Spinal Anaesthesia With Chloroprocaine HCl 1% for Elective Lower Limb Procedures of Short Duration: a Prospective, Randomised, Observer-blind Study in Adult Patients
Phase: PHASE2
Conditions: Short Duration Lower Limb Surgery Via Spinal Anaesthesia
Sponsor: Sintetica SA

Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
Study CRO-14-122 - Sponsor code CHL.1/02-2014 
 
Spinal anaesthesia with Chloroprocaine HCl 1% for elective lower 
limb procedures of short duration: a prospective, randomised, 
observer-blind study in adult patients 
 
Prospective, single centre, randomised, parallel-group, observer-blind, three doses,  
efficacy and pharmacokinetic study 
 
EudraCT Number: 2014-003778-17 
 
 
Investigational medicinal product: Chloroprocaine HCl 1% solution for injection (10 
mg/mL), Sintetica S.A., Switzerland 
 
 
Indication: 
Spinal anaesthesia 
 
 
Sponsor: 
Sintetica S.A., via Penate 5, CH-6850 Mendrisio, 
Switzerland 
Phone: +41.91.640.42.50  
Fax: 
+41.91.646.85.61 
 
 
Study investigators: 
Principal Investigator: Stefano Bonarelli, MD 
Istituto Ortopedico Rizzoli, SC Anestesia e Terapia 
Intensiva post-operatoria e del dolore IOR-IRCCS, 
via G.C. Pupilli 1 - 40136 Bologna, Italy 
Phone: +39.051.6366356 
Fax: 
+39.051.6366647 
Email: stefano.bonarelli@ior.it 
 
 
Development phase: 
Phase II 
 
 
Version and date: 
Final version 1.0, 03OCT14 
 
 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 67 pages plus Appendices 
CROSS S.A 
Page 1 

Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
STUDY SYNOPSIS 
 
Title: Spinal anaesthesia with Chloroprocaine HCl 1% for elective lower limb procedures of short duration: a 
prospective, randomised, observer-blind study in adult patients 
 
Protocol number: CRO-14-122 - Sponsor code CHL.1/02-2014 
 
Clinical phase: Phase II 
 
Study design: Prospective, single centre, randomised, parallel-group, observer-blind, three doses, efficacy and 
pharmacokinetic study 
 
Planned nr. of centres / countries: One / Italy 
 
Investigator and centre: Principal investigator: Stefano Bonarelli, MD; Istituto Ortopedico Rizzoli, SC 
Anestesia e Terapia Intensiva post-operatoria e del dolore IOR-IRCCS, Bologna, Italy 
 
Test investigational medicinal product (IMP; T):  
Chloroprocaine HCl 1% (10 mg/mL), injectable solution, Sintetica S.A., Switzerland.  
Three single doses of the investigational product will be investigated:  
 
D1: 30 mg chloroprocaine HCl (3 mL)  
 
D2: 40 mg chloroprocaine HCl (4 mL) 
 
D3: 50 mg chloroprocaine HCl (5 mL) 
 
Dose regimen: Patients undergoing elective short-duration lower limb surgery will be randomised into 3 
treatment groups (15 patients per group) to receive one of the 3 single doses of Chloroprocaine HCl 1%, i.e. 
either D1, D2 or D3, via intrathecal injection 
 
Objective:  
The objective of this study is to evaluate the effect of 3 doses of Chloroprocaine HCl 1% (30, 40 and 50 mg) for 
spinal anaesthesia in adult patients undergoing short duration elective surgery of the lower limb. 
 
End-points:  
Primary end-point: To evaluate the efficacy of the three Chloroprocaine HCl 1% doses (i.e. D1, D2 and D3) in 
terms of time to complete regression of spinal block (i.e. end of anaesthesia) 
Secondary end-points:  
 To evaluate the efficacy of the three Chloroprocaine HCl 1% doses (D1, D2 and D3) in terms of Time to 
onset of sensory block, Time to onset of motor block, Time to readiness for surgery, Time to resolution of 
motor block, Time to unassisted ambulation, Time to resolution of sensory block to S1, Sensory block 
metameric levels during the block, Maximum level of sensory block, Time to regression of two dermatomers 
with respect to the maximum level of sensory block, Time to first spontaneous urine voiding, Time to 
administration of rescue anaesthesia or rescue analgesia, Time to first post-operative analgesia, Time to 
eligibility for home discharge, proportion of patients achieving an effective anaesthesia, quality of spinal 
block 
 To assess the concentration of chloroprocaine and its metabolite 2-chloro-4-aminobenzoic acid (CABA) in 
plasma after administration of D1, D2 and D3 
 To assess the excretion of CABA in urine (as % of the chloroprocaine administered dose) 
 To investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses on the basis of 
the incidence of treatment-emergent adverse events, in particular transient neurological symptoms (TNS); 
vital signs and ECG.  
 
Study variables: 
Primary efficacy variable:  
Time to regression of spinal block (i.e. end of anaesthesia; Tea), defined as the time when Bromage score returns 
to 0 and sensitive level returns to S2.  
Secondary efficacy variables: 
 Time to onset of sensory block (Tsb) 
 Time to onset of motor block (Tmb) 
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
STUDY SYNOPSIS (cont.) 
 
Secondary efficacy variables, continued: 
 Time to readiness for surgery (Trs), defined as presence of an adequate motor block (Bromage’s score ≥ 2) 
and loss of Pinprick sensation at the required metameric level ≥ T12 
 Time to resolution of motor block (Bromage score=0; Trmb) 
 Time to unassisted deambulation (Tua) 
 Time to resolution of sensory block to S1 (TS1) 
 Sensory block metameric levels (assessed until resolution of sensory block to S1) 
 Maximum level of sensory block (SBmax) 
 Time to maximum level of sensory block (Tsbmax) 
 Time to regression of two dermatomers with respect to the maximum level of sensory block (Trd) 
 Time to eligibility for home discharge (Thd) 
 Time to first spontaneous urine voiding (Tuv) 
 Time to administration of rescue anaesthesia or rescue analgesia (Tra) 
 Time to first post-operative analgesia (Tpa) 
 Proportion of patients achieving an effective anaesthesia 
 Quality of spinal block 
 
Pharmacokinetic variables 
 Plasma concentrations of chloroprocaine and CABA at baseline (i.e. before spinal puncture) and at 5, 10, 30 
and 60 min after spinal puncture 
 Urine excretion of CABA from spinal puncture to time of first urine voiding 
 
Safety variables: 
 Treatment-emergent adverse events throughout the study 
 Incidence of transient neurologic symptoms (TNS) at 24 h and day 7 after spinal puncture (Tsp) 
 Vital signs (blood pressure [BP], heart rate [HR] and peripheral oxygen saturation [SpO2]); ECG 
 
Sample size:  
45 male/female patients (15 patients per dose group), aged 18-80 years, scheduled for elective lower limb 
surgery (less than 40 min) under spinal anaesthesia. 
 
To calculate the required study sample size, results from a previous study with spinal injection of chloroprocaine 
HCl 1% were taken into consideration and normal distribution of data was assumed. Sample size was calculated 
using n-Query Advisor 7.0. When the sample size in each of the 3 dose groups is 13, a one-way analysis of 
variance will have 80% power to detect at the 0.050 level a difference in time to complete spinal block 
regression (Tea) means characterized by a variance of means, V=Σ(μi -μ)2 / G (where G=3) of 249.962, assuming 
that the common standard deviation is 30.011. To be more conservative and to take into account possible 
deviations from normality, the sample size is increased of about 15%. Fifteen (15) patients per dose group will 
be enrolled. 
 
Main selection criteria:  
Inclusion criteria: 
1. Sex, age and surgery: male/female patients, 18-80 years old, scheduled for short duration (less than 40 min) 
lower limb surgery requiring ≥ T12 metameric level of sensory block 
2. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive 
3. ASA physical status: I-III 
4. Informed consent: signed written informed consent before inclusion in the study 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study. 
Exclusion criteria 
1. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives 
of the study. Contraindications to spinal anaesthesia. History of neuromuscular diseases to the lower 
extremities 
2. ASA physical status: IV-V 
3. Further anaesthesia: patients expected to require further anaesthesia  
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria:  
Exclusion criteria, continued: 
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations ingredients; 
ascertained or presumptive hypersensitivity to the ester type and major anaesthetics  
5. 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 and neurological diseases, sepsis, blood coagulation disorders, severe cardiopulmonary disease, 
thyroid disease, diabetes or other neuropathies. 
6. 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 
7. Drug, alcohol: history of drug or alcohol abuse 
8. Blood donation: blood donations in the 3 months before this study 
9. Pregnancy and lactation: missing or positive pregnancy test at screening, pregnant or lactating women 
10. Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, antidepressants, 
anticonvulsant agents or chronic analgesic therapy) 
11. Medications: medication known to interfere with the extent of spinal blocks for 2 weeks before the start of 
the study. Hormonal contraceptives for females are allowed. 
 
Study schedule: 
The study will include a screening phase (Visit 1, days -14/1), a treatment phase (anaesthesia and surgical 
procedure: Visit 2, day 1), a final visit (day 1/2), a follow up at 24 h (day 2) and a final follow-up at day 7±1. 
Screening Phase (visit 1, day -14/1): Patients scheduled for short duration lower limb surgery will be informed 
about the aims, procedures and possible risks of the study and will be asked to sign the informed consent form 
for the inclusion in the trial. Routine pre-surgery assessments will be performed according to the standard 
procedures of the hospital. A urine pregnancy test for women will be performed. Inclusion/exclusion criteria will 
be verified and patients will be assigned a consecutive screening number. 
The following baseline characteristics will be recorded: demography, lifestyle, physical abnormalities, body 
weight, 
height, 
vital 
signs, 
peripheral 
oxygen 
saturation 
(SpO2), 
medical/surgical 
history 
and 
previous/concomitant medications.  
Treatment Phase (visit 2, day 1): Before the anaesthesia, patients will be questioned about adverse events and 
concomitant medications and will be assigned a consecutive randomisation number. According to the 
randomisation list they will be allocated to receive one of three doses of Chloroprocaine HCl 1%. 
Blood pressure, heart rate, SpO2 and ECG (if foreseen by the hospital procedures) will be monitored at baseline 
and during block placement using standard monitors. Before anaesthesia, if needed, patients will be pre-
medicated with os midazolam; in addition, only if needed according to the investigator’s opinion, Ringer’s 
solution (7 mL/kg) will be infused. 
The anaesthetic will be administered with a Pencil point needle, 25-Gauge Whitacre spinal needle (caudocranial 
direction of the needle). Lumbar puncture will be performed in the lateral decubitus position (or sitting, if more 
appropriate) using a midline approach at the L3/L4 or L4/L5 interspaces. After the lumbar puncture and after 
verifying the spontaneous flow of liquor at the beginning and at the end of the procedure, two short aspirations 
will be done to verify the proper positioning of the needle. Barbotage must be avoided. In case of incomplete 
anaesthesia, sedative, analgesics or anaesthetics should be administered. Post-operative analgesia will be given 
to all patients, if necessary, according to the hospital standard procedures. 
 
The physician placing the spinal block will not be further involved in patient’s care and data recording. The 
evolution of both sensory and motor blocks, including sensory block metameric level, will be evaluated by a 
blinded observer every 2 min until readiness for surgery, every 5 min until the maximum level is reached (two 
consecutive observations with the same level of sensory block) and then every 5 min until regression of two 
dermatomers with respect to the maximum level of sensory block. After that, sensory and motor block 
assessments will be repeated every 30 min until regression of spinal block and complete regression of sensory 
block to S1 (if compatible with surgical procedure).  
The efficacy and safety variables listed in the “Variables” section and described below will be recorded in the 
CRFs. 
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
STUDY SYNOPSIS (cont.) 
 
Study schedule, continued: 
Before the block (pre-dose assessment) and during the spinal block every 10 min until the end of anaesthesia, 
hemodynamic variables (HR, BP, SpO2; ECG if available) will be monitored according to the hospital standard 
procedures. 
Blood samples for PK analysis will be collected at baseline and at 5 10, 30 and 60 min after spinal puncture. 
Urine will be collected at the time of spontaneous voiding. 
Sensorial block will be verified by bilateral Pinprick test using a 20-G hypodermic needle and will be recorded. 
Pinprick sensation will be scored as being present (score 1) or absent (score 0). 
Motor block will be verified using a modified Bromage scale (0=no block; 1=hip blocked; 2=hip and knee 
blocked; 3=hip, knee and ankle blocked).  
Readiness for surgery is defined as the presence of an adequate motor block (Bromage’s score ≥ 2) and loss of 
Pinprick sensation at the required metameric level ≥ T12. 
Effective anaesthesia is defined as the presence of adequate sensory and motor blocks as defined above with 
adequate duration to cover surgery. 
The quality of spinal block will be verified according to the need for supplementary intravenous analgesics and 
sedation as follows: adequate spinal block=neither sedation nor analgesics required to complete surgery; 
inadequate spinal block = additional anaesthesia or analgesia (e.g. 2 µg/kg mg IV bolus of fentanyl) required to 
complete surgery; failed spinal block = general anaesthesia required to complete surgery. Duration of surgery 
will also be recorded.  
A detailed description of the surgical procedure and of the concomitant medication during surgery will be given 
in the CRF. Time to regression of spinal block (i.e. end of anaesthesia), defined as the time when Bromage score 
returns to 0 and sensitive perception returns to S2 will be recorded. Time when analgesia is required will be 
noted. The analgesic used and its dosage will be recorded.  
All AEs will be reported. Particular attention will be given to the occurrence of paraesthesia, haemorrhage, 
headache, miction/defecation difficulties, tiredness, nausea/vomiting, vertigo. The time to unassisted ambulation 
and to first spontaneous urine voiding will be recorded. 
Treatment Phase (Final visit, day 1/2 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. Vital signs, ECG (if foreseen) and SpO2 will be recorded. Haemodynamic 
variables must be stable and SpO2 must be acceptable (> 92%) without oxygen therapy. Patients will be asked 
about any adverse events. If all the criteria are met and no adverse reactions occur, the patient will be discharged 
according to the hospital’s standard procedures. 
Follow-up Phase: 24 h (Day 2) and 6±1 days (Day 7±1) after anaesthesia and surgery, a deputy of the 
investigator, not aware of the treatment administered, will question patients about symptoms of TNS and unusual 
sensations not associated with the operation area (buttock, thigh posterior, thigh anterior, lower limb, sacrum, 
calves, other areas) following prepared questions.  
Patients will be contacted (by telephone if they have already left the hospital) by a deputy of the investigator not 
aware of the treatment administered.   
 
