Clinical trial NCT02919072
Conditions: Unplanned Caesarean Section
Sponsor: Sintetica SA
Start date: 2016-10-01; Completion date: 2021-06-01
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study evaluate the quality of epidural anaesthesia and the safety of Chloroprocaine HCl 3% compared with Ropivacaine HCl 0.75% in patients with an epidural catheter in situ undergoing unplanned Caesarean section.

Detailed description:
Labouring women who have an epidural catheter in situ and established analgesia, in need of an unplanned Caesarean section, will be randomly allocated to receive either Chloroprocaine HCl 3% (T-group) or Ropivacaine HCl 0.75% (R-group) epidurally. Prior to the epidural injection, the patient will be transferred to the operating theatre. The local anaesthetic solution will be freshly prepared and 20 mL will be administered by epidural injection, according to the standard hospital procedures, as detailed in the "Study Schedule" section below. Time T0 is defined as the start time of the first epidural injection of the investigational product. In case of pain or discomfort, a 6 mL epidural top-up of the same anaesthetic, i.e. Chloroprocaine HCl 3% in T-group and Ropivacaine HCl 0.75% in R-group, will be administered. The anaesthesiologist(s) administering the anaesthetic and collecting the data will be blinded with respect to the treatment given to each patient.

Arms: arm 1: Chloroprocaine, 20 ml epidural anaesthetic solution administered according to the standard procedures of the hospital. In case of pain or discomfort, a 6 mL epidural top-up will be administered. arm 2: Ropivacaine, 20 ml epidural anaesthetic solution administered according to the standard procedures of the hospital. In case of pain or discomfort, a 6 mL epidural top-up will be administered.
Interventions: intervention 1: Chloroprocaine intervention 2: Ropivacaine
Intervention descriptions: intervention 1: The 20 mL epidural anaesthetic solution will be administered as follows: 5 mL of the study anaesthetic solution will be given epidurally and the block will be assessed after 2 minutes from the first injection using cold, pinprick and touch. Then intrathecal placement will be excluded and a further 15 mL of the study anaesthetic solution will be administered epidurally. Two minutes after the start of the second injection, the sensory block will be re-assessed using cold, pinprick and touch. In case of pain or discomfort a 6 mL epidural top-up of the same anaesthetic will be administered. intervention 2: The 20 mL epidural anaesthetic solution will be administered as follows: 5 mL of the study anaesthetic solution will be given epidurally and the block will be assessed after 2 minutes from the first injection using cold, pinprick and touch. Then intrathecal placement will be excluded and a further 15 mL of the study anaesthetic solution will be administered epidurally. Two minutes after the start of the second injection, the sensory block will be re-assessed using cold, pinprick and touch. In case of pain or discomfort a 6 mL epidural top-up of the same anaesthetic will be administered.

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 1 
 
CLINICAL STUDY PROTOCOL 
 
Study CRO-16-128 - Sponsor code CHL.3/01-2016 
 
Comparison of epidural Chloroprocaine 3% and  
Ropivacaine 0.75% for unplanned Caesarean section  
in labouring women who have an epidural catheter in situ 
 
Prospective, multi-centre, randomised, double-blind, controlled, superiority study 
 
EudraCT Number: 2016-000298-20 
 
Test product: 
Chloroprocaine HCl 3% Injection (30 mg/mL), Sintetica 
S.A., Switzerland 
Reference product: 
Naropin®, Ropivacaine HCl 0.75% injectable solution (7.5 
mg/mL), AstraZeneca  
Sponsor: 
Sintetica S.A.,  
Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: +41.91.640.42.50  
Fax: 
+41.91.646.85.61 
International coordinator and 
Principal investigator site N. 1 
Prof. Dr. Marc Van de Velde, MD, PhD, EDRA,  
Chair Department of Anesthesiology, 
UZ Leuven, campus Gasthuisberg,  
Herestraat 49B - 3000 Leuven, Belgium  
Phone: +32.16.34.1234 
Email: marc.vandevelde@uzleuven.be 
Development phase: 
Phase III 
Version and date: 
Final version 6.0, 07AUG2020 
 
 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 (R2) 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 75 pages 
 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 2 
 
VERSIONS’ HISTORY 
 
Version 
Date 
Description of Changes 
1.0 
17 June 2016 
Original submitted document 
2.0 
03 October 2016 
The amended protocol introduces the 
following changes: 
 
If the anesthesia has reached an adequate 
level 
with 
5 
or 
10 
mL 
of 
the 
investigational 
anaesthetic 
and 
the 
administration of the additional 10-15 mL 
give rise to safety concerns, no additional 
volume will be administered and the 
patient will be excluded from the study 
− The Full Analysis set and the Per 
Protocol set definitions have been 
slightly modified to exclude from the 
analyses patients who are withdrawn 
from the study because not administered 
the entire volume (20 mL) of study 
anaesthetic. 
− The reasons for discontinuation have 
been completed to include patients 
discontinued because did not receive the 
entire planned dose of study anaesthetic 
(20 mL). 
− It has been clarified that atropine 0.5 mg 
will be administered as an i.v. bolus 
− A few typos were corrected. 
3.0 
18 October 2017 
Both test and reference investigational 
anaesthetic agents will be administered as 
5 mL plus 15 mL over 3 minutes instead of 
5 mL plus 5 mL plus 10 mL over 5 
minutes. Total volume will be 20 mL as in 
the previous protocol version.  
This change has been performed in order 
to achieve surgical anaesthesia rapidly, 
taking into consideration the common 
clinical practice and the medical literature. 
With the new dose regimen, safety of the 
study 
subjects 
should 
be 
increased 
considering a more rapid and adequate 
anaesthesia for urgent Caesarean sections. 
The use of only one test dose as opposed to 
two test doses as present in the original 
protocol was balanced against the possible 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 3 
delay in establishing the blockade, which 
in the setting of foetal compromise may 
not 
be 
acceptable. 
In 
addition, 
no 
published works describe the use of two 
test doses. 
The one-5 mL initial dose before the 
injection of the remaining dose is deemed 
sufficient also considering that in the study 
population the epidural catheter has 
already been tested and used to provide 
analgesia.  
 
In the study, in fact, before undergoing 
unplanned Caesarean section patients have 
a continuous infusion of analgesic through 
a previously placed epidural catheter for 
CSE analgesia. For a rapid onset of 
anaesthesia, it is fundamental that the 
epidural catheter is in place and has been 
used to maintain labour analgesia until 
anaesthetic injection. This was not clearly 
specified in the previous protocol version. 
Details on the maximal allowed time 
between end of analgesic infusion and 
anaesthetic injection have been added. 
 
Note to file N. 8 was issued on 
08AUG2017 to clarify how to grade the 
correlation between VAS values for pain 
assessment 
and 
AE 
severity. 
The 
clarification has been added in the current 
protocol version.  
 
Note to file Nr. 4 was issued on 
07DEC2016 to clarify that, according to 
the clinical practice Hetastarch/plasmalyte 
is used not only at the end but also during 
surgery. In addition, according to a 
communication 
from 
the 
Principal 
Investigator, it has been clarified that 
according 
to 
the 
clinical 
practice, 
Hetastarch 
and 
plasmalyte 
are 
administered only if needed and their 
volume 
cannot 
be 
predicted 
or 
standardised. The protocol has been 
amended accordingly. 
 
Drug and alcohol abuse will be defined 
according to the Investigator's opinion on 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 4 
the basis of the Dietary Guidelines for 
Americans 2015-2020, U.S. Department of 
Health and Human Services and U.S. 
Department 
of 
Agriculture. 
This 
information, not present in the previous 
protocol version, has been added. 
 
Non-substantial amendment Nr. 2, dated 
06MAR2017, was released and notified to 
the concerned Health Authorities. With the 
amendment, the information on the block 
size of the randomisation list was deleted 
from the protocol. A new randomisation 
list starting from patient randomisation 
number 005 was prepared and used for the 
study. No information on the block size of 
the new randomisation list was given in the 
protocol or in any other document 
provided to the Investigator and/or the 
clinical staff. At the time a new version of 
the protocol was not released. Changes are 
captured in the present version of the 
clinical study protocol. 
 
Compliance to GCP, ICH Topic E6 (R2) 
has been introduced. 
 
Finally, a few typos found during protocol 
revision were corrected and a few, minor 
impact, text modifications were made. 
4.0 
19SEP19 
The amended protocol introduces the 
following changes: 
− Three additional centres will participate 
in the study. The reason is the very low 
study enrolment rate due to the study 
inclusion/exclusion criteria, which are 
particularly restrictive considering the 
study population, i.e. women in labour 
undergoing 
unplanned 
Caesarean 
section. 
− As a consequence of the addition of the 
three new clinical centres the study 
design has been changed from single- to 
multi-centre 
− This amendment impacts the statistical 
methodology for the primary and 
secondary efficacy analysis and the 
study sample size. The previously 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 5 
planned Wilcoxon-rank sum test is in 
fact not applicable to the analysis of 
stratified data and needs to be replaced 
by the Van Elteren test, a widely used 
extension of the Wilcoxon rank-sum 
test for non-parametric 2-way analysis. 
Thus, the sample size was recalculated 
and the statistical methods for the 
primary 
and 
secondary 
efficacy 
outcome 
analysis 
were 
modified 
accordingly. 
− The CRO Clinical Project Leader and 
responsible 
Biostatistician 
have 
changed. 
− Finally, a few typos found during 
protocol revision were corrected and a 
few, minor-impact, text modifications 
were made. 
5.0 
(Germany 
only) 
06MAY20 
Changes were introduced in the protocol 
according to the requests of Würzburg 
Ethics Committee, Germany. The changes 
were centre-specific and do not have an 
impact 
on 
the 
other 
involved 
sites/countries. 
6.0 
07AUG2020 
The amended protocol introduces the 
following changes: 
− In the previous protocol versions 4.0 
and 5.0, the sample size was calculated 
considering a non-competitive design, 
i.e. each study site was to recruit an 
equal number of patients. The amended 
protocol 
introduces 
a 
competitive 
enrolment, i.e. the sites will be able to 
enrol an unlimited number of patients 
until the total number of patients 
planned for the study has been reached. 
As a consequence, a new version of the 
randomisation 
list 
(version 
5.0), 
containing the randomisation scheme 
for patients still to be enrolled at centre 
001 and for all patients at centres 002, 
003 and 004, will be released. 
This amendment impacts the statistical 
methodology for the study sample size 
calculation and for the primary and 
secondary efficacy analysis. Thus, the 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 6 
sample size was recalculated and the 
statistical methods for the primary and 
secondary efficacy outcome analysis 
were modified accordingly (please 
refer to the corresponding protocol 
sections). 
− Dr. Eva Roofthooft, site N. 2 Principal 
Investigator (PI), moved from the 
Department of Anesthesiology, ZNA 
Middelheim, Antwerpen (Belgium), to 
Service 
Anaesthesiology 
GZA 
Ziekenhuizen campus Sint-Augustinus, 
Wilrijk (Belgium). As a consequence 
site N. 2 name and address have been 
changed in the protocol. Site N. 2 PI 
will be Dr. Patrick Van Houwe, 
whereas Dr. Eva Roofthooft will be the 
study sub-Investigator. 
− Site N. 3 PI is Prof. Daniela Marhofer 
(and not Prof. Oliver Kimberger, as 
presented in the previous protocol 
version) 
− The unique subject identifier has been 
clarified (par. 12.2). Minor changes 
were introduced in the paragraph's 
wording. 
− Monica 
Boveri, 
Senior 
Clinical 
Research 
Associate 
and 
Medical 
Writer, 
replaced Angelo 
Vaccani, 
Senior CPL, for the study coordination. 
− CTS Clinical Trial Service replaces 
AML Clinical Services in the blind 
monitoring of clinical centres N. 1 and 
2 starting from AUG2020. 
 
 


CONFIDENTIAL 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 7 
PROTOCOL APPROVAL 
SPONSOR 
Sintetica S.A., Switzerland 
Clinical Project Leader 
Elisabetta Donati, Corporate Director Scientific Affairs 
Date 
Signature 
14 AUG 2020


CONFIDENTL4L
CROss ALLIANCE
CIratL kcsearcli Organisauoii for Sciriiijfir Scrlccs
PRINCIPAL INVESTIGATORS
Swdy protocol CRO-16-128
Sponsor CHL.3 01-2016
Chioroprocaine 3%
- Epidural
Finalversion 6.0, 07AUG2020
International study coordinator, Principal Investigator and National coordinator
-
Clinical centre N. 1
1 have read this protocol and agt-ee to conduc! this study in accordance witli all the
stiulations of the protocol and in accordance ui!h the Declaration of Helsinki, the current
revision of Good Clinical Practice (GCP,), ICH topic E6 (R2), ineluding supervising any
individual or party to whoni 1 ii’ill de/egate trial—related duties andfunctions al the trial site,
and the applicable local law requiren;ents.
Prof. Dr. Marc Van de Velde. MD, PhD. EDRA, Chair
Leuven. Leuven. Belgium
Date
PROR DR.
uz
Signature
CROSS Research LA.
Page 8








CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 12 
STUDY SYNOPSIS 
 
Title: Comparison of epidural Chloroprocaine 3% and Ropivacaine 0.75% for unplanned Caesarean section in 
labouring women who have an epidural catheter in situ 
 
Protocol number: CRO-16-128 - Sponsor code CHL.3/01-2016 / EudraCT N. 2016-000298-20 
 
Clinical phase: Phase III 
 
Study design: Prospective, multi-centre, randomised, double-blind, controlled, superiority study 
 
Planned nr. of centres / countries: 4/Belgium, Austria and Germany 
 
International study coordinator and Principal Investigator - site N. 1: Prof. Dr. Marc Van de Velde, MD, 
PhD, EDRA, Chair Department of Anesthesiology, UZ Leuven, campus Gasthuisberg, Herestraat 49B - 3000 
Leuven, Belgium 
 
Investigational product(s):  
TEST (T):  
Chloroprocaine HCl 3% Injection (30 mg/mL), injectable solution, Sintetica S.A., 
Switzerland. 
REFERENCE (R): 
Naropin®, Ropivacaine HCl 0.75% (7.5 mg/mL) injectable solution, AstraZeneca.  
 
Dose regimen: Labouring women who have an epidural catheter in situ and established analgesia, in need of an 
unplanned Caesarean section, will be randomly allocated to receive either Chloroprocaine HCl 3% (T-group) or 
Ropivacaine HCl 0.75% (R-group) epidurally. Prior to the epidural injection, the patient will be transferred to the 
operating theatre. The local anaesthetic solution will be freshly prepared and 20 mL will be administered by 
epidural injection, according to the standard hospitals' procedures, as detailed in the “Study Schedule” section 
below. Time T0 is defined as the start time of the first epidural injection of the investigational product. In case of 
pain or discomfort, a 6 mL epidural top-up of the same anaesthetic, i.e. Chloroprocaine HCl 3% in T-group and 
Ropivacaine HCl 0.75% in R-group, will be administered. The anaesthesiologist(s) administering the anaesthetic 
and any other staff member collecting study-related data (beside the person preparing the syringes for injection) 
will be blinded with respect to the treatment given to each patient.  
 
