Influence of Food on the Oral Bioavailability of Ladarixin 200 mg Capsule in Healthy Volunteers of Both Sexes. A Single Dose (400 mg), Randomized, Open Label, Two-Way Crossover Study
Phase: PHASE1
Conditions: no Condition
Sponsor: Dompé Farmaceutici S.p.A

CONFIDENTIAL 
 
Study report CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 05OCT21 
 
16. 
APPENDICES 
 
16.1 
Study information 
 
16.1.1 
Protocol and protocol amendments 
 
The following documents are enclosed: 
 
 Protocol final version 1.0, 28MAY20 
 Note to file, 13OCT20 
 Note to file, 19JAN21 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 1 
 
CLINICAL STUDY PROTOCOL 
 
 
CRO-PK-20-345 - Sponsor code LDX0219 
 
Influence of Food on the Oral Bioavailability of Ladarixin 200 mg 
Capsule in Healthy Volunteers of Both Sexes. A Single dose (400 
mg), Randomized, Open Label, Two-Way Crossover Study  
 
Single center, single dose, open label, randomized, two-way, crossover, food effect study 
 
Test treatment 
(fed conditions): 
Ladarixin 200 mg hard gelatin capsules, Dompé farmaceutici 
S.p.A., Italy 
 
 
Reference treatment 
(fasting conditions): 
Ladarixin 200 mg hard gelatin capsules, Dompé farmaceutici 
S.p.A., Italy 
 
 
Sponsor: 
Dompé farmaceutici S.p.A.,  
via Santa Lucia 6; 20122 Milan, Italy  
Phone: +39 02.58383.1 
Fax: 
+39 02.58383.324 
Email: pieradelchi.ruffini@dompe.com 
 
Sponsor Medical Expert:  
Pier Adelchi Ruffini, MD -Global Clinical Development Director 
 
 
Investigator: 
Milko Radicioni, MD - Principal investigator 
CROSS Research S.A., I Unit, Via F.A. Giorgioli 14 
CH-6864 Arzo, Switzerland 
Phone: +41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: clinic@croalliance.com 
 
 
Development phase: 
Phase I 
 
 
Version and date: 
Final version 1.0, 28MAY20 
 
 
This study will be conducted in accordance with the current version of Good Clinical Practice (GCP),  
ICH topic E6 (R2) 
 
Property of the Sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the Sponsor 
This document comprises 68 pages  
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 5 
STUDY SYNOPSIS 
 
Title: Influence of food on the oral bioavailability of ladarixin 200 mg capsule in healthy volunteers of both 
sexes. A single dose (400 mg), randomized, open label, two-way crossover study 
 
Protocol number: CRO-PK-20-345 - Sponsor code LDX0219 
 
Clinical phase: Phase I 
 
Study design: Single center, single dose, open label, randomized, two-way, crossover, food effect on 
bioavailability study 
 
Planned nr. of centers / countries: 1/Switzerland 
 
Investigator and center: Principal Investigator: Milko Radicioni, MD; CROSS Research Phase I Unit, Via 
F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Investigational medicinal product:  
Ladarixin 200 mg hard gelatin capsules, Dompé farmaceutici S.p.A., Italy 
 
Dose regimen:  
A single oral dose of 400 mg of ladarixin (two 200 mg capsules) will be administered to healthy male and female 
volunteers under fed (Test treatment) and fasting (Reference treatment) conditions in two consecutive study 
periods, according to a two-way crossover design, with a wash-out interval of at least 14 days between the two 
administrations. 
 
Objectives:  
Primary objective: 
 to investigate the effect of food on the bioavailability of DF 2156Y after single dose administration of 400 
mg of ladarixin to healthy male and female volunteers under fed and fasting conditions. 
Secondary objectives:  
 to investigate the effect of gender on the bioavailability of DF 2156Y and its metabolites (DF 2108Y and DF 
2227Y) after single dose administration of 400 mg of ladarixin to healthy male and female volunteers  
 to evaluate safety and tolerability of a single dose administration of ladarixin 400 mg to healthy male and 
female volunteers. 
 
End-points:  
Primary end-point:  
 to evaluate and compare the rate (Cmax) and extent (AUC0-t, AUC0-∞) of absorption of DF 2156Y after single 
dose administration of 400 mg of ladarixin under fed and fasting conditions.  
Secondary end-points:  
 to evaluate and compare between genders the rate (Cmax) and extent (AUC0-t; AUC0-∞) of absorption of DF 
2156Y and its metabolites (DF 2108Y and DF 2227Y) after single dose administration of 400 mg of 
ladarixin to healthy male and female volunteers; 
 to describe the pharmacokinetic profile of DF 2156Y (total and unbound) and its metabolites (DF 2108Y 
and DF 2227Y) after single dose administration of 400 mg of ladarixin under fed and fasting conditions; 
 to collect safety and tolerability data of a single oral dose administration of 400 mg of ladarixin. 
 
Study variables: 
Primary variables: 
 Cmax and AUC0-t of plasma DF 2156Y, after single dose administration of 400 mg of ladarixin under fed and 
fasting conditions 
Secondary variables:  
 AUC0-∞, tmax, t1/2, λz and Frel of plasma DF 2156Y after single dose administration of 400 mg of ladarixin 
under fed and fasting conditions; 
 Cmax, AUC0-t, AUC0-∞, tmax, t1/2, λz and Frel of plasma DF 2156Y and of its metabolites (DF 2108Y and DF 
2227Y) after single dose of 400 mg of ladarixin under fed and fasting conditions measured and calculated in 
healthy men and in healthy women; 
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 6 
STUDY SYNOPSIS (cont.) 
 
Secondary variables:  
 Treatment-emergent adverse events, vital signs (blood pressure, pulse rate, body temperature), body weight, 
electrocardiograms, physical examinations, laboratory parameters (hematology, blood chemistry and urine 
analysis). 
 
Analytics: The concentration of DF 2156Y (total and unbound) and its metabolites (DF 2108Y and DF 2227Y) 
in plasma will be determined at Dompé farmaceutici S.p.A. Bioanalytical Laboratories, L’Aquila, Italy using a 
fully validated HPLC-UV method. Analyses will be performed according to the general Principles of “OECD 
Good Laboratory Practices for testing of chemicals" C (81) 30 (final) and GCP. The method validation report 
and the analytical report will be attached to the final clinical study report (CSR). 
A total of 1512 plasma samples (756 samples for each study period) will be analyzed. 
 
Safety and tolerability assessments: Treatment-emergent adverse events; vital signs (blood pressure, pulse 
rate, body temperature), physical examinations including body weight; laboratory tests (hematology, blood 
chemistry and urine analysis), electrocardiograms 
 
Sample size: The sample size was not calculated through any statistical calculation. In order to have at least 32 
subjects completed (16 men and 16 women), a sample size of 36 healthy volunteers (18 men and 18 women) 
was estimate as sufficient for the descriptive purposes of the present study. Drop-out subjects will be replaced 
starting from the 3rd man and/or woman discontinuing prematurely the study. 
 
Main selection criteria: 
Inclusion criteria: 
1. Informed consent: signed written informed consent before inclusion in the study 
2. Sex and Age: men/women, 18-55 years old inclusive 
3. Body Mass Index: 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, pulse rate 50-90 
bpm and body temperature 35.5-37.5° C, measured after 5 min at rest in the sitting position 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study 
6. Contraception and fertility (women only): women of child-bearing potential must not wish to get pregnant 
within 30 days after the end of the study and must be using at least one of the following reliable methods of 
contraception: 
a) Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the 
screening visit until 30 days after final visit 
b) A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with 
spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before 
the screening visit until 30 days after final visit 
c) A male sexual partner who agrees to use a male condom with spermicide until 30 days after final visit 
d) A sterile sexual partner 
Women participants of non-childbearing potential or in post-menopausal status for at least one year will be 
admitted. For all women, pregnancy test result must be negative at screening and day -1. 
Exclusion criteria: 
1. Electrocardiogram (ECG) 12-leads (supine position): clinically significant abnormalities 
2. Physical findings: clinically significant abnormal physical findings which could interfere with the 
objectives of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness 
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (ladarixin or derivatives) and/or 
formulations' ingredients; known hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs); 
history of hypersensitivity to drugs (in particular methanesulfonyl propanamide) or allergic reactions in 
general, which the Investigator considers may affect the outcome of the study 
5. Diseases: hypoalbuminemia or significant history of renal, hepatic, gastrointestinal, respiratory, skin, 
hematological, endocrine, neurological or cardiovascular diseases that may interfere with the aim of the 
study 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 7 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria (continued):  
Exclusion criteria: 
6. Medications: medications, including over the counter drugs (in particular nonsteroidal anti-inflammatory 
drugs), herbal remedies and food supplements taken 14 days before the start of the study (in any case at 
least 5 times the half-life of the drug or a minimum of 14 days, whichever is longer), with the exception of 
paracetamol. Hormonal contraceptives and hormonal replacement therapy for women will be allowed. 
7. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study. The 3-month interval is calculated as the time between the first calendar day of the month that 
follows the last visit of the previous study and the first day of the present study 
8. Blood donation: blood donations for 3 months before this study 
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol (>1 drink/day for women and >2 drinks/day for 
men, defined according to the USDA Dietary Guidelines 2015-2020), caffeine (>5 cups coffee/tea/day) or 
tobacco abuse (≥10 cigarettes/day) 
10. SARS-COV2 test: positive SARS-COV2 test on day -3 or -2 of each study period  
11. Virology: positive Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo) 
at screening.  
12. Drug test: positive result at the drug test at screening or day -1 of each study period 
13. Alcohol test: positive alcohol breath test at screening or day -1 of each study period 
14. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks 
before this study; vegetarians; vegans 
15. Pregnancy (women only): positive or missing pregnancy test at screening or day -1 of each study period, 
pregnant or lactating women 
Schedule: 
Screening – Visit 1 
From day -21 to 
 day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, 
physical abnormalities) 
 Vital signs (blood pressure, pulse rate, body 
temperature) measurement 
 ECG recording 
 Laboratory analyses: hematology, coagulation, blood 
chemistry, microbiology, urinalysis, serum virology 
and serum pregnancy test (women only) 
 Alcohol breath test 
 Urine multi-drug kit test 
 Adverse events monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: The first two 
letters of the surname 
followed by the first 
two letters of the first 
name will be used in 
the Phase I Unit source 
document only and will 
not be transferred to the 
Sponsor. 
Screening  
Visit 1.1 
Day -3 or -2 
 Nasal and pharyngeal swab for SARS-COV2 test 
 Adverse events monitoring 
 Previous/concomitant medications 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 8 
STUDY SYNOPSIS (cont.) 
 
Schedule (continued): 
Period 1 - Visit 2 
Day -1 
 Alcohol breath test 
 Urine pregnancy test (women only) 
 Urine multi-drug kit test 
 ECG recording 
 Vital signs measurement 
 Adverse event and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomization 
Arrival at the Phase I Unit 
in the evening. 
Confinement until the 
morning of day 4. 
Standardized low-fat 
dinner. 
Fasting for at least 10 h 
(overnight). 
Period 1 - Visit 3 
Day 1 
 Investigational medicinal product administration at 
8:00 ± 1 h (day 1) 
 Vital signs measurement at pre-dose  
 ECG recording at pre-dose  
 Blood sample collection for pharmacokinetic 
analysis at pre-dose (0) and 0.25 (15 min), 0.5 (30 
min), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 18 h post-
dose 
 Adverse event and concomitant medications 
Standardized high-fat and 
high 
caloric 
breakfast 
starting at 30 min pre-
dose 
for 
subjects 
receiving 
the 
investigational medicinal 
product 
under 
fed 
conditions in this study 
period. Breakfast must be 
completed within 30 min. 
Subjects receiving the 
investigational medicinal 
product 
under 
fasting 
conditions will not have 
breakfast. 
Standardized lunch and 
dinner at about 13:00 (5 
h post-dose) and 20:00 
(12 
h 
post-dose), 
respectively 
Days 2 and 3 
 Blood sample collection for pharmacokinetic 
analysis at 24, 30, 36, 48, 54 and 60 h post-dose 
 Adverse event and concomitant medications 
Standardized 
breakfast, 
lunch and dinner at about 
9:00, 13:00 and 20:00, 
respectively 
Day 4 
 Vital signs measurement upon discharge 72 h post-
dose 
 ECG recording upon discharge 72 h post-dose 
 Blood sample collection for pharmacokinetic 
analysis at 72 h post-dose 
 Adverse event and concomitant medications 
 Full physical examination (body weight and 
physical abnormalities) upon discharge  
Discharge from the Phase 
I Unit in the morning, 
after the 72-h post-dose 
blood sample collection, 
ECG recording, vital signs 
check and full physical 
examination.  
Upon leaving, the subjects 
will 
be 
instructed 
to 
contact immediately the 
investigator in case of 
occurrence of any adverse 
reactions. 
Wash-out 
At least 14 days A wash-out interval of at least 14 days between the two 
administrations of the two study periods 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 9 
STUDY SYNOPSIS (cont.) 
 