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. Missing values of time to complete spinal block regression (Tea) will be replaced 
with the highest Tea detected in the corresponding treatment group. This analysis set will be used for sensitivity 
analysis. 
Per Protocol set (PP): all randomised patients who fulfil the study protocol requirements in terms of anaesthetic 
administration and primary efficacy evaluation, with no major deviations that could affect the primary efficacy 
results. This analysis set will be used for the primary efficacy analysis.  
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
STUDY SYNOPSIS (cont.) 
 
Data analysis, continued 
Definition of analysis sets, continued:  
PK Set 1 (PK 1): the PK set 1 will include all randomised patients who fulfil the study protocol requirements in 
terms of anaesthetic administration and have at least one post-dose blood PK sample collected. 
PK Set 2 (PK 2): the PK set 2 will include all randomised patients who fulfil the study protocol requirements in 
terms of anaesthetic administration and have the urine for PK analysis collected. 
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 
Continuous variables will be summarised by dose group using classic descriptive statistics (i.e. mean, SD, CV%, 
min, median and max) and categorical variables will be summarised by dose group using tables of frequencies. 
Due to the small sample size, collected data will be compared using nonparametric tests. 
Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, Tsbmax, Trd, Thd, Tuv, Tra and Tpa will be analysed using the Kruskal-Wallis 
test. Pairwise comparisons between dose groups will be performed using the Wilcoxon rank-sum test. 
Comparisons will be performed according to the following hierarchical order: 
1. Overall comparison 
2. D1 (30 mg) vs. D3 (50 mg) comparison 
3. D2 (40 mg) vs. D3 (50 mg) comparison 
4. D1 (30 mg) vs. D2 (40 mg) comparison 
Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary 
(CPMP/EWP/908/99 guideline, 19SEP02). However, if a null hypothesis of a comparison cannot be rejected all 
the null hypotheses of the subsequent comparisons cannot be rejected. 
The proportion of patients achieving an effective anaesthesia and the quality of spinal block will be summarised 
by dose group using tables of frequencies. 
Pharmacokinetic analysis 
Data will be listed and summarised by descriptive statistics. PK analysis will be performed using Phoenix 
WinNonlin® version 6.3 (Pharsight Corporation). 
 
 
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
Phase 
Treatment 
Phase 
Follow-up 
Phase 
Visit 
Visit 1 
Days -14/1 
Visit 2 
Day 1 
Final Visit 
or ETV 
Day1/2 
Day 2 
24 h  
post-
surgery 
Day 7±1 
post-
surgery 
Informed consent 
x 
 
 
 
 
Demography and lifestyle 
x 
 
 
 
 
Medical/surgical history 
x 
 
 
 
 
Physical examination 
x 
 
 
 
 
Previous and concomitant medication 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
Body weight 
x 
 
 
 
 
Vital signs (blood pressure, heart rate)1 
x 
x 
x 
 
 
SpO2
1 
x 
x 
x 
 
 
ECG1 
 
x 
x 
 
 
Pregnancy test (urine) 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
Enrolment and Randomisation 
 
x 
 
 
 
Os Midazolam premedication 
 
x2 
 
 
 
Ringer’s solution infusion 
 
x2 
 
 
 
Spinal injection 
 
x 
 
 
 
Surgery (< 40 min) 
 
x 
 
 
 
Sensory block assessment  
 
x5 
 
 
 
Motor block assessment 
 
x5 
 
 
 
Blood sampling3 
 
x 
 
 
 
Urine collection4 
 
x 
 
 
 
TNS questionnaire 
 
 
 
x 
x 
Home discharge6 
 
 
x 
x 
 
Adverse events monitoring 
x 
x 
x 
x 
x 
 
1. 
Vital signs and SpO2 at screening, at baseline, during the block until the end of the anaesthesia and during 
post-operative recovery (final visit). ECG (if foreseen by the standard hospital procedures) at baseline, 
during the block until the end of the anaesthesia and during post-operative recovery (final visit)  
2. 
If needed 
3. 
Blood samples for PK analysis will be collected at baseline and at 5, 10, 30 and 60 min after spinal 
puncture 
4. 
Urine will be collected for PK analysis at the time of first spontaneous voiding 
5. 
The evolution of both sensory and motor blocks, including sensory block metameric level, will be evaluated 
by a blinded observer every 2 min until readiness for surgery, every 5 min until the maximum level is 
reached (two consecutive observations with the same level of sensory block) and then every 5 min until 
regression of two dermatomers with respect to the maximum level of sensory block. After that, sensory and 
motor block assessments will be repeated every 30 min until regression of motor block and complete 
regression of sensory block to S1 (if compatible with surgical procedure)  
6. 
Patients will be discharged on Day 1 or on a following day after the criteria for discharge, including 
Aldrete’s scoring scale criteria, are met and according to the hospital’s standard procedures. In case of 
discontinuation, subjects will undergo an early termination visit (ETV) 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
TABLE OF CONTENTS 
 
Page 
1 
INTRODUCTION 
16 
1.1 
Background 
16 
1.1.1 
Spinal anaesthesia 
16 
1.1.2 
Chloroprocaine HCl 
16 
1.2 
Rationale 
21 
1.3 
Risk and benefits 
21 
2 
STUDY OBJECTIVES 
23 
2.1 
Primary end-point 
23 
2.2 
Secondary end-points 
23 
3 
CLINICAL SUPPLIES 
24 
3.1 
Treatment 
24 
3.1.1 
Description of products 
24 
3.1.2 
Dose regimen 
24 
3.1.3 
Route and method of administration 
24 
3.1.4 
Investigational product distribution 
25 
3.2 
Packaging and labelling 
25 
3.3 
Storage conditions 
26 
3.4 
Drug accountability 
26 
4 
INVESTIGATIONAL PLAN 
27 
4.1 
Overall study design 
27 
4.2 
Discussion of design 
27 
5 
STUDY POPULATION 
29 
5.1 
Target population 
29 
5.2 
Inclusion criteria 
29 
5.3 
Exclusion criteria 
29 
5.3.1 
Not allowed treatments and other treatments 
30 
6 
STUDY SCHEDULE 
31 
6.1 
Study visits and procedures 
31 
6.2 
Diet and lifestyle 
33 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
34 
7.1 
Physical examination 
34 
7.1.1 
Vital signs 
34 
7.1.2 
ECGs 
34 
7.1.3 
Assessment of adverse events 
35 
7.2 
Block assessment 
36 
7.3 
Procedures for discharge 
38 
7.4 
Sampling for pharmacokinetic analysis 
38 
7.4.1 
Venous blood sampling 
38 
7.4.2 
Urine collection 
39 
7.4.3 
Analytics 
39 
7.4.4 
Labelling, storage and transport of samples 
39 
8 
ASSIGNMENT OF STUDY TREATMENT 
41 
8.1 
Randomisation 
41 
8.2 
Treatment allocation 
41 
8.3 
Blinding 
41 
9 
EVALUATION PARAMETERS 
42 
9.1 
Study variables 
42 
9.1.1 
Primary variable 
42 
9.1.2 
Secondary variables 
42 
9.2 
Efficacy assessments 
43 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
9.3 
Pharmacokinetic assessments 
44 
9.4 
Safety assessments 
44 
10 
STATISTICAL METHODS 
45 
10.1 
Analysis Sets 
45 
10.1.1 
Definitions 
45 
10.1.2 
Reasons for exclusion from the Full Analysis Set 
46 
10.1.3 
Reasons for exclusion from the Per Protocol set 
46 
10.1.4 
Reasons for exclusion from the PK sets 
46 
10.2 
Sample size and power considerations 
47 
10.3 
Demographic, baseline and background characteristics 
47 
10.4 
Analysis of efficacy parameters 
47 
10.5 
Analysis of pharmacokinetic parameters 
47 
10.6 
Safety and tolerability evaluation 
48 
11 
DEFINITION AND HANDLING OF AES AND SAES 
50 
11.1 
Applicable SOPs 
50 
11.2 
Definitions 
50 
11.3 
AEs monitoring window 
51 
11.4 
AEs recording 
51 
11.5 
SAEs reporting 
53 
11.6 
SUSARs management 
53 
11.7 
Other events qualified for expedited reporting 
54 
11.8 
SAEs: contacts 
54 
12 
DATA MANAGEMENT PROCEDURES 
55 
12.1 
Data collection - CRFs 
55 
12.2 
Unique subject identifier 
55 
12.3 
Database management 
55 
12.3.1 
Coding dictionaries 
55 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
56 
13.1 
Monitoring 
56 
13.2 
Quality Control and Quality Assurance 
56 
13.3 
Applicable SOPs 
57 
13.4 
Data access 
57 
13.5 
Audits and inspections 
57 
14 
ETHICAL CONSIDERATIONS 
58 
14.1 
Ethics and Good Clinical Practice (GCP) 
58 
14.2 
Informed consent 
58 
14.3 
Insurance policy 
59 
14.4 
Withdrawal of subjects 
59 
14.4.1 
Discontinuation type 
59 
14.4.2 
Primary reason for discontinuation 
59 
14.4.3 
Discontinuation procedures 
60 
14.5 
Study termination 
60 
15 
ADMINISTRATIVE PROCEDURES 
61 
15.1 
Material supplied to the clinical centre 
61 
15.2 
Protocol amendments 
61 
15.3 
Study documentation and record keeping 
61 
15.4 
Study subjects’ recruitment 
62 
15.5 
Confidentiality and data protection 
62 
15.6 
Publication policy 
62 
16 
STUDY RESPONSIBLE PERSONS 
64 
16.1 
Sponsor 
64 
16.2 
Institutes performing the study 
64 
16.2.1 
Clinical centre 
64 
16.2.2 
Drug assay 
64 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
16.3 
Co-ordination, data analysis & reporting 
65 
16.4 
Monitoring 
65 
17 
REFERENCES 
66 
18 
APPENDICES 
68 
 
 
 
TABLES 
Page 
Table 3.1.2.1 
Dose groups 
24 
Table 7.1.3.1 
Differential diagnosis criteria for TNS and other events following intrathecal injection 
36 
Table 7.4.1.1 
Recommended maximal deviations from the scheduled sampling times 
38 
 
 
 
FIGURES 
Page 
Figure 1.1.2.1 
Chemical structure of chloroprocaine hydrochloride ................................................................ 16 
Figure 1.1.2.2 
Chemical structure of 2-chloroprocaine metabolites ................................................................ 19 
 
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOA 
Attributable-Legible-Contemporaneous-Original-Accurate 
ANOVA 
Analysis of Variance 
ASA 
American Society of Anesthesiologists 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BW 
Body Weight 
CA 
Competent Authority 
CABA 
2-chloro-4-aminobenzoic acid 
CDISC 
Clinical Data Interchange Standards Consortium 
CSF 
Cerebrospinal fluid 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CRS 
Clinical Study Report 
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 
IUD 
Intra-Uterine Device 
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 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SBmax 
Maximum level of sensory block 
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 
Tea 
Time to regression of spinal block (i.e. end of anaesthesia) 
Thd 
Time to eligibility for home discharge 
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Tmb 
Time to onset of motor block 
Tsbmax 
Time to maximum level of sensory block 
Tpa 
Time to first post-operative analgesia 
Tra 
Time to administration of rescue anaesthesia or rescue analgesia 
Trd 
Time to regression of two dermatomers with respect to the maximum level of sensory block 
Trs 
Time to readiness for surgery 
TS1 
Time to resolution of sensory block to S1 
Tsb 
Time to onset of sensory block 
Tua 
Time to resolution of motor block or time to unassisted ambulation   
Tuv 
Time to first spontaneous urine voiding 
TNS 
Transient Neurological Symptoms 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
 
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1 
INTRODUCTION 
 
1.1 
Background 
 
1.1.1 
Spinal anaesthesia 
 
Spinal anaesthesia has the definitive advantage that profound nerve block can be produced in 
a part of the body by the relatively simple injection of a small amount of local anaesthetic. 
However, the greatest challenge of the technique is to control the spread of that local 
anaesthetic through the cerebrospinal fluid (CSF), to provide block that is adequate (in both 
extent and degree) for the proposed surgery but without producing unnecessarily extensive 
spread and so without increasing the risk of complications. 
 
