A Prospective, Randomised, Non-inferiority Study of Chloroprocaine 2% and the Active Control Ropivacaine 0.75% (AstraZeneca) in Ultrasound-guided Axillary Nerve Block for Short-duration Distal Upper Limb Surgery
Phase: PHASE3
Conditions: Axillary Nerve Block
Sponsor: Sintetica SA

CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
Study CRO-14-120 - Sponsor code CHL.2/01-2014/M 
 
A 
prospective, 
randomised, 
non-inferiority 
study 
of 
Chloroprocaine 2% and the active control Ropivacaine 0.75% 
(AstraZeneca) in ultrasound-guided axillary nerve block for 
short-duration distal upper limb surgery 
 
Prospective, randomised, multi-centre, active-controlled, observer-blind, parallel-group,  
non-inferiority study 
 
EudraCT Number: 2014-002519-40 
 
Test product: 
Chloroprocaine HCl 2% injection (20 mg/mL), Sintetica S.A., 
Switzerland 
 
 
Reference product: 
Naropin®, Ropivacaine HCl 0.75% injectable solution (7.5 
mg/mL), AstraZeneca GmbH, Germany 
 
 
Sponsor: 
Sintetica S.A., Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: +41.91.640.42.50; Fax: 
+41.91.646.85.61 
 
 
Principal investigator –  
Clinical centre N. 1: 
Prof. Hinnerk Wulf, MD. Professor and Chairman,  
Department of Anesthesiology and Intensive Care Medicine, 
University Hospital, D-35033 Marburg, Germany 
Phone: +49.6421.58.62003, Fax: +49.6421.58.62014 
Email: H.Wulf@med.uni-marburg.de 
 
 
Principal investigator –  
Clinical centre N. 2: 
Claudio Camponovo, MD. Chairman of the 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 
 
 
Principal investigator –  
Clinical centre N. 3: 
Andrea Saporito, MD MHA. Deputy Chairman of the 
Department of Anaesthesiology,  
Ospedale Regionale di Bellinzona e Valli-Bellinzona,  
CH-6500 Bellinzona, Switzerland 
Phone: +41.91.811.8978, Fax: 
+41.91.825.4989 
Email: Andrea.Saporito@eoc.ch 
 
 
Development phase: 
Phase III 
 
 
Version and date: 
Final version 2.0, 17SEP14 
 
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 
CROSS S.A. 
Page 1 

CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
VERSIONS’ HISTORY 
 
 
Version 
Date 
Description of Changes 
1.0 
18 June 2014 
Original document 
2.0 
17 Sep 2014 
The following points have been added: 
 
 Inclusion in the study of inpatients 
beside outpatients 
 Urine pregnancy test for women at 
screening visit 
 An impartial witness can sign the 
informed consent form when the subject 
is physically unable to sign due to the 
distal upper limb injury. In these cases, 
the witness should sign and personally 
date the consent form after the subject 
has orally consented to the participation 
in the trial and, if capable of signing, has 
signed 
and 
personally 
dated 
the 
informed consent form 
 Normal 
ranges 
for 
haemodynamic 
variables and ECG 
 Recommended maximal deviations from 
the scheduled block assessment times  
 
The secondary study variable “time to 
home discharge” has been changed into 
“time to eligibility for home discharge” 
 
A typing mistake at § 8.2 has been 
corrected 
 
An address at § 16.4 has been changed 
 
A reference at § 17 has been changed 
 
CROSS S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
PROTOCOL APPROVAL 
 
 
SPONSOR 
Sintetica S.A., Switzerland 
 
Clinical Project Leader 
Elisabetta Donati, Corporate Director Scientific Affairs 
 
 
 
 
Date 
 
Signature 
 
CROSS S.A. 
Page 3 

CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
PRINCIPAL INVESTIGATORS 
 
 
I have read this protocol and agree to conduct this study in accordance with all the 
stipulations of the protocol and in accordance with the Declaration of Helsinki. 
 
 
Principal investigator – Centre N. 1 - Germany 
Hinnerk Wulf, MD, Professor and Chairman 
Department of Anesthesiology and Intensive Care Medicine, University Hospital, Marburg, 
Germany 
 
 
 
 
Date 
 
Signature 
 
CROSS S.A. 
Page 4 

CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
 
I have read this protocol and agree to conduct this study in accordance with all the 
stipulations of the protocol and in accordance with the Declaration of Helsinki. 
 
 
Principal investigator – Centre N. 2 - Switzerland 
Claudio Camponovo, MD, Chairman 
Department of Anaesthesiology, Clinica Ars Medica, Gravesano, Switzerland 
 
 
 
 
Date 
 
Signature 
 
CROSS S.A. 
Page 5 

CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
 
I have read this protocol and agree to conduct this study in accordance with all the 
stipulations of the protocol and in accordance with the Declaration of Helsinki. 
 
 
Principal investigator – Centre N. 3 - Switzerland 
Andrea Saporito, MD MHA, Deputy Chairman 
Department of Anaesthesiology, Ospedale Regionale di Bellinzona e Valli-Bellinzona, 
Bellinzona, Switzerland 
 
 
 
 
Date 
 
Signature 
 
 
 
CROSS S.A. 
Page 6 

CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
CRO 
CROSS S.A., Switzerland, and its affiliated companies CROSS Research S.A. and  
CROSS Metrics S.A. 
 
Coordination 
Emanuela Terragni, Clinical Project Leader 
 
 
 
 
Date 
 
Signature 
 
 
Medical Writing Unit Representative 
Chiara Leuratti, Medical Writing Manager, Unit Head 
 
 
 
 
Date 
 
Signature 
 
 
Biometry Unit Representative 
Matteo Rossini, Biometry Manager, Unit Head 
 
 
 
 
Date 
 
Signature 
 
 
Quality Assurance Unit Representative 
Mario Corrado, Quality Assurance Manager, Unit Head 
 
 
 
 
Date 
 
Signature 
CROSS S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SYNOPSIS 
 
Name of Investigational Product: Chloroprocaine HCl 2% injection 
 
Name of Active Ingredient: Chloroprocaine 
 
Indication: Local anaesthesia by axillary nerve block 
 
Title of Study: A prospective, randomised, non-inferiority study of Chloroprocaine 2% and the active 
control Ropivacaine 0.75% (AstraZeneca) in ultrasound-guided axillary nerve block for short-duration 
distal upper limb surgery  
 
Protocol Sponsor code: CHL.2/01-2014/M 
 
Clinical phase: Phase III 
 
Trial design: Prospective, randomised, multi-centre, active-controlled, observer-blind, parallel-group, 
non-inferiority study  
 
Planned n. of centres / countries: Three centres / Germany and Switzerland 
 
Investigators and centres:  
1) Centre N. 1 - Principal investigator: Prof. Hinnerk Wulf, MD. Professor and Chairman, Department 
of Anesthesiology and Intensive Care Medicine, University Hospital, D-35033 Marburg, Germany 
2) Centre N. 2 - Principal investigator: Claudio Camponovo MD. Chairman, Department of 
Anaesthesiology, Clinica Ars Medica, Via Cantonale, CH-6929 Gravesano, Switzerland 
3) Centre N. 3 - Principal investigator: Andrea Saporito, MD MHA. Chairman, Department of 
Anaesthesiology Ospedale Regionale di Bellinzona e Valli-Bellinzona, CH-6500 Bellinzona, 
Switzerland 
Test investigational medicinal product (IMP) – dose and mode of administration:  
Chloroprocaine HCl 2% Injection (20 mg/mL), injectable solution, Sintetica S.A., Switzerland.  
Total dose = 20 mL (400 mg), approximately 5 mL (100 mg) per nerve. The mode of administration is 
detailed below (Study procedures, Procedure for ultrasound-guided axillary block). 
Reference IMP, dosage and mode of administration:  
Naropin®, Ropivacaine HCl 0.75% (7.5 mg/mL) injectable solution, AstraZeneca GmbH, Germany.  
Total dose = 20 mL (150 mg), approximately 5 mL (37.5 mg) per nerve. The mode of administration 
is detailed below (Study procedures, Procedure for ultrasound-guided axillary block). 
OBJECTIVES:  
Primary objective: 
Non-inferiority evaluation of Test versus Reference product in terms of proportion of subjects with a 
successful block for distal upper limb surgeries, without any supplementation in the first 45 min (see 
definitions below), calculated from the time of readiness for surgery (complete sensory block).  
Secondary objectives: Comparison between Test and Reference products in terms of the time to onset 
of sensory block [time to readiness for surgery], time to regression of sensory block, time to onset and 
regression of motor block, need for supplemental anaesthesia/analgesia and time to eligibility for 
home discharge; safety evaluation of the study treatments. 
Successful block: anaesthesia adequate for the surgery (complete sensory block), without any 
supplementation in the first 45 min (even if surgery lasts for > 45 min), calculated from the time of 
readiness for surgery (complete sensory block).  
Supplementation: i.v. premedication or general anaesthesia or pre- or intra-operative systemic 
analgesia or additional local anaesthetic infiltration 
STUDY END-POINTS:  
Primary end-point: Proportion of patients with a successful block for distal upper limb surgeries, 
without any supplementation (i.e. no general anaesthesia or pre- and intra-operative systemic analgesia 
and no additional anaesthetic infiltration) in the first 45 min, calculated from the time of readiness for 
surgery (complete sensory block).  
CROSS S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SYNOPSIS, continued 
 