Schedule (continued): 
Period 2 - Visit 4 
Day -3 or -2 
As visit 1.1, day -3 or -2 
 
Period 2 - Visit 5 
Day -1 
As visit 2, excluding enrolment and randomization. In 
addition a full physical examination (body weight and 
physical abnormalities) will be performed. 
As visit 2 
Period 2 - Visit 6 
Days 1-4 
As 
visit 
3. 
Investigational 
medicinal 
product 
administered according to the randomization list and 
crossover design 
As visit 3 
Final Visit/ETV 
Day 4 of period 
2 
/at Early 
Termination 
Visit in case of 
discontinuation 
 Full physical examination (body weight and physical 
abnormalities; also vital signs and ECG in case of 
Early Termination Visit) 
 Alcohol breath test 
 Urine multi-drug kit test 
 Laboratory analyses as at screening, with the 
exception of virology, coagulation, microbiology, 
albumin and globulin 
 AEs and concomitant medications 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator until 
the normalization of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed 
to 
contact 
immediately 
the 
investigator in case of 
occurrence 
of 
any 
adverse reactions. 
During each study period, the subjects will be confined from the evening preceding the investigational product 
administration (study day -1) until the morning of day 4. On day -1 of each period, a standardized low-fat 
dinner will be served after confinement. On day 1 of each study period, all the subjects will not take any food or 
drinks (except water) for at least 10 h (i.e. overnight). The subjects allocated to the fed conditions, after the 
overnight fasting period, will receive a high-fat and high-caloric breakfast starting 30 min pre-doses and will 
complete their breakfast within 30 min, while the subjects allocated to the fasting conditions will fast overnight 
and then receive their treatment. Water will be allowed as desired except for 1 h before and 1 h after 
investigational product administration. In order to maintain an adequate hydration, the subjects will be 
encouraged to drink at least 150 mL of still mineral water every 2 h for 5 h post-dose, starting at 1 h post-dose. 
On day 1, all subjects will remain fasted until 5 h post-dose. A standardized lunch and dinner will be served at 
approximately 5 h and 12 h post-dose (at approximately 13:00 and 20:00). On days 2 and 3, standardized 
breakfast, lunch and dinner will be served to all subjects at about 9:00, 13:00 and 20:00, respectively. One cup 
of coffee or tea will be allowed after each meal only; any other coffee, tea or food containing xanthines (i.e. 
coke, chocolate, etc.), alcohol and grapefruit and alcohol will be forbidden during confinement. In particular, 
grapefruit will be forbidden for 24 h before the first investigational product administration until the end of the 
study. The subjects will be allowed to smoke 9 cigarettes during confinement, one after each meal, with the 
exclusion of the high-fat and high-caloric breakfast. 
During confinement, routine ambulant daily activities will be strongly recommended.  
For the 4 h following the administration, when not involved in study activities, the subjects will remain seated. 
They will not be allowed to lie down. Hazardous, strenuous or athletic activities will not be permitted. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 10 
STUDY SYNOPSIS (cont.) 
 
Data analysis : 
The pharmacokinetic analysis and the statistical analysis of pharmacokinetic parameters will be performed using 
Phoenix WinNonlin® version 6.3 or higher, Pharsight Corporation, and SAS® version 9.3 (TS1M1) or higher. 
The statistical analysis of safety and tolerability data will be performed using SAS® version 9.3 (TS1M1) or 
higher. The data documented in this trial and the clinical parameters measured will be analyzed using classic 
descriptive statistics for quantitative variables and frequencies for qualitative variables. 
Analysis of primary end-point 
For the evaluation of food effect, Cmax, AUC0-t and AUC0-∞ of total plasma DF 2156Y will be compared between 
treatments using analysis of variance (ANOVA) for a crossover design on log-transformed data. Period, 
treatment, sequence and subject within sequence will be taken into account as sources of variation. The 90% 
confidence intervals (CI) will be calculated for the point estimates (PE, i.e. the T/R ratio of least square 
geometric means) of the PK parameters. Established criteria for the absence of a food effect are that the 90% CI 
for the T/R ratio of the geometric means of the PK parameters under consideration are within the 80.00-
125.00% range 
Gender effect analysis 
For the purpose of exploring the gender effect on bioavailability of ladarixin and its metabolites, following 
logarithmic transformation, Cmax, AUC0-t and AUC0-∞ of total plasma DF 2156Y and of DF 2108Y and DF 
2227Y will be analyzed using ANOVA including sequence, period, treatment, subject within sequence, sex and 
sex*treatment interaction as fixed effect. 
 
Timing:  
EC meeting: 16JUN20; planned clinical phase: NOV20 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 11 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
PERIOD 1 
(wash-
out≥14 
days) 
PERIOD 2 
Final visit/ETV1 
Visit 
V1 
V1.1 
V2 
V3 
V4 
V5 
V6 
 
Day -
21/-2 
Day -3  
or -2 
Day -1 
Day 1 
Days 2, 3, 4 
Day -3  
or -2 
Day -1 
Day 1 Days 2, 3, 4 
Day 4 of period 22 or 
early termination 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
 
 
Lifestyle 
x 
 
 
 
 
 
 
 
 
 
 
Medical history and 
underlying disease 
x 
 
 
 
 
 
 
 
 
 
 
Physical abnormalities 
x 
 
 
 
x3 
 
 
x 
 
 
x 
Previous and concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height and Body Mass Index 
x 
 
 
 
 
 
 
 
 
 
 
Body Weight 
x 
 
 
 
x3 
 
 
x 
 
 
x 
Laboratory analysis4 
x 
 
 
 
 
 
 
 
 
 
x 
Virology 
x 
 
 
 
 
 
 
 
 
 
 
SARS-COV2 test 
 
x 
 
 
 
 
x 
 
 
 
 
Pregnancy test 
x5 
 
x6 
 
 
 
 
x6 
 
 
x5 
Urine drug screening7 
x 
 
x 
 
 
 
 
x 
 
 
x 
Alcohol breath test 
x 
 
x 
 
 
 
 
x 
 
 
x 
Coagulation 
x 
 
 
 
 
 
 
 
 
 
 
Vital signs10 
x 
 
x 
x8 
x9 
 
 
x 
x8 
x9 
x11 
ECG 
x 
 
x 
x8 
x9 
 
 
x 
x8 
x9 
x11 
Inclusion/exclusion criteria 
x 
 
x 
 
 
 
 
x 
 
 
 
Subject eligibility 
x 
 
x 
 
 
 
 
x 
 
 
 
Enrolment / randomization 
 
 
x 
 
 
 
 
 
 
 
 
Confinement 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
Discharge 
 
 
 
 
x12 
 
 
 
 
 
x 
Study dosing 
 
 
 
x13 
 
 
 
 
x13 
 
 
Blood samplings  
 
 
 
x14 
x14 
 
 
 
x14 
x14 
 
Standardized meals  
 
 
x15 
x16 
x17 
 
 
x15 
x16 
x17 
 
Adverse events monitoring18 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 12 
1. 
Early termination visit (ETV) in case of premature discontinuation 
2. 
Final visit on day 4 of period 2 after the 72-h post-dose blood sampling 
3. 
On day 4 of period 1, upon discharge 
4. 
Hematology, blood chemistry and urinalysis 
5. 
Serum β-HCG test (women only) 
6. 
Urine pregnancy test (women only)  
7. 
Multi-drug kit (cocaine, amphetamine, methamphetamine, cannabinoids [Δ-9-tetrahydrocannabinol-THC], opiates and ecstasy) 
8. 
At pre-dose 
9. 
At 72 h post-dose (corresponding to the final visit assessment in period 2)  
10. Blood pressure, pulse rate, body temperature 
11. ETV only 
12. In the morning of day 4 of period 1 
13. At 08:00±1 h 
14. At pre-dose (0), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, 48, 54, 60 and 72 h post-dose 
15. Standardized low-fat dinner served in the evening  
16. Subjects allocated to the fed condition (T treatment) only:  a high-fat and high-caloric breakfast to be started 30 min pre-dose and completed within 30 min.  
Standardized lunch and dinner at approximately 13:00 (5 h post-dose on day 1) and 20:00 (12 h post-dose on day 1) in both periods 
17. Standardized breakfast, lunch and dinner served on days 2 and 3 at approximately 09:00, 13:00 and 20:00, respectively 
18. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 13 
 
 
TABLE OF CONTENTS 
 
Page 
TITLE PAGE 
1 
PROTOCOL APPROVAL 
2 
STUDY SYNOPSIS 
5 
STUDY SCHEDULE 
11 
TABLE OF CONTENTS 
13 
TABLES 
15 
LIST OF ABBREVIATIONS 
16 
1 
INTRODUCTION 
18 
1.1 
Background 
18 
1.2 
Relevant non-clinical pharmacology 
18 
1.2.1 
Mechanism of action and in vitro activity 
18 
1.2.2 
In vivo studies of ladarixin mechanism of action 
18 
1.3 
A summary of toxicology data 
19 
1.4 
Previous clinical experience with ladarixin 
20 
1.4.1 
Pharmacokinetics and metabolism 
20 
1.4.2 
Phase I safety, tolerability and bioavailability single ascending dose study in healthy men 
20 
1.4.3 
Phase I safety, tolerability and bioavailability single and multiple dose study in healthy men 
21 
1.5 
Rationale 
22 
1.6 
Risks and benefits 
22 
2 
STUDY OBJECTIVES 
24 
2.1 
Objectives 
24 
2.1.1 
Primary objective 
24 
2.1.2 
Secondary objectives 
24 
2.2 
Endpoints 
24 
2.2.1 
Primary end-point 
24 
2.2.2 
Secondary end-points 
24 
3 
CLINICAL SUPPLIES 
25 
3.1 
Treatment 
25 
3.1.1 
Description of product 
25 
3.1.1.1 
Test product 
25 
3.1.2 
Dose regimen 
25 
3.1.3 
Route and method of administration 
25 
3.1.4 
Investigational product distribution 
25 
3.2 
Packaging and labeling 
26 
3.3 
Storage conditions 
26 
3.4 
Drug accountability 
26 
4 
INVESTIGATIONAL PLAN 
28 
4.1 
Overall study design 
28 
4.2 
Discussion of design 
28 
5 
STUDY POPULATION 
29 
5.1 
Target population 
29 
5.2 
Inclusion criteria 
29 
5.3 
Exclusion criteria 
29 
5.3.1 
Not allowed treatments 
30 
6 
STUDY SCHEDULE 
31 
6.1 
Study visits and procedures 
31 
6.2 
Diet and lifestyle 
34 
6.2.1 
Standardized high-fat and high-caloric breakfast 
35 
6.2.2 
Restrictions 
35 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 14 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
36 
7.1 
Physical examination 
36 
7.1.1 
Vital signs 
36 
7.1.2 
ECGs 
36 
7.1.3 
Clinical laboratory assays 
37 
7.2 
Sampling for pharmacokinetic analysis 
38 
7.2.1 
Venous blood sampling 
38 
7.2.2 
Analytics 
39 
7.2.3 
Labeling, storage and transport of samples 
39 
7.2.3.1 
Samples labeling 
39 
7.2.3.2 
Samples storage and transport 
39 
7.3 
Total number of samples and blood withdrawn 
40 
8 
ASSIGNMENT OF STUDY TREATMENT 
41 
8.1 
Randomization 
41 
8.2 
Treatment allocation 
41 
8.3 
Blinding 
41 
9 
EVALUATION PARAMETERS 
42 
9.1 
Study variables 
42 
9.1.1 
Primary variables 
42 
9.1.2 
Secondary variables 
42 
9.2 
Pharmacokinetic assessments 
42 
9.2.1 
Pharmacokinetic parameters 
42 
9.3 
Safety assessments 
43 
10 
STATISTICAL METHODS 
44 
10.1 
Analysis Sets 
44 
10.1.1 
Definitions 
44 
10.1.2 
Reasons for exclusion from the PK sets 
45 
10.2 
Sample size and power considerations 
45 
10.3 
Demographic, baseline and background characteristics 
45 
10.3.1 
Demography 
45 
10.4 
Analysis of pharmacokinetic parameters 
45 
10.4.1 
Descriptive pharmacokinetics 
45 
10.4.2 
Statistical comparison of pharmacokinetic parameters 
46 
10.5 
Safety and tolerability evaluation 
46 
11 
DEFINITION AND HANDLING OF AES AND SAES 
48 
11.1 
Applicable SOPs 
48 
11.2 
Definitions 
48 
11.2.1 
Adverse Events 
48 
11.2.2 
Adverse Drug Reaction 
48 
11.2.3 
Serious Adverse Event (SAE) Definition 
48 
11.3 
Unexpected Adverse Reaction 
49 
11.3.1 
Reference Safety Information (RSI) 
49 
11.3.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
49 
11.4 
Monitoring for Adverse Events 
50 
11.5 
AEs recording 
50 
11.5.1 
Severity of AEs 
50 
11.5.2 
Relationship of AEs to the IMP 
51 
11.6 
SAEs reporting 
51 
11.6.1 
Adverse events exemption 
52 
11.7 
Reporting Procedure to IRB/IEC and to Regulatory Authorities 
52 
11.8 
Follow-up of Subjects with Adverse events 
52 
11.9 
Pregnancy in the Clinical Trial 
53 
11.10 
OVERDOSE 
53 
11.11 
SAEs: clinical site contacts 
54 
12 
DATA MANAGEMENT PROCEDURES 
55 

