A Prospective, Observer-blind, Randomized Clinical Trial to Investigate and Compare the Clinical Efficacy of Chloroprocaine 3% Gel and Oxybuprocaine 0.4% Eye Drops Anesthesia for Clinical Practice in Pediatric Population
Phase: PHASE3
Conditions: Local Anesthetic
Sponsor: Sintetica SA

 
 
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Study Protocol No CHL.3-01-2021-M 
 
CRO Clinical Study Protocol No. CRO-23-153 
 
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CLINICAL STUDY PROTOCOL 
 
Clinical Study Protocol No: CHL.3-01-2021-M 
CRO Clinical Study Protocol No.: CRO-23-153 
 
A prospective, observer-blind, randomized clinical trial to investigate and 
compare the clinical efficacy of Chloroprocaine 3% gel and Oxybuprocaine 0.4% 
eye drops anesthesia for clinical practice in pediatric population. 
 
EU Trial Number: 2023-504477-21-01 
 
 
Test product: 
Chloroprocaine 3% ophthalmic gel, Sintetica S.A., Switzerland 
 
 
Reference product: 
Benoxinato Cloridrato 4 mg/mL eye drops (Oxybuprocaine 
Chlorhydrate 0.4%), ALFA INTES, Italy 
 
 
Sponsor: 
Sintetica S.A., Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: +41.91.640.42.50; Fax: +41.91.646.85.61 
 
 
Coordinating Investigator 
Prof. E. Pedrotti, Clinica Oculistica dell'Azienda Ospedaliera 
Integrata di Verona, Policlinico di Borgo Roma (Verona), 
Italy 
 
 
Development phase: 
Phase III 
 
 
Version and date: 
Version 5.0 – November 10, 2023 
 
 
This study will be conducted in compliance with the protocol, the Clinical Trial Regulation (EU) 536/2014 and 
the principles of Good Clinical Practice (GCP) [ICH topic E6 (R2)], and with the applicable EU and local 
regulatory requirements. 
 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
 
 

 
 
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CLINICAL STUDY PROTOCOL AMENDMENT HISTORY 
 
CSP version N. 
Date issued 
Description 
1.0 
30JUL2021 
Original version 
1.1 
25AUG21 
Final version submitted to FDA for advice 
2.0 
22DEC22 
According to the FDA advice, the definition of 
successful anesthesia was modified. Accordingly, the 
study sample size was re-calculated and the statistical 
analysis methods were completed. 
Several sections were clarified and completed. 
A few typos were corrected. 
3.0 
03MAY23 
 National study coordinating investigator has 
changed. 
 Information about electronic consent use has been 
included. 
 Conjunctival anaesthesia assessment is now 
foreseen for both eyes. The primary efficacy 
analysis will be performed on the right eye only, as 
already foreseen in the previous protocol version. 
 Binocular indirect ophthalmoscopy was added 
beside slit lamp examination for assessment in 
small children, according to the Investigator’s 
opinion. 
 A few typos were corrected. 
4.0 
30AUG23 
According to the MSC requests for information the 
following changes were made: 
 A schematic diagram of the study design has been 
included 
 The rationale for the Test IMP dose selection has 
been expanded 
 The section entitled “Discussion of design” has 
been amended to better explain the blinding of the 
study participants 
 The pregnancy test was included in Table 1 – Study 
schedule 
 The complete list of contraceptive measures 
required, in line with CTFG recommendation on 
Contraception and pregnancy-2020, taking into 
account the characteristics of the IMPs has been 
included as requested 
 The Risk/Benefit section has been expanded, as 
requested 
 Concomitant therapies were further specified as 
suggested 
 It has been specified that the right eye will be 
treated first, followed by the left eye. In the same 
way, the right eye will be assessed first for efficacy 
and safety evaluation, followed by the left eye 

 
 
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 An additional descriptive analysis by age group has 
been specified 
5.0 
10NOV23 
According to the final assessment report of the 
concerned RMS, the authority’s requests were 
addressed as follows: 
 A different comparator (reference product), which 
does not have contraindications in any study 
population age range, will be used. All related 
protocol parts were modified accordingly. 
 Post-dose assessment for vital signs has been 
added. 
 A few typos were corrected. 
 
 
 
 

2.2 
INVESTIGATOR(S) 
STUDY COORDINATOR 
Prof. E. Pedrotti 
CONFIDENTIAL 
Study Protocol N° CHL.3-01-2021-M 
CRO Clinica! Study Protocol No. CRO-23-153 
Version 5.0, 10/November/2023 
Clinica Oculistica dell'Azienda Ospedaliera Integrata di Verona, Policlinico di Borgo Roma 
(Verona), ltaly 
I have read this protocol and agree to conduct this study in compliance with the protocol, the 
Declaration of Helsinki, the current revision of Good Clinica/ Practice (GCP), ICH topic E6 
(R2), the Clinica/ Tria/ Regulation (EU) 536/2014 and the applicable locai law requirements, 
including supervising any individuai or party to whom I will delegate trial-related duties and 
functions at the tria/ site. 
Date 
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3 Contacts page for the study 
 
 
Sponsor 
 
Sintetica SA 
Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: 
+41.91.640.42.50 
Fax: 
+41.91.646.85.61 
 
Sponsor representative 
 
Sergio Cantoreggi, PhD  
Corporate Chief Scientific Officer  
Via Penate 5, CH-6850 Mendrisio, Switzerland 
 
Coordinating Investigator 
Prof. E. Pedrotti 
Clinica Oculistica dell'Azienda Ospedaliera Integrata di 
Verona, Policlinico di Borgo Roma (Verona), Italy 
Sponsor Medical Expert 
Claudio Camponovo, MD 
Department of Anaesthesiology, Clinica Ars Medica,  
Via Cantonale, CH-6929 Gravesano, Switzerland  
 
Biostatistician 
Alessandra Gentili 
Biometry Manager, Unit Head 
CROSS Research S.A., Switzerland 
 
Author of Clinical Study 
Protocol 
Chiara Leuratti 
Clinical Projects Unit Head and Senior Medical Writer 
CROSS Research S.A., Switzerland 
 
All details regarding the CRO for monitoring will be presented in the Investigator’s File 
 
 
 
  
 
 
 

 
 
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4 STUDY SYNOPSIS 
 
 
Study Title  
A prospective, observer-blind, randomized clinical trial to investigate and 
compare the clinical efficacy of Chloroprocaine 3% gel and Oxybuprocaine 
0.4% eye drops anesthesia for clinical practice in pediatric population. 
Sponsor 
Sintetica S.A. 
Protocol Sponsor 
code 
CHL.3-01-2021-M 
CRO clinical 
study protocol N. 
CRO-23-153 
EU Trial Number 
2023-504477-21-01 
Clinical phase 
Phase III  
Study design 
Prospective, 
multicenter, 
randomized, 
active-controlled, 
parallel-group, 
observer-blind, Phase III pediatric non-inferiority study 
Planned Schedule Planned initiation: Q1 2024 
Planned Last Patient Last Visit (LPLV): Q3 2024 
Planned 
n. 
of 
centers / countries 
Approximately 3 centers in Italy  
Indication 
Local anesthesia by topical ophthalmic instillation  
Test Product 
Chloroprocaine 3% gel, Sintetica S.A., Switzerland 
Reference 
product 
Benoxinato Cloridrato 4 mg/mL eye drops (oxybuprocaine chlorhydrate 0.4%), 
ALFA INTES, Italy   
Randomization 
Patients will be allocated to the Test (Chloroprocaine) arm or Reference 
(Oxybuprocaine chlorhydrate) arm according to a 1:1 ratio  
Dose regimen 
The assigned investigational product (2 drops) will be instilled in both eyes of 
each subject. Administrations will be performed at the clinical centre by the 
Investigator or his/her deputy on study day 1. For each administration, the 2 
drops will be instilled one at the time, at a 1 min interval. Administration will be 
performed as follows: 1 drop in the right eye, followed by a drop in the left eye. 
After 1 minute from each administration, the second drop will be administered 
in the right eye followed by the left eye. 
Sample Size 
Seventy-four (74) male/female outpatients, aged 0-17 years (18 years not 
completed at screening and during the study period), scheduled to undergo ocular 
exams with a need of ocular surface anesthesia. 
Study Duration 
Up to 8 days (+/-3 days) or up to 15 days (optional) duration per patient: 
- 
Inclusion visit: D -7/D1 
- 
Follow-up: D2 (phone contact) 
- 
Final visit: D8 (+/-3 days) 
- 
Optional visit/unscheduled visit: up to D15 (on-site visit or phone 
contact) 
Inclusion criteria To be enrolled in this study, patients must fulfil all these inclusion criteria: 
1. Age ≥ one day of life (newborn, infant, child) and 17 years included 
(not anticipated to turn 18 during the study). 
2. Female subjects currently either of: 
• Non-childbearing 
potential 
(i.e., 
premenarchal 
or 
physiologically incapable of becoming pregnant, including any 
female 
who 
is 
surgically 
sterilized 
via 
documented 
hysterectomy or bilateral tubal ligation), 
or 

 
 
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• 
Childbearing potential (i.e., postmenarchal girls): the subject is 
eligible to enter and participate in this study if she is not lactating, 
has a negative pregnancy test and agrees to abstain from 
intercourses or uses, until study completion, a valid contraceptive 
method according to CTFG recommendation on Contraception 
and pregnancy, v 1.2-2020, i.e.:  
o Hormonal oral, implantable, transdermal or injectable 
contraceptives for at least 2 months before the screening 
visit 
o 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 
o A male sexual partner who agrees to use a male condom 
with spermicide 
o A sterile sexual partner 
3. Signed written informed consent by both parents or legal 
representative(s) (unless only one has legal authority). Written 
informed assent for adolescents aged 12-17 years included and, 
whenever possible, informed assent for children aged 6 to 11 years 
included. Ability of the subjects and their parents/legal 
representative(s) to understand and comply with the protocol 
requirements, study-specified visit schedule and procedures. 
4. Scheduled to undergo a routine clinical procedure which needs local 
ocular surface anesthesia, including but not limited to applanation 
tonometry, gonioscopy, Ultrasound Biomicroscopy (UBM), ocular 
ultrasonography, retinal peripheral examination with blepharostat 
and scleral indentation. 
Exclusion criteria 
 
Patients fulfilling at the inclusion visit ONE OR MORE of the following 
exclusion criteria will not be enrolled in the study: 
Ophthalmic exclusion criteria 
1. Previous ocular surgery less than 6 months before screening  
2. Eye movement disorder (nystagmus) 
3. History of herpetic keratitis 
4. Corneal, epithelial, stromal or endothelial, residual or evolutionary 
disease (including corneal ulceration, corneal damage and 
superficial punctuate keratitis) 
5. History of ocular traumatism, infection or inflammation within the 
last 3 months 
Systemic/non ophthalmic exclusion criteria  
• 
General history: 
6. Any other medical or surgical history, disorder or disease such as 
acute or chronic severe organic disease: hepatic, endocrine 
neoplasia, hematological diseases, severe psychiatric illness, cardiac 
rhythm disorders and/or any complicating factor or structural 
abnormality judged by the investigator to be incompatible with the 
study 
• 
Allergic history: 
7. Known hypersensitivity to one of the components of the 
investigational products 
Exclusion criteria related to general conditions  

 
 
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8. Non-compliant patient and/or parent(s)/legal representative(s) (e.g., 
not willing to attend the follow-up visits, way of life interfering with 
compliance) 
9. Participation in another clinical study in the last three 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 
10. Already included once in this study 
Exclusion criteria related to previous and concomitant medications / non-
product therapies  
11. Patient using any of the following previous and concomitant 
medication / treatment (according to the described periods) will not 
be included in the study:  
NOT ALLOWED CONCOMITANT MEDICATIONS (washout times) 
Before Inclusion 
Inclusion  
30 days 
15 days  
7 days Day 1 
Any change in concomitant anti-depressant medication ……………………….. 
Any topical ocular treatment ………………….……………………………… 
Systemic opioids and morphinic drugs  ........................................ . 
Sulphonamides 
Anticholinesterase drugs 
 
Any change in other systemic medication 
already ongoing before inclusion visit 
 
Others systemic antalgics drugs (except 
paracetamol) 
 
Silver nitrate (bactericides), Mercury 
salts (some disinfectants), Alkaline 
substances (e.g. detergents) 
* Paracetamol after primary endpoint assessment and oral, implantable, transdermal, 
or injectable contraceptives for child-bearing potential girls during the entire study 
will be allowed 
 
Primary objective The primary objective of the study is to evaluate the efficacy of Chloroprocaine 
3% ophthalmic gel as compared to Oxybuprocaine chlorhydrate 0.4% eye drops 
anesthesia for clinical practice in pediatric population. 
Secondary 
objective  
The secondary objective of the study is to evaluate the safety of Chloroprocaine 
3% ophthalmic gel as compared to Oxybuprocaine chlorhydrate 0.4% eye drops 
anesthesia for clinical practice in pediatric population. 
Primary endpoint Primary endpoint will be to assess the proportion of patients in each treatment 
group with a successful conjunctiva anesthesia in the right eye, 5 minutes after 
study product administration, i.e. right before the ocular examination, to be 
assessed by eye spear sponge. 
A successful conjunctiva anesthesia is defined as ocular discomfort equal to 0 
(=no hurt) on the Wong-Baker faces pain rating scale (WBFPS) for patients 
equal to or older than 3 years old.  
For patients less than 3 years old, a successful conjunctiva anesthesia is defined 
as ocular discomfort equal to 0 (= relaxed and comfortable) as per the Faces, 
Legs, Activity, Cry, Consolability scale (FLACC). 
Note: Conjunctival anaesthesia will be assessed in both eyes, but primary 
assessment will be the one performed on the right eye, as specified above 
Secondary 
endpoints 
 
Safety endpoints: 
- Objective ocular signs (palpebral edema, chemosis, conjunctival hyperemia, 
conjunctival discharge, follico-papillary conjunctivitis, corneal staining 
punctuations, anterior chamber cells, flare) and other objective ocular signs, 

 
 
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assessed by slit lamp examination (SLE) or binocular indirect 
ophthalmoscopy (BIO), will be graded according to the following scale: 
0=none, 1=mild, 2=moderate, 3=severe. Timepoints: D1 before and after 
IMP administration, D8 and if needed at the unscheduled visit up to D15. 
- Adverse events occurrence throughout the study 
- Product global tolerance will be graded by the Investigator by answering the 
following question “How do you consider the study product global tolerance” 
using the following scale: 0=very unsatisfactory, 1=unsatisfactory, 2= 
satisfactory, 3=very satisfactory. Timepoint: D1 post-dose 
Study Procedures 
 
The study will include an Inclusion visit (Day -7/Day 1), a Follow-up visit (Day 
2, phone visit), a Final visit (Day 8± 3 days) and an Optional/Unscheduled visit, 
if applicable (up to day 15). In case of premature discontinuation, as far as 
possible, 
an 
early 
termination 
visit 
(ETV), 
involving 
the 
same 
procedures/activities of the final visit, will be performed.  
Visit 1: Inclusion visit (Day -7 to Day 1) 
Patients scheduled to undergo an ocular examination in one eye or both eyes (e.g. 
tonometry) will be informed about the aims, procedures and possible risks of the 
study and will be asked to sign the informed consent form (parents/legal 
representative) and informed assent, as applicable, for the inclusion in the trial 
up to 7 days before the visit. On Day 1, the study inclusion/exclusion criteria will 
be verified. Blood pressure, heart rate, AEs occurrence will be assessed. Patients 
will be randomized to either chloroprocaine 3% gel (Test) or oxybuprocaine 
0.4% eye drop (Reference) treatment group and the allocated treatment will be 
administered by instillation in both eyes. 
Efficacy (conjunctival anesthesia assessment with an eye spear sponge, just 
before the scheduled diagnostic examination) and safety endpoints (SLE/BIO) 
will be assessed in both eyes. Product global tolerance will be graded by the 
Investigator and vital signs post-dose will be measured (see table 1- study 
schedule). For all assessments, the right eye will be evaluated first followed by 
the left eye.  
Note: Informed consent form and assent form can be signed, as applicable, within 7 days 
before inclusion visit. All other procedures must be done at D1. 
 