Objective: The objective of this study is to test the superiority in terms of the onset time of anaesthesia and to 
evaluate the quality of epidural anaesthesia and the safety of Chloroprocaine HCl 3% compared with 
Ropivacaine HCl 0.75% in patients with an epidural catheter in situ undergoing unplanned Caesarean section. 
 
End-points: 
Primary efficacy end-point: Time to onset of anaesthesia (i.e. time to reach adequate surgical conditions), 
defined as time from T0 to complete loss of cold sensation to the metameric level T4 (block to T4), bilateral 
Secondary efficacy end-points:  
 
Time from T0 to loss of pinprick and light touch sensation to the metameric level T5 (block to T5), bilateral 
 
Quality of the block assessed between 10 and 20 min after the end of surgery by the anaesthesiologist and 
patient together using a 0-10 cm visual analogue scale (VAS; 10=excellent anaesthetic quality, 0=very poor 
anaesthetic quality) 
 
Maximum metameric level of the sensory block assessed by three modalities (complete loss of cold, 
pinprick and light touch sensation) 
 
Motor block assessment (modified Bromage scale) at baseline, prior to incision and after surgery 
 
Proportion of patients who need top-up epidural anaesthesia (same anaesthetic as first epidural injection)  
 
Proportion of patients who need supplementation of the block intraoperatively with intravenous opioids or 
general anaesthesia 
 
Proportion of patients who need general anaesthesia 
Safety end-points:  
 
Discomfort and pain assessed during surgery through spontaneous patient’s reporting and questioning by 
the Investigator/anaesthesiologist 
 
First breakthrough pain assessed by the patient, recorded on a 0-10 cm VAS (0=no pain, 10=most severe 
pain imaginable) 
 
Maternal treatment-emergent adverse events, with particular attention to pain (see above), pruritus, nausea, 
vomiting 
 
Maternal vital signs, pulse rate, pulse oximetry (SpO2) and electrocardiogram, monitored from baseline to 
end of surgery according to the hospitals' standard procedures 
 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 13 
STUDY SYNOPSIS (cont.) 
 
Safety end-points, continued:  
 
Total dose of phenylephrine and total dose of atropine 
 
Total volume of intravenous fluids  
 
Neonatal Apgar scores at 1 and 5 minutes  
 
Umbilical artery and venous blood gases (partial pressure of carbon dioxide [pCO2], partial pressure of 
oxygen [pO2], acidity [pH], base excess [BE]) as an indication of foetal hypoxic stress 
 
Pain at the site of surgery at final visit/early termination visit, recorded on a 0-10 cm VAS (0=no pain, 10= 
most severe pain imaginable) 
 
Pain at the site of epidural injection at final visit/early termination visit, recorded on a 0-10 cm VAS (0=no 
pain, 10= most severe pain imaginable) 
 
Concomitant medications 
 
Neonatal adverse events 
 
Sample size:  
To calculate the required study sample size, results from a previous study with Ropivacaine 0.75% (Sanders et 
al., 2004) were taken into consideration. In this study the mean time to onset of anaesthesia (OA) of Ropivacaine 
0.75% was estimated to be approximately 10 minutes. Time to OA was modelled with a positive right-skewed 
gamma distribution. Assuming an expected difference between Test group and Reference group of μT-μR = -5 
minutes (i.e. a decrease from 10 minutes to 5 minutes), and nT = nR, a sample size of 44 subjects in each group 
will have a power of 90% with a 0.050 two-sided significance level. Sample size was calculated using nGLM.r’. 
R code (Cundill and Alexander, 2015). Forty-eight (48) subjects per group will be enrolled (for a total of 96 
subjects) in order to have at least 44 subjects per group in the Full Analysis Set. 
 
Main criteria for inclusion:  
All women requesting epidural analgesia for labour will be evaluated for inclusion in this study once analgesia 
for labour has been established. When analgesia is effective and if parturients are considered potentially eligible 
for inclusion according to the criteria below, they will be informed about the study and asked if they would like 
to participate in the study in the event that an unplanned Caesarean section is required. Written informed consent 
would then be obtained. 
Inclusion criteria: 
1. Informed consent: Signed written informed consent before inclusion in the study (obtained from women 
fulfilling the criteria, only when effective analgesia has been established) 
2. Sex, pregnancy status and age: Labouring women with singleton pregnancy, ≥ 18 years old 
3. Epidural catheter: Previously sited epidural catheter 
4. ASA physical status: I-II 
5. Analgesia: Effective analgesia established following combined spinal epidural analgesia (CSE) 
6. Term gestation: ≥ 36 weeks 
7. Caesarean section: Unplanned Caesarean section category 2 or 3, according to Lucas Classification (Lucas et 
al. J R Soc Med. 2000;93(7):346-50) 
8. Body Mass Index (BMI): ≤ 40 kg/m2 
9. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study. 
Exclusion criteria: 
1. Physical findings: Clinically significant abnormal physical findings which could interfere with the objectives 
of the study. Contraindications to epidural anaesthesia 
2. ASA physical status: III-V  
3. Further anaesthesia: Patients expected to require further anaesthesia 
4. Epidural catheter: Epidural catheter failure (epidural catheter replacement required or inability to provide 
effective analgesia)  
5. Pregnancy: Labouring women with multiple pregnancy 
6. Caesarean section: Elective Caesarean section 
7. Allergy: ascertained or presumptive hypersensitivity to the active principle and /or formulations ingredients; 
ascertained or presumptive hypersensitivity to the amide and ester-type anaesthetics 
 
 
 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 14 
STUDY SYNOPSIS (cont.) 
 
Exclusion criteria, continued: 
8. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, 
haematological, endocrine or neurological diseases that may interfere with the aim of the study; ascertained 
psychiatric diseases, eclampsia, antepartum haemorrhage, sepsis, blood coagulation disorders, insulin 
dependent diabetes mellitus, terminal kidney failure 
9. Medications: Medication known to interfere with the extent of regional blocks (see chloroprocaine and 
ropivacaine SmPCs) for 2 weeks before the start of the study.  
10. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study, calculated from the first day of the month following the last visit of the previous study 
11. Drug, alcohol: history of drug or alcohol abuse1 
12. Plasma cholinesterase: Known plasma cholinesterase deficiency 
Study schedule: 
The study will include a screening phase (Visit 1, day -1 or day 1), a treatment phase (epidural anaesthesia and 
Caesarean section: Visit 2, day 1), a final visit (after surgery: day 1) and a follow-up (day 3±1).  
 
Screening Phase (Visit 1, day -1 or day 1) 
All parturients who receive neuraxial combined spinal-epidural (CSE) labour analgesia will be evaluated for 
study participation according to the inclusion/exclusion criteria above (except for inclusion criterion N. 7 and 
exclusion criteria N. 3 and 4, which will be evaluated after the decision to proceed with Caesarean section has 
been taken). 
If considered potentially eligible, patients will receive oral and written study information on the aims, procedures 
and possible risks of the study and will be asked whether they would like to participate in case of an unplanned 
Caesarean section. This is done following establishment of effective analgesia BUT prior to the decision to 
perform a Caesarean section.  
When consent is confirmed, a screening number will be assigned to the subjects and the following baseline 
characteristics will be recorded for all subjects: demography, physical abnormalities, body weight, height, BMI, 
vital signs, SpO2, medical/surgical history and previous/concomitant medications. Weeks of gestation will be 
recorded for all subjects. 
If parturients have agreed to participate in the study, but epidural catheter failure is noted during labour analgesia 
(epidural catheter replacement required or inability to provide effective analgesia), patients will be excluded 
from further study participation.  
If an unplanned Caesarean section is required, inclusion/exclusion criteria, including inclusion criterion N. 7 and 
exclusion criteria N. 3 and 4, will be confirmed. Eligible patients will be randomly assigned to receive either 
Ropivacaine HCl 0.75% (R-group) or Chloroprocaine HCl 3% (T-group), according to the assigned 
randomisation number. The decision to proceed with the Caesarean section will be made by an 
obstetrician/gynaecologist not involved in the study. Indication for Caesarean section will be recorded. 
 
Treatment Phase (Visit 2, day 1):  
The investigational epidural anaesthetic must be administered within 10 minutes of the end of the analgesia. If 
the time between the end of the previously established analgesia and the start of the anaesthetic epidural injection 
is > 10 min, the patient will be excluded from the study.  
Prior to epidural injection, the patient is transferred to the operating theatre and standard monitoring 
(electrocardiography, SpO2 and non-invasive blood pressure and pulse rate) will be applied according to the 
standard hospitals' procedures. Clinically significant values will be reported as adverse events and treated 
according to the standard clinical practice. In particular, hypotension (defined as > 10% decrease from baseline 
systolic pressure) will be treated with 100 µg phenylephrine bolus and bradycardia (defined as heart rate < 50 
bpm) with atropine 0.5 mg bolus. Pre-existing CSE analgesia details, i.e. duration of labour-CSE (as hours), pain 
on a 0-10 cm VAS (0=no pain, 10=most severe pain imaginable), total dose of local analgesic, pre-existing 
(baseline) level of sensory block (loss of cold sensation only) and motor block (modified Bromage scale 
[(1=complete motor block (unable to move feet or knees; 2=almost complete block (able to move feet only); 
3=partial block (just able to move knees); 4=detectable weakness of hip flexion (between scores 3 and 5); 5=no 
detectable weakness of hip flexion while supine (full flexion of knees); 6=able to perform partial knee bend)] 
will be evaluated and recorded. 
                                                 
1 Alcohol abuse is defined as use of alcoholic beverages to excess, above moderate drinking. According to the Dietary 
Guidelines for Americans 2015-2020, U.S. Department of Health and Human Services and U.S. Department of Agriculture, 
moderate drinking is up to 1 drink/day for women and up to 2 drinks/day for men 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 15 
STUDY SYNOPSIS (cont.) 
 
Treatment phase, continued: 
Also an aspiration test of the epidural catheter will be performed. No prophylactic i.v. fluid bolus and no 
prophylactic vasopressor will be administered. 
The 20 mL epidural anaesthetic solution will be administered using a standardised approach, according to the 
standard procedures of the hospitals, as follows: 5 mL of the study anaesthetic solution will be given epidurally 
(the start of this initial injection is recorded as being T0) and the sensory block will be assessed after 
approximately 2 minutes from the first injection using cold, pinprick and touch. Then the remaining 15 mL of 
the study anaesthetic solution will be administered epidurally. So after 3 minutes from the start of the first 
epidural injection, the full 20 mL of study anaesthetic solution will have been administered. The administered 
volume will be recorded in the case report form (CRF). Approximately two minutes after the start of the second 
injection, the sensory block will be re-assessed using cold, pinprick and touch. 
In the event of a patient with a block obtained already after 5 mL and for whom administration of the remaining 
15 mL would result in possible safety risks, according to the Investigator's opinion, the patient will not be 
administered the remaining volume of anaesthetic and will be discontinued from the study. 
In case of pain or discomfort, a 6 mL epidural top-up of the same anaesthetic, i.e. Chloroprocaine HCl 3% in T-
group and Ropivacaine HCl 0.75% in R-group, will be administered.  
The anaesthesiologist(s) administering the anaesthetic and collecting study-related data will be blinded with 
respect to the treatment given to each patient. 
Sensory block will be assessed every 2 min, using cold, pinprick and light touch, as much as possible also during 
surgery without disturbing the surgical procedure. Sensory block will also be assessed after surgery end. 
Presence/complete absence of sensation with the three testing modalities (cold, pinprick and light touch) will be 
recorded. Complete absence of sensation will be scored as 0, presence of sensation will be scored as 1. Time to 
achieve loss of cold sensation to T4 and loss of touch sensation (pinprick and light touch) to T5 will be recorded. 
Surgery will start when time to achieve loss of cold sensation to T4 (primary end-point, also defined as time to 
onset of anaesthesia) is achieved.  
Maximum metameric level of the sensory block will be assessed with the three modalities (cold, pinprick, touch) 
as far as possible without disturbing the surgical procedure.  
Motor block will be assessed at baseline, prior to incision and after surgery using the modified Bromage scale. 
Any discomfort or pain or any other adverse effects during surgery will be noted. First breakthrough pain will be 
assessed by the patient using a 0-10 cm VAS and noted. Any pain or discomfort (reported by the patient) during 
surgery will be treated with 6 mL epidural chloroprocaine 3% (T-group) or 6 mL ropivacaine 0.75% (R-group) 
as described above. If this measure does not provide adequate analgesia, intravenous opioids or a general 
anaesthetic will be given according to the Investigator’s opinion.  
Only if needed, patients will receive intravenously Hetastarch solution (or any other equivalent isotonic/colloidal 
solution) and/or plasmalyte solution during and/or at the end of the surgery, according to the standard hospitals' 
procedures. Between 10 and 20 minutes after the end of surgery, the anaesthetist and the patient will assess 
together the quality of the block using a 10-cm VAS (10=excellent quality, 0=very poor anaesthetic quality).  
Patient’s characteristics, surgery, obstetric details and the need for fluids will be recorded. Number of patients 
who need supplementation of the block intraoperatively with intravenous opioids or general anaesthesia and 
details on the administered analgesic/anaesthetic will be recorded.  
Before, during and after surgery, all adverse events will be recorded. Particular attention will be given to the 
occurrence of pain, pruritus, nausea and vomiting.  
 
Follow-up phase (Final visit, day 1 or early termination visit): 
At the end of the surgical procedure, patients will stay in the post-operative recovery room until the criteria for 
discharge are met according to the hospitals’ standard procedures. Maternal vital signs and SpO2 will be 
recorded. Pain at the site of injection and pain at the site of surgery will be assessed using a 0-10 cm VAS. 
Neonate Apgar scores and umbilical artery and venous blood gases will be recorded. Neonatal AEs will be 
recorded. 
Patients will be asked about any adverse events. If all the criteria are met and no adverse reactions occur, the 
patient and neonate will be transferred to a hospital room according to the hospital’s standard procedures. 
 
Follow-up phase (Follow-up visit): On day 3±1, the investigator or a deputy of the investigator, not aware of 
the treatment administered, will question the patients about adverse events and in particular any adverse 
reactions which might have occurred after the final visit, with particular attention to any sign of late systemic 
toxicity, local toxicity, neurological symptoms (e.g. paraesthesia, motor function problems and pain at the 
injection site) and allergic reactions. Neonatal adverse events will also be assessed. 
 


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STUDY SYNOPSIS (cont.) 
 
Study schedule, continued:  
Blinding 
Syringes for anaesthetic epidural injection will be prepared by a person not involved in any other study activity 
and out of the sight of the anaesthesiologist administering the anaesthetic. All the clinical staff (Investigator/co-
investigators/study nurses) involved in anaesthesia and study-related data collection will be blind with respect to 
the administered treatment.  
Data recording 
Demography and the other baseline data, efficacy and safety data, details on the investigational anaesthetic 
administered volume and on the surgical procedure (start and end time, comments) will be reported in the 
individual CRFs. 
Data analysis:  
Statistical analyses will be done using SAS® version 9.3 (TS1M1) or higher for Windows.  
Definition of analysis sets:  
Enrolled set: all enrolled subjects. This analysis set will be used for demographic, baseline and background 
characteristics. 
Full Analysis set (FAS): all randomised patients who fulfil the study protocol requirements in terms of study 
anaesthetic administration, i.e. patients who are administered the whole scheduled volume (at least 20 mL) and 
who are not discontinued due to time between the end of the previously established analgesia and the start of the 
anaesthetic epidural injection > 10 minutes. Missing values of time to onset of anaesthesia will be replaced with 
the highest time to onset of anaesthesia detected in the corresponding treatment group. This analysis set will be 
used for the primary efficacy analysis. 
Per Protocol set (PP): all randomised patients who 1) fulfil the study protocol requirements in terms of study 
anaesthetic administration, i.e. patients who are administered the whole scheduled volume (at least 20 mL, 
administered as 5 + 15 mL) and for whom time between the end of the previously established analgesia and the 
start of the anaesthetic epidural injection is ≤ 10 minutes and 2) fulfil the study protocol requirements in terms of 
primary efficacy evaluation (time to onset of anaesthesia), with no major deviations that could affect the primary 
efficacy results. This analysis set will be used for sensitivity analysis.  
Safety set: all patients who receive at least one dose of the investigational medicinal product. This analysis set 
will be used for the safety analyses. 
 