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12.1 
Data collection – eCRF 
55 
12.2 
Unique subject identifier 
55 
12.3 
Database management 
55 
12.3.1 
Coding dictionaries 
56 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
57 
13.1 
Monitoring 
57 
13.2 
Quality Control and Quality Assurance 
57 
13.3 
Applicable SOPs 
58 
13.4 
Data access 
58 
13.5 
Audits and inspections 
58 
14 
ETHICAL CONSIDERATIONS 
59 
14.1 
Ethics and Good Clinical Practice (GCP) 
59 
14.2 
Informed consent 
59 
14.3 
Insurance policy 
60 
14.4 
Withdrawal of subjects 
60 
14.4.1 
Primary reason for discontinuation 
60 
14.4.2 
Discontinuation procedures 
60 
14.5 
Study termination 
61 
15 
ADMINISTRATIVE PROCEDURES 
62 
15.1 
Material supplied to the clinical center 
62 
15.2 
Protocol amendments 
62 
15.3 
Study documentation and record keeping 
62 
15.4 
Study subjects’ recruitment 
63 
15.5 
Confidentiality and data protection 
63 
15.6 
Publication policy 
64 
16 
STUDY RESPONSIBLE PERSONS 
65 
16.1 
Sponsor 
65 
16.2 
Institutes performing the study 
65 
16.2.1 
Clinical centre 
65 
16.3 
SAE reporting 
65 
16.4 
Drug assay 
66 
16.5 
Centralised clinical laboratory 
66 
16.6 
Co-ordination, data analysis & reporting 
66 
16.7 
Provider of eCRF system 
66 
16.8 
Monitoring 
67 
17 
REFERENCES 
68 
 
 
 
TABLES 
Page 
 
Table 1.4.2.1 
PK parameters of ladarixin and its metabolites measured and calculated after single 
dose of 400 mg of ladarixin to healthy men (N=6) 
21 
Table 1.4.3.1 
PK parameters of ladarixin and its metabolites measured and calculated after single 
dose of 400 mg of ladarixin to healthy men (N=9) 
22 
Table 6.2.1.1 
High-caloric and high-fat breakfast composition 
35 
Table 7.2.1.1 
Tolerance ranges for the scheduled sampling times 
38 
 
 

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LIST OF ABBREVIATIONS 
 
β-HCG 
Human chorionic gonadotropin β 
γ-GT 
γ-Glutamyl transpeptidase 
ApTT 
Activated partial thromboplastin time 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOAC 
Attributable-Legible-Contemporaneous-Original-Accurate-Complete 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
AUC0-∞ 
Area under the concentration vs. time curve up to infinity 
BLQL 
Below Lower Quantification Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BT 
Body temperature 
C5a 
Fifth Component of Complement  
CCL2 
Chemokine (c-c motif) ligand 2  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
Cmax 
Peak drug concentration 
CMS 
Clinical Medical Service 
CPL 
Clinical Project Leader 
CRA 
Clinical Research Associate 
eCRF 
electronic Case Report Form 
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CS 
Clinically Significant 
CV 
 
Coefficient of Variation 
CXCL1 
C-x-c motif chemokine ligand 1 
CXCL8 
CXC ligand 8 [formerly interleukin (IL)-8] 
CXCR1/2 
CXCL8 receptors 
DBP 
Diastolic Blood Pressure 
DF 2108Y  
(2R)-2-{4-[(trifluoromethanesulfonyl)oxy]phenyl} propanoic acid  
DF 2156A  
 
R-(-)-2-[(4’-trifluoromethane sulfonyloxy)phenyl]-N-methanesulfonyl 
propanamide, sodium salt, also named Meraxin and Ladarixin  
DF 2156Y 
R-(-)-2-[(4’-trifluoromethane sulfonyloxy)phenyl]-N-methanesulfonyl 
propanamide  
DF 2227Y 
(2S)-2-{4-[(trifluoromethanesulfonyl)oxy]phenyl} propanoic acid  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicine Agency 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
fMLP  
N-formylmethionylleucylphenylalanine  
Frel 
Relative Bioavailability 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBs Ag 
Hepatitis B virus surface antigen 
HCV Ab 
Hepatitis C virus antibodies 

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HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IL8 
Interleukin-8 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device 
i.v. 
Intravenous  
MLD 
Multiple Low Dose-Streptozotocin 
LSLV 
Last Subject Last Visit 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Normal 
NC 
Not calculated 
NCS 
Not clinically significant 
NOAEL 
No observed adverse effect level 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
PE 
Point Estimate 
PDCO 
Pediatric Committee 
PMN 
Polymorphonuclear neutrophil 
p.o. 
Per os 
PK 
Pharmacokinetics 
PR 
Pulse rate 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
QTcV 
QT interval corrected by the heart rate 
R 
Reference 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SARS-COV2 
Severe acute respiratory syndrome coronavirus 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Test 
T1D 
Type 1 Diabetes  
TEAE 
Treatment-Emergent Adverse Event 
THC 
delta-9-tetrahydrocannabinol 
TNF 
Tumor Necrosis Factor  
t1/2 
Half-life 
tmax 
Time to achieve Cmax 
USDA 
United States Department of Agriculture 
VEGF 
Vascular Endothelial Growth Factor  
WBC 
White Blood Cells 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 
 
 

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1 
INTRODUCTION 
 
1.1 
Background 
 
DF 2156A or ladarixin is a proprietary novel small molecule that inhibits the biological 
activity of interleukin-8 (IL-8), more recently renamed CXC (c-x-c motif chemokine) ligand 8 
(CXCL8), through inhibition of its receptors: CXCR1 and CXCR2. 
Relevant pre-clinical, toxicological and clinical data are summarized below. Please also refer 
to the Investigator’s Brochure (1) for detailed information. 
 
1.2 
Relevant non-clinical pharmacology 
 
1.2.1 
Mechanism of action and in vitro activity 
 
Ladarixin is a potent and specific inhibitor of the biological activity of the chemokine 
CXCL8. Mechanism of action studies showed that ladarixin is a non-competitive allosteric 
inhibitor of the CXCL8 receptors: CXCR1 and CXCR2 (2).  
 
In vitro ladarixin, in the low nanomolar range, inhibits human polymorphonuclear neutrophil 
(PMN) migration induced by human CXCL8 receptors activation. Chemotaxis of rodent PMN 
induced by mouse and rat counterparts of human CXCL8 is also inhibited, indicating that 
mice and rats are appropriate animal species for preclinical studies. 
Interaction of DF 2156A with CXCL8 receptors inhibits the intracellular signal transduction 
events activated by the binding of CXCL8 to CXCR1/2. The selectivity of DF 2156A on 
CXCR1 and CXCR2 is proven by its lack of efficacy against PMN migration induced by N-
formylmethionylleucylphenylalanine (fMLP) or C5a or PMA and NET formation and against 
human monocyte chemotaxis induced by CCL2.  
 
 
1.2.2 
In vivo studies of ladarixin mechanism of action 
 
In vivo, ladarixin prevents by 38 up to 80% PMN infiltration and by 35 up to 90% tissue 
damage in experimental models of ischemia/reperfusion injury of liver and brain in rats (3). In 
addition, ladarixin reduces by about 60% PMN infiltration in a murine acute model of smoke 
exposure, whereas in a chronic model the compound completely prevents the development of 
pulmonary lesions. 
The efficacy of ladarixin in preventing PMN infiltration and tissue damage was investigated 
in a passive transfer mouse model of bullous pemphigoid. In this murine model, ladarixin 
showed a protective effect both on clinical disease score (90% of reduction at the higher dose 
16.7 mg/kg) and on PMN recruitment (60% of reduction at the higher dose 16.7 mg/kg). The 
inhibition was dose-dependent. When ladarixin was administered in a therapeutic schedule of 
treatment (co-injected with immunogrlobulin G), an inhibitory effect comparable to that 
obtained when the compound was administered in a preventive regimen was observed.  
 
The antiphlogistic activity of orally administered ladarixin was proven in the acute mouse 
model of cantharidin-induced ear inflammation where it reduced ear edema (16% of 
inhibition), cell infiltration (34% of inhibition on lymphocytes T and 32% of inhibition on 
PMNs) and ear tissue levels of keratinocyte chemokines (4). 

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In addition to the above mentioned studies, more specific studies were performed to 
investigate the ability of the compound to modulate the onset of diabetes mellitus type 1 
(T1D) after oral administration in various animal models. 
 
1.3 
A summary of toxicology data 
 
Ladarixin was tested for toxicity in rodent and non-rodent animal species after single or 
repeated dose administrations. Acute and up to 1 week administration studies were conducted 
either by i.v. bolus or oral route. Longer (3 month) repeated dose studies were conducted only 
by the oral route in rats and dogs, according to the intended human administration route.  
After an orally administration of ladarixin to Wistar rats (35, 70 and 150 mg/kg/day) for a 3-
month period, no mortality and no relevant changes in body weight, food consumption, 
ophthalmology, hematology and urinalysis were observed. Changes in biochemistry 
parameters were only minimal and occurred mostly in males. They included increased activity 
of some liver enzymes (males at 150 mg/kg), dose-dependent decrease in protein levels in 
males, and dose-dependent decrease in cholesterol and phospholipid concentrations in males 
from 70 mg/kg. After a 4-week recovery period, all values were similar to those of controls 
and a full recovery or a clear trend to recovery was noted for all microscopic findings. 
In the 3-month toxicity study followed by a 4-week treatment-free recovery period, ladarixin 
was administered via daily oral capsules to Beagle dogs at initial dose levels of 0, 30, 60 and 
120 mg/kg/day. However, due to test item-related morbidity of one high dose male and 
changes in body weight and food intake of a few other animals in this group, the highest dose 
level was lowered from 120 to 80 mg/kg/day from Day 24 onwards.  
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). No observed adverse effect level (NOAEL) was considered to be 60 
mg/kg/day after 3 month of dosing. 
 
Testing for mutagenic potential (Ames test, in vitro chromosomal aberration test, in vivo 
micronucleus test in rats) gave negative results.  
 
No relevant changes related to the administration of the compound at doses (20, 50 and 150 
mg/kg) far above those foreseen in humans were reported on renal function and on central 
nervous system in male rats. 
 
As for the in vivo safety pharmacology, cardiovascular safety studies were conducted in dogs 
in 2 studies and in one study in guinea-pigs.  
Treatment with ladarixin resulted in an increase in heart rate, P amplitude and QT corrected 
for heart rate (QTcV) intervals and a slight decrease in magnesium blood values. Vomiting of 
the capsules was observed in one animal one hour after dosing. No changes in blood pressure 
(BP) were recorded.  
The results obtained indicated that ladarixin has a safe cardiovascular profile on guinea-pig. 
No effect was observed on BP, heart rate and QT corrected for heart rate using the Bazzet’s 
formula up to the dose of 10 mg/kg. Only at 30 mg/kg a transient significant reduction of 
diastolic blood pressure (DBP), disappearing after the first minute of injection, was observed.  
 
Ladarixin did not affect fertility either in male and female rats or rabbits.  

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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 at 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 at 100 mg/kg/day for both the maternal and 
developmental toxicity.  
 
1.4 
Previous clinical experience with ladarixin 
 
Ladarixin was previously investigated in 3 Phase I and 2 Phase II studies. Altogether, these 
studies involved 195 subjects. In detail, 143 subjects were exposed to ladarixin at various 
doses, of whom 89 healthy during the Phase I studies, 4 suffering from bullous pemphigoid 
and 50 suffering from T1D in the Phase II studies 26 of whom are female patients. Details of 
all previous clinical studies can be found in the Investigator’s Brochure (1).  
 
1.4.1 
Pharmacokinetics and metabolism  
 
The PK evaluation of ladarixin and its metabolites was performed in 89 subjects during the 3 
Phase I studies and in 4 subjects during one Phase II study. 
 
The 1st Phase I study investigated for the 1st time the PK and the safety of ladarixin 
administered as single ascending doses (25, 50, 100, 200 and 400 mg) to healthy men 
subdivided into 8 cohorts. The parent drug DF 2156Y as well as the metabolites DF 2108Y 
and DF 2227Y were determined in plasma, urine and feces. Blood and urine were collected up 
to 168 h post-dose, while feces up to 96 h post-dose.  
 
Afterwards, in a 2nd Phase I study, the PK of ladarixin and metabolites was investigated after 
multiple ascending doses (50, 100 and 200 mg twice daily) for 5 days of treatment in 3 
cohorts of 12 subjects each, of whom 9 received ladarixin and 3 the matching placebo. A 4th 
cohort of 12 subjects was recruited to investigate the drug-drug interaction of ladarixin with 
CYP2C9 using tolbutamide as probe drug.  
 
The 3rd Phase I study investigated the PK of ladarixin and metabolites after single dose and at 
steady state, administering multiple doses (300 and 400 mg once daily) for 7 days to 2 
cohorts.  
 
1.4.2 
Phase I safety, tolerability and bioavailability single ascending dose study in 
healthy men 
 
Plasma, urine and faces samples were collected during a double-blind, randomized, placebo-
controlled, ascending dose study to evaluate the tolerability and preliminary PK of ladarixin 
and its metabolites (DF 2108Y and 2227Y) after oral administration to male healthy 
volunteers. Five (5) dose levels were tested (25, 50, 100, 200 and 400 mg) and administered 
to cohorts of 8 subjects of whom 6 received ladarixin and 2 the matching placebo. Analytical 
determinations of the parent compound and metabolites in plasma, urine, and faces were 
performed by a liquid chromatography mass spectrometry (LC-MS/MS) validated method. 
The lower limit of quantification (LQL) in plasma was 0.1 μg/mL for DF 2156Y and DF 

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2108Y, respectively, and 0.05 μg/mL for DF 2227Y. In urine and faces, the LQL was 0.1 
μg/mL and 0.05 μg/mL, respectively, for the 3 analytes.  
Plasma samples were collected at pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 36, 48, 
60, 72, 84, 96, 120, 144 and 168 h post-dose. Urine samples were collected in the following 
time periods: 0-12, 12-24, 24-36, 36-48, and during subsequent intervals of 24 up to 168 h 
post-dose. Faces samples were collected in the intervals 0-24, 24-48, 48-72 and 72-96 h post-
dose. 
 