Spinal anaesthesia is widely used for minor procedures on the lower limb providing a fast 
onset and effective sensory and motor blocks.  
Lidocaine was extensively used for outpatient procedures under spinal block because of its 
fast onset and short duration profile. However, transient neurological symptoms (TNS) were 
consistently reported with its use (1,2). Small doses of long-acting drugs (such as 
bupivacaine, levobupivacaine or ropivacaine), with or without additives, have been suggested 
as a possible alternative (3-6), but may be associated with an increased failure rate and with a 
delay in recovery (4,6). 
Preservative-free solutions of chloroprocaine are also available for intrathecal use, as detailed 
in § 1.1.2 below. 
 
1.1.2 
Chloroprocaine HCl 
 
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 (8,9) 
(usually 6 to 12 minutes) and anaesthesia duration up to 60 min, depending on the amount 
used and the route of administration. In-vitro chloroprocaine half-life is approximately 25 
seconds (27). The apparent half-life in vivo was found to be 3.1±1.6 min (range 1.5 – 6.4 min) 
in maternal plasma after intrapartum epidural anaesthesia (28). 
 
 
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 (10), chloroprocaine has been 
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 (11-13). It was later demonstrated that neurological complications 
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were associated with the preservative agents added to chloroprocaine formulations (14). As a 
consequence, preservative-free and 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 (13).  
 
Similar to lidocaine, chloroprocaine is used for short-duration surgical procedures (45-60 
minutes), mainly in the ambulatory setting, when a fast recovery and prompt home readiness 
are required (15,9). 
 
Indeed, 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 
(8,9) and related risks of toxic systemic spread (9,16,17,18). 
 
Chloroprocaine HCl 1% solution for injection, as well as Chloroprocaine HCl 2% and 3% 
solutions for injection, were first approved in 1955 (NDA 009435) in the USA, under the 
proprietary name of Nesacaine® (AstraZeneca). The firstly developed Nesacaine® formulation 
contained methylparaben as preservative. Preservative-free formulations, which take 
advantage of chloroprocaine short duration of action, without the problematic side effects 
caused by the formulation excipients, were also developed.  
Nesacaine 1% and 2% Injections, in multidose vials with methylparaben as preservative, are 
indicated for the production of local anaesthesia by infiltration and peripheral nerve block. 
These formulations are not to be used for lumbar or caudal epidural anaesthesia.  
Nesacaine-MPF 2% and 3% Injections, in single dose vials without preservatives and without 
EDTA, are indicated for the production of local anaesthesia by infiltration, peripheral and 
central nerve block, including lumbar and caudal epidural blocks. Nesacaine and Nesacaine-
MPF Injections are not to be used for subarachnoid administration. These products are 
marketed in USA and Canada. 
 
Of note, in 2007 the AstraZeneca reference drug product has been withdrawn from the Swiss 
market. The action has been undertaken for production technical reason only, as reported by 
the Company, and not for safety reasons. This is also stated in the Swissmedic Journal of July 
2007, where the withdrawal of the product is classified as ‘Marketing Authorization 
revocation following the decision of the company to forgo the distribution’ (Swissmedic 
Journal, July 2007). 
 
Sintetica SA has registered Chloroprocaine HCl 0.5% and 1% in Switzerland. In details, 
Ivracain® Sintetica (Chloroprocaine HCl 0.5% Swissmedic registration n.53,283) has been 
authorised and marketed since 1994 for intravenous regional anaesthesia (IVRA) during upper 
and lower limbs surgery. Chloroprocaine HCl 1% Sintetica has been on the Swiss market 
since 2002 (Swissmedic registration n. 56,545) for local anaesthesia and peripheral nerve 
block. This formulation has been distributed locally according to Swiss law “Formula 
Hospitalis” since 2002 and then registered as medicinal product in 2008. Chloroprocaine HCl 
1% Sintetica has also been imported by different hospitals in Belgium.  
 
In 2012 Sintetica received approval for Chloroprocaine HCl 1% Injection, preservative-free, 
(complying with US Pharmacopeia) for spinal-intrathecal use under the brand name of 
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Ampres/Clorotekal/Decelex in several European Countries, i.e. Germany, Austria, Belgium, 
France, Ireland, Italy, Poland, Spain and UK. 
 
1.1.2.1 
Use of Chloroprocaine in Spinal anaesthesia 
 
When chloroprocaine was first introduced, Foldes and McNall (10) described its use for 
spinal anaesthesia in 214 patients, and reported no cases of neurotoxicity. At first 
chloroprocaine was not extensively used for spinal anesthesia because of the wide use of 
lidocaine; moreover, the only solution available on the market when introduced into clinical 
practice contained methylparaben, a preservative, or sodium bisulfite, an antioxidant, which 
made them inappropriate for intrathecal use. In the ’80 the literature described a number of 
cases with persistent neurological deficits after unintentional subarachnoid injection of large 
volumes of bisulfite-containing chloroprocaine resulting in total spinal anesthesia (11,12). 
Subsequent laboratory studies demonstrated that persistent neurologic deficits were associated 
with intrathecal injection of sodium bisulfite at low pH, while chloroprocaine alone did not 
produce irreversible neurological deficits (20,14). 
 
Preservative-free solutions of chloroprocaine are now available for intrathecal use, as detailed 
above, and clinical studies in volunteers demonstrated that chloroprocaine use for spinal 
anesthesia at doses ranging between 30 and 60 mg provides a spinal block profile similar or 
even better than that of lidocaine, with a lower incidence of transient neurologic symptoms 
(21,22). Clinical reports on off-label intrathecal use of preservative-free chloroprocaine in 
more than 1000 patients (10,24,17) as well as rigorous investigations in more than 100 
volunteers and outpatients (21,22,25,26) have not reported any cases of neurological toxicity. 
 
Comparing 40 mg of either lidocaine or chloroprocaine in 8 volunteers, Kouri and Kopacz 
reported a similar duration of surgical block (ranging between 30 and 60 min), but faster 
recovery from spinal anaesthesia and simulated home discharge with chloroprocaine than 
lidocaine. In a prospective, randomised, double-blind study intrathecal injection of 50 mg of 
preservative-free chloroprocaine 1%, Sintetica SA, resulted in quicker recovery of 
sensory/motor function, unassisted ambulation and fewer incidences of TNS than the same 
dose of 1% lidocaine (26). 
 
In a randomised, double blind clinical study by Casati A. et al. (26), the dose response 
relationship of three doses (30 mg, 40 mg or 50 mg) of Chloroprocaine HCl 1% (Sintetica 
SA), administered intrathecally to 45 patients (15 patients in each dose group) undergoing 
elective lower limb short-duration surgery, was evaluated. The onset of anaesthesia was very 
similar in the 3 treatment groups while supplementary intraoperatory analgesia was required 
in 5 and 2 patients respectively in the 30 and 40 mg group. Time to recovery of spinal block 
was faster in the 30 mg than in the 40 mg or 50 mg group. However, no differences in home 
discharge time were observed. No transient neurological symptoms were reported at 24h and 
7-day follow-up. The investigators concluded that 40 and 50 mg chloroprocaine given 
intrathecally provide adequate spinal anaesthesia for outpatient surgical procedures of 30-60 
minutes duration. Reducing the dose to 30 mg resulted in a spinal block of insufficient 
duration with no advantages in terms of home discharge time. 
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1.1.2.2 
Pharmacokinetics of chloroprocaine 
 
The most important clinical properties of local anaesthetic agents are potency, onset, duration 
of action and relative blockade of sensory and motor fibres. These qualities are related 
primarily to physicochemical properties of the various compounds. In general, lipid solubility 
determines the relative intrinsic potency of the various agents, while proteins binding 
influences the duration of anaesthesia. The pKa is correlated with the onset of action. The pKa 
of 2-chloroprocaine is 8.97. 
The onset of action with 2-chloroprocaine is rapid (usually within very few minutes) for 
infiltration, epidural, spinal anaesthesia and peripheral blocks and the duration of action is 
short, depending on the route and dosage used (usually not longer than 60 minutes). 
 
Spinal anesthesia consists in the injection of the local anesthetic solutions close to the target 
nerve structures, located within the subarachnoid space; consequently their effect is not 
dependent upon the general circulation for transport to the site of action and on the plasma 
concentration. Therefore, the knowledge of the pharmacokinetics of the drug is more useful 
for safety reason rather than for the therapeutic efficacy. If 2-chloroprocaine is injected 
intrathecally, its effectiveness is not conditioned by plasma concentrations that actually could 
affect its safety when it is administered in excessive doses or after inadvertent intravascular 
injection. 
 
Chloroprocaine plasma half-life in vitro is about 25 seconds (27), whereas the apparent half-
life in vivo was found to be 3.1±1.6 min (range 1.5 – 6.4 min) in maternal plasma after 
intrapartum epidural anaesthesia (28). 
 
Chloroprocaine is in fact rapidly metabolized in the plasma by hydrolysis of the ester linkage 
by the enzyme pseudocholinesterase with the production of two major metabolites, i.e. β-
diethylaminoethanol and 2-chloro-4-aminobenzoic acid (CABA), which inhibits the action of 
the sulfonamides.  
 
 
Figure 1.1.2.2 
Chemical structure of 2-chloroprocaine metabolites 
 
 
 
 
 
2-chloro-4-aminobenzoic acid (CABA) 
beta-diethylaminoethanol 
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CABA and possibly CABA conjugates (29) are eliminated through the kidney. The 
pharmacologically inactive hydrolytic products of 2-chloroprocaine, 2-chloroaminobenzoic 
acid (CABA) and 2-diethylaminoethanol, are excreted effectively in mothers and newborns 
(30). 
 
Chloroprocaine may undergo some metabolism in the cerebrospinal fluid by alkaline 
hydrolysis, whereas pseudocholinesterase plays little role as there is almost none present in 
the subarachnoid space (31). At pH below 6.0 almost no alkaline hydrolysis occurs. It is 
conceivable that the acid pH greatly delays the hydrolysis of the drug in the cerebrospinal 
fluid while epinephrine prevents early uptake of the agent by the blood stream, thereby 
slightly delaying the usual route of elimination of the drug from the subarachnoid space.  
 
Elimination of local anaesthetics from the cerebrospinal fluid, following intrathecal injection, 
occurs by diffusion and vascular absorption (32). Once in neural tissue or the epidural space, 
local anaesthetics are subject to vascular absorption. The predominant factors determining the 
rate of absorption are local blood flow and competing binding to local tissues (33). Since 
blood flow to the epidural space is by far greater compared with the subarachnoid space and 
CSF (where is approaches zero), vascular absorption in the epidural space maintains a 
concentration gradient between CSF and epidural space, thereby resulting in continuous 
elimination of local anaesthetic from the CSF after intrathecal injection (32).  
 
Only few PK studies have been performed with local anaesthetics administered intrathecally 
(34-36) and some understanding comes from computational models of CSF dynamics.  
To our knowledge, no studies on the pharmacokinetics of chloroprocaine or its metabolite 
CABA after intrathecal injection have been performed. 
 
A study of Chloroprocaine 2 and 3% in obstetric patients after epidural anaesthesia (37) 
showed that in maternal plasma chloroprocaine was detectable for 5-10 min after each dose 
(doses: 468±284 mg for vaginal delivery and 948±347 mg for caesarean section, respectively, 
administered through an epidural catheter). Mean chloroprocaine levels were 51±13 (range 0-
470) and 23±80 (range 0-335) ng/mL for vaginal delivery and caesarean section, respectively. 
In contrast, CABA was detectable at higher levels, i.e. 2±3 (0-8) µg/mL for vaginal delivery 
and 8±12 (1-46) µg/mL for caesarean section.  
 
Low concentrations of chloroprocaine were detected in the venous blood of 2 out of 29 
mothers at delivery after administration of 40 mL of chloroprocaine 2%. Measurable amounts 
of the metabolite CABA were found in all 13 samples of maternal blood 5 min after 
paracervical block and in 6 of 27 maternal samples at delivery (34). Similarly chloroprocaine 
levels of 2.7±0.7 ng/mL were found in maternal blood at delivery in another study with 
Chloroprocaine administered by continuous infusion (38). 
 
It is assumed that the plasma concentrations of chloroprocaine after spinal injection are much 
lower than after epidural administration, also considering that approximately 10 times lower 
doses are administered intrathecally. In geriatric patients for example, the absorption of 
another local anesthetic, i.e. lidocaine 2%, after spinal injection was much lower than after 
epidural administration (35). 
 
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The major chloroprocaine metabolite CABA should be more easily detected after spinal 
anaesthesia than the parent compound, considering the results observed for epidural 
anaesthesia in the study described above (37). 
 
1.2 
Rationale 
 
A previous dose-finding study, conducted as part of the development of Chloroprocaine HCl 
1% Sintetica SA in spinal anaesthesia, concluded that chloroprocaine at the doses of 40 and 
50 mg provide adequate spinal block for outpatient procedures lasting 45-60 min.  
Chloroprocaine HCl 1%, Sintetica SA, has been approved in 2012 in Europe (PAR - Ampres 
10 mg/mL solution for injection, Chloroprocaine Hydrochloride, DE/H/2866/001/DC) and is 
presently on the market in several European Countries under the brand name of 
Ampres/Clorotekal/Decelex, at the recommended doses of 40 and 50 mg, for spinal 
anaesthesia in adults where the planned surgical procedure should not exceed 40 min (SmPC 
Ampres 10 mg/10 mL). 
 
