Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Elective Knee Procedures of Short Duration
Phase: PHASE2
Conditions: Pain, Postoperative
Sponsor: Sintetica SA

CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
CLINICAL STUDY PROTOCOL 
 
Study CRO-17-133 - Sponsor code PAR.3-01-2017 
 
Dose-finding study of intrathecal paracetamol administered 
immediately before spinal anaesthesia with chloroprocaine HCl 
1% for elective knee procedures of short duration 
 
Phase II, single centre, randomised, parallel-group, double-blind, three doses, placebo-
controlled, exploratory efficacy and safety study 
 
 
Test product: 
Paracetamol 3%, solution for injection, Sintetica S.A., 
Switzerland 
 
 
Control: 
Placebo, 0.9% saline solution, Sintetica S.A., Switzerland 
 
 
Sponsor: 
Sintetica S.A., via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: +41.91.640.42.50  
Fax: 
+41.91.646.85.61 
 
 
Investigator: 
Claudio Camponovo, MD. Chairman of the Department of 
Anaesthesiology, Clinica Ars Medica,  
Via Cantonale, CH-6929 Gravesano, Switzerland 
Email: ccamponovo@arsmedica.ch 
 
 
Development phase: 
Phase II 
 
 
Version and date: 
Final version 1.0, 16OCT17 
 
 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 (R2) 
 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
 
This document comprises 70 pages 
CROSS Research S.A. 
Page 1 

CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
STUDY SYNOPSIS 
 
Title: Dose-finding study of intrathecal paracetamol administered immediately before spinal anaesthesia with 
chloroprocaine HCl 1% for elective knee procedures of short duration 
Protocol number: CRO-17-133 Sponsor code PAR.3-01-2017 
Clinical phase: Phase II 
Study design: Phase II, single centre, randomised, parallel-group, double-blind, three doses, placebo-controlled,  
exploratory efficacy and safety study 
Planned nr. of centres / countries: One / Switzerland 
Investigator and centre: Principal investigator: Claudio Camponovo MD. Chairman, Department of 
Anaesthesiology, Clinica Ars Medica, Via Cantonale, CH-6929 Gravesano, Switzerland 
Investigational products: Paracetamol 3% (30 mg/mL), solution for injection, Sintetica S.A., Switzerland. 
Three ascending doses of the paracetamol solution, administered by intrathecal injection, will be investigated. A 
fourth treatment group will only receive a placebo solution. Study treatment will be as follows: 
 
D1: 30 mg Paracetamol 3% (1 mL) 
 
D2: 60 mg Paracetamol 3% (2 mL) 
 
D3: 90 mg Paracetamol 3% (3 mL) 
 
P: Placebo (0.9% saline solution) (1 mL, 2 mL and 3 mL) 
 
Other products (Non-investigational medicinal product, NIMP) 
Chloroprocaine HCl 1% (10 mg/mL), injectable solution, Sintetica S.A., Switzerland, will be administered by 
intrathecal injection to all patients according to the Summary of Product Characteristics indications. The 
anaesthetic will be administered immediately after intrathecal paracetamol or placebo administration (maximal 
interval between administrations: 2 min). 
Dose regimen: Eligible patients undergoing elective short-duration knee procedures up to 40 min (i.e. ≤ 40 min) 
duration (e.g. diagnostic knee arthroscopy and meniscectomy not requiring the micro-fracture technique) will be 
randomised into 4 treatment groups (15 patients per group) to receive either one of the 3 single doses of 
paracetamol 3% (D1, D2, D3) or the placebo solution (P) by intrathecal injection (IT), according to the 
randomised, parallel-group design. Immediately after IMP IT administration, all patients will receive a single IT 
dose of Chloroprocaine HCl 1% according to the Summary of Product Characteristics indications. The time 
interval between paracetamol IT and chloroprocaine IT injections should not exceed 2 min. Administrations’ 
times will be recorded. 
Objective: The objective of this study is to investigate the efficacy and safety of a single intrathecal injection of 
paracetamol, administered at 3 doses to 3 active treatment groups, as compared to placebo, for post-operative 
analgesia in knee procedures up to 40 min duration performed under spinal anaesthesia. 
Study endpoints/variables: 
Primary efficacy endpoints/variable:  
 Pain intensity at rest evaluated using a 0-100 mm VAS at baseline (within 30 min before NIMP IT injection, 
0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, then every 30 min (i.e. 2.5, 3 h, etc.) after NIMP IT 
injection until eligibility for home discharge. Punctual VAS scores at the pre-specified time-points will be 
compared between treatments 
Secondary efficacy endpoints/variables: 
 Pain at rest VAS scores AUCt1-t2, where AUCt1-t2 is defined as the area under the pain intensity curve at the 
specified time-intervals (intervals: 0-2h, 0-4h) 
 Pain at rest VAS scores AUClast, where AUClast is defined as the area under the pain intensity curve from 0 h 
up to the last assessment time 
 Time to first postoperative analgesia (level 1 or 2) (Tpa) 
 Time to level 1 analgesia (TA1) 
 Time to level 2 analgesia (TA2) 
 Total amount of analgesic 1 consumption (A1) 
 Total amount of analgesic 2 consumption (A2) 
 Proportion of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery end (π2h)  
 Proportion of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery end (π4h) 
 Proportion of patients requiring analgesia (level 1 or level 2) from surgery end until eligibility for home 
discharge (πed) 
 Proportion of patients requiring level 1 analgesia (πA1) from surgery end until eligibility for home discharge 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
STUDY SYNOPSIS (cont.) 
 
