A Phase I/II, Randomized, Placebo-controlled, Double-masked, Efficacy, Safety and Local Tolerability Study of Chloroprocaine 3% Gel Eye Drops in Healthy Volunteers
Phase: PHASE1
Conditions: Healthy Subjects
Sponsor: Sintetica SA

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 1 
 
CLINICAL STUDY PROTOCOL 
 
 
Study CRO-PK-20-343 - Sponsor code CHL.3-01-2020 
 
A Phase I/II, randomized, placebo-controlled, double-masked, 
efficacy, safety and local tolerability study of Chloroprocaine 3% 
gel eye drops in healthy volunteers 
 
Single dose, randomised, placebo-controlled, parallel-group, double-masked, efficacy, safety  
and local tolerability study 
 
 
Test investigational product: 
Chloroprocaine 3% ocular gel (30 mg/mL), Sintetica S.A., 
Switzerland 
 
 
Control: 
Placebo, vehicle for chloroprocaine 3% ocular gel, 
Sintetica S.A., Switzerland 
 
 
Sponsor: 
Sintetica S.A., Via Penate 5, 6850 Mendrisio, Switzerland 
Phone: +41.91.6404250 
Fax: 
+41.91.6468561 
 
 
Principal Investigator: 
Milko Radicioni, MD - Principal Investigator 
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 
 
 
Development phase: 
Phase I/II 
 
 
Version and date: 
Final version 1.0, 21FEB20 
 
 
 
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 54 pages 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 5 
STUDY SYNOPSIS 
 
Title: A Phase I/II, randomized, placebo-controlled, double-masked, efficacy, safety and local tolerability study 
of Chloroprocaine 3% gel eye drops in healthy volunteers 
 
Protocol number: CRO-PK-20-343 / Sponsor code CHL.3-01-2020 
 
Clinical phase: Phase I/II 
 
Study design: Single dose, randomised, placebo-controlled, parallel-group, double-masked, efficacy, safety and 
local tolerability study 
 
Planned nr. of centres / countries: One/Switzerland 
 
Principal Investigator and study centre: Milko Radicioni, MD; CROSS Research S.A., Phase I Unit, Via F.A. 
Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Investigational product(s):  
TEST (T):  
Chloroprocaine 3% ocular gel (30 mg/mL), Sintetica S.A., Switzerland 
Control (P): 
Placebo, vehicle for chloroprocaine 3% ocular gel, Sintetica S.A., Switzerland 
 
Auxillary meidicinal product (AxMP) 
Fluoresceine-Oxybuprocaine SDU Faure (Omnivision, Neuhausen) 
Dose regimen(s): One hundred and five (105) healthy male and female subjects will be randomised in a 4:1 ratio 
to receive a single ocular instillation of Chloroprocaine 3% ophthalmic gel or matching placebo (vehicle) (84 
subjects will receive chloroprocaine and 21 subjects will receive placebo). The assigned investigational product 
(3 drops) will be instilled in the right eye of each subject. Administrations will be performed at the clinical centre 
by the Investigator or his deputy on study day 1. For each administration, the 3 drops will be instilled at a 1 min 
± 15 sec interval. 
 
Definitions: 
Time 0h (T0) is defined as the time of the end the last drop (drop 3) instillation. 
Pre-dose (baseline) assessments are performed before the first drop instillation. 
Post-dose times are calculated from T0, i.e. from the end of the instillation of the last drop (drop 3). 
 
Objectives:  
The objective of the study is to evaluate the efficacy, safety and local tolerability of Chloroprocaine 3% 
ophthalmic gel as compared to matching placebo in healthy subjects.  
 
End-points:  
Primary end-point: Proportion of subjects gaining full conjunctival anesthesia of the ocular surface, evaluated 
by conjunctiva pinching (0.3-mm forceps), 5 minutes after administration of Chloroprocaine 3% ophthalmic gel, 
in comparison to placebo - only study eye (right eye) 
Secondary end-points:  
 
Time to anesthesia, evaluated by conjunctiva pinching (0.3-mm forceps)  - only study eye (right eye) 
 
Duration of anesthesia, evaluated by conjunctiva pinching (0.3-mm forceps) - only study eye (right eye) 
 
Visual acuity – both eyes 
 
Ocular symptoms (burning, stinging, itching, foreign body sensation) evaluated using a 0-100 mm VAS - 
both eyes 
 
Objective ocular signs (Conjunctival redness, anterior chamber flare, conjunctival chemosis, eyelid 
swelling) by Slit lamp examination - both eyes 
 
Corneal fluorescein staining by slit lamp examination - both eyes 
 
Intraocular pressure (IOP) - both eyes 
 
Fundus ophthalmoscopy (vitreous, macula, retina and optic nerve head) with the slit lamp - both eyes 
 
Treatment-emergent adverse events (TEAEs), assessed throughout the study 
 
Vital signs (blood pressure and heart rate)  
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 6 
STUDY SYNOPSIS (cont.) 
 
Study variables: 
Primary variable:  
Conjunctival anaesthesia evaluation by conjunctival pinching (with 0.3 mm forceps) at 5 min post-dose (see 
below) - only study eye (right eye) 
Secondary variables: 
 
Conjunctival anaesthesia evaluation by conjunctival pinching (with 0.3 mm forceps) at the pre-specified 
assessment time-points (see below) - only study eye (right eye) 
 
Ocular symptoms (burning, stinging, itching, foreign body sensation) using a 0-100 mm VAS - both eyes 
 
Visual acuity (EDTRS chart) – both eyes 
 
Objective ocular signs (Conjunctival redness, anterior chamber flare, conjunctival chemosis, eyelid 
swelling) by SLE - both eyes 
 
Corneal fluorescein staining by SLE - both eyes 
 
Intraocular pressure (IOP) - both eyes 
 
Fundus ophthalmoscopy (vitreous, macula, retina and optic nerve head) with the slit lamp - both eyes 
 
Treatment-emergent adverse events (TEAEs), assessed throughout the study 
 
Vital signs (blood pressure and heart rate) 
 
Anaesthesia evaluation:  
Anaesthesia will be tested by conjunctival pinching (with 0.3 mm forceps) at 20, 40 and 60 seconds. The 
evaluation will be performed again at 5 min post-dose. If anaesthesia is already present at 20 and 40 seconds, 
pain will not be assessed at 60 sec but directly at 5 minutes. Further assessments will be performed every 5 min 
up to 60 min post-dose. Alternatively, if the subject experiences pain at two consecutive assessments, pinching 
will be suspended and the subsequent assessment will not be performed. If the subject experiences pain at 5 
minutes, no more testing will be performed and the subject will be considered not to have gained anaesthesia.  
 
Safety and tolerability assessments: Physical examinations at screening and final visit; adverse events (AE) 
recording throughout the study; vital signs (blood pressure and heart rate) at screening, pre-dose, post-dose and 
at follow-up or early termination visit (ETV); urine pregnancy test for women at screening; corneal fluorescein 
staining, IOP and fundus ophthalmoscopy at screening and follow-up/ETV. Ocular symptoms and SLE 
(excluding corneal fluorescein staining) at screening, pre-dose, post-dose and at follow-up/ETV 
 
Sample size:  
A total of 105 healthy men and women will be included in the study. Active vs. placebo treatment will have a 4:1 
ratio. 
Initially, local tolerability and safety will be evaluated on the first 20 enrolled subjects (16 treated with 
chloroprocaine 3% ocular gel and 4 with placebo).  
After the first 20 subjects have completed the study, local tolerability and safety data will be evaluated and if 
treatment safety is confirmed, efficacy, beside local tolerability and safety, will be assessed on the 85 subsequent 
subjects (68 active gel and 17 with placebo).  
 
Sample size for the efficacy evaluation was formally calculated as follows:  
Sample size per group was calculated by comparing two independent proportions (experimental and placebo 
success rate) with a two-sided alpha=0.05 and a power of 0.95. This is based on the assumption, that the 
experimental success rate is 80% and the vehicle success rate is 30%, taking a dropout rate of 20% into account. 
For sample size estimation, NQuery (Version 4.0) was used implementing formulas described in Chow et al 
(2008). 
 