All study data will be listed by patient and will be summarised using classic descriptive statistics for quantitative 
variables and frequencies for qualitative variables. 
Efficacy analysis 
Gamma Generalized Linear models (GLMs) with clustered robust error will be used to analyse the time to onset 
of anaesthesia. Marginal means and 95% confidence interval of the difference between the two groups will be 
reported. Centre will be considered as cluster in the model. The primary analysis will be performed on the FAS 
and the alpha level will be set at 0.05. A sensitivity analysis will be performed on the PP set keeping the same 
alpha level of the primary analysis. When applicable and relevant, secondary endpoints will be compared 
between the two treatment groups using non-parametric tests (Wilcoxon rank-sum test, Chi square test or Fisher 
exact test) with a nominal alpha level of 0.05. No corrections for multiple testing are considered for the 
secondary endpoints; hence a strong claim will be possible only for the primary endpoint. 
 
 
 
 


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Study protocol CRO-16-128 
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CROSS Research S.A. 
Page 17 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
Phase 
Treatment 
Phase 
Follow-up 
Phase 
Visit 
Visit 1 
Days -1/1 
Visit 2 
Day 1 
Final Visit 
Day 1 
or ETV8 
Follow-up 
Visit 
Day 3±1 
Informed consent 
x 
 
 
 
Demography and lifestyle 
x 
 
 
 
Medical/surgical history 
x 
 
 
 
Physical examination 
x 
 
 
 
Obstetric assessment 
x 
 
 
 
Pre-existing CSE analgesia 
 
x 
 
 
Previous and concomitant medication 
x 
x 
x 
 
Height 
x 
 
 
 
Body weight, BMI 
x 
 
 
 
Maternal vital signs, SpO2
1 
x 
x 
x 
 
Maternal ECG2 
 
x 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
Enrolment and Randomisation 
x 
 
 
 
Epidural injection 
 
x 
 
 
Unplanned Caesarean section 
 
x 
 
 
Sensory block assessment3 
 
x 
 
 
Motor block assessment4 
 
x 
 
 
Pain and discomfort assessment 
 
x5 
x6 
 
Quality of the block7 
 
 
x 
 
Neonate Apgar score assessment 
 
 
x 
 
Umbilical artery and venous blood gas 
analysis 
 
 
x 
 
Patient’s adverse events monitoring 
x 
x 
x 
x 
Neonatal Adverse events assessment 
 
 
x 
x 
 
1. 
At screening, final visit/ETV and during the study according to the standard procedures of the hospitals. 
Clinically significant values will be reported as adverse events and treated according to the clinical 
practice of the hospitals 
2. 
At baseline and up to the end of surgery according to the hospitals' standard procedures. Clinically 
significant values will be reported as adverse events and treated according to the clinical practice of the 
hospitals 
3. 
The block will be assessed after 2 min from the administration of the first 5 mL epidural anaesthetic bolus. 
Sensory block will be assessed again after 2 min from the administration of the remaining 15 mL epidural 
anaesthetic and then every 2 minutes, using cold, pinprick and light touch, as much as possible also during 
surgery, without disturbing the surgical procedure. Sensory block will also be assessed after surgery end. 
4. 
The motor block will be assessed using a modified Bromage scale at baseline, before incision and after 
surgery 
5. 
In general, pain and discomfort will be assessed through spontaneous patient’s reporting and 
Investigator/anaesthesiologist questioning. First breakthrough pain will be evaluated using a 0-10 cm VAS 
6. 
At final visit/early termination visit, only pain will be assessed. Pain at the site of injection and pain at the 
site of surgery will be assessed using a 0-10 cm VAS 
7. Quality of the block will be assessed by the patient and anaesthesiologist together using a 0-10 cm VAS 
8. 
In case of discontinuation, subjects will undergo an early termination visit (ETV) 


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Study protocol CRO-16-128 
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Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 18 
TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL 
1 
STUDY SYNOPSIS 
12 
STUDY SCHEDULE 
17 
TABLE OF CONTENTS 
18 
FIGURES 
22 
LIST OF ABBREVIATIONS 
23 
1 
INTRODUCTION 
24 
1.1 
Background 
24 
1.1.1 
Epidural anaesthesia in unplanned Caesarean section 
24 
1.1.2 
Chloroprocaine 
24 
1.2 
Rationale 
25 
1.3 
Risks and benefits 
25 
2 
STUDY OBJECTIVES 
28 
2.1 
Primary end-point 
28 
2.2 
Secondary end-points 
28 
2.3 
Safety end-points 
28 
3 
CLINICAL SUPPLIES 
30 
3.1 
Treatment 
30 
3.1.1 
Description of products 
30 
3.1.1.1 
Test product 
30 
3.1.1.2 
Reference product 
30 
3.1.2 
Dose regimen 
30 
3.1.3 
Route and method of administration 
31 
3.1.4 
Investigational product distribution 
32 
3.2 
Packaging and labelling 
32 
3.3 
Storage conditions 
32 
3.4 
Drug accountability 
33 
4 
INVESTIGATIONAL PLAN 
34 
4.1 
Overall study design 
34 
4.2 
Discussion of design 
34 
5 
STUDY POPULATION 
36 
5.1 
Target population 
36 
5.2 
Inclusion criteria 
36 
5.3 
Exclusion criteria 
36 
5.3.1 
Not allowed treatments 
37 
5.3.2 
Additional anaesthesia 
37 
5.3.3 
Premedication/sedation 
37 
5.3.4 
Allowed treatments 
37 
6 
STUDY SCHEDULE 
38 
6.1 
Study visits and procedures 
38 
6.1.1 
Schedule 
38 
6.1.1.1 
Visit 1 - Screening - Day -1 / Day 1 
38 
6.1.1.2 
Visit 2 - day 1 
40 
6.1.1.3 
Final assessments (Final visit, day 1 or early termination visit) 
41 


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6.1.1.4 
Follow-up visit (day 3±1) 
41 
6.2 
Diet and lifestyle 
42 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
43 
7.1 
Demography and baseline characteristics 
43 
7.2 
Physical examination 
43 
7.3 
Standard safety monitoring 
43 
7.4 
Assessment of treatment-emergent adverse events 
43 
7.5 
Discomfort and pain assessment 
44 
7.6 
Block assessment 
44 
7.6.1 
Sensory block 
44 
7.6.2 
Motor block 
45 
7.6.3 
Quality 
45 
7.7 
Final assessments 
45 
7.8 
Follow-up assessments 
46 
8 
ASSIGNMENT OF STUDY TREATMENT 
47 
8.1 
Randomisation 
47 
8.2 
Treatment allocation 
47 
8.3 
Blinding 
47 
8.3.1 
Emergency code and unblinding procedures 
48 
8.3.2 
Individual emergency envelopes 
48 
8.3.3 
Individual kit replacement envelopes 
48 
9 
EVALUATION PARAMETERS 
50 
9.1 
Study variables 
50 
9.1.1 
Primary efficacy variables 
50 
9.1.2 
Secondary efficacy variables 
50 
9.1.3 
Safety variables 
50 
9.2 
Efficacy assessments 
51 
9.2.1 
Efficacy parameters 
51 
9.3 
Safety assessments 
51 
10 
STATISTICAL METHODS 
52 
10.1 
Analysis Sets 
52 
10.1.1 
Definitions 
52 
10.1.2 
Reasons for exclusion from the Full Analysis Set 
53 
10.1.3 
Reasons for exclusion from the Per Protocol set 
53 
10.2 
Sample size and power considerations 
53 
10.3 
Demographic, baseline and background characteristics 
54 
10.4 
Analysis of efficacy parameters 
54 
10.5 
Safety and tolerability evaluation 
54 
10.5.1 
Adverse events 
54 
10.5.2 
Physical examination 
55 
10.5.3 
Discomfort and pain assessment 
55 
10.5.4 
Vital signs and ECG 
55 
10.5.5 
Baby assessment 
55 
10.5.6 
Concomitant medication 
55 
11 
DEFINITION AND HANDLING OF AEs AND SAEs 
56 
11.1 
Applicable SOPs 
56 


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Page 20 
11.2 
Definitions 
56 
11.3 
AEs monitoring window 
57 
11.4 
AEs recording 
58 
11.5 
SAEs reporting 
59 
11.6 
SUSARs management 
60 
11.7 
Other events qualified for expedited reporting 
60 
11.8 
SAEs: contacts 
61 
12 
DATA MANAGEMENT PROCEDURES 
62 
12.1 
Data collection - CRFs 
62 
12.2 
Unique subject identifier 
62 
12.3 
Database management 
62 
12.3.1 
Coding dictionaries 
62 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
63 
13.1 
Monitoring 
63 
13.2 
Quality Control and Quality Assurance 
63 
13.3 
Applicable SOPs 
64 
13.4 
Data access 
64 
13.5 
Audits and inspections 
64 
14 
ETHICAL CONSIDERATIONS 
65 
14.1 
Ethics and Good Clinical Practice (GCP) 
65 
14.2 
Informed consent 
65 
14.3 
Insurance policy 
66 
14.4 
Withdrawal of subjects 
66 
14.4.1 
Discontinuation type 
66 
14.4.2 
Primary reason for discontinuation 
66 
14.4.3 
Discontinuation procedures 
67 
14.5 
Study termination 
67 
15 
ADMINISTRATIVE PROCEDURES 
68 
15.1 
Material supplied to the clinical centres 
68 
15.2 
Protocol amendments 
68 
15.3 
Study documentation and record keeping 
68 
15.4 
Study subjects’ recruitment 
69 
15.5 
Confidentiality and data protection 
69 
15.6 
Publication policy 
70 
16 
STUDY RESPONSIBLE PERSONS 
71 
16.1 
Sponsor 
71 
16.2 
Institutes performing the study 
71 
16.2.1 
Clinical centres 
71 
16.2.1.1 
Clinical centre N. 1 
71 
16.2.1.2 
Clinical centre N. 2 
71 
16.2.1.3 
Clinical centre N. 3 
72 
16.2.1.4 
Clinical centre N. 4 
72 
16.3 
Co-ordination, data analysis & reporting 
72 
16.4 
Monitoring 
73 
16.4.1 
Blind monitoring 
73 
16.4.1.1 
Clinical centres N. 1 and 2 
73 


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Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 21 
16.4.1.2 
Clinical centres N. 3 and 4 
73 
16.4.2 
Open conditions monitoring 
73 
17 
REFERENCES 
74 
 
 
 
 
  
 
 


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Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 22 
FIGURES 
Page 
 
Figure 1.1.2.1 
Chemical structure of chloroprocaine hydrochloride 
24 
 


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Study protocol CRO-16-128 
Sponsor CHL.3/01-2016 
Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 23 
LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOAC 
Attributable-Legible-Contemporaneous-Original-Accurate-Complete 
ANOVA 
Analysis of Variance 
ASA 
American Society of Anesthesiologists 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BE 
Base excess 
BW 
Body Weight 
CA 
Competent Authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CNSD 
Cumulative Normal Standard Distribution 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CRS 
Clinical Study Report 
CSE 
Combined Spinal Epidural analgesia 
CSP 
Clinical Study Protocol 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
IVRA 
Intravenous Regional Anaesthesia 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over The Counter 
pCO2 
Partial pressure of carbon dioxide 
pO2 
Partial pressure of oxygen 
PP 
Per Protocol 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Peripheral oxygen saturation 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment-Emergent Adverse Event 
Tra 
Time to administration of rescue anaesthesia or rescue analgesia 
VAS 
Visual Analogue Scale 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 


CONFIDENTIAL 
 
Study protocol CRO-16-128 
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Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 24 
1 
INTRODUCTION 
 
1.1 
Background 
 
1.1.1 
Epidural anaesthesia in unplanned Caesarean section 
 
Many patients having planned vaginal delivery will request neuraxial labour analgesia during 
the course of labour. Unfortunately, a relatively large proportion of patients in labour will 
require an unplanned Caesarean delivery either due to impaired foetal wellbeing or failed 
progress of labour. When an epidural catheter is already functional, topping up the epidural 
catheter to provide good anaesthetic conditions for operative delivery is the option of choice 
for many anaesthesiologists. So conversion of labour epidural analgesia to anaesthesia for 
Caesarean section is a common procedure in routine clinical practice. Since unplanned 
Caesarean delivery can be urgent in order to save the foetus or mother, conversion from 
analgesia to anaesthesia needs to be reliable and fast, providing effective anaesthetic 
conditions within minutes from the decision to proceed with surgery.  
 
Various local anaesthetic solutions are available and have been compared in several studies 
looking at speed of onset of anaesthesia and quality of anaesthesia. A recent meta-analysis of 
available trials identified two potential epidural top-up solutions as being the most optimal: 
plain ropivacaine 0.75% or lidocaine 2% with epinephrine and bicarbonate (1). The latter 
solution works slightly faster but with more breakthrough pain, whilst ropivacaine provided 
good surgical conditions but with a small delay when compared to the lidocaine solution (2). 
The disadvantage of the lidocaine solution is that preparation time is required to mix 
bicarbonate, resulting in potential time-delay between decision to deliver and actual onset of 
anaesthesia (3). Therefore the standard of practice in the UZ Leuven (study site N.1), is 20 
mL epidural ropivacaine 0.75% (25). In the meta-analysis by Hillyard et al. (1), 
chloroprocaine 3% was not evaluated because not yet available in Europe for the proposed 
indication. 
 
1.1.2 
Chloroprocaine 
 
Chloroprocaine hydrochloride (Chloroprocaine HCl [benzoic acid, 4-amino-2-chloro-2-
(diethylamino) ethyl ester, monohydrochloride]; Figure 1.1.2.1) is a short-acting local 
anaesthetic belonging to the amino-ester class, characterized by a rapid onset of action, 
usually 6 to 12 minutes (5,6), and anaesthesia duration up to 60 min, depending on the 
amount used and the route of administration. In-vitro chloroprocaine half-life is 
approximately 21-25 seconds. 
 