STUDY END-POINTS, continued:  
Secondary endpoints: 
Efficacy end-points: 
 Time to onset of sensory block (corresponding to readiness for surgery), 
 Time to onset of motor block,  
 Time to regression of sensory block 
 Time to regression of motor block, 
 Time to administration of rescue anaesthesia or rescue analgesia,  
 Time to first post-operative analgesia, 
 Time to eligibility for home discharge. 
Safety end-points: 
Safety and general tolerability of the study treatments on the basis of treatment-emergent adverse 
events (TEAEs), vital signs measurements (blood pressure, heart rate, oxygen saturation [SpO2]) and 
ECG recordings. 
Study participants:  
180 male/female patients, 90/treatment group, aged ≥ 18 years, scheduled for distal upper limb surgery 
(< 60 min) under axillary brachial plexus block. 
DIAGNOSIS AND CRITERIA FOR INCLUSION: 
Inclusion criteria: 
1. Sex and surgery: male and female patients scheduled for short duration (< 60 min) distal upper 
limb surgery under axillary nerve block anaesthesia 
2. Age: ≥ 18 years old 
3. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive 
4. ASA physical status: I-III 
5. Informed consent: signed written informed consent before inclusion in the study 
6. 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 peripheral nerve block anaesthesia. History of 
neuromuscular diseases to the upper extremities 
2. Axillary status: Axillary local infections, surgical scarring and pathological lymph node 
enlargement 
3. ASA physical status: IV-V 
4. Further anaesthesia: Patients anticipated to be requiring further anaesthesia (general or local 
anaesthesia) 
5. Chronic pain syndromes: Patients with chronic pain syndromes (taking opioids, antidepressants, 
anticonvulsant agents) 
6. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations 
ingredients; ascertained or presumptive hypersensitivity to the amide and major anaesthetics 
7. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, 
haematological, endocrine or neurological diseases that may interfere with the aim of the study; 
ascertained psychiatric diseases, sepsis, blood coagulation disorders, insulin dependent diabetes 
mellitus, terminal kidney failure 
8. Medications: Medication known to interfere with the extent of regional blocks (see chloroprocaine 
and ropivacaine SmPCs) for 2 weeks before the start of the study. Hormonal contraceptives for 
females will be allowed 
 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SYNOPSIS, continued 
 
DIAGNOSIS AND CRITERIA FOR INCLUSION, continued: 
Exclusion criteria, continued: 
9. 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 
10. Drug, alcohol: history of drug or alcohol abuse 
11. Pregnancy: missing or positive pregnancy test at screening, pregnant or lactating women 
STUDY PROCEDURES 
The study will include a screening visit (days -14/1), a treatment phase (anaesthesia and surgical 
procedure: visit 2, day 1), post-operative recovery / final visit (day 1/2) and a follow up (day 7±1).   
Screening (visit 1, day -14/1) 
Patients scheduled for surgery of the distal upper limb 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. Patients will be assigned a screening number. Routine pre-surgery assessments will be 
performed according to the hospitals’ standard procedures, and the study inclusion/exclusion criteria 
will be verified. A urine pregnancy test for women will be performed. The following baseline 
characteristics will be recorded: medical history, physical abnormalities, body weight, height, body 
mass index, blood pressure, heart rate, previous and concomitant medications.  
Treatment Phase (visit 2, day 1) 
Before the anaesthesia, patients will be questioned about adverse events occurrence and concomitant 
medications intake and will be assigned a consecutive randomisation number. According to the 
randomisation number, patients will be randomised to either Chloroprocaine HCl 2% (Test) or 
Ropivacaine HCl 0.75% (Reference) treatment group. Oral midazolam premedication will be 
administered (if necessary). 
Procedure for ultrasound-guided axillary block 
The arm will be externally rotated and the elbow flexed to 90 degrees. The skin surface of the axilla 
will be aseptically prepared. Axillary block will be performed under ultrasound guidance using 
standard procedures. The median, ulnar, radial and musculocutaneous nerves will be identified. A 5 
cm needle will be inserted towards the 4 nerves. Once appropriate perineural needle placement is 
visualized, the volume (20 mL) of either Chloroprocaine HCl 2% (Test) or Ropivacaine HCl 0.75% 
(Reference) will be injected using a syringe. The time from needle insertion to final perineural 
injection (time 0 h) will be recorded. 
Block assessment 
Sensory and motor blocks will be evaluated in each nerve territory by an independent assessor, blinded 
to the anaesthetic (Test or Reference) injected. If needed, sensory and motor functions will be 
compared in the contralateral distal upper limb. Blocks will be assessed every 5 min until the patient is 
ready for surgery. Then, blocked limbs will be evaluated as soon as possible after surgery (taking into 
consideration the end of the surgery procedures), then every 15 min for the first hour after surgery, 
every 30 min for the next 2 hours and then every hour until regression of surgical anaesthesia. Time to 
onset of sensory and motor blocks and time to regression of sensory and motor blocks will be 
recorded. Sensory and motor function assessments will be performed as detailed below: 
Sensory block will include thermal perception (cold spray) and sensitive perception (pin prick) 
assessments. The anaesthetised arm will be compared with the contralateral arm, if necessary. 
Assessments will be performed for each nerve territory and perceptions will be scored as being present 
(score 1) or absent (score 0). 
 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SYNOPSIS, continued 
 
Study procedures, continued 
Motor block will be evaluated through specific motor tests for each nerve territory. In detail, motor 
tests will be: flexion of radial 3 fingers for the median nerve, extension of wrist for radial, abduction of 
fingers for ulnar and elbow flexion for musculocutaneous nerve. Each assessment will be scored 
according to the following modified Bromage scale: 
Table 1 Modified Bromage scale for motor block assessment 
Score 
Definition 
0 
No movement in relevant muscle group 
1 
Flicker of movement in relevant muscle group 
2 
Ability to move relevant muscle group against gravity but inability to move against 
resistance 
3 
Reduced power but ability to move muscle group against resistance 
4 
Full power in relevant muscle group 
Definitions 
Sensory block is defined as absent thermal and sensitive perception (score 0; see above) in each nerve 
territory.  
Onset of sensory block, corresponding to readiness for surgery, is defined as an absent cold and touch 
sensation in the 4 nerve territories (complete sensory block).  
Motor block is defined as a motor block score of ≤ 2 on the modified Bromage scale in each nerve 
territory (see above; no motor block required for successful block). Onset of motor block is achieved 
when motor block is present in ≥ 3 nerve territories. 
Time to onset of sensory block and time to onset of motor block are defined as the time period from 
completion of the final perineural injection (time 0 h) to achievement of complete sensory block and 
motor block, respectively.  
Regression of sensory block will be deemed to have occurred when cold sensation and sensitive 
perception have returned (if assessable) in any nerve territory. 
Regression of motor block will be deemed to have occurred when motor score is ≥ 3 in any nerve 
territory. 
Successful block is defined as: anaesthesia adequate for the surgery (complete sensory block), without 
any supplementation in the first 45 min (even if surgery lasts for > 45 min), calculated from the time 
of readiness for surgery (complete sensory block).  
Supplementation includes: i.v. premedication or general anaesthesia or pre- or intra-operative systemic 
analgesia or additional local anaesthetic infiltration.  
Block failure is defined as absence of or inadequate surgical anaesthesia with the need for 
supplementation (as defined above) in the first 45 min, calculated from the time of readiness for 
surgery (complete sensory block). 
Post-operative recovery and final visit (day 1/2) 
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 ≥ 9 on the modified 
Aldrete’s scoring scale (Aldrete, 1998) and no feeling of pain. Vital signs, ECG (if foreseen by 
hospital standard procedures) 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, with particular attention to local toxicity and neurological symptoms, such as paraesthesia of 
the arm, 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. 
Follow-up (Day 7±1): 6±1 days after the day of surgery, a deputy of the Investigator, not aware of the 
administered treatment, will contact the patients by telephone and will question them about any 
adverse reactions which might have occurred after discharge, with particular attention to any sign of 
late systemic toxicity, local toxicity, neurological symptoms and allergic reactions. 
CROSS S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SYNOPSIS, continued 
 
Study Procedures, continued:  
Other assessments and procedures 
Safety assessments 
Vital signs will be recorded at the screening visit. ECG (if foreseen by standard hospital procedures), 
blood pressure, heart rate and SpO2 will be monitored at baseline, during the block until the end of 
anaesthesia and during post-operative recovery using standard monitors, according to ASA guideline 
recommendations (SpO2 should be ≥ 92%). 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 adverse events. 
Particular attention will be given to systemic and local toxicity symptoms, neurological symptoms and 
allergic reactions. In particular, patients will be instructed to report signs of systemic (central nervous 
system) toxicity, e.g. metallic taste, ringing in the ears etc. In addition, at every assessment time, 
occurrence of slurred speech will be noted.   
Additional anaesthesia and Rescue analgesia 
If a successful block is attained, no i.v. premedication or general anaesthesia or pre- or intra-operative 
systemic analgesia or additional local anaesthetic infiltration will be administered in the first 45 min 
calculated from the time of readiness for surgery. In the event of block failure, or after the first 45 min 
calculated from the time of readiness for surgery, if necessary either local anaesthesia or general 
anaesthesia or rescue analgesia will be administered, according to the investigator’s judgment. 
Premedication/sedation and Analgesia 
Oral premedication with midazolam will be allowed, if necessary. No prophylactic i.v. midazolam, 
propofol or fentanyl will be allowed for premedication/sedation on a routine basis (if a patient needs 
these drugs, the block will be classified as insufficient for surgery/unsuccessful). At the end of the 
surgical procedure, an appropriate analgesic (e.g. mefenamic acid or paracetamol) will be administered 
to the patients, according to the investigator’s opinion. 
Blinding 
Syringes for injection will be prepared by a co-investigator/pharmacist/study nurse not involved in 
axillary block placement or study outcome measures evaluation. An independent blinded observer will 
evaluate sensory and motor blocks for each patient.  
Data recording 
Efficacy and safety data as well as details on the surgical procedure (type, start and end time, 
comments) will be reported on the individual case report forms (CRF).   
Sample size 
 