Visit 2: Follow-up phone visit (Day 2) 
The phone call will be made by a blinded investigator.  
 Patient’s or parents/legal representative(s) questioning about concomitant 
ocular and non-ocular treatments.  
 AEs occurrence  
(see table 1- study schedule). 
 
Visit 3: Final visit (Day 8 ± 3 days) 
The procedures will be carried out by a blinded investigator.  
 Patient’s or parents/legal representative(s) questioning about concomitant 
ocular and non-ocular treatments.  
 AEs occurrence.  
 SLE/BIO in both eyes (right eye first, followed by left eye).  
(see table 1- study schedule). 
 
If it is needed as per investigator’s judgement, a final follow-up with the same 
procedures will be performed up to D15 (see table 1- study schedule – and 
below). 
 

 
 
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Optional visit/Unscheduled visit – phone call or on-site visit – (Visit 4, up to 
Day 15 as per Investigator’s judgement) 
 Patient’s or parents/legal representative(s) questioning about concomitant 
ocular and non-ocular treatments. 
 AEs occurrence.  
 SLE/BIO in both eyes (on-site visit only) (right eye first, followed by left 
eye).  
(see table 1- study schedule). 
Definition of 
analysis sets 
 
Safety set:  
All patients who received at least a fraction of the 
dose of the investigational product. 
Intention-to-treat (ITT): 
all randomized patients.  
Per Protocol Set (PPS): 
all randomized patients who received the treatment 
without any major deviation from the protocol.  
The exclusion of patients from the analysis sets will be discussed during a blind 
review meeting that will be held before database lock and complete unblinding. 
Subjects will be evaluated according to the treatment they were assigned to for 
the efficacy analysis (ITT, PPS) and according to the treatment they actually 
receive in the Safety set. 
Data analysis for primary efficacy outcome will be performed on the ITT set. 
A sensitivity analysis on the PP Set will also be performed for the primary 
endpoint. Safety parameters will be analyzed on the Safety set. 
Statistical 
analysis  
 
Data documented in this study and the parameters measured will be evaluated 
and presented using descriptive statistics, i.e. arithmetic mean, SD, minimum, 
median and maximum values for quantitative variables, and absolute and relative 
frequencies (%) for qualitative variables. The statistics will be reported by 
treatment group.  
The primary endpoint of the study is defined as the proportion of subjects in each 
treatment group with a successful surface anesthesia (right eye), i.e., score 0 on 
the WBFPS for children aged ≥ 3 years and score 0 on the FLACC scale for 
children aged < 3 years, determined 5 minutes after study product administration, 
i.e., right before the ocular examination.  
 
Conjunctival anaesthesia scores for the right eye (study eye) and for the left eye 
(non-study eye) will be listed by subjects and summarized by frequency and 
descriptive statistics overall (i.e. for the 0-3 and 3-17 years age groups 
together) and by age group (corresponding to the two different scales).  
The primary analysis will be performed on the ITT set. A non-inferiority test 
will be used to compare the proportion of success in each treatment group. 
The difference in proportions and its one-sided 95% confidence interval 
will be derived from the SAS FREQ procedure using RISKDIFF option and 
specifying the NONINFERIORITY (or NONINF) to request the Farrington-
Manning score test for noninferiority. The significance of the test and 
therefore the non-inferiority of the Test versus the Reference product will be 
confirmed if the lower limit of the 95% confidence interval is greater than 
the noninferiority margin (-0.25). 
 
A sensitivity analysis will be done on the PP set, using the same methodology 
applied for the ITT set. 
 

 
 
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According to the EMA addendum to ICH E9(R1) about estimands and 
sensitivity analysis (ICH E9 (R1). EMA/CHMP/ICH/436221/2017 17 
February 2020), the primary efficacy analysis will be conducted under a 
“Treatment policy strategy”.  
Under the treatment policy strategy, if an intercurrent event has occurred or 
not is irrelevant, the data will be collected and analyzed regardless. For 
example, if a patient took rescue medication, or discontinued from the trial, 
the data post the event would be included in the analyses. This policy reflects 
the intention‑to‑treat (ITT) principle.  
 
Indeed, in this trial, in the case of unsuccessful anesthesia requiring the use 
of rescue anesthesia to proceed with the diagnostic procedure, the patients 
will be regarded as failure due to a score greater than 0.   
 
If the primary efficacy parameter cannot be collected due to complications 
preventing the assessment of anesthesia success, a “composite strategy” for 
the handling of missing data will be used and the patient will be regarded as 
failure. 
 
 
 
 
 
 

 
 
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TABLE 1. – STUDY SCHEDULE 
Study procedures 
Visit 1 
Inclusion visit 
D-7/D1* 
 
Visit 2  
Follow-up 
visit 
D2 (phone 
visit) 
 
Visit 3 
Final visit 
D8  
(+/-3 days) 
 
 
Unscheduled 
visit (Visit 4) 
up to D15 (if 
needed as per 
investigator’s 
judgement) 
 
Information on the study and Informed consent/assent 
signature (as applicable) 
X 
 
 
 
Demography***** 
X 
 
 
 
Ocular medical and surgical history***** 
X 
 
 
 
Systemic medical and surgical history***** 
X 
 
 
 
Previous and concomitant ocular and non-ocular 
treatments 
X 
X 
X 
X 
Pregnancy test (postmenarchal girls only)***** 
X 
 
 
 
Slit 
lamp 
examination/Binocular 
indirect 
ophthalmoscopy 
X** 
 
X 
X*** 
Adverse events 
X 
X 
X 
X 
Verification of inclusion and exclusion criteria / Status 
of the patient  
X 
 
 
 
Allocated treatment group  
X 
 
 
 
IMP administration (2 drops in each eye) 
X 
 
 
 
Vital signs****** 
X 
 
 
 
Efficacy assessment (conjunctival anaesthesia)**** 
X 
 
 
 
Product global tolerance 
X (Day 1, 
post-dose) 
 
 
 
*Informed consent form and assent form can be signed, as applicable, within 7 days before inclusion visit as per local practice. 
All other procedures must be done at D1.  
 
**Before (0 min) and after (60 min) the instillation (Before instillation to check patient’s eligibility and after instillation to 
assess the safety) 
 
***Only if the visit is on-site  
 
****Both eyes. Five (5) min after study product administration, i.e., right before the ocular examination (Day 1). WBFPS for 
patients ≥ 3 years or FLACC scale for patients <3 
 
*****At screening only 
 
****** At screening and post-dose 

 
 
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TABLE 2. – SCHEMATIC DIAGRAM OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
Screening period 
Day -7 / Day 1 
Day 1 
Randomisation 
Baseline assessments 
Treatment 
Efficacy assessment 
Safety assessments 
Day 2 
Day 8±3 days 
 
Interventional and observational period 
Safety assessments 
(Phone call) 
 
Final visit 
Safety assessments 
Safety assessments 
 
Unscheduled visit 
visit 
Up to Day15 

 
 
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5 TABLE OF CONTENTS 
 
1 
CLINICAL STUDY PROTOCOL ..................................................................................... 1 
2 
PROTOCOL APPROVAL ................................................................................................. 4 
2.1 
SPONSOR .................................................................................................................. 4 
2.2 
INVESTIGATOR(S) .................................................................................................. 5 
2.3 
CRO ............................................................................................................................ 6 
3 
Contacts page for the study ................................................................................................ 7 
4 
STUDY SYNOPSIS ........................................................................................................... 8 
5 
TABLE OF CONTENTS ................................................................................................. 16 
6 
LIST OF ABBREVIATIONS .......................................................................................... 20 
7 
INTRODUCTION ............................................................................................................ 21 
7.1 
Background .............................................................................................................. 21 
7.1.1 Nonclinical background information.................................................................... 21 
7.1.2 Clinical background information ......................................................................... 22 
7.1.3 Clinical pharmacology ......................................................................................... 23 
7.1.4 Pharmacokinetics ................................................................................................. 23 
7.1.5 Pharmacodynamics ............................................................................................... 23 
7.1.6 Clinical efficacy ................................................................................................... 23 
7.1.7 Clinical safety ....................................................................................................... 24 
7.2 
Risks and benefits ..................................................................................................... 25 
7.3 
Study rationale .......................................................................................................... 27 
8 
STUDY OBJECTIVES .................................................................................................... 28 
8.1 
Primary objective ..................................................................................................... 28 
8.2 
Secondary objective ................................................................................................. 28 
9 
INVESTIGATIONAL PLAN .......................................................................................... 29 
9.1 
Overall study design ................................................................................................. 29 
9.2 
Visit schedule: .......................................................................................................... 29 
9.3 
Discussion of design ................................................................................................. 29 
9.4 
Study endpoints ........................................................................................................ 31 
9.4.1 Primary endpoint .................................................................................................. 31 
9.4.2 Secondary endpoints ............................................................................................ 33 
10 STUDY POPULATION .................................................................................................. 34 
10.1 
Target population ..................................................................................................... 34 
10.2 
Inclusion criteria ....................................................................................................... 34 
10.3 
Exclusion criteria ...................................................................................................... 35 

 
 
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10.4 
Withdrawal criteria ................................................................................................... 36 
10.4.1 
Discontinuation procedures .............................................................................. 37 
11 CLINICAL SUPPLIES .................................................................................................... 38 
11.1 
Study Treatment ....................................................................................................... 38 
11.1.1 
Description of products .................................................................................... 38 
11.1.1.1 
Test product .............................................................................................. 38 
11.1.1.2 
Reference product .................................................................................... 38 
11.1.2 
Dose regimen .................................................................................................... 38 
11.1.3 
Investigational product distribution ................................................................. 39 
11.1.4 
Packaging and labelling ................................................................................... 39 
11.1.5 
Storage conditions ............................................................................................ 39 
11.1.6 
Drug accountability .......................................................................................... 39 
11.2 
Randomization ......................................................................................................... 39 
11.3 
Treatment allocation ................................................................................................. 40 
11.4 
Blinding .................................................................................................................... 40 
11.4.1 
Emergency code and unmasking procedures ................................................... 40 
11.4.2 
Emergency individual envelopes...................................................................... 40 
11.5 
Other Treatments ...................................................................................................... 41 
12 STUDY CONDUCT ........................................................................................................ 42 
12.1 
Study visits ............................................................................................................... 42 
12.2 
Study procedures ...................................................................................................... 44 
12.2.1 
Efficacy measures ............................................................................................ 44 
12.2.1.1 
Conjunctival anesthesia assessment ......................................................... 44 
12.2.2 
Safety measures ................................................................................................ 44 
12.2.2.1 
Objective ocular signs (SLE/BIO) – Both eyes ....................................... 45 
12.2.2.2 
Slit lamp examination/Binocular indirect ophthalmoscopy for additional 
assessments – both eyes ............................................................................................... 45 
12.2.2.3 
Vital signs measurements ......................................................................... 45 
12.2.2.4 
Product global tolerability assessment – both eyes .................................. 45 
12.2.2.5 
Adverse events ......................................................................................... 46 
12.3 
Description of procedures for telephonic follow-up ................................................ 46 
13 STATISTICAL METHODS ............................................................................................ 47 
13.1 
Analysis Sets ............................................................................................................ 47 
13.2 
Sample size and power considerations ..................................................................... 47 
13.3 
Expected success rate and non-inferiority margin ................................................... 48 
13.4 
Intercurrent events .................................................................................................... 49 
13.5 
Handling of missing data .......................................................................................... 49 

 
 