Figure 1.1.2.1 
Chemical structure of chloroprocaine hydrochloride 
 
There is a long history of use of chloroprocaine and the amino ester class of anaesthetics in 
USA, Canada and Switzerland. Firstly introduced in 1952 (7), chloroprocaine has been 


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Study protocol CRO-16-128 
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Chloroprocaine 3% - Epidural 
Final version 6.0, 07AUG2020 
CROSS Research S.A. 
Page 25 
employed as local anaesthetic for decades now, though past episodes of neurological toxicity 
in patients exposed to spinal anaesthesia with bisulfite-containing chloroprocaine had 
discouraged a larger use (8-10) It was later demonstrated that neurological complications 
were associated with the preservative agents added to chloroprocaine formulations (11). As a 
consequence, preservative-free and also EDTA-free formulations have been developed, and 
are now available, which prevent these severe adverse episodes and guarantee a safer profile 
compared to other local anaesthetics (12). Information on chloroprocaine formulations are 
included in the listed reference drugs SmPCs (Nesacaine® 1%, 2%, 3% for infiltration, 
peripheral nerve block, epidural block, AstraZeneca [USA and Canada]; Chloroprocaine 1%, 
2%, 3% Sintetica SA [Switzerland]; Ivracain® 0.5% Sintetica SA for IVRA [Switzerland]). 
More recently (2012), Chloroprocaine HCl 1% Injection, preservative-free, Sintetica SA, has 
received approval for spinal-intrathecal use in several European Countries.  
In particular, chloroprocaine 3% solutions have been marketed in USA and Canada for 
several years and are indicated for the production of local anaesthesia by via the epidural and 
other administration routes.  
 
The pharmacological properties of chloroprocaine render it unique. Chloroprocaine presents 
the shortest onset of action and is rapidly metabolized in the circulation by plasma esterase 
hydrolytic activity. This shortens the duration of action (depending on the amount used and 
the administration route) and, importantly, prevents the drug’s plasma accumulation (5,6) and 
related risks of toxic systemic spread (5,12-14). Chloroprocaine is used when a fast onset of 
anaesthesia is necessary and for short-duration surgical procedures (45-60 minutes), when a 
fast recovery is required (15). There has been a renovated interest for the use of 
chloroprocaine as local anaesthetic for the epidural block in labouring patients, particularly 
for patients undergoing an urgent conversion to caesarean section. In this particular setting, 
chloroprocaine may represent the optimal choice, due to the rapidity of onset and the safest 
profile for the woman as well as the child (16). 
 
1.2 
Rationale 
 
In parturients with an epidural catheter previously placed for labour analgesia, extension of 
the epidural block is often the preferred option in unplanned Caesarean delivery, provided that 
adequate speed of onset and adequate surgical anaesthesia are obtained, with minimal side-
effects for the mother and the baby. Chloroprocaine has been reported to have a very rapid 
onset of action and could be an interesting alternative to other anaesthetics currently used for 
epidural anaesthesia during unplanned Caesarean section.  
The objective of the present study is to test the superiority in terms of the onset time of 
anaesthesia and to evaluate the quality of epidural anaesthesia and the safety of 
chloroprocaine 3% compared to ropivacaine 0.75% in labouring women with and epidural 
catheter in situ undergoing unplanned Caesarean section. 
 
1.3 
Risks and benefits 
 
There are no direct benefits to the patients participating in the study. 
Chloroprocaine, however, showed a positive effect on the vascular resistance of the umbilical 
artery (19), and on the intervillous blood flow during epidural anaesthesia (20).  
On the other hand, the short duration of chloroprocaine anaesthesia would require, in some 
cases, the repetition of the epidural administration. For example with 8 - 10 mL of 2% 


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Study protocol CRO-16-128 
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Page 26 
chloroprocaine the anaesthesia lasts about 45 - 50 min and the recovery of normal sensitivity 
is very rapid with pain occurrence. 
 
Local anaesthetics in general cross the placenta, and when used for epidural, paracervical, 
pudendal or causal block, could cause varying degrees of maternal, foetal and neonatal 
toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type 
and amount of anaesthetic used and the technique of drug administration. Adverse reactions in 
the parturients, fetus and neonate may involve alterations of the central nervous system, 
peripheral vascular tone and cardiac function (Nesacaine® SmPC). 
 
Epidural anaesthesia with chloroprocaine is widely used during labour, with no untoward 
effects on the foetal-maternal parameters (16,18).  
 
The risks for the study patients are anticipated to be low, considering that systemic adverse 
reactions following appropriate use of epidural chloroprocaine are unlikely, due to the small 
dose absorbed. Chloroprocaine has been on the market under different brand names in USA 
and Canada for several years. Considering all administration routes, the most commonly 
encountered acute adverse experiences are related to the central nervous system (CNS) and 
the cardiovascular system. These adverse experiences are generally dose related and may 
result from rapid absorption from the injection site, diminished tolerance, or from 
unintentional intravascular injection of the local anaesthetic solution. In addition to systemic 
dose related toxicity, unintentional subarachnoid injection of the drug during the intended 
performance of caudal or lumbar epidural block or nerve blocks near the vertebral column 
(especially in the head and neck region) may result in under-ventilation or apnoea ("Total 
Spinal"). Factors influencing plasma protein binding, such as acidosis, systemic diseases that 
alter protein production, or competition of other drugs for protein binding sites, may diminish 
individual tolerance. Plasma cholinesterase deficiency may also account for diminished 
tolerance to ester type local anaesthetics.  
 
Systemic adverse reactions following appropriate use of intrathecal chloroprocaine are 
unlikely, due to the small dose absorbed. Systemic adverse effects of chloroprocaine are 
similar in nature to those observed with other local anaesthetic agents including CNS 
excitation and/or depression (light-headedness, nervousness, apprehension, euphoria, 
confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of 
heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory 
depression and arrest). Excitatory CNS reactions may be brief or not occur at all, in which 
case the first manifestation may be drowsiness merging into unconsciousness. Cardiovascular 
manifestations may include bradycardia, hypotension and cardiovascular collapse. 
 
Allergic type reactions are rare and may occur as a result of sensitivity to the local anaesthetic 
or to other formulation ingredients. These reactions are characterized by signs such as 
urticaria, pruritus, erythema, angioneurotic edema (including laryngeal oedema), tachycardia, 
sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and 
possibly, anaphylactoid type symptomatology (including severe hypotension).  
 
The study design foresees the administration of 20 mL anaesthetic (test or reference) 
epidurally injected as 5 mL followed by a further 15 mL. There could be cases where the 
anaesthesia could reach the expected level after one fraction of the planned 20 mL has been 


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administered. In these cases if the administration of the remaining 15 mL could result in 
possible safety risks according to the Investigator's opinion, the additional volume will not be 
administered in order to avoid a too high block and the patient will be discontinued from the 
study. 
 
Anaesthesia will be carried out in the operating theatre. Monitoring of patient's safety, 
including peripheral oxygen saturation, will start before anaesthesia and patients will be 
monitored during the whole procedure. 
 
 
 
 


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2 
STUDY OBJECTIVES 
 
The objective of this study is to test the superiority in terms of the onset time of anaesthesia 
and to evaluate the quality of epidural anaesthesia and the safety of Chloroprocaine HCl 3% 
compared with Ropivacaine HCl 0.75% in patients with an epidural catheter in situ 
undergoing unplanned Caesarean section. 
 
2.1 
Primary end-point 
 
The primary study end-point is the time to the onset of anaesthesia (i.e. the time to reach 
adequate surgical conditions), defined as the time from T0 (start time of the epidural injection) 
to complete loss of cold sensation to the metameric level T4 (block to T4), bilateral. 
 
2.2 
Secondary end-points 
 
The secondary end-points are: 
 
 Time from T0 to loss of pinprick and light touch sensation to the metameric level T5 
(block to T5), bilateral 
 Quality of the block assessed between 10 and 20 min after the end of surgery by the 
anaesthesiologist and patient together using a 0-10 cm visual analogue scale (VAS; 
10=excellent anaesthetic quality, 0=very poor anaesthetic quality) 
 Maximum metameric level of the sensory block assessed by three modalities (complete 
loss of cold, pinprick and light touch sensation) 
 Motor block assessment (modified Bromage scale) at baseline, prior to incision and after 
surgery 
 Proportion of patients who need top-up epidural anaesthesia (same anaesthetic as first 
epidural injection)  
 Proportion of patients who need supplementation of the block intraoperatively with 
intravenous opioids or general anaesthesia 
 Proportion of patients who need general anaesthesia 
 
2.3 
Safety end-points 
 
 Discomfort and pain assessed during surgery through spontaneous patient’s reporting and 
questioning by the Investigator/anaesthesiologist 
 First breakthrough pain assessed by the patient, recorded on a 0-10 cm VAS (0=no pain, 
10= most severe pain imaginable) 
 Maternal treatment-emergent adverse events, with particular attention to pain (see above), 
pruritus, nausea, vomiting 
 Maternal vital signs, pulse rate, pulse oximetry (SpO2) and electrocardiogram, monitored 
from baseline to end of surgery according to the hospitals' standard procedures 
 Total dose of phenylephrine and total dose of atropine 


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 Total volume of intravenous fluids 
 Neonate Apgar scores at 1 and 5 minutes 
 Umbilical artery and venous blood gases (partial pressure of carbon dioxide [pCO2], 
partial pressure of oxygen [pO2], acidity [pH], base excess [BE]) as an indication of 
foetal hypoxic stress 
 Pain at the site of surgery at final visit/early termination visit, recorded on a 0-10 cm 
VAS (0=no pain, 10=most severe pain imaginable) 
 Pain at the site of epidural injection at final visit/early termination visit, recorded on a 0-
10 cm VAS (0=no pain, 10=severe pain) 
 Concomitant medications 
 Neonatal adverse events 


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3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of products 
 
The analytical certificates will be supplied with the investigational medicinal products 
(IMPs). 
 
3.1.1.1 
Test product 
 
TEST (T) 
IMP 
Chloroprocaine HCl 3% (30 mg/mL), 20 mL vial  
Distributor 
Sintetica S.A., Switzerland 
Manufacturer 
Sintetica-Bioren S.A., Switzerland 
Pharmaceutical form 
Solution for injection 
Dose 
20 mL (600 mg)  
Administration route 
Epidural 
 
3.1.1.2 
Reference product 
 
REFERENCE (R) 
IMP 
Naropin® 0.75% (7.5 mg/mL), 20 mL ampoule 
Active substance 
Ropivacaine HCl 
Distributor 
AstraZeneca 
Pharmaceutical form 
Solution for injection 
Dose 
20 mL (150 mg) 
Administration route 
Epidural 
 
3.1.2 
Dose regimen 
 
Labouring women who have an epidural catheter in situ and established analgesia, in need of 
an unplanned Caesarean section, will be randomly allocated to receive either Chloroprocaine 
HCl 3% (T-group) or Ropivacaine HCl 0.75% (R-group) epidurally. The local anaesthetic 
solution will be freshly prepared and the planned volume will be administered by epidural 
injection, according to the standard hospitals' procedures, as detailed in § 3.1.3 below. Time 
T0 is defined as the start time of the epidural injection. In case of pain or discomfort a 6 mL 
epidural top-up of the same anaesthetic, i.e. Chloroprocaine HCl 3% in T-group and 
Ropivacaine HCl 0.75% in R-group, will be administered. The anaesthesiologist(s) 
administering the anaesthetic and any other staff member collecting study-related data (beside 
the person preparing the syringes for injection) will be blinded with respect to the treatment 
given to each patient. 
 
 


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3.1.3 
Route and method of administration 
 
The decision to proceed with the Caesarean section will be made by an 
obstetrician/gynaecologist not involved in the study.  
The investigational epidural anaesthetic must be administered within 10 minutes of the end of 
the analgesia. If the time between the end of the previously established analgesia and the start 
of the anaesthetic epidural injection is > 10 min, the patient will be excluded from the study. 
Prior to epidural injection, the patient will be transferred to the operating theatre and standard 
monitoring (electrocardiography, SpO2 and non-invasive blood pressure and pulse rate) will 
be applied according to the standard hospitals' procedures. An aspiration test of the epidural 
catheter will be performed. No prophylactic i.v. fluid bolus and no prophylactic vasopressor 
will be administered. 
 
The 20 mL epidural anaesthetic solution will be prepared out of sight of the anaesthesiologist 
(e.g. in a curtain cubicle space) by a person not involved in any other study-related activity 
will be administered by the anaesthesiologist(s) using a standardised approach, according to 
the hospitals' standard procedures, as follows: 5 mL of the study anaesthetic solution will be 
given epidurally (the start of this initial injection is recorded as being T0) and the block will be 
assessed after approximately 2 minutes from the first injection using cold, pinprick and touch. 
Then the remaining 15 mL of the study anaesthetic solution will be administered epidurally. 
So after 3 minutes from the start of the first epidural injection, the full 20 mL of study 
anaesthetic solution will have been administered. The administered volume will be recorded 
in the case report form (CRF). 
 
Approximately, two minutes after the start of the second injection, the sensory block will be 
re-assessed using cold, pinprick and touch.  
In the event of a patient with a block obtained already after 5 mL and for whom 
administration of the remaining 15 mL would result in possible safety risks, according to the 
Investigator's opinion, the patient will not be administered the remaining volume of 
anaesthetic and will be discontinued from the study. 
 
In case of pain or discomfort a 6 mL epidural top-up of the same anaesthetic, i.e. 
Chloroprocaine HCl 3% in T-group and Ropivacaine HCl 0.75% in R-group, will be 
administered. The residual amount from the 20 mL vials/ampoules used for the top-up will be 
collected from each vial/ampoule using another graduated syringe, completely sealable, and 
retained for drug accountability together with the empty vial/ampoule. 
 
The anaesthesiologist(s) administering the anaesthetic and collecting study-related data will 
be blinded with respect to the treatment given to each patient. Only if needed, patients will 
receive intravenously Hetastarch solution (or any other equivalent isotonic/colloidal solution)  
and/or plasmalyte solution during and/or at the end of the surgery, according to the standard 
hospitals' procedures. 
 
 


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3.1.4 
Investigational product distribution 
 
The investigational product will be administered by the investigator or by his/her deputy. The 
investigational product will be exclusively used for the present clinical study and will only be 
administered to the subjects enrolled in the study.  
 
3.2 
Packaging and labelling 
 
Each patient’s kit will contain two 20 mL-vials/ampoules of either Test (vials) or Reference 
(ampoules) investigational product. Packaging and labelling will be carried out by the 
Sponsor according to the randomisation list. Labelling in local language(s) will be applied in 
such a way that it should not obscure the original label, and will report all the information 
requested according to the Annex 13 to the Good Manufacturing Practice (published by the 
Commission in The rules governing medicinal products in the European Community, Volume 
4; 24). 
 
Labelling on packages will report: 
 
a) 
Name, address and telephone number of the sponsor and CRO;  
b) 
Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency;  
c) 
Batch number;  
d) 
Study Nr.;  
e) 
The study subject identification number/treatment number;  
f) 
Expiry in month/year format and in a manner that avoids any ambiguity;  
g) 
Investigator's name;  
h) 
Directions for use;  
i) 
“For clinical trial use only” wording;  
j) 
The storage conditions;  
 
Labels of the individual syringes, prepared at each clinical site out of the sight of the 
anaesthesiologist by a person not involved in any study activity, will report only the patient’s 
randomisation number. Details will be presented in the study manual. 
 
3.3 
Storage conditions 
 
The test product should be stored at 15 - 25°C in a dry locked place, sheltered from light. The 
reference product should be stored at < 30°C and will not be frozen.  
Study kits will be stored at room temperature (15 - 25°C) in a dry locked place, sheltered from 
light, and will not be frozen. 
The storage area will not be accessible to the anaesthesiologist and any other clinical staff 
involved in study assessments. 
 