Given the following definitions: 
πT = Proportion of success - Test (Chloroprocaine);  
πR = Proportion of success - Reference (Ropivacaine);  
є = πT - πR (difference between Test and Reference proportion of success);  
δ = Non-inferiority limit;  
 
the sample size for the one-sided hypothesis test H0: є ≤ δ vs. Ha: є > δ can be computed according to 
the following formula (Wang, 2007):  
 
NT = k x NR 
and 
NR = ceiling {[(Z1-α+ Z1-β) 2/ (є - δ) 2] x [πT x(1- πT)/k + πR x (1- πR)]};  
 
where:  
k = Balancing ratio between treatment arms (1 for balanced group) 
NT = Number of subjects included into the Per Protocol set for Test treatment group;  
NR = Number of subjects included into the Per Protocol set for Reference treatment group; 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SYNOPSIS, continued 
 
Randomisation 
 
Randomisation will be stratified by centre. Patients will be allocated to the Test (Chloroprocaine) arm 
or Reference (Ropivacaine) arm according to a 1:1 ratio. Randomisation list will be computer 
generated using the PLAN procedure of the SAS® system version 9.3 (TS1M1) or higher for 
Windows. 
Statistical analysis  
Definition of analysis sets: 
  
Safety Set: the safety set is defined as all patients who receive at least one dose of the study drug. This 
analysis set will be used for the safety evaluation. 
Full Analysis Set (FAS): the FAS will include all randomised patients who fulfil the study protocol 
requirements in terms of study anaesthetics administration. This analysis set will be used for 
sensitivity analyses. 
Per Protocol Set (PP): the PP set will include 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. 
All study data will be listed by patient and will be summarised using classic descriptive statistics for 
quantitative variables and frequencies for qualitative variables. 
Analysis will be done using SAS® version 9.3 (TS1M1) or higher for Windows. 
Efficacy analysis 
The efficacy analysis will be performed on the PP set (primary efficacy analysis) and FAS (sensitivity 
analyses). The observed response rate for each treatment group will be calculated as the proportion of 
subjects with a successful block (as defined above). 
The proportion of subjects with a successful block will be compared between treatment groups by a 
binomial regression model, with the factors treatment and centre as fixed effects If the binomial 
regression model fails to converge, a Poisson regression model with a robust error variance (sandwich 
estimation) will be used instead of the binomial model. Non-inferiority of the Test in comparison with 
the Reference treatment will be considered proved if the lower confidence limit of the 97.5% one-
sided confidence interval of the difference between treatments is greater than the non-inferiority 
margin δ = - 0.1. 
Secondary variables (time to onset of sensory block [readiness for surgery], time to onset of motor 
block, time to sensory and motor block regression, time to eligibility for home discharge, time to 
rescue anaesthesia or analgesia, time to post-surgery analgesia) will be presented using Kaplan-Meier 
curves and will be compared between treatment groups by log rank test. All tests on the secondary 
variables will be performed with a nominal two-sided type I error α = 0.05. 
 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
STUDY SCHEDULE 
 
ACTIVITIES 
Visit 1 - 
Screening 
Visit 2 - 
Treatment 
Post-operative 
recovery, 
final visit 
Telephonic 
Follow-up 
Visit 
Days -14/1 
Day 1 
Day 1/2 
Day 7±1 
Informed consent 
x 
 
 
 
Demography 
x 
 
 
 
Medical/surgical history  
x 
 
 
 
Physical abnormalities 
x 
 
 
 
Previous and concomitant 
medications 
x 
x 
x 
x 
Height 
x 
 
 
 
Body weight 
x 
 
 
 
Vital signs  
(blood pressure, heart rate)1 
x 
x 
x 
 
SpO2
2 
 
x 
x 
 
ECG1 
 
x 
x 
 
Pregnancy test (urine) 
x 
 
 
 
Eligibility evaluation 
x 
x 
 
 
Enrolment and randomisation3 
 
x 
 
 
Oral midazolam premedication (if 
necessary)4 
 
x 
 
 
Anaesthesia (IMP administration)5 
 
x 
 
 
Sensory block assessment6 
 
x 
 
 
Motor block assessment6 
 
x 
 
 
Surgery (< 60 min) 
 
x 
 
 
Aldrete’s scoring scale7 
 
 
x 
 
Home discharge7 
 
 
x 
 
Meals9 
 
 
x 
 
Adverse events monitoring8 
x 
x 
x 
x 
1. 
Vital signs at screening; vital signs and 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. 
SpO2 before the block (baseline), during the block until the end of the anaesthesia and during post-
operative recovery (final visit) 
3. 
On day 1, before any study procedures subjects will be randomised to either Chloroprocaine HCl 2% or 
Ropivacaine HCl 0.75% treatment group 
4. 
Oral premedication with midazolam is allowed, if necessary 
5. 
Patients will receive anaesthetic block with either Chloroprocaine or Ropivacaine, before surgery, 
according to the randomisation list and parallel-group design 
6. 
Sensory and motor blocks will be assessed by a blinded assessor after block placement, every 5 min until 
the patient is ready for surgery, as soon as possible after surgery, then every 15 min for the first hour after 
surgery, every 30 min for the next 2 h and then every 1 h until regression of the blocks.  
7. 
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. In case of discontinuation, subjects will undergo an early 
termination visit (ETV) 
8. 
AEs monitored from the screening visit, immediately after informed consent signature, up to the telephonic 
follow-up 
9. 
Meals will be served according to the hospital’s standard procedures 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
TABLE OF CONTENTS 
 
Page 
 
1 
INTRODUCTION 
19 
1.1 
Background 
19 
1.1.1 
Local anaesthesia 
19 
1.1.2 
Chloroprocaine 
19 
1.1.3 
Safety of local anaesthetics 
20 
1.1.4 
Ultrasound-guided axillary block 
21 
1.2 
Rationale 
21 
1.3 
Risk and benefits 
22 
2 
STUDY OBJECTIVES 
24 
2.1 
Primary objective 
24 
2.2 
Secondary objectives 
24 
3 
CLINICAL SUPPLIES 
25 
3.1 
Treatment 
25 
3.1.1 
Description of products 
25 
3.1.1.1 
Test product 
25 
3.1.1.2 
Reference product 
25 
3.1.2 
Dose regimen 
25 
3.1.3 
Route and method of administration 
25 
3.1.4 
Investigational product distribution 
26 
3.2 
Packaging and labelling 
26 
3.3 
Storage conditions 
27 
3.4 
Drug accountability 
27 
4 
INVESTIGATIONAL PLAN 
28 
4.1 
Overall study design 
28 
4.2 
Discussion of design 
28 
5 
STUDY POPULATION 
29 
5.1 
Target population 
29 
5.2 
Inclusion criteria 
29 
5.3 
Exclusion criteria 
29 
5.3.1 
Not allowed treatments 
30 
5.3.2 
Additional anaesthesia and rescue analgesia 
30 
5.3.3 
Premedication/sedation and analgesia 
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 
Body weight 
34 
7.1.2 
Vital signs 
34 
7.1.3 
ECGs 
34 
7.1.4 
Pregnancy test 
35 
7.1.5 
Block assessment 
35 
7.2 
Procedures for post-operative recovery and final visit 
36 
7.3 
Procedures for telephonic follow-up 
37 
7.4 
Assessment of symptoms of systemic and local toxicity 
37 
7.5 
Data recording 
37 
8 
ASSIGNMENT OF STUDY TREATMENT 
38 
8.1 
Randomisation 
38 
8.2 
Treatment allocation 
38 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
8.3 
Blinding 
38 
9 
EVALUATION PARAMETERS 
39 
9.1 
Study variables 
39 
9.1.1 
Primary end-point 
39 
9.1.2 
Secondary end-points 
39 
9.2 
Efficacy assessments 
39 
9.3 
Safety assessments 
41 
10 
STATISTICAL METHODS 
42 
10.1 
Analysis Sets 
42 
10.1.1 
Definitions 
42 
10.1.2 
Reasons for exclusion from the Full Analysis Set 
43 
10.1.3 
Reasons for exclusion from the Per Protocol set 
43 
10.2 
Sample size and power considerations 
43 
10.3 
Handling of missing data 
44 
10.3.1 
Methods for replacing missing data 
44 
10.3.2 
Replacement rules for each analysis set 
44 
10.4 
Demographic, baseline and background characteristics 
44 
10.5 
Analysis of efficacy parameters 
46 
10.6 
Safety and tolerability evaluation 
46 
11 
DEFINITION AND HANDLING OF AES AND SAES 
48 
11.1 
Applicable SOPs 
48 
11.2 
Definitions 
48 
11.3 
AEs monitoring window 
49 
11.4 
AEs recording 
49 
11.5 
SAEs reporting 
51 
11.6 
SUSARs management 
51 
11.7 
Other events qualified for expedited reporting 
52 
11.8 
SAEs: contacts 
52 
12 
DATA MANAGEMENT PROCEDURES 
53 
12.1 
Data collection – CRFs 
53 
12.2 
Unique subject identifier 
53 
12.3 
Database management 
53 
12.3.1 
Coding dictionaries 
53 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
54 
13.1 
Monitoring 
54 
13.2 
Quality Control and Quality Assurance 
54 
13.3 
Applicable SOPs 
55 
13.4 
Data access 
55 
13.5 
Audits and inspections 
55 
14 
ETHICAL CONSIDERATIONS 
56 
14.1 
Ethics and Good Clinical Practice (GCP) 
56 
14.2 
Informed consent 
56 
14.3 
Insurance policy 
57 
14.4 
Withdrawal of subjects 
57 
14.4.1 
Discontinuation type 
57 
14.4.2 
Primary reason for discontinuation 
57 
14.4.3 
Discontinuation procedures 
58 
14.5 
Study termination 
58 
15 
ADMINISTRATIVE PROCEDURES 
59 
15.1 
Material supplied to the clinical centre 
59 
15.2 
Protocol amendments 
59 
15.3 
Study documentation and record keeping 
59 
15.4 
Study subjects’ recruitment 
60 
15.5 
Confidentiality and data protection 
60 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
15.6 
Publication policy 
60 
16 
STUDY RESPONSIBLE PERSONS 
62 
16.1 
Sponsor 
62 
16.2 
Institutes performing the study 
62 
16.2.1 
Clinical centre 
62 
16.3 
Co-ordination, data analysis & reporting 
63 
16.4 
Monitoring 
63 
17 
REFERENCES 
65 
 
