) 
    cgmupload <- cgmupload[-1,] 
  } 
  filename <- base::paste(outputdirectory,"/",outputname,".csv",sep = "") 
  utils::write.csv(cgmupload, file = filename,row.names = FALSE,na = "") 
} 
 
 
 
 
 
library(cgmanalysis) 
library(stringi) 
library(base) 
 
cleandata( 
Cleandata will fill in 
gaps shorter than 30 
minutes but will not 
remove the 24-hour 
chunks containing 
larger gaps. 
 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
54 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
R code 
Notes 
  inputdirectory = "path\\to\\data", 
  outputdirectory = "path\\to\\cleaned_data", 
           removegaps = FALSE, gapfill = TRUE, maximumgap = 30)  
 
cgmvariables_mod( 
  inputdirectory = "path\\to\\cleaned_data ", 
  outputdirectory = "path\\to\\output", 
  outputname = "Dexcom", 
  customintervals = list(c(
), 
  aboveexcursionlength = 
 
  belowexcursionlength = 
 
  magedef = 
, 
  daystart = , 
  dayend = 
 
  id_filename = F, 
  format = "rows", 
  printname = F 
) 
 
 
Parameters 
customintervals, 
aboveexcursionlength, 
belowexcursionlength,  
daystart, dayend will not 
be used.  
 
 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
55 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
12.2 List of TFLs 
12.2.1 Tables 
Title 
Analysis Set 
DMC* Final Analysis 
Table 14.1.1: Subject Enrolment and Disposition – overall and by country 
Screened set 
X 
X 
Table 14.1.2: Analysis Sets 
Randomized Set 
 
X 
Table 14.1.3.1: Study Discontinuations 
Randomized Set 
X 
X 
Table 14.1.3.2: Time to Discontinuation 
Randomized Set 
 
X 
Table 14.1.4: Permanent treatment discontinuation criteria 
Safety Set 
 
X 
Table 14.1.5.1: Major protocol deviations 
Randomized Set 
X 
X 
Table 14.1.5.2: Minor protocol deviations 
Randomized Set 
X 
X 
Table 14.1.6: Patient phone calls 
Safety Set 
 
X 
Table 14.1.7: Demographics and baseline characteristics 
Full Analysis Set 
X 
X 
Table 14.1.8.1: Medical or Surgical History 
Full Analysis Set 
X 
X 
Table 14.1.8.2: Concomitant Diseases 
Full Analysis Set 
X 
X 
Table 14.1.9.1: Prior Medications 
Full Analysis Set 
X 
X 
Table 14.1.9.2: Concomitant Medications 
Full Analysis Set 
X 
X 
Table 14.1.10: Other baseline characteristics 
Full Analysis Set 
X 
X 
Table 14.2.1.1: Compliance to IMP - dispensation and accountability by cycle 
Safety Set 
X 
X 
Table 14.2.1.2: Compliance to IMP – overall treatment period 
Safety Set 
X 
X 
Table 14.2.2.1.1: Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia at week 27/28 - Logistic regression model with 
Multiple Imputation under missing not at random 
Full Analysis Set 
 
X 
Table 14.2.2.2.1: Sensitivity Analysis: Proportion of patients with HbA1c reduction from baseline of ≥ 
0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 - Logistic 
regression model with Multiple Imputation under missing at random 
Full Analysis Set 
 
X 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
56 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
Title 
Analysis Set 
DMC* Final Analysis 
Table 14.2.2.2.2: Sensitivity Analysis: Proportion of patients with HbA1c reduction from baseline of ≥ 
0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 - 
Tipping point analysis 
Full Analysis Set 
 
X 
Table 14.2.2.2.3: Sensitivity Analysis: Proportion of patients with HbA1c reduction from baseline of ≥ 
0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 - 
Logistic regression model with Reference-based Multiple Imputation under missing not at random 
Full Analysis Set 
 
X 
Table 14.2.2.3.1 : Supportive Analysis: Proportion of patients with HbA1c reduction from baseline of ≥ 
0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 - 
Logistic regression model with Multiple Imputation under missing not at random 
Per Protocol Set 
 