Main PK parameters of ladarixin and its metabolites measured and calculated after single dose 
of 400 mg of ladarixin are presented in the following table. 
 
Table 1.4.2.1 
PK parameters of ladarixin and its metabolites measured and calculated after single dose 
of 400 mg of ladarixin to healthy men (N=6) 
Variable (Unit) 
DF 2156Y 
(N=6) 
DF 2108Y 
(N=6) 
DF 2227Y 
(N=6) 
Cmax 
(µg/mL) 
54.86±7.41 
0.938±0.104 
0.692±0.116 
tmax 
(h) 
1.75±1.12 
14.92±772 
45.98±15.91 
AUC0-t 
(µg/mLxh) 
912.40±155.62 
49.58±10.07 
51.93±9.40 
AUC0-∞ 
(µg/mLxh) 
921.54±159.99 
50.36±10.61 
NC 
t1/2 
(h) 
13.62±2.66 
18.32±2.65 
NC 
Vz/F 
(L) 
8.19±1.84 
ND 
ND 
Cl/F 
(L/h) 
0.42±0.07 
ND 
ND 
Ae0-t 
(% of dose) 
79.67±9.99 
2.00±0.45 
1.08±0.33 
ClR 
(L/h) 
0.34±0.05 
0.131±0.03 
0.068±0.023 
AeFeces0-t 
(µg) 
120.76±52.31 
0.0 
0.0 
mean±SD are reported; NC: not calculated; ND: not determined 
 
1.4.3 
Phase I safety, tolerability and bioavailability single and multiple dose study in 
healthy men 
 
Twenty-four (24) men were randomized into 2 cohorts including 12 subjects (9 subjects 
received ladarixin and 3 subjects received placebo). Ladarixin was administered at the dose of 
300 and 400 mg for 7 days. The subjects received a single dose on days 1 and 8 and twice 
daily every 12 h on days 3 to 7. Plasma samples were collected as follows:  
Day 1: pre-dose and 0.5, 1, 1. 5, 2, 3, 4, 5, 6, 8, 10, 12, 24 h post dosing  
Day 3: Day 4, Day 5, Day 6: before the first and the second daily dosing  
Day 7: before and 1h after the first and the second daily dose  
Day 8: pre-dose and 0.5, 1, 1. 5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60 and 72 h post dosing 
 

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Main PK parameters of ladarixin and its metabolites measured and calculated after single dose 
of 400 mg of ladarixin are presented in the following table. 
 
Table 1.4.3.1 
PK parameters of ladarixin and its metabolites measured and calculated after single dose 
of 400 mg of ladarixin to healthy men (N=9) 
Variable (Unit) 
DF 2156Y 
(N=9) 
DF 2108Y 
(N=9) 
DF 2227Y 
(N=9) 
Cmax 
(µg/mL) 
81.10±13.99 
0.82±0.19 
0.40±0.08 
tmax  
(h) 
0.52 (0.50 – 1.52) 
10 (8 – 12) 
8.02 (5.02 – 12) 
AUC0-48 
(µg/mLxh) 
977.5±152.3 
32.46±5.18 
19.60±3.61 
AUC0-∞  
(µg/mLxh) 
1063.2±188.0 
NC 
NC 
t1/2  
(h) 
13.55±2.21 
NC 
NC 
Vz/F  
(L) 
7.03±0.926 
ND 
ND 
Cl/F 
(L/h) 
0.37±0.0734 
ND 
ND 
mean±SD are reported except for tmax for which mean, minimum and maximum are reported; NC: not calculated; ND: not 
determined 
 
1.5 
Rationale 
 
Considering the positive tolerability results obtained at all doses studied in the previous 3 
Phase I studies and the results obtained in 2 completed randomized Phase II studies, the main 
aim of this study is to assess the food effect on the bioavailability of ladarixin after single 
dose of 400 mg of the test capsule formulation when administered under fed and fasting 
conditions to healthy subjects. 
Since the PK profile of ladarixin in  previous Phase I and II studies were evaluated only in 
men, the study will include healthy women in order to evaluate the PK of ladarixin and 
metabolites in females for the 1st time. 
 
The study is designed according to the EMA guidelines on the investigation of bioavailability 
and bioequivalence (8) and on the investigation of drug interactions (9). 
 
1.6 
Risks and benefits 
 
Ladarixin was generally well tolerated at all doses studied as derived from Phase I clinical 
studies. Similarly, in the Phase II clinical studies, ladarixin was generally well tolerated with 
only mild adverse events (AEs). Nevertheless, the limited sample size prevents any overall 
conclusions on the safety of the investigational medicinal product (IMP).  
Overall, 95 adverse drug reactions (ADRs) were reported in a total of 48 subjects out of 143 
exposed to ladarixin in all the previous clinical studies. Most frequent ADRs concerned the 
following System Organ Class (SOC) terms: 
Gastrointestinal disorders: occurred at a frequency of about 52% and including, among most 
frequent ADRs: dyspepsia, dysphagia, abdominal pain, constipation, diarrhea and nausea. 
Nervous System Disorders: occurred at a frequency of about 26% and including, among most 
frequent ADRs: headache and dizziness. 

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Dyspepsia and dysphagia were both considered as definitely related to ladarixin, because they 
occurred shortly after administration. Also dyspepsia consistently recurred after multiple drug 
administrations. 
 
On the basis of these safety results, no particular safety risks are expected for healthy subjects 
taking part in the present study at the planned dose of 400 mg of ladarixin, which will be 
administered twice to each volunteer, once in each study period. 
 
Blood sampling with cannula insertion may cause minor discomfort. The risks associated with 
blood draws include pain, bleeding and bruising. 
 
No specific benefits for the participants in the current study are foreseen. Their remuneration 
will be paid after study completion. The remuneration covers loss of time and any 
inconvenience caused by the participation in the study. 

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2 
STUDY OBJECTIVES 
 
2.1 
Objectives 
 
2.1.1 
Primary objective 
 
Primary objective of the study is to investigate the effect of food on the bioavailability of DF 
2156Y after single dose administration of 400 mg of ladarixin to healthy male and female 
volunteers under fed and fasting conditions. 
 
2.1.2 
Secondary objectives 
 
 to investigate the effect of gender on the bioavailability of DF 2156Y and its metabolites 
(DF 2108Y and DF 2227Y) after single dose administration of 400 mg of ladarixin to 
healthy male and female volunteers; 
 To evaluate safety and tolerability of a single dose administration of 400 mg ladarixin to 
healthy male and female volunteers. 
 
2.2 
Endpoints 
 
2.2.1 
Primary end-point 
 
 to evaluate and compare the rate (Cmax) and extent (AUC0-t; AUC0-∞) of absorption of DF 
2156Y after single dose administration of 400 mg of ladarixin under fed and fasting 
conditions.  
 
2.2.2 
Secondary end-points 
 
 to evaluate and compare between genders the rate (Cmax) and extent (AUC0-t; AUC0-∞) of 
absorption of DF 2156Y and its metabolites (DF 2108Y and DF 2227Y) after single dose 
administration of 400 mg of ladarixin to healthy male and female volunteers; 
 to describe the pharmacokinetic profile of DF 2156Y (total and unbound) and its 
metabolites (DF 2108Y and DF 2227Y) after single dose administration of 400 mg of 
ladarixin under fed and fasting conditions; 
 to collect safety and tolerability data of a single oral dose administration of 400 mg of 
ladarixin. 
 

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3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of product 
 
The analytical certificate will be supplied with the investigational medicinal product (IMP). 
 
3.1.1.1 
Test product 
 
IMP 
Ladarixin 200 mg hard gelatin capsules 
Distributor 
Dompé farmaceutici S.p.A., Italy 
Manufacturer 
(active substance) 
AMSA S.p.A, Como, Italy 
Manufacturer 
(finished product) 
Depo Pack s.n.c., Saronno (Va), Italy 
Pharmaceutical form 
Hard gelatin capsules  
Dose 
400 mg (two 200 mg capsules)  
Administration route 
Oral 
 
 
3.1.2 
Dose regimen 
 
A single oral dose of 400 mg of ladarixin (two 200-mg capsules) will be administered to 
healthy male and female volunteers under fed (T treatment) and fasting (R treatment) 
conditions in 2 study periods, according to a two-way crossover design, with a wash-out 
interval of at least 14 days between the two administrations. 
 
3.1.3 
Route and method of administration 
 
The IMP will be orally administered on day 1 of each period, at 8:00 ± 1 h. 
In detail, at each dosing, 2 capsules will be swallowed with 240 mL of still mineral water, 
without chewing. 
 
The subjects allocated to the fed conditions will receive the IMP 30 min after having started 
to eat a high-fat and high-caloric breakfast (§ 6.2.1), while the subjects allocated to the fasting 
conditions will receive the IMP under prolonged fasting conditions (at least 10 h pre-dose).  
 
The investigator will check that all subjects take the IMP appropriately. 
 
3.1.4 
Investigational product distribution 
 
The IMP will be administered by the investigator or by his/her deputy at the Phase I Unit. The 
IMP will be exclusively used for the present clinical study and will only be administered to 
the subjects enrolled in the study.  
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
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3.2 
Packaging and labeling 
 
The Phase I Unit will be provided with 36 subject’s individual boxes (subject kits). Each 
subject’s kit will contain 2 boxes (one for each study period), each containing 2 blisters of 1 
200-mg capsule of ladarixin.  
 
The sponsor will provide a reserve kit for each subject to be used if needed. Subject kits will 
be numbered from 001 up to 036. Reserve subject kits will be numbered as 001R-036R. 
 
The formulation labeling will report all the information requested according to the Annex 13 
to the Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4; 10) as follows: 
a. 
Name, address and telephone number of the Sponsor, contract research organization or 
investigator (the main contact for information on the product and clinical study) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and Sponsor 
if not given elsewhere 
e. 
The study subject identification number and where relevant, the period number 
f. 
The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 
i. 
The storage conditions 
j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
k. “Keep out of reach of children” 
 
Labels will be in English language. 
 
3.3 
Storage conditions 
 
The IMP will be stored at < 30°C in a dry locked place, sheltered from light.  
 
3.4 
Drug accountability 
 
The IMP will be provided as individual subject’s kits directly to the investigator by the 
sponsor, in excess of the amount necessary for the study (100% excess). 
 
After receipt of the IMP supply, the pharmacist will confirm in writing by signing and dating 
standard drug accountability forms. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 27 
At the end of the study, used, unused and partially used supplies of the IMP provided by the 
Sponsor will either be destroyed on site (upon written authorization) or returned to the 
Sponsor after assessment of drug accountability. 
In the event that the IMP will be destroyed on site, a destruction certificate will be provided to 
the sponsor. 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 28 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
Single center, single dose, open label, randomized, two-way, crossover, food effect study. 
 
4.2 
Discussion of design 
 
The study has been designed in agreement with the EMA Guideline on the Investigation of 
Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr., 20 January 2010) (8) and FDA  
guidance on the Assessing the Effects of Food on Drugs in INDs and NDAs (14). 
 
The sample size was not calculated through any statistical calculation. The planned sample 
size is estimated as sufficient for the descriptive purposes of the study in compliance with the 
relevant EMA guideline for PK studies (8). 
 
Each randomized subject will be allocated to a sequence of treatments (fasting (R) or fed (T)) 
in the two study periods (TR or RT) according to a computer generated randomization list 
(see § 8.1).  
 
The dose of 400 mg planned for the present study was selected because proved to be well 
tolerated in the previous Phase I and II clinical studies (1). 
 
The EMA Guideline on the Investigation of Drug Interactions (CPMP/EWP/560/95/Rev. 1. 
Corr.2, 21 June 2012) (9) has been taken into account for the study administration of the IMP 
in fed conditions.  
 
The wash-out interval of 14 days is considered appropriate according to the known half-life of 
ladarixin (§ 1.4).  
 
The open-label design was chosen since the study endpoints are based on the objective 
measurement of ladarixin and its active metabolites in plasma. The outcome variables are not 
influenced by the subjects or investigator being aware of the administered treatment. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
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Final version 1.0, 28MAY20 
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5 
STUDY POPULATION 
 
5.1 
Target population 
 
The study population will include healthy volunteers (men and women), aged 18-55 years 
inclusive.  
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfill all these criteria: 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and Age: men/women, 18-55 years old inclusive  
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 
50-89 mmHg, pulse rate (PR) 50-90 bpm and body temperature (BT) 35.5-37.5° C, 
measured after 5 min at rest in the sitting position 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study 
6. Contraception and fertility (women only): women of child-bearing potential must not wish 
to get pregnant within 30 days after the end of the study and must be using at least one of 
the following reliable methods of contraception: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 
months before the screening visit until 30 days after final visit 
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or 
contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap 
with spermicide for at least 2 months before the screening visit until 30 days after final 
visit 
c. A male sexual partner who agrees to use a male condom with spermicide until 30 days 
after final visit 
d. A sterile sexual partner 
Women participants of non-childbearing potential or in post-menopausal status for at least 
one year will be admitted. 
For all women, pregnancy test result must be negative at screening and day -1. 
 