 
 
TABLES 
Page 
 
Table 7.1.5.1 
Recommended maximal deviations from the scheduled block assessment times 
35 
Table 7.1.5.2 
Modified Bromage scale for motor block assessment 
36 
 
 
 
 
FIGURES 
Page 
 
Figure 1.1.2.1 
Chemical structure of chloroprocaine hydrochloride 
19 
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
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 
CDISC 
Clinical Data Interchange Standards Consortium 
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 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Missing as Failure 
MI 
Multiple Imputation 
NA 
Not Applicable 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over The Counter 
PP 
Per Protocol 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SmPC 
Sumary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Perypheral oxygen saturation 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment-Emergent Adverse Event 
WC 
Worst Case 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
1 
INTRODUCTION 
 
1.1 
Background 
 
1.1.1 
Local anaesthesia  
 
Local anaesthesia is employed successfully in a wide variety of surgical procedures to 
produce the regional blockade of sensory and motor fibres without impacting the 
consciousness of patients. Compared to general anaesthesia, local anaesthetics present many 
significant advantages, especially in terms of reduced recovery time and enhanced safety.  
 
While practice of outpatient surgery is steadily growing, the ideal local anaesthetic should 
provide a rapid onset plus adequate potency and duration of action, combined with a 
favourable safety profile and very low risk of systemic toxicity. Furthermore, the patient 
should be able to recover motor and sensory functions shortly after surgery, and be discharged 
on the same day with manageable post-surgery pain and discomforts (1-3).  
 
Anesthesiologists may choose among diverse local anaesthetics for infiltration, peripheral 
nerve blockade and epidural anaesthesia. Among these, lidocaine has been the most widely 
used for decades, though several other agents present the same efficacy and a safer profile.  
 
In general, the selection of the local anaesthetic primarily depends on the duration of the 
procedure planned. Bupivacaine, for instance, is the privileged choice for lengthy procedures, 
i.e. procedures of more than 90 minutes of duration, while it also presents a longer latency 
period, besides being one of the most painful agents during injection (3). Other agents exist 
with moderate potency and duration, such as ropivavaine, mepivacaine and prilocaine, that are 
diffusely used (1,4). Chloroprocaine and articaine are among the anaesthetic agents 
characterized by shortest latency and duration of action, though articaine presents a higher 
reported risk of neural toxicity (1,3).  
 
1.1.2 
Chloroprocaine 
 
Chloroprocaine hydrochloride (Chloroprocaine HCl [benzoic acid, 4-amino-2-chloro-2-
(diethylamino) ethyl ester, monohydrochloride]; Figure 1.1.2.1) is a short-acting local 
anaesthetic belonging to the amino-ester class, characterized by a rapid onset of action (1,4) 
(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 21-25 
seconds. 
 
Figure 1.1.2.1 
Chemical structure of chloroprocaine hydrochloride 
 
 
There is a long history of use of chloroprocaine and the amino ester class of anaesthetics in 
USA, Canada and Switzerland. Firstly introduced in 1952 (8), chloroprocaine has been 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
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 (9-11). It was later demonstrated that neurological complications 
were associated with the preservative agents added to chloroprocaine formulations (12). As a 
consequence, preservative-free and also EDTA-free formulations have been developed, and 
are now available, which prevent these severe adverse episodes and guarantee a safer profile 
compared to other local anaesthetics (11).  
 
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 (2,4). In the literature, following the chloroprocaine-operated peripheral nerve 
block, reported median time to eligibility for home discharge ranged from about 2 to 5 hours 
(13-16).  
 
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 
(1,4) and related risks of toxic systemic spread (4,6,18,19). 
 
Chloroprocaine dose level for each anaesthesia technique are included in the SmPCs of the 
listed reference drugs (Nesacaine® 1,2 and 3%, AstraZeneca; Chloroprocaine HCl 1 and 2%, 
Bedford Laboratories; Ivracain® 1% Sintetica SA). In particular, chloroprocaine 2% solutions 
have been marketed in USA and Canada for several years and are indicated for the production 
of local anaesthesia by peripheral nerve block as well as via other administration routes.  
 
1.1.3 
Safety of local anaesthetics 
 
If appropriately administered, in terms of dosage and anatomical location, local anaesthetics 
are relatively free of adverse effects. In general, toxicity following local anaesthesia is more 
often engendered by the accidental intravascular or subarachnoid injection of the drug or the 
administration of an excessive dose. Fortunately severe complications are rare and their 
incidence has been significantly reduced in the last decades (5). To simplify, three main 
categories of potential toxicity from loco-regional anaesthesia techniques may be considered: 
systemic toxicities, peripheral nerve injuries and other local tissue toxicities, such as allergic 
reactions (3,5-7).  
 
Systemic toxicity ranges from mild systemic symptoms, such as visual and auditory 
disturbances, drowsiness, circumoral numbness, and agitation, to serious signs of central 
nervous system (CNS) depression, such as seizures, respiratory depression and respiratory 
arrest. Furthermore, the systemic spread of local anaesthetics may exert a direct action on 
cardiovascular functions, leading to hypertension, hypotension, tachycardia, bradycardia, 
ventricular arrhythmias and cardiac arrest (3,5,6).  
 
Peripheral nerve injuries following peripheral nerve blocks are also rare, though distinctions 
can be made between major complications, which result in permanent nerve damage and 
occur with a 1.5:10000 incidence, and more frequent transient neurological deficits (7). For 
instance, an incidence of 8-10% is reported for episodes of transient paraesthesia. However, 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
regardless of the anaesthetic administered, the use of ultrasound guidance for peripheral nerve 
blocks has now improved the efficacy and safety of the anaesthetic techniques (7; § 1.1.4). 
Furthermore, the onset of toxicity generally occurs during, or shortly after, the surgical 
operation, thus can be immediately caught and appropriately managed.   
 
Chloroprocaine favourable safety profile for spinal anaesthesia is largely recognized in the 
literature (18-21). Currently available literature sources, mostly clinical trials, occasionally 
report episodes of mild systemic toxicity following chloroprocaine loco-regional anaesthesia, 
while other studies found no toxicities at all (0-1% for peripheral nerve blocks (14,15,22-24); 
up to 8-37.3% for intravenous regional anaesthesia – IVRA (25); up to 12.5-55% for epidural 
[13,17]).  
 
1.1.4 
Ultrasound-guided axillary block 
 
Axillary block for brachial plexus anaesthesia is a very popular anaesthetic technique for hand 
and forearm surgery, especially due to the very low incidence of complications compared to 
other brachial plexus block techniques (26). For this technique to be successful, deposition of 
local anaesthetic adjacent to four nerves (the median, radial, ulnar and musculocutaneous 
nerves) is required. 
 
Historically, single-injection techniques have not provided reliable blockade in the 
musculocutaneous and radial verve territories, but success rates have greatly improved with 
multiple-injection techniques using nerve stimulation and more recently using ultrasound 
guidance. The latter has become very common in clinical practice thanks to the refinement of 
ultrasound technology and ultrasound-guided block techniques, and is gradually replacing 
nerve stimulator-guided approach (26). 
 
Ultrasound visualization of target nerves, needle and injectate spread has in fact been 
associated with improved block success rates, decreased block onset times and a decrease in 
the local anaesthetic dose needed (27; 28-35). With ultrasound-guideded axillary block, 
damage to important structures like nerves and vessels, during the injections, can be avoided 
and the risk of accidental nerve damage can be reduced, although care should be continually 
exercised using standard safety precautions to minimize any possible risk associated with the 
technique (26).  
 
1.2 
Rationale 
 
Ambulatory surgical procedures are steadily increasing in Europe and USA. The use of short-
acting local anaesthetic agents such as chloroprocaine permits a rapid onset of anaesthesia for 
short duration surgery and early recovery profiles, offering the advantage of early home 
discharge. 
 