Study endpoints/variables, continued: 
Secondary efficacy endpoints/variables, continued: 
 Proportion of patients requiring level 2 analgesia (πA2) from surgery end until eligibility for home discharge 
 Time to first supplementary analgesia, other than the planned level 1 or 2 analgesia (Tao) 
 Proportion of patients requiring supplementary analgesia, other than the planned level 1 or 2 analgesia (πao) 
 Time to rescue anaesthesia (Tras) 
 Proportion of patients requiring rescue anaesthesia (πras) 
 Time to onset of spinal block (i.e. time to readiness for surgery) (Trs) 
 Maximum level of sensory block (SBmax) 
 Time to maximum level of sensory block (TSBmax) 
 Time to regression of spinal block (Treg) (defined as complete regression of sensory block to S1) 
 Time to unassisted ambulation (Tua) 
 Time to first spontaneous urine voiding (Tuv) 
 Time to eligibility for home discharge (Ted) 
Safety endpoints/variables 
 Treatment-emergent adverse events throughout the study 
 Incidence of neurological complications including transient neurologic symptoms (TNS) at 24 h post-dose 
and at day 7±1 
 Vital signs (blood pressure, heart rate), peripheral oxygen saturation (SpO2) 
 Concomitant medications 
Additional safety assessments 
 ECG at screening for patients > 60 years old 
 ECG monitoring 
Sample size: At least sixty (60) male/female patients (at least 15 patients per dose group), aged 18-80 years, 
scheduled for elective knee procedures up to 40 min duration (e.g. diagnostic knee arthroscopy and 
meniscectomy not requiring the micro-fracture technique) under spinal anaesthesia will be enrolled in order to 
have at least 15 treated patients per treatment group included in the Per Protocol Set. The sample size for the 
study is not based on any formal sample size calculation. The number of at least 15 treated patients/treatment 
group included in the Per Protocol Set is deemed appropriate considering the exploratory and descriptive nature 
of the study. 
Main selection criteria:  
Inclusion criteria: 
1. Informed consent: signed written informed consent before inclusion in the study 
2. Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for short duration (up to 
40 min) knee procedures 
3. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive  
4. ASA physical status: I-III 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study. 
Exclusion criteria: 
1. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives 
of the study. Contraindications to spinal anaesthesia. History of neuromuscular diseases to the lower 
extremities  
2. ASA physical status: IV-V 
3. Further anaesthesia: patients expected to require further anaesthesia  
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol and/or ester type 
anaesthetics) and/or formulations’ ingredients or related drugs, non-steroidal anti-inflammatory drugs and/or 
opioid derivatives; history of anaphylaxis to drugs or allergic reactions in general, which the investigator 
considers could affect the outcome of the study 
5. Chronic pain syndromes: patients with chronic pain syndromes taking opioids, anticonvulsant agents or 
chronic analgesic therapy 
6. Pain assessment: patients anticipated to be unable to make a reliable self-report of pain intensity 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria, continued:  
Exclusion criteria, continued: 
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 and neurological diseases, sepsis, blood coagulation disorders, severe cardiopulmonary disease, 
thyroid disease, diabetes, other neuropathies, history or evidence of heart failure. History of severe head 
trauma that required hospitalisation, intracranial surgery or stroke within the previous 30 days, or any 
history of intracerebral arteriovenous malformation, cerebral aneurism or CNS mass lesion 
8. Medications: medication known to interfere with the extent of spinal blocks for 2 weeks before the start of 
the study. Paracetamol formulations, other than the investigational product, for 2 weeks before the start of 
the study and during the study. Hormonal contraceptives for females are allowed. Anti-hypotensive, anti-
bradycardia (e.g. ephedrine, atropine, Ringer’s solution), anti-haemetic and anti-nausea medications will be 
allowed 
9. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study. The 3-month interval is calculated as the time between the first calendar day of the month that 
follows the last visit of the previous study and the first day of the present study 
10. Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion 
11. Pregnancy and lactation: positive pregnancy test at screening (if applicable), pregnant or lactating women 
[The pregnancy test will be performed to all fertile women and to all women up to 55 years old, if not in 
proven menopause (available laboratory test confirming menopause or surgically sterilised)] 
Study schedule: 
The study will include a screening phase (Visit 1, Day -21/-1), a treatment phase (IMP IT administration, 
anaesthesia and surgical procedure: Visit 2, Day 1) and a follow-up phase including an observation period (Visit 
3), a final visit and two follow-ups (24 h post-dose and day 7±1). 
 