The present prospective, randomised, blind observer study will be conducted according to the 
principles of Good Clinical Practice, with the same study design and procedures as the 
previously performed study (26), in order to confirm the efficacy of preservative-free 
chloroprocaine HCl 1% at the previously investigated doses. The dose of 30 mg will be 
further investigated in the present study, with the aim of verifying and confirming its efficacy 
(i.e. adequate duration of spinal block) in consideration of the approved indication in Europe 
and its use in the clinical practice for surgeries not exceeding 40 min. Moreover, plasma 
concentrations of chloroprocaine and its metabolite CABA and urinary CABA excretion will 
be investigated using a sensitive LC-MS/MS analytical method, to confirm the low systemic 
exposure to chloroprocaine following spinal injection. Drug exposure data will provide 
information on systemic safety of chloroprocaine HCl 1% administered intrathecally.  
 
1.3 
Risk and benefits 
 
There are no direct benefits to the patients participating in the study. 
 
The risks for the study patients are anticipated to be low, considering that systemic adverse 
reactions following appropriate use of intrathecal 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 for the proposed indications. In addition Chloroprocaine HCl 1% Sintetica SA 
has been approved for the indication of spinal anaesthesia in several EU member states. 
 
Described serious and persistent neurological complications following intrathecal 
administration of chloroprocaine were shown to be caused by the added preservative agents 
(such as sodium bisulphate and metabisulphite). No evidences exist that preservative free 
chloroprocaine is neurotoxic in doses appropriate for spinal anaesthesia. 
 
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 
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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, pruritis, erythema, angioneurotic edema (including laryngeal oedema), tachycardia, 
sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and 
possibly, anaphylactoid type symptomatology (including severe hypotension).  
 
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2 
STUDY OBJECTIVES 
 
The objective of this study is to evaluate the effect of the three doses of Chloroprocaine HCl 
1% (30, 40 and 50 mg) for spinal anaesthesia in adult patients undergoing short duration 
elective surgery of the lower limb. 
 
2.1 
Primary end-point 
 
The primary end-point of the study is to evaluate the efficacy of the three Chloroprocaine HCl 
1% doses (30 mg [D1], 40 mg [D2] and 50 mg [D3]) in terms of time to complete regression 
of spinal block (Tea). 
 
2.2 
Secondary end-points 
 
The secondary study end-points are: 
 
 
To evaluate the efficacy of three Chloroprocaine HCl 1% doses (D1, D2 and D3) in terms 
of Time to onset of sensory block (Tsb), Time to onset of motor block (Tmb), Time to 
readiness for surgery (Trs), Time to resolution of motor block, Time to unassisted 
ambulation (Tua), Time to resolution of sensory block to S1 (TS1), Sensory block 
metameric levels during the block, Maximum level of sensory block (SBmax), Time to 
maximum level of sensory block (Tsbmax), Time to regression of two dermatomers with 
respect to the maximum level of sensory block (Trd), Time to first spontaneous urine 
voiding (Tuv), Time to administration of rescue anaesthesia or rescue analgesia (Tra), 
Time to first post-operative analgesia (Tpa), Time to eligibility for home discharge (Thd), 
proportion of patients achieving effective anaesthesia, quality of spinal block 
 
To assess the concentration of chloroprocaine and its metabolite 2-chloro-4-
aminobenzoic acid (CABA) in plasma after administration of D1, D2 and D3 
 
To assess the excretion of the CABA in urine (as % of the administered dose) 
 
To investigate the safety and tolerability of the administered Chloroprocaine HCl 1% 
doses on the basis of treatment emergent adverse events, transient neurological symptoms 
(TNS), vital signs (blood pressure, heart rate and peripheral oxygen saturation [SpO2]) 
check and ECG recording. 
 
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3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of products 
 
TEST (T) 
 
IMP 
Chloroprocaine HCl 1% (10 mg/mL)  
Manufacturer and Supplier 
Sintetica S.A., Switzerland 
Pharmaceutical form 
Solution for injection (5-mL ampoule) 
Dose 
D1: 3 mL corresponding to 30 mg chloroprocaine HCl 
D2: 4 mL corresponding to 40 mg chloroprocaine HCl 
D3: 5 mL corresponding to 50 mg chloroprocaine HCl 
Administration route 
Intrathecal 
 
3.1.2 
Dose regimen 
 
Patients will be randomised to one of three treatment groups to receive Chloroprocaine HCl 
1% as anaesthetic before surgery, at one of three dose levels according to the randomised, 
parallel-group design of the study. 
 
In details: 
 
Patients in D1 group will receive a single dose of 3 mL Chloroprocaine HCl 1% 
(corresponding to 30 mg chloroprocaine HCl)  
 
Patients in D2 group will receive a single dose of 4 mL Chloroprocaine HCl 1% 
(corresponding to 40 mg chloroprocaine HCl) 
 
Patients in D3 group will receive a single dose of 5 mL Chloroprocaine HCl 1% 
(corresponding to 50 mg chloroprocaine HCl). 
The doses are summarised in the following scheme: 
 
Table 3.1.2.1 
Dose groups 
Dose group 
N of patients 
IMP 
Dose 
D1 
15 
Chloroprocaine HCl 1% 
30 mg 
D2 
15 
40 mg 
D3 
15 
50 mg 
 
The investigational product will be provided in 5-mL ampoules. The volume corresponding to 
the three doses to be injected in the three treatment groups (i.e. 3, 4 and 5 mL) will be taken 
from the ampoule using a graduated syringe. The residual amount will be collected from the 
ampoule using another graduated syringe, completely sealable, and retained for drug 
accountability together with the empty ampoule (§ 3.4). 
 
3.1.3 
Route and method of administration 
 
Before the placement of the spinal block, according to the investigator’s opinion, patients will 
be premedicated with os midazolam and, if needed, 7 mL/kg of Ringer’s solution, according 
to standard medical procedures. 
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The investigational product Chloroprocaine HCl 1% will be administered by intrathecal 
injection to the patients at the three doses reported above (15 patients/dose group).  
 
The skin area where the injection is performed will be aseptically prepared according to the 
routine procedure of the hospital (e.g. chlorhexidine; iodine-based disinfectants must not be 
used; see § 5.3.1). Before and during spinal block, vital signs (blood pressure, heart rate), 
SpO2 and ECG (if foreseen by the hospital procedures) will be monitored every 10 min until 
the end of the anaesthesia, according to the standard procedures of the hospital. 
 
The investigational product will be injected with a syringe provided with a 25-gauge Whitacre 
spinal needle (Pencil point needle). The needle hole will be oriented towards the skull 
(caudocranial direction of the needle). 
The injection will be performed using a midline approach, at the L3/L4 or L4/L5 interspaces, 
with the patient in the lateral decubitus position (or sitting position if more appropriate) and 
the area to be operated distally located.  
After the lumbar puncture and after verifying the spontaneous flow of liquor at the beginning 
and at the end of the procedure, two short aspirations will be done to verify the proper 
positioning of the needle. Barbotage must be avoided. In case of incomplete anaesthesia, 
sedative, analgesics or anaesthetics should be administered. 
 
Post-operative analgesia will be given to all patients, if necessary, according to the hospital 
standard procedures.  
 
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. Since this is an observer-blind study, the 
physician placing the spinal block will not be further involved in patient’s care and data 
recording.  
 
3.2 
Packaging and labelling 
 
Packaging and labelling will be carried out by the Sponsor according to the randomisation 
list. The primary packaging for the investigational product will be a 5-mL glass ampoule 
packed in individual carton packages (patients’ kits). Each patient kit will contain the glass 
ampoule with the IMP and a sealable graduated syringe for the collection of the residual 
product after administration (see § 3.1.2). 
 
Labelling in local language will report all the information requested according to the Annex 
13 to the Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4). 
 
Labelling on packages will report   
a) 
Name, address and telephone number of the sponsor and CRO;  
b) 
Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency;  
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
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;  
 
3.3 
Storage conditions 
 
The test product must be stored at a temperature ≤ 25°C. The test product will be stored in a 
dry locked place, sheltered from light. The product will not be refrigerated or frozen. 
 
3.4 
Drug accountability 
 
The investigational product will be provided directly to the pharmacy of the clinical site 
investigator by the sponsor, in excess of the amount necessary for the study (at least 25% 
excess). 
 
After receipt of the investigational products supply, the pharmacist will confirm in writing by 
signing and dating standard drug delivery forms. 
 
At the end of the study, used, unused and partially used supplies of test investigational 
product provided by the sponsor/manufacturer will be either destroyed on site (upon written 
authorisation) or returned to the sponsor/manufacturer (upon written authorisaztion), after 
assessment of drug accountability. 
 
 
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Study protocol CRO-14-122 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
This is a prospective, single centre, randomised, parallel-group, observer-blind, three doses, 
efficacy and pharmacokinetic study. 
 
4.2 
Discussion of design 
 
Several dose-finding studies in adult volunteers evaluated spinal block characteristics of 
chloroprocaine at different doses, supporting its potential usefulness for outpatient surgery. In 
a randomised, double blind investigation on the intrathecal injection of 3 doses of 
Chloroprocaine HCl 1% in adult patients (parallel groups), doses of 40 and 50 mg of 
Chloroprocaine HCl 1% (Sintetica SA) provided adequate spinal anaesthesia for lower limb 
elective outpatient procedures lasting <40 - 60 min (26). In that study, the 30 mg dose 
provided a faster regression of the spinal block compared with the 40 and 50 mg doses and in 
the clinical practice the 30 mg dose resulted in a spinal anaesthesia of sufficient duration for 
surgical procedures < 40 min.  
 
Chloroprocaine HCl 1%, Sintetica SA, has been approved in 2012 in Europe (PAR - Ampres 
10 mg/mL solution for injection, Chloroprocaine Hydrochloride, DE/H/2866/001/DC) and is 
presently on the market in several EU countries (see § 1.2) at the recommended doses of 40 
and 50 mg, with the therapeutic indication of spinal anaesthesia in adults where the planned 
surgical procedure should not exceed 40 min (SmPC Ampres 10 mg/mL). 
The design of the present study is based on the previously performed study (26), in order to 
confirm the results obtained with the doses of 40 and 50 mg and to further investigate the 
dose of 30 mg, with the aim of verifying and confirming its efficacy (i.e. adequate duration of 
spinal block) in consideration of the approved indication in Europe and its use in the clinical 
practice for surgeries not exceeding 40 min. In the study in fact only patients scheduled for 
surgical procedures of a duration < 40 min will be included. 
 
The study is randomised to control for bias. 
 
Due to the different volumes of the anaesthetic solution that will be used for the three doses, 
the study will be observer-blinded. In fact, the investigator placing the spinal block will be 
aware of the treatment administered. There will be no possibilities of administering the 
different doses in a way that will make them unrecognizable. However, the physician placing 
the spinal block will not be further involved in patient’s care and data recording and all the 
study variables will be evaluated and recorded by an investigator, or his/her deputy, blinded to 
the dose injected. 
 
Elimination of local anaesthetics from the cerebrospinal fluid following intrathecal injection 
occurs by diffusion and vascular absorption. However, only few PK studies have been 
performed with local anaesthetics administered intrathecally (34-36) and some understanding 
comes from computational models of CSF dynamics.  
No studies on chloroprocaine or its metabolite plasma pharmacokinetics after intrathecal 
injection have been performed and studies with chloroprocaine 2 and 3% chloroprocaine in 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
epidural anaesthesia indicated a low plasma exposure and early disappearance of the parent 
drug. Plasma levels of chloroprocaine after spinal injection are expected to be negligible. 
 
Thus, concentrations of chloroprocaine in plasma after spinal injection will be investigated in 
the present study at the three administered doses using a sensitive LC-MS/MS analytical 
method to confirm the low systemic exposure to this anaesthetic following spinal injection. 
Most importantly, drug exposure data will provide information on systemic safety of 
chloroprocaine HCl 1% administered intrathecally.  
 
Considering the short half-life of chloroprocaine (approximately 25 sec in vitro, 2-6 min in 
vivo), the sampling time of 5 min post-dose has been chosen in order to try to detect the drug 
in plasma before its complete hydrolysis. Additional sampling times are 10, 30 min and 1 h 
post-dose.  
 
In addition, the product of cholinesterase hydrolysis, i.e. the metabolite 2-chloroaminobenzoic 
acid (CABA), will be determined in plasma up to 1 h post-dose. Plasma levels of the 
metabolite should be much higher than for the parent drug, according to a previous work 
performed with chloroprocaine administered through an epidural catheter (37). 
 
The metabolite will also be analysed in urine collected at the first urine voiding time, in order 
to evaluate chloroprocaine bioavailability in terms of percentage of metabolite product 
excreted in the urine in relation to the administered dose of chloroprocaine (molar ratio).  
 
In the present study the occurrence of TNS, which have been reported after spinal anaesthesia, 
(see SmpC) will be carefully monitored.  
In addition, for all intrathecal injections a Pencil point needle, 25 Gauge diameter, will be 
used in order to decrease the risk of PDPH occurrence.  
It is to note, however, that no TNS were reported in previous clinical trials in adults using 
Sintetica Chloroprocaine HCl 1% (1,26).  
 