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13.5.1 
Methods for replacing missing data ................................................................. 49 
13.5.2 
Replacement rules for each analysis set ........................................................... 49 
13.6 
Demographic, baseline and background characteristics........................................... 50 
13.7 
Analysis of efficacy parameters ............................................................................... 50 
13.7.1 
Primary analysis ............................................................................................... 50 
13.8 
Safety and tolerability evaluation ............................................................................. 50 
13.8.1 
AEs ................................................................................................................... 50 
13.8.2 
Slit lamp examination/Binocular Indirect Ophthalmoscopy ............................ 51 
13.8.3 
Vital signs (blood pressure and heart rate) ....................................................... 51 
13.8.4 
Product global tolerability ................................................................................ 51 
13.8.5 
Slit lamp examination/Binocular Indirect Ophthalmoscopy – additional 
assessments ....................................................................................................................... 51 
14 DATA MANAGEMENT PROCEDURES ...................................................................... 52 
14.1 
Data collection – electronic CRFs ............................................................................ 52 
14.2 
Unique patient identifier ........................................................................................... 52 
14.3 
Data management ..................................................................................................... 52 
14.3.1 
Coding dictionaries .......................................................................................... 52 
15 STUDY MONITORING AND AUDITING .................................................................... 53 
15.1 
Monitoring ................................................................................................................ 53 
15.2 
Quality Control and Quality Assurance ................................................................... 53 
15.3 
Applicable SOPs ...................................................................................................... 53 
15.4 
Data access ............................................................................................................... 54 
15.5 
Audits and inspections ............................................................................................. 54 
16 DEFINITION AND HANDLING OF AEs AND SAEs .................................................. 55 
16.1 
Applicable SOPs ...................................................................................................... 55 
16.2 
Definitions ................................................................................................................ 55 
16.3 
AEs monitoring window .......................................................................................... 56 
16.4 
AEs recording ........................................................................................................... 56 
16.5 
SAEs reporting ......................................................................................................... 58 
16.6 
SUSARs management .............................................................................................. 58 
16.7 
Other events qualified for expedited reporting ........................................................ 59 
16.8 
Reporting of SUSARs to the Eudravigilance database ............................................ 59 
16.9 
SAEs: contacts .......................................................................................................... 59 
17 ETHICAL CONSIDERATIONS ..................................................................................... 60 
17.1 
Ethics and Good Clinical Practice (GCP) ................................................................ 60 
17.2 
Informed Consent and Child Assent Form ............................................................... 60 
17.3 
Criteria for patient’s withdrawal .............................................................................. 62 

 
 
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17.4 
Premature discontinuation of the trial ...................................................................... 63 
17.5 
Insurance policy ....................................................................................................... 63 
17.6 
Study termination ..................................................................................................... 63 
18 ADMINISTRATIVE PROCEDURES ............................................................................. 64 
18.1 
Material supplied to the clinical center .................................................................... 64 
18.2 
Protocol amendments/modifications ........................................................................ 64 
18.3 
Study documentation and record keeping ................................................................ 64 
18.4 
Study patients’ recruitment ...................................................................................... 65 
18.5 
Confidentiality and data protection .......................................................................... 65 
18.6 
Measures implemented for data security breaches ................................................... 65 
18.7 
Publication policy ..................................................................................................... 67 
18.8 
Submission of summary results ................................................................................ 67 
19 REFERENCES ................................................................................................................. 68 
 
 
 
 

 
 
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6 LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOA 
Attributable-Legible-Contemporaneous-Original-Accurate 
ANOVA 
Analysis of Variance 
BP 
Blood Pressure 
BSS 
Balanced Salt Solution 
CA 
Competent Authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CRS 
Clinical Study Report 
CV 
Coefficient of Variation 
D 
Day 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ETV 
Early Termination Visit 
FLACC 
Face, Legs, Activity, Crying and Consolability scale 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Hg 
Mercury 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IOL 
Intra Ocular Lens 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
ITT 
Intention To Treat 
IV 
Intravenous 
LPLV 
Last Patient Last Visit 
LA 
Local Anaesthesia 
MAH 
Marketing Authorization Holder 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Missing as Failure 
MI 
Multiple Imputation 
NA 
Not Applicable 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
PK 
Pharmacokinetics 
PNB 
Peripheral Nerve Block 
PP 
Per Protocol 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment-Emergent Adverse Event 
T 
Time 
WBPS 
Wong-Baker faces pain rating scale 
WC 
Worst Case 
WHODDE 
World Health Organization Drug Dictionary Enhanced 

 
 
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7 INTRODUCTION 
 
7.1 
Background 
 
Topical local anaesthetics (LAs) play an important role in the practice of ophthalmology, 
especially for less invasive outpatient surgeries and routine examinations that require contact 
onto the ocular surface. 
Anaesthetics topically applied to the eye act directly on the corneal epithelium and stroma, with 
a duration of effect up to 15–20 minutes depending on the properties of the drug used. Their 
safety profile is generally considered acceptable, especially in occasional use (1). 
 
Current practices for ocular topical anaesthesia include oxybuprocaine (in Europe), 
proparacaine (in US) or tetracaine (both in EU and US) used as eyedrops. Importantly, during 
recent years there has been an increase in the off-label use of lidocaine 2% gel for ophthalmic 
procedures (2, 3). The majority of these reports highlighted favorable patient-pain profiles with 
the use of viscous preparation as the sole anaesthetic agent. This led to the development and 
approval by the Food and Drug Administration of Lidocaine hydrochloride 3.5% ophthalmic 
gel (Akten, Akorn Inc.) for ocular surface anaesthesia during ophthalmologic procedures (4). 
Although many adult ocular procedures may be performed equally well under local or general 
anesthesia, with children, the anesthesiologist almost always must administer general 
anesthesia to guarantee satisfactory surgical conditions. Moreover, in routine clinical practice 
with children, it may be difficult to perform tests that require touching the ocular surface. As 
strategies may be used to divert infants’ attention during the examination, and teenagers can 
frequently be persuaded to go along with the examination, children between these two age 
groups can be nearly impossible to examine and often require general anesthesia.  
 
Considering a gel formulation as potentially more effective than usual drops used for topical 
anesthaesia (5), we aim at demonstrating the benefits of a chloroprocaine 3% gel in children 
undertaking routine clinical examinations such as applanation tonometry, gonioscopy, retinal 
peripheral examination with blepharostat and scleral indentation, and ultrasound imaging 
(ocular ultrasonography and ultrasound biomicroscopy). 
 
7.1.1 Nonclinical background information 
 
Animal studies conducted by the intended route of administration demonstrated that 
chloroprocaine 3% hydrochloride eye gel is efficacious and locally well tolerated. In none of 
these studies, systemic signs of toxicity were recorded at clinical observation. 
Furthermore, repeat-dose toxicity studies performed in rats and dogs by the intrathecal route 
did not reveal any macroscopic or microscopic finding in any organ. 
Taking into consideration that chloroprocaine is a local anaesthetic which is intended for a “one-
shot” administration, there are acute toxicity studies performed by intraperitoneal route in mice 
and intravenous route in guinea pigs and dogs which can be useful to roughly estimate safety 
margins, with respect to the maximum recommended human dose for chloroprocaine 
hydrochloride 3% eye gel. 
 
 

 
 
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7.1.2 Clinical background information 
 
There is a long history of use of chloroprocaine and the amino ester class of anaesthetics in 
USA, Canada and Switzerland. In particular, chloroprocaine has been FDA-approved since 
1955 and is currently marketed in the US and Canada as Nesacaine® (1% and 2%), Nesacaine®-
MPF (2% and 3%), both sponsored by Fresenius Kabi for infiltration, nerve block (up to 800 
mg) and epidural block and in US as Sintetica’s Clorotekal® 1% for intrathecal injection since 
2017.  
In Europe, Sintetica’s Ampres® 1% is approved for intrathecal administration. Since July 2015, 
it has been present on the Swiss market for local anaesthesia by infiltration, for Peripheral Nerve 
Block (PNB) and for epidural block. 
In 2020, the Extension Application of the existing MA of Ampres 10 mg/mL was granted in 
Europe, by introducing a new strength (Ampres 20 mg/mL), a new route of administration 
(perineural injection) and a new indication (perineural anaesthesia for short-duration surgeries, 
not exceeding 60 minutes). 
 
Thanks to very favourable pharmacokinetic (PK) characteristics, chloroprocaine is currently 
considered the local anaesthetic with the safest toxicological profile. 
 
Sintetica S.A. has previously conducted a phase I/II, a phase II/III and a phase III clinical trial 
for Chloroprocaine Hydrochloride ophthalmic gel 3% (30 mg/mL) intended for ocular surface 
anesthesia during ophthalmologic procedures in adults. The phase I/II and phase II/III efficacy, 
safety and local tolerability study determined that chloroprocaine gel was overall well tolerated 
with an optimal profile of efficacy, while the larger phase III efficacy and safety study proved 
the efficacy of chloroprocaine for surface anesthesia during ophthalmologic procedures 
(cataract surgery) in comparison with tetracaine. 
Totally, more than 300 subjects (patients and healthy volunteers) have been exposed to 
Chloroprocaine Hydrochloride ophthalmic gel 3%. 
 
Moreover, Sintetica performed 3 different clinical trials testing the efficacy and safety of 
intrathecal administration of chloroprocaine 1% and 1 trial testing efficacy and safety of 
perineural injection of chloroprocaine 2% on about 600 patients in total. Moreover, another 
pediatric study assessing the efficacy and safety of chloroprocaine 1% and 2% for PNB is 
currently ongoing. 
Chloroprocaine proved to be highly efficacious in all the above-mentioned clinical trials, and 
its very favourable safety profile has been strongly confirmed. 
 
Chloroprocaine 3% proved to be efficacious and well tolerated also in the full package of 
preclinical studies introduced in section “Non-clinical background information” of this 
protocol. Moreover, an anaesthesia effect was observed from 5 min after the instillation until 
60 min for chloroprocaine 3% gel and this is coherent with the known anaesthetic action of the 
product and comparable to other ocular topical product tested on animal models both in liquid 
and in jelly formulation (6). 
Importantly, the drug product is topically applied to the site of action and has minimal systemic 
absorption. The proposed gel formulation contains hydroxyethylcellulose to allow extended 
contact with the cornea, which is theorized to result in extended anaesthesia. The gel 
formulation allows a reduction of absorption of the anaesthetic through the nasolacrimal 
system, thereby resulting in undetectable or negligible systemic exposure of chloroprocaine. 

 
 
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7.1.3 Clinical pharmacology 
 
Topical anaesthetic agents block trigeminal nerve endings in the cornea and the conjunctiva 
only, leaving the intraocular structures in the anterior segment unanaesthetised (7). 
 
The sensitive terminations of the fifth cranial nerve are concentrated in the cornea and ciliary 
body in the anterior part of the eye. These fibers are generally nonmyelinated type A-delta and 
type C. They are able to transmit the sensations of pain, temperature, and touch, and are blocked 
by lower concentrations of drugs in comparison with motor fibers. To suppress pain, sensitive 
nerves have to be blocked by anaesthetic agents along the nerve itself, or at its sensory 
terminations. Sensory termination block is the most important feature of topical anaesthesia. It 
involves the inhibition of sodium channels at nerve endings or receptors by the anaesthetic 
agents, thus blocking the production (and not the transmission) of nervous impulses (8). 
 
The drug product is topically applied to the cornea. There is little or no measurable systemic 
absorption. 
 
7.1.4 Pharmacokinetics 
 
Chloroprocaine onset of action is rapid (usually within very few minutes) and the duration of 
its action is short, (usually not longer than 100 minutes). Chloroprocaine is rapidly metabolized 
in the plasma by hydrolysis of the ester linkage by the enzyme pseudocholinesterase resulting 
in the production of two major metabolites that can be considered pharmacologically inactive, 
i.e. β-diethylaminoethanol and 2-chloro-4-aminobenzoic acid (ACBA)(9). 
 
7.1.5 Pharmacodynamics  
 
The mechanism of action of 2-chloroprocaine is the same of LAs that produce reversible loss 
of sensation, when applied to nervous tissue. Their primary site of action is the cell membrane, 
and they produce their effect interacting directly with voltage-gated Na+ channels. It is now 
generally accepted that the mechanism of action of these compounds is based on the interaction 
with specific binding sites within the Na+ channels resulting in a blockade of the Na+ current. 
In higher concentrations, the other ion channels (K+, Ca++) might be affected as well (10). 
 
7.1.6 Clinical efficacy 
 
Similar to lidocaine, chloroprocaine is used for short duration surgical procedures, mainly in 
the ambulatory setting, when a fast recovery and prompt home readiness are required. 
 
Based on data obtained from the clinical trials, the data available in the literature and the post-
marketing experience, several aspects underline the importance of chloroprocaine in the clinical 
practice supporting its reliable efficacy and safety profile. 
Chloroprocaine may be advantageous regarding ultra-short procedures and short surgeries, 
matching the important key benefits required for a local anaesthetic of choice in this setting. 
 
In a Phase I/II clinical study (12) conducted in healthy adult male and female volunteers 
administered a single dose of chloroprocaine 3% ocular gel as ocular anesthetic, the 
proportion of subjects who achieved anesthesia of the treated eye at 5 min after instillation 

 
 
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was 89.7%. The median time to anaesthesia was 0.67 min (i.e., 40 sec). Mean value was 2.41 
min (95% CI: 1.89, 2.92). 
A double-masked, vehicle-controlled, phase II/III study conducted in healthy volunteers (13) 
showed that successful anaesthesia in the chloroprocaine 3% gel group was achieved by 95% 
of subjects vs. 20% of subjects in the control group. Median time to anaesthesia onset with 
chloroprocaine 3% was 0.67 min. Anaesthesia in the active treatment group lasted for a median 
(min, max) time of 19.3 min. 
 
In a previous Phase III study conducted on 338 adult patients scheduled for cataract surgery 
and treated with either chloroprocaine 3% gel or tetracaine 0.5% eye drops as topical anesthetics 
(14), the proportion of patients with a successful surface anesthesia (defined as score 0=no 
pain/discomfort plus score 1=occasional pressure sensation), without any supplementation just 
before intraocular lens implantation (T4 ; primary endpoint) was 92.0% and 90.5% in the Test 
and Reference treatment group, respectively.  
 
7.1.7 Clinical safety 
 
The general overview of the safety profile of chloroprocaine comes from a large amount of data 
collected during the development of chloroprocaine 1% formulation indicated for intrathecal 
block and chloroprocaine 2% indicated for perineural block and also from the post marketing 
experience.  
According to historical and literature evidence, data collected from the clinical studies 
confirmed the improved safety profile and the more favorable pharmacokinetic properties of 
chloroprocaine for the intended indications. All adverse events registered in clinical studies 
were consistent with the known safety profile of chloroprocaine. 
 