Main selection criteria:  
Inclusion criteria: 
1. Informed consent: Signed written informed consent before inclusion in the study  
2. Sex and age: Healthy men and women, 18 - 55 years 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, heart rate 50-90 
bpm, 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 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 7 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria, continued:  
Inclusion criteria, continued: 
6. Contraception and fertility: women of child-bearing potential 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; 
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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be 
admitted. For all women, urine pregnancy test result must be negative at screening. 
Exclusion criteria: 
1. Physical findings: Clinically significant abnormal physical findings which could interfere with the 
objectives of the study 
2. Visual acuity: Best corrected visual acuity < 1/10 
3. Concomitant medications: Medications, including over the counter medications and herbal remedies, 
systemic opioids and morphine drugs, topical ocular products with anaesthetic action, systemic analgesic 
drugs, for 2 weeks before study screening 
4. Ophthalmic diseases: Clinically significant ocular disease; eye movement disorder (i.e. nystagmus); 
dacryocystitis and all others pathologies of tears drainage system; corneal, epithelial, stromal or endothelial, 
residual or evolutionary disease (including corneal ulceration and superficial punctuate keratitis); history of 
inflammatory ocular disease (iritis, uveitis, herpetic keratitis), history of ocular traumatism, infection or 
inflammation within the last 3 months or history of any other ocular disease that may affect the outcome of 
the study or the subject's safety 
5. Ophthalmic surgery: History of ophthalmic surgical complications (e.g. cystoid macular oedema) in the last 
6 months 
6. Diseases: Significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, 
haematological, endocrine, psychiatric or neurological diseases or surgeries that may interfere with the aim 
of the study 
7. Allergy: Ascertained or presumptive hypersensitivity to the active principle and/or ingredients of 
investigational products; history of anaphylaxis to drugs or allergic reactions in general, which the 
Investigator considers may affect the outcome of the study 
8. 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 
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. Alcohol test: positive alcohol breath test at Day 1 
11. Pregnancy (women only): positive or missing pregnancy test at screening, pregnant or lactating women 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 8 
STUDY SYNOPSIS (cont.) 
 
Schedule: 
 
Day 
Procedures/Assessments 
Screening – Visit 1 
Day -21 / 
Day - 1  
 Explanation to the subject of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data 
 Ocular medical and surgical history 
 Other medical and surgical history 
 Previous and concomitant medications 
 Physical examination (including ocular examination, body weight, height) 
 Vital signs (blood pressure and heart rate) check 
 Urine pregnancy test for women 
 Adverse event (AE) monitoring 
 Ocular symptoms (0-100 mm VAS) - all subjects - both eyes 
 Visual acuity (EDTRS) – both eyes 
 Slit lamp examination (SLE; Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) - all subjects - both eyes 
 Corneal fluorescein staining with SLE - all subjects - both eyes 
 Intraocular pressure measurement - all subjects - both eyes 
 Fundus ophthalmoscopy (with slit lamp) - all subjects -both eyes 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Visit 2 
Day 1 
 Alcohol test 
 Inclusion/exclusion criteria evaluation 
 Subject eligibility confirmation 
 Enrolment and randomisation 
 Vital signs (blood pressure, heart rate) check - pre-dose - all subjects 
 Ocular symptoms (0-100 mm VAS) - pre-dose - all subjects - both eyes 
 Slit lamp examination (SLE; Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) - pre-dose - all subjects - both eyes 
 Instillation of the investigational product (right eye only) 
 Assessment of conjunctival anaesthesia by conjunctival pinching (0.3 mm forceps) at 
the pre-specified post-dose assessment times - efficacy evaluation subjects only - 
study eye only (right eye) 
 Ocular symptoms (0-100 mm VAS) - at the end of the study day - all subjects - both 
eyes 
 Vital signs (blood pressure, heart rate) check - at the end of the study day - all subjects 
 Slit lamp examination - at the end of the study day (SLE; Conjunctival redness, 
anterior chamber flare, conjunctival chemosis, eyelid swelling) - all subjects - both 
eyes 
 AE and concomitant medications (throughout the study day) 
Visit 3 
Day 2 - 
Phone 
call 
 AE and concomitant medications check 
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 9 
STUDY SYNOPSIS (cont.) 
 
Schedule, continued: 
Visit 4 
Day 7±1 
Follow 
up 
 AE and concomitant medications 
 Vital signs (blood pressure, heart rate) check 
 Physical examination 
 Ocular symptoms (0-100 mm VAS) - both eyes 
 Visual acuity (EDTRS) – both eyes 
 Slit lamp examination (SLE; Conjunctival redness, anterior chamber flare, 
conjunctival chemosis, eyelid swelling) - both eyes 
 Corneal fluorescein staining (with SLE) - both eyes 
 Intraocular pressure measurement - both eyes 
 Fundus ophthalmoscopy (with slit lamp) - all subjects - both eyes  
 
Data analysis:  
The statistical analysis of efficacy and safety/tolerability data will be performed using SAS® version 9.3 
(TS1M1) or higher. The data documented in this study will be summarised using classic descriptive statistics, i.e. 
arithmetic mean, SD, CV (%), minimum, median and maximum values for quantitative variables, and 
frequencies for qualitative variables. Not available data will be evaluated as “missing values”.  
 
Primary anaesthesia results will be coded as success/failure, listed by subject and summarized using contingency 
tables overall and by treatment group. Resulting proportions will be presented with 95% confidence interval. The 
2 groups will be compared using Pearson’s χ2 test. The null hypothesis of equal success between the 2 treatment 
arms at the α=0.05 level will be rejected if: 
 
ተተ
𝑝1
ෞ−𝑝2
ෞ
ට𝑝1
ෞ(1 −𝑝1
ෞ)
𝑛1
+ 𝑝2
ෞ(1 −𝑝2
ෞ)
𝑛2
ተተ> 𝑍𝛼/2 
 
where p1 is the proportion of subjects who meet the primary endpoint in the active group, while p2 is the 
proportion of subject who meet the primary endpoint in the vehicle group. 
Time to anesthesia and duration of anesthesia will be listed and summarized overall and by group using 
descriptive statistics (mean, median, standard deviation, minimum, maximum, 95% confidence interval on the 
mean, and number of observations). The 2 groups will be compared using non-parametric Mann-Whitney’s test 
for continuous variables.  
 
 
 
 
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 10 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
Intervention and 
assessments 
Telephone call 
Follow-up/ETV5 
Visit 
V1 
V2 
V3 
V4 
 
Day -21 / -1 
Day 1 
Day 2 
Day 7±1 
Informed consent 
x 
 
 
 
Demography 
x 
 
 
 
Ocular medical and surgical history 
x 
 
 
 
Other medical and surgical history  
x 
 
 
 
Physical examination 
x 
 
 
x 
Previous medications 
x 
 
 
 
Concomitant medications 
x 
x 
x 
x 
Height 
x 
 
 
 
Body Weight 
x 
 
 
 
Body mass index 
x 
 
 
 
Alcohol test 
 
x 
 
 
Vital signs (blood pressure, heart 
rate) check1 
x 
x 
 
x 
Urine pregnancy test (women) 
x 
 
 
 
Ocular symptoms (0-100 mm 
VAS)1,2 
x 
x 
 
x 
Slit lamp examination1,2 
x 
x 
 
x 
Corneal fluorescein staining2 
x 
 
 
x 
Intraocular pressure2 
x 
 
 
x 
Fundus ophthalmology2 
x 
 
 
x 
Visual acuity (EDTRS)2 
x 
 
 
x 
Inclusion / exclusion criteria check 
x 
x 
 
 
Subject eligibility 
x 
x 
 
 
Enrolment and randomisation  
 
x 
 
 
Investigational product 
administration3 
 
x 
 
 
Conjunctival pinching4 
 
x 
 
 
Adverse events monitoring6 
x 
x 
x 
x 
1. At screening, on day 1 at pre-dose and at the end of the study day, and at follow-up/ETV 
2. Both eyes 
3. On day 1, after pre-dose (baseline) assessments 
4. Study eye (right eye) only - On day 1, at 20, 40 and 60 seconds and then at 5-min intervals up to 60 min post-
dose, as applicable (please refer to CSP main text). 
5. Early termination visit (ETV) in case of premature discontinuation 
6. AEs monitored starting at the screening visit, immediately after informed consent, up to the follow-up 
visit/ETV.  
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 11 
TABLE OF CONTENTS 
 
Page 
 
CLINICAL STUDY PROTOCOL 
1 
PROTOCOL APPROVAL 
2 
STUDY SYNOPSIS 
5 
STUDY SCHEDULE 
10 
TABLE OF CONTENTS 
11 
1 
INTRODUCTION 
15 
1.1 
Background 
15 
1.1.1 
Background on Chloroprocaine 
15 
1.1.1.1 
Regulatory status of Chloroprocaine 
15 
1.1.2 
Non-clinical development 
16 
1.1.2.1 
Non-clinical safety and Toxicology on the eye 
16 
1.2 
Rationale of the study 
16 
1.3 
Benefit/risk assessment 
17 
2 
STUDY OBJECTIVES 
18 
2.1 
Primary end-point 
18 
2.2 
Secondary end-points 
18 
3 
CLINICAL SUPPLIES 
19 
3.1 
Treatment 
19 
3.1.1 
Description of products 
19 
3.1.1.1 
Test product 
19 
3.1.1.2 
Control 
19 
3.1.1.3 
Auxilliary medicinal product 
19 
3.1.2 
Dose regimen 
19 
3.1.3 
Route and method of administration 
19 
3.1.4 
Investigational product distribution 
20 
3.2 
Packaging and labelling 
20 
3.3 
Storage conditions 
20 
3.4 
Drug accountability 
21 
4 
INVESTIGATIONAL PLAN 
22 
4.1 
Overall study design 
22 
4.2 
Discussion of design 
22 
5 
STUDY POPULATION 
23 
5.1 
Target population 
23 
5.2 
Inclusion criteria 
23 
5.3 
Exclusion criteria 
23 
5.3.1 
Not allowed treatments 
24 
6 
STUDY SCHEDULE 
25 
6.1 
Study visits and procedures 
25 
6.2 
Diet and lifestyle 
27 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
28 
7.1 
Physical examination 
28 
7.1.1 
Body weight 
28 
7.1.2 
Vital signs 
28 
7.1.3 
Alcohol test 
28 
7.2 
Ocular assessments 
28 
7.2.1 
Ocular symptoms assessment 
28 
7.2.2 
Visual acuity 
28 
7.2.3 
Slit lamp examination 
29 
7.2.4 
Corneal fluorescein staining 
29 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 12 
7.2.5 
Assessment of conjunctival anaesthesia 
29 
7.2.6 
Fundus ophthalmology 
29 
7.2.7 
Intraocular pressure 
29 
8 
ASSIGNMENT OF STUDY TREATMENT 
31 
8.1 
Randomisation 
31 
8.2 
Treatment allocation 
31 
8.3 
Blinding 
31 
8.3.1 
Emergency code and unblinding procedures 
31 
8.3.2 
Emergency individual envelopes 
31 
9 
EVALUATION PARAMETERS 
33 
9.1 
Study variables 
33 
9.1.1 
Primary variables 
33 
9.1.2 
Secondary variables 
33 
9.2 
Safety assessments 
33 
10 
STATISTICAL METHODS 
34 
10.1 
Analysis Sets 
34 
10.1.1 
Definitions 
34 
10.1.2 
Reasons for exclusion from the Full Analysis Set 
35 
10.1.3 
Reasons for exclusion from the Per Protocol set 
35 
10.2 
Sample size and power considerations 
35 
10.3 
Demographic, baseline and background characteristics 
36 
10.4 
Analysis of efficacy parameters 
36 
10.4.1 
Primary end-point 
36 
10.4.2 
Secondary end-points 
36 
10.5 
Safety and tolerability evaluation 
36 
10.5.1 
Adverse events 
36 
10.5.2 
Physical examination 
37 
10.5.3 
Ocular symptoms 
37 
10.5.4 
Visual acuity 
37 
10.5.5 
Slit lamp examination, corneal fluorescein staining and fundus ophthalmoscopy results 
37 
10.5.6 
Intraocular pressure 
37 
10.5.7 
Vital signs 
37 
11 
DEFINITION AND HANDLING OF AES AND SAES 
38 
11.1 
Applicable SOPs 
38 
11.2 
Definitions 
38 
11.3 
AEs monitoring window 
39 
11.4 
AEs recording 
39 
11.5 
SAEs reporting 
41 
11.6 
SUSARs management 
41 
11.7 
Other events qualified for expedited reporting 
42 
11.8 
SAEs: contacts 
42 
12 
DATA MANAGEMENT PROCEDURES 
43 
12.1 
Data collection – CRFs 
43 
12.2 
Unique subject identifier 
43 
12.3 
Database management 
43 
12.3.1 
Coding dictionaries 
43 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
44 
13.1 
Monitoring 
44 
13.2 
Quality Control and Quality Assurance 
44 
13.3 
Applicable SOPs 
45 
13.4 
Data access 
45 
13.5 
Audits and inspections 
45 
14 
ETHICAL CONSIDERATIONS 
46 
14.1 
Ethics and Good Clinical Practice (GCP) 
46 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 13 
14.2 
Informed consent 
46 
14.3 
Insurance policy 
47 
14.4 
Withdrawal of subjects 
47 
14.4.1 
Primary reasons for discontinuation 
47 
14.4.2 
Discontinuation procedures 
47 
14.5 
Study termination 
48 
15 
ADMINISTRATIVE PROCEDURES 
49 
15.1 
Material supplied to the clinical centre 
49 
15.2 
Protocol amendments 
49 
15.3 
Study documentation and record keeping 
49 
15.4 
Study subjects’ recruitment 
50 
15.5 
Confidentiality and data protection 
50 
15.6 
Publication policy 
51 
16 
STUDY RESPONSIBLE PERSONS 
52 
16.1 
Sponsor 
52 
16.2 
Institutes performing the study 
52 
16.2.1 
Clinical centre 
52 
16.2.2 
Ophthalmological assessments 
52 
16.3 
Co-ordination, monitoring, data analysis & reporting 
53 
16.4 
Monitoring 
53 
17 
REFERENCES 
54 
 
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 14 
LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AxMPs 
Auxillary meidicinal products 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CA 
Competent Authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPL 
Clinical Project Leader 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CRS 
Clinical Study Report 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
EC 
Ethics Committee 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular pressure 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
Intra-Uterine Device 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over The Counter 
P 
Placebo solution 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
SAE 
Serious Adverse Event 
SLE 
Slit lamp examination 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Test 
TEAE 
Treatment-Emergent Adverse Event 
USDA 
United States Department of Agriculture 
VA 
Visual Acuity 
VAS 
Visual Analogue Scale 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 15 
1 
INTRODUCTION 
 
1.1 
Background 
 
Safe and efficient topical local anaesthesia is crucial for surgical procedures in 
ophthalmology, such as cataract surgery, intravitreal injections, refractive surgery or others. 
The development of less invasive surgical techniques, which allow for most interventions to 
be performed as outpatient surgeries, has stimulated the development of new approaches in 
topical anaesthesia. Currently, oxybuprocaine, lidocaine or tretracaine - mostly formulated as 
liquid eye drops - are used to provide local anesthesia of the eye (1). However, it has been 
hypothesized that formulations with optimized physical and chemical properties such as high 
viscosity gel based formulations might be superior to eye drops in terms of efficacy and 
safety.  
 
1.1.1 
Background on Chloroprocaine 
 
Chloroprocaine is a local anaesthetic that has been widely used in the past for spinal 
anaesthesia by intrathecal administration (2). Chloroprocaine, like other local anesthetics in 
this group, reduces signal conduction in neurons by altering the Na+ channels in the neuronal 
cell membrane responsible for the action potential propagation. Pharmacologically speaking, 
one of the key advantages of Chloroprocaine is the fast onset (usually within minutes) and the 
fast metabolization by ester hydrolysis, which leads to a very short plasma half-life of less 
than 30 seconds. This leads to good controllability and also high concentrations can be used 
with minimal risk of toxicity. As such, Chloroprocaine is the ideal anaesthetic for regional 
anesthesia in patients undergoing short-duration surgeries, providing rapid onset of action, 
adequate potency, predictable duration, fast recovery, and a safe toxicological profile when 
compared to other local anesthetics. 
The current study aims to investigate the efficacy, safety and local tolerability of a newly 
developed Chloroprocaine ophthalmic gel in humans. Based on theoretical considerations, 
one can hypothesize that a gel formulation could provide additional benefits compared to a 
drop solution. First, because of its high viscosity, gel formulations stay longer on the ocular 
surface and may therefore provide a longer anesthetic effect. Secondly, because of the gel 
nature of the formulation, the drainage of the drug through the nasolacrimal drainage system 
is reduced, which might limit absorption through the nasal mucosa and thus lead a low 
systemic exposure of the drug. 
 
1.1.1.1 
Regulatory status of Chloroprocaine 
 
Chloroprocaine has been marketed since 1955 in the USA and Canada for epidural 
anaesthesia and peripheral blocks (Nesacaine® 1%, 2%, 3% injection). In the European 
Community, Chloroprocaine has received marketing authorization (Ampres® 10 mg/ml 
Injektionslösung) for spinal anesthesia in adults where the planned surgical procedure should 
not exceed 40 minutes. An extension application for the existing marketing authorization 
(new strength of 20 mg/ml, new route of administration: perineural anesthesia) is currently 
under review. 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 16 
 
1.1.2 
Non-clinical development 
 
As Chloroprocaine has been widely used in the past and holds a marketing authorization for 
spinal anesthesia via intrathecal administration, the toxicological profile is well described. 
Animal studies report a good safety profile and no particular sign of systemic toxicity beside 
those already known for this class of local anesthetics. For more details on systemic 
toxicology please refer to the Investigator’s Brochure. 
 
1.1.2.1 
Non-clinical safety and Toxicology on the eye 
 
Local tolerability and safety and proof-of-concept of Chloroprocaine 3% eye drops was 
investigated in a non-clinical development program. Data of a GLP ocular irritation study in 
rabbits report good tolerability of the formulation on the ocular surface (3). Further, a 7-day 
GLP local tolerance study including histopathological assessments in rabbits confirms good 
tolerance on the ocular surface (4). A non-GLP efficacy study performed in a rabbit animal 
model supports the concept of Chloroprocaine 3% ophthalmic gel (5), showing an anaesthetic 
effect up to 60 minutes after instillation depending on the viscosity of the gel formulation. An 
in-depth description of the non-clinical development program is given in the Investigator´s 
Brochure. 
 
1.2 
Rationale of the study 
 
Scientific advice on the planned clinical development plan has been obtained from the FDA in 
Sept. 2019 and from the Federal Institute for Drugs. As part of this development plan, and 
following the advice of the competent authority, a combined phase I/II study will be 
performed as described here in this protocol. In addition, a phase II/III study in healthy 
volunteers is planned to be performed in Austria. 
 
In the present study, the efficacy, safety and tolerability of Chloroprocaine 3% ophthalmic gel 
for topical anaesthesia of the eye will be evaluated in healthy subjects. Based on theoretical 
assumptions it is reasonable to expect that the formulation under study offers significant 
advantages compared to currently available formulations. Most importantly, because of its gel 
nature it should stay longer on the ocular surface than commonly used eye drops due to its 
viscosity and should not be drained by the punctae as quickly as drops with low viscosity (6). 
Due to its high viscous nature, the formulation systemic absorption through the nasolacrimal 
system is expected to be low, therefore reducing the potential for systemic toxicity. 
 
The study will enrol a total of 105 healthy men and women. Safety and local tolerability data 
will be collected on the first 20 randomised subjects and evaluated. If safety and local 
tolerability is confirmed after the first enrolled subjects, the study will continue with the 
following 85 men and women on which treatment efficacy as well as safety and local 
tolerability will be assessed.  
The rationale for dose selection is also presented in § 4.2. 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 17 
 
1.3 
Benefit/risk assessment 
 
There is no direct benefit for the subjects under study. However, the findings of this study will 
help in assessing the safety, tolerability and efficacy of the ophthalmic Chloroprocaine 3% 
gel. 
 
Chloroprocaine has been used for spinal anaesthesia for several years and is well tolerated. 
Chloroprocaine 3% ophthalmic gel is intended to be used for topical anaesthesia for patients 
undergoing eye surgery in the future. Due to its viscosity the gel tends to stay on the eye for a 
longer time than eye drops and should not be absorbed by the punctae as quickly as the tears. 
Thus, systemic absorption through the nasolacrimal system should be reduced, therefore 
reducing the potential for systemic toxicity.  
 
Data from the non-clinical development program reports good local tolerability of 
Chloroprocaine 3% ophthalmic gel on the ocular surface. Further, non-clinical data from a 
proof-of-concept study indicates a strong and long-lasting anesthetic effect of Chloroprocaine 
3% ophthalmic gel.  
 
However, at this stage of development, local toxicity of Chloroprocaine 3% Gel in human 
eyes cannot be ruled out but the risk is considered low based on the safety factor calculated 
using preclinical data. Considering the expected low systemic exposure, systemic side effects 
are unlikely to occur. The most common systemic side effect that was observed after 
intrathecal injection was systemic hypertonia. Although it is unlikely to occur after 
ophthalmic use, in the present study blood pressure and heart rate will be assessed before after 
investigational products administration. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 18 
2 
STUDY OBJECTIVES 
 
The objective of the study is to evaluate the efficacy, safety and local tolerability of 
Chloroprocaine 3% ophthalmic gel as compared to matching placebo in healthy subjects.  
 
2.1 
Primary end-point 
 
Proportion of subjects gaining full conjunctival anesthesia of the ocular surface, evaluated by 
conjunctiva pinching (0.3-mm forceps), 5 minutes after administration of Chloroprocaine 3% 
ophthalmic gel, in comparison to placebo - only study eye (right eye). 
 
2.2 
Secondary end-points 
 
 Time to anesthesia, evaluated by conjunctiva pinching (0.3-mm forceps) - only study eye 
(right eye) 
 Duration of anesthesia, evaluated by conjunctiva pinching (0.3-mm forceps) - only study 
eye (right eye) 
 Visual acuity – both eyes 
 Ocular symptoms (burning, stinging, itching, foreign body sensation) evaluated using a 0-
100 mm VAS - both eyes 
 Objective ocular signs (Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) by Slit lamp examination - both eyes 
 Corneal fluorescein staining by slit lamp examination - both eyes 
 Intraocular pressure (IOP) - both eyes 
 Fundus ophthalmoscopy (vitreous, macula, retina and optic nerve head) with the slit lamp 
- both eyes  
 Treatment-emergent adverse events (TEAEs), assessed throughout the study 
 Vital signs (blood pressure and heart rate) 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 19 
3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of products 
 
The analytical certificates will be supplied with the investigational products.  
 
3.1.1.1 
Test product 
 
TEST (T) 
 
Investigational product 
Chloroprocaine 3% ocular gel, Sintetica S.A., Switzerland 
Manufacturer 
Unither Pharmaceuticals, France 
Pharmaceutical form 
Ocular gel 
Dose 
3 drops 
Administration route 
Ocular instillation 
 
3.1.1.2 
Control 
 
Placebo (P) 
 
 
Investigational product 
Placebo, Vehicle for chloroprocaine 3% ocular gel, Sintetica 
S.A., Switzerland 
Manufacturer 
Unither Pharmaceuticals, France 
Pharmaceutical form 
Ocular gel 
Dose 
3 drops 
Administration route 
Ocular instillation 
 
3.1.1.3 
Auxilliary medicinal product 
 
Fluoresceine-Oxybuprocaine SDU Faure (Omnivision, Neuhausen). 
 
3.1.2 
Dose regimen 
 
One hundred and five (105) healthy male and female subjects will be administered by ocular 
instillation a single dose (3 drops) of Chloroprocaine 3% ophthalmic gel or matching placebo 
(vehicle) in a 4:1 ratio, according to the parallel-group randomised study design.  
 
3.1.3 
Route and method of administration 
 
The assigned investigational product (3 drops) will be instilled in the right eye of each 
subject. Administrations will be performed at the clinical centre by the Investigator or his 
deputy on study day 1. For each administration, subsequent drops will be instilled at a 1 min ± 
15 sec interval. 
 
Definitions: 
Time 0h (T0) is defined as the time of the end the last drop (drop 3) instillation. 
Pre-dose (baseline) assessments are performed before the first drop instillation. 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 20 
Post-dose times are calculated from T0, i.e. from the end of the instillation of the last drop 
(drop 3). 
 
3.1.4 
Investigational product distribution 
 
The two investigational products will be administered by the Investigator or by his deputy. 
The investigational products will be exclusively used for the present clinical study and will 
only be administered to the subjects enrolled in the study.  
 
3.2 
Packaging and labelling 
 
Packaging and labelling of the investigational products will be carried out by the Sponsor. 
The primary packaging of the investigational products will be a 0.9-mL sterile gel presented 
in polyethylene blow-fill-seal vials packed in individual carton packages (subjects’ kits).  
 
Labelling in local language 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). 
 
Labelling on packages will report: 
a) 
Name, address and telephone number of the Sponsor and CRO;  
b) 
Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency;  
c) 
Batch number;  
d) 
Study Nr.;  
e) 
The study subject identification number;  
f) 
Expiry in month/year format and in a manner that avoids any ambiguity;  
g) 
Investigator's name;  
h) 
Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product);  
i) 
“For clinical trial use only” or similar wording;  
j) 
The storage conditions; 
k) 
“Keep out of reach of children”. 
 
3.3 
Storage conditions 
 
The investigational products will be stored at 15-25°C in a dry locked place, sheltered from 
light. The products will not be refrigerated or frozen. 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 21 
 
3.4 
Drug accountability 
 
The investigational products will be provided directly to the Investigator/clinical centre by the 
Sponsor, in excess of the amount necessary for the study (at least 25% excess). 
 
After receipt of the investigational products' supply, the Investigator/pharmacist will confirm 
in writing by signing and dating standard drug accountability forms. 
 
At the end of the study, used, unused and partially used supplies of the investigational 
products provided by the Sponsor will either be destroyed on site (upon written authorisation) 
or returned to the Sponsor, after assessment of drug accountability. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 22 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
This is a phase I/II, single dose, randomised, placebo-controlled, parallel-group, double-
masked, efficacy, safety and local tolerability study 
 
 
4.2 
Discussion of design 
 
This study will be performed as part of a clinical development program for Chloroprocaine 
3% ophthalmic gel, following scientific advice obtained from the FDA in Sept. 2019. As part 
of this development plan, and following the advice of the competent authority, beside the 
present study, a phase II/III study in healthy volunteers is planned to be performed in Austria. 
 
The study will enrol a total of 105 healthy men and women. According to the study design, 
initially safety and local tolerability will be evaluated on the data collected for the first 20 
randomised subjects (16 treated with the active product and 4 with placebo). For these 
subjects, no efficacy evaluation will be carried out. If safety and local tolerability are 
confirmed after the first enrolled subjects, the study will continue with the following 85 men 
and women (68 treated with the active product and 17 with placebo) on which treatment 
efficacy as well as safety will be assessed. 
 
Each randomised subject will be allocated to a treatment group according to a computer 
generated randomisation list and a 4: 1 ratio for active treatment vs. placebo (see § 8.1). The 
study will be double-masked and the two investigational products will be indistinguishable. 
 
The selected dose of Chloroprocaine gel is derived from animal data. In an ocular tolerance 
study (4) on New Zealand White Rabbits a 5 day 5times daily administration of 
Chloroprocaine ophthalmic gel was in general well tolerated. A transient absence of pupillary 
reflex and partial mydriasis were observed for eyes treated with Chloroprocaine 3% gel after 
each last daily administration. In summary, five daily instillations over 5 days of 
Chloroprocaine gel 3% in the right eyes of albino rabbits were both macroscopically and 
microscopically well tolerated. 
A non-clinical dose finding study investigating Chloroprocaine 5% gel, Chloroprocaine 3% 
high viscosity gel and Chloroprocaine 3% low viscosity gel was performed on New Zealand 
White rabbits (Study number: A66C06315). Whereas Chloroprocaine 5% gel showed only 
limited tolerability on the ocular surface and was therefore not further investigated, 
Chloroprocaine 3% showed good tolerability together with a long anaesthetic effect (up to 60 
minutes for the high viscosity gel, up to 45 minutes for the low viscosity gel). Based on this 
data, Chloroprocaine 3% high viscosity gel was chosen for further development. The 
performance of the selected formulation (Chloroprocaine 3% high viscosity gel) was then 
confirmed in a further study in group of 6 albino rabbits (7), again showing a good anaesthetic 
effect of Chloroprocaine 3% gel. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 23 
5 
STUDY POPULATION 
 
5.1 
Target population 
 
Healthy male and female subjects, aged 18-55 years inclusive 
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and age: Healthy men and women, 18 - 55 years 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, heart rate 50-90 bpm, 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 of child-bearing potential 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; 
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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at 
least 1 year will be admitted. For all women, urine pregnancy test result must be negative 
at screening. 
 
5.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
 
1. Physical findings: Clinically significant abnormal physical findings which could interfere 
with the objectives of the study 
2. Visual acuity: Best corrected visual acuity < 1/10 
3. Concomitant medications: Medications, including over the counter medications and herbal 
remedies, systemic opioids and morphine drugs, topical ocular products with anaesthetic 
action, systemic analgesic drugs, for 2 weeks before study screening 
4. Ophthalmic diseases: Clinically significant ocular disease; eye movement disorder (i.e. 
nystagmus); dacryocystitis and all others pathologies of tears drainage system; corneal, 
epithelial, stromal or endothelial, residual or evolutionary disease (including corneal 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 24 
ulceration and superficial punctuate keratitis); history of inflammatory ocular disease 
(iritis, uveitis, herpetic keratitis), history of ocular traumatism, infection or inflammation 
within the last 3 months or history of any other ocular disease that may affect the outcome 
of the study or the subject's safety 
5. Ophthalmic surgery: History of ophthalmic surgical complications (e.g. cystoid macular 
oedema) in the last 6 months 
6. Diseases: Significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, 
skin, haematological, endocrine, psychiatric or neurological diseases or surgeries that may 
interfere with the aim of the study 
7. Allergy: Ascertained or presumptive hypersensitivity to the active principle and/or 
ingredients of investigational products; history of anaphylaxis to drugs or allergic 
reactions in general, which the Investigator considers may affect the outcome of the study 
8. 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 
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and 
>2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015-2020 
(8)], caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day) 
10. Alcohol test: positive alcohol breath test at Day 1 
11. Pregnancy (women only): positive or missing pregnancy test at screening, pregnant or 
lactating women 
 
5.3.1 
Not allowed treatments 
 
Any medications, including OTC and herbal remedies, in particular systemic opioids and 
morphine drugs, topical ocular products with anaesthetic action and systemic analgesic drugs, 
will NOT be allowed for 2 weeks before the start of the study and during the whole study 
duration. Paracetamol will be allowed as therapeutic counter-measure for adverse events 
(AEs) according to the Investigator’s opinion. Hormonal contraceptives will be allowed.  
 
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 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 25 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
6.1 
Study visits and procedures 
 
Each study subject will undergo 4 visits. 
 
The study protocol foresees 1 period for each subject. Maximum study duration will be 29 
days, screening visit and follow-up 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 clinical centre by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the clinical centre 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: day -21 / day -1 
 
 Interventional phase 
 Visit 2: day 1 
 
 Final phase 
 Visit 3: day 2: Telephone call 
 Visit 4: day 7 ± 1 or at early discontinuation: follow-up/early termination visit (ETV).  
The schedule of the study procedures and assessments is presented below: 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 26 
Schedule: 
 
 
Day 
Procedures/Assessments 
Screening – Visit 1 
Day -21 / 
Day -1 
 Explanation to the subject of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data 
 Ocular medical and surgical history 
 Other medical and surgical history 
 Previous and concomitant medications 
 Physical examination (including ocular examination, body weight, height) 
 Vital signs (blood pressure and heart rate) check 
 Urine pregnancy test for women 
 Adverse event (AE) monitoring 
 Ocular symptoms (0-100 mm VAS) - all subjects - both eyes 
 Visual acuity (EDTRS) – both eyes 
 Slit lamp examination (SLE; Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) - all subjects - both eyes 
 Corneal fluorescein staining with SLE - all subjects - both eyes 
 Intraocular pressure measurement - all subjects - both eyes 
 Fundus ophthalmoscopy (with slit lamp) - all subjects - both eyes 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Visit 2 
Day 1 
 Alcohol test 
 Inclusion/exclusion criteria evaluation 
 Subject eligibility confirmation 
 Enrolment and randomisation 
 Vital signs (blood pressure, heart rate) check - pre-dose - all subjects 
 Ocular symptoms (0-100 mm VAS) - pre-dose - all subjects  - both eyes 
 Slit lamp examination (SLE; Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) - pre-dose - all subjects  - both eyes 
 Instillation of the investigational product (right eye only) 
 Assessment of conjunctival anaesthesia by conjunctival pinching (0.3 mm forceps) at 
the pre-specified post-dose assessment times - efficacy evaluation subjects only - 
study eye only (right eye) 
 Ocular symptoms (0-100 mm VAS) - at the end of the study day - all subjects - both 
eyes 
 Vital signs (blood pressure, heart rate) check - at the end of the study day - all subjects 
 Slit lamp examination - at the end of the study day (SLE; Conjunctival redness, 
anterior chamber flare, conjunctival chemosis, eyelid swelling) - all subjects - both 
eyes 
 AE and concomitant medications (throughout the study day) 
Visit 3 
Day 2 - 
Phone 
call 
 AE and concomitant medications check 
 
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 27 
 
Schedule, continued: 
 
 
Day 
Procedures/Assessments 
Visit 4 
Day 7 ± 1 
Follow up 
 AE and concomitant medications 
 Vital signs (blood pressure, heart rate) check 
 Physical examination 
 Ocular symptoms (0-100 mm VAS) - both eyes 
 Visual acuity (EDTRS) – both eyes 
 Slit lamp examination (SLE; Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) - both eyes 
 Corneal fluorescein staining (with SLE) - both eyes 
 Intraocular pressure measurement - both eyes 
 Fundus ophthalmoscopy (with slit lamp) - all subjects - both eyes 
 
 
 
6.2 
Diet and lifestyle 
 
Not applicable. 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 28 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Physical examinations, including ocular examinations, will be performed at the screening and 
final visit/ETV. 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 CRFs. 
 
7.1.1 
Body weight 
 
Body weight will be recorded at the screening visit. Subjects will be weighed (kg) lightly 
clothed without shoes. Height will also be measured at screening and BMI will be recorded. 
BMI will be calculated as weight [kg]/(height [m] x height [m]). 
 
7.1.2 
Vital signs 
 
Subjects blood pressure and heart rate will be measured by the Investigator or his/her deputy 
after 5 min at rest at the screening visit, on day 1 at pre-dose and at the end of the study day 
and at follow-up/ETV.  
 
7.1.3 
Alcohol test 
 
An alcohol test will be performed on Day 1. 
 
7.2 
Ocular assessments 
 
7.2.1 
Ocular symptoms assessment 
 
The following ocular symptoms will be assessed: burning, stinging, itching, foreign body 
sensation. 
 
Scores will be determined using a 100 mm VAS where 0 means “no symptoms” and 100 
means “worst possible discomfort”.  
 
The assessments will be performed for all subjects and both eyes at the screening visit, on day 
1 at pre-dose and at the end of the study day and at follow-up/ETV. 
 
7.2.2 
Visual acuity 
 
Visual acuity will be assessed, for all subjects and both eyes, at the screening visit and at 
follow-up/ETV, using an EDTRS chart. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 29 
 
7.2.3 
Slit lamp examination 
 
Slit lamp biomicroscopy will be performed for the assessment of the following parameters: 
conjunctival redness, anterior chamber flare, conjunctival chemosis, eyelid swelling. 
Presence and severity will be graded according to a 4 point scale, where (0) none, (1) mild, 
(2) moderate, (3) severe. 
 
The assessment will be performed for all subjects and both eyes at the screening visit, on day 
1 at pre-dose (baseline) and study day end and at follow-up/ETV. 
 
7.2.4 
Corneal fluorescein staining 
 
Fluorescein (see § 3.1.1.3) will be used to detect corneal epithelial defects using slit lamp 
biomicroscopy. As grading scale for corneal damage, the NEI/Industry Workshop guidelines 
will be used (9). The cornea will be divided into five sectors (central, superior, inferior, nasal 
and temporal), each of which is scored on a scale of 0–3, where 0 means no staining and 3 
means maximum staining, with a maximal score of 15. 
 
Corneal fluorescein staining will be performed for all subjects and both eyes at the screening 
visit and at follow-up/ETV. 
 
7.2.5 
Assessment of conjunctival anaesthesia 
 
Conjunctival anaesthesia will be assessed in the study eye only (right eye) by pinching of the 
conjunctiva with 0.3-mm forceps. Subjects will be asked to immediately report if they feel 
pain (efficacy evaluation subjects only).  
 
Subjects will initially be tested at 20 seconds, 40 seconds, and 60 seconds post-dose (day 1).  
 
The evaluation will be performed again at 5 min post-dose.  If anaesthesia is already present 
at 20 and 40 seconds, pain will not be assessed at 60 sec but directly at 5 minutes. Further 
assessments will be performed every 5 min up to 60 min post-dose. Alternatively, if the 
subject experiences pain at two consecutive assessments, pinching will be suspended and the 
subsequent assessment will not be performed. If the subject experiences pain at 5 minutes, no 
more testing will be performed and the subject will be considered not to have gained 
anaesthesia. (10). 
 
7.2.6 
Fundus ophthalmology 
 
Indirect fundus ophthalmoscopy will be performed, for all subjects and both eyes, at the slit 
lamp using a +90 diopters Volk lens (11), at the screening visit and at follow-up/ETV. 
 
7.2.7 
Intraocular pressure 
 
Intraocular pressure will be measured with a slit-lamp mounted Goldmann applanation 
tonometer. Before each measurement one drop of oxybuprocaine hydrochloride combined 
with sodium fluorescein will be used for local anaesthesia of the cornea. 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 30 
 
The assessment will be performed for all subjects and both eyes at the screening visit and at 
follow-up/ETV. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 31 
8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomisation 
 
The randomisation list will be computer-generated by the Biometry Unit of the Clinical 
Contract Research Organization (CRO), using the PLAN procedure of the SAS® version 9.3 
(TS1M1) (12) or higher (the actual version will be stated in the final report). The 
randomisation list will be attached to the final clinical study report. 
 
8.2 
Treatment allocation 
 
Subjects will be assigned to one of the two treatment groups (Choroprocaine/placebo) in a 4:1 
ratio according to the randomisation list. A randomisation number will be given to the 
subjects on study day 1 in chronological order, after eligibility confirmation. 
 
8.3 
Blinding 
 
The study will be carried out in a double-masked (double-blind) fashion, therefore the 
Investigator/deputy administering the investigational products, the ophthalmologists 
performing the measurements as well as the study participants will not know the allocated 
product.  
 
Three (3) copies of the randomisation list will be generated and sealed in individual 
envelopes: 
 one copy will be sent to the manufacturer for the preparation of the individual treatment 
boxes 
 one copy will be kept at the CRO Quality Assurance Unit 
 one copy will be stored in the statistical study file 
 
Neither the members of the clinical unit nor the CPL or the CRA/monitor will have access to 
the randomisation code.  
 
The CRO will open the envelope containing the randomisation list only when data-entry is 
complete and decisions to be made in blinding, before data analysis, are final.  
 
The CRO will notify breaking of the randomisation list to the Sponsor. 
 
8.3.1 
Emergency code and unblinding procedures 
 
Unblinding of the code for specific subjects, if applicable, will be fully documented in the 
source documents and in the clinical study report. 
 
8.3.2 
Emergency individual envelopes 
 
Inside the envelope, the randomisation code must be clearly indicated, reporting the allocated 
treatment. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 32 
The true randomisation code will be filed in the Investigator’s study file in a sealed envelope 
for each subject, with the key for its identification. Copies of the emergency individual 
envelopes will be sent to the pharmacovigilance representative and to the Sponsor 
representative (if not coinciding). 
 
Breaking of an individual randomisation code, by the Investigator during the study, is allowed 
only when knowledge of the code by the Investigator is essential for the subject's health. In 
these cases, the Investigator will open only the envelope related to the concerned subject. 
Individual code breaking will be clearly reported in the subject-related CRF and the envelope 
itself; the latter is sealed again. 
 
In any case, the CRA/monitor must be informed within 24 h from code breaking. 
 
The date and the reason for breaking the code must be recorded in the CRF and on the 
envelope. All envelope sets containing the randomisation code of each subject must be kept 
closed even after database lock. At the end of the study, all envelope sets will be sent to the 
Sponsor. 
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 33 
9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary variables 
 
 Conjunctival anaesthesia evaluation by conjunctival pinching (with 0.3 mm forceps) at 5 
min post-dose - only study eye (right eye). 
 
9.1.2 
Secondary variables 
 
 Conjunctival anaesthesia evaluation by conjunctival pinching (with 0.3 mm forceps) at 
the pre-specified assessment time-points (see below) - only study eye (right eye) 
 Ocular symptoms (burning, stinging, itching, foreign body sensation) using a 0-100 mm 
VAS- both eyes 
 Visual acuity (EDTRS chart) – both eyes 
 Objective ocular signs (Conjunctival redness, anterior chamber flare, conjunctival 
chemosis, eyelid swelling) by SLE- both eyes 
 Corneal fluorescein staining by SLE- both eyes 
 Intraocular pressure (IOP) - both eyes 
 Fundus ophthalmoscopy (vitreous, macula, retina and optic nerve head) with the slit 
lamp- both eyes 
 Treatment-emergent adverse events (TEAEs), assessed throughout the study 
 Vital signs (blood pressure and heart rate). 
 
9.2 
Safety assessments 
 
Safety and general tolerability of the investigational products will be based on TEAEs, ocular 
symptoms (0-100 mm VAS), physical examinations including body weight, vital signs, visual 
acuity, SLE, corneal fluorescein staining, fundus ophthalmoscopy and IOP results. 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 34 
10 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. arithmetic mean, SD, 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, efficacy and safety data will be performed using SAS® version 9.3 (TS1M1) 
(12) or higher (the actual versions will be stated in the final report). 
 
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 in the interventional 
phase of the study. The enrolment will be performed through randomised allocation to a 
treatment arm. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatment arm. 
 
The following data sets will be used for the analysis: 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
 Full Analysis Set (FAS): all randomised subjects, who receive the dose of the 
investigational product and have at least one post randomisation assessment of the 
primary efficacy data. This analysis set will be used for the primary efficacy analysis 
 Per Protocol set (PP): all randomised subjects who fulfil the study protocol requirements 
in terms of investigational product intake and collection of primary efficacy data and with 
no major deviations that may affect study results. This analysis set will be used for 
sensitivity analyses 
 Safety set: all subjects who receive at least one dose (drop) of the investigational product. 
This analysis set will be used for the safety analyses 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Enrolled 
set, FAS, PP set and Safety set. Subjects will be evaluated according to the treatment they 
actually receive (Enrolled set, FAS, PP set and Safety set).  

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 35 
 
10.1.2 
Reasons for exclusion from the Full Analysis Set  
 
Reasons for the exclusion of subjects from the Full Analysis Set are the following: 
 
failure to take the investigational product 
 
lack of any primary efficacy data post enrolment 
 
failure to satisfy major inclusion/exclusion criteria (eligibility deviations). Subjects who 
fail to satisfy an inclusion/exclusion criterion may be excluded from the analysis without 
the possibility of introducing bias only under the following circumstances: 
• 
the inclusion/exclusion criterion was measured prior to enrolment 
• 
the detection of the relevant eligibility deviations is completely objective 
• 
all subjects receive equal scrutiny for eligibility deviations (blind review) 
• 
all detected deviations of the particular inclusion/exclusion criterion are excluded 
 
10.1.3 
Reasons for exclusion from the Per Protocol set  
 
Reasons for the exclusion of subjects from the Per Protocol set include (but are not limited to) 
the following: 
 
lack of compliance to the investigational product 
 
exposure to an investigational product different from the one assigned to the subject 
 
missing primary efficacy data 
 
failure to satisfy any inclusion/exclusion criteria (eligibility deviations) 
 
intake of prohibited medications 
 
10.2 
Sample size and power considerations 
 
A total of 105 healthy men and women will be included in the study. Active vs. placebo 
treatment will have a 4:1 ratio. 
Initially, local tolerability and safety will be evaluated on the first 20 enrolled subjects (16 
treated with chloroprocaine 3% ocular gel and 4 with placebo).  
After the first 20 subjects have completed the study, local tolerability and safety data will be 
evaluated and if treatment safety is confirmed, efficacy, beside local tolerability and safety, 
will be assessed on the 85 subsequent subjects (68 active gel and 17 with placebo).  
 
Sample size for the efficacy evaluation was formally calculated as follows:  
Sample size per group was calculated by comparing two independent proportions 
(experimental and placebo success rate) with a two-sided alpha=0.05 and a power of 0.95. 
This is based on the assumption, that the experimental success rate is 80% and the vehicle 
success rate is 30%, taking a dropout rate of 20% into account. For sample size estimation, 
NQuery (Version 4.0) was used implementing formulas described in Chow et al (2008) (13). 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 36 
 
10.3 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarised in contingency tables. Quantitative data will be 
summarised using classic descriptive statistics. 
 
10.4 
Analysis of efficacy parameters 
 
10.4.1 
Primary end-point 
 
Primary end-point is defined as the proportion of subjects gaining full anesthesia of the ocular 
surface 5 minutes after administration of the investigational product for the 2 treatment arms 
(cornea pinching assessment).   
 
The result of the anesthesia will be coded as success/failure, listed by subject and summarized 
overall and by treatment group using contingency tables. Resulting proportions will be 
presented together with 95% confidence interval. The 2 groups (active and placebo) will be 
compared using Pearson’s χ2 test. The null hypothesis of equal success between the 2 
treatment arms at the α=0.05 level will be rejected if: 
 
ተተ
𝑝1
ෞ−𝑝2
ෞ
ට𝑝1
ෞ(1 −𝑝1
ෞ)
𝑛1
+ 𝑝2
ෞ(1 −𝑝2
ෞ)
𝑛2
ተተ> 𝑍𝛼/2 
 
where p1 is the proportion of subjects who meet the primary endpoint in the active group, 
while p2 is the proportion of subjects who meet the primary endpoint in the vehicle (placebo) 
group. 
 
10.4.2 
Secondary end-points 
 
Time to anesthesia and duration of anesthesia will be listed and summarized overall and by 
group using descriptive statistics (mean, median, standard deviation, minimum, maximum, 
95% confidence interval on the mean, and number of observations). The 2 groups (active and 
placebo) will be compared using non-parametric Mann-Whitney’s test for continuous 
variables.  
 
10.5 
Safety and tolerability evaluation 
 
10.5.1 
Adverse events 
 
Adverse events (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 treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 37 
 PTAEs: all AEs occurring before the first dose of investigational product and not 
worsening after the first dose of investigational product 
 TEAEs: all AEs occurring or worsening after the first dose of investigational product 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised 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 (if applicable), relationship to treatment and severity.  
 
10.5.2 
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. Body weight values will be listed and summarised by 
descriptive statistics. 
 
10.5.3 
Ocular symptoms 
 
VAS scores for ocular tolerability parameters (burning, stinging, itching, foreign body 
sensation) and their changes from baseline will be listed and summarised by treatment and 
eye using descriptive statistics (mean, SD, CV%, minimum, median and maximum). 
 
Changes from baseline will be evaluated and compared between treatments. 
 
10.5.4 
Visual acuity 
 
Visual acuity results will be listed by subject and summarised for each eye by descriptive 
statistics. 
 
10.5.5 
Slit lamp examination, corneal fluorescein staining and fundus 
ophthalmoscopy results 
 
Scores or values for Slit lamp examination (SLE) parameters, Fundus ophthalmoscopy 
parameters and Corneal fluorescein staining parameters and their changes from baseline will 
be listed and summarised for each eye using descriptive statistics (mean, SD, CV%, 
minimum, median and maximum). 
 
10.5.6 
Intraocular pressure 
 
IOP values will be listed and summarised for each eye by descriptive statistics. 
 
10.5.7 
Vital signs 
 
Vital signs values will be listed and summarised by descriptive statistics.  
 
 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 38 
11 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
11.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the SOP of CROSS Research S.A., 
based upon applicable local and international regulations. The full SOP or an operative 
summary will be made available to the clinical centres. 
 
A brief summary of AE definition, classification and management is reported below. 
 
11.2 
Definitions 
 
 Adverse event (AE) 
 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with treatment. 
 
 Adverse Drug Reaction (ADR) 
 
Any noxious and unintended response to a medicinal product (i.e. a causal relationship 
between a medicinal product and an AE is at least reasonably possible in the Investigator's or 
Sponsor's opinion, the relationship cannot be ruled out) resulting not only from the authorised 
use of a medicinal product at normal doses, but also from medication errors and uses outside 
the terms of the marketing authorisation, including the misuse and abuse of the medicinal 
product. 
 
 Pre-treatment AE (PTAE) 
 
Any AE occurring before the first dose of a medicinal product and not worsening after the 
first dose. The following medical occurrences and clinical investigations are the only 
clinically significant events which, according to the Investigator judgement, can be defined 
and recorded as PTAEs: 
 trauma (fractures, sprains, strains, falls, domestic accidents, car accidents, etc.) 
occurred after the signature of the informed consent and before the first medicinal 
product administration 
 new measurements (vital signs, laboratory parameters, etc.), performed after the 
signature of the informed consent and before the first medicinal product 
administration, which show a clinically significant worsening in comparison with a 
previous (baseline) measurement performed after the signature of the informed 
consent 
 any disease diagnosed after the anamnesis recorded at visit 1 and before the first 
medicinal product administration  
 physical and mental status changes (pre-syncope, anxiety, dizziness, fainting, etc.) 
occurred after the signature of the informed consent and before the first medicinal 
product administration 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 39 
 
 Treatment-emergent AE (TEAE) 
 
Any AE occurring or worsening after the first dose of a medicinal product 
 
 Serious Adverse Event (SAE) 
 
Any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event that may jeopardize the subject’s health status or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are cancer, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse 
 
 Unexpected ADR: an ADR the nature or severity of which is not consistent with the 
Reference Safety Information (RSI) 
 
 Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, Chloroprocaine Investigator’s Brochure (IB) will be used. 
 
 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
An ADR that is both unexpected (not consistent with the RSI) and also meets the definition of 
a SAE. 
 
11.3 
AEs monitoring window 
 
 Start of monitoring: from immediately after the signature of the informed consent 
 End of monitoring: last follow-up visit/ETV  
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. 
 
11.4 
AEs recording 
 
All AEs derived by spontaneous, unsolicited reports of the subjects, by observation and by 
routine open questioning should be collected and reported. 
The following minimal information will be recorded for an AE (detailed explanation for each 
element is available in the SOP or in the operative summary made available to the clinical 
centre) in the source documents and later transcribed into the CRF: 
 
1. 
Adverse Event: progressive number of the adverse event  
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 40 
2. 
Description: verbatim description of the adverse event or  
 
Follow-up: progressive number of follow-up of the adverse event  
 
3. 
Acknowledgment Date/Time: acknowledgment date/time of the adverse event or  
 
Follow-up Date/Time: follow-up date/time of the adverse event  
 
4. 
Start Date/Time: start date/time of the adverse event   
 
5. 
End Date/Time: end date/time of the adverse event  
 
6. 
Affected Body Area: anatomical location relevant for the event 
 
7. 
Whether the adverse event start before or after the first intake of the study drug or 
whether the adverse event has worsened or not after the first intake of the study drug 
 
8. 
Last Study Drug Administration Date/Time Before Onset: if the adverse event started 
after the first administration of the study drug, the date/time of last administration of the 
study drug before the onset of the adverse event or 
Last Study Drug Administration Date/Time Before Worsening: In case of treatment 
emergent adverse event, the date/time of the last administration of the study drug(s) 
before the worsening of the adverse event.  
 
9. 
Investigator's opinion about the reasonable possibility of a causal relationship with the 
study drug.  
 
10. 
Investigator's opinion about other causal relationship (e.g. non study drug, concomitant 
therapy, study device, etc.).  
 
11. 
Severity: the severity or intensity of the event 
 
• 
1 Mild  
• 
2 Moderate 
• 
3 Severe 
 
12. 
Pattern: Used to indicate the pattern of the event over time 
 
• 
1 Single Event 
• 
2 Continuous 
• 
3 Intermittent 
 
13. 
Serious Adverse Event  
 
 
14. 
Action Taken with Study Drug: describes changes to the study drug as a result of the 
event. It is specifically for actions taken with the study drug 
 
• 
1 Dose Not Changed 
• 
2 Dose Increased 
• 
3 Dose Reduced 
• 
4 Drug Interrupted (i.e. temporary stop) 
• 
5 Drug Withdrawn (i.e. definitive stop) 
• 
6 Not Applicable (e.g. drug administration not started yet or completed) 
• 
7 Unknown 
  
 
15. 
Concomitant Therapy: if a concomitant therapy is given, it must be reported in the 
specific CRF forms 
 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 41 
16. 
Study Discontinuation: if the adverse event cause the subject to be discontinued from 
the study 
 
17. 
Other Action Taken: other actions taken as a result of the event that are unrelated to 
dose adjustments of study drug 
 
 
18. 
Outcome: Outcome of the event 
 
• 
1 Recovered/Resolved 
• 
2 Recovered/Resolved With Sequelae 
• 
3 Recovering/Resolving 
• 
4 Not Recovered/Not Resolved 
• 
5 Fatal 
• 
6 Unknown 
 
 
11.5 
SAEs reporting 
 
IMPORTANT: National regulations and requirements for SAE reporting prevail, however, 
in general, the following indications should be followed. 
 
The Investigator must report to the Sponsor any SAE within 24 h of becoming aware of the 
event. The Investigator, within the same timeframe, should also inform the study monitor and 
the CRO. The Investigator shall notify the competent Ethics Committee (EC) within 7 days of 
any SAE with lethal outcome occurred during a study. If the Investigator is initially unable to 
obtain all the necessary details for completing the form, he/she should in any case transmit all 
the available information. The Investigator should provide an appropriate follow-up of SAEs 
to all concerned parties. 
Seriousness and causality must be assessed by the Investigator. Expectedness is usually 
assessed by the Sponsor. 
If the Investigator is unable to assess the causality it is recommended to adopt a conservative 
approach and treat the event as a suspected adverse reaction until follow-up information is 
available. 
The Sponsor may also make an assessment of causality, independent of that of the 
Investigator. The most conservative approach should be taken when it comes to regulatory 
reporting. Under no circumstances should the Sponsor downgrade the Investigator's opinion 
or put the Investigator under pressure to change his/her assessment. In case of disagreement, 
both the opinion of the Investigator and the Sponsor should be provided in the report. 
The Sponsor will evaluate the SAE expectedness on the basis of the RSI. 
 
11.6 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the Sponsor (day 0).  
For fatal and life-threatening SUSARs the EC and Competent Authority (CA) should be 
informed as soon as possible and in any case within 7 days. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days. 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 42 
The minimum information to be reported includes: 
 Valid EudraCT number (where applicable) 
 Sponsor study number 
 One identifiable coded subject 
 One identifiable reporter 
 One SUSAR 
 One suspect investigational product (including active substance name, code) 
 A causality assessment (a reasonable possibility of a causal relationship with the study 
drug can be excluded only if there is information supporting this decision, otherwise it 
cannot be excluded). 
 
11.7 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting when they might materially alter the 
current benefit-risk assessment of a medicinal product or would be sufficient to consider 
changes in the medicinal product administration or in the overall conduct of the trial, for 
instance: 
 single case reports of an expected serious adverse reaction with an unexpected 
outcome (e.g.: a fatal outcome) 
 an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
 post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the Investigator by the subject. 
 new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
− a SAE which could be associated with the trial procedures and which could modify 
the conduct of the trial 
− a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) or from other clinical trials. 
 
11.8 
SAEs: contacts 
 
SAEs must be reported on SAE reporting forms and faxed/emailed within 24 H to Corporate 
Drug Safety Unit of the sponsor - contact details below: 
 
 
 
 
 
 
Fax: 
+41(0)91.646.85.61 
Phone: +41(0)91.640.42.50 
Email:  corporate_drug_safety@sintetica.com 

CONFIDENTIAL 
 
Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
Chloroprocaine 3% ocular gel 
Final version 1.0, 21FEB20 
CROSS Research S.A. 
Page 43 
12 
DATA MANAGEMENT PROCEDURES 
 
12.1 
Data collection – CRFs 
 
The Investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the CRFs. He must also check that the data reported in the CRFs correspond to 
those in the subject’s source documents.  
To ensure legibility, the CRFs should be filled out in English, in block capitals with a ball-
point pen (not pencil, felt tip or fountain pen). Any correction to the CRFs' entries must be 
carried out by the Investigator or a designated member of staff. Incorrect entries must not be 
covered with correcting fluid, or obliterated, or made illegible in any way. A single stroke 
must be drawn through the original entry. Corrections have to be dated and initialled. In the 
interest of completeness of data acquisition, the questions which are repeated in each section 
of the CRFs 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 CRFs will be completed, signed by the Investigator, sent to the CRO Biometry Unit for 
data management procedures and finally sent to the Sponsor.  
 
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. CHL.3-01-2020), 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 randomisation number (e.g. 001, 002, 
etc.). Study code, site number, screening number and subject randomisation number are 
separated by slashes (“/”). The last 8 digits of the unique subject identifier (enrolled subjects), 
corresponding to the subject screening and subject randomisation 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 clinical study report. 
 
12.3 
Database management 
 
The CRO will provide a double data entry with 100% sight verification of data and 
discrepancy resolution by a second data entrist and will update and verify the database and 
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. 

CONFIDENTIAL 
 
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Sponsor code CHL.3-01-2020 
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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
13.1 
Monitoring 
 
The monitoring visits will be conducted by Clinical Medical Services of Maria Pia Savorelli 
and the Sponsor (see § 16.3).  
 
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 authorised 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(s) 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 requirement(s). 
 
The CROs 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 centre and the CRO 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. 
 
13.4 
Data access 
 
The Investigator and the CRO will ensure that all raw data records, medical records, CRFs 
and all other documentation that is relevant to this study will be made accessible for 
monitoring activities, audits, IEC review, and regulatory inspections. 
 
13.5 
Audits and inspections 
 
The Sponsors, 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 Investigators and the CROs agree, by written consent to this protocol, to fully co-operate 
and support audits and inspections compliance checks by allowing authorised 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 in 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 and regulatory authorities. 
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 organised 
 the type of treatment (information on the investigational product(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 jeopardising 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. 
 
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). 
The Investigator will allow inspection of the forms by authorised representatives of the 
Sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 
A blank copy of the information sheet and the informed consent form is appended to this 
protocol. 
 

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14.3 
Insurance policy 
 
An insurance cover has been issued in favour 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 completed the clinical study. If, for a 
subject, study treatment or observations are discontinued, the primary reason for 
discontinuation will be recorded. 
 
14.4.1 
Primary reasons 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 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by Sponsor: an indication that a 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 
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 CRF date and time of the last dose administration, and date and primary 
reason of study discontinuation 

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 record in the CRF any follow-up, if the subject is withdrawn for an AE 
Subjects withdrawn from the study will retain their randomisation number and will not be 
replaced.  
 
14.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject 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 and immediately reported to 
Swissmedic and EC (i.e. within 15 days).  
 
 

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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical centre 
 
Beside the investigational products, the following study material will be supplied to the 
clinical centre: 
 final version of the study protocol 
 CRF for each subject plus some spare copies 
 copy of the Investigator’s Brochure (IB) 
 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 CRFs and in all required reports. 
 
The Investigator must keep source documents for each subject in the study. All information 
on the CRFs 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 and the original signed informed consent forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 
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 requirement(s).  

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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, insurance contracts, certificate of analysis of the investigational products, drug 
accountability records, signed informed consent forms, confidential subjects identification 
code, CRFs, 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 enrol 
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 being informed 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, CRFs 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 CRFs during the study will be documented in an anonymous 
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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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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Sponsor code CHL.3-01-2020 
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16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Sintetica S.A., Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: 
+41.91.640.42.50 
Fax: 
+41.91.646.85.61 
 
Sponsor representatives  
Corporate Director Scientific Affairs  
Elisabetta Donati 
Email: 
edonati@sintetica.com 
 
Clinical Project Leader 
Erika Botti 
Email: 
ebotti@sintetica.com 
 
Medical Expert 
Claudio Camponovo, MD 
Department of Anaesthesiology, Clinica Ars Medica,  
Via Cantonale, CH-6929 Gravesano, Switzerland  
Phone: 
+41.91.611.6211 
Fax: 
+41.91.605.1559 
Email: 
ccamponovo@arsmedica.ch 
 
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 
 
16.2.2 
Ophthalmological assessments 
 
Ophthalmologists 
Elena Gibin, MD 
gibin@centromedico.ch 
 
Matteo Ghidoni 
ghidoni@centromedico.ch 
 
PDS Medical SA, Via Vela 42, 6834 Morbio Inferiore, Switzerland 
Phone: 
+41 91 683 07 40  

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Study protocol CRO-PK-20-343 
Sponsor code CHL.3-01-2020 
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Page 53 
Fax: 
+41 91 683 07 41 
 
16.3 
Co-ordination, monitoring, data analysis & reporting 
 
CROSS Research S.A., Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.6300510 
Fax: 
+41.91.6300511 
 
Coordination 
Chiara Castiglioni, Clinical Project Leader and Senior CRA 
Email: 
projectmanagement@croalliance.com 
 
Medical Writing Representative 
Chiara Leuratti, Clinical Projects Unit Head 
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 
 
16.4 
Monitoring 
 
Clinical Medical Services di Maria Pia Savorelli, Via Indipendenza 29/A, CH-6883 
Novazzano, Switzerland 
Mobile: +41 79 827 27 67 
Email: 
cmed@cmed.ch 
 
 
 

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17 
REFERENCES 
 
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