There is a long history of use of chloroprocaine and the amino ester class of anaesthetics in 
USA, Canada and Switzerland. In particular, chloroprocaine solutions (i.e. Nesacaine® 1, 2, 
3%, Astra-Zeneca; Chloroprocaine HCl 2, 3%, Bedford Laboratories) have been marketed in 
USA and Canada for several years and are indicated for the production of local anaesthesia by 
peripheral nerve block as well as via other administration routes (see corresponding SmPCs).  
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
Sintetica SA, Switzerland, received marketing approval for 0.5% Chloroprocaine HCl 
Injection for IVRA (Ivracain®) in Switzerland in 1996. In 2012, preservative-free 
Chloroprocaine HCl 1% injection, Sintetica SA (Switzerland) has been approved for spinal-
intrathecal anaesthesia, under the brand name of Ampres/Clorotekal, in several European 
countries (i.e. Germany, UK, Austria, Belgium, France, Ireland, Italy, Poland and Spain). 
 
Whereas Chloroprocaine HCl 2% solutions are presently on the market in USA and Canada 
for the production of local anaesthesia by peripheral nerve block and other administration 
routes, in Europe this local anaesthetic is not presently marketed as a 2% solution for the 
above reported indications.  
 
As part of a development programme for the preservative-free Chloroprocaine HCl Injection 
products (i.e. Chloroprocaine 0.5, 2 and 3%, Sintetica SA, Switzerland) in EU member states, 
the present study has been designed to evaluate the non-inferiority of Chloroprocaine HCl 2% 
(Sintetica SA; Test) with respect to Ropivacaine HCl 0.75% (Naropin®, AstraZeneca GmbH, 
Germany; Reference) in axillary brachial plexus blockade in men and women undergoing 
short duration distal upper limb surgery including hand, wrist and forearm procedures. 
Ropivacaine HCl 0.75% has been chosen as the active control because commonly used in 
Germany, Switzerland and other European countries in brachial plexus block procedures (see 
Ropivacaine 7.5 mg/mL SmPC). 
 
The doses of the two local anaesthetics for this study (20 mL) have been chosen according to 
the products’ SmPCs and the use of ultrasound-guided as compared to the nerve stimulation 
technique for the axillary plexus block. 
 
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 the ultrasound-
guided axillary approach for brachial plexus blockade is a well-known technique routinely 
used in the clinical setting and that the two local anaesthetics investigated in the study have 
been on the market under different brand names in USA and Canada for several years for the 
proposed indications, and the potential side effects, contraindications and special warnings are 
well described in the corresponding product information (see Nesacaine® and Naropin® 
SmPCs). 
 
Axillary block for brachial plexus anaesthesia has been reported to be the safest of the 
brachial plexus blockade techniques because of the reduced risk to surrounding structures 
such as the risk of phrenic nerve blockade and/or pneumothorax. The rates of complications 
with axillary block are quite low and consist mainly in haematomas and pain at the injection 
site. The general risks of accidental intravascular and intraneural injection, however, still 
exist, but are markedly reduced with the use of ultrasound visualization of the 4 concerned 
nerves. In any case, care will be continually exercised using standard safety precautions to 
minimize the risks associated with the technique. 
 
Allergic reactions with local anaesthetics are rare but could occur in patients hypersensitive to 
ester groups and could consist of pruritus, urticaria, edema and tachycardia.  
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
Central nervous system and cardiovascular system adverse reactions are generally dose-
related and occur only with high plasma concentrations of local anaesthetics. These reactions 
are not expected in the present study. However, careful and constant monitoring of 
cardiovascular and respiratory vital signs and patients status will be performed throughout the 
study procedures.   
 
 
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
2 
STUDY OBJECTIVES 
 
2.1 
Primary objective 
 
The primary objective of the study is to evaluate the non-inferiority of Chloroprocaine HCl 
2%, Sintetica SA (Test) versus Ropivacaine HCl 0.75% (Naropin®, AstraZeneca; Reference) 
in terms of proportion of subjects with a successful block* for distal upper limb surgeries, 
without any supplementation** in the first 45 min (see definitions below), calculated from the 
time of readiness for surgery (complete sensory block). 
 
*Successful block: anaesthesia adequate for the surgery (complete sensory block), without any 
supplementation in the first 45 min (even if surgery lasts for > 45 min), calculated from the 
time of readiness for surgery (complete sensory block).  
 
**Supplementation: i.v. premedication or general anaesthesia or pre- or intra-operative 
systemic analgesia or additional local anaesthetic infiltration.   
 
2.2 
Secondary objectives 
 
The secondary study objectives are: 
 
 To compare Test and Reference products in terms of the time to onset of sensory block 
(readiness for surgery), time to regression of sensory block, time to onset and regression 
of motor block, need for supplemental anaesthesia/analgesia and time to eligibility for 
home discharge  
 To evaluate the safety and tolerability profile of the study treatments. 
 
 
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of products 
 
The analytical certificates will be enclosed with the investigational medicinal products 
(IMPs). 
 
3.1.1.1 
Test product 
 
TEST (T) 
 
IMP 
Chloroprocaine HCl 2% (20 mg/mL)  
Distributor 
Sintetica S.A., Switzerland 
Manufacturer 
Sintetica S.A., Switzerland 
Pharmaceutical form 
Solution for injection (ampoule) 
Dose 
20 mL (400 mg), approximately 5 mL (100 mg) per nerve 
Administration route 
Axillary injection (axillary brachial plexus block) 
 
3.1.1.2 
Reference product 
 
REFERENCE (R) 
 
 
IMP 
Naropin®, 0.75% (7.5 mg/mL)  
Active substance 
Ropivacaine HCl 
Distributor 
AstraZeneca GmbH, Germany 
Pharmaceutical form 
Solution for injection (ampoule) 
Dose 
20 mL (150 mg), approximately 5 mL (37.5 mg) per nerve 
Administration route 
Axillary injection (axillary brachial plexus block) 
 
3.1.2 
Dose regimen 
 
Patients will be randomised to one of the two treatment groups to receive either 
Chloroprocaine HCl 2% (Test) or Ropivacaine HCl 0.75% (Reference) as anaesthetic before 
surgery, according to the randomised, parallel-group design of the study. 
 
Patients in the Test product group will receive a single total dose of 20 mL Chloroprocaine 
HCl 2% (corresponding to 400 mg) and patients in the Reference group will receive a single 
total dose of 20 mL Ropivacaine HCl 0.75% (corresponding to 150 mg). 
 
3.1.3 
Route and method of administration 
 
Both anaesthetics will be administered by the axillary nerve route, as described below. 
 
Test and reference individual ampoules (one ampoule of anaesthetic per patient) will be 
opened just before the administration. Syringes for injection will be prepared by a co-
investigator/pharmacist/study nurse not involved in axillary block placement or study 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
outcome measures evaluation. Details on the anaesthetic preparation in syringes for injection 
will be given in the study manual. 
 
For the placement of the axillary block, the following procedure will be used in both 
anaesthetic treatment groups: 
The arm will be externally rotated and the elbow flexed to 90 degrees. The skin surface of the 
axilla will be aseptically prepared. Axillary block will be performed under ultrasound 
guidance using standard procedures. The median, ulnar, radial and musculocutaneous nerves 
will be identified. A 5 cm needle will be inserted towards the 4 nerves. Once appropriate 
perineural needle placement is visualized, the volume (20 mL) of either Chloroprocaine HCl 
2% (Test) or Ropivacaine HCl 0.75% (Reference) will be injected using a syringe. The time 
from needle insertion to final perineural injection (time 0 h) will be recorded. 
 
3.1.4 
Investigational product distribution 
 
The test and reference products will be administered by the investigator or by his/her deputy. 
The investigational products will be exclusively used for the present clinical study and will 
only be administered to the subjects enrolled in the study.  
 
3.2 
Packaging and labelling 
 
Packaging and labelling will be carried out by the Sponsor according to the randomisation 
list. Labelling in local language will be applied in such a way that it should not obscure the 
original label and will report all the information requested according to the Annex 13 to the 
Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4). 
 
Labelling on packages will report: 
 
a) 
Name, address and telephone number of the sponsor and CRO;  
b) 
Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency;  
c) 
Batch number;  
d) 
Study Nr.;  
e) 
The study subject identification number/treatment number;  
f) 
Expiry in month/year format and in a manner that avoids any ambiguity;  
g) 
Investigator's name;  
h) 
Directions for use;  
i) 
“For clinical trial use only” wording;  
j) 
The storage conditions;  
 
Further details on the products packaging will be given in the study manual. 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
3.3 
Storage conditions 
 
The test product will be stored at 15 - 25°C in a dry locked place, sheltered from light. The 
reference product will be stored at < 30°C and must not be frozen. 
 
3.4 
Drug accountability 
 
The test and reference investigational products will be provided directly to the 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 accountability forms. 
 
At the end of the study, used, unused and partially used supplies of test and reference 
investigational products provided by the sponsor/manufacturer will either be destroyed on site 
(upon written authorisation) or returned to the sponsor/manufacturer, after assessment of drug 
accountability. 
 
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
This will be a prospective, randomised, multi-centre, active-controlled, blind-observer, 
parallel-group, non-inferiority study. 
 
4.2 
Discussion of design 
 
The study has been designed to evaluate the non-inferiority of Chloroprocaine HCl 2% (Test) 
with respect to Ropivacaine HCl 0.75% (Reference) in axillary brachial plexus blockade in 
men and women undergoing short duration distal upper limb surgery. In designing the study 
the following guidelines were taken into consideration: ICH E9 guideline on Statistical 
principles for clinical trials (36); the Guideline on the choice of the non-inferiority margin 
(CPMP/EWP/2158/99; 37); and the Points to consider on switching between superiority and 
non-inferiority guideline (CPMP/EWP/482/99; 38). A non-inferiority margin of 10% (δ = - 
0.1) was set in accordance to the information in published works (27,30,39-42) on the success 
rates with local amide anaesthetics using ultrasound-guided axillary block. No placebo could 
be investigated in this trial in a third treatment arm because the study treatment consists of 
local anaesthesia before a surgical procedure and an active agent must be used in all cases. 
 