X 
Table 14.2.2.3.2: Supportive Analysis: Proportion of patients with HbA1c reduction from baseline of ≥ 
0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 - 
Logistic regression model considering complete cases only 
Full Analysis Set 
 
X 
Table 14.2.3.1.1 : Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia 
Full Analysis Set 
 
X 
Table 14.2.3.1.2: Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia at week 11/12 (visit 3) 
Logistic regression model with Multiple Imputation under missing not at random 
Full Analysis Set 
 
X 
Table 14.2.3.2.1 : Summary of HbA1c and changes from baseline 
Full Analysis Set 
 
X 
Table 14.2.3.2.2: Mean difference from baseline in HbA1c at Week 11/12 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.3.2.3: Mean difference from baseline in HbA1c at Week 27/28 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.3.3.1: Summary of Average daily insulin requirement (IU/kg/day) and change from baseline 
Full Analysis Set 
 
X 
Table 14.2.3.3.2: Average daily insulin requirement (IU/kg/day) 
Mixed model for repeated measurements 
Full Analysis Set 
 
X 
Table 14.2.3.4.1: Summary of Time in range (TIR), Time above range (TAR), Time below range (TBR) 
by CGM and change from baseline 
Full Analysis Set 
 
X 
Table 14.2.3.4.2: Time in range (TIR) by CGM at Week 11/12 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
57 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
Title 
Analysis Set 
DMC* Final Analysis 
Table 14.2.3.4.3: Time in range (TIR) by CGM at Week 27/28 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.3.4.6: Time above range (TAR) by CGM at Week 11/12 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.3.4.7: Time above range (TAR) by CGM at Week 27/28 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.3.4.10: Time below range (TBR) by CGM at Week 11/12 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.3.4.11: Time below range (TBR) by CGM at Week 27/28 
Adjusted ANOVA model with Multiple Imputation using retrieve dropouts 
Full Analysis Set 
 
X 
Table 14.2.4.1.1: Summary of Additional Glucose Variability Indices and change from baseline 
Full Analysis Set 
 
X 
Table 14.2.4.1.2: 
Full Analysis Set 
 
X 
Table 14.2.4.1.3: 
 
Full Analysis Set 
 
X 
Table 14.2.4.1.4:
 
 
Full Analysis Set 
 
X 
Table 14.2.4.1.5: 
 
Full Analysis Set 
 
X 
Table 14.2.5.1.1 : Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia by Age class 
Full Analysis Set 
 
X 
Table 14.2.5.1.2: Summary of HbA1c and changes from baseline by Age class 
Full Analysis Set 
 
X 
Table 14.2.5.1.3: Summary of Average daily insulin requirement (IU/kg/day) and change from baseline 
by Age class 
Full Analysis Set 
 
X 
Table 14.2.5.1.4 : Summary of Time in range (TIR), Time above range (TAR), Time below range (TBR) 
by CGM and change from baseline by Age class 
Full Analysis Set 
 
X 
Table 14.2.6.1.1: Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia by Sex  
Full Analysis Set 
 
X 
Table 14.2.6.1.2: Summary of HbA1c and changes from baseline by Sex 
Full Analysis Set 
 
X 
Table 14.2.6.1.3 : Summary of Average daily insulin requirement (IU/kg/day) and change from baseline 
by Sex 
Full Analysis Set 
 
X 
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Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
58 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
Title 
Analysis Set 
DMC* Final Analysis 
Table 14.2.6.1.4 : Summary of Time in range (TIR), Time above range (TAR), Time below range (TBR) 
by CGM and change from baseline by Sex 
Full Analysis Set 
 
X 
Table 14.2.7.1.1 : Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia by Race  
Full Analysis Set 
 
X 
Table 14.2.7.1.2: Summary of HbA1c and changes from baseline by Race 
Full Analysis Set 
 
X 
Table 14.2.7.1.3: Summary of Average daily insulin requirement (IU/kg/day) and change from baseline 
by Race 
Full Analysis Set 
 