As a matter of fact, chloroprocaine is the most rapidly metabolized local anaesthetic currently 
used. In vitro chloroprocaine half-life is approximately 25 sec and the product is cleared 
efficiently even in former preterm neonates also when receiving high epidural infusion rates (5, 
11). Rapid plasma degradation, rapid onset, lack of accumulation, makes chloroprocaine 
systemic toxicity less likely compared to other amide-type LAs (2). Importantly, chloroprocaine 
is considered the local anaesthetic with the safest toxicological profile compared to other LAs, 
with a very low risk to induce cardiotoxic effects, due to its broad margin of safety and due to 
its ultra-rapid metabolism (ester hydrolysis) after systemic resorption. Toxicity due to 
inadvertent systemic injection as well as toxicity due to absorption of LA may be avoided using 
the ester-type LA, chloroprocaine. 
Plasma concentrations of chloroprocaine and its metabolite ACBA, as well as urinary ACBA 
excretion, were assessed as secondary endpoints in a phase 2 study, to confirm low systemic 
exposure to chloroprocaine following intrathecal administration, the most sensitive model to 
assess systemic toxicity. As expected, chloroprocaine was not detectable in any plasma sample 
of any patient. On the contrary, the metabolite ACBA was quantifiable in most plasma samples. 
The results of the study confirm the correlation between the peculiar plasmatic metabolism of 
chloroprocaine and its well-known safety profile. Indeed, even after administration via spinal 
route, the drug metabolite ACBA was quantifiable already after 10 minutes, meaning that as 
soon as chloroprocaine reaches the blood stream, its degradation is almost instantaneous. 
Of note, the ultra-rapid plasmatic degradation of chloroprocaine allows to avoid any systemic 
toxicity risk even in the rare case of inadvertent intravascular injection or unusually rapid 
absorption in areas with a high density of blood vessels. 
 

 
 
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Considering pooled data from the clinical Phase I/II study (CHL.3-01-2020; ref. 12), Phase 
II/III (CHL.3-02-2019; ref. 13) and Phase III study (CHL.3/01-2019/M; ref 14), AEs were 
reported for 26.8% of the 317 subjects exposed to chloroprocaine HCl 3% ophthalmic gel, 
overall. The most common treatment-emergent AEs were eye disorders, and in particular 
mydriasis (12.3%), followed by conjunctival hyperemia (5%), eye irritation (2.8%), punctate 
keratitis (2.2%), conjunctival haemorrhage (1.9%) and corneal edema (1.6%).  
However, mydriasis was recorded only in the Phase I/II and Phase II/III studies. In fact, in the 
Phase 3 study, mydriasis was not reported as an AE because according to the clinical practice 
in cataract surgery, a mydriatic product was also administered as allowed concomitant 
medication before surgery. 
The AEs reported in the 3 cited clinical trials did not give rise to any safety concerns. 
 
Also post marketing data strongly confirms the favorable safety profile of chloroprocaine as 
local anaesthetic (LA). Chloroprocaine hydrochloride 10 mg/mL, solution for injection (under 
the brand names of Ampres®/Clorotekal®/Decelex®), has been commercialized in the EU 
countries as new chemical entity starting from 2013. No other product with chloroprocaine as 
active substance for intrathecal administration is present on the European market. Ampres 10 
mg/mL, solution for injection is a LA used as one-shot product. According to the clinical 
practice, no defined daily dose has been established for chloroprocaine HCl because 
administered dose depends on different factors, such as indication and patient’s characteristics. 
Nonetheless calculation of exposure is based upon estimated number of ampoules sold in EU 
countries. According to the current European SmPCs for intrathecal use the maximum 
recommended dose of chloroprocaine hydrochloride in adult population is 50 mg (= 5 mL, one 
ampoule). Therefore, based on this exposure calculation, during the European and Swiss 
marketing experience approximately 300’000 patients were treated with intrathecal 
Chloroprocaine HCl in EU Countries.  
In Switzerland, where chloroprocaine is marketed as 0.5%, 1%, 2% and 3% solutions for 
injection, for local anaesthesia by infiltration, for intravenous anaesthesia, for peripheral nerve 
block and for epidural block, approximately 250’000 patients were exposed to the drug product 
till now.  
Evaluation of all safety data collected during the European post-marketing experience shows 
that no new safety concerns have been identified in relation to the drug product and its safety 
profile. 
 
7.2 
Risks and benefits 
 
The Test IMP evaluated in the present study is marketed in the US, under the brand name of 
IHEEZOTM for topical ophthalmic use, indicated for ocular surface anaesthesia in adults.  
Benoxinato Cloridrato INTES 4 mg/mL (oxybuprocaine chlorhydrate 0.4%) eye drops is 
marketed in Italy and is commonly used for ocular surface anaesthesia in adults and children of 
all ages, without restrictions, for the same indication, i.e. ocular surface anesthesia. 
 
Possible severe side-effects related to the two investigational products may be caused or 
increased due to the following factors:  
• Subject factors: condition of the ocular surface, certain medical conditions, certain 
medications. 
• Practitioner factors: training, years of experience, number of procedures performed.  
To avoid these side-effect factors, the following conditions are foreseen: 

 
 
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• Subjects have to meet very specific inclusion/non-inclusion criteria before entering the 
clinical trial (see § 10.2 and § 10.3). 
• The Investigators participating in this clinical trial are trained and experienced practitioners 
in the field of paediatric ophthalmology.  
 
The most common adverse reactions that have been reported in the 2 placebo-controlled clinical 
trials in adult patients (see § 7.1.6 and § 7.1.7) with the Test product (chloroprocaine 
hydrochloride 3% eye gel) were mydriasis, followed by conjunctival hyperemia and eye 
irritation (IheezoTM; Highlights of Prescribing Information). These events were transient and 
resolved by study end or by the study follow-up. 
 
Other undesirable effects that could possibly occur would be local intolerance effects (e.g., mild 
burning, blurred vision). These effects cannot be totally excluded when applying a topical 
ocular product, even if not previously reported.  
 
Reported adverse events after administration of the Reference product were mainly occasional 
and transitory local irritation events, e.g., burning sensation, pain and conjunctival hyperemia. 
Allergic sensibilization could occur, but only after repeated doses.  
Following oxybuprocaine absorption through damaged mucosae or the skin, nausea, vomiting, 
nervous system excitation phenomena, pallor, sweating, somnolence, hypotension, arrhythmia 
(very rarely), respiratory insufficiency and methemoglobinemia (very rarely) have occasionally 
been observed. In addition, the Reference product contains potassium dihydrogen phosphate as 
an excipient, which could very rarely cause opaque spots on the cornea (due to calcium 
accumulation) during prolonged treatment in patients with severe corneal damage of the cornea. 
However, in the present study healthy volunteers with intact cornea are included and the product 
is administered as a single dose.  
Accidental overdosing of either product is excluded considering that instillations will be 
performed by very experienced practitioners.  
 
Considering that the products are topical ocular products administered by instillation and that 
plasma exposure is negligible, no systemic effects are expected.  
 
Adverse events following investigational products topical instillation in the eyes of the study 
paediatric population cannot be ruled out, but, based on the experience with oxybuprocaine 
chlorohydrate 0.4%, the side effects are expected to be similar to those reported in the adult 
population for both Test and Reference product.  
 
Expected benefits of the Test investigational product (chloroprocaine 3% anaesthetic gel 
formulation) include: 
 
• 
Coating of the eye without requiring repeated doses.  
• 
Longer duration than the drops solution due to its viscosity. This permits to obtain a 
better anaesthesia and higher local exposure to the drug. 
• 
Reduced systemic absorption through the nasolacrimal system which translates into a 
reduced potential for systemic toxicity.  
• 
The majority of patients treated with gel preparations do not suffer from the corneal 
epithelial and surface irregularities that typically occur due to the toxic nature of other 
anaesthetic drop preparations.  
 

 
 
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Considering the information above, the benefit/risk ratio of this clinical trial appears to be 
favorable. 
 
7.3 
Study rationale 
 
A chloroprocaine gel formulation may represent an improved product that could lead to better 
anaesthesia. Chloroprocaine can be considered as the ideal anaesthetic for local anaesthesia in 
patients undergoing ocular exams, because it provides rapid onset of action, adequate potency, 
predictable duration, fast recovery, and the safest toxicological profile when compared to 
lidocaine and other LAs.  
This led Sintetica to the development of chloroprocaine 3% gel, a preservative-free, single-use 
ophthalmic preparation, as the sole anaesthetic agent to achieve ocular surface anaesthesia. The 
formulation was investigated in the 3 previous clinical studies in adults (11-13) demonstrating 
a very good safety profile and efficacy similar to that of the Reference products. 
 
According to FDA request and following scientific advice with the Authority, Sintetica now 
intends to perform a phase 3 study on pediatric patients undergoing ocular exams to assess the 
safety and efficacy of topical anaesthesia using chloroprocaine 3% gel.  
 
This prospective, observer-blind, randomized, controlled, non-inferiority phase 3 study will be 
conducted in approximately 3 sites in Italy. We consider that neither intrinsic ethnic factors 
such as race, genetic polymorphisms and genetic diseases, nor extrinsic ethnic factors such as 
culture, socio-economic factors, local medical practice and therapeutic approach may affect the 
efficacy and the safety of the drug product. As reported by internationally recognized guideline 
(CPMP/ICH/364/96, § 2.5.1) the effect of anaesthesia is dramatic, occurs as expected after 
treatment and is unlikely to have occurred spontaneously, the success of the anaesthesia can be 
evaluated with objective assessments. The anaesthetic qualities are related primarily to 
physicochemical properties of the various compounds. 
 
 

 
 
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8 STUDY OBJECTIVES 
 
8.1 
Primary objective 
 
The primary objective of the study is to evaluate the efficacy of Chloroprocaine 3% ophthalmic 
gel as compared to Oxybuprocaine chlorhydrate 0.4% eye drops anesthesia for clinical practice 
in pediatric population. 
 
8.2 
Secondary objective 
 
The secondary objective of the study is to evaluate the safety of Chloroprocaine 3% ophthalmic 
gel as compared to Oxybuprocaine chlorhydrate 0.4% eye drops anesthesia for clinical practice 
in pediatric population. 
 
 
 

 
 
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9 INVESTIGATIONAL PLAN 
 
9.1 
Overall study design 
 
This will be a prospective, multicenter, randomized, active-controlled, parallel-group, observer-
blind, Phase III non-inferiority study. 
 
The first patient first visit (FPFV) is defined as the 1st visit performed at the clinical center by 
the 1st screened patient (1st signed informed consent/assent).  
The last patient last visit (LPLV) is defined as the last visit performed by the last patient, i.e., 
the last visit foreseen by the study protocol, independently of the fact that the patient is a 
completer or a withdrawn patient. 
 
9.2 
Visit schedule:  
• 
Inclusion visit (Visit 1: Day-7 / Day 1), 
• 
Follow-up visit (Visit 2: Day 2, phone visit), 
• 
Final visit (Visit 3: Day 8±3 days) 
• 
Optional visit/Unscheduled visit - phone call or on-site visit (Visit 4: up to Day 
15) 
 
9.3 
Discussion of design 
 
The study has been designed to assess the non-inferiority of chloroprocaine 3% ophthalmic gel 
(Test) versus Benoxinato Cloridrato 4 mg/mL (oxybuprocaine chlorhydrate 0.4%) eye drop 
solution (Reference) in eye surface anesthesia in children undergoing ocular exams. 
 
As also reported in § 7.3, the study was designed in line with a request from FDA and following 
a scientific advice with the Authority. 
 
In designing the study, the following guidelines were taken into consideration: ICH E9 and ICH 
E9(R1) Guideline on Statistical principles for clinical trials (28, 29); the Guideline on the choice 
of the non-inferiority margin (CPMP/EWP/2158/99; 30); and the Points to consider on 
switching between superiority and non-inferiority guideline (CPMP/EWP/482/99; 31). 
Considerations on proposed success rate and the statistical test non-inferiority margin for the 
study are given in § 13.3. 
 
With regards to anesthesia, topical anesthesia has become the most common form for routine 
practice. In this study, each patient will be allocated to a treatment arm (chloroprocaine 3% 
ophthalmic gel or oxybuprocaine chlorhydrate 0.4% eye drop solution) according to a 
computer-generated randomization list. Patients in both groups will receive two drops in each 
eye of the assigned study products before ocular exam. 
 
The study will be observer-blind: an independent blind investigator will perform the study 
assessments, i.e., will assess the primary endpoint (successful conjunctival anesthesia) at D1 
together with the patient when applicable, i.e., for patients ≥3 years old, and all safety endpoints. 

 
 
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Considering that the study participants will also assess treatment efficacy in terms of 
pain/discomfort (see § 12.2.1.1) and for this reason will act as “observers”, also the patients 
will be blinded with respect to the received treatment. 
 
Another staff member, in open conditions, will be in charge of product instillation. 
The dose of chloroprocaine 3% ophthalmic gel was selected taking into consideration the 
following:  
The Test investigational product for this study, i.e. IHEEZOTM 3% (chloroprocaine 
hydrochloride) ophthalmic gel is authorized in the United States for ocular surface anesthesia 
in adults. The recommended dose of IHEEZOTM is 3 drops applied topically to the ocular 
surface in the area of the planned procedure. IHEEZOTM may then be reapplied as needed to 
maintain the anesthetic effect. The 3 drops are administered at a 1 min interval, according to 
the posology applied in the clinical trials performed for the clinical development of the test 
product. 
According to the present CSP, the IMP paediatric dose will be 2 drops to be instilled in both 
eyes of each subject, at a 1 min interval. Administration will be performed as follows: 1 drop 
in the right eye, followed by a drop in the left eye. After 1 minute from each administration, the 
second drop will be administered in the right eye followed by the left eye. 
 
The test IMP dose for this study has been selected considering:  
 
The favourable safety profile of the IMP, supported by: 
o 
The extremely safe profile of the IMP, as shown in adult clinical studies program 
after administration of a three drops regimen which resulted in good local 
tolerability. 
o 
The unlikely systemic absorption of chloroprocaine after ophthalmic gel 
administration thanks to formulation properties and the high penetration of the 
local anaesthetic from the gel preparation into the corneal epithelia as 
demonstrated in local ocular pharmacokinetics studies in rabbits treated with 
Chloroprocaine Hydrochloride ophthalmic gel 3%. 
o 
The very short half-life of chloroprocaine demonstrated in the dose-finding, safety 
and PK Phase 2 study conducted by the Sponsor in the context of spinal anesthesia. 
o 
The single use administration which prevents possible accumulation of the drug 
in the corneal epithelium. 
o 
The safety margin of the proposed dose when compared to the well known toxicity 
profile of chloroprocaine. 
 