5.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
1. Electrocardiogram (ECG) 12-leads (supine position): clinically significant abnormalities 
2. Physical findings: clinically significant abnormal physical findings which could interfere 
with the objectives of the study 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
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Page 30 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of 
physical illness 
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (ladarixin or 
derivatives) and/or formulations' ingredients; known hypersensitivity to non-steroidal anti-
inflammatory drugs (NSAIDs); history of hypersensitivity to drugs (in particular 
methanesulfonyl propanamide) or allergic reactions in general, which the Investigator 
considers may affect the outcome of the study 
5. Diseases: hypoalbuminemia or significant history of renal, hepatic, gastrointestinal, 
respiratory, skin, hematological, endocrine, neurological or cardiovascular diseases that 
may interfere with the aim of the study 
6. Medications: medications, including over the counter drugs (in particular NSAIDs), herbal 
remedies and food supplements taken 14 days before the start of the study (in any case at 
least 5 times the half-life of the drug or a minimum of 14 days, whichever is longer), with 
the exception of paracetamol. Hormonal contraceptives and hormonal replacement 
therapy for women will be allowed 
7. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study. The 3-month interval is calculated as the time between the 
first calendar day of the month that follows the last visit of the previous study and the first 
day of the present study 
8. Blood donation: blood donations for 3 months before this study 
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol (>1 drink/day for women and >2 
drinks/day for men, defined according to the USDA Dietary Guidelines 2015-2020 (11)], 
caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day)  
10. SARS-COV2 test: positive SARS-COV2 test on day -3 or -2 of each study period 
11. Positive to one of these test:  Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), 
HIV 1/2 (HIV Ag/Ab combo) at screening.  
12. Drug test: positive result at the drug test at screening or day -1 of each study period 
13. Alcohol test: positive alcohol breath test at screening or day -1 of each study period 
14. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in 
the 4 weeks before this study; vegetarians; vegans 
15. Pregnancy (women only): positive or missing pregnancy test at screening or day -1 of 
each period, pregnant or lactating women 
 
5.3.1 
Not allowed treatments 
 
No medication, including over the counter drugs (in particular NSAIDs), herbal remedies and 
food supplements, will be allowed for 14 days before the start of the study (in any case at least 
5 times the half-life of the drug or a minimum of 14 days, whichever is longer), and during 
the whole study duration. Paracetamol will be allowed as therapeutic counter-measure 
(maximum 2 g per day) for AEs according to the investigator’s opinion. Hormonal 
contraceptives and hormonal replacement therapy for women will be allowed. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 31 
The intake of any other medication will be reported as a protocol deviation. However, it will 
lead to subject's discontinuation from the study only if the investigator, together with the 
Sponsor, considers it could affect the study assessments or outcome. 
 
 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarized at page 11. 
 
6.1 
Study visits and procedures 
 
Each study subject will undergo 8 visits. 
 
The study protocol foresees 2 periods separated by a wash-out interval of at least 14 days. 
Minimum study duration will be 20 days, screening visit included. A written informed 
consent will be obtained before any study assessment or procedure. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the Phase I Unit by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the Phase I Unit by the last subject, i.e. the last visit foreseen by the study protocol, 
independently of the fact that the subject is a completer or a withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening – visit 1: between day -21 and day -2  
 Screening – visit 1.1: day -3 or day -2 
 Period 1 – visit 2: day -1 
 
 Interventional phase 
 Period 1 – visit 3: days 1-4 
 Wash-out interval of at least 14 days 
 Period 2 – visit 4: day -3 or day -2 
 Period 2 – visit 5: day -1 
 Period 2 – visit 6: days 1-4 
 
 Final phase 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an ETV. 
 
 
 

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Sponsor code LDX0219 
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Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From day -21 
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, 
physical abnormalities) 
 Vital signs measurement including blood pressure 
(BP), pulse rate (PR) and body temperature (BT) 
 ECG recording 
 Laboratory analyses: hematology, blood chemistry, 
urinalysis, serum virology and serum pregnancy test 
(women only) 
 Alcohol breath test 
 Urine multi-drug kit test 
 AE monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: The first two letters 
of the surname followed 
by the first two letters of 
the first name will be used 
in the Phase I Unit source 
document only and will 
not be transferred to the 
Sponsor. 
Screening –  
Visit 1.1 
Day -3 or -2 
 Nasal and pharyngeal swab for SARS-COV2 test 
 Adverse events monitoring 
 Previous/concomitant medications 
 
Period 1 - Visit 2 
Day -1 
 Alcohol breath test 
 Urine pregnancy test (women only) 
 Urine multi-drug kit test 
 ECG recording 
 Vital signs measurement 
 AE and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomization 
Arrival at the Phase I Unit 
in the evening. 
Confinement until the 
morning of day 4. 
Standardized low-fat 
dinner. 
Fasting for at least 10 h 
(overnight). 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
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Final version 1.0, 28MAY20 
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Page 33 
 
Day 
Procedures/Assessments 
Notes 
Period 1 - Visit 3 
Day 1 
 Investigational medicinal product administration at 
8:00 ± 1 h 
 Vital signs measurement at pre-dose  
 ECG recording at pre-dose  
 Blood sample collection for PK analysis at pre-dose 
(0) and 0.25 (15 min), 0.5 (30 min), 1, 1.5, 2, 3, 4, 5, 
6, 8, 10, 12 and 18 h post-dose 
 AE and concomitant medications 
Standardized high-fat and 
high 
caloric 
breakfast 
starting at 30 min pre-
dose 
for 
subjects 
receiving 
the 
investigational medicinal 
product 
under 
fed 
conditions in this study 
period. Breakfast must be 
completed within 30 min. 
Subjects receiving the 
investigational medicinal 
product 
under 
fasting 
conditions will not have 
breakfast. 
Standardized lunch and 
dinner at about 13:00 (5 h 
post-dose) and 20:00 (12 
h post-dose), respectively 
Days 2 and 3 
 Blood sample collection for PK analysis at 24, 30, 
36, 48, 54 and 60 h post-dose 
 AE and concomitant medications 
Standardized 
breakfast, 
lunch and dinner at about 
9:00, 13:00 and 20:00, 
respectively 
Day 4 
 Vital signs measurement upon discharge 72 h post-
dose 
 ECG recording upon discharge 72 h post-dose 
 Blood sample collection for PK analysis at 72 h 
post-dose 
 AE and concomitant medications 
 Full physical examination (body weight and physical 
abnormalities) upon discharge 
Discharge from the Phase 
I Unit in the morning, 
after the 72-h post-dose 
blood sample collection, 
ECG recording, vital signs 
check and full physical 
examination. 
Upon leaving, the subjects 
will 
be 
instructed 
to 
contact immediately the 
investigator in case of 
occurrence of any adverse 
reactions. 
Wash-out 
At least 14 
days 
A wash-out interval of at least 14 days between the two 
administrations of the two study periods 
 
Period 2 - Visit 4 
Day -3 or -2 
As visit 1.1, day -3 or -2 
 

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Day 
Procedures/Assessments 
Notes 
Period 2 - Visit 5 
Day -1 
As visit 2, excluding enrolment and randomization. In 
addition full physical examination (body weight and 
physical abnormalities) will be performed. 
As visit 2 
Period 2 - Visit 6 
Days 1-4 
As visit 3. IMP administered according to the 
randomization list and crossover design 
As visit 3 
Final Visit/ETV 
Day 4 of 
period 2 
/at ETV in case 
of 
discontinuation 
 Full physical examination (body weight and physical 
abnormalities; also vital signs and ECG in case of 
ETV) 
 Alcohol breath test 
 Urine multi-drug kit test 
 Laboratory analyses as at screening, with the 
exception of virology, coagulation, microbiology, 
albumin and globulin 
 AEs and concomitant medications 
 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator 
until the normalization of the concerned clinical 
parameter(s) 
Upon leaving, the subjects 
will 
be 
instructed 
to 
contact immediately the 
investigator in case of 
occurrence of any adverse 
reactions. 
 
6.2 
Diet and lifestyle 
 
On day -1 of each period, a standardized low-fat dinner will be served after confinement. On 
day 1 of each study period, all the subjects will not take any food or drinks (except water) for 
at least 10 h (i.e. overnight). The subjects allocated to the fed conditions, after the overnight 
fasting period, will receive a high-fat and high-caloric breakfast (see § 6.2.1) starting 30 min 
pre-dose and will complete their breakfast within 30 min, while the subjects allocated to the 
fasting conditions will fast overnight and then receive their treatment. Water will be allowed 
as desired, except for 1 h before and 1 h after IMP administration. In order to maintain an 
adequate hydration, the subjects will be encouraged to drink at least 150 mL of still mineral 
water every 2 h for 5 h post-dose, starting at 1 h post-dose. 
 
On day 1, all subjects will then remain fasted until 5 h post-dose. A standardized lunch and 
dinner will be served at approximately 5 h and 12 h post-dose (at approximately 13:00 and 
20:00).  
On days 2 and 3, standardized breakfast, lunch and dinner will be served to all subjects at 
about 9:00, 13:00 and 20:00, respectively.  
 
One cup of coffee or tea will be allowed after each meal only; any other coffee, tea or food 
containing xanthines (i.e. coke, chocolate, etc.), alcohol and grapefruit will be forbidden 

CONFIDENTIAL 
 
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Sponsor code LDX0219 
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Page 35 
during confinement. In particular, grapefruit and alcohol will be forbidden for 24 h before the 
first IMP administration until the end of the study. 
 
The subjects will be allowed to smoke 9 cigarettes during confinement, one after each meal, 
with the exclusion of the high-fat and high-caloric breakfast.  
 
During confinement, routine ambulant daily activities will be strongly recommended. 
 
6.2.1 
Standardized high-fat and high-caloric breakfast 
 
As mentioned above, on day 1 of each study period after blood sample collection at pre-dose 
(0), subjects randomized to the Test (T) treatment will start to eat a high-fat and high-caloric 
breakfast 30 min pre-dose and will be instructed to complete their meal within 30 min. 
 
Breakfast caloric content will be approximately 1000 kilocalories (kcal) and fat content will 
be approximately 60% of the total caloric content. The standardized breakfast will provide 
approximately 15%, 25% and 60% of the calories from proteins, carbohydrates and fats, 
respectively, and is detailed in the table below:  
 
Table 6.2.1.1 
High-caloric and high-fat breakfast composition  
Food 
Amount 
(g) 
Fats 
(g) 
Carbohydrates 
(g) 
Proteins (g) 
kcal 
Whole milk 
250 
8 
12 
8 
160 
Two fried eggs 
140 
14 
1 
13 
180 
Butter 
30 
25 
0 
0 
227 
Two strips of bacon 
50 
12 
0 
8 
138 
Two slices of toast 
50 
0 
35 
4 
150 
Olive oil white bread 
40 
2 
20 
4 
100 
 
6.2.2 
Restrictions 
 
During each study period, the subjects will be confined from the evening preceding the IMP 
administration (study day -1) until the morning of day 4. 
 
For the 4 h following the administration, when not involved in study activities, the subjects 
will remain seated. They will not be allowed to lie down.  
 
During confinement, hazardous, strenuous or athletic activities will not be permitted. 
 
 

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Sponsor code LDX0219 
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7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Full physical examinations will be performed at: 
 
 screening visit 
 on day 4 of period 1 (before discharge) 
 on day -1 of period 2 
 final visit/ETV. 
 
Body weight will be recorded each time. Subjects will be weighed (kg) lightly clothed 
without shoes. Height will be measured at screening only and BMI will be recorded. BMI will 
be calculated as weight [kg]/(height [m] x height [m]).  
Information about the physical examination will be recorded by the investigator. Any 
abnormalities will be recorded. 
 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see § 11), will be recorded in the subject source documents. 
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual electronic case report forms (eCRF). 
 
7.1.1 
Vital signs 
 
Subjects' blood pressure (BP), pulse rate (PR) and tympanic body temperature (BT) will be 
measured by the investigator or his/her deputy after 5 min at rest in sitting position at:  
 
 screening visit 
 day -1  
 day 1 at pre-dose (0) 
 day 4 at 72 h post-dose (in period 2, it will be considered as the final visit measurement) 
 ETV, if applicable 
 
7.1.2 
ECGs 
 
12-Lead ECGs will be performed in supine position a: 
 
 screening visit 
 day -1  
 day 1 at pre-dose (0) 
 day 4 at 72 h post-dose (in period 2, it will be considered as the final visit recording) 
 ETV, if applicable 
 
Date/time of the ECG recording, overall investigator's interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and all abnormalities 
found (if any) will be reported in the individual eCRF. 

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7.1.3 
Clinical laboratory assays 
 
Samples of blood (17 mL) and urine will be collected. The following laboratory analyses will 
be performed at the screening visit at the clinical laboratory (§ 16.5): 
 
Hematology 
Leukocytes and leukocyte differential count (percentage values and absolute values), 
erythrocytes, hemoglobin (conv. units), hemoglobin (IS units), hematocrit, MCV, MCH, 
MCHC, thrombocytes,  
 
Coagulation 
Prothrombin time, aPTT 
 
Blood chemistry 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, fasting glucose, urea, uric acid, total 
cholesterol, triglycerides 
Proteins: total proteins, albumin, globulin (calculated by the laboratory by detracting albumin 
from total proteins) 
 
Serum virology  
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo).  
 