X 
Table 14.2.7.1.4 : Summary of Time in range (TIR), Time above range (TAR), Time below range (TBR) 
by CGM and change from baseline by Race 
Full Analysis Set 
 
X 
Table 14.2.8.1.1: Proportion of patients with HbA1c reduction from baseline of ≥ 0.50% (absolute 
difference) without episodes of severe hypoglycemia by Ethnicity  
Full Analysis Set 
 
X 
Table 14.2.8.1.2: Summary of HbA1c and changes from baseline by Ethnicity  
Full Analysis Set 
 
X 
Table 14.2.8.1.3: Summary of Average daily insulin requirement (IU/kg/day) and change from baseline 
by Ethnicity 
Full Analysis Set 
 
X 
Table 14.2.8.1.4 : Summary of Time in range (TIR), Time above range (TAR), Time below range (TBR) 
by CGM and change from baseline by Ethnicity 
Full Analysis Set 
 
X 
Table 14.3.1.1: Exposure to IMP 
Safety Set 
X 
X 
Table 14.3.1.2: Overview of Treatment Emergent Adverse Events 
Safety Set 
X 
X 
Table 14.3.1.3: Summary of Treatment Emergent Adverse Events by primary System Organ Class and 
Preferred Term 
Safety Set 
X 
X 
Table 14.3.1.4: Summary of Treatment Emergent Adverse Events by primary System Organ Class and 
Preferred Term and Severity 
Safety Set 
X 
X 
Table 14.3.1.5: Summary of Serious Treatment Emergent Adverse Events by primary System Organ 
Class and Preferred Term 
Safety Set 
X 
X 
Table 14.3.1.6: Summary of Adverse Drug Reaction by primary System Organ Class and Preferred Term 
Safety Set 
X 
X 
Table 14.3.1.7: Summary of Adverse Drug Reaction by primary System Organ Class and Preferred Term 
and Severity 
Safety Set 
X 
X 
Table 14.3.1.8: Summary of Treatment Emergent Adverse Events leading to IMP Discontinuation by 
primary System Organ Class and Preferred Term 
Safety Set 
X 
X 
PPD
CCI
PPD
CCI
PPD


Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
59 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
Title 
Analysis Set 
DMC* Final Analysis 
Table 14.3.1.9: Summary of Treatment Emergent Adverse Events leading to Death by primary System 
Organ Class and Preferred Term 
Safety Set 
X 
X 
Table 14.3.1.10: Summary of Hypoglycemic Episodes by ADA Criteria  
Safety Set 
X 
X 
Table 14.3.2: Deaths, Listing 
Safety Set 
X 
X 
Table 14.3.3.1: Time to Onset of Hypoglycemic Episodes 
Safety Set 
 
X 
Table 14.3.5.1.1: Summary of Hematology results and changes from baseline 
Safety Set 
X 
X 
Table 14.3.5.1.2: Proportion of patients reporting an abnormal laboratory value by visit - Hematology 
Safety Set 
X 
X 
Table 14.3.5.1.3: Hematology results: Shift from baseline to each post-baseline visit - investigator’s 
interpretation 
Safety Set 
X 
X 
Table 14.3.5.2.1: Summary of Biochemistry results and changes from baseline 
Safety Set 
X 
X 
Table 14.3.5.2.2: Proportion of patients reporting an abnormal laboratory value by visit - Biochemistry 
Safety Set 
X 
X 
Table 14.3.5.2.3: Biochemistry results: Shift from baseline to each post-baseline visit - investigator’s 
interpretation 
Safety Set 
X 
X 
Table 14.3.6.1.1: Summary of Vital Signs and change from baseline 
Safety Set 
X 
X 
Table 14.3.6.1.2: Summary of Vital Signs and change from baseline 
Full Analysis Set 
X 
X 
Table 14.3.6.2.1: Summary of 
 BMI evaluations and change from baseline 
Safety Set 
X 
X 
Table 14.3.6.3: Summary of QTcF Interval (msec) and change from baseline 
Safety Set 
X 
X 
Table 14.3.6.4: 12-Lead Electrocardiogram: Shift from baseline to each post-baseline visit on 
Investigator’s interpretation 
Safety Set 
X 
X 
Table 14.3.6.5: Pregnancy test over the study 
Safety Set 
X 
X 
* Corresponding listing will be provided (see next section) 
 