Occurrence of clinically relevant hypotension (defined as a decrease in systolic arterial blood 
pressure by approximately 30% or more from baseline values) and bradycardia (defined as 
heart rate decrease below 45 beats per minute) will be monitored throughout the study and if 
observed appropriately treated. 
 
Premedication with midazolam will be used for sedation in patients to reduce possible anxiety 
before the operation. This is common clinical practice. 
 
 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
5 
STUDY POPULATION 
 
5.1 
Target population 
 
Forty-five (45) male/female patients, 15/dose group, aged 18-80 years, scheduled for lower 
limb surgery (< 40 min) under spinal block, i.e. requiring ≥ T12 metameric level of sensory 
block. 
 
5.2 
Inclusion criteria  
 
To be enrolled in this study, subjects must fulfil all these criteria: 
 
1. Sex, age and surgery: male/female patients, 18-80 years old, scheduled for short duration 
(less than 40 min) lower limb surgery requiring ≥ T12 metameric level of sensory block 
2. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive 
3. ASA physical status: I-III 
4. Informed consent: signed written informed consent before inclusion in the study 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study  
 
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 spinal anaesthesia. History of 
neuromuscular diseases to the lower extremities 
2. ASA physical status: IV-V 
3. Further anaesthesia: patients expected to require further anaesthesia  
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or 
formulations ingredients; ascertained or presumptive hypersensitivity to the ester type and 
major anaesthetics  
5. 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 and neurological diseases, sepsis, blood coagulation 
disorders, severe cardiopulmonary disease, thyroid disease, diabetes or other neuropathies 
6. 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 
7. Drug, alcohol: history of drug or alcohol abuse 
8. Blood donation: blood donations in the 3 months before this study 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
9. Pregnancy and lactation: missing or positive pregnancy test at screening, pregnant or 
lactating women 
10. Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, 
antidepressants, anticonvulsant agents or chronic analgesic therapy) 
11. Medications: medication known to interfere with the extent of spinal blocks for 2 weeks 
before the start of the study. Hormonal contraceptives for females are allowed. 
 
5.3.1 
Not allowed treatments and other treatments 
 
No medication known to interfere with the extent of spinal block (see chloroprocaine SmPC), 
in particular no therapeutic use of opioids, will be allowed for 2 weeks before the start of the 
study and during the whole study duration. Hormonal contraceptives for women are allowed. 
 
The area to be operated will be aseptically prepared with disinfectants, e.g. chlorhexidine, not 
containing iodine. Iodine-based disinfectants must not be used. The information on the iodine-
free disinfectant used for each patient will be reported in the individual CRFs. 
 
Before the placement of the spinal block, if needed, patients will be premedicated with os 
midazolam and, only if necessary, 7 mL/kg of Ringer’s solution administered by infusion, 
according to the investigator’s opinion. 
Post-operative analgesia will be given to all patients, if necessary, according to the hospital 
standard procedures. 
 
 
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Study protocol CRO-14-122 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
6.1 
Study visits and procedures 
 
The study protocol foresees a screening visit, one study treatment for each patient, followed 
by post-operative recovery, final visit and 2 follow-ups. Maximum study duration will be 22 
days, screening visit and follow-up included. A written informed consent will be obtained 
before any study assessment or procedure. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last telephonic 
follow-up 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. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening - visit 1: between day -14 and day 1 
 
 Treatment phase 
 Visit 2 - day 1: anaesthesia and surgery 
 
 Follow-up phase 
 Post-operative recovery – day 1 (immediately after surgery) 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 Day 2 (i.e. 24 h after surgery) - Telephonic follow-up, if the patient has left the 
hospital on day 1 
 Day 7±1 (6±1 days after surgery) - Telephonic follow-up 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
 
Day 
Procedures/Assessments 
Notes 
Screening - Visit 1 
From day -14 
 to day 1 
 
Explanation to the subject of study aims, 
procedures and possible risks 
 
Informed consent signature 
 
Screening number (as S001, S002, etc.) 
 
Demographic data and life style recording 
 
Previous/concomitant medications 
 
Routine pre-surgery assessments according to the 
hospital 
standard 
procedures, 
including 
medical/surgical history, physical examination, 
height, weight, vital signs (blood pressure, heart 
rate), SpO2  
 
Urine pregnancy test for women  
 
Inclusion/exclusion criteria evaluation 
 
AE monitoring 
 
Treatment - Visit 2 
Day 1 
 Concomitant medications 
 Adverse events (before, during and after block 
placement and surgery) 
 Inclusion/exclusion criteria evaluation 
 Subject randomisation 
 Vital signs, SpO2 and ECG (if foreseen by the 
standard hospital procedures)  
 Premedication: os midazolam and 7 mL/kg 
Ringer’s solution, if needed 
 Anaesthesia administration (intrathecal injection) 
 Post-operative analgesia according to the hospital 
standard procedures 
 Sensory and motor block assessments, including 
sensory block metameric level 
 Quality of spinal block assessment 
 Surgery (< 40 min) 
 Blood sampling for PK analysis at pre-dose (0h) 
and at 5, 10, 30 and 60 min after spinal puncture 
 Urine collection for PK analysis at the time of first 
urine voiding 
 
Final Visit/ETV 
Day 
1/2 
or 
upon 
discontinuation 
for ETV  
 Final assessments before discharge according to the 
hospital’s standard procedures  
 Aldrete’s scoring scale 
 Vital signs (BP, HR, SpO2) and ECG (if foreseen 
by the standard hospital procedures)   
 AE and concomitant medications 
 Discharge (when criteria for discharge are met and 
according to the hospital’s standard procedures) 
 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator until 
the normalisation of the concerned clinical parameter(s) 
Standardised meals will 
be served according to 
the hospital procedures. 
Patients 
will 
be 
discharged on Day 1 or 
on a following day after 
the criteria for discharge 
are met and according to 
the hospital’s standard 
procedures. 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
Day 
Procedures/Assessments 
Notes 
Follow-
up 
Day 2 (24 h 
after surgery) 
 AE, in particular TNS (questionnaire)  
 concomitant medications 
 
Follow-
up 
Day 7±1  
post-surgery 
 AE, in particular TNS (questionnaire)  
 concomitant medications 
 
 
6.2 
Diet and lifestyle 
 
Study participants will undergo study procedures as outpatients or in-patients, according to 
the decision of the study investigator. Patients will arrive at the clinical centre either in the 
morning of the scheduled surgery day or the previous evening, according to the hospital 
requirements, and will be discharged on Day 1 or on a following day after meeting the criteria 
for discharge, according to the hospital procedures.  
 
On day 1, patients will be under fasting conditions before surgery. Clear fluids intake is 
allowed until 2 h before surgery. The patients will remain under fasting conditions until 
surgery has been completed and according to the investigator’s opinion. Meals will be served 
according to the hospital’s standard procedures. 
 
 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Full physical examinations, including body weight and evaluation of the physical status 
according to ASA general relative values, will be performed at the pre-surgery (screening) 
visit.  
 
7.1.1 
Vital signs 
 
Patients’ blood pressure (BP), heart rate (HR) and peripheral oxygen saturation (SpO2)  will 
be measured by the investigator or his/her deputy after 5 min at rest (sitting position) 
according to the hospital procedures.  
The following normal ranges for haemodynamic variables will be used: 
 
• 
Systolic Blood Pressure: 100-139 mmHg 
• 
Diastolic Blood Pressure: 50-89 mmHg 
• 
Heart Rate: 50-90 beats/min 
• 
Peripheral Oxygen Saturation: ≥ 95% 
 
SpO2 values < 95% but ≥ 92% will be considered not clinically significant. 
 
Haemodynamic variables (BP, HR and SpO2), will be recorded at screening, at baseline 
(before the block) then every 10 min from spinal injection until the end of the anaesthesia. 
Standard monitors will be used according to ASA recommendations. SpO2 should be ≥ 92% 
during the monitoring period. 
Blood pressure, heart rate and SpO2 will be monitored also at post-operative recovery and 
final visit. To meet criteria for discharge, the patients’ haemodynamic variables must be stable 
and SpO2 must be acceptable (> 92%). 
 
Screening, baseline and final/early termination assessments of haemodynamic variables and 
any other assessment judged clinical significant will be reported into the CRF. 
 
Occurrence of clinically relevant hypotension (defined as a decrease in systolic arterial blood 
pressure by approximately 30% or more from baseline values) and bradycardia (defined as 
heart rate decrease below 45 beats per minute) will be monitored throughout the study and if 
observed appropriately treated. 
 
7.1.2 
ECGs 
 
ECG (if foreseen by standard hospital procedures) will be monitored using standard monitors 
at baseline (before block placement), during the block (every 10 min) and at post-operative 
recovery / final visit  
 
The following normal ranges for ECG parameters will be used: 
 
• 
Heart Rate: 50-90 beats/min 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
• 
PR Interval: 100-220 msec 
• 
QRS Duration: ≤ 120 msec 
• 
QT Interval: ≤ 500 msec 
 
Any assessment judged as clinical significant will be reported in the CRF. 
 
7.1.3 
Assessment of adverse events 
 
For the definition of adverse events please refer to § 11. 
 
Adverse events will be assessed throughout the study from the signature of the informed 
consent up to the second follow-up (day 7±1).  
 
Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.  
 
Any complication during anaesthesia, e.g. paraesthesia and micturition disorders will be 
recorded. 
 
Patients will be questioned about the occurrence of treatment-emergent adverse events 
(TEAEs; see § 10.6). Particular attention will be given to systemic and local toxicity 
symptoms, neurological symptoms and allergic reactions. The occurrence of headache and of 
lower limbs and gluteus paraesthesia will be carefully checked. Patients will also be instructed 
to report signs of systemic (central nervous system) toxicity.  
 
Particular attention will be given to the possible occurrence of transient neurological 
symptoms (TNS). In particular the incidence of TNS and unusual sensations not associated to 
the operation area will be assessed at 24 h and day 7 after surgery through a telephonic 
interview (if the patient has already left the hospital). A specific questionnaire will be filled-in 
and the following symptoms will be questioned (see Appendix 1): 
 
 Well being 
 fatigue 
 nausea/vomiting 
 dizziness 
 urination/defecation difficulty 
 pain at the site of injection 
 pain at the site of surgery 
 unusual sensations (burning, tingling, dull, aching, numbness, hypoesthesia or other 
sensations) 
 location of the symptoms (buttocks, thighs anterior, thighs posterior, lower limbs, 
sacrum, calves or back [one sided or bilateral]) 
 previous experience of such symptoms 
 
The questionnaire will be reviewed by the investigator who will judge whether the reported 
symptoms could be classified as TNS on the basis of the available evidence and referring to 
the diagnosis criteria reported by Pollock et al. (15) and ASA, and summarized in the table 
below: 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
Table 7.1.3.1 
Differential diagnosis criteria for TNS and other events following intrathecal injection     
Event 
Onset – Duration 
Symptoms 
Treatment 
TNS 
6-36 h after spinal or 
epidural 
anaesthesia/1-7 
days 
Unilateral or bilateral 
pain in the anterior or 
posterior thigh ± 
extension into legs ± back 
pain 
No motor weakness 
No neurological 
abnormalities 
NSAIDs, opioids, warm 
heat, trigger-point 
injections 
Epidural haematoma 
0 - 2 days 
Muscle weakness, 
radicular back pain, 
sensory deficit 
CT scan, neurological 
consult, surgical 
decompressive 
laminectomy 
Epidural abscess 
2 - 7 days 
Backache, progressive 
neurological symptoms ± 
fever 
Antibiotics, possible 
surgical drainage 
Spinal nerve injury 
0 - 2 days/1 - 12 weeks 
Pain during insertion of 
needle or catheter, pain 
on injection, paraesthesia, 
pain and numbness over 
distribution of nerve root 
May need EMG to assess 
baseline neurological 
status 
Anterior 
spinal 
artery 
syndrome 
Immediate 
Postoperative painless 
paraplegia 
If secondary to 
vasospasm may respond 
to vasodilating drugs and 
hypertensive therapy 
Adhesive arachnoiditis 
0 months 
Pain on injection, variable 
degree of neurological 
deficit, often progressive, 
with pain and paraplegia 
Diagnosis by CT, MRI or 
myelography. No 
effective treatment 
Cauda equine syndrome 
0 days 
Loss of bowel and 
bladder function, 
paraplegia, motor 
weakness, sensory loss 
No effective treatment 
 
7.2 
Block assessment 
 
The evolution of both sensory and motor blocks, including sensory block metameric level, 
will be evaluated by a blinded observer every 2 min until readiness for surgery, every 5 min 
until the maximum level is reached (two consecutive observations with the same level of 
sensory block) and then every 5 min until regression of two dermatomers with respect to the 
maximum level of sensory block. After that, the efficacy assessments will be repeated every 
30 min until regression of spinal block and complete regression of sensory block to S1 (if 
compatible with surgical procedure).  
 