Urine analysis 
Urine chemical analysis (stick): pH, specific weight, appearance, color, nitrites, proteins, 
glucose, urobilinogen, bilirubin, ketones, hematic pigments, leukocytes 
Urine sediment (analysis performed only if positive): leukocytes, erythrocytes, flat cells, 
round cells, crystals, cylinders, mucus, bacteria 
 
Microbiological analysis 
Coronavirus SARS-COV-2 (nasopharyngeal swab) will be performed at the laboratory (§ 
16.5) on day -3 or -2 of the visit 1.1 (screening visit) and on day -3 or -2 of period 2 
 
A urine drug test will be performed at the Phase I Unit at screening, day -1 of each study 
period and final visit/ETV using a urine multi-drug kit. The following drugs will be assessed: 
cocaine, amphetamine, methamphetamine, cannabinoids (delta-9-tetrahydrocannabinol - 
THC), opiates and ecstasy.  
 
A serum pregnancy test will be performed at the laboratory (§ 16.5) at screening and final 
visit/ETV. Urine pregnancy tests will be performed on day -1 of each study period at the 
Phase I Unit.  
 
The same analyses, with the exception of coagulation, microbiology, albumin, globulin and 
virology will be performed at the final visit/ETV. 
 

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Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and all abnormalities 
found (if any) will be reported in the individual eCRF. All clinically significant abnormalities 
after the screening visit will be recorded as AEs. 
 
7.2 
Sampling for pharmacokinetic analysis 
 
7.2.1 
Venous blood sampling 
 
Venous blood samples (8 mL) will be collected from a forearm vein at the following times:  
 
 pre-dose (0), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, 48, 54, 60 and 72 h 
post-dose 
 
Actual sampling times for each subject will be recorded in the individual electronic case 
report forms (eCRF). The actual sampling times should not exceed the recommended 
tolerance ranges presented in the table below. Any deviation outside the recommended ranges 
will be verified through Data Clarification Forms and, if confirmed, will be reported as 
protocol deviation, although it will not automatically lead to the exclusion of the concerned 
subjects from the PK Set. 
 
Table 7.2.1.1 
Tolerance ranges for the scheduled sampling times 
Sampling time 
Tolerance range 
Pre-dose (0) 
Within 40 min before IMP administration 
0.25 h (15 min) 
0 min 
0.5 h (30 min) 
± 1 min 
1, 1.5 h 
± 3 min 
2, 3, 4, 5 h 
± 5 min 
6, 8, 10, 12, 18, 24, 30 h 
± 10 min 
36, 48, 54, 60, 72 h 
± 30 min 
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch 
valve. The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline 
solution containing 20 I.U./mL Na-heparin. The first 2 mL of blood will be discarded at each 
collection time to avoid contamination of the sample with heparin. 
 
The remaining 6 mL will be collected from the catheter and transferred with a syringe into 
heparinized tubes (Li-heparin). 
 
The samples will be stored on ice for a maximum of 15 min. Then the samples will be 
centrifuged at 4° C for 10 min at 2500 g to obtain plasma. Each plasma sample will be 
immediately divided into 3 aliquots, P1 (500 µL), P2 (500 µL) and P3 (the remaining 
amount), in pre-labeled polypropylene tubes, and stored frozen at ≤-20° C until shipment to 
the analytical laboratory.  
 
If any clinical assessment, such as vital signs measurement or ECG recording, is foreseen at 
the same time-point as blood sampling for PK analysis, blood collection will be performed at 
the scheduled time. However, vital signs and ECG parameters can be influenced by the blood 
sampling. Therefore, these assessments can be performed within 30 min before the pre-dose 

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Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 39 
PK time point (0 h) and within 10 min before the other scheduled PK time-points. Any 
deviations outside the recommended time will be verified through Data Clarification Forms. 
However, since vital signs measurements and ECG recordings will be performed for safety 
reasons only, deviations from the planned time schedule will be considered not relevant. 
 
7.2.2 
Analytics  
 
The concentration of DF 2156Y (total and unbound) and its metabolites (DF 2108Y and DF 
2227Y) in plasma will be determined at Dompé farmaceutici S.p.A. Bioanalytical 
Laboratories, Italy, using a fully validated HPLC-UV method.  
 
The concentrations of unbound DF2156Y will be determined initially only at the following 
time points: 1, 3, 6, 12, 24 h post dose: additional analysis could be performed at different 
time points only if necessary.  
 
Analyses will be performed according to the general Principles of “OECD Good Laboratory 
Practices for testing of chemicals" C(81) 30 (final) and GCP.  
 
The method validation report and the analytical report will be attached to the final clinical 
study report (CSR). 
 
A total of 1512 plasma samples (756 samples for each study period) will be analyzed. 
 
7.2.3 
Labeling, storage and transport of samples 
 
7.2.3.1 
Samples labeling 
 
Each sample tube will be clearly and unequivocally identified with a label resistant to the 
storage temperature and reporting: 
 
Study code 
Study CRO-PK-20-345 - Sponsor code LDX0219 
Subject number 
001-036 
Tube identification 
P1/P2/P3 
Period  
1/2 
Scheduled sampling time as h; see § 7.2.1. 
 
7.2.3.2 
Samples storage and transport 
 
At the Phase I Unit, the samples will be stored at ≤-20° C. At the end of each collection day, 
aliquots P1 will be stored in a freezer, separated from the other aliquots. 
 
All aliquots P1, packed in sufficient solid CO2, will be shipped by an authorized courier from 
CROSS Research S.A., Switzerland, to Dompé farmaceutici S.p.A. Bioanalytical 
Laboratories, Italy. 
 

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After receipt by the analytical laboratory of the first aliquots (P1) in good conditions, aliquots 
P2 will be shipped to the laboratory, applying the same procedures described for the shipment 
of aliquots P1. 
 
All aliquots 1 and 2 will remain stored at the analytical laboratory (Dompé farmaceutici 
S.p.A. Bioanalytical Laboratories, Italy) at least until finalization of the CSR. Afterwards, the 
samples will be destroyed after authorization by the Sponsor’s Project Manager and a 
confirmation of the disposal will be provided by email. 
 
All aliquots P3 will remain stored (≤-20° C) at CROSS Research S.A., Switzerland. These 
samples could either be: 
 sent to the laboratory for reanalysis if necessary for analytical reasons or if any problems 
occur during the delivery of aliquots P1 and/or P2, or 
 destroyed at an authorised site, or 
 stored at CROSS Research S.A., for a maximum time of 5 years. 
 
No analyses different from those stated in this protocol and agreed by the subjects when 
signing the informed consent form will be performed, unless a new informed consent and a 
new approval from the Ethics Committee is obtained. The subjects may ask to destroy their 
own samples at any time. 
 
7.3 
Total number of samples and blood withdrawn 
 
During the study the following volume of blood will be collected:  
 
for routine laboratories analysis: 
 
Screening visit: 
12.5 mL 
Final visit/ETV: 12.5 mL 
 
for coagulation: 
 
Screening visit: 
4.5 mL 
 
for PK analysis: 
 
Treatment T: 
21 samples x 8 mL = 168 mL 
Treatment R: 
21 samples x 8 mL = 168 mL 
 
In total 365.5 mL of blood (not exceeding a normal blood donation) will be withdrawn from 
each subject. 
 
 
 

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8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomization 
 
The randomization list will be computer-generated by the Biometry Unit of the contract 
research organization (CRO), using the PLAN procedure of SAS® version 9.3 (TS1M1) (12) 
or higher (the actual version will be stated in the final CSR). The randomization list will be 
supplied to the study site before study start and will be attached to the final CSR. 
Randomization will be stratified by sex in order to have the same number of men and women 
for every sequence of treatments.  
 
8.2 
Treatment allocation 
 
Subjects will be assigned to one sequence of treatments (e.g. TR or RT) i.e. to receive the 
IMP in fed conditions (T treatment) during period 1 and in fasting conditions (R treatment) in 
period 2 or vice versa according to their randomization number. 
Randomization number will be given to the subjects on study Day -1 of period 1 and will be 
used to assign the treatment sequence. 
 
8.3 
Blinding 
 
This is an open-label trial. No masking procedure will be applied since an open-label design 
was considered adequate for evaluating objective measures such as pharmacokinetic 
parameters. All the personnel involved in the analytical determinations of ladarixin and its 
metabolites in plasma samples collected from the volunteers will be maintained in blind 
conditions. 
 
 

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9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary variables 
 
Cmax and AUC0-t of plasma DF 2156Y after single dose administration of 400 mg of ladarixin 
under fed and fasting conditions 
 
9.1.2 
Secondary variables 
 
 AUC0-∞, tmax, t1/2, λz and Frel of plasma DF 2156Y after single dose administration of 400 
mg of ladarixin under fed and fasting conditions  
 Cmax, AUC0-t, AUC0-∞, tmax, t1/2, λz and Frel of plasma DF 2156Y and its metabolites (DF 
2108Y and DF 2227Y) after single dose of 400 mg of ladarixin under fed and fasting 
conditions measured and calculated in healthy men and healthy women 
 Treatment-emergent adverse events (TEAEs), vital signs (BP, PR, BT), body weight, 
ECGs, physical examinations, laboratory parameters (hematology, blood chemistry and 
urine analysis) 
 
9.2 
Pharmacokinetic assessments 
 
9.2.1 
Pharmacokinetic parameters 
 
The following PK parameters will be measured and/or calculated for DF 2156Y and its 
metabolites, DF 2108Y and DF 2227Y, using the validated software Phoenix WinNonlin® 
version 6.3 (13) or higher (actual version will be stated in the final report): 
 
Cmax: 
Maximum plasma concentration 
tmax: 
Time to achieve Cmax 
λz: 
Terminal rate constant, calculated, if feasible, by log-linear regression using at
least 3 points 
t1/2: 
Half-life, calculated, if feasible, as ln2/λz 
AUC0-t: 
Area under the concentration-time curve from administration to the last
observed concentration time t, calculated with the linear trapezoidal method 
AUC0-∞: 
Area under the concentration-time curve extrapolated to infinity, calculated, if
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration 
%AUCextra: 
Percentage of the residual area (Ct/λz) extrapolated to infinity in relation to the
total AUC0-∞, calculated, if feasible, as 100×[(Ct/λz)/AUC0-∞] 
 

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Frel: 
Relative bioavailability, calculated as ratio AUC0-t (T)/ AUC0-t (R) 
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0-∞ equals or exceeds a 
factor of 0.8 (i.e. if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that the primary variable AUC0-t covers a sufficient percentage of the theoretical total 
extent of exposure.  
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 > 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  
 
9.3 
Safety assessments 
 
Safety and general tolerability of the IMP will be based on TEAEs, physical examinations 
including body weight, vital signs, routine hematology, blood chemistry, urinalysis laboratory 
tests and ECGs. 
 

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Page 44 
10 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. geometric mean (PK data only), arithmetic 
mean, standard deviation (SD), coefficient of variation (CV) %, minimum, median and 
maximum values for quantitative variables, and frequencies for qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of 
demographic and safety data will be performed using SAS® version 9.3 (TS1M1) (12) or 
higher (the actual version will be stated in the final report). 
The statistical analysis of PK parameters will be performed using Phoenix WinNonlin® 
version 6.3 (13) or higher and SAS® version 9.3 (TS1M1) or higher. 
 
10.1 
Analysis Sets 
 
10.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomized allocation to one 
treatment sequence. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
A subject will be defined as randomized in the study when he/she is assigned to one 
randomized treatment sequence. 
 
In the present study, randomized subjects will be the same as enrolled subjects.  
 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
 Safety set: all subjects who receive at least one dose of study treatments. This analysis set 
will be used for the safety and tolerability analyses 
 PK set 1: all subjects randomized who fulfill the study protocol requirements in terms of 
investigational treatment intake and have evaluable PK data readouts for DF 2156Y with 
no major deviations that may affect the PK results. This analysis set will be used for the 
statistical analysis of the PK results for DF 2156Y. 
 PK set 2: all subjects randomized who fulfill the study protocol requirements in terms of 
investigational treatment intake and have evaluable PK data readouts for DF 2108Y and 
DF 2227Y, with no major deviations that may affect the PK results. This analysis set will 
be used for the statistical analysis of the PK results for DF 2108Y and DF 2227Y. 

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Each subject will be coded by the CRO Biometry Unit as valid or not valid for the safety set 
and the PK sets. Subjects will be evaluated according to the treatment they actually receive. 
 
10.1.2 
Reasons for exclusion from the PK sets  
 
Reasons for the exclusion of subjects from the PK sets before the bioanalysis are the 
following: 
 vomiting and diarrhea before or after drug intake which could render the plasma 
concentration-time profile unreliable 
 intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the eCRF as the study is being conducted. 
 
10.2 
Sample size and power considerations 
 
The sample size was not calculated through any statistical calculation. A sample size of 36 
subjects (18 men and 18 women) was estimated as sufficient for the descriptive purposes of 
the present study in compliance with the relevant EMA guideline for PK studies (8). 
 
Drop-out subjects will not be replaced. 
 