 
The effective dose required to provide a good anaesthesia, supported by: 
o 
Efficacy profile of the IMP demonstrated in adult clinical studies program, 
showing the rapid onset of the clinical effect and the good duration of anaesthetic 
effect. 
o 
The wide therapeutic window of topical 2-chloroprocaine. 
o 
The history of use and dosing of ophthalmic local anaesthetics in the paediatric 
population. 
 

 
 
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 
Technical aspects related to the paediatric formulation: 
o 
The size of eyes and conjunctival sac in paediatric patients, especially in the infant 
population, as well as the area of contact between the posterior conjunctiva and 
the eye globe in children. 
o 
The properties of the gel formulation, which result in extended contact with the 
cornea. 
 
Benoxinato Cloridrato 4 mg/mL eye drops (oxybuprocaine chlorhydrate 0.4%) was chosen as 
Reference product for the study because commonly used for this indication in clinical practice 
in Italy, also in children. 
 
For the study, the Wong-Baker faces pain rating scale (WBFPS) and the Faces, Legs, Activity, 
Cry, Consolability (FLACC) scale were chosen for children aged ≥ 3 years and < 3 years, 
respectively. The WBFPS scale is one of the most widely used scales for pain reporting in 
children aged 3-18 years (14-18). It has adequate psychometric properties (14, 19), and it’s easy 
and quick to use (20, 21). The FLACC scale is one of the most well-known and widely 
recommended observational pain measurement scales, frequently used for smaller children (22, 
23). 
 
Conjunctival anaesthesia will be assessed in both eyes. Results obtained on the right eye (study 
eye) will be the primary efficacy outcome and will be analysed as specified in § 9.4.1, results 
obtained on the left eye (non-study eye) will be listed and analysed descriptively. 
 
9.4 
Study endpoints 
 
9.4.1 Primary endpoint 
 
Τhe primary endpoint is the proportion of patients in each treatment group with a successful 
conjunctival anesthesia in the right eye (study eye), 5 minutes after IMP administration, i.e., 
right before ocular examination, assessed by eye spear sponge. Conjunctival anaesthesia will 
also be assessed in the left eye (non-study eye). 
The eye spear sponge (Figure 1) was suggested as the best tool for assessing conjunctival 
anesthesia since it is used in the pediatric population as per common daily practice and deemed 
the most ethical tool for dealing with such sensitive population as the pediatric one. 
 
Figure 1 – Eye Spear Sponge 
 
For patients aged equal to and more than 3 years old until 18 years old not completed, a 
successful conjunctiva anesthesia is defined as ocular discomfort equal to 0 (=no hurt) on the 
WBFPS, shown in Figure 2 below.  
 

 
 
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Figure 2 - Wong-Baker faces pain rating scale (WBFPS) 
 
For patients less than 3 years old, a successful conjunctiva anesthesia is defined as ocular 
discomfort equal to an overall score of 0 (= relaxed and comfortable) on the FLACC scale (see 
tables below). 
 
 
Table 1 - Faces, Legs, Activity, Cry, Consolability (FLACC) scale  
The scores are interpreted as follows: 
 
Table 2 - FLACC scale overall scores  

 
 
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Anesthesia will be defined as not successful when the score is greater than 1 on either scale 
(WBFPS or FLACC). 
 
9.4.2 Secondary endpoints 
 
Ocular and systemic safety 
 
• 
Objective 
ocular 
signs 
(Slit 
Lamp 
Examination 
[SLE]/Binocular 
Indirect 
Ophthalmoscopy [BIO]): palpebral edema, chemosis, conjunctival hyperemia, 
conjunctival discharge, follico-papillary conjunctivitis, corneal staining punctuations, 
anterior chamber cells and flare, and other objective ocular signs, assessed using the 
following scale: 
(0) = None 
(1) = Mild 
(2) = Moderate 
(3) = Severe 
 
• 
Adverse events occurrence throughout the study 
• 
Product global tolerance will be graded by the Investigator by answering the following 
question “How do you consider the study product global tolerance” using the following 
scale: 
(0) = Very unsatisfactory 
(1) = Unsatisfactory 
(2) = Satisfactory 
(3) = Very satisfactory 
 
 
 

 
 
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10 STUDY POPULATION 
 
10.1 Target population 
 
The study population will consist of approximately 74 evaluable pediatric patients (0-17 years 
[18 years not completed at screening and during the study period]) who will undergo ocular 
exams with a need for ocular surface anaesthesia. 
 
Routine clinical procedures that require topical anesthesia include but are not limited to: 
 
- 
Applanation tonometry: after the anesthesia has been performed, the patient's head is 
immobilized against a headrest or against the examiner's hand. The patient's eyelids are 
gently spread. The measurement of intraocular pressure is carried out by gently pressing 
the tip of the device against the central part of the cornea for a few seconds. The exam 
is painless but may elicit a blink reflex if the anesthesia is not correct. 
 
- 
Gonioscopy: after the anesthesia has been performed, the patient's head is immobilized, 
and the patient is asked to look up. The lower eyelid is gently pulled downwards, thus 
exposing the inferior bulbar conjunctiva. An examination contact lens is then brought 
against the ocular surface, centering it over the cornea, thus allowing visualization of 
the endocular structures and the iridocorneal angle. 
 
- 
Ultrasound Biomicroscopy (UBM): this examination is usually performed while lying 
down. After the anesthesia has been performed, the eyelids are gently pulled apart so 
that a watertight cup can be inserted in-between them. The cup is then filled with sterile 
water so that the imaging probe can be immersed. There is no contact between the probe 
and the eye surface, the water creating an interface between the two. 
 
- 
Ocular ultrasonography: this examination can be performed either with closed or open 
eyelids. However, if the examination is to be performed with the eyelids open, surface 
anesthesia is necessary in order to allow contact between the ultrasound probe and the 
ocular surface without pain for the patient. 
 
- 
Retinal peripheral examination with blepharostat and scleral indentation: the exam is 
aimed at evaluating the peripheral retina using an adequate instrument to hold the 
eyelids apart (blepharostat). Scleral indentation is a technique used to examine the 
peripheral fundus in conjunction with binocular indirect ophthalmoscopy. This 
technique enhances the contrast between normal and abnormal retina and also enables 
stereoscopic examination of the peripheral retina. 
 
10.2 Inclusion criteria 
 
To be enrolled in this study, patients must fulfil all these criteria: 
 
1. Age ≥ one day of life (newborn, infant, child)* and 17 years included (not 
anticipated to turn 18 during the study).  
*(Definition of newborn’s age = 0-2 months old) 

 
 
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2. Female subjects currently either of: 
• Non-childbearing potential (i.e., premenarchal or physiologically incapable of 
becoming pregnant, including any female who is surgically sterilised via 
documented hysterectomy or bilateral tubal ligation), 
or 
• 
Childbearing potential (i.e., postmenarchal girls): the subject is eligible to enter 
and participate in this study if she is not lactating and has a negative pregnancy 
test, and agrees to abstain from intercourses or uses, until study completion, a 
valid contraceptive method, according to CTFG recommendation on 
Contraception and pregnancy v 1.1-2020 (32), i.e.:  
o Hormonal oral, implantable, transdermal or injectable contraceptives for at 
least 2 months before the screening visit 
o 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 
o A male sexual partner who agrees to use a male condom with spermicide 
o A sterile sexual partner 
3. Signed written informed consent by both parents or legal representative(s) (unless 
only one has legal authority). Written informed assent for adolescents aged 12-17 
years included and, whenever possible, informed assent for children aged 6 to 11 
years included. Ability of the subjects and their parents/legal representative(s) to 
understand and to comply with the protocol requirements, study-specified visit 
schedule and procedures. 
4. Scheduled to undergo a routine clinical procedure which needs local ocular surface 
anesthesia, including but not limited to applanation tonometry, gonioscopy, 
Ultrasound Biomicroscopy (UBM), ocular ultrasonography, retinal peripheral 
examination with blepharostat and scleral indentation. 
 
10.3 Exclusion criteria 
Patients fulfilling ONE OR MORE of the following exclusion criteria at the inclusion visit will 
not be enrolled in the study: 
Ophthalmic exclusion criteria 
1. Previous ocular surgery less than 6 months before screening 
2. Eye movement disorder (nystagmus) 
3. History of herpetic keratitis 
4. Corneal, epithelial, stromal or endothelial, residual or evolutionary disease 
(including corneal ulceration, corneal damage and superficial punctuate keratitis) 
5. History of ocular traumatism, infection or inflammation within the last 3 months 
Systemic/non ophthalmic exclusion criteria  
• 
General history: 
6. Any other medical or surgical history, disorder or disease such as acute or chronic 
severe organic disease: hepatic, endocrine neoplasia, hematological diseases, severe 

 
 
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psychiatric illness, cardiac rhythm disorders and/or any complicating factor or 
structural abnormality judged by the investigator to be incompatible with the study 
• 
Allergic history: 
7. Known hypersensitivity to one of the components of the investigational products  
Exclusion criteria related to general conditions 
8. Non-compliant patient and/or parent(s)/legal representative(s) (e.g., not willing to 
attend the follow-up visits, way of life interfering with compliance) 
9. Participation in another clinical study in the last three 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 
10. Already included once in this study 
Exclusion criteria related to previous and concomitant medications / non-product therapies  
11. Patient using any of the following previous and concomitant medication / treatment 
(according to the described periods) will not be included in the study:  
 
NOT ALLOWED CONCOMITANT MEDICATIONS (washout times) 
Before Inclusion 
Inclusion  
30 days 
15 days  
7 days 
Day 1 
Any change in concomitant anti-depressant medication ……………………….. 
Any topical ocular treatment ………………….……………………………… 
Systemic opioids and morphinic drugs  ....................................................................... . 
Sulphonamides 
Anticholinesterase drugs 
 
Any change in other systemic medication already ongoing 
before inclusion visit 
 
Others systemic antalgics drugs (except 
paracetamol) 
 
Silver nitrate (bactericides), Mercury salts 
(some disinfectants), Alkaline substances 
(e.g. detergents) 
 
* Paracetamol after primary endpoint assessment and oral, implantable, 
transdermal, or injectable contraceptives for child-bearing potential girls 
during the entire study will be allowed 
 
10.4 Withdrawal criteria 
 
It will be documented whether or not each patient completed the clinical study. If, for a patient, 
study treatment or observations are discontinued, the type of discontinuation and the primary 
reason for discontinuation will be recorded. 
In case of lack of efficacy of the investigational products, the patient will be regarded as not 
having had a successful anesthesia. The patient will receive rescue anesthesia and will not be 
discontinued from the study. 
Patients who will present complications preventing primary endpoint assessment to be 
performed, will be withdrawn and the standard treatment of the hospital will be applied.  
However, these patients will be followed for safety parameters assessments. 

 
 
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Moreover, if, in the opinion of the investigator, there is any other situation or condition which 
puts the patient at significant risk, the patient should be withdrawn from the study. 
Any patient or legal representative may voluntarily discontinue the study at any time he or she 
chooses (Declaration of Helsinki), without prejudice. The investigator may elect to discontinue 
a patient for reasons related to the study product (AE or unsatisfactory therapeutic response). 
In either event, details should be recorded on the patient source data and eCRF.  
A complete list of discontinuation criteria is presented in § 17.3 and § 17.4. 
If a patient discontinues prematurely from the study after randomization, and consent is 
obtained, the investigator will perform all the evaluations/assessments planned at the final visit.  
 
10.4.1 Discontinuation procedures 
 
For any patient discontinuing from interventions and findings, the investigator will:  
• 
ask the patient to undergo, as far as possible, a final medical visit (Visit 3) to examine the 
patient's health condition  
• 
arrange for alternative medical care of the withdrawn patient, if necessary 
• 
report in the source data and eCRF date and time of the investigational product 
administration, and date and primary reason of study discontinuation 
• 
record in the source data and eCRF any follow-up, if the patient is withdrawn for an AE 
 
Discontinued patients will not be replaced. 
 
 

 
 
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11 CLINICAL SUPPLIES 
 
11.1 
Study Treatment 
 
11.1.1 Description of products 
 
The analytical certificates will be enclosed with the investigational medicinal products (IMPs). 
 
11.1.1.1 Test product 
 
TEST (T) 
 
IMP 
Chloroprocaine 3% 
Distributor 
Sintetica S.A., Switzerland 
Manufacturer 
Laboratoire Unither, France  
Pharmaceutical form 
Ophthalmic gel  
Dose 
Frequency 
2 drops 
1 drop at the time, with a one-minute interval  
Administration route 
Topical instillation 
 
11.1.1.2 Reference product 
 
REFERENCE (R) 
 
 
IMP 
Benoxinato Cloridrato 4 mg/mL eye drops 
Active substance 
Oxybuprocaine Chlorhydrate (same as benoxinate 
chlorohydrate) 
Distributor 
ALFA INTES, industria Terapeutica Splendore S.r.l., Via 
F.lli Bandiera 26, 80026 Casoria (NA), Italy 
Pharmaceutical form 
Ophthalmic solution  
Dose 
Frequency 
2 drops 
1 drop at the time, with a one-minute interval 
Administration route 
Topical instillation 
 
11.1.2 Dose regimen 
 
Patients will be randomized to one of the two treatment groups to receive either chloroprocaine 
3% gel (Test) or oxybuprocaine chlorhydrate 0.4% solution (Reference) as topical anesthetic 
before ocular exam, according to the randomized, parallel-group, observer-blind design of the 
study. 
 
The assigned investigational product (2 drops) will be instilled in both eyes of each subject. 
Administrations will be performed at the clinical center by the Investigator or his/her deputy on 
study day 1 (D1). Administration will be performed as follows: one drop in the right eye, 
followed by one drop in the left eye. After 1 minute from each administration, the second drop 
will be administered in the right eye followed by the left eye. The 2 drops in each eye will be 
instilled one at the time with 1 min interval. 
 

 
 
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11.1.3 Investigational product distribution 
 
The two investigational products will be administered by the Investigator or by his/her deputy 
not involved in the primary and secondary endpoints assessments. The investigational products 
will be exclusively used for the present clinical study and will only be administered to the 
patients enrolled in the study.  
 
11.1.4 Packaging and labelling 
 
Packaging and labelling will be carried out by an external provider according to the kit list.  
 
All labels will be written in the local language. The content of the labelling is in accordance 
with the GMP specifications, according to Annex VI to the Regulation (EU) no 536/2014 on 
clinical trials on medicinal products for human use and local requirements. 
 