Distal upper limb surgeries, which include hand, wrist and forearm surgeries, have been 
selected because routinely performed under axillary plexus block.  
 
Ropivacaine HCl 0.75% has been chosen as the active control because commonly used in 
Germany, Switzerland and other European countries in brachial plexus block procedures (see 
Naropin® [Ropivacaine HCl] 0.75% SmPC). 
 
Ultrasound-guided axillary block for brachial plexus anaesthesia is a popular anaesthetic 
technique for distal upper limb surgery and is considered the safest approach because of 
reduced risk to surrounding structures (26).  
 
Each patient will be allocated to a treatment arm according to a computer-generated 
randomisation list. 
 
The study will be observer-blind. Syringes for injection will be prepared by a co-
investigator/pharmacist/study nurse not involved in axillary block placement or study 
outcome measures evaluation. An independent blinded observer will evaluate sensory and 
motor blocks for each patient.  
 
 
 
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Study protocol CRO-14-120 
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Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
5 
STUDY POPULATION 
 
5.1 
Target population 
 
One hundred and eighty (180) male/female patients, 90/treatment group, aged ≥ 18 years, 
scheduled for distal upper limb surgery (< 60 min) under axillary brachial plexus block. 
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
1. Sex and surgery: male and female patients scheduled for short duration (< 60 min) distal 
upper limb surgery under axillary nerve block anaesthesia 
2. Age: ≥ 18 years old 
3. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive 
4. ASA physical status: I-III 
5. Informed consent: signed written informed consent before inclusion in the study 
6. 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 peripheral nerve block anaesthesia. 
History of neuromuscular diseases to the upper extremities 
2. Axillary status: Axillary local infections, surgical scarring and pathological lymph node 
enlargement 
3. ASA physical status: IV-V 
4. Further anaesthesia: Patients anticipated to be requiring further anaesthesia (general or 
local anaesthesia) 
5. Chronic pain syndromes: Patients with chronic pain syndromes (taking opioids, 
antidepressants, anticonvulsant agents) 
6. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or 
formulations ingredients; ascertained or presumptive hypersensitivity to the amide and 
major anaesthetics 
7. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, 
skin, haematological, endocrine or neurological diseases that may interfere with the aim of 
the study; ascertained psychiatric diseases, sepsis, blood coagulation disorders, insulin 
dependent diabetes mellitus, terminal kidney failure 
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Study protocol CRO-14-120 
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Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
8. Medications: Medication known to interfere with the extent of regional blocks (see 
chloroprocaine and ropivacaine SmPCs) for 2 weeks before the start of the study. 
Hormonal contraceptives for females will be allowed 
9. 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 
10. Drug, alcohol: history of drug or alcohol abuse 
11. Pregnancy: missing or positive pregnancy test at screening, pregnant or lactating women 
 
5.3.1 
Not allowed treatments 
 
No medication known to interfere with the extent of regional blocks (see chloroprocaine and 
ropivacaine SmPCs) will be allowed for 2 weeks before the start of the study and during the 
whole study duration. Hormonal contraceptives for females are allowed. 
 
5.3.2 
Additional anaesthesia and rescue analgesia 
 
If a successful block is attained, no i.v. premedication or general anaesthesia or pre- or intra-
operative systemic analgesia or additional local anaesthetic infiltration will be administered in 
the first 45 min calculated from the time of readiness for surgery. In the event of block failure, 
or after the first 45 min calculated from the time of readiness for surgery, if necessary local 
anaesthesia, general anaesthesia or rescue analgesia will be administered, according to the 
investigator’s judgment. 
 
5.3.3 
Premedication/sedation and analgesia 
 
Oral premedication with midazolam will be allowed, if necessary. No prophylactic i.v. 
midazolam, propofol or fentanyl will be allowed for premedication/sedation on a routine basis 
(if a patient needs these drugs, the block will be classified as insufficient for surgery). At the 
end of the surgical procedure, an appropriate analgesic (e.g. mefenamic acid or paracetamol) 
will be administered to the patients, according to the investigator’s opinion.  
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 14. 
 
6.1 
Study visits and procedures 
 
The study protocol foresees a screening visit, 1 study treatment for each patient, followed by 
post-operative recovery, final visit and follow up. Maximum study duration will be approx. 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 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 
 
 Interventional 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) 
 Telephonic follow-up – day 7±1 (6±1 days after surgery)  
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Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
 
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  
 
Medical/surgical history 
 
Previous/concomitant medications 
 
Full physical examination (BW, height, body mass 
index, vital signs, physical abnormalities) 
 
Urine pregnancy test for women  
 
Eligibility evaluation 
 
AE monitoring 
 
 
Treatment - Visit 2 
Day 1 
 
Eligibility evaluation 
 
Enrolment and randomisation 
 
Oral midazolam premedication (if necessary) 
 
Anaesthesia administration 
 
Sensory and motor block assessments 
 
Vital signs, SpO2 and ECG (if foreseen by standard 
hospital procedures) 
 
Surgery (< 60 min)  
 
AEs and concomitant medications 
 
Post-operative recovery and Final Visit/ETV 
Day 1/2 
or upon 
discontinuation 
in case of ETV 
 Patients moved to post-recovery room (after 
surgery) 
 Aldrete’s scoring scale 
 Vital signs, ECG (if foreseen by standard hospital 
procedures) and SpO2 
 AE and concomitant medications 
 Discharge (when criteria for discharge are met and 
according to the hospital’s standard procedures) 
Meals (lunch [and dinner 
only if applicable]) will 
be served after surgery 
and recovery according 
to the hospital’s standard 
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. 
Upon 
leaving, the subjects will 
be instructed to contact 
immediately 
the 
investigator in case of 
occurrence 
of 
any 
adverse reactions 
Telephonic
Follow-up 
Day 7±1 
 AE and concomitant medications 
 
 
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Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
6.2 
Diet and lifestyle 
 
Study participants will undergo study procedures as outpatients or inpatients, 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 according to the hospital procedures after meeting the 
criteria for discharge (on Day 1 or on a following day).  
 
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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Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Full physical examinations will be performed at the screening visit (ETV). Information about 
the physical examination will be recorded by the investigator. Any abnormalities will be 
recorded. 
 
Information about the type of distal upper limb surgery will be recorded. 
 
7.1.1 
Body weight 
 
Body weight (BW) will be recorded at the screening visit.  
 
Patients will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and BMI will be recorded. BMI will be calculated as weight [kg]/(height [m] x 
height [m]). 
 
7.1.2 
Vital signs 
 
Patients’ blood pressure (BP) and heart rate (HR) will be measured by the investigator or 
his/her deputy after 5 min at rest (sitting position) at the screening visit. Blood pressure, HR 
and SpO2 will be monitored using standard monitors, according to ASA recommendations, at 
baseline (before block placement), during the block until the end of the anaesthesia.  
 
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% 
 
Blood pressure, heart rate and SpO2 will be monitored also at post-operative recovery and 
final visit. SpO2 should be ≥ 92% during the monitoring period.  
To meet criteria for discharge, the patients’ haemodynamic variables must be stable and SpO2 
must be acceptable (> 92%). 
 
Occurrence of clinical relevant hypotension and bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.   
 
7.1.3 
ECGs 
 
ECG will be monitored using standard monitors at baseline (before block placement), during 
the block and at post-operative recovery / final visit (if foreseen by standard hospital 
procedures). 
 
The following normal ranges for ECG parameters will be used: 
 
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Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
Heart Rate: 50-90 beats/min 
 
PR Interval: 100-220 msec 
 
QRS Duration: ≤ 120 msec 
 
QT Interval: ≤ 500 msec 
 
7.1.4 
Pregnancy test 
 
A urine pregnancy test for women will be performed at screening (Visit 1).  
 
7.1.5 
Block assessment 
 
Sensory and motor blocks will be evaluated in each nerve territory by an independent 
assessor, blinded to the anaesthetic (Test or Reference) injected. If needed, sensory and motor 
functions will be compared in the contralateral distal upper limb. Blocks will be assessed 
every 5 min until the patient is ready for surgery. Then, blocked limbs will be evaluated as 
soon as possible after surgery (taking into consideration the end of surgery procedures), every 
15 min for the first hour after surgery, every 30 min for the next 2 hours and then every hour 
until regression of surgical anaesthesia. Time to onset of sensory and motor blocks and time 
to regression of sensory and motor blocks will be recorded.  
Block assessment times should not deviate more than the recommended deviation time ranges 
summarised in the following table.  
 
Table 7.1.5.1 Recommended maximal deviations from the scheduled block assessment times 
Blocks assessment times 
Deviation 
Every 5 min until readiness for surgery 
± 1 min 
Immediately after surgery 
--- 
15 min after surgery 
± 1 min 
30 min after surgery 
± 2 min 
45 min after surgery 
± 2 min 
1 h after surgery 
± 3 min 
1.5 h after surgery 
± 3 min 
2 h after surgery 
± 5 min 
2.5 h after surgery 
± 5 min 
3 h after surgery and then every hour  
until regression of  anaesthesia 
± 5 min 
 
Any deviation 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. 
 