10.3 
Demographic, baseline and background characteristics 
 
10.3.1 
Demography 
 
Demographic characteristics will be listed and examined according to qualitative or 
quantitative data. Qualitative data will be summarized in contingency tables. Quantitative data 
will be summarized using classic descriptive statistics. 
 
10.4 
Analysis of pharmacokinetic parameters 
 
10.4.1 
Descriptive pharmacokinetics 
 
A descriptive PK will be presented for plasma total and unbound DF 2156Y and its 
metabolites DF 2108Y and DF 2227Y. The results will be displayed and summarized in tables 
and figures. Individual and mean curves (+SD at sampling times), indicating inter-subject 
variability, will be plotted. Mean curves will be presented by treatment and by treatment and 
sex.  
 
PK parameters of total plasma DF 2156Y and its metabolites DF 2108Y and DF 2227Y will 
be summarized by treatment and by treatment and sex.  

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Data below the lower quantification limit (BLQL) will be considered as 0 in the calculations 
and presented as BLQL in listings and tables. As a consequence of BLQL (i.e. 0) values, 
calculated geometric means (if requested) could be null. For this reason, in the presence of 
any null value, the geometric mean will be reported as NC. If for an individual PK curve, a 
log-linear regression with a correlation coefficient R2 > 0.8 cannot be obtained, the 
extrapolated PK parameters will be reported as NC and considered missing in the calculations 
of descriptive statistics. 
 
10.4.2 
Statistical comparison of pharmacokinetic parameters 
 
For the primary end-point evaluation of food effect, Cmax, AUC0-t and AUC0-∞ of total plasma 
DF 2156Y will be compared between fed and fasting conditions (T vs. R) using analysis of 
variance (ANOVA) for a cross-over design on log-transformed data for evaluation of the food 
effect. Period, treatment, sequence and subject within sequence will be taken in account as 
sources of variation and they will be treated as fixed effect. 
 
The 90% confidence intervals (CI) will be calculated for the point estimates (PE, i.e. the T/R 
ratio of least square geometric means) of the PK parameters.  
 
Established criteria for the absence of a food effect are that the 90% CI for the T/R ratio of the 
geometric means of the PK parameters under consideration are within the 80.00-125.00% 
range.  
 
For the purpose of exploring the gender effect on bioavailability of ladarixin and its 
metabolites, following logarithmic transformation, Cmax, AUC0-t and AUC0-∞ of total plasma 
DF 2156Y and of DF 2108Y and DF 2227Y will be analyzed using ANOVA including 
sequence, period, treatment, subject within sequence, sex and sex*treatment interaction as 
fixed effect. 
 
10.5 
Safety and tolerability evaluation 
 
 AEs 
AEs will be coded by System Organ Class (SOC) and Preferred Term (PT), using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and TEAEs, according to the period of 
occurrence, as follows:  
 PTAEs: all AEs occurring after informed consent signature by the enrolled subject but 
before the first dose of IMP and not negatively affected by the first dose of IMP;  
 TEAEs: all AEs occurring or worsening after the administration of the first dose of 
IMP. 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarized by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC 
and PT, seriousness, relationship to treatment and severity.  
 
 

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 Physical examination 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
 Laboratory data  
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and all abnormalities 
found (if any) will be listed. All laboratory results will be listed and a table of all the abnormal 
values will be presented. The overall investigator’s interpretation will be summarized using 
tables of frequency.  
 
 Vital signs 
Vital signs values will be listed and summarized by descriptive statistics.  
 
 Body weight  
Body weight values will be listed and summarized by descriptive statistics. 
 
 ECG 
Date/time of ECG recording, overall investigator’s interpretation (as normal or abnormal and, 
if abnormal, clinically significant or not clinically significant) and all abnormalities found (if 
any) will be listed. The overall investigator’s interpretation will be summarized using tables 
of frequency 
 
 

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11 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
11.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the Sponsor SOPs, based upon 
applicable local and international regulations. CRO shall submit SUSARs according to local 
law.  
 
A brief summary of AE definition, classification and management is reported below. 
 
11.2 
Definitions 
 
11.2.1 
Adverse Events 
 
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.  
11.2.2 
Adverse Drug Reaction 
 
An Adverse Drug Reaction (ADR) is defined as an adverse experience which is a reasonably 
likely to have been caused by the drug. Adverse events are to be considered unsuspected if the 
relationship to the study drug as described in the table in section 11.5.2 is none or unlikely; 
whereas any AE reported in the study having a possible, probable or highly probable 
relationship to study drug will be considered as an ADR. The definition covers also 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. 
 
11.2.3 
Serious Adverse Event (SAE) Definition 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose: 
 
 results in death 
 is life-threatening (i.e. the subject 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-subject 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. 

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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) 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 subject 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 subject’s wellbeing 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 subject hospitalization, or the development of drug dependency or 
drug abuse 
 
11.3 
Unexpected Adverse Reaction 
 
An 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. 
 
11.3.1 
Reference Safety Information (RSI) 
 
As reported in the Reference Safety Information section of the Investigator’s Brochure, 
considering the development phase of the compound and the low number of total subjects  
exposed to ladarixin, adverse events/reactions (notwithstanding seriousness) should be 
considered unexpected at this stage. 
 
11.3.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
A SUSAR is defined as an ADR that is both unexpected (not consistent with the RSI) and 
also meets the definition of a SAE. 
 

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11.4 
Monitoring for Adverse Events  
 
At each visit following study informed consent form signature, after the subject has had the 
opportunity to spontaneously mention any problems, 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 that is clinically relevant is to be reported as an AE. These 
clinically relevant changes will be reported regardless of causality. 
 
11.5 
AEs recording 
 
AEs will be collected and recorded for any untoward event that occurs in a subject from the 
time he or she signs the ICF for the trial until last follow-up visit/ETV. Thus, any untoward 
medical occurrences or unfavorable and unintended signs, symptoms, or diseases that occur in 
the pre-treatment [pre-treatment AE (PTAE)], in treatment or post-treatment [treatment-
emergent AE (TEAE)] period are to be considered AEs and/or SAEs, and consequently 
recorded and reported as such. Should a non-serious AE become serious, the Investigator will 
then follow the same reporting procedures as for SAEs. 
An AE occurring after the last follow-up visit/ETV and coming to knowledge of the 
investigator (e.g. by spontaneous reporting by study subjects) must be recorded only if it is an 
ADR, according to the investigator’s judgment 
Each AE will be described by:  
• 
Its duration (start and stop dates).  
• 
Severity grade. 
• 
Its relationship to the study drug; (suspected/unsuspected). 
• 
Action(s) taken. 
• 
Outcome. 
11.5.1 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the table below. 
For each episode, the highest severity grade attained should be reported. 
Mild 
Grade 1 - Does not interfere with subject’s usual function (awareness of 
symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with subject’s usual function 
(enough discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with subject’s usual function 
(incapacity to work or to do usual activities [unacceptable]) 
 
 

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11.5.2 
Relationship of AEs to the IMP 
The Investigator will assess the causal relationship between the AE and the IMP, according to 
the criteria in table below: 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational 
Product, e.g. subject is a passenger in a road traffic accident.  
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory 
test abnormality with temporal relationship to drug administration 
which makes a causal relationship improbable and in which other 
drugs, chemicals or underlying disease provide more plausible 
explanations 
Possible 
Relationship may exist, but could have been produced by the 
subject’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 subject’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of 
Investigational Product and, if applicable, re-appears upon repeat 
exposure 
 
11.6 
SAEs reporting 
 
The Investigator must report all SAEs, regardless of presumed causal relationship, to Dompé 
Pharmacovigilance and to the CRO, by email (preferred) or fax within 24 hours of learning of 
the event. Contact details for SAE reporting are the following  
Sponsor  
Dompé Pharmacovigilance 
Email: farmacovigilanza@dompe.com 
Fax: +39.02.36026913 
 
CRO:  
Email: projectmanagement@croalliance.com  
Fax: 
 +41.91.630.05.11 
 
The investigator should also report information on SAEs that continue after subject has 
completed his/her participation in the study (whether study completion or withdrawal), unless 
subject has withdrawn his/her consent. 
Information on SAEs will be recorded on the SAE form. Follow-up reports (as many as 
required) should be completed and faxed/e-mailed following the same procedure above, 
marking the SAE form as “follow up Number XX”.   
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 IMP, 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. 

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In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does 
not usually need to actively monitor subjects for AEs once the trial has ended, if the 
Investigator becomes aware of a SAE occurring to a subject after that subject has ended 
his/her participation in the study (whether study completion or withdrawal), the SAE should 
be reported by the Investigator to the Dompé Pharmacovigilance. 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.  
 
11.6.1 
Adverse events exemption 
Not applicable; no adverse event reporting exemption.  
 
11.7 
Reporting Procedure to IRB/IEC and to Regulatory Authorities 
 
During the course of the clinical trial, Dompé farmaceutici S.p.A shall report any serious 
unexpected ADR (SUSAR) to the Competent Authority (according to specific law 
requirements) while the CRO shall submit SUSARs (as per final report released by Dompé) to 
the concerned IEC which approved the protocol as soon as possible and in no event later than: 
(a)  seven (7) calendar days after becoming aware of the information if the event is fatal 
or life threatening;  
(b)  fifteen (15) calendar days after becoming aware of the information if the event is 
neither fatal nor life threatening. 
 
Dompé farmaceutici S.p.A. shall, within eight days after having informed the IEC/Competent 
Authority under paragraph (a), submit a complete report in respect of that information that 
includes an assessment of the importance and implication of any findings, made on the basis 
of follow up information provided by the Investigator. 
 
The Sponsor shall be responsible to prepare and submit periodical update reports as 
appropriate. 
 
Copies of all correspondence relating to reporting of any SAEs to the IEC/IRB should be 
maintained in the Investigator’s Files. 
 
11.8 
Follow-up of Subjects with Adverse events 
 
AE will be followed by the Investigator (by phone or visit) until resolved or considered stable. 
 
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. It is the Investigator's responsibility to assure that the subjects 
experiencing AEs receive definite treatment for any AE, if required. 
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 

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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. 
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 referred 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. 
 
11.9 
Pregnancy in the Clinical Trial 
 
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are 
summarized in the protocol’s exclusion criteria.  
Prior to enrolment in the clinical trial, female subjects 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 30 days after the study treatment period ends and of the 
potential risks associated with an unintentional pregnancy. During the trial, female subjects 
are to be instructed to contact the Investigator immediately if they suspect they might be 
pregnant. 
Pregnant female subject will discontinued the study. Pregnancy is not reportable as an adverse 
event; however, complications may be reportable and will be assessed for reportability on a 
case by case basis. A form prepared by the Sponsor will be utilized to capture all pregnancy-
related information until the birth of the child during the study treatment period and follow-up 
period. 
 
11.10 
OVERDOSE  
 
Accidental or intentional overdose, which may or may not result in serious adverse reactions, 
is to be reported to Dompé Drug Safety/CRO and 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.  
The Investigator shall provide in the SAE form information about symptoms, corrective 
treatment and outcome of overdose. Dompé Medical Expert should be contacted to discuss 
corrective treatment, if necessary. 
 
 
 

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11.11 
SAEs: clinical site contacts 
 
The clinical site can be contacted by the study participant using the phone and fax numbers 
stated in this protocol or calling the mobile phone number +41.79.822.35.07 (operative 24-
h/day, 365 days/year). This mobile phone can be called by the study participants to 
communicate to the clinical staff any SAE occurring outside the clinical facility. 
 
The contacts for SAEs for the subjects in study are the following: 
Dr. Milko Radicioni 
Phone: +41.91.64.04.450 
Fax: 
+41.91.63.00.511 
Email: milko.radicioni@croalliance.com and clinic@croalliance.com 
 

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12 
DATA MANAGEMENT PROCEDURES 
 
12.1 
Data collection – eCRF 
 
The study data will be recorded at the clinical site by trained study personnel in a study-
specific electronic Case Report Form (eCRF) validated as per 21 CFR Part 11. 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRF. He must also check that the data reported in the eCRF correspond to 
those in the subject’s source documents. The eCRF should be filled out in English. In the 
interest of completeness of data acquisition, the questions which are repeated in each section 
of the eCRF should be answered in full, even if there are no changes from a previous 
examination. The investigator must provide a reasonable explanation for all missing data. 
The eCRF will be completed during the study and will be signed by the investigator with 
electronic signature (ID and password) after all queries have been solved.   
Data management activities will be performed by the CRO Biometry Unit. After the 
completion of data management procedures, data of the eCRF will be archived by the Sponsor 
in the format agreed with the eCRF provider (§ 16.7) and the site will remain in control and 
file a copy of the eCRF data, as per paragraph 8.1 of ICH-GCP. 
 
Training of the use of eCRF will be performed before the start of the study and every user will 
be provided with private User ID and Password to access the eCRF, according to the assigned 
role (i.e. Investigator, Study Nurse, Study Monitor, Data Manager, etc.). 
 
12.2 
Unique subject identifier 
 
All the subjects who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains 
of the CDISC SDTM model. The unique subject identifier consists of the sponsor study code 
(i.e. LDX0219), the 3-digit site number (i.e. 001), the 4-digit screening number (e.g. S001, 
S002, etc.) and, if applicable, the 3-digit subject randomization number (e.g. 001, 002, etc.). 
Study code, site number, screening number and subject randomization number are separated 
by slashes (“/”) [example: LDX0219/001/S001/001]. The last 8 digits of the unique subject 
identifier (enrolled subjects), corresponding to the subject screening and subject 
randomization numbers separated by a slash, or the last 4 digits of the unique subject 
identifier (not enrolled subjects), corresponding to the subject screening number, will appear 
as subject identifier in the individual listings and figures of the CSR and will be used to 
identify the subjects in in-text tables or wording (if applicable). 
 