11.1.5 Storage conditions 
 
The test product will be stored at 15 - 25°C in a dry locked place, sheltered from light. The 
reference product will be stored according to the instructions present on the corresponding 
SmPC/patient information leaflet. 
 
11.1.6 Drug accountability 
 
The Test and Reference investigational products will be provided directly to the clinical sites 
by the Sponsor. 
 
Each clinical site will receive a set of Test and Reference kits. Each treatment kit will be 
individually labelled and packaged (see § 11.1.4).  
 
After receipt of the investigational products supply, the pharmacist or the person identified as 
the recipient of the investigational products supply at each study center will confirm receipt 
through the IWRS system. 
At the end of the study, used, unused and partially used supplies of Test and Reference 
investigational products provided by the sponsor/manufacturer will either be destroyed on site 
(upon Sponsor’s written authorization) or returned to the sponsor/manufacturer (upon written 
authorization), after assessment of drug accountability. 
 
11.2 
Randomization 
 
Both the kit list and the randomization list will be computer-generated by the Biometry Unit of 
the Clinical Contract Research Organization (CRO), using the PLAN procedure of SAS® 
version 9.3 (TS1M1) or higher. 
The kit list will be supplied to the Supplier before subject’s kit preparation.  
The randomization list will be attached to the final Clinical Study Report (CSR). 
 

 
 
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The randomization number will include a unique progressive 3-digit number (i.e., 101, 102, 
103 …, 201. 202, 203,… etc.), in which the first digit of the number is the clinical site identifier 
(i.e.: 1 for site 1, 2 for site 2 and so on) and the other two digits is the randomization number 
within the site. The kit number will be a unique progressive 5-digit code (i.e., K0401, K0402, 
K0403 …).  
 
11.3 
Treatment allocation 
 
The subjects will be assigned to Test (chloroprocaine) arm or Reference (oxybuprocaine) arm 
in a 1:1 ratio according to the randomization list. The randomization numbers will be assigned 
to the subjects using IWRS in a progressive order. The IWRS system will assign the kit numbers 
to the subjects on the basis of their treatment arm (derived from the assigned randomization 
number) starting from the smallest available number (based on the unique progressive 4-digit 
kit number). 
 
11.4 
Blinding 
 
This is an observer-blind study.  
 
• An independent blinded investigator will evaluate successful conjunctival and corneal 
anesthesia (with the patient, if applicable) and safety parameters for each patient. 
• The patient will be blinded. 
 
The observer-blind design of the trial will be maintained for the entire duration of the study for 
the blinded investigator until database lock. However, blinded investigator and participants may 
be unblinded during the trial for the occurrence of a medical emergency.  
 
Each IMP kit will be numbered according to a randomized kits list created by the appointed 
CRO blinded team and provided to the supplier before the start of the study. The tracking, 
delivery and allocation of IMP kit numbers will be handled through the IWRS system.  
 
11.4.1 Emergency code and unmasking procedures 
 
Unblinding of the code for specific subjects will be fully documented in the source documents, 
in the eCRF and in the clinical study report.  
Breaking of an individual randomization code by the investigator during the study is allowed 
only when knowledge of the code is essential for the subject's health. In these cases, the 
investigator will access the individual code of the concerned subject in the integrated eCRF 
system, where the unblinding action will be audit trailed. The date and the reason for breaking 
the code will be recorded in the system.  
The system will automatically email the monitor and the Sponsor any code breaking.  
 
11.4.2 Emergency individual envelopes 
 
The following applies only in case of online emergency unblinding failure. 
Inside the envelope, the randomization code must be clearly indicated, reporting the allocated 
treatment. 
The true randomization 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 

 
 
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envelopes will be sent to the pharmacovigilance representative and to the Sponsor 
representative (if not coinciding). 
 
The Investigator will open only the envelope related to the concerned subject in case of 
emergency. Individual code breaking will be clearly reported in the subject-related eCRF 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 eCRF and on the 
envelope. All envelope sets containing the randomization 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. 
 
11.5 
Other Treatments 
 
No other drugs than the Test and Reference products will be provided for the study. 
Patients included in the study will undergo medical care before and after ocular exams, 
according to each clinical site practice.  
 
 

 
 
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12 STUDY CONDUCT 
 
The study procedures and their schedule are summarized in Table 1. 
 
12.1 
Study visits  
 
The study protocol foresees one study treatment for each patient. Maximum study duration will 
be 8±3 days (from D1 to D8) plus the screening phase (Inclusion visit) and the optional 
unscheduled visit up to D15.  
 
In details, the study will include an Inclusion visit (Day -7/Day 1), a Follow-up visit (Day 2, 
phone visit), a Final visit (Day 8± 3 days) and an Optional/Unscheduled visit (up to Day 15). 
In case of premature discontinuation, as far as possible, an early termination visit (ETV), 
involving the same procedures/activities of the final visit, will be performed. 
 
• 
Visit 1: Inclusion Visit (Day-71to Day 1) 
The procedures will be conducted by the blinded investigator, except for product preparation 
and administration which will be performed by another appointed member of staff in open 
conditions.  
• 
Patient and patient’s parents/legal representative(s) information about the aims, 
procedures and possible risks of the study and signature of the informed consent 
form/assent form (when applicable) before any study related procedures  
Patient assent and written informed consent by his/her parents/legal 
representative(s) (mother and father, or tutor(s)) can be signed within 7 days before 
inclusion visit as per local practice. All other procedures must be done at D1. 
• 
Recording of demography data  
• 
Ocular and systemic medical and surgical histories  
• 
Previous and concomitant ocular and non-ocular treatments 
• 
Vital signs (blood pressure and heart rate) at screening 
• 
Pregnancy test for post-menarchal girls only 
• 
Slit lamp examination/Binocular indirect ophthalmoscopy before instillation (pre-
dose; 0 min) – both eyes 
• 
Verification of the study inclusion/exclusion criteria 
• 
Patient’s allocation to one treatment group (chloroprocaine 3% gel (Test) or 
oxybuprocaine chlorhydrate 0.4% solution (Reference) 
• 
Assigned product administration by instillation (2 drops in each eye) – both eyes 
• 
Slit lamp examination/Binocular indirect ophthalmoscopy after instillation (60 min 
post-dose) – both eyes 
 
1 Informed consent form and assent form can be signed, as applicable, within 7 days before inclusion visit. All 
other procedures must be done at D1 

 
 
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• 
Efficacy assessment - conjunctival anesthesia assessment with an eye spear sponge 
(just before the scheduled diagnostic examination) – both eyes 
• 
Vital signs (blood pressure and heart rate) post-dose 
• 
AEs occurrence 
• 
Product global tolerance – post-dose – both eyes 
  
The instillation of the product will be done by appointed unblinded staff member(s) in order 
to maintain the blind. 
 
• 
Visit 2: Follow-up phone visit (Day 2) 
The phone call will be done by a blinded investigator. 
  
• 
Patient’s or parents/legal representative(s) questioning about concomitant ocular 
and non-ocular treatments 
• 
AEs occurrence  
 
• 
Visit 3: Final Visit (Day 8 ± 3 days)  
The procedures will be carried out by a blinded investigator. 
• 
Patient’s or parents/legal representative(s) questioning about concomitant ocular 
and non-ocular treatments 
• 
Slit lamp examination/Binocular indirect ophthalmoscopy – both eyes 
• 
AEs occurrence 
 
• 
Optional visit/Unscheduled visit - phone call or on-site visit - (Visit 4, up to Day 15 as 
per Investigator’s judgement) 
 
In case of on-site visit, the following procedures will be carried out by a blinded investigator: 
 
• 
Patient’s or parents/legal representative(s) questioning about concomitant ocular 
and non-ocular treatments 
• 
Slit lamp examination/Binocular indirect ophthalmoscopy – both eyes 
• 
AEs occurrence  
In case of phone call, a blinded investigator will question the patient/legal representative about: 
 
• 
Patient’s or parents/legal representative(s) questioning about concomitant ocular 
and non-ocular treatments 
• 
AEs occurrence  
 
 

 
 
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12.2 
Study procedures 
 
12.2.1 Efficacy measures 
 
12.2.1.1 Conjunctival anesthesia assessment  
For the assessments, the right eye will always be evaluated first, followed by the left eye. 
 
For patients aged ≥3 up to 17 years included, the WBFPS will be used for the evaluation of 
conjunctiva anesthesia (see §9.4.1, Figure 2). 
The patient will be asked to have the eye look up and the investigator with an eye spear sponge 
(see §9.4.1, Figure 1) will touch the left and the right lower conjunctiva of the eye. Both eyes 
will be assessed. 
 
• The discomfort of the patient will be assessed using the WBFPS, as detailed at § 9.4.1, 
with the following scores:  
  
• 
0: No hurt  
• 
2: Hurts little bit 
• 
4: Hurts little more 
• 
6: Hurts even more 
• 
8: Hurts whole lot 
• 
10: Hurts worst 
The score will be reported in the individual CRF for both eyes.  
Based on the aforementioned scale, successful conjunctival anesthesia (right eye) is defined 
as no hurt (scale score=0) 5 min after study product administration, i.e., right before the 
ocular examination.   
 
• For patients less than 3 years old, the discomfort of the patient will be evaluated using 
the FLACC rating scale and giving the final score as follows (see also § 9.4.1): 
 
• 
0: Relaxed and comfortable  
• 
1-3: Mild discomfort 
• 
4-6: Moderate pain 
• 
7-10: Severe pain or discomfort or both 
The score will be reported in the individual CRF for both eyes.  
Based on the aforementioned scale, successful conjunctival anesthesia (right eye) is defined 
as relaxed and comfortable (scale score=0) 5 min after study product administration, i.e. 
right before the ocular examination.   
 
12.2.2 Safety measures 
 
For the ocular assessments, the right eye will always be evaluated first, followed by the left eye. 
 

 
 
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12.2.2.1 
Objective ocular signs (SLE/BIO) – Both eyes 
• 
Objective ocular signs (Slit Lamp Examination/Binocular Indirect Ophthalmoscopy): 
palpebral edema, chemosis, conjunctival hyperemia, conjunctival discharge, folliculo-
papillary conjunctivitis, corneal staining punctuations, anterior chamber cells, flare, and 
other objective ocular signs. Each sign for each eye will be evaluated using the 
following scale: 
 
(0) = None 
(1) = Mild 
(2) = Moderate 
(3) = Severe 
 
This assessment will be performed at D1, pre-dose (0 min) and after IMP instillation (60 min 
post-dose), at D8 and if applicable at D15. 
 
12.2.2.2 Slit lamp examination/Binocular indirect ophthalmoscopy for additional 
assessments – both eyes 
 
These assessments will be additional to the ocular symptoms assessment by SLE/BIO, and 
results of this assessment will not be part of the secondary endpoints. 
 
The following ocular signs will be evaluated at the slit lamp examination or by binocular 
indirect ophthalmoscopy on a 0-3 scale, in addition to the SLE/BIO described at § 12.2.2.1: 
 
• 
Blepharitis 
• 
Eyelid oedema 
• 
Iris pigmentation modification  
• 
Abnormal eyelashes aspect 
• 
Folliculo-papillary conjunctivitis 
• 
Other ocular abnormality. 
 
This assessment will be performed at D1 (pre-dose and post-dose) and D8, or other time-points 
as applicable. 
 
12.2.2.3 
Vital signs measurements  
 
Vital signs (blood pressure and heart rate) will be assessed at Visit 1, at screening and post-
dose. 
 
12.2.2.4 
Product global tolerability assessment – both eyes 
 
Product global tolerability will be assessed for each eye by the blinded Investigator by 
answering the question “How do you consider the study product global tolerance?”, using the 
following score scale: 
 
(0) = Very unsatisfactory 
(1) = Unsatisfactory 
(2) = Satisfactory 

 
 
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(3) = Very satisfactory 
 
This assessment will be performed at D1 post-dose. 
 
12.2.2.5 
Adverse events 
 
Adverse events will be assessed throughout the study. Please refer to § 16. 
 
12.3 
Description of procedures for telephonic follow-up 
 
On Day 2 (and possibly up to D15 for the unscheduled visit), the blinded Investigator or a 
deputy, not aware of the administered treatment, will contact the patients by telephone and will 
question them about any adverse reactions which might have occurred after product instillation, 
with particular attention to any sign of late systemic toxicity, local toxicity, neurological 
symptoms and allergic reactions. Concomitant ocular and non-ocular treatments will also be 
assessed.  
 
 

 
 
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13 STATISTICAL METHODS 
 
The data documented in this trial and the measured clinical parameters will be presented using 
classic descriptive statistics (i.e., total number of subjects treated [N], number of observations 
[n], mean standard deviation [SD], minimum [Min], median, maximum [Max]) for quantitative 
variables and frequencies (i.e., count and percentages) for qualitative variables if not stated 
otherwise. The statistical analysis of demographic, safety and efficacy data will be performed 
at the Biometry Unit of the CRO.  
 
Not available data will be evaluated as detailed in § 13.5. The statistical analysis of 
demographic, safety and efficacy data will be performed using SAS® version 9.3 (TS1M1) or 
higher (the actual version will be stated in the final report). 
 
13.1 
Analysis Sets 
 
The following analysis sets will be considered: 
Safety set:  
All patients who received at least a fraction of the dose of the 
investigational product. 
Intention-to-treat (ITT): 
all randomized patients.  
Per Protocol Set (PPS): 
all randomized patients who received the treatment without any 
major deviation from the protocol.  
The exclusion of patients from the analysis sets will be discussed during a blind review meeting 
that will be held before database lock and complete unblinding. Subjects will be evaluated 
according to the treatment they were assigned to for the primary efficacy analysis (ITT, PPS) 
and according to the treatment they actually receive for the Safety set. 
Data analysis for primary efficacy outcomes will be performed using the ITT set. A sensitivity 
analysis using the PP Set will also be performed for the primary endpoint. Safety parameters 
will be analyzed on the Safety set. 
 
13.2 
Sample size and power considerations 
 
Considering the non-inferiority nature of the study, the hypotheses testing to be assessed is: 
H0: p2-p1 ≤ 0 - m 
H1: p2-p1 > 0 - m 
where m is the non-inferiority margin. 
 