Sensory and motor function assessments will be performed as detailed below: 
 
Sensory block will include thermal perception (cold spray) and sensitive perception (pin 
prick) assessments. The anaesthetised arm will be compared with the contralateral arm, if 
necessary. Assessments will be performed for each nerve territory and will be scored as being 
present (score 1) or absent (score 0).  
Sensory block is defined as a sensory block score of 0. 
 
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Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
Onset of sensory block, corresponding to readiness for surgery, is defined as an absent cold 
and touch sensation in the 4 nerve territories (complete sensory block).  
 
Motor block will be evaluated through specific motor tests for each nerve territory. In detail, 
motor tests will be: flexion of radial 3 fingers for the median nerve, extension of wrist for 
radial, abduction of fingers for ulnar and elbow flexion for musculocutaneous nerve. Each 
assessment will be scored according to the following modified Bromage scale (39): 
 
Table 7.1.5.2 Modified Bromage scale for motor block assessment 
Score 
Definition 
0 
No movement in relevant muscle group 
1 
Flicker of movement in relevant muscle group 
2 
Ability to move relevant muscle group against gravity but inability to move against resistance 
3 
Reduced power but ability to move muscle group against resistance 
4 
Full power in relevant muscle group 
 
Motor block is defined as a motor block score of ≤ 2 on the modified Bromage scale.  
 
Onset of motor block is achieved when motor block is present in ≥ 3 nerve territories. No 
motor block is required for successful block.  
 
Regression of sensory block will be deemed to have occurred when cold sensation and 
sensitive perception have returned (if assessable) in any nerve territory. 
 
Regression of motor block will be deemed to have occurred when motor score is ≥ 3 in any 
nerve territory. 
 
7.2 
Procedures for post-operative recovery and final visit 
 
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 ≥ 9 
on the modified Aldrete’s scoring scale (43) and no pain. 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 arm, 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. 
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CONFIDENTIAL 
 
Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
7.3 
Procedures for telephonic follow-up 
 
On day 7±1 (6±1 days after the day of surgery), a deputy of the Investigator, not aware of the 
administered treatment, will contact the patients by telephone and will question them about 
any adverse reactions which might have occurred after discharge, with particular attention to 
any sign of late systemic toxicity, local toxicity, neurological symptoms and allergic 
reactions. 
 
7.4 
Assessment of symptoms of systemic and local toxicity 
 
Particular attention will be given to systemic and local toxicity symptoms, neurological 
symptoms and allergic reactions. In particular, patients will be instructed to report signs of 
systemic (central nervous system) toxicity, e.g. metallic taste, ringing in the ears etc. In 
addition, at every assessment time, occurrence of slurred speech will be noted. 
 
7.5 
Data recording 
 
Efficacy and safety data will be reported on the individual case report forms (CRF). 
 
Details on the surgical procedure, i.e. type of surgery, start time, end time and comments will 
also be reported on the individual CRF. 
 
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
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) (44) 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. 
Randomisation will be stratified by centre.  
 
8.2 
Treatment allocation 
 
Patients will be allocated to the Test (Chloroprocaine) arm or Reference (Ropivacaine) arm in 
a 1:1 ratio according to the study randomisation list.  
 
Each study centre will receive a set of Test and Reference treatments. Each treatment ampoule 
will be individually labelled and packaged (see § 3.2).  
 
Randomisation number will be given to the patients on study Day 1 and will be used to 
allocate each patient to a treatment group, as detailed above. 
 
8.3 
Blinding 
 
This is an observer-blind study. No masking procedure will be applied.  
 
Syringes for injection will be prepared by a co-investigator/pharmacist/study nurse not 
involved in axillary block placement or study outcome measures 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 
centres. 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 centres will also receive individual kit replacement envelopes. If a reserve kit 
needs to be used, the kit replacement envelope will be opened and the injectable solution will 
be prepared 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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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary end-point 
 
The primary study end-point will be the proportion of subjects (%) with a successful block for 
distal upper limb surgeries, without any supplementation (i.e. no i.v. premedication or general 
anaesthesia or pre- or intra-operative systemic analgesia or additional local anaesthetic 
infiltration) in the first 45 min, calculated from the time of readiness for surgery. 
 
9.1.2 
Secondary end-points 
 
Efficacy end-points: 
 
 Time to onset of sensory block (corresponding to readiness for surgery),  
 Time to onset of motor block,  
 Time to regression of sensory block, 
 Time to regression of motor block, 
 Time to administration of rescue anaesthesia or rescue analgesia,  
 Time to first post-operative analgesia, 
 Time to eligibility for home discharge. 
 
Safety end-points: 
 
 Treatment-emergent adverse events (TEAEs),  
 Vital signs measurements (blood pressure, heart rate, SpO2)  
 ECG recordings (if foreseen by hospital standard procedures) 
 
9.2 
Efficacy assessments 
 
Sensory and motor block assessment procedures and evaluations are detailed in § 7.1.4. 
 
Efficacy assessments are based on the following variables: 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
Parameter 
Description 
Proportion of subjects 
with successful block 
Number of subjects with a successful block (as defined below*) 
divided by the number of subjects in the efficacy analysis set 
(FAS and PP set, see § 10.1.1) 
Time to onset of sensory 
block (corresponding to 
time to readiness for 
surgery) (min)  
Time period from completion of the final perineural injection 
(time 0 h) to achievement of sensory block in the 4 nerve 
territories (as defined in § 7.1.4) 
Time to onset of motor 
block (min) 
Time period from completion of the final perineural injection 
(time 0 h) to achievement of motor block (as defined in § 7.1.4). 
Time to regression of 
sensory block (min) 
Will be deemed to have occurred when cold sensation and 
sensitive perception have returned (if assessable) in any nerve 
territory. 
Time to regression of 
motor block (min) 
Will be deemed to have occurred when motor score is ≥ 3 in any 
nerve territory. 
Time (h) to 
administration of rescue 
anaesthesia or rescue 
analgesia 
Time from completion of the final perineural injection (time 0 h) 
to administration of first rescue anaesthesia or analgesia 
(supplementation) (if applicable) 
Time (h) to first post-
operative analgesia 
Time from completion of the final perineural injection (time 0 h) 
to first post-operative analgesia 
Time (h) to eligibility for 
home discharge 
Time from completion of the final perineural injection (time 0 h) 
to the time when the criteria for discharge are met, even if, 
according to the hospital procedures, the patient is discharged 
from the hospital at a later time 
 
*Successful block is defined as: anaesthesia adequate for the surgery (complete sensory 
block), without any supplementation in the first 45 min (even if surgery lasts for > 45 min), 
calculated from the time of readiness for surgery (complete sensory block).  
 
Supplementation includes: i.v. premedication or general anaesthesia or pre- or intra-operative 
systemic analgesia or additional local anaesthetic infiltration.  
 
Block failure is defined as: absence of or inadequate surgical anaesthesia with the need for 
supplementation (as defined above) in the first 45 min, calculated from the time of readiness 
for surgery (complete sensory block). 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
9.3 
Safety assessments 
 
Safety and general tolerability of the investigational anaesthetic will be based on TEAEs, vital 
signs measurements (blood pressure, heart rate, SpO2) and ECG recordings (if applicable).  
 
In particular, ECG, blood pressure, heart rate and SpO2 will be monitored before the block for 
baseline assessment, during the block until the end of anaesthesia (ECG if foreseen by 
standard hospital procedures), using standard monitors, according to ASA guideline 
recommendations (SpO2 should be ≥ 92%). These variables will be monitored also during 
post-operative recovery. To meet criteria for home discharge, haemodynamic variables must 
be stable and SpO2 must be acceptable (> 92%) without oxygen therapy. 
 
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 systemic and local toxicity symptoms, 
neurological symptoms and allergic reactions. In particular, patients will be instructed to 
report signs of systemic (central nervous system) toxicity, e.g. metallic taste, ringing in the 
ears etc. In addition, at every assessment time, occurrence of slurred speech will be noted.  
 
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Study protocol CRO-14-120 
Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
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) (44) 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 meets all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomised allocation to a 
treatment arm. 
 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatment arm. 
 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
 Full Analysis Set (FAS): all randomised patients who fulfil the study protocol 
requirements in terms of study anaesthetics administration. This analysis set will be used 
for sensitivity analyses 
 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 
 Safety set: all patients who receive at least one dose of the investigational medicinal 
product(s). This analysis set will be used for the safety analyses 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Enrolled 
set, FAS, PP set and Safety set. Subjects will be evaluated according to the treatment they will 
actually receive (Enrolled set, FAS, PP set and Safety set). 
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Sponsor code CHL.2/01-2014/M 
Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
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 § 7.1.4) 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
 
intake of prohibited medications before the end of surgery during the first 45 min 
calculated from the time of readiness for surgery and not foreseen by the study protocol 
(see § 5.3.1 and 5.3.3) with the exception of sedation before anaesthesia, additional 
anaesthesia and rescue analgesia (see §5.3.2). If sedation before anaesthesia (excluding 
oral midazolam) or additional anaesthesia or analgesia is required before the end of 
surgery during the first 45 min calculated from the time of readiness for surgery, the 
subject will be included in the PP set and evaluated as block failure. 
 