Block assessment times should not deviate more than the recommended deviation time ranges 
summarised in the following table. 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
Table 7.2.1 
Recommended maximal deviations from the scheduled block assessment times 
Block assessment times 
Deviation 
Every 2 min until readiness for surgery 
--- 
Every 5 min until the maximum level is reached 
± 1 min 
Every 5 min until regression of two dermatomers with respect to 
the maximum level of sensory block 
± 1 min 
Every 30 min until regression of spinal block and complete 
regression of sensory block to S1  
(if compatible with surgical procedure) 
± 5 min 
 
Any deviations from the scheduled block assessment times outside the recommended ranges 
will be verified through Data Clarification Forms. If for a subject more than 20% of the actual 
block assessment times will be outside the recommended ranges, the concerned subject will 
be excluded from the Per Protocol set. 
 
Sensorial block will be verified by bilateral Pinprick test using a 20-G hypodermic needle and 
will be recorded. Pinprick sensation will be scored as being present (score 1) or absent (score 
0). 
 
Motor block will be verified using a modified Bromage scale (0=no block; 1=hip blocked; 
2=hip and knee blocked; 3=hip, knee and ankle blocked).  
 
Readiness for surgery is defined as the presence of an adequate motor block (Bromage’s 
score ≥ 2, Tmb) and loss of Pinprick sensation at the required metameric level ≥ T12 (Tsb). 
 
Effective anaesthesia is defined as the presence of adequate sensory and motor blocks, as 
defined above, with adequate duration to cover surgery. The quality of spinal block will be 
verified according to the need for supplementary intravenous analgesics and sedation as 
follows:  
 adequate spinal block=neither sedation nor analgesics required to complete surgery; 
 inadequate spinal block= additional anaesthesia or analgesia (e.g. 2 µg/kg mg IV bolus of 
fentanyl) required to complete surgery; 
 failed spinal block = general anaesthesia required to complete surgery.  
 
Duration of surgery will also be recorded.  
 
A detailed description of the surgical procedure and of the concomitant medication during 
surgery will be given in the CRF. Time of end of anaesthesia (complete regression of spinal 
block), defined as the time when Bromage score returns to 0 (resolution of motor block) and 
sensitive perception returns to S2 will be recorded on the CRF. 
Time when analgesia is required will be noted. The analgesic used and its dosage will be 
recorded in the CRF.  
The time to unassisted ambulation and to first urine voiding will be recorded. 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
7.3 
Procedures for discharge 
 
At the end of the surgical procedure, patients will be moved to the post-operative recovery 
room, where they will stay until the criteria for discharge are met according to the hospitals’ 
standard procedures. In general, to meet criteria for discharge, patients must have a score ≥ 18 
on the modified Aldrete’s scoring scale (39,40; Appendix 2). Haemodynamic variables must 
be stable and SpO2 must be acceptable (> 92%) without oxygen therapy.  
Patients will be asked about any adverse events, with particular attention to local toxicity and 
neurological symptoms, such as paraesthesia of the gluteus and of the lower limb, and to 
possible allergic reactions (e.g. urticaria). If all the criteria are met and no adverse reactions 
occur, the patient will be discharged according to the hospital’s standard procedures. 
 
7.4 
Sampling for pharmacokinetic analysis 
 
7.4.1 
Venous blood sampling 
 
Venous blood samples (8 mL) for PK analysis will be collected from a forearm vein at the 
following times:  
 
 Before spinal puncture (pre-dose, 0 h), 5, 10, 30 and 60 min post-dose 
 
Actual sampling times for each subject will be recorded in the individual case report forms 
(CRFs).  
Deviations in actual sampling times should not exceed the recommended ranges reported in 
the following table. Any deviations outside the recommended ranges will be verified through 
Data Clarification Forms and will not automatically lead to the exclusion of the concerned 
subjects from the PK Sets. 
 
Table 7.4.1.1 Recommended maximal deviations from the scheduled sampling times 
Sampling time 
Deviation 
Pre-dose (0) 
Within 60 minutes before IMP administration 
5 min, 10 min 
0 min 
30 min 
± 1 min 
60 min 
± 3 min 
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch 
valve or by direct venipuncture. If using the catheter, if feasible, the cannula will be rinsed, 
after each sampling, with about 1 mL of sterile saline solution containing 20 I.U./mL Na-
heparin. The first 2 mL of blood will be discarded at each collection time to avoid 
contamination of the sample with heparin. 
Six (6) mL of blood will be either directly collected or transferred from the catheter with a 
syringe into heparinised tubes (Li-heparin) containing an esterase inhibitor. The tubes will be 
gently inverted for 10 times and then put on ice. Then, within 15 min from collection, the 
samples will be centrifuged at 4° C for 10 min at 2000xg to obtain plasma. Each plasma 
sample will be immediately divided into two aliquots of 1 mL each, P1 and P2, in pre-labelled 
polypropylene tubes, and stored frozen at ≤-70° C until analyses.  
 
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Final version 1.0, 03OCT14 
7.4.2 
Urine collection 
 
Bladder must be emptied before the anaesthetic injection, if possible.  
 
Urine for PK analysis will be collected at the time of first urine voiding.  
 
The urine will be collected into containers, urine volume will be measured and after thorough 
mixing two aliquots of 10 mL each (U1 and U2) will be prepared in polypropylene tubes. The 
two aliquots will be stored at ≤-70° C until analyses.  
If the collected urine cannot be immediately processed, the complete sample will be kept 
refrigerated at approximately 4° C before measurement of volume and aliquots preparation.  
 
7.4.3 
Analytics  
 
The concentration of chloroprocaine and its metabolite CABA in plasma and of CABA in 
urine will be determined at Accelera Srl, Italy, using a fully validated LC-MS/MS method. 
The lower quantification limit (LQL) will be specified in the validation report and analytical 
plan. 
Analyses will be performed according to the general Principles of “OECD Good Laboratory 
Practices for testing of chemicals" C(81) 30 (final) and to the FDA guideline for the 
validation of bioanalytical methods. 
The method validation report, the analytical plan and the analytical report will be attached to 
the final report. 
 
7.4.4 
Labelling, storage and transport of samples 
 
7.4.4.1 
Samples labelling 
 
Each sample tube will be clearly and unequivocally identified with a label resistant to the 
storage temperature and reporting: 
Study code 
Study CRO-14-122 - Sponsor code CHL.1/02-2014 
Subject number 
1-45 
Tube identification 
P1/P2, U1/U2 
Scheduled sampling time as h; see § 7.4.1 
 
7.4.4.2 
Samples storage and transport 
 
During the study the samples will be stored at ≤-70° C.  
 
All aliquots 1, packed in sufficient solid CO2, will be shipped by an authorised courier from 
the clinical site (Istituto Ortopedico Rizzoli, Bologna), Italy to the analytical laboratory, 
Accelera, Italy. Aliquots 1 will remain stored at the analytical laboratory for a maximum time 
of 6 months. Afterwards, the samples will be destroyed and a certificate of destruction will be 
provided to the sponsor. 
The counter-samples (aliquots 2) will remain stored either at the analytical laboratory or at the 
clinical site. These samples could either be: 
 sent to the laboratory for reanalysis should this become necessary for analytical reasons 
or if any problems occur during the delivery of aliquots 1, or 
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 destroyed at an authorised site, or 
 transferred to the sponsor upon written request, or 
 stored at the clinical site, for a maximum time of 5 years 
 
No analyses different from those stated in this protocol and agreed by the subjects when 
signing the informed consent form will be performed unless a new informed consent and a 
new approval from the Ethical Committee is obtained. The subjects may ask to destroy their 
own samples at any time. 
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8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomisation 
 
The randomisation list will be computer generated by the Biometry Unit of the Clinical 
Contract Research Organization (CRO), using the PLAN procedure of the SAS® system 
version 9.3 (TS1M1) (41) or higher for Windows (the version will be stated in the final 
clinical study report). The randomisation list will be attached to the final clinical study report. 
 
8.2 
Treatment allocation 
 
Patients will be allocated to D1, D2 or D3 dose group in a 1:1:1 ratio according to the study 
randomisation list.  
 
Randomisation number will be given to the patients on study Day 1 and will be used to 
allocate each patient to a dose group, as detailed above. 
 
The 5-mL ampoules with the investigational product will be numbered. Each patient will be 
allocated the product ampoule corresponding to his/her randomisation number. 
 
8.3 
Blinding 
 
This is an observer-blind study. No masking procedure will be applied.  
 
The physician preparing and the physician administering the doses will not be involved in 
data recording and evaluation. An independent blinded observer will evaluate sensory and 
motor blocks for each patient. 
 
Emergency envelopes containing individual randomisation codes will be sent to the clinical 
centre. 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 clinical centre 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 in such a way that the observer blind condition of the study is maintained. The 
date and the reason for kit replacement envelope opening will be recorded on the envelope. 
 
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9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary variable 
 
Time to regression of spinal block (Tea), defined as the time when Bromage score returns to 0 
and sensitive perception returns to S2.  
 
9.1.2 
Secondary variables 
 
Efficacy variables: 
 Time to onset of sensory block (Tsb),  
 Time to onset of motor block (Tmb),  
 Time to readiness for surgery (Trs), defined as loss of pinprick sensation at the required 
metameric level ≥ T12 with a modified Bromage score ≥ 2, 
 Time to resolution of motor block (Bromage score = 0; Trmb), 
 Time to unassisted deambulation (Tua),  
 Time to resolution of sensory block to S1 (TS1), 
 Sensory block metameric level (assessed until resolution of sensory block to S1) 
 Maximum level of sensory block (SBmax), 
 Time to maximum level of sensory block (Tsbmax) 
 Time to regression of two dermatomers with respect to the maximum level of sensory 
block (Trd), 
 Time to eligibility for home discharge (Thd), 
 Time to first spontaneous urine voiding (Tuv), 
 Time to administration of rescue anaesthesia or rescue analgesia (Tra),  
 Time to first post-operative analgesia (Tpa), 
 Proportion of patients achieving an effective anaesthesia, 
 Quality of spinal block. 
 
Pharmacokinetic variables 
 Plasma concentrations of chloroprocaine and CABA at baseline (i.e. before spinal 
puncture) and at 5, 10, 30 and 60 min after spinal puncture 
 Urine excretion of CABA from spinal puncture to time of first urine voiding 
 
Safety variables: 
 Treatment-emergent adverse events throughout the study, 
 Incidence of TNS at 24 h and day 7 after spinal puncture (Tsp), 
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 Vital signs (BP, HR and SpO2); ECG. 
 
9.2 
Efficacy assessments 
 
Sensory and motor block assessment procedures and evaluations are detailed in § 7.2. 
 
Efficacy assessments are based on the following variables: 
 
Parameter 
Description 
Time to onset of sensory 
block (min) (Tsb) 
Time period from spinal injection (Tsp; time 0 h) to achievement 
of sensory block (as defined in § 7.2). 
Time to onset of motor 
block (min) (Tmb) 
Time period from spinal injection (Tsp; time 0 h) to achievement 
of motor block (as defined in § 7.2). 
Time to readiness for 
surgery (min) (Trs) 
Time period from completion of spinal injection (Tsp; time 0 h) to 
achievement of sensory and motor block adequate for surgery, i.e. 
loss of Pinprick sensation and Bromage’s score ≥ 2 at the required 
metameric level ≥ T12 
Time to regression of 
spinal block (min) (Tea) 
Time period from spinal injection (Tsp; time 0 h) to the time when 
the Bromage score returns to 0 and sensitive perception returns to 
S2 
Time to resolution of 
sensory block to S1(min) 
(TS1) 
Time period from spinal injection (Tsp; time 0 h) to the time when 
sensitive perception has returned to S1 
Time to resolution of 
motor block  
Time period from spinal injection (Tsp; time 0 h) to the time when 
the Bromage score has returned to 0 
Time 
to 
unassisted 
ambulation (Tua) 
Time period from spinal injection (Tsp; time 0 h) to the time when 
the patient can walk unassisted 
Sensory block metameric 
level 
Metameric level of sensory block assessed from spinal injection 
(Tsp; time 0 h) until regression of sensory block to S1 
Maximum 
level 
of 
sensory block (SBmax) 
Maximum metameric level of sensory block (decreased or absent 
sensation) achieved 
Time to maximum level 
of sensory block (Tsbmax) 
Time period from spinal injection (Tsp; time 0 h) to the time when 
the maximum metameric level of sensory block is achieved 
(consider the time of the first of the two consecutive observations 
with the same level of sensory block) 
Time to regression of 
two dermatomers with 
respect to the maximum 
level of sensory block 
(Trd) 
Time period from spinal injection (Tsp; time 0 h) to the time when 
the sensory block decrease of two dermatomers with respect to the 
maximum level of sensory block 
Time to eligibility for 
home discharge (Thd) 
Time period from spinal injection (Tsp; time 0 h) to the time when 
the criteria from discharge are met, even if according to the 
hospital procedures the patient is discharged at a later time 
 
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Time 
to 
first 
spontaneous 
urine 
voiding (Tuv) 
Time period from spinal injection (Tsp; time 0 h) to the first time 
when the patient can pass urine unassisted 
Time 
(h) 
to 
administration of rescue 
anaesthesia 
or 
rescue 
analgesia (Tra) 
Time from spinal injection(Tsp; time 0 h) to administration of first 
rescue anaesthesia or analgesia (if applicable) 
Time (h) to first post-
operative analgesia (Tpa) 
Time from spinal injection (Tsp; time 0 h) to first post-operative 
analgesia 
 
9.3 
Pharmacokinetic assessments 
 
 Plasma concentrations of chloroprocaine at pre-dose and at 5, 10, 30 and 60 min after 
spinal puncture for the three dose levels (D1, D2 and D3) 
 Plasma concentrations of CABA at pre-dose and at 5, 10, 30 and 60 min after spinal 
puncture for the three dose levels (D1, D2 and D3) 
 Urinary excretion of CABA, as percentage of administered chloroprocaine dose for the 
three dose levels (D1, D2 and D3) 
 
9.4 
Safety assessments 
 
Safety and general tolerability of the investigational anaesthetic will be based on TEAEs, 
TNS, physical examinations, vital signs and ECG.  
 