Screening Phase (Visit 1, Day -21/-1): Patients scheduled for short duration knee procedures (e.g. diagnostic 
knee arthroscopy and meniscectomy not requiring the micro-fracture technique) will be informed about the aims, 
procedures and possible risks of the study and will be asked to sign the informed consent form for the inclusion 
in the trial. Routine pre-surgery assessments will be performed according to the standard procedures of the 
hospital. A urine pregnancy test for women will be performed (if applicable according to the study 
inclusion/exclusion criteria). Inclusion/exclusion criteria will be verified and patients will be assigned a 
consecutive screening number. The following baseline characteristics will be recorded: demography, physical 
abnormalities, body weight, height, vital signs, peripheral oxygen saturation (SpO2), medical/surgical history and 
previous/concomitant medications. Pain history will be recorded. ECG will be performed at screening for 
patients > 60 years old. 
 
Treatment Phase (Visit 2, Day 1): Patients will be questioned about adverse events and concomitant 
medications and will be assigned a consecutive randomisation number. According to the randomisation list they 
will be allocated to receive one of three doses of paracetamol or one of the three volumes of the placebo solution. 
Blood pressure, heart rate, SpO2 and ECG will be monitored using standard monitors at baseline and during 
block placement (see below) until at least the end of anaesthesia or longer, if necessary, according to the 
standard hospital procedures. Pain intensity will be measured at baseline using a 100 mm VAS. An antibiotic 
will be administered, if necessary, according to the standard hospital procedures. Before surgery, patients will be 
pre-medicated with propofol (1-2 mg/kg/h), if needed. In addition, if needed, Ringer’s solution will be infused 
from the beginning until the end of surgery.   
One of the three doses of paracetamol, depending on the treatment group, or placebo will be administered 
intrathecally (IT) just before spinal anaesthesia. After intrathecal administration of the paracetamol dose or 
placebo, the anaesthetic (Chloroprocaine HCl 1%) will be administered, as described in "Dose regimen" above. 
Time interval between the 2 administrations should not exceed 2 min. The time of paracetamol/placebo IT 
administration and the time of chloroprocaine IT administration will be recorded in the CRF. For the intrathecal 
injection of the paracetamol/placebo followed by the intrathecal injection of the anaesthetic, two needles will be 
used: one introducer needle, which will serve to introduce the second needle through the skin, plus one 
intrathecal Pencil point needle (27-G or 25-G Reganesth or Nizell needle) to which the first syringe containing 
paracetamol/placebo will be attached first, followed by the second syringe with the anaesthetic. In this way only 
one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital 
procedures. 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
STUDY SYNOPSIS (cont.) 
 
Study schedule, continued: 
As also written above, during the spinal block hemodynamic variables (heart rate, blood pressure, SpO2; ECG) 
will be monitored every 10 min until at least the end of anaesthesia, or longer if necessary, according to the 
standard hospital procedures. The time of start and the time of end of surgery will be recorded in the CRF. 
 
Follow-up Phase - Observation period (Visit 3: from Day 1 after surgery until final visit/ETV): 
Postoperatively, patients will be administered an analgesic as needed (see VAS scores below). Post-operative 
analgesia could include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 
analgesia). The administered analgesic (level 1 or 2), the dose and intake frequency will be decided according to 
the reported surgery-related pain intensity (see below). Time of analgesic administration and details on the 
administered analgesic (name, dose, frequency) will be recorded in the CRF. 
 