 
 
PPD
CCI
PPD
CCI
PPD


Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
60 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
 
12.2.2 Listings 
Title 
Analysis Set 
DMC 
Final 
Analysis 
Listing 16.1.7: Randomization schedule 
Randomized Set 
 
X 
Listing 16.2.1.1: Disposition of subjects 
Screened Set 
X 
X 
Listing 16.2.1.2.1: Subjects enrolled but not randomized 
Enrolled Set 
 
X 
Listing 16.2.1.2.2: Study discontinuation 
Randomized Set 
X 
X 
Listing 16.2.1.2.3: Permanent treatment discontinuation criteria 
Randomized Set 
 
X 
Listing 16.2.1.2.4: Patients phone calls 
Randomized Set 
 
X 
Listing 16.2.2.1: Inclusion criteria 
Randomized Set 
X 
X 
Listing 16.2.2.2: Exclusion criteria 
Randomized Set 
X 
X 
Listing 16.2.2.3.1: Major protocol deviations 
Randomized Set 
X 
X 
Listing 16.2.2.3.2: Minor protocol deviations 
Randomized Set 
X 
X 
Listing 16.2.3.1: Analysis sets 
Enrolled Set 
 
X 
Listing 16.2.3.2: Subjects excluded from full analysis set 
Enrolled Set 
X 
X 
Listing 16.2.4.1: Demographic and baseline characteristics 
Randomized Set 
X 
X 
Listing 16.2.4.2: Medical or Surgical History 
Randomized Set 
X 
X 
Listing 16.2.4.3: Concomitant diseases 
Randomized Set 
X 
X 
Listing 16.2.4.4: Prior medications 
Randomized Set 
X 
X 
Listing 16.2.4.5: Concomitant medications 
Randomized Set 
X 
X 
Listing 16.2.4.6: Other baseline characteristics 
Randomized Set 
X 
X 
Listing 16.2.5.1: Compliance to study medication 
Randomized Set 
X 
X 
Listing 16.2.6.1.1: HbA1c results 
Randomized Set 
 
X 
Listing 16.2.6.1.2: Daily insulin requirement (IU/Kg/day) 
Randomized Set 
 
X 
Listing 16.2.6.1.3: Time in Range (TIR), Time above Range (TAR), Time below 
Range (TBR) by Continuous Glucose Monitoring (CGM) 
Randomized Set 
 
X 
Listing 16.2.6.1.4: Additional glucose variability indices derived from CGM 
Randomized Set 
 
X 
Listing 16.2.6.1.5: 
 
Randomized Set 
 
X 
PPD
CCI
PPD
CCI
PPD


Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
61 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
Title 
Analysis Set 
DMC 
Final 
Analysis 
Listing 16.2.6.1.6: Exploratory efficacy endpoints 
Randomized Set 
 
X 
Listing 16.2.6.1.7: Self-reported Hypoglycemia 
Randomized Set 
X 
X 
Listing 16.2.6.2: Exposure to study medication 
Randomized Set 
X 
X 
Listing 16.2.7.1: Pre-treatment adverse events 
Randomized Set 
X 
X 
Listing 16.2.7.2: Treatment emergent adverse events 
Randomized Set 
X 
X 
Listing 16.2.7.3: Serious treatment emergent adverse events 
Randomized Set 
 
X 
Listing 16.2.7.4: Treatment emergent adverse drug reactions 
Randomized Set 
 
X 
Listing 16.2.7.5: Serious treatment emergent adverse drug reactions 
Randomized Set 
 
X 
Listing 16.2.7.6: Severe treatment emergent adverse events 
Randomized Set 
 
X 
Listing 16.2.7.7: Treatment emergent adverse events leading to discontinuation 
Randomized Set 
 
X 
Listing 16.2.7.8: Treatment emergent adverse events leading to death 
Randomized Set 
 