12.3 
Database management 
 
Database and eCRF design will be performed by the eCRF provider (§ 16.7) before the start 
of the study. Verification and cross-verification of the data entered by the study personnel will 
be automatically performed by the system, according to predefined nature/type of the data, 
value ranges and rules. All rules applied by the system to check specific items will be detailed 
in the Data Validation Plan (DVP). Queries will be automatically generated by the system for 
all data found to be inconsistent, incorrect or missing. All changes performed by the 
Investigator/authorized user(s) will be tracked by the system. 

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Once all data are entered in the eCRF and all outstanding queries are solved and the Monitor 
complete the Source Data Verification (SDV), the Data Manager will verify the correctness of 
the answers and the Investigator will approve (sign) the data of the subjects’ eCRF. 
Afterwards, it may be still necessary to issue additional queries following general quality 
control checks performed by the trained Data Manager of the study on the approved eCRF 
data that will be managed within the system. The Data Manager or the Clinical Programmer 
will create the final SAS data sets. The final data file will be transferred to the Sponsor in the 
agreed format with all the other study documentation. 
 
12.3.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™). 
Previous and concomitant medications will be coded using the WHO Drug Dictionary 
Enhanced (WHODDE). The version of the coding dictionaries will be stated in the study 
report. 

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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
13.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff of Clinical Medical Services of 
Maria Pia Savorelli, Switzerland (see § 16.8). 
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorized individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
Sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOAC principles (Attributable-Legible-
Contemporaneous-Original-Accurate-Complete). 
 
The clinical site is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirements. 
 
The CRO and the Sponsor will be responsible for their respective activities. 
 
The Sponsor may transfer any or all of the Sponsor’s trial-related duties and functions to a 
CRO, but the ultimate responsibility for the quality and integrity of the trial data always 
resides with the Sponsor. 
 
 

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13.3 
Applicable SOPs 
 
The Sponsor, the clinical center, the CRO and the eCRF provider will follow their respective 
SOPs in the conduct of the respective activities, unless otherwise stated in written agreements. 
SOPs will be made available for review, if required. AEs, SAEs, pregnancy management and 
SAEs reconciliation will follow Dompé SOPs. 
 
13.4 
Data access 
 
The investigator, the CRO and the eCRF provider will ensure that all raw data records, 
medical records, eCRF and all other documentation that is relevant to this study will be made 
accessible for monitoring activities, audits, Independent Ethics Committee (IEC) review, and 
regulatory inspections. 
 
13.5 
Audits and inspections 
 
The Sponsor, independent bodies acting on behalf of the Sponsor and the CRO have the right 
to perform audits according to ICH-GCP responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigator, the CRO and the eCRF provider agree, by written consent to this protocol, 
to fully co-operate and support audits and inspections compliance checks by allowing 
authorized individuals to have access to all the study documentation. 
 
 

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14 
ETHICAL CONSIDERATIONS 
 
14.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
The approval of the study protocol by the local (Canton Ticino) IEC and by the Federal 
Health Authorities (Swissmedic) will be obtained before the start of the study.  
 
The present clinical study will be carried out according to the current revision of Good 
Clinical Practice (GCP), ICH topic E6 (R2), and the applicable local law requirements. 
 
14.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC. It will include all the 
elements required by law according to the ICH-GCP recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organized 
 the type of treatment (information on the IMP(s) and treatment procedures, as applicable) 
 any potential negative effects attributable to the study product or treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardizing their further course of medical treatment  
 the existence of a subject insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
Subjects will be provided with an additional informed consent prepared in the local language 
by the CRO and already approved by the EC, regarding the information to the processing of 
personal data according to the Swiss Federal Law on Data Protection (Law 235.1 of 19 June 
1992 and subsequent updates) and the European General Data Protection Regulation (GDPR, 
EU Regulation n 2016/679). 
 
The investigator will be supplied with an adequate number of blank informed consent forms 
to be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements (see § 15.3). 

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The investigator will allow inspection of the forms by authorized representatives of the 
Sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 
 
14.3 
Insurance policy 
 
An insurance cover has been issued in favor of the subjects participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the 
Health Authorities 
 
14.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject complete the clinical study. If, for a 
subject, study treatment or observations are discontinued and the primary reason for 
discontinuation will be recorded. 
 
14.4.1 
Primary reason for discontinuation 
 
 Adverse event: Any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 11.2. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
 protocol deviation: an event or decision that stands in contrast to the protocol 
 study terminated by Sponsor: an indication that the clinical study was stopped by its 
Sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
14.4.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 

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assays. This examination will verify that all values tested at screening have remained 
within a clinically acceptable range (i.e. not clinically significant changes compared to 
screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
 record the subject decision about the use of collected biological samples 
 report in the eCRF date and time of the last dose administration, and date and primary 
reason of study discontinuation 
 record in the eCRF any follow-up, if the subject is withdrawn for an AE 
Discontinued subjects will be replaced starting from the 3rd discontinuing man or the 3rd 
discontinuing woman. 
 
14.5 
Study termination 
 
The study will be considered terminated at the date of LSLV or upon completion of any 
follow-up procedure described in protocol. The investigator and the Sponsor have the right to 
discontinue the study at any time for reasonable medical and/or administrative reasons. As far 
as possible, this should occur after mutual consultation. Reasons for discontinuation have to 
be documented appropriately. 

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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical center 
 
Beside IMP, the following study material will be supplied to the clinical center: 
 final version of the study protocol 
 access to the eCRF  
 eCRF guideline 
 copy of the investigator’s brochure (IB) relative to the IMP 
 informed consent forms 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments 
(if any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
15.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the Sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the Sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to EC and Swissmedic, as appropriate. The 
amendment will be applicable only when it is approved, unless the changes consist of urgent 
safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
15.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the Sponsor in the eCRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information 
on the eCRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the eCRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 

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The investigator and the Sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirements.  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects including lab tests and ECG tracing, insurance contracts, certificate of analysis of the 
IMP(s), drug accountability records, signed informed consent forms, confidential subjects 
identification code, eCRFs, curricula vitae of the investigator and other participants in the 
study, study staff lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the Sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the Sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the Sponsor agree to adhere to these requirements. 
 
15.4 
Study subjects’ recruitment 
 
Study participants will be recruited from the volunteers’ database maintained by the CRO. 
This database contains a pool of volunteers that are contacted whenever necessary to enroll 
subjects in a new study. Before the start of the new study, the principal investigator and other 
relevant staff discuss with the volunteers’ recruiter the study recruitment needs and specific 
requirements. On the basis of this information, the volunteers’ recruiter queries the database, 
contacts potential participants to propose the study and evaluate their interest and availability. 
In addition to the volunteers’ database, new subjects often call or email the CRO asking to 
become a research volunteer, after hearing of the clinical site activities from other volunteers 
or friends or after checking the company web site. 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 
15.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator and the CRO agree to keep all the information 
provided by the Sponsor in strict confidentiality and to request the same confidentiality from 
his/her staff. Study documents provided by the Sponsor (protocols, IB, eCRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the Sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the Sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected in the eCRFs during the study will be documented in a coded way 
(see § 12.2). If, as an exception, for safety or regulatory reasons identification of a subject 
becomes necessary, the monitor, the Sponsor and the investigator will be bound to keep this 
information confidential. 

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The processing of personal data by the Sponsor, the CRO and the Clinical Site shall always be 
in line with the local regulations, the EU General Data Protection Regulation (GDPR; 
Regulation EU 679/2016), and the applicable Swiss data protection regulations (Swiss Law 
235.1, Federal Act on Data Protection of June 19th, 1992). Suitable written information will 
be provided to the study subjects at the time of consenting. 
 
15.6 
Publication policy 
 
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. 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the Sponsor agrees that the study results can be published by the investigator, the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the Sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The Sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator will also be provided by the Sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
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 data could, in some 
circumstances, prevent or negatively impact patentability. 
 
According to The Federal Act on Research involving Human Beings and the Ordinance on 
Clinical Trials in Human Research, the study will be registered and published in a WHO 
primary register or clinicaltrials.gov as well as in the supplementary federal database.  
 
 

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16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Dompé farmaceutici S.p.A. - Via Campo di Pile; I-67100 L'Aquila, Italy 
Milan Offices: Via S. Santa Lucia 6,  I-20122 Milan, Italy 
Phone:   +39.02.583831 
Fax:   
+39.02.58383324 
 
Trial Manager 
Giuseppe Terpolilli, Pharm D. – Clinical Operations Specialist 
Email: 
giuseppe.terpolilli@dompe.com 
 
Medical Expert 
Pier Adelchi Ruffini, MD – Global Clinical Development Director  
Email: Pieradelchi.ruffini@dompe.com 
 
Drug Safety Manager  
Laura Boga, Global Head of Pharmacovigilance & EU Qualified Person for 
Pharmacovigilance 
Email: 
laura.boga@dompe.com 
Fax: 
+39.02.3602691 
 
16.2 
Institutes performing the study 
 
16.2.1 
Clinical centre 
 
CROSS Research S.A. – Phase I Unit, Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: 
clinic@croalliance.com 
 
Principal investigator 
Milko Radicioni, MD 
 
16.3 
SAE reporting 
 
Dompé farmaceutici S.p.A. Drug Safety  
Email: farmacovigilanza@dompe.com  
Fax:  +39.02.36026913 
 
CRO:  
Email: projectmanagement@croalliance.com  
Fax: 
 +41.91.630.05.11 
 
 

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16.4 
Drug assay 
 
Bioanalytical Laboratories Dompé farmaceutici S.p.A. - Via Campo di Pile; I-67100 
L'Aquila, Italy 
Phone: 
+39.0862.338323 
Fax: 
+39.0862.338367 
Mobile:  +39.342.7634949 
Email: 
franca.cattani@dompe.com  
 
Analytics representative  
Franca Cattani 
 
Analytical facilities and procedures are in compliance with the general principles of GLP 
regulations. 
 
16.5 
Centralised clinical laboratory 
 
Unilabs Ticino, via Rovere 8, CH-6932 Breganzona, Switzerland 
Phone: 
+41.91.960.73.73 
Fax: 
+41.91.960.73.74 
Email: 
bmathis@unilabs.ch 
 
16.6 
Co-ordination, data analysis & reporting 
 
CROSS Research S.A., Switzerland 
 
Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Coordination 
Chiara Castiglioni, Clinical Project Leader and Clinical Research Associate 
Email: 
projectmanagement@croalliance.com 
 
Medical Writing 
Andrea Di Stefano, Senior Medical Writer 
Email: 
medicalwriting@croalliance.com 
 
Biometry Unit Representative 
Alessandra Gentili, Biometry Manager, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Mario Corrado, Quality Assurance Manager, Unit Head 
Email: 
qau@croalliance.com 
 
16.7 
Provider of eCRF system 
 
CROS NT SRL, via Germania 2, 37136 Verona, Italy 
Phone: 
+39. 045 820 26 66 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 67 
 
Responsible person 
Monica Pimazzoni, Director of Clinical Data Management 
Email: 
monica.pimazzoni@crosnt.com 
 
16.8 
Monitoring 
 
Clinical Medical Services di Maria Pia Savorelli,  
Via Industria 5, CH-6850 Mendrisio, Switzerland 
Mobile: +41.79.82.72.767 
Email: 
cmed@cmed.ch 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-345 
Sponsor code LDX0219 
Ladarixin 200 mg capsules - food effect 
Final version 1.0, 28MAY20 
CROSS Research S.A. 
Page 68 
17 
REFERENCES 
 
1. Dompé, Ladarixin (DF 2156A – formerly meraxin) Investigator’s Brochure, final version No. 7, 09APR20 
2. Moriconi A et al. Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med 
Chem 2007; 50:3984-4002. 
3. Garau A et al. Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its 
efficacy in a model of transient cerebral ischemia in the rat. Eur Cytokine Netw 2006; 17(1):35-41. 
4. A0811/E. Dompé Internal Report 
5. Citro A et al. CXCR2/1 inhibition modulates diabetes induced by multiple low doses of streptozotocin 
(MDL-STZ) injection in mouse. 2nd Joint AIDPIT and EPITA Winter Symposium. Igls/Innsbruck 2012a, 
Abstract book, abstract PP-18. 
6. Citro A et al. CXCR2/1 inhibition prevents and reverts diabetes in NOD mouse. 2nd Joint AIDPIT and 
EPITA Winter Symposium. Igls/Innsbruck 2012b, Abstract book, abstract OP-27. 
7. Citro A et al., CXCR1/2 inhibition blocks and reverts type 1 diabetes in mice. Diabetes 2015, 64(4): 1329-
1340. 
8. Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr **, 20JAN2010 
9. Guideline on the investigation of drug interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2**, 21JUN2012 
10. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the 
European Community, Volume 4 
11. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: 2015-2020 Dietary Guidelines, Appendix 9 
12. SAS/STAT® User’s Guide 
13. Phoenix 1.3 User’s Guide, Pharsight Corporation 
14.  Guidance for industry. Assessing the Effects of Food on Drugs in INDs and NDAs — Clinical 
Pharmacology Considerations. U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research. CDER, February 2019