 


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3.4 
Drug accountability 
 
The test and reference investigational products will be provided directly to the clinical centres 
by the sponsor, in excess of the amount necessary for the study. 
 
After receipt of the investigational products supply, the pharmacist or the person identified as 
the recipient of the study drug supply will confirm in writing by signing and dating standard 
drug accountability forms. 
 
At the end of the study, used, unused and partially used (if applicable) supplies of test and 
reference investigational products provided by the sponsor/manufacturer will either be 
destroyed on site (upon written authorisation) or returned to the sponsor/manufacturer, after 
assessment of drug accountability. 


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4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
This is a prospective, multi-centre, randomised, double-blind, controlled, superiority study. 
 
4.2 
Discussion of design 
 
The study has been designed to evaluate the superiority of chloroprocaine 3% in terms of 
onset of anaesthesia (i.e. time to reach adequate surgical conditions) after epidural 
administration, in comparison to ropivacaine 0.75%, in labouring women undergoing 
unplanned Caesarean section. In designing the study, the following guidelines have been 
taken into consideration: ICH E9 guideline on Statistical principles for clinical trials (21), 
ICH E10 guideline on the choice of control groups (22) and EMA guideline “Points to 
consider on switching between superiority and non-inferiority” (CPMP/EWP/482/99; 23). 
 
A recent meta-analysis of available trials has identified ropivacaine 0.75% or lidocaine 2% 
with epinephrine and bicarbonate as the two potential most optimal epidural solutions (1). 
Lidocaine 2% with epinephrine and bicarbonate solution works slightly faster than 
ropivacaine, with an onset comparable to that of chloroprocaine, but has more breakthrough 
pain than ropivacaine (2). In addition, the disadvantage of the lidocaine solution is that 
preparation time is required to mix bicarbonate, resulting in potential time-delay between 
decision to deliver and actual onset of anaesthesia (3). Therefore the standard of practice in 
the UZ Leuven is 20 mL epidural ropivacaine 0.75% (4). In the meta-analysis by Hillyard et 
al. (1), chloroprocaine 3% was not evaluated because not yet available in Europe for the 
proposed indication. 
 
Ropivacaine HCl 0.75% has thus been chosen as the active control based on the above 
considerations and taking in mind that it is commonly used in Belgium and other European 
countries for epidural anaesthesia in elective and unplanned Caesarean section (see Naropin® 
[Ropivacaine HCl] 0.75% SmPC). 
 
It is expected that chloroprocaine will have a shorter time to onset of anaesthesia than 
ropivacaine. The primary variable has therefore been chosen considering the potential 
advantage of epidural chloroprocaine in emergency surgical procedures (e.g. unplanned 
Caesarean section), where a very rapid onset of anaesthesia is essential in order to have an 
immediate start of the intervention. Chloroprocaine has been previously shown to have a very 
rapid onset of action, of usually 6-12 minutes, depending on the dose and administration route 
(see Investigator’s Brochure).  
 
According to ICH E9 guideline (21), efficacy will be demonstrated by showing superiority to 
the active control treatment in terms of the chosen primary variable which can provide a valid 
and reliable measure of clinically relevant and important treatment benefit in the patient 
population.  
 
The doses of the Test and Reference anaesthetics have been selected on the basis of the doses 
of anaesthetics epidurally administered, used in the common clinical practice. 


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The volume of 20 mL has been chosen on the basis of the paper published by Sanders et al. 
(2) and the standard of practice in UZ Leuven (25). 
However, for safety reasons a smaller volume could be administered if an adequate block has 
been reached with a smaller volume and that the administration of additional anaesthetic 
could result in safety issues for the patient. 
 
The 20 mL dose of test and reference investigational anaesthetic agents will be administered 
as 5 mL plus 15 mL over 3 minutes. This dose regimen will be used in order to achieve 
surgical anaesthesia rapidly, taking into consideration the common clinical practice and the 
medical literature (1, 26, 27). In this way, a delay in establishing the blockade is reduced, 
delay that in the setting of foetal compromise may not be acceptable (28). The one-5 mL 
initial dose before the injection of the remaining dose is deemed sufficient as a test dose, 
considering that in the study population the epidural catheter has already been tested and used 
to provide analgesia.  
 
In the study, before undergoing unplanned Caesarean section, patients have a continuous 
infusion of analgesic through a previously placed epidural catheter for combined spinal-
epidural (CSE) analgesia. For a rapid onset of anaesthesia with both Test and Reference 
products, it is fundamental that the epidural catheter is in place and has been used to maintain 
labour analgesia until anaesthetic injection (26, 27). In this study, maximal allowed time 
between end of analgesic infusion and anaesthetic injection is 10 minutes. 
 
Each patient will be allocated to a treatment arm (chloroprocaine or ropivacaine) according to 
a computer-generated randomisation list. 
 
The study will be double-blind. Neither the Investigator/co-investigators/study nurses 
involved in the clinical study procedures, nor will the patients be aware of the administered 
treatment. Syringes for injection will be prepared out of the sight of the anaesthesiologist (e.g. 
in a curtain cubicle space) by a person not involved in any other study-related activity.  
 
Epidural anaesthesia for unplanned Caesarean section will be performed according to the 
standard hospitals' procedures.  
 
 


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5 
STUDY POPULATION 
 
5.1 
Target population 
 
Healthy labouring women (96, in order to have 48 women in each treatment group), aged ≥ 18 
years, with an epidural catheter in situ undergoing unplanned Caesarean section. 
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
1. Informed consent: Signed written informed consent before inclusion in the study 
(obtained from women fulfilling the criteria, only when effective analgesia has been 
established) 
2. Sex, pregnancy status and age: Labouring women with singleton pregnancy, ≥ 18 years 
old 
3. Epidural catheter: Previously sited epidural catheter 
4. ASA physical status: I-II 
5. Analgesia: Effective analgesia established following combined spinal epidural analgesia 
(CSE) 
6. Term gestation: ≥ 36 weeks 
7. Caesarean section: Unplanned Caesarean section category 2 or 3, according to Lucas 
Classification (4) 
8. Body Mass Index (BMI): ≤ 40 kg/m2 
9. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study. 
 
5.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
1. Physical findings: Clinically significant abnormal physical findings which could interfere 
with the objectives of the study. Contraindications to epidural anaesthesia 
2. ASA physical status: III-V  
3. Further anaesthesia: Patients expected to require further anaesthesia 
4. Epidural catheter: Epidural catheter failure (epidural catheter replacement required or 
inability to provide effective analgesia)  
5. Pregnancy: Labouring women with multiple pregnancy 
6. Caesarean section: Elective Caesarean section 
7. Allergy: ascertained or presumptive hypersensitivity to the active principle and /or 
formulations ingredients; ascertained or presumptive hypersensitivity to the amide and 
ester-type anaesthetics 


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8. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, 
respiratory, skin, haematological, endocrine or neurological diseases that may interfere 
with the aim of the study; ascertained psychiatric diseases, eclampsia, antepartum 
haemorrhage, sepsis, blood coagulation disorders, insulin dependent diabetes mellitus, 
terminal kidney failure 
9. Medications: Medication known to interfere with the extent of regional blocks (see 
chloroprocaine and ropivacaine SmPCs) for 2 weeks before the start of the study  
10. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study, calculated from the first day of the month following the 
last visit of the previous study 
11. Drug, alcohol: history of drug or alcohol abuse2 
12. Plasma cholinesterase: Known plasma cholinesterase deficiency. 
 
5.3.1 
Not allowed treatments 
 
No medication known to interfere with the extent of spinal block (see chloroprocaine and 
ropivacaine SmPCs) will be allowed for 2 weeks before the start of the study and during the 
whole study duration.  
 
5.3.2 
Additional anaesthesia 
 
Any discomfort during surgery will be treated with 6 mL epidural chloroprocaine 3% (T-
group) or 6 mL ropivacaine 0.75% (R-group). If this measure does not provide adequate 
analgesia, intravenous opioids or a general anaesthetic will be given, according to the 
Investigator’s opinion. 
 
5.3.3 
Premedication/sedation 
 
No prophylactic i.v. fluid bolus and no prophylactic vasopressor will be administered. 
 
5.3.4 
Allowed treatments 
 
Phenylephrine 100 µg bolus will be administered to the study subjects in case of hypotension 
(defined as > 10% decrease from baseline systolic pressure). 
Atropine 0.5 mg bolus will be given to the study subjects in case of bradycardia (defined as 
heart rate < 50 bpm). 
Total dose of phenylephrine and total dose of atropine will be decided by the investigator 
depending on the subject’s conditions and will be reported in the CRF.  
Only if needed, patients will receive intravenously Hetastarch solution (or any other 
equivalent isotonic/colloidal solution) and/or plasmalyte solution during and/or at the end of 
surgery, according to the standard hospitals' procedures. 
Allowed concomitant treatments will be reported in the individual CRFs. 
 
                                                 
2 Alcohol abuse is defined as use of alcoholic beverages to excess, above moderate drinking. According to the Dietary 
Guidelines for Americans 2015-2020, U.S. Department of Health and Human Services and U.S. Department of Agriculture, 
moderate drinking is up to 1 drink/day for women and up to 2 drinks/day for men 


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6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 17. 
 
6.1 
Study visits and procedures 
 
The study protocol foresees a screening visit, 1 study treatment for each patient, followed by 
final assessment and follow-up. Study duration will be approx. 2-6 days. A written informed 
consent will be obtained as detailed in § 6.1.1.1 and 14.2. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed by the 1st screened 
subject. The last subject last visit (LSLV) is defined as the final assessment performed by the 
last subject, i.e. the last visit foreseen by the study protocol, independently of the fact that the 
subject is a completer or a withdrawn subject. Additional safety follow-up visits (if needed) 
may be performed after the LSLV. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening - visit 1: day -1 / day 1 
 
 Treatment phase 
 Visit 2 - day 1: anaesthesia and surgery 
 
 Follow-up phase 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 Follow-up visit - day 3±1: Adverse drug reactions check 
 
Details are given below. 
 
6.1.1 
Schedule 
 
6.1.1.1 
Visit 1 - Screening - Day -1 / Day 1 
 
All parturients who receive neuraxial combined spinal-epidural (CSE) labour analgesia will 
be evaluated for study participation according to the inclusion/exclusion criteria above (except 
for inclusion criterion N. 7 and exclusion criteria N. 3 and 4, which will be evaluated at Visit 
2 after the decision to proceed with Caesarean section has been taken). If considered 
potentially eligible, patients will receive oral and written study information on the aims, 
procedures and possible risks of the study and will be asked whether they would like to 
participate in case of an unplanned Caesarean section. This is done following establishment of 
effective analgesia BUT prior to a decision to perform the Caesarean section.  
When consent is confirmed, a screening number will be assigned to the subjects and the 
following baseline characteristics will be recorded for all subjects: demography, physical 


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abnormalities, body weight, height, BMI, vital signs, SpO2, medical/surgical history and 
previous/concomitant medications.  
 
If parturients have agreed to participate in the study, but epidural catheter failure is noted 
during labour analgesia (epidural catheter replacement required or inability to provide 
effective analgesia), patients are excluded from further study participation.  
 
If an unplanned Caesarean section is required, inclusion/exclusion criteria, including inclusion 
criterion N. 7 and exclusion criteria N. 3 and 4, will be confirmed. Eligible patients will be 
randomly assigned to receive one of the two study anaesthetics (see § 8.1), according to the 
assigned randomisation number. The decision to proceed with the Caesarean section will be 
made by an obstetrician/gynaecologist not involved in the study. Indication for Caesarean 
section will be recorded. 
 
Procedures/Assessments 
 
Before decision to proceed with Caesarean section: 
 Obstetric variables 
o 
weeks of gestation 
 Explanation to the subject of study aims, procedures and possible risks when subject’s 
analgesia has been established 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data 
 ASA physical status assessment 
 Physical abnormalities 
 Body weight, height, BMI  
 Medical/surgical history 
 Previous/concomitant medications 
 Vital signs and SpO2 (baseline assessment) according to the standard hospitals' 
procedures 
 Inclusion/exclusion criteria evaluation, except for inclusion criterion N. 7 and exclusion 
criteria N. 3 and 4, which will be evaluated after the decision to proceed with Caesarean 
section has been taken 
 Potential eligibility evaluation 
 
After decision to proceed with Caesarean section has been taken: 
 Obstetric variables 
o indication for Caesarean section (4) 
 Inclusion/exclusion criteria evaluation, including inclusion criterion N. 7 and exclusion 
criteria N. 3 and 4 
 Eligibility evaluation 
 Enrolment and randomisation 
 Maternal AEs monitoring 
 
 


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6.1.1.2 
Visit 2 - day 1 
 
The investigational epidural anaesthetic must be administered within 10 minutes of the end of 
the analgesia. If the time between the end of the previously established analgesia and the start 
of the anaesthetic epidural injection is > 10 min, the patient will be excluded from the study.  
Prior to epidural injection, the patient will be transferred to the operating theatre and standard 
safety monitoring will be applied according to the standard hospitals' procedures (§ 7.3). 
Baseline pain and the pre-existing (baseline) level of sensory block (loss of cold sensation 
only) and motor block (Bromage score) will be assessed. Also an aspiration test of the 
epidural catheter will be performed. No prophylactic i.v. fluid bolus and no prophylactic 
vasopressor will be administered. 
 
The epidural investigational anaesthetic solution, and the additional 6 mL if needed (see 
below), will be administered using a standardised approach, according to the standard 
hospitals' procedures, as described in § 3.1.2 and 3.1.3.  
The anaesthesiologist(s) administering the anaesthetic and collecting study-related data will 
be blinded with respect to the treatment given to each patient.  
 
Sensory block will be assessed as described in § 7.6.1. Surgery will start when time to achieve 
cold sensation to T4 is achieved.  
Motor block will be assessed prior to incision and after surgery using a modified Bromage 
scale (§ 7.6.2).  
 
Any discomfort or pain or any other adverse effects during surgery will be noted as described 
in § 7.4. First breakthrough pain will be assessed by the patient using a 0-10 cm VAS and 
noted. Any discomfort or pain (reported by the patient) during surgery will be treated with 6 
mL epidural chloroprocaine 3% (T-group) or 6 mL ropivacaine 0.75% (R-group) If this 
measure does not provide adequate analgesia, intravenous opioids or a general anaesthetic 
will be given according to the Investigator’s opinion.  
 
Before, during and after surgery, all adverse events will be recorded (§ 7.4). Only if needed, 
patients will receive intravenously Hetastarch solution (or any other equivalent 
isotonic/colloidal solution) and/or plasmalyte solution during and/or at the end of the surgery, 
according to the standard hospitals' procedures. 
 