Rescue analgesia/anaesthesia 
In case of incomplete anaesthesia during surgery or incomplete analgesia during surgery or postoperatively, 
either sedative, analgesics or anaesthetics will be administered according to the standard hospital’s procedures. 
Details will be recorded in the CRF. 
 
Efficacy and safety assessments 
Pain intensity will be recorded for all patients using a 0-100 mm VAS at pre-specified time points, i.e. baseline 
(within 30 min before NIMP IT injection, 0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, then every 30 min 
(i.e. 2.5, 3 h, etc.) after NIMP IT injection until eligibility for home discharge. Additional pain assessments could 
be performed if the patient spontaneously report surgery-related pain outside the pre-specified time-points. Also 
in this case, the patient will report pain intensity on the 0-100 mm VAS scale. If the score on the VAS scale is ≥ 
4 at the pre-specified or additional assessment times, an analgesic will be administered as detailed above, 
according to the investigator's opinion. 
Evolution of sensory and motor blocks will be evaluated by a blinded observer. 
Treatment-emergent adverse events will be recorded and treated according to the standard procedures of the 
hospital. Particular attention will be given to systemic and local toxicity symptoms, neurological symptoms, 
including TNS, and allergic reactions. The occurrence of headache and lower limbs and gluteus paraesthesia, as 
well as nausea and vomiting will be carefully checked. 
 
All primary, secondary study variables and additional assessments outcomes will be recorded in the CRF. 
 
Follow-up Phase - Final visit/ETV: Patients will be eligible for home discharge when the criteria for discharge 
are met according to the standard hospital procedures. Patients will be actually discharged according to the 
hospitals’ standard procedures. Before discharge patients will undergo a final visit (or early termination visit 
[ETV] in case of premature discontinuation from the study). Surgery-related pain intensity will be evaluated 
using a 0-100 mm VAS, vital signs and SpO2 will be checked. Day and time of eligibility for home discharge 
and of actual discharge from the hospital will be recorded. 
 
Follow-up Phase - Follow-up: At 24 h (Day 2) and on Day 7±1 (i.e. 6±1 days after analgesic/anaesthetic IT 
injection and surgery), the investigator or his deputy will question patients about symptoms of neurological 
complications including TNS and unusual sensations not associated with the operation area (buttock, thigh 
posterior, thigh anterior, lower limb, sacrum, calves, other areas) following prepared questions. Pain intensity at 
the injection site and surgery-related pain will also be assessed. Patients will be contacted by telephone if they 
have already left the hospital. 
Data analysis:  
Statistical analyses will be done using SAS® version 9.3 (TS1M1) or higher for Windows. 
 
Definition of analysis sets:  
Enrolled Set: all enrolled subjects. This analysis set will be used for demographic and baseline characteristics. 
Full Analysis Set (FAS): all randomised patients who fulfil the study protocol requirements in terms of 
investigational product (i.e. paracetamol/placebo) administration and anaesthetic administration and have at least 
one post-baseline assessment of the primary efficacy evaluation (i.e. surgery-related pain at rest). This analysis 
set will be used for the sensitivity analysis and for the secondary efficacy analysis. 
Per Protocol Set (PP): all randomised patients who fulfil the study protocol requirements in terms of 
investigational product administration, anaesthetic administration and primary efficacy evaluation (i.e. surgery-
related pain at rest), with no major deviations that could affect the primary efficacy results. This analysis set will 
be used for the primary efficacy analysis and for the secondary efficacy analysis. 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
STUDY SYNOPSIS (cont.) 
 
Data analysis, continued:  
Definition of analysis sets, continued:  
Safety Set: all patients who receive at least one dose of the investigational product and/or anaesthetic. This 
analysis set will be used for the safety analyses. 
Efficacy analysis 
All study data will be listed by patient, treatment group and assessment time point/interval (if applicable) and 
will be summarised by treatment group and assessment time point/interval (if applicable) using classic 
descriptive statistics (i.e. mean, SD, CV%, min, median and max) for quantitative variables and frequencies for 
qualitative variables. Summary statistics will be performed on the Per Protocol Set and on the Full Analysis Set.  
Primary efficacy analysis 
The primary efficacy analysis will be performed on the Per Protocol Set. 
Pain at rest (VAS scores at each pre-defined time point) will be analysed using rank-transformed repeated 
measures ANCOVA with rank-transformed baseline pain at rest as covariate, and treatment, assessment time 
point and treatment*assessment time point as fixed effect. Pairwise comparisons between treatment groups for 
pain at rest will be performed at a two-sided type I error α = 0.05 according to the following hierarchical order: 
 