The test treatment will be considered not to be inferior to the reference treatment if the two 
treatments do not differ by more than a margin m. 
 
Given the following parameters: 
• Ratio is the ratio between the number of subjects in the test treatment arm and that in the 
reference treatment arm; 
• α is Type I error rate; 
• Power is the statistical power of the test (1 - type II error rate); 
• p1 is the expected success rate in the reference treatment; 
• p2 is the expected success rate in the test treatment; 
• m is the non-inferiority margin, 

 
 
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and assuming an expected success rate of 0.85 in both the test (p2) and reference treatment (p1) 
arms, a non-inferiority margin of m = 0.25 and a ratio=1, a sample size of 33 subjects in each 
treatment arm is estimated to be sufficient at a one-sided 2.5% significance level and a power 
of 80% to reject the null hypothesis of inferiority. 
 
The total number of subjects to be enrolled is therefore 66. 
 
Furthermore, assuming a drop-out rate of 10%, 74 subjects would be needed to have 66 
completers. 
 
13.3 
Expected success rate and non-inferiority margin 
 
The successful rate of 85% for the study sample size calculation was based on the results 
obtained in the previous 3 clinical trials with chloroprocaine 3% gel (89-92%) in adult 
populations (12-14), taking into consideration the fact that the present study is conducted in a 
pediatric population and that the primary endpoint is only defined as score 0 (no pain) on both 
the WBFPS scale for children or minors aged 3-17 years and the observational FLACC scale 
for the smaller children (0-<3 years), whereas it is expected that several children will score also 
mild discomfort (score 2 on WBFPS scale and score 1 on the FLACC scale – see below). 
 
The non-inferiority margin was chosen on the basis of clinical considerations, taking into 
account that the proportion of success based only on score 0, which was selected for the primary 
endpoint evaluation according to FDA request, could be lower than expected, both for the Test 
and for the Reference formulation.  
In fact, it has been reported by clinicians that in children a mild discomfort could be felt after 
eye drops administration and during anesthesia evaluation using an eye spear sponge. This mild 
discomfort may not be completely discernible from pain sensation, especially in younger 
children, no matter how efficient the ocular conjunctiva anesthesia is. This could lead the 
children (WBFPS) or the observer (FLACC scale) to indicate a higher score than score 0 even 
when conjunctival anesthesia is present.   
In a study of pain ratings using vignettes, Chambers and Craig (25) suggested that the presence 
of smiling faces slightly biased pain ratings away from the no pain range of spectrum. A similar 
conclusion was reported in a study of pain ratings among children after venipuncture (26). 
Therefore, reaching discrete score 2 of the scale (second step after the first face on the WBFPS; 
see Figure 2) is something expected, not to be considered pain-related in the clinical context, 
and in line with the anesthetic features observed when ocular local anesthetics are topically 
administered.  
 
A neonate or infant is normally “Relaxed and comfortable” (overall score 0 on the FLACC 
scale) when he/she is in a normal/known situation, in the absence of noxious stimuli. Even only 
bringing a non-familiar object (e.g., eye drop or spear sponge) close to the neonate or infant 
eye(s) is likely to provoke an untoward reaction. Following a prospective observational study 
at a urban tertiary children’s hospital in infants aged 6 to 22 months, Babl et al. (27) concluded 
that FLACC scores can be higher than expected during nonpainful procedures and during the 
restraint phase of painful procedures. Similarly, Crellin et al. (23) reported that scores for 
children presumed not to be in pain (baseline, preparation and non-painful procedures) 
corresponded to 1.6±2.5, indicating a wide variability in baseline values in the absence of pain.  
 

 
 
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Thus, from the above reported considerations, it follows that the percentage of success based 
on score 0 in the study pediatric population could be slightly lower than the previously reported 
success rates in adult studies, both for the Test and for the Reference product. 
  
In any case, the present study is aimed at claiming the non-inferiority of chloroprocaine 3% 
versus oxybuprocaine chlorhydrate 0.4%, which means that the proportion of success for the 
Test product will be considered not to be inferior to the Reference treatment if they do not differ 
by more than the chosen margin (see § 13.7).  
 
13.4 
Intercurrent events 
 
According to the EMA addendum to ICH E9(R1) about estimands and sensitivity analysis (24), 
the primary efficacy analysis will be conducted under a “treatment policy strategy”.  
 
Under the treatment policy strategy, if an intercurrent event has occurred or not is irrelevant, 
the data will be collected and analysed regardless. For example, if a patient took rescue 
medication, or discontinued from the trial, the data post the event would be included in the 
analyses. This policy reflects the intention‑to‑treat (ITT) principle.  
 
Indeed, in this trial, in the case of unsuccessful anesthesia requiring the use of rescue anesthesia 
to proceed with the diagnostic procedure, the patients will be regarded as failure due to a score 
greater than 0.   
 
If the primary efficacy parameter cannot be collected due to complications preventing to assess 
anesthesia success, a “composite strategy” for the handling of missing data will be used and the 
patient will be regarded as failure. 
 
13.5 
Handling of missing data 
 
13.5.1 Methods for replacing missing data 
 
 
Primary efficacy parameter: patients with missing data for the primary efficacy parameter 
will be imputed as failure. 
 
Safety parameters: no imputation will be done for the safety parameters. 
 
13.5.2 Replacement rules for each analysis set 
 
In general, missing data will be replaced according to methods specified in § 13.5.1. In 
particular: 
 
 
Intention to Treat (ITT): all missing values of the primary endpoint will be treated as a failure 
of the anesthesia 
 
Per Protocol Set (PP): no replacement of missing data is required for the primary endpoint. 
 
Safety Set: no replacement of missing data is required for the safety endpoints.  
 
 

 
 
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13.6 
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.  
 
 
13.7 
Analysis of efficacy parameters 
 
Conjunctival anaesthesia scores for the right eye (study eye) and for the left eye (non-study eye) 
will be listed by subjects and summarized by frequency and descriptive statistics overall (i.e. 
for the 0-3 and 3-17 years age groups together) and by age group (corresponding to the two 
different scales). Scores will be dichotomized as success (score = 0) / no success (score > 1) on 
either scale (WBFPS or FLACC) and summarized by frequency overall (i.e. for the 0-3 and 3-
17 year age groups together) and by age group (corresponding to the two different scales). 
 
13.7.1 Primary analysis 
 
The primary analysis (right eye only) will be performed on the ITT set. A non-inferiority test 
will be used to compare the proportion of success in each treatment group. The difference in 
proportions and its one-sided 95% confidence interval will be derived from the SAS FREQ 
procedure using RISKDIFF option and specifying the NONINFERIORITY (or NONINF) to 
request the Farrington-Manning score test for noninferiority. The significance of the test and 
therefore the non-inferiority of the Test treatment versus the Reference treatment will be 
confirmed if the lower limit of the 95% confidence interval is greater than the noninferiority 
margin (-0.25). 
 
A sensitivity analysis will be done on the PP set, using the same methodology applied for the 
ITT set. 
 
13.8 
Safety and tolerability evaluation 
 
13.8.1 AEs 
 
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:  
 PTAEs: all AEs occurring before 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 summarized by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC 
and PT, seriousness, relationship to treatment and severity.  
 

 
 
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13.8.2 Slit lamp examination/Binocular Indirect Ophthalmoscopy  
 
Scores or values for Slit lamp examination/Binocular Indirect Ophthalmoscopy parameters and 
their changes from baseline will be listed and summarized for each eye using descriptive 
statistics (mean, SD, CV%, minimum, median and maximum). 
 
13.8.3 Vital signs (blood pressure and heart rate) 
 
Vital signs values at screening and post-dose will be listed and summarized by descriptive 
statistics. 
 
13.8.4 Product global tolerability 
 
Scores of the product overall tolerance assessment will be listed and summarized by treatment 
and eye using descriptive statistics. 
 
13.8.5 Slit lamp examination/Binocular Indirect Ophthalmoscopy – additional assessments 
 
Scores or values for the additional assessments at the Slit lamp or performed by Binocular 
indirect ophthalmoscopy will be listed, if applicable. 
 
 
 

 
 
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14 DATA MANAGEMENT PROCEDURES 
 
14.1 
Data collection – electronic CRFs 
 
The Investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRF. He must also check that the data reported in the eCRF correspond to those 
in the subject’s source documents.  
The eCRF should be filled out in English. Any correction to the eCRF entries must be carried 
out by the Investigator or a designated member of staff. The Investigator must provide a 
reasonable explanation for all missing data. 
 
14.2 
Unique patient identifier 
 
All the study subjects who sign the informed assent form and/or with the informed consent form 
signed by parents/legal representative(s)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.3-01-2021-M), the 
2-digit site number (i.e., 01), the 6-digit screening number (e.g., 01-001, 01-002…., etc.) and, 
if applicable, the 3-digit subject randomization number (e.g., 101, 102, etc.). Study code, site 
number, screening number and subject randomization number are separated by slashes (“/”). 
The last 10 digits of the unique subject identifier (randomized subjects), corresponding to the 
subject screening and subject randomization numbers separated by a slash, or the last 6 digits 
of the unique subject identifier (not randomized subjects), corresponding to the subject 
screening number, will appear as subject identifier in the individual listings and figures of the 
clinical study report (CSR). 
 
14.3 
Data management 
 
Database and eCRF design will be set-up by the CRO Biometry Unit before the start of the 
study. Verification and cross-verification of the data entered by the study personnel will be 
automatically performed by the system, according to predefined nature/type of the data, value 
ranges and rules. All rules applied by the system to check specific items will be detailed in the 
Data Validation Plan (DVP). Queries will be automatically generated by the system for all data 
found to be inconsistent, incorrect or missing. All changes performed by the 
Investigators/authorized users will be tracked by the system’s audit trail. 
Once all data are entered in the eCRF and all outstanding queries are solved and the Monitor 
complete the Source Data Verification (SDV), the Data Manager will verify the correctness of 
the answers and the Investigators will approve (sign) the data of the subjects’ eCRF. 
Data management standards and procedures will be stated in the Data Management Plan (DMP) 
in agreement with the Sponsor. 
 
14.3.1 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 (WHODD). The version of the coding dictionaries will be stated in the study report. 

 
 
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15 STUDY MONITORING AND AUDITING 
 
15.1 
Monitoring 
 
The monitoring visits will be conducted by the appointed CRO/CRAs and the Sponsor. 
 
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 always assure support to the monitor. 
 
The Investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorized individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the Sponsor could perform 
some quality control activities to verify the compliance with the study procedures and the ICH-
GCP guidelines. 
 
15.2 
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-Consistent-Enduring-Available-Traceable). 
 
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 CRO and the Sponsor will be responsible for their respective activities. 
 
The Sponsor may transfer any or all 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. 
 
15.3 
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. The SOPs will be 
made available for review, if required. 
 

 
 
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15.4 
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, regulatory authorities’ review and inspections. 
 
15.5 
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 CRO 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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16 DEFINITION AND HANDLING OF AEs AND SAEs 
 
16.1 
Applicable SOPs 
 
AEs will be recorded throughout the study. 
 
AEs definition, classification and management will follow the Sponsor SOP, based upon 
applicable local and international regulations. The full SOP or an operative summary will be 
made available to the study sites. A summary of AE definition, classification and management 
is reported below. 
 
16.2 
Definitions 
 
• Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical investigation patient 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 authorized use of a 
medicinal product at normal doses, but also from medication errors and uses outside the terms 
of the marketing authorization, including the misuse and abuse of the medicinal product. 
 
• Pre-treatment AE (PTAE) 
Any AE occurring before the first dose of a medicinal product. 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/assent and before the first 
medicinal product administration 
• 
new measurements performed after the signature of the informed consent/assent 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/assent 
• 
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/assent and before the first 
medicinal product administration 
 
• 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:  

 
 
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• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event that may jeopardize the patient’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 
hospitalization; 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, § 7 of the Investigator’s Brochure 
(IB) for the test formulation and the SmPC for the reference formulation 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. 
 
16.3  AEs monitoring window 
 
• Start of monitoring: from immediately after the signature of the informed consent/assent 
• 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 patients) must be recorded only if it is an ADR, 
according to the investigator’s judgment. 
 
16.4  AEs recording 
 
All AEs derived by spontaneous, unsolicited reports of the patients, 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 
center) in the source documents and later transcribed in the eCRF: 
 
1. Adverse Event: progressive number of the adverse event or progressive number of follow-
up of the adverse event  
2. Description: verbatim description of the adverse event  
3. Start Date/Time: start date/time of the adverse event or  
4. Follow-up Date/Time: follow-up 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; in case of an 
ophthalmological AE, left or right eye must be recorded  

 
 
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7. Whether the adverse event starts 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 
eCRF forms 
16. Study Discontinuation: if the adverse event causes the patient 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 
 
 

 
 
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16.5 SAEs reporting 
 
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. 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 on the report. 
The sponsor will evaluate the SAE expectedness on the basis of the RSI. 
 
16.6 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. 
The minimum information to be reported includes: 
• 
Valid EU trial number 
• 
Sponsor study number 
• 
One identifiable coded patient 
• 
One identifiable reporter 
• 
One SUSAR 
• 
One suspect IMP (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). 
 
 

 
 
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16.7  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 patient has completed a clinical trial and 
are reported to the investigator by the patient. 
• 
new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the patients, such as: 
o a SAE which could be associated with the trial procedures, and which could 
modify the conduct of the trial 
o a significant hazard to the patient population such as lack of efficacy of a 
medicinal product used for the treatment of a life-threatening disease 
o a major safety finding from a newly completed animal study (such as 
carcinogenicity) or from other clinical trials. 
 
16.8 Reporting of SUSARs to the Eudravigilance database 
 
Reporting of suspected unexpected serious adverse reactions to the Eudravigilance database is 
performed by the Sponsor according to the regulatory requirements. 
 
16.9 SAEs: contacts 
 
Sponsor Pharmacovigilance (PV) can be contacted using the phone and fax numbers stated in 
this protocol. SAEs must be reported on SAE forms in the eCRF where Sponsor PV can access 
them directly. In case of unexpected technical problems with the eCRF, SAEs must be reported 
on SAE reporting forms and faxed/emailed within 24 h to sponsor - contact details below: 
 
Corporate Drug Safety Unit 
Fax: +41(0)91.646.85.61 - Phone: +41(0)91.640.42.50 
Email: corporate_drug_safety@sintetica.com 
 
 
 
 

 
 
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17 ETHICAL CONSIDERATIONS 
 
17.1 
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 relevant Ethics Committees and Health Authorities 
will be obtained before the start of the study.  
 