Procedures/Assessments 
 
 Pre-existing CSE analgesia details 
o 
duration of labour - CSE (as hours) 
o 
pain assessed using a 0-10 cm VAS (0=no pain, 10=most severe pain imaginable) 
o 
total dose of local analgesic used during labour 
o 
pre-existing (baseline) level of sensory block (loss of cold sensation only) and motor 
block (Bromage score) 
 Epidural anaesthesia administration 
 Sensory block assessment (during surgery every 2 min, as much as possible without 
disturbing the surgical procedure, and after surgery) 
 Motor block assessment (before incision and after surgery) 


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 Standard maternal vital signs, SpO2 and ECG monitoring, according to the standard 
hospitals' procedures 
 Caesarean section 
 Discomfort and pain during surgery 
 First breakthrough pain (VAS) 
 Maternal AEs with particular attention to pain, pruritus, nausea and vomiting 
 Only if needed, iv administration of Hetastarch solution (or any other equivalent 
isotonic/colloidal solution) and plasmalyte solution according to clinical practice 
 Concomitant medications recording, as applicable, particularly intravenous opioids or 
general anaesthetic (for pain and discomfort during surgery), phenylephrine (for 
hypotension) and atropine (for bradycardia) 
 
Details on the surgery (if performed, start time, end time and any other relevant information) 
and need for fluids (if performed, type of administered solution, administration start time, 
administration end time, administered volume) will be recorded.  
 
6.1.1.3 
Final assessments (Final visit, day 1 or early termination visit) 
 
At the end of the surgical procedure, patients will stay in the post-operative recovery room 
until the criteria for discharge are met according to the hospitals’ standard procedures (see § 
7.7). The following activities/procedures will be performed: 
 
 Patients moved to post-recovery room (after surgery) 
 Maternal vital signs and SpO2 according to the hospitals' procedures 
 Pain at the site of surgery (0-10 cm VAS) 
 Pain at the site of epidural injection (0-10 cm VAS) 
 Quality of the block assessed between 10 and 20 min after the end of surgery by the 
anaesthesiologist and patient together (0-10 cm VAS) 
 Neonate Apgar scores 
 Umbilical artery and venous blood gases 
 Maternal AEs, in particular pain (see above), pruritus, nausea and vomiting 
 Neonatal AEs 
 Concomitant medications 
 Transfer to hospital room, if criteria for discharge from the post-operative recovery room 
are met 
 
6.1.1.4 
Follow-up visit (day 3±1) 
 
The investigator or a deputy of the investigator, not aware of the treatment administered, will 
question the patients about adverse events and in particular any adverse reactions. 
 
Procedures/Assessments 
 Maternal and neonatal adverse events, in particular adverse drug reactions 
 Concomitant medications 
 
 


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6.2 
Diet and lifestyle 
 
On Day 1, patients will be under fasting conditions before surgery. Clear fluids intake is 
allowed if needed. The patients will remain under fasting conditions according to the 
investigator’s opinion.  
 


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7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Demography and baseline characteristics 
 
During screening and before/after randomisation, the following data will be recorded: 
Before randomisation: 
 Demographic variables: age, height, weight, BMI 
 Obstetric variables: weeks of gestation, indication for Caesarean section (4) 
After randomisation: 
 Pre-existing CSE analgesia details:  
o 
duration of labour - CSE (as hours),  
o 
pain assessed using a 0-10 cm VAS (0=no pain, 10=most severe pain imaginable), 
o 
total dose of local analgesic used during labour,  
o 
pre-existing (baseline) level of sensory block (loss of cold sensation only) and motor 
block (Bromage score) (see below) 
 
7.2 
Physical examination  
 
A physical examination, including evaluation of the physical status according to ASA general 
relative values, will be performed at the visit 1 (screening visit).  
 
7.3 
Standard safety monitoring 
 
Subjects’ blood pressure, heart rate and pulse oximetry (SpO2) will be measured and recorded 
at baseline.  
 
Patient’s safety monitoring (electrocardiography, pulse oximetry and non-invasive blood 
pressure and pulse rate) will be performed from start to end of surgery according to the 
hospitals' standard procedures.  
 
Clinically significant values will be reported as adverse events and treated according to the 
standard clinical practice. In particular, hypotension (defined as > 10% decrease from baseline 
systolic blood pressure) will be treated with 100 µg phenylephrine bolus and bradycardia 
(defined as heart rate < 50 bpm) with atropine 0.5 mg bolus.  
 
7.4 
Assessment of treatment-emergent adverse events 
 
For the definition of adverse events (AEs) and treatment-emergent adverse events (TEAEs) 
please refer to § 11. 
 
Maternal AEs will be assessed throughout the study from the signature of the informed 
consent up to the final visit/ETV.  
 


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Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures (see § 7.3).  
 
Particular attention will be given to the occurrence of pain and discomfort during surgery and 
to the occurrence of pruritus, nausea and vomiting.  
Any discomfort or pain or any other adverse effects reported by the patient spontaneously or 
upon Investigator’s soliciting before, during or after surgery, will be noted.  
 
Any discomfort during surgery will be treated with 6 mL epidural chloroprocaine 3% (T-
group) or 6 mL ropivacaine 0.75% (R-group). If this measure does not provide adequate 
analgesia, intravenous opioids or a general anaesthetic will be given, according to the 
Investigator’s opinion.  
 
Maternal systemic and local toxicity symptoms, neurological symptoms and allergic reactions 
will be monitored throughout the study.  
 
Neonatal AEs, if applicable, will also be recorded and reported in the respective mother CRF. 
 
7.5 
Discomfort and pain assessment 
 
Pain assessed during or after surgery through spontaneous patient’s reporting and questioning 
by the Investigator/anaesthesiologist will be reported as adverse event (see § 7.4). 
 
Pre-existing pain, first breakthrough pain, pain at the site of surgery at final visit/early 
termination visit and pain at the site of epidural injection at final visit/early termination visit 
will be assessed by the patient using a 0-10 cm VAS (0=no pain, 10=most severe pain 
imaginable). 
 
The following grading system will be used: 
 
0 cm ≤ VAS ≤ 3 cm  
=> 
No adverse event 
3 cm < VAS ≤ 5 cm  
=> 
Adverse event with severity 'Mild' 
5 cm < VAS ≤ 8 cm  
=> 
Adverse event with severity 'Moderate' 
8 cm < VAS ≤ 10 cm  
=> 
Adverse event with severity 'Severe' 
 
The verbatim descriptions of the pain adverse events related to the VAS assessment will be 
consistent with the assessment time points and locations (i.e. pre-existing pain, first 
breakthrough pain, pain at the site of surgery, pain at the site of injection). 
 
Time of first breakthrough pain will be noted and reported into the CRF. 
 
7.6 
Block assessment 
 
7.6.1 
Sensory block 
 
The primary outcome measure is the time to onset of anaesthesia, also defined as time to 
reach adequate surgical conditions.  
 


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Onset of anaesthesia, i.e. adequate conditions for surgery, is defined as complete loss of cold 
sensation to the metameric level T4, bilateral.  
As a secondary outcome measure, the time to complete loss of touch sensation (pinprick and 
light touch) to the metameric level T5, bilateral, will be assessed. 
 
Cold sensation will be verified using an ethyl chloride swab. Touch sensation will be assessed 
as pinprick touch sensation and light touch sensation using an ethyl chloride swab.  
 
Presence/complete absence of sensation with the three testing modalities (cold, pinprick and 
light touch) will be recorded. Complete absence of sensation will be scored as 0, presence of 
sensation will be scored as 1. 
 
The pre-existing (baseline) level of sensory block (loss of cold sensation only) will be 
assessed and recorded.   
 
The block will be assessed after 2 min from the administration of the first 5 mL epidural 
anaesthetic bolus. Sensory block will be assessed again after 2 min from the administration of 
the remaining 15 mL epidural anaesthetic and then every 2 minutes, using cold, pinprick and 
light touch, as much as possible also during surgery, without disturbing the surgical 
procedure. Sensory block will also be assessed after surgery end.  
 
Time to complete loss of cold sensation to T4 and to complete loss of touch sensation 
(pinprick and light touch) to T5 will be calculated from T0 which is defined as the time of the 
start of the first epidural anaesthetic injection. 
 
In addition, maximum metameric level of the sensory block will be assessed with the three 
modalities (cold, pinprick, touch), as far as possible without disturbing the surgical procedure, 
and recorded in the CRF.  
 
7.6.2 
Motor block 
 
Motor block will be assessed at baseline, before Caesarean incision and after surgery, using a 
modified Bromage scale (1=complete motor block (unable to move feet or knees; 2=almost 
complete block (able to move feet only); 3=partial block (just able to move knees); 
4=detectable weakness of hip flexion (between scores 3 and 5); 5=no detectable weakness of 
hip flexion while supine (full flexion of knees); 6=able to perform partial knee bend). Motor 
block scores will be reported in the CRF. 
 
7.6.3 
Quality 
 
Quality of the block will be assessed between 10 and 20 min postoperatively by the 
anaesthesiologist and patient together using a 0-10 cm visual analogue scale (VAS; 
10=excellent anaesthetic quality, 0=very poor anaesthetic quality) 
 
7.7 
Final assessments 
 
At the end of the surgical procedure, patients will stay in the post-operative recovery room 
until the criteria for discharge are met according to the hospitals’ standard procedures. Vital 


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signs and SpO2 will be recorded according to the standard hospitals' procedures. Pain at the 
site of injection and pain at the site of surgery will be assessed using a 0-10 cm VAS. 
 
Neonatal Apgar scores at 1 and 5 minutes and umbilical artery and venous blood gases 
(partial pressure of carbon dioxide [pCO2], partial pressure of oxygen [pO2], acidity [pH], 
base excess [BE]) will be recorded. 
 
Patients will be asked about any adverse events. Neonatal adverse events will also be recorded 
and reported in the respective mother CRF. If all the criteria are met and no adverse reactions 
occur, the patient and neonate will be transferred to a hospital room according to the hospitals' 
standard procedures. 
 
7.8 
Follow-up assessments 
 
On day 3±1, the investigator or a deputy of the investigator, not aware of the treatment 
administered, will question the patients about adverse events and in particular any adverse 
reactions which might have occurred after the final visit, with particular attention to any sign 
of late systemic toxicity, local toxicity, neurological symptoms (e.g. paraesthesia, motor 
function problems and pain at the injection site) and allergic reactions. Concomitant 
medications, if any, will be recorded. Neonatal adverse events will be also assessed. 


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8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomisation 
 
The enrolment will be competitive. A block randomization scheme will be created for each 
centre. A new version of the randomisation list (version 5.0), containing the randomisation 
scheme for patients still to be enrolled at centre 001 and for all patients of centres 002, 003, 
and 004, will be released. 
The randomisation lists versions 1.0 and 2.0 were related to centre 1 and included patients 
already enrolled at the time of the amendment, while randomisation lists version 3.0 and 4.0 
have been withdrawn. 
 
All the lists were computer generated by the Biometry Unit of the Clinical Contract Research 
Organization (CRO), using the PLAN procedure of the SAS® system version 9.3 (TS1M1) 
(26). The randomisation lists will be attached to the final clinical study report. 
 
8.2 
Treatment allocation 
 
At each clinical centre, patients will be allocated to the Test (Chloroprocaine) arm or 
Reference (Ropivacaine) arm in a 1:1 ratio according to the applicable study randomisation 
list and to a competitive enrolment.  
 
Randomisation number will be given to the patients on study day 1 and will be used to 
allocate each patient to a treatment group, as detailed above. The vials/ampoules with the 
investigational products will be numbered. Each vial/ampoule will be assigned to the patients 
according to the corresponding randomisation number. 
 
The randomisation numbers will be 3 digits numbers with the structure [C] [NN], where [C] 
(0, 2, 3, 4) indicates the centre (0 for centre 001, like all the patients already enrolled at site 
001), and [NN] is a unique progressive number within centre (e.g. 001, 002, .., 201, 202,…, 
301, 302,…., 401, 402,…). 
 
8.3 
Blinding 
 
This is a double-blind study. Both the Investigator and the patients will not be aware of the 
treatment administered. 
 
Three (3) copies of the lists were generated and sealed in individual envelopes: 
 one copy was sent to the manufacturer for the preparation of the individual treatment 
boxes 
 one copy is kept at the CRO Quality Assurance Unit 
 one copy is stored in the statistical study file 
 
Neither the members of the clinical staff nor the CPL or the CRA/monitor, monitoring the 
study evaluations and procedures, will have access to the randomisation code.  


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Only the person(s) preparing the syringe (and not involved in any other study procedure) and 
the CRA/monitor who performs the drug accountability will be aware of the administered 
treatments. 
The CRO will open the envelope containing the randomisation list only when data-entry is 
complete and decisions to be made in blinding, before data analysis, are final.  
 
The CRO will notify breaking of the randomisation list to the sponsor. 
 
At each clinical centre, syringes for injection will be prepared by a person not involved in any 
other study activity out of the sight of the investigator/anaesthesiologist administering the 
investigational products. The anaesthesiologist(s) administering the IMP will be under blind 
conditions and will receive the masked syringe for administration. 
 
8.3.1 
Emergency code and unblinding procedures 
 
Unblinding of the code for specific patients will be fully documented in the source 
documents, in the CRFs and in the clinical study report. 
 
8.3.2 
Individual emergency envelopes 
 
The emergency envelopes containing the individual randomisation codes will be sent to the 
clinical centres. 
 
The randomisation code will be filed in the investigator’s study file in a sealed envelope for 
each patient, with the key for its identification. Copies of the individual emergency envelopes 
were sent to the pharmacovigilance representative of the sponsor. 
Inside each envelope, the individual randomisation code is clearly indicated, reporting the 
allocated treatment. 
 
Breaking of an individual randomisation code during the study is allowed only when 
knowledge of the code is essential for the patient's health. In this case, only the envelope 
related to the concerned subject will be opened. Individual code breaking will be clearly 
reported in the patient CRF and on the envelope; the latter is sealed again. 
In any case, the monitor must be informed within 24 h from code breaking. 
 
The date and the reason for breaking the code must be recorded in the CRF and on the 
envelope. All envelope sets containing the randomisation code of each patient must be kept 
closed even after database lock. At the end of the study, all envelope sets will be sent to the 
sponsor. 
 
8.3.3 
Individual kit replacement envelopes 
 
The clinical centres will also receive individual kit replacement envelopes. If a reserve kit 
needs to be used, the kit replacement envelope will be opened and the injectable solution will 
be prepared, out of the sight of the investigator/anaesthesiologist administering the 
investigational products, by a person not involved in any other study activity in such a way 
that the double-blind condition of the study is maintained. The date and the reason for 


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opening the kit replacement envelope will be recorded on the envelope and then the envelope 
will be sealed again. 
 
All kit replacement envelope sets must be kept closed even after database lock. At the end of 
the study, all envelope sets will be sent to the sponsor. 
 