1. P vs. D3 (90 mg) 
2. P vs. D2 (60 mg) 
3. P vs. D1 (30 mg) 
4. D1 (30 mg) vs. D3 (90 mg) 
5. D2 (60 mg) vs. D3 (90 mg) 
6. D1 (30 mg) vs. D2 (60 mg) 
 
Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary for the primary 
endpoint (CPMP/EWP/908/99 guideline, 19SEP02). However, if a null hypothesis of a comparison cannot be 
rejected all the null hypotheses of the subsequent comparisons cannot be rejected. 
 
Sensitivity analysis 
The primary efficacy analysis will be repeated on the Full Analysis Set. The same pairwise comparisons foreseen 
for the primary variable will be performed at a two-sided type I error α = 0.05 according to the same hierarchical 
order. 
 
Secondary efficacy analysis 
Due to the small sample size, collected data will be compared using nonparametric tests. 
Tpa, TA1, TA2, Tao, Tras, Trs, TSBmax, Treg, Tua, Tuv and Ted will be presented using Kaplan-Meier curves and will be 
compared between treatment groups by log rank test. 
A1, A2, AUCt1-t2 (AUC0-2h, AUC0-4h) and AUClast will be summarised by treatment group using classic descriptive 
statistics (i.e. mean, SD, CV%, min, median and max). SBmax, π2h, π4h, πed, πA1, πA2, πao and πras will be 
summarised by treatment group using frequency tables.  
SBmax, A1 and A2 will be compared between treatment groups by Wilcoxon rank sum test.  
π2h, π4h, πed, πA1, πA2, πao and πras will be compared between treatment groups using the Fisher exact test.  
VAS scores for pain at rest AUCt1-t2 (AUC0-2h, AUC0-4h) and AUClast will be analysed by rank-transformed 
ANOVA with treatment as fixed effect and by ANOVA with treatment as fixed effect.  
 
Safety analysis 
All study data will be listed by patient and treatment group and will be summarised by treatment group using 
classic descriptive statistics (i.e. mean, SD, CV%, min, median and max) for quantitative variables and 
frequency for qualitative variables.  
 
 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
STUDY SCHEDULE 
 
Visit 
Visit 1 
Day 
-21/-1 
Visit 2 
Day 1 
Follow-up phase 
Visit 3 
Observation 
period* 
Final 
visit/ETV9 
24 h, Day 2 
and 
Day 7±1 
Informed consent 
x 
 
 
 
 
Demography 
x 
 
 
 
 
Medical/surgical history 
x 
 
 
 
 
Physical examination 
x 
 
 
 
 
Previous and concomitant 
medication 
x 
x 
x 
x 
x 
Height, Body mass index 
x 
 
 
 
 
Body weight 
x 
 
 
 
 
Vital signs (blood pressure, heart 
rate)1 
x 
x 
x 
x 
 
SpO2
1 
x 
x 
x 
x 
 
ECG2 
x2 
x 
x 
 
 
Pregnancy test (urine)3 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
Eligibility evaluation 
x 
x 
 
 
 
Enrolment and Randomisation 
 
x 
 
 
 
Antibiotic, if needed, according to 
the standard hospital procedures 
 
x 
 
 
 
Propofol medication before 
surgery, if needed 
 
x 
 
 
 
Ringer’s solution infusion, if 
needed 
 
x 
 
 
 
Paracetamol/Placebo IT 
administration 
 
x 
 
 
 
Chloroprocaine IT administration 
 
x 
 
 
 
Pain intensity (VAS) 
 
x4 
x4 
x5 
x6 
Blocks assessment7 
 
x 
x 
 
 
Surgery (< 40 min) 
 
x 
 
 
 
Post-operative analgesia8 
 
 
x 
 
 
Neurological complications 
(including TNS) questionnaire 
 
 
 
 
x 
Adverse events monitoring 
x 
x 
x 
x 
x 
Home discharge9 
 
 
 
x 
x 
 
*Observation period from the end of surgery to final visit/ETV. During the observation period, efficacy 
assessments and safety monitoring will be performed according to the protocol and standard safety monitoring 
procedures of the hospital.  
 