10.2 
Sample size and power considerations 
 
Given the following definitions: 
 
πT = Proportion of success - Test (Chloroprocaine);  
πR = Proportion of success - Reference (Ropivacaine);  
є = πT - πR (difference between Test and Reference proportion of success);  
δ = Non-inferiority limit;  
 
the sample size for the one-sided hypothesis test H0: є ≤ δ vs. Ha: є > δ can be computed 
according to the following formula (45):  
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NT = k x NR and 
NR = ceiling {[(Z1-α+ Z1-β) 2/ (є - δ) 2] x [πT x(1- πT)/k + πR x (1- πR)]};  
 
where:  
 
k = Balancing ratio between treatment arms (1 for balanced group) 
NT = Number of subjects included into the Per Protocol set for Test treatment group;  
NR = Number of subjects included into the Per Protocol set for Reference treatment group; 
 
Considering a one-sided type I error α = 0.025, a type II error β = 0.2, a non-inferiority 
margin δ = -0.1 and a proportion of success of 0.95 in both treatment groups, 75 patients per 
treatment group are required. Assuming an exclusion rate from the Per Protocol Set of 15%, 
90 patients per group will be recruited for a total number of 180 patients. 
 
10.3 
Handling of missing data 
 
10.3.1 
Methods for replacing missing data 
 
 Multiple imputation (MI) under missing at random (MAR) assumption: multiple 
imputation is a general approach to the problem of missing data that aims to allow for the 
uncertainty about the missing data by creating several different plausible imputed data sets 
and appropriately combining results obtained from each of them. Missing at random 
(MAR) approach assumes that any systematic difference between the missing values and 
the observed values can be explained by differences in observed data. The use of multiple 
imputation under MAR assumption provides unbiased estimations of the parameters and 
allows evaluating the uncertainty of parameters’ estimation due to the presence of missing 
data. Separate multiple imputations will be performed for each treatment arm. 
 Missing as Failure (MF): missing values of the primary end-point are considered as block 
failures regardless of the treatment arm. 
 Worst Case (WC): missing values of the primary end-point are considered as block 
failures if the patients receive Test product and as block successes if the patients receive 
Reference product. 
 
10.3.2 
Replacement rules for each analysis set 
 
 Enrolled set: all missing data will not be replaced. 
 Full Analysis Set (FAS): missing data of the primary end-point (if any) will be replaced 
according to MI under MAR assumption method, MF method and WC method in three 
different sensitivity analyses. Missing data of the secondary end-points will not be 
replaced. 
 Per Protocol set (PP): no replacement of missing data is required for the primary end-
point. Missing data of the secondary end-points will not be replaced. 
 Safety set: all missing data will not be replaced. 
 
10.4 
Demographic, baseline and background characteristics 
 
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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. 
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10.5 
Analysis of efficacy parameters 
 
The efficacy analysis will be performed on the PP set (primary efficacy analysis) and FAS 
(sensitivity analyses). The observed response rate for each treatment group will be calculated 
as the proportion of subjects with a successful block (as defined in § 9.2). 
 
The proportion of subjects with a successful block will be compared between treatment 
groups by a binomial regression model, with the factors treatment and centre as fixed effects. 
If the binomial regression model fails to converge, a Poisson regression model with a robust 
error variance (sandwich estimation) will be used instead of the binomial model (46, 47). 
Non-inferiority of the Test in comparison with the Reference treatment will be considered 
proved if the lower confidence limit of the 97.5% one-sided confidence interval of the 
difference between treatments is greater than the non-inferiority margin δ = - 0.1.  
 
Secondary variables (time to onset of sensory block [readiness for surgery], time to onset of 
motor block, time to sensory and motor block regression, time to eligibility for home 
discharge, time to rescue anaesthesia or analgesia, time to post-surgery analgesia) will be 
presented using Kaplan-Meier curves and will be compared between treatment groups by log 
rank test. All tests on the secondary variables will be performed with a nominal two-sided 
type I error α = 0.05. 
 
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. Date of the physical 
examination and overall investigator’s interpretation (as normal, abnormal not clinically 
significant [NCS] or abnormal clinically significant [CS]) will be reported in the CRF. 
 
 Vital signs 
Values of vital signs will be listed and summarised by descriptive statistics.  
 
 Body weight  
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Values of body weight will be listed and summarised by descriptive statistics. 
 
 ECG 
Date and time of ECG recording and overall investigator’s interpretation (normal, abnormal 
NCS, abnormal CS) will be reported in the CRF and listed in the final 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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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) 
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 
 
 Treatment-emergent AE (TEAE) 
Any AE occurring or worsening after the first dose of a medicinal product 
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 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event that may jeopardize the subject’s health status or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are cancer, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse 
 
 Unexpected ADR: an ADR the nature or severity of which is not consistent with the 
Reference Safety Information (RSI) 
 
 Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, the Investigator’s Brochure (IB) for the test formulation and the SmPC for the 
reference formulation will be used. 
 
 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An ADR that is both unexpected (not consistent with the RSI) and also meets the definition of 
a SAE. 
 
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 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  
 
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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 
  
 
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 
 
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 
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. 
 
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) 
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 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 
 
The CRO can be contacted using the phone and fax numbers stated in this protocol or calling 
the mobile phone number +41.79.822.35.07 (operative 24-h/day, 365 days/year).  
 
SAEs must be reported on SAE reporting forms and faxed to the sponsor - contact details 
below: 
 
Dr. Elisabetta Donati 
Fax: 
+41(0)91.646.85.61 
Phone: +41(0)91.640.42.50 
E-mail: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.2/01-2014/M), the 3-digit centre number (i.e. 001, 002 or 003), the 4-digit screening 
number (e.g. S001, S002, etc.) and, if applicable, the 3-digit subject randomisation number 
(e.g. 101, 102, …, 201, 202, …, 301, 302, etc. ). 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 Monitor Services, Germany (centre N. 1) 
and Clinical Medical Service Sagl/Cross Research S.A. in Switzerland (centres N. 2 and 3).  
 
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 centres are responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirement(s). 
 
The CROs 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 present clinical study will be carried out according to the general principles of “ICH 
Topic E6, CPMP/ICH/135/95”, July 1996 including post Step 4 errata, status September 1997 
and post Step errata (linguistic corrections), July 2002. 
 
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. 
 
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. 
 
If a subject is physically unable to sign the informed consent form due to the distal upper limb 
injury, an impartial witness should be present during the entire informed consent discussion 
and, after the subject has orally consented to the participation in the trial and, if capable of 
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doing so, has signed and personally dated the ICF, the witness should sign and personally date 
the consent form. 
 
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 
 site terminated by sponsor: an indication that a clinical site was stopped by the study 
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 had a successful block (block failure). 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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Final version 2.0, 17SEP14 
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 test investigational product 
 product information for the reference 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 Authorities, according to 
the current regulations in the EU and Switzerland. 
 
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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Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
 
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 each clinical centre among those patients attending the 
clinic for distal upper limb surgery of short duration. Sixty patients should be recruited at each 
clinical centre.  
 
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. 
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Final version 2.0, 17SEP14 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator(s) will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual 
property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 
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Chloroprocaine 2% - Axillary block 
Final version 2.0, 17SEP14 
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 
Dr. Claudio Camponovo, Department of Anaesthesiology, Clinica Ars Medica, Switzerland 
(for a complete address and contact details, please see clinical centre N. 2 below) 
 
 
16.2 
Institutes performing the study 
 
16.2.1 
Clinical centre 
 
CLINICAL CENTRE N. 1 
Department of Anesthesiology and Intensive Care Medicine, Phillips-University Hospital, 
Biegenstrasse 10, D-35032 Marburg, Germany  
Phone: 
+49.6421.58.62003 
Fax: 
+49.6421.58.62014 
 
Principal investigator and overall study coordinator 
Hinnerk Wulf, MD. Professor and Chairma, Department of Anesthesiology and Intensive 
Care Medicine 
Email: 
H.Wulf@med.uni-marburg.de 
 
Co-investigators 
PD Dr. T. Steinfeldt – Anaesthesiologist 
Dr. T. Wiesmann – Anaesthesiologist 
 
 
CLINICAL CENTRE N. 2 
Department of Anaesthesiology, Clinica Ars Medica, Via Cantonale, CH-6929 Gravesano, 
Switzerland  
Phone: 
+41.91.611.6211 
Fax: 
+41.91.605.1559 
 
Principal investigator and coordinating investigator in Switzerland 
Claudio Camponovo, MD. Chairman of the Department of Anaesthesiology  
Email: 
ccamponovo@arsmedica.ch 
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Final version 2.0, 17SEP14 
 
CLINICAL CENTRE N. 3 
Department of Anaesthesiology, Ospedale Regionale di Bellinzona e Valli-Bellinzona, CH-
6500 Bellinzona, Switzerland 
Phone: 
+41.91.811.8978 
Fax: 
+41.91.825.4989 
 
Principal investigator 
Andrea Saporito, MD MHA, Chairman of the Department of Anaesthesiology 
Email: 
Andrea.Saporito@eoc.ch 
 
 
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 
 
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 CENTRE N. 1 
Clinical Monitor Services 
Schärfen 20a, D-83708 Kreuth, Postfach 80, D-83696 Rottach Egern, Germany 
Phone: 
+43.8029.997575 
Fax: 
+43.8029.997576 
Email: 
info@clinical-monitoring.de 
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CLINICAL CENTRE N. 2 and N. 3 
Clinical Medical Service Sagl 
Via Indipendenza 29A, 6883 Novazzano, Switzerland 
Legal address: Via Motta 24, CH-6830 Chiasso, Switzerland 
Mobile: +41.79.827.27.67 
Fax: 
+41.91.649.57.14 
Email: 
cmed@cmed.ch 
 
Chiara Castiglioni, Clinical Research Associate 
CROSS S.A. Research S.A., Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91. 6300510 
Fax: 
+41.91.6300511 
Email: 
projectmanagement@croalliance.com 
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17 
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Chloroprocaine 2% - Axillary block 
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