In particular, ECG (if foreseen by the standard hospital procedures), blood pressure, heart rate 
and SpO2 will be monitored as detailed in § 7.1.1 and 7.1.2.  
 
Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.  
 
Patients will be questioned about the occurrence of treatment-emergent adverse events 
(TEAEs). Particular attention will be given to TNS symptoms. Further details on the AE 
assessments are given in § 7.1.3.  
 
 
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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) (41) 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 he/she respects all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the treatment phase 
of the study. The enrolment will be performed through randomised allocation to a dose group. 
 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
dose group. 
 
 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 anaesthetics administration. Missing values of time to 
complete spinal block regression (Tea) will be replaced with the highest Tea detected in 
the corresponding treatment group. This analysis set will be used for sensitivity analysis. 
 Per Protocol set (PP): all randomised patients who fulfil the study protocol requirements 
in terms of anaesthetic administration and primary efficacy evaluation, with no major 
deviations that could affect the primary efficacy results. This analysis set will be used for 
the primary efficacy analysis.  
 PK Set 1 (PK 1): the PK set 1 will include all randomised patients who fulfil the study 
protocol requirements in terms of anaesthetic administration and have at least one post-
dose blood PK sample collected. 
 PK Set 2 (PK 2): the PK set 2 will include all randomised patients who fulfil the study 
protocol requirements in terms of anaesthetic administration and have the urine for PK 
analysis collected. 
 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, PK set 1, PK set 2 and Safety set. Subjects will be evaluated according to the 
treatment they actually receive (Enrolled set, FAS, PP set, PK set 1, PK set 2 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: 
 
failure to be administered the investigational product 
 
lack of any primary efficacy data post enrolment 
 
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: 
 
lack of compliance to the IMP 
 
exposure to an IMP different from the one assigned to the subject 
 
missing primary efficacy data 
 
more than 20% of the actual block assessment times outside the recommended ranges 
(see § 7.2) 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
 
10.1.4 
Reasons for exclusion from the PK sets 
 
Reasons for the exclusion from the PK sets include the following: 
 
lack of compliance to the IMP 
 
exposure to an IMP different from the one assigned to the subject 
 
missing of any post-dose blood sample (PK set 1) 
 
missing of urine collection for PK analysis (PK set 2) 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
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10.2 
Sample size and power considerations 
 
To calculate the required study sample size, results from a previous study with spinal 
injection of Chloroprocaine HCl 1% (26) were taken into consideration and normal 
distribution of data was assumed. Sample size was calculated using n-Query Advisor 7.0. 
When the sample size in each of the 3 dose groups is 13, a one-way analysis of variance will 
have 80% power to detect at the 0.050 level a difference in time to complete spinal block 
regression (Tea) means characterized by a variance of means, V=Σ(μi -μ)2 / G (where G=3) of 
249.962, assuming that the common standard deviation is 30.011. To be more conservative 
and to take into account possible deviations from normality, the sample size is increased of 
about 15%. Fifteen (15) patients per dose group have to be enrolled. 
 
10.3 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarised in contingency tables. Quantitative data will be 
summarised using classic descriptive statistics. 
 
10.4 
Analysis of efficacy parameters 
 
Continuous variables will be summarised by dose level groups using classic descriptive 
statistics (i.e. mean, SD, CV%, min, median and max) and categorical variables will be 
summarised by dose level groups using tables of frequencies. 
 
Due to the small sample size, collected data will be compared using nonparametric tests. 
Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, Tsbmax, Trd, Thd, Tuv, Tra and Tpa will be analysed using 
the Kruskal-Wallis test. Pairwise comparisons between dose level groups will be performed 
using the Wilcoxon rank-sum test. Comparisons will be performed according to the following 
hierarchical order: 
 
1. 
Overall comparison 
2. 
D1 (30 mg) vs. D3 (50 mg) comparison 
3. 
D2 (40 mg) vs. D3 (50 mg) comparison 
4. 
D1 (30 mg) vs. D2 (40 mg) comparison 
 
Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary 
(42). However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses 
of the subsequent comparisons cannot be rejected. 
 
The proportion of patients achieving an effective anaesthesia and the quality of spinal block 
will be summarised by dose level groups using tables of frequencies. 
 
10.5 
Analysis of pharmacokinetic parameters 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables 
and figures. Individual and mean curves (+SD at sampling times), indicating inter-subject 
variability, will be plotted. Data below the lower quantification limit (BLQL) will be 
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considered as 0 in the calculations and presented as BLQL in listings and tables. As a 
consequence of BLQL (i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). PK analysis will be performed using Phoenix WinNonlin® version 6.3 
(Pharsight Corporation). 
 
Urinary excretion of CABA will be calculated as the amount of metabolite excreted as a 
percentage of the administered dose (molar ratio). 
 
10.6 
Safety and tolerability evaluation 
 
 AEs 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of 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.  
 
 Physical examination 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see § 11), will be recorded in the subject source documents. Overall investigator’s 
interpretation (as normal, abnormal not clinically significant [NCS] or abnormal clinically 
significant [CS]) will be reported in the CRF. 
 
 Vital signs 
Screening, baseline and final/early termination assessments of haemodynamic variables and 
any other assessment judged clinical significant will be reported into the CRF and listed in the 
clinical study report. 
Screening, baseline and final/early termination values of vital signs will be summarised by 
descriptive statistics.  
 
 Body weight  
Values of body weight will be listed and summarised by descriptive statistics. 
 
 ECG 
Any ECG assessment judged clinical significant will be reported into the CRF. 
Date and time of ECG recording, overall investigator’s interpretation (as normal, abnormal 
not clinically significant [NCS] or abnormal clinically significant [CS]) and HR, PR, QRS 
and QT parameters will be reported in the CRF and listed in the clinical study report. Hard 
copies of the ECGs will be attached to the CRF. All clinically significant abnormalities after 
the screening visit will be recorded as AEs.  
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 Incidence of TNS at 24 h and day 7 after spinal puncture (Tsp) 
The incidence of TNS at 24 h and day 7 after spinal puncture (Tsp) will be summarised by 
dose level groups using tables of frequency. 
 
 
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11 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
11.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the CRO SOPs, based upon 
applicable local and international regulations. The full SOP or an operative summary will be 
made available to the clinical centre. 
 
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) 
A PTAE is any AE occurring before the first dose of a medicinal product, and not worsening 
after the first dose. The following medical occurrences and clinical investigations are the only 
clinically significant events which, according to the investigator judgement, can be defined 
and recorded as PTAEs: 
 trauma (fractures, sprains, strains, falls, domestic accidents, car accidents, etc.) 
occurred after the signature of the informed consent and before the first medicinal 
product administration 
 new measurements (vital signs, 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 
 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 
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 Treatment-emergent AE (TEAE) 
TEAE are defined as any AE occurring or worsening after the first dose of a medicinal 
product. 
 
 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event that may jeopardize the subject’s health status or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are cancer, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse 
 
 Unexpected ADR: an ADR the nature or severity of which is not consistent with the 
Reference Safety Information (RSI) 
 
 Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, the Investigator’s Brochure and SmPC (IB) of the investigational 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 
 
 Start of monitoring: from immediately after the signature of the informed consent 
 End of monitoring: last follow-up visit/ETV  
An AE occurring after the last follow-up visit/ETV and coming to knowledge of the 
investigator (e.g. by spontaneous reporting by study subjects) must be recorded only if it is an 
ADR, according to the investigator’s judgment. 
 
11.4 
AEs recording 
 
All AEs derived by spontaneous, unsolicited reports of the subjects, by observation and by 
routine open questioning should be collected and reported. 
The following minimal information will be recorded for an AE (detailed explanation for each 
element is available in the SOP or in the operative summary made available to the clinical 
centre) in the source documents and later transcribed into the CRF: 
 
1. 
Adverse Event: progressive number of the adverse event  
 
2. 
Description: verbatim description of the adverse event 
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or 
 
Follow-up: progressive number of follow-up of the adverse event  
 
3. 
Start Date/Time: start date/time of the adverse event 
or  
 
Follow-up Date/Time: follow-up date/time of the adverse event  
 
4. 
End Date/Time: end date/time of the adverse event  
 
5. 
Affected Body Area: anatomical location relevant for the event 
 
6. 
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 
 
7. 
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.  
 
8. 
Investigator's opinion about the reasonable possibility of a causal relationship with the 
study drug.  
 
9. 
Investigator's opinion about other causal relationship (e.g. non study drug, concomitant 
therapy, study device, etc.).  
 
10. 
Severity: the severity or intensity of the event 
 
• 
1 Mild  
• 
2 Moderate 
• 
3 Severe 
 
11. 
Pattern: Used to indicate the pattern of the event over time 
 
• 
1 Single Event 
• 
2 Continuous 
• 
3 Intermittent 
 
12. 
Serious Adverse Event  
 
 
13. 
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 
  
 
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14. 
Concomitant Therapy: if a concomitant therapy is given, it must be reported in the 
specific CRF forms 
 
15. 
Study Discontinuation: if the adverse event cause the subject to be discontinued from 
the study 
 
16. 
Other Action Taken: other actions taken as a result of the event that are unrelated to 
dose adjustments of study drug 
 
17. 
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/she should in any case transmit all 
the available information. The investigator should provide an appropriate follow-up of SAEs 
to all concerned parties. 
Seriousness and causality must be assessed by the investigator. Expectedness is usually 
assessed by the sponsor. 
If the investigator is unable to assess the causality it is recommended to adopt a conservative 
approach and treat the event as a suspected adverse reaction until follow-up information is 
available. 
The sponsor may also make an assessment of causality, independent of that of the 
investigator. The most conservative approach should be taken when it comes to regulatory 
reporting. Under no circumstances should the sponsor downgrade the investigator's opinion or 
put the investigator under pressure to change his/her assessment. In case of disagreement, 
both the opinion of the investigator and the sponsor should be provided on the report. 
The sponsor will evaluate the SAE expectedness on the basis of the RSI. 
 
11.6 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the sponsor (day 0).  
For fatal and life-threatening SUSARs the EC and Competent Authority (CA) should be 
informed as soon as possible and in any case within 7 days. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days. 
 
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The minimum information to be reported includes: 
 Valid EudraCT number (where applicable) 
 Sponsor study number 
 One identifiable coded subject 
 One identifiable reporter 
 One SUSAR 
 One suspect 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. 
 
11.8 
SAEs: contacts 
 
SAEs must be reported on SAE reporting forms and faxed WITHIN 24 H to the sponsor - 
contact details below: 
 
 
 
 
 
 
 
Dr. Elisabetta Donati 
Fax: 
+41(0)91.646.85.61 
Phone: +41(0)91.640.42.50 
Email: edonati@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 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.1/2-2014), the 3-digit centre number (i.e. 001), the 4-digit screening number (e.g. 
S001, S002, etc.) and, if applicable, the 3-digit subject randomisation number (i.e. 001, 002, 
…, 045). Study code, centre number, screening number and subject randomisation number are 
separated by slashes (“/”). The last 8 digits of the unique subject identifier (enrolled subjects), 
corresponding to the subject screening and subject randomisation numbers separated by a 
slash, will appear as subject identifier in the individual listings and figures of the clinical 
study report and will be used to identify the subjects in in-text tables or wording (if 
applicable). 
 
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, 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). Version of 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 Clinical Medical Service.  
 
Monitoring will comply with ICH-GCP chapter 5.18 requirements for what concerns 
monitoring purpose, selection and qualifications of monitors, extent and nature of monitoring, 
monitoring procedures, monitoring reports. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorised individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOA principles (Attributable-Legible-
Contemporaneous-Original-Accurate). 
 
The clinical centre is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirement(s). 
 
The CRO and the sponsor will be responsible each one for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a 
CRO, but the ultimate responsibility for the quality and integrity of the trial data always 
resides with the sponsor. 
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13.3 
Applicable SOPs 
 
The sponsor, the clinical centre and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for review, if required. 
 
13.4 
Data access 
 
The investigator and the CRO will ensure that all raw data records, medical records, CRFs 
and all other documentation that is relevant to this study will be made accessible to 
monitoring activities, audits, IEC review, and regulatory inspection. 
 
13.5 
Audits and inspections 
 
The sponsor, any independent body acting on behalf of the sponsor and the CRO have the 
right to perform audits according to ICH-GCP responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigators 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 Committees and Health Authorities 
will be obtained before the start of the study.  
 
Study notification to the Competent Authorities will be performed according to the current 
regulations. 
 
The involved parties will conduct the present clinical study according to the declaration of 
Helsinki, the general principles of “ICH Topic E6, CPMP/ICH/135/95” (ICH-GCP), July 
1996 including post Step 4 errata, status September 1997 and post Step errata (linguistic 
corrections), July 2002; Italian Ministerial Decree 15JUL97, Italian Legislative Decree 
24JUN03 n. 211, Italian Legislative Decree 30JUN03 n. 196 and subsequent modifications 
and supplements, Guideline of the Italian Data Protection Authority for the protection of 
personal data of 24JUL08 – and according to the methods and the criteria described and 
specified in the present protocol, agreed by the principal investigator and in any case 
according to the current law. 
 