1. Vital signs and SpO2 at screening, at baseline (before the spinal injection), then every 10 min from spinal 
injection until at least the end of anaesthesia, or longer if necessary, according to the standard hospital 
procedures and before discharge (at final visit/ETV) 
2. ECG at screening only for patients > 60 years old. ECG monitoring starting at baseline (before the spinal 
injection), then every 10 min from spinal injection until at least the end of anaesthesia, or longer if 
necessary, according to the standard hospital procedures  
3. Pregnancy test performed according to the inclusion/exclusion criteria 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
4. Pain intensity at rest will be recorded using a 0-100 mm VAS at baseline (within 30 min before NIMP IT 
injection, 0h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, then every 30 min (i.e. 2.5, 3 h, etc.) after 
NIMP IT injection until eligibility for home discharge 
5. Pain intensity will be recorded before discharge (at final visit/ETV) using a 0-100 mm VAS 
6. Surgery-related pain and pain at the injection site will be evaluated at the 24 h (Day 2) and Day 7±1 follow-
ups (questionnaire) 
7. The evolution of both sensory and motor blocks, including sensory block metameric level, will be evaluated 
every 5 min until readiness for surgery, then every 10 min until the maximum level is reached (two 
consecutive observations with the same level of sensory block only if applicable or if possible, otherwise one 
observation) and then every 15 min until complete regression of sensory block to S1 
8. Patients will be administered an analgesic as needed. Post-operative analgesia will include Ketorolac i.v. 
[Toradol] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia) 
9. Patients will be eligible for home discharge after the hospital criteria for discharge are met. Patients, 
however, will be discharged according to the hospital’s standard procedures. In case of discontinuation, 
subjects will undergo an early termination visit (ETV) 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL 
1 
PROTOCOL APPROVAL 
2 
STUDY SYNOPSIS 
5 
1 
Introduction 
18 
1.1 
Background 
18 
1.1.1 
Paracetamol 
18 
1.1.2 
Spinal anesthesia 
18 
1.1.3 
Paracetamol for post-operative pain 
19 
1.1.4 
Paracetamol solution for spinal administration 
20 
1.2 
Rationale 
20 
1.3 
Risks and benefits 
21 
2 
STUDY OBJECTIVES 
23 
2.1 
Primary endpoint 
23 
2.2 
Secondary endpoints 
23 
2.2.1 
Secondary efficacy endpoints 
23 
2.2.2 
Secondary safety end-points 
24 
3 
CLINICAL SUPPLIES 
25 
3.1 
Treatment 
25 
3.1.1 
Description of products 
25 
3.1.2 
Dose regimen 
25 
3.1.3 
Route and method of administration 
26 
3.1.4 
Investigational product distribution 
27 
3.2 
Packaging and labelling 
27 
3.3 
Storage conditions 
28 
3.4 
Drug accountability 
28 
4 
INVESTIGATIONAL PLAN 
29 
4.1 
Overall study design 
29 
4.2 
Discussion of design 
29 
5 
STUDY POPULATION 
31 
5.1 
Target population 
31 
5.2 
Inclusion criteria 
31 
5.3 
Exclusion criteria 
31 
5.3.1 
Not allowed treatments and other treatments 
32 
6 
STUDY SCHEDULE 
33 
6.1 
Study visits and procedures 
33 
6.2 
Diet and lifestyle 
35 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
37 
7.1 
Physical examination 
37 
7.1.1 
Vital signs and peripheral oxygen saturation (SpO2) 
37 
7.1.2 
ECGs 
37 
7.2 
Assessment of treatment-emergent adverse events 
38 
7.2.1 
Treatment-emergent adverse events (TEAEs) 
38 
7.2.2 
Neurological complications and transient neurological symptoms 
38 
7.3 
Pain intensity at rest 
39 
7.4 
Post-operative pain control 
40 
7.5 
Rescue analgesia/anaesthesia 
41 
7.6 
Block assessment 
41 
7.7 
Procedures for assessing eligibility for home discharge 
42 
8 
ASSIGNMENT OF STUDY TREATMENT 
43 
8.1 
Randomisation 
43 
8.2 
Treatment allocation 
43 
8.3 
Blinding 
43 
8.3.1 
Emergency code and unblinding procedures 
44 
8.3.2 
Emergency individual envelopes 
44 
8.3.3 
Individual kit replacement envelopes 
44 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
9 
EVALUATION PARAMETERS 
45 
9.1 
Study variables 
45 
9.1.1 
Primary efficacy variables 
45 
9.1.2 
Secondary efficacy variables 
45 
9.1.3 
Safety variables 
46 
9.2 
Efficacy assessments 
46 
9.2.1 
Efficacy parameters 
46