 
 
 


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9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary efficacy variables 
 
 Time to onset of anaesthesia (i.e. time to reach adequate surgical conditions), defined as 
time from T0 to complete loss of cold sensation to the metameric level T4 (block to T4), 
bilateral 
 
9.1.2 
Secondary efficacy variables 
 
 Time from T0 to loss of touch sensation (pinprick and light touch) to the metameric level 
T5 (block to T5), bilateral 
 Quality of the block assessed between 10 and 20 min postoperatively by the 
anaesthesiologist and patient together using a 0-10 cm visual analogue scale (VAS; 
10=excellent anaesthetic quality, 0=very poor anaesthetic quality) 
 Maximum metameric level of the sensory block assessed by three modalities (complete 
loss of cold, pinprick and light touch sensation) 
 Motor block assessment (modified Bromage scale) at baseline, prior to incision and after 
surgery 
 Proportion of patients who need top-up epidural anaesthesia (same anaesthetic as first 
epidural injection)  
 Proportion of patients who need supplementation of the block intraoperatively with 
intravenous opioids or general anaesthesia 
 Proportion of patients who need general anaesthesia 
 
9.1.3 
Safety variables 
 
 Discomfort and pain assessed during surgery through spontaneous patient’s reporting and 
questioning by the Investigator/anaesthesiologist 
 First breakthrough pain assessed by the patient, recorded on a 0-10 cm VAS (0=no pain, 
10=most severe pain imaginable) 
 Treatment-emergent adverse events, with particular attention to pain (see above, pruritus, 
nausea, vomiting 
 Maternal vital signs, pulse rate, pulse oximetry (SpO2) and electrocardiogram, monitored 
from baseline to end of surgery according to the hospitals' standard procedures 
 Total dose of phenylephrine and total dose of atropine 
 Total volume of intravenous fluids 
 Neonatal Apgar scores at 1 and 5 minutes 
 Umbilical artery and venous blood gases (partial pressure of carbon dioxide [pCO2], 
partial pressure of oxygen [pO2], acidity [pH], base excess [BE]) as an indication of 
foetal hypoxic stress 
 Pain at the site of surgery at final visit/early termination visit, recorded on a 0-10 cm 
VAS (0=no pain, 10=most severe pain imaginable) 
 Pain at the site of epidural injection at final visit/early termination visit, recorded on a 0-
10 cm VAS (0=no pain, 10= most severe pain imaginable) 
 Concomitant medications 


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 Neonatal adverse events. 
 
9.2 
Efficacy assessments 
 
9.2.1 
Efficacy parameters 
 
Efficacy assessments are based on the primary and secondary efficacy variables listed in § 
9.1.1 and 9.1.2 above. Assessment procedures are detailed in § 7. 
 
9.3 
Safety assessments 
 
Patients will be questioned about the occurrence of treatment-emergent adverse events 
(TEAEs) throughout the study. Particular attention will be given to the occurrence of pain and 
discomfort during surgery and also to the occurrence of pruritus, nausea and vomiting. 
Neonatal adverse events will also be assessed. Further details on the AE assessments are 
given in § 7.4.  
 
Vital signs, ECG and SpO2 will be monitored as detailed in § 7.3. Occurrence of clinically 
relevant hypotension or bradycardia will be monitored throughout the surgical procedure.  
 
Neonatal Apgar scores will be evaluated at 1 and 5 minutes according to the standard 
hospitals' procedures. Umbilical artery and venous blood gases (partial pressure of carbon 
dioxide [pCO2], partial pressure of oxygen [pO2], acidity [pH], base excess [BE]) will be 
assessed, according to the common clinical practice, as an indication of foetal hypoxic stress. 
 
Pain at the site of surgery and pain at the site of epidural injection at final visit/early 
termination visit, recorded on a 0-10 cm VAS (0=no pain, 10=most severe pain imaginable). 
 
Concomitant medication intake, particularly intravenous opioids or general anaesthetic (for 
pain and discomfort during surgery), phenylephrine (for hypotension) and atropine (for 
bradycardia), will be recorded. 
 
 


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10 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. arithmetic mean, SD, CV (%), minimum, 
median and maximum values for quantitative variables, and frequencies for qualitative 
variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis will be 
performed using SAS® system version 9.3 (TS1M1) (26) or higher for Windows (the version 
will be stated in the final clinical study report). 
 
10.1 
Analysis Sets 
 
10.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if she meets all the inclusion/exclusion criteria. 
Otherwise she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if she is included into the treatment phase of 
the study. The enrolment will be performed through randomised allocation to a treatment arm. 
A subject will be defined as randomised in the study when she is assigned to a randomised 
treatment arm. 
 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics. 
 Full Analysis set (FAS): all randomised patients who fulfil the study protocol 
requirements in terms of study anaesthetic administration, i.e. patients who are 
administered the whole scheduled volume (at least 20 mL) and who are not discontinued 
due to time between the end of the previously established analgesia and the start of the 
anaesthetic epidural injection > 10 minutes (see § 10.1.2). Missing values of time to onset 
of anaesthesia will be replaced with the highest time to onset of anaesthesia detected in 
the corresponding treatment group. This analysis set will be used for the primary efficacy 
analysis. 
 Per Protocol set (PP): all randomised patients who 1) fulfil the study protocol 
requirements in terms of study anaesthetic administration, i.e. patients who are 
administered the whole scheduled volume (at least 20 mL, administered as 5 + 15 mL), 
for whom time between the end of the previously established analgesia and the start of 
the anaesthetic epidural injection is ≤ 10 minutes (see § 10.1.3) and 2) fulfil the study 
protocol requirements in terms of primary efficacy evaluation (time to onset of 
anaesthesia), with no major deviations that could affect the primary efficacy results. This 
analysis set will be used for sensitivity analysis. 
 Safety set: all patients who receive at least one dose of the investigational medicinal 
product. This analysis set will be used for the safety analyses 
 


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Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Enrolled 
set, FAS, PP set and Safety set. Subjects will be evaluated according to the treatment they are 
assigned to (Enrolled set, FAS) and according to the treatment they actually receive (PP set 
and Safety set). 
 
10.1.2 
Reasons for exclusion from the Full Analysis Set  
 
Reasons for the exclusion from the Full Analysis Set are the following: 
 
discontinuation due to failure to be administered the whole scheduled volume according 
to the scheduled regimen (at least 20 mL) of the investigational product 
 
discontinuation due to time between the end of the previously established analgesia and 
the start of the anaesthetic epidural injection > 10 minutes 
 
failure to satisfy major inclusion/exclusion criteria (eligibility violations). Subjects who 
fail to satisfy an inclusion/exclusion criterion may be excluded from the analysis without 
the possibility of introducing bias only under the following circumstances: 
• 
the inclusion/exclusion criterion was measured prior to enrolment 
• 
the detection of the relevant eligibility violations can be made completely objectively 
• 
all subjects receive equal scrutiny for eligibility violations (blind review) 
• 
all detected violations of the particular inclusion/exclusion criterion are excluded 
 
10.1.3 
Reasons for exclusion from the Per Protocol set 
 
Reasons for the exclusion from the Per Protocol set include the following: 
 
failure to be administered the whole scheduled volume according to the scheduled 
regimen (at least 20 mL as 5 + 15 mL) of the investigational product 
 
time between the end of the previously established analgesia and the start of the 
anaesthetic epidural injection > 10 minutes 
 
exposure to an investigational product different from the one assigned to the subject 
 
missing primary efficacy data 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
 
10.2 
Sample size and power considerations 
 
To calculate the required study sample size, results from a previous study with Ropivacaine 
0.75% (2) were taken into consideration. In this study the mean time to onset of anaesthesia 
(OA) of Ropivacaine 0.75% was estimated to be approximately 10 minutes. Time to OA was 
modelled with a positive right-skewed gamma distribution. Assuming an expected difference 
between Test group and Reference group of μT-μR = -5 minutes (i.e. a decrease from 10 
minutes to 5 minutes), and nT = nR, a sample size of 44 subjects in each group will have a 
power of 90% with a 0.050 two-sided significance level. Sample size was calculated using 
nGLM.r’. R code (30).  
 


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Forty-eight (48) subjects per group will be enrolled (for a total of 96 subjects) in order to have 
at least 44 subjects per group in the Full Analysis Set 
 
10.3 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data (e.g. race) will be summarised in contingency tables. Quantitative data 
(e.g. body weight, height, BMI) will be summarised using classic descriptive statistics. 
 
10.4 
Analysis of efficacy parameters 
 
Gamma Generalized Linear models (GLMs) with clustered robust error will be used to 
analyse the time to onset of anaesthesia. Marginal means and 95% confidence interval of the 
difference between the two groups will be reported. Centre will be considered as cluster in the 
model. 
 
The primary analysis will be performed on the FAS and the alpha level will be set at 0.05.  
 
A sensitivity analysis will be performed on the PP set, keeping the same alpha level of the 
primary analysis.  
 
When applicable and relevant, secondary endpoints will be compared between the two 
treatment groups using non-parametric tests (Wilcoxon rank-sum test, Chi square test or 
Fisher exact test) with a nominal alpha level of 0.05. No corrections for multiple testing are 
considered for the secondary endpoints; hence a strong claim will be possible only for the 
primary endpoint. 
 
10.5 
Safety and tolerability evaluation 
 
10.5.1 
Adverse events 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of IMP and not worsening after the first 
dose of IMP 
 TEAEs: all AEs occurring or worsening after the first dose of IMP 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC 
and PT, seriousness, relationship to treatment and severity. For TEAEs that change severity 
during the study (e.g. from mild to moderate or from moderate to mild), the more severe 
intensity will be reported in the summary tables. 
Maternal and neonatal AEs will be listed and summarised in separate listings and tables. 
 


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10.5.2 
Physical examination 
 
Date of the physical examination, overall investigator’s interpretation (as normal [N], 
abnormal not clinically significant [NCS] or abnormal clinically significant [CS]), clinically 
significant abnormalities (if any) and the ASA physical status will be reported in the CRF and 
listed. 
 
10.5.3 
Discomfort and pain assessment 
 
Discomfort and pain reported by the patients during the study will be reported as AEs. 
 
First breakthrough pain 0-10 cm VAS values will be listed in the clinical study report and 
summarised by treatment using descriptive statistics. 
 
Pain at the site of surgery and pain at the site of epidural injection at final visit/early 
termination visit, recorded on a 0-10 cm VAS (0=no pain, 10=most severe pain imaginable) 
will be listed in the clinical study report and summarised by treatment using descriptive 
statistics. 
 
10.5.4 
Vital signs and ECG 
 
Clinical significant findings during maternal standard monitoring and any other assessment of 
vital signs (blood pressure, heart rate, SpO2) and ECG will be reported in the CRF and listed 
in the clinical study report. Baseline (screening) and final/early termination values of vital 
signs (if applicable) will be summarised by descriptive statistics.  
 
10.5.5 
Baby assessment 
 
Individual neonatal Apgar scores at 1 and 5 minutes and umbilical artery and venous blood 
gases (pCO2, pO2, pH, BE) will be listed. 
 
10.5.6 
Concomitant medication 
 
Individual intake of any medication during the study other than the IMPs will be listed. 
Particularly, individual total dose of intravenous opioids, general anaesthetic (administered 
for pain and discomfort during surgery), phenylephrine (administered for hypotension), 
atropine (administered for bradycardia) and total volume of intravenous fluids will be listed. 
 


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11 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
11.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the CRO SOPs, based upon 
applicable local and international regulations, with a minor deviation due to the present study 
design. In the study, AEs will be monitored from the confirmation of study enrolment (see § 
11.3) and not from the signature of the informed consent, as specified in the SOP.  
In addition the CRO SOP does not cover the management of neonatal AEs, which in the 
present study will be monitored from birth to final assessment (see below) and will be 
managed as the AEs occurring to study participants, according to CRO SOP. Neonatal AEs, if 
applicable, will be reported on the corresponding mother CRF and each AE will be reported 
as being "Maternal" or "Neonatal" in order to allow a correct classification of the AEs. 
 
The full SOP or an operative summary will be made available to the clinical centres. 
 
A brief summary of AE definition, classification and management is reported below. 
 
11.2 
Definitions 
 
 Adverse event (AE) 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with treatment. 
 
 Adverse Drug Reaction (ADR) 
Any noxious and unintended response to a medicinal product (i.e. a causal relationship 
between a medicinal product and an AE is at least reasonably possible in the investigator's or 
sponsor's opinion, the relationship cannot be ruled out) resulting not only from the authorised 
use of a medicinal product at normal doses, but also from medication errors and uses outside 
the terms of the marketing authorisation, including the misuse and abuse of the medicinal 
product. 
 
 Pre-treatment AE (PTAE) 
Pre-treatment AEs are defined as any AEs occurring before the first dose of a medicinal 
product and not worsening after the first dose. The following medical occurrences and clinical 
investigations are the only clinically significant events which, according to the investigator 
judgement, can be defined and recorded as PTAEs: 
 trauma (fractures, sprains, strains, falls, domestic accidents, car accidents, etc.) 
occurred after the signature of the informed consent and before the first medicinal 
product administration 
 new measurements (vital signs, ECG, laboratory parameters, etc.), performed after the 
signature of the informed consent and before the first medicinal product 
administration, which show a clinically significant worsening in comparison with a 
previous (baseline) measurement performed after the signature of the informed 
consent 


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 any disease diagnosed after the anamnesis recorded at visit 1 and before the first 
medicinal product administration  
 physical and mental status changes (pre-syncope, anxiety, dizziness, fainting, etc.) 
occurred after the signature of the informed consent and before the first medicinal 
product administration 
 
 Treatment-emergent AE (TEAE) 
Treatment-emergent AEs (TEAEs) are defined as any AEs occurring or worsening after the 
first dose of a medicinal product. 
 
 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event that may jeopardize the subject’s health status or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are cancer, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse 
 
 Unexpected ADR: an ADR the nature or severity of which is not consistent with the 
Reference Safety Information (RSI) 
 
 Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, the Investigator’s Brochure (IB) for the Test and the SmPC for the Reference 
product will be used. 
 
 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An ADR that is both unexpected (not consistent with the RSI) and also meets the definition of 
a SAE. 
 
11.3 
AEs monitoring window 
 
Study patient: 
 Start of monitoring: from the confirmation of study enrolment (after informed consent 
signature, decision to proceed with the Caesarean section and confirmation of eligibility)  
 End of monitoring: Follow-up 
Neonate: 
 From after birth until Follow-up 
AEs occurring to babies after birth will be reported in the respective mother’s CRF as detailed 
above.  


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An AE occurring after the final visit/ETV and coming to knowledge of the investigator (e.g. 
by spontaneous reporting by study subjects) must be recorded only if it is an ADR, according 
to the investigator’s judgment. 
 
11.4 
AEs recording 
 
All maternal AEs derived by spontaneous, unsolicited reports of the subjects, by observation 
and by routine open questioning should be collected and reported. In addition, all neonatal 
AEs derived by observation and by predefined assessments, if applicable, 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 
centres) in the source documents and later transcribed into the CRF: 
 
1. 
Adverse Event: progressive number of the adverse event  
2. 
Description: verbatim description of the adverse event or  
 
Follow-up: progressive number of follow-up of the adverse event  
3. 
AE type: Maternal or Neonatal 
4. 
Start Date/Time: start date/time of the adverse event or  
 
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 
7. 
Whether the adverse event start before or after the first intake of the study drug or 
whether the adverse event has worsened or not after the first intake of the study drug 
8. 
Last Study Drug Administration Date/Time Before Onset: if the adverse event started 
after the first administration of the study drug, the date/time of last administration of the 
study drug before the onset of the adverse event or 
Last Study Drug Administration Date/Time Before Worsening: In case of treatment 
emergent adverse event, the date/time of the last administration of the study drug(s) 
before the worsening of the adverse event.  
9. 
Investigator's opinion about the reasonable possibility of a causal relationship with the 
study drugs.  
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  


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14. 
Action Taken with Study Drug: describes changes to the study drug as a result of the 
event. It is specifically for actions taken with the study drug 
• 
1 Dose Not Changed 
• 
2 Dose Increased 
• 
3 Dose Reduced 
• 
4 Drug Interrupted (i.e. temporary stop) 
• 
5 Drug Withdrawn (i.e. definitive stop) 
• 
6 Not Applicable (e.g. drug administration not started yet or completed) 
• 
7 Unknown 
15. 
Concomitant Therapy: if a concomitant therapy is given, it must be reported in the 
specific CRF forms 
16. 
Study Discontinuation: if the adverse event cause the subject to be discontinued from 
the study 
17. 
Other Action Taken: other actions taken as a result of the event that are unrelated to 
dose adjustments of study drug 
18. 
Outcome: Outcome of the event 
• 
1 Recovered/Resolved 
• 
2 Recovered/Resolved With Sequelae 
• 
3 Recovering/Resolving 
• 
4 Not Recovered/Not Resolved 
• 
5 Fatal 
• 
6 Unknown 
 
11.5 
SAEs reporting 
 
The investigator must report to the sponsor any SAE within 24 h of becoming aware of the 
event. The Investigator, within the same timeframe, should also inform the study monitor and 
the CRO. The investigator shall notify the competent Ethics Committee (EC) within 7 days of 
any SAE with lethal outcome occurred during a study. If the Investigator is initially unable to 
obtain all the necessary details for completing the form, he 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 assessment. In case of disagreement, both the 
opinion of the investigator and the sponsor should be provided in the report. 
The sponsor will evaluate the SAE expectedness on the basis of the RSI. 
 