X 
Listing 16.2.7.9: Hypoglycemic Episodes 
Randomized Set 
X 
X 
Listing 16.2.8.1: Laboratory parameters: Hematology 
Randomized Set 
X 
X 
Listing 16.2.8.2: Laboratory parameters: Biochemistry 
Randomized Set 
X 
X 
Listing 16.2.8.3: Patients with clinically significant laboratory values 
Randomized Set 
X 
X 
Listing 16.2.8.4: Pregnancy test results 
Randomized Set 
X 
X 
Listing 16.2.8.5: Vital signs 
Randomized Set 
X 
X 
Listing 16.2.8.6: 
 and BMI evaluation 
Randomized Set 
X 
X 
Listing 16.2.8.7: 12-lead electrocardiogram 
Randomized Set 
X 
X 
 
 
 
 
PPD
CCI
PPD
CCI
PPD


Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
 
 
 
62 of 62 
 
Protocol Number: 
LDX0122 
Version: Final 1.0 
 
 
 
 
12.2.3 Figures 
Title 
Analysis Set 
DMC 
Final Analysis 
Figure 14.2.2.2.4: Tipping point analysis 
Full Analysis Set 
 
X 
Figure 14.2.3.1.3: Proportion of patients at each timepoint by treatment with HbA1c reduction from 
baseline of >=0.50% without episodes of severe hypoglycemia 
Full Analysis Set 
X 
X 
Figure 14.2.3.2.4: Boxplots at each timepoint by treatment of the HbA1c 
Full Analysis Set 
X 
X 
Figure 14.2.3.2.5: Boxplots for Change from baseline at each timepoint by treatment of the HbA1c 
Full Analysis Set 
X 
X 
Figure 14.2.3.2.6 Waterfall plot for Proportion of patients with HbA1c reduction from baseline of ≥ 
0.50% (absolute difference) without episodes of severe hypoglycemia at week 27/28 - 
Logistic regression model considering complete cases only 
Full Analysis Set 
 
X 
Figure 14.2.3.3.3: Boxplots at each timepoint by treatment of the daily insulin requirement 
(IU/kg/day) 
Full Analysis Set 
X 
X 
Figure 14.2.3.4.4: Boxplots at each timepoint by treatment of the Time in range (TIR) by CGM 
Full Analysis Set 
X 
X 
Figure 14.2.3.4.5: Boxplots for Change from baseline at each timepoint by treatment of the Time in 
range (TIR) by CGM 
Full Analysis Set 
X 
X 
Figure 14.2.3.4.8: Boxplots at each timepoint by treatment of the Time above range (TAR) by CGM 
Full Analysis Set 
X 
X 
Figure 14.2.3.4.9: Boxplots for Change from baseline at each timepoint by treatment of the Time 
above range (TAR) by CGM 
Full Analysis Set 
X 
X 
Figure 14.2.3.4.12: Boxplots at each timepoint by treatment of the Time below range (TBR) by CGM 
Full Analysis Set 
X 
X 
Figure 14.2.3.4.13: Boxplots for Change from baseline at each timepoint by treatment of the Time 
below range 
Full Analysis Set 
X 
X 
Figure 14.3.5.1.4: Hematology: Spaghetti Plot of observed data 
Full Analysis Set 
X 
X 
Figure 14.3.5.1.5: Hematology: Spaghetti Plot of change from baseline 
Full Analysis Set 
X 
X 
Figure 14.3.5.2.4: Biochemistry: Spaghetti Plot of observed data 
Full Analysis Set 
X 
X 
Figure 14.3.5.2.5: Biochemistry: Spaghetti Plot of change from baseline 
Full Analysis Set 
X 
X 
Figure 14.3.6.1.3: Vital signs: Spaghetti Plot of observed data 
Full Analysis Set 
X 
X 
Figure 14.3.6.1.4: Vital signs: Spaghetti Plot of change from baseline 
Full Analysis Set 
X 
X 
Figure 14.3.3.2: Time to onset of Hypoglycemic Episodes (Kaplan-Meier) 
Full Analysis Set 
 
X 
 
 
 
PPD
CCI
PPD
CCI
PPD