14.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC 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. 
 
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The investigator will be supplied with an adequate number of blank informed consent forms 
to be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements (see § 15.3). 
The investigator will allow inspection of the forms by authorised representatives of the 
sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 
 
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 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
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 study terminated by sponsor: an indication that a clinical study was stopped by its 
sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
In case of lack of efficacy of the investigational anaesthetic, the patient will be regarded as not 
having achieved an effective anaesthesia and rescue anaesthesia will be administered. The 
patient will not be discontinued from the study. 
 
14.4.3 
Discontinuation procedures 
 
For any subject discontinuing from interventions and findings, 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 
 
Discontinued subjects will not be replaced. 
 
14.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. 
Reasons for discontinuation have to be documented appropriately. 
 
 
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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical centre 
 
Beside the investigational products, the following study material will be supplied to the 
clinical centre: 
 final version of the study protocol 
 CRF for each patient plus some spare copies 
 copy of the investigator’s brochure (IB) relative to the investigational product 
 informed consent forms 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments 
(if any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
15.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All amendments will be sent to the EC and concerned Competent Authority, according to the 
current regulations in the EU. 
 
The amendment will be applicable only when it is approved by the concerned authorities, 
unless the changes consist of urgent safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
15.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including ECGs etc., and the original signed informed consent forms. 
 
Data reported on the CRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. 
 
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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects including ECG tracing, insurance contracts, certificate of analysis of the IMP(s), 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 centre among those patients attending the 
clinic for lower limb surgery of short duration. Forty-five patients should be recruited.  
 
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 similar confidentiality from 
his/her staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected on the CRFs during the study will be documented in an anonymous 
way (see § 12.2). If, as an exception, it becomes necessary to identify a subject for safety or 
regulatory reasons, the monitor, the sponsor and the investigator will be bound to keep this 
information confidential. 
 
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. 
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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. At least 30 days before submitting a written publication or 
presenting the study results, e.g. as part of a written or oral presentation at a conference, the 
investigator will submit to the Sponsor a final version of the document or article.    
 
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. 
The investigator(s) will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
The sponsor, within 30 days of the final manuscript/presentation, may ask for a delay in the 
publication or presentation of the data. 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 centre 
 
Istituto Ortopedico Rizzoli, SC Anestesia e Terapia Intensiva 
post-operatoria e del dolore IOR-IRCCS, 
via G.C. Pupilli 1 - 40136 Bologna, Italia 
Phone: 
+39.051.6366356 
Fax: 
+39.051.6366647 
 
Principal investigator 
Stefano Bonarelli, MD 
Email: 
stefano.bonarelli@ior.it 
 
16.2.2 
Drug assay 
 
Accelera s.r.l., Viale Pasteur 10, 20014 Nerviano, Italy 
Phone: 
+39.0331.1984.444 
Fax: 
+39.0331.1984.200 
 
Head of Bioanalytical laboratory  
Enrico Frigerio 
Email: 
enrico.frigerio@accelera.org 
 
Analytical facilities and procedures were in compliance with GLP regulations. 
 
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16.3 
Co-ordination, data analysis & reporting 
 
CROSS S.A., Switzerland, and its affiliated companies CROSS Research S.A. and CROSS 
Metrics S.A., sharing the same quality systems, SOPs, standards and procedures. 
 
CROSS S.A., Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.6300510 
Fax: 
+41.91.6300511 
 
Coordination 
Emanuela Terragni, Clinical Project Leader 
Email: 
projectmanagement@croalliance.com 
 
Medical Writing Unit Representative 
Chiara Leuratti, Medical Writing Manager, Unit Head 
Email: 
medicalwriting@croalliance.com 
 
Pharmacokinetic Analysis 
Luca Loprete, Senior Pharmacokineticist 
Email: 
luca.loprete@croalliance.com 
 
Biometry Unit Representative 
Matteo Rossini, Biometry Manager, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Mario Corrado, Quality Assurance Manager, Unit Head 
Email: 
qau@croalliance.com 
 
16.4 
Monitoring 
 
Clinical Medical Services of Maria Pia Savorelli 
via Indipendenza 29A, 6883 Novazzano, Switzerland 
Mobile: +41.79.827.27.67 
Fax: 
+41.91.649.57.14 
Email: 
cmed@cmed.ch 
 
 
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17 
REFERENCES 
 
1. Casati A, Fanelli G, Danelli G, Berti M, Ghisi D, Brivio M, Putzu M, Barbagallo A. Spinal anesthesia with 
lidocaine or preservative-free 2-chloroprocaine for outpatient knee arthroscopy: a prospective, randomized, 
double-blind comparison. Anesth Analg. 2007 Apr;104(4):959-64. 
2. Freedman JM1, Li DK, Drasner K, Jaskela MC, Larsen B, Wi S. Transient neurologic symptoms after spinal 
anesthesia: an epidemiologic study of 1,863 patients. Anesthesiology. 1998 Sep;89(3):633-41. 
3. Zaric D, Christiansen C, Pace NL, Punjasawadwong Y. Transient neurologic symptoms (TNS) following 
spinal anaesthesia with lidocaine versus other local anaesthetics. Cochrane Database Syst Rev. 2005 Oct 
19;(4):CD003006. Review. Update in: Cochrane Database Syst Rev. 2009;(2):CD003006. 
4. Liu SS, Ware PD, Allen HW, Neal JM, Pollock JE. Dose-response characteristics of spinal bupivacaine in 
volunteers. Clinical implications for ambulatory anesthesia. Anesthesiology. 1996 Oct;85(4):729-36. 
5. Casati A, Vinciguerra F. Intrathecal anesthesia. Curr Opin Anaesthesiol. 2002 Oct;15(5):543-51. 
6. Cappelleri G, Aldegheri G, Danelli G, Marchetti C, Nuzzi M, Iannandrea G, Casati A. Spinal anesthesia 
with hyperbaric levobupivacaine and ropivacaine for outpatient knee arthroscopy: a prospective, 
randomized, double-blind study. Anesth Analg. 2005 Jul;101(1):77-82, table of contents. 
7. Breebaart MB, Vercauteren MP, Hoffmann VL, Adriaensen HA. Urinary bladder scanning after day-case 
arthroscopy under spinal anaesthesia: comparison between lidocaine, ropivacaine, and levobupivacaine. Br J 
Anaesth. 2003 Mar;90(3):309-13. 
8. Covino BG. Pharmacology of local anaesthetic agents. Br J Anaesth 1986, 58(7):701-16. 
9. Förster JG, Rosenberg PH. Revival of old local anesthetics for spinal anesthesia in ambulatory surgery. Curr 
Opin Anaesthesiol 2011;24:633-7 
10. Foldes FF, McNall PG. 2-Chloroprocaine: a new local anesthetic agent. Anesthesiology 1952; 13(3):287-96. 
11. Reisner LS, Hochman BN, Plumer MH. Persistent neurologic deficit and adhesive arachnoiditis following 
intrathecal 2-chloroprocaine injection. Anesth Analg 1980;59(6):452-4 
12. Moore DC, Spierdijk J, vanKleef JD, Coleman RL, Love GF. Chloroprocaine neurotoxicity: four additional 
cases. Anesth Analg 1982;61(2):155-9 
13. Drasner K. Chloroprocaine spinal anesthesia: back to the future? Anesth Analg 2005;100(2):549-52 
14. Wang BC, Hillman DE, Spielholz NI, Turndorf H. Chronic neurological deficits and Nesacaine-CE - an 
effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 1984; 
63(4):445-7 
15. Pollock JE, Mulroy MF, Bent E, Polissar NL. A comparison of two regional anesthetic techniques for 
outpatient knee arthroscopy. Anesth Analg 2003;97:397-401 
16. Covino BG. Toxicity of local anesthetic agents. Acta Anaesthesiol Belg 1988;39:159-64 
17. Yoos JR, Kopacz DJ. Spinal 2-chloroprocaine for surgery: an initial 10-month experience. Anesth Analg 
2005;100(2):553-8 
18. Hejtmanek MR, Pollock JE. Chloroprocaine for spinal anesthesia: a retrospective analysis. Acta 
Anaesthesiol Scand 2011;55(3):267-72 
19. Foldes FF and McNall PG. 2-Chloroprocaine: a new local anesthetic agent, Anesthesiology, 1952; 13:287-
96. 
20. Gissen AJ, Datta S, lamber D. The chloroprocaine controversy. II. Is chloroprocaine neurotoxic? Reg 
Anesth 1984;9:135-145. 
21. Kouri ME, Kopacz DJ. Spinal 2-chloroprocaine: a comparison with lidocaine in volunteers. Anesth Analg 
2004;98:75-80. 
22. Smith KN, Kopacz DJ, McDonald S. Spinal 2-chloroprocaine: a dose-ranging study and the effect of added 
epinephrine. Anesth Analg 2004;98:81-8. 
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23. Foldes FF, McNall PG. 2-chloroprocaine: a new local anesthetic agent. Anesthesiology 1952;13:287-96. 
24. Palas TAR. Four years’ experience with 1% chloroprocaine for spinal anesthesia in ambulatory anesthesia. 
Reg Anesth Pain Med 2005;30:A160. 
25. Kopacz DJ. Spinal 2-chloroprocaine: minimum effective dose. Reg Anesth Pain Med. 2005; 30(1):36-42. 
26. Casati A, Danelli G, Berti M, Fioro A, Fanelli A, Benassi C, Petronella G, Fanelli G. Intrathecal 2-
chloroprocaine for lower limb outpatient surgery: a prospective, randomized, double-blind, clinical 
evaluation. Anesth Analg. 2006 Jul;103(1):234-8, table of contents. 
27. Goodman and Gilman’s The Pharmacological basis of therapeutics. Chloroprocaine (Page 339). 9th Edition 
1996. Hardman JG, Godman Gilman A, Limbird LE, Molinoff PB, Ruddon RW Editors.  
28. Kuhnert BR, Kuhnert PM, Philipson EH, Syracuse CD, Kaine CJ, Yun CH. The half-life of 2-
chloroprocaine. Anesth Analg. 1986 Mar;65(3):273-8. 
29. Krohg K, Jellum E. Urinary metabolites of chloroprocaine studied by combined gas chromatography--mass 
spectrometry. Anesthesiology. 1981 Apr;54(4):329-32.  
30. Kuhnert BR, Kuhnert PM, Reese AL, Philipson EH, Rosen MG. Maternal and neonatal elimination of 
CABA after epidural anesthesia with 2-chloroprocaine during parturition. Anesth Analg. 1983;62(12):1089-
94. 
31. Foldes FF and Aven MH: The hydrolysis of procaine and 2-chloroprocaine in spinal fluid. J Pharmacol Exp 
Ther 1952; 105:259 - 265. 
32. Greene NM. Uptake and elimination of local anesthetics during spinal anesthesia. Anesth Analg. 1983 
Nov;62(11):1013-24. 
33. Burm AGL. Clinical pharmacokinetics of epidural and spinal anesthesia. Clin Pharmacokin 1989; 16:283-
311 
34. Weiss RR, Halevy S, Almonte RO, Gundersen K, Hinsvark ON, O'Brien JE. Comparison of lidocaine and 
2-chloroprocaine in paracervical block: clinical effects and drug concentrations in mother and child. Anesth 
Analg. 1983 Feb;62(2):168-73. 
35. Sum DC, Chung PC. Plasma lidocaine level during spinal or epidural anesthesia in geriatric patients. Ma Zui 
Xue Za Zhi. 1993 Mar;31(1):59-63. 
36. Ledan C, Collet D, Vincelot A, Debord J, Lachatre G, Feiss P. [Pharmacokinetics of epidural or intrathecal 
bupivacaine in elective cesarean section]. Ann Fr Anesth Reanim. 1993;12(6):552-9. [Article in French] 
37. Kuhnert BR, Kuhnert PM, Prochaska AL, Gross TL. Plasma levels of 2-chloroprocaine in obstetric patients 
and their neonates after epidural anesthesia. Anesthesiology. 1980 Jul;53(1):21-5.  
38. Abboud TK, Afrasiabi A, Sarkis F et al. Continuous infusion epidural analgesia in parturients receiving 
bupivacaine, 2-chloroprocaine or lidocaine: Maternal, fetal and neonatal effects. Anesth Analg 1984; 63:421 
- 8. 
39. Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth. 1995 Feb;7(1):89-91. 
40. Ead H. From Aldrete to PADSS: Reviewing discharge criteria after ambulatory surgery. J Perianesth Nurs. 
2006 Aug;21(4):259-67. 
41. SAS/STAT® User’s Guide 
42. EMA CPMP/EWP/908/99 guideline "Points to consider on multiplicity issues in clinical trials", 19 
September 2002  
 
 
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Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
18 
APPENDICES 
 
Appendix 1 
TNS questionnaire 
 
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Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
 
 
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Study protocol CRO-14-122 
Sponsor code CHL.1/02-2014 
Chloroprocaine 1% - Spinal block 
Final version 1.0, 03OCT14 
Appendix 2 
Modified Aldrete score scale 
 
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