 


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11.6 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the sponsor (defined as 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 EudraCT number 
 Sponsor study number 
 One identifiable coded subject 
 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). 
 
11.7 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting when they might materially alter the 
current benefit-risk assessment of a medicinal product or would be sufficient to consider 
changes in the medicinal product administration or in the overall conduct of the trial, for 
instance: 
 single case reports of an expected serious adverse reaction with an unexpected 
outcome (e.g.: a fatal outcome) 
 an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
 post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the investigator by the subject. 
 new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
− a SAE which could be associated with the trial procedures and which could modify 
the conduct of the trial 
− a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) or from other clinical trials. 
 
 


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11.8 
SAEs: contacts 
 
SAEs must be reported on SAE reporting forms and faxed WITHIN 24 H to the Corporate 
Drug Safety Unit of the sponsor - contact details below: 
 
 
 
 
 
 
 
Fax: 
+41(0)91.646.85.61 
Phone: +41(0)91.640.42.50 
Email:  Corporate_drug_safety@sintetica.com 


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12 
DATA MANAGEMENT PROCEDURES 
 
12.1 
Data collection - CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the CRFs. He/she must also check that the data reported in the CRFs correspond to 
those in the subject’s source documents.  
To ensure legibility, the CRFs should be filled out in English, in block capitals with a ball-
point pen (not pencil, felt tip or fountain pen). Any correction to the CRFs' entries must be 
carried out by the investigator or a designated member of staff. Incorrect entries must not be 
covered with correcting fluid, or obliterated, or made illegible in any way. A single stroke 
must be drawn through the original entry. Corrections have to be dated and initialled. In the 
interest of completeness of data acquisition, the questions which are repeated in each section 
of the CRFs should be answered in full, even if there are no changes from a previous 
examination. The investigator must provide a reasonable explanation for all missing data. 
The CRFs will be completed, signed by the investigator, sent to the CRO Biometry Unit for 
data management procedures and finally sent to the sponsor.  
 
12.2 
Unique subject identifier 
 
All the subjects who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains 
of the CDISC SDTM model. The unique subject identifier consists of the sponsor study code 
(i.e. CHL.3/01-2016), the 3-digit site number (e.g. 001, 002, 003, 004), the 4-digit screening 
number (e.g. S001, S002, etc.) and, if applicable, the 3-digit subject randomisation number 
(e.g. 001, 002, etc.). Study code, site number, screening number and subject randomisation 
number are separated by slashes (“/”). The last 8 digits of the unique subject identifier 
(enrolled subjects), corresponding to the subject screening and randomisation numbers 
separated by a slash, will appear as subject identifier in the individual listings and figures of 
the clinical study report.. 
 
12.3 
Database management 
 
The CRO will provide double data entry with total re-entry of data by a second data entrist 
and discrepancy resolution by a third individual and will update and verify the database and 
create the final SAS data sets. The final data file will be transferred to the sponsor in the 
agreed format with all the other study documentation.  
 
12.3.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™). Previous and concomitant medications will be coded using the WHO Drug 
Dictionary Enhanced (WHODDE). The version of the coding dictionaries will be stated in the 
study report. 


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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
13.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff (see § 16.4). Two monitors will 
be involved at the clinical centres: one monitor will perform the checks of the study 
evaluations and procedures and will not be involved in the drug accountability.  
A second monitor (Sintetica S.A.) will be responsible of performing the drug accountability. 
He/she will not be involved in other monitoring activities. This will be done to safeguard the 
double-blind. Due care will be applied in order to avoid any disclosure of unblinded 
information to blind staff members. 
 
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 and will be detailed in the study monitoring plan. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorised individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO (CROSS Research S.A., Switzerland) has implemented and maintains Quality 
Systems that include quality controls and audits at different study steps with written SOPs to 
ensure that the study is conducted in compliance with the protocol and all effective 
amendments, ICH-GCP, and the applicable regulatory requirement(s) and that data have been 
reliably and correctly generated, recorded, processed and reported, in agreement with the 
ALCOAC principles (Attributable-Legible-Contemporaneous-Original-Accurate-Complete). 
 
The clinical sites are responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirements. 
 
The CROs and the sponsor will be responsible for their respective activities. 
 


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The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a 
CRO, but the ultimate responsibility for the quality and integrity of the trial data always 
resides with the sponsor. 
 
13.3 
Applicable SOPs 
 
The sponsor, the clinical centres and the CROs will follow their respective SOPs in the 
conduct of the respective activities, unless otherwise stated in written agreements. SOPs will 
be made available for review, if required. 
 
13.4 
Data access 
 
The investigator and the CRO will ensure that all raw data records, medical records, CRFs 
and all other documentation that is relevant to this study will be made accessible for 
monitoring activities, audits, IEC review, and regulatory inspections. 
 
13.5 
Audits and inspections 
 
The sponsors, independent bodies acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigator 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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14 
ETHICAL CONSIDERATIONS 
 
14.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the relevant Ethics Committee and Health Authority 
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 local law requirements. 
 
14.2 
Informed consent 
 
Before being enrolled in the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. In the present study, 
information to the patients will be given and informed consent will be obtained following 
establishment of effective analgesia BUT prior to decision to perform a Caesarean section. 
Information will be given in both oral and written form. The information sheet and informed 
consent form will be prepared in the local language and must be approved by the EC and 
regulatory authorities. It will include all the elements required by law according to the ICH-
GCP recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment 
 any potential negative effects attributable to the study treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of subject insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms 
to be used. The forms will be signed and dated by both the investigator and the subject. A 
copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements (see § 15.3). 
The investigator will allow inspection of the forms by authorised representatives of the 


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sponsor, EC members and regulatory authorities. He/she will confirm, by signing and dating 
the forms, that informed consent has been obtained. 
 
14.3 
Insurance policy 
 
An insurance cover has been issued in favour of the subjects participating in this clinical 
study. The insurance is in compliance with the local regulation and with the requirements of 
the Health Authorities. 
 
14.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a 
subject, study treatment or observations are discontinued, the type of discontinuation and the 
primary reason for discontinuation will be recorded. 
 
14.4.1 
Discontinuation type 
 
 Discontinuation from data collection: the subject discontinues from the collection of 
primary and secondary end-points 
 discontinuation from interventions and data collection: the subject discontinues from 
the intake of the IMP(s) and from the collection of primary and secondary end-points 
 
14.4.2 
Primary reason for discontinuation 
 
 Adverse event: Any significant adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 11.2. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication (e.g. administration of an 
investigational anaesthetic volume smaller than 20 mL) 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 site terminated by sponsor: an indication that a clinical site was stopped by the study 
sponsor 
 study terminated by sponsor: an indication that a clinical study was stopped by its 
sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 


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 other: different than the ones previously specified 
 
14.4.3 
Discontinuation procedures 
 
For any subject discontinuing from data collection only or from interventions and data 
collection, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions  
 arrange for alternative medical care of the withdrawn subject, if necessary 
 report in the CRF date and time of the investigational product administration, and date and 
primary reason of study discontinuation 
 record in the CRF any follow-up, if the subject is withdrawn for an AE 
 
Subjects discontinued after the administration of the whole anaesthetic injection (at least 20 
mL) will not be replaced, whilst subjects discontinued before anaesthetic injection (e.g. due to 
time between the end of the previously established analgesia and the start of the anaesthetic 
epidural injection > 10 minutes) or after the first 5 mL anaesthetic injection can be replaced in 
order to have 40 patients per dose group administered with at least 20 mL. 
 
14.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. 
Reasons for discontinuation have to be documented appropriately. 


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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical centres 
 
Beside the investigational products, the following study material will be supplied to the 
clinical centres: 
 final version of the study protocol 
 CRF for each patient plus some spare copies 
 Investigator’s Brochure and summary of product characteristic for the test IMP and 
product information for the reference IMP 
 informed consent forms 
 individual emergency envelopes 
 individual kit replacement envelopes 
 study manual 
 VAS scales (as applicable) 
 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments 
(if any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
15.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to the EC and the concerned Competent Authority, as 
appropriate. The amendment will be applicable only when approved, unless the changes 
consist of urgent safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
15.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information 
on the CRFs must be traceable to these source documents, which are generally stored in the 


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subject's medical file. The source documents should contain all demographic and medical 
information, etc., and the original signed informed consent forms. 
 
Data reported in the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 
The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirements.  
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects, insurance contracts, certificate of analysis of the IMPs, drug accountability records, 
signed informed consent forms, confidential subjects identification code, CRFs, curricula 
vitae of the investigator and other participants in the study, study staff lists and 
responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the sponsor agree to adhere to these requirements. 
 
15.4 
Study subjects’ recruitment 
 
Study participants will be recruited at the clinical centres among labouring women who have 
an epidural catheter in situ and who, during labour, need an unplanned Caesarean section.  
 
15.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator and the CRO agree to keep all the information 
provided by the sponsor in strict confidentiality and to request the same confidentiality from 
their staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected in the CRFs during the study will be documented in an anonymous 
way (see § 12.2). If, as an exception, for safety or regulatory reasons identification of a 
subject becomes necessary, the monitor, the sponsor and the investigator will be bound to 
keep this information confidential. 
 
 


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15.6 
Publication policy 
 
The sponsor agrees that the study results (including negative and inconclusive as well as 
positive results) can be made publicly available by the investigator publishing in peer 
reviewed journals, presenting results at scientific congresses and posting information and 
results on internet-based public registers and databases. 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual 
property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 


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16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Sintetica SA, via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: 
+41.91.640.42.50 
Fax: 
+41.91.646.85.61 
 
Sponsor representatives  
 
Clinical Project Leader 
Elisabetta Donati, Corporate Director Scientific Affairs 
Email: 
edonati@sintetica.com 
 
Medical Expert 
Claudio Camponovo, MD 
Department of Anaesthesiology, Clinica Ars Medica,  
Via Cantonale, CH-6929 Gravesano, Switzerland  
Phone: 
+41.91.611.6211 
Fax: 
+41.91.605.1559 
Email: 
ccamponovo@arsmedica.ch 
 
16.2 
Institutes performing the study 
 
16.2.1 
Clinical centres 
 
16.2.1.1 
Clinical centre N. 1 
 
Department of Anesthesiology, UZ Leuven, campus Gasthuisberg,  
Herestraat 49B - 3000 Leuven, Belgium  
Phone: 
+32.16.34.4270 (Secretary) 
 
International coordinator, Principal Investigator and National Co-ordinator in Belgium 
Prof. Dr. Marc Van de Velde, MD, PhD, EDRA 
Department of Anesthesiology Chair 
Phone: 
+32.16.34.1234 
Email: 
marc.vandevelde@uzleuven.be 
 
16.2.1.2 
Clinical centre N. 2 
 
Service Anaesthesiology, GZA Ziekenhuizen  
campus Sint-Augustinus, Oosterveldlaan 24, 2610 Wilrijk, Belgium  
 
Principal Investigator 
Dr. Patrick Van Houwe 
Phone: 
+32.3.443.3613 (internal number: 35954) 
Email: 
patrick.vanhouwe@gza.be 
 


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16.2.1.3 
Clinical centre N. 3 
 
Orthopedic and Trauma Anesthesia, Department of General Anesthesia and Intensive Care 
Medicine, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria 
Phone: 
+43.1.40400.4100 
Fax:  
+43.1.40400.4028 
 
Principal Investigator and National coordinator in Austria 
Prof. Daniela Marhofer, Assoc. Prof. Priv.-Doz. Dr.med.univ. MBA,  
Email: 
daniela.marhofer@meduniwien.ac.at  
 
16.2.1.4 
Clinical centre N. 4 
 
Department of Anaesthesia and Critical Care 
University Hospitals of Würzburg 
Oberdürrbacher Str. 6, 97080 Würzburg, Germany 
Phone: 
+49.931.201.0 (Operator) 
Phone: 
+49.931.201.30309 (Clinical Trials Office) 
 
Principal Investigator and National coordinator in Germany 
Prof. Peter Kranke, MD, MBA, Professor of Anaesthesia 
Mobile: +49.160.90551174 
Email: 
kranke_p@ukw.de 
 
16.3 
Co-ordination, data analysis & reporting 
 
CROSS Reserach S.A., Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.6300510 
Fax: 
+41.91.6300511 
 
Coordination 
Monica Boveri, Senior Clinical Research Associate and Medical Writer 
Email: 
projectmanagement@croalliance.com 
 
Medical Writing Team and Clinical Projects Unit Representative 
Chiara Leuratti, Clinical Projects Unit Head 
Email: 
medicalwriting@croalliance.com 
 
Biometry Unit Representative 
Alessandra Gentili, Biometry Manager, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Mario Corrado, Quality Assurance Manager, Unit Head 
Email: 
qau@croalliance.com 
 
 


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16.4 
Monitoring 
 
16.4.1 
Blind monitoring 
 
16.4.1.1 
Clinical centres N. 1 and 2 
 
CTS Clinical Trial Service 
Gronausestraat 98, 7581 CJ Losser, The Netherlands 
 
Monitoring representative 
Béate ten Bokum, Manager Clinical Operations & Home Care 
Phone: 
+31(0)53.53.62.220 
Fax: 
+31(0)53.53.82.022 
Mobile: +31(0)62.82.48.469 
Email: 
beate.tenbokum@clinicaltrialservice.com 
 
16.4.1.2 
Clinical centres N. 3 and 4 
 
Dr. Madjid Djeddi  
Ina-Seidel-Str. 3 91126 Schwabach,Germany 
 
Monitoring representative 
Dr. Madjid Djeddi, Senior Clinical Research Associate, Quality Assurance 
Phone: 
+49.911.632937.4 
Mobile: +49.177.388425.9 
Fax: 
+49.911.632937.6 
Email: 
m-djeddi@outlook.com 
 
16.4.2 
Open conditions monitoring 
 
Sintetica SA, via Penate 5, CH-6850 Mendrisio, Switzerland 
 
 


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17 
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