Study notification to the Competent Authorities will be performed according to the current 
regulations. 
 
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 international and local law requirements. 
 
17.2 
Informed Consent and Child Assent Form 
 
Before being enrolled in the clinical study, the subjects (children/parent(s)/legal 
representative(s)) must have expressed their consent/assent (if applicable) 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. If requested, older adolescents may have a private conversation (without parents) with 
the trial personnel about confidential/sensitive issues. 
 
The informed consent must be signed by both parents/legal representative(s), according to the 
ICH-GCP recommendations, unless only one has legal authority. A suitable informed assent 
will be submitted to the pediatric patients for the signature/approval, if applicable, on the basis 
of their age: 
  
 
In children <6 years of age, not capable of understanding the information related to the 
study, it is not possible to obtain assent, and the understanding of research is not 
expected. Where the child has some capacity for understanding (pre-school children), 
age-appropriate information will be given even though it will not be possible to obtain 
assent. According to their age and maturity they will be given the opportunity to form 
an opinion or decision and their agreement should be requested systematically. Their 
refusal or dissent should be respected, objections should be analysed. Resistance of very 
young children should be identified and discussed with legal representatives. 
 
In children from 6 up to 11 included the assent will be obtained, whenever possible, in 
writing. 
 
Adolescents aged from 12 up 17 years will provide oral and written informed consent 
to participate in the clinical trial in addition to the requirement for the consent of parents 
or the legal representatives. 
 
The information sheets and informed consent/assent forms will be prepared in the local 
language and submitted to the regulatory authorities for approval. The documents will include 
all the elements required by law according to the ICH-GCP recommendations.  
 

 
 
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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 IMPs and administration procedures, as 
applicable) 
 any potential negative effects attributable to the IMPs 
 the freedom to ask for further information at any time 
 the subjects’ or his/her parent(s)/legal representative(s)’ 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 
(children/parent(s)/legal representative(s)). 
 
During the consent/assent discussion it will be verified that everyone (including the child) has 
understood the information. 
 
Dissent is the explicit wish of a minor who is capable of forming an opinion to refuse 
participation in, or to withdraw from, the clinical trial at any time. The lack of assent, written 
or oral as foreseen, is equivalent to the minor’s refusal to participate, i.e. dissent. A lack of 
agreement by the child may or may not be equivalent to dissent, depending on the maturity of 
the minor to express agreement. The minor capable of forming an opinion may express dissent 
verbally, but also in other ways. Dissent will be respected by the investigator and properly 
recorded. Objections should be analysed (reason), and possible help sought for anticipated 
burden (fear, distress etc.). 
 
Subjects and their parents/legal representative(s) will be provided with additional information 
in local language regarding the information to on the processing of their personal data according 
to the European General Data Protection Regulation (GDPR, EU Regulation n 2016/679). 
 
Informed assent, when applicable, will be obtained in writing from the patient. 
 
For what concerns parents/legal representative(s) informed consent, unless only one has legal 
authority, the following situations are possible in order of preference: 
 
1 
Both parents/legal representative(s) are present 
at the site 
Both parents/legal representative(s) will sign 
the paper informed consent 
2 
Only one of the parents/legal representative(s) 
can be present at the site 
The Investigator or a deputy will anticipate the 
study 
information 
remotely 
(e.g., 
electronically, in paper through the partner 
etc.) to the other parent/legal representative. 
After suitable time to review the documents, 
he/she will be contacted by the Investigator 
(or a deputy) by phone or other remote 
systems and will have the possibility and 
ample time to discuss the study with the 
concerned 
clinical 
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member(s)/Investigator and ask questions. 
The Investigator (or deputy) will make any 
reasonable effort to confirm the identity of the 
parent/legal representative. 
 
Thereafter the informed consent will be 
expressed through an electronic Informed 
Consent platform with strong electronic 
signature features.  
3 
Only one of the parents/legal representative(s) 
can be present at the site and the other one is not 
comfortable or unwilling to use electronic 
methods 
The Investigator or a deputy will anticipate the 
study 
information 
remotely 
(e.g., 
electronically, in paper through the partner 
etc.) to the other parent/legal representative. 
After suitable time to review the documents, 
he/she will be contacted by the Investigator 
(or a deputy) by phone or other remote 
systems and will have the possibility and 
ample time to discuss the study and ask 
questions. 
 
The parent/legal representative who cannot 
attend the clinical site will sign a paper copy 
of the informed consent and provide it to the 
site through the partner together with a 
delegation letter and a signed copy of a 
personal ID document. 
 
Whatever procedure is followed, the complete assent/informed consent process will be 
documented and completed before any procedure specific to the clinical study is performed.  
 
To ensure medical confidentiality and data protection, the signed informed consent/assent 
forms will be stored in the Investigator's study file (if in paper) or in a secure electronic system 
(in case of eConsent) according to the regulatory requirements. The Investigator will allow 
inspection of the forms by authorised representatives of the Sponsor, EC members and 
regulatory authorities. He/she will confirm, by signing and dating the forms (in paper or through 
the eConsent platform as applicable), that informed consent/assent has been obtained. 
 
17.3 Criteria for patient’s withdrawal 
 
Participants will be free to discontinue the trial at any time without giving their reasons. A 
participant must be withdrawn in the event of any of the following: 
− withdrawal of the subject’s consent 
− discovery of ineligibility  
− administrative reasons  
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible. In case of premature 
withdrawal from the trial, the investigations scheduled for the last visit should be performed, if 
possible with focus on the most relevant assessments. In any case, the appropriate eCRF section 
must be completed. 
 

 
 
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17.4 Premature discontinuation of the trial 
 
The whole trial may be discontinued prematurely in the event of any of the following: 
- 
New information leading to unfavorable risk-benefit judgment of the IMP, e.g. due to: 
o Evidence of inefficacy of the IMP, 
o Occurrence of significant previously unknown adverse reactions or unexpectedly 
high intensity or incidence of known adverse reactions, or 
o Other unfavorable safety findings. 
- 
Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical 
reasons. 
- 
Poor enrollment of subjects making completion of the trial within an acceptable time 
frame unlikely. 
- 
Discontinuation of development of the Sponsor’s IMP. 
- 
Withdrawal of IMP(s) from the market for safety reasons. 
 
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) will be informed about the discontinuation of the trial in accordance with applicable 
regulations. The whole trial may be terminated or suspended upon request of Health 
Authorities. 
 
17.5 
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. 
 
17.6 
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 reported to the Regulatory Authorities 
within the required timeframe.  
 
 
 

 
 
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18 ADMINISTRATIVE PROCEDURES 
 
18.1 
Material supplied to the clinical center 
 
Beside the investigational products, the following study material will be supplied to the clinical 
centre: 
• final version of the study protocol 
• access to eCRF 
• copy of the Investigator’s Brochure (IB) for the Test IMP and of the SmPC or Patient 
Information Leaflet for the Reference IMP 
• informed consent, assent forms and access to the eConsent platform 
 
Moreover, before the start of the study, the Investigator(s) will be provided with the documents 
such as: 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. 
 
18.2 
Protocol amendments/modifications 
 
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/modifications should 
be made by mutual agreement between the investigator and the sponsor. Any 
amendment/modification must be set out in writing, giving the reasons, and being signed by all 
concerned parties. The amendment/modification becomes then part of the protocol. 
 
All amendments/modifications will be sent to the EC and concerned Competent Authorities, 
according to the current regulations in the EU. 
 
The amendment/modification will be applicable only when it is approved by the concerned 
authorities unless the changes consist of urgent safety measures to protect study patients. 
 
Non substantial amendments/modifications will be notified according to the current regulations. 
 
18.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the eCRF and in all required reports. 
 
The investigator must keep source documents for each patient in the study. All information on 
the eCRF must be traceable to these source documents, which are generally stored in the 
patient's medical file. The source documents should contain all demographic and medical 
information, including ECGs etc., and the original signed informed consent/assent forms. 
 
Data reported in the eCRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. 
 

 
 
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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
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 patients 
including ECG tracing, insurance contracts, certificate of analysis of the IMP(s), drug 
accountability records, signed informed consent/assent forms (including eConsents), 
confidential patients identification code, CRFs, curricula vitae of the investigator and other 
participants in the study, study staff lists and responsibilities, monitoring reports and final 
clinical 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. 
 
18.4 
Study patients’ recruitment 
 
Study participants will be recruited at each clinical center among the patients attending the 
clinic.  
 
18.5 
Confidentiality and data protection 
 
By signing this protocol, the Investigators and the CRO agree to keep all the information 
provided by the Sponsor in strict confidentiality and to request the same confidentiality from 
their staff. Study documents provided by the Sponsor (protocols, IB, eCRF and other materials) 
will be stored appropriately to ensure confidentiality. The information provided by the Sponsor 
to the Investigators and to the CRO cannot be disclosed to others without direct written 
authorization from the Sponsor, except for the extent necessary to obtain the informed 
consent/assent from the subjects wishing to participate in the study and their parents/legal 
representative(s). 
 
Data on subjects collected in the eCRF during the study will be documented in a coded way. 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. 
 
18.6 
Measures implemented for data security breaches 
 
The CRO operates in Switzerland and could manage Personal Data of subjects from 
Switzerland, Europe and the rest of the world. 
 
Swiss data protection legislation is closely tied to EU regulations and transfer and processing 
of data in Switzerland is permitted according to art. 45 (1) of GDPR that states that transfer 

 
 
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may take place where the Commission has decided that the third country ensures an adequate 
level of protection. On 26 July 2000, the European Commission decided in Commission 
Decision 2000/518/EC (Official Journal L 215/1 of 25.8.2000) that the Swiss law provides 
adequate protection of personal data. 
 
The CRO has implemented numerous technical and organizational measures to ensure the most 
complete protection of personal data. 
The processing of personal data by the CRO is always in line with the GDPR and the applicable 
Swiss data protection regulations. 
Data Protection by design and by default principles is built-in in all CRO processes. 
Routine Study Risk Evaluation Meetings ensure that adequate measures are built-in in the 
studies since the early design. Data Protection training is foreseen for all employee to ensure 
that a workplace culture and awareness of Data Protection is diffused in the CRO. 
 
Contractors and consultants are made aware of and required to comply with the CRO data 
protection requirements.  
 
The CRO Management has established an independent Data Protection Officer on the basis of 
professional qualities and, in particular, expert knowledge of data protection law and practices 
and the ability to fulfil the GDPR DPO tasks. 
 
The CRO has established a specific Register of Processing Activities according to GDPR art.30. 
Where a type of data processing is likely to result in a high risk to the rights and freedoms of 
natural persons, the CRO carries out an assessment of the impact of the envisaged processing 
operations on the protection of personal data (Data Protection Impact Assessment, DPIA). 
 
The CRO ensures that all key data subjects’ rights are respected in agreement with requirements 
and timelines stated in applicable Data Protection Regulations. 
The CRO has a public Privacy Policy that is accessible on the corporate web site 
(https://www.croalliance.com/privacy-policy/). 
 
The CRO has a specific Data Retention Policy for the different types of data. 
The CRO tracks, properly processes, and reports any Data Protection related incident. 
The CRO adopts suitable technical security measures (limitations and controls of the access to 
the data, protection from any unauthorized data access and/or modifications, safeguard of the 
data and theft, loss and destruction prevention, periodical check of restore procedures, offsite 
daily backups, routine tests, firewall, antivirus, periodical penetration testings, encryption 
techniques etc.) to ensure the maximum confidentiality of the Personal Data and guarantee a 
level of security commensurate with the risks, to prevent the risks of destruction and loss, 
accidental or otherwise, of the Personal Data and of unauthorised access or unlawful processing. 
 
The CRO adopts suitable organizational measures (checks on accesses to premises and offices, 
adequate systems for authentication and authorization of the staff authorized, good data 
protection practices, tidy desk practice, secure document shredding, secure storage etc.) to 
ensure the maximum confidentiality of the Personal Data and guarantee a level of security 
commensurate with the risks, to prevent the risks of destruction and loss, accidental or 
otherwise, of the Personal Data and of unauthorised access or unlawful processing. 
 

 
 
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18.7 
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(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done 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(s) 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. 
The study will be registered and published in clinicaltrials.gov. 
 
18.8 
Submission of summary results 
 
Summary results will be submitted through the CTIS (Clinical Trial Information System) within 
6 months from study end, according to the requirements of the Clinical Trial Regulation (EU) 
536/2014. 
 
 

 
 
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CONFIDENTIAL 
Study Protocol No CHL.3-01-2021-M 
 
CRO Clinical Study Protocol No. CRO-23-153 
 
Version 5.0, 10/November/2023 
 
- CONFIDENTIAL - 
 
Appendix – Investigators signature pages 
 
 
 

 
 
CONFIDENTIAL 
Study Protocol No CHL.3-01-2021-M 
 
CRO Clinical Study Protocol No. CRO-23-153 
 
Version 5.0, 10/November/2023 
 
- CONFIDENTIAL - 
Investigator Signature Page 
 
 
The signature below: 
 
Confirms my agreement to conduct the trial in compliance with the protocol, the Declaration 
of Helsinki, the current revision of Good Clinical Practice (GCP), ICH topic E6 (R2), the 
Clinical Trial Regulation (EU) 536/2014, General Data Protection Regulation and the 
applicable local law requirements, including. Confirms my agreement to comply with 
procedures for data recording/reporting, 
• 
Confirms my agreement to permit monitoring, auditing, and regulatory inspection, 
• 
Confirms my agreement to retain the study essential documents in the Investigator files 
until the Sponsor informs me these documents are no longer needed, according to the 
applicable local and international regulations, 
• 
Ensure that all persons assisting with the study are adequately informed about protocol, 
the investigational product(s) and their trial-related duties and functions, 
• 
Confirms to supervise any individual or party to whom I will delegate trial-related duties 
and functions at the trial site, 
• 
Confirms that I have read this protocol and I agree to comply with all parts or items. 
 
All information regarding this protocol and the investigational product(s) will be treated as 
strictly confidential. 
 
TRIAL SITE 
 
Principal Investigator 
 
 
 
__________________________ 
_______________ 
___________________________ 
First Name – Last Name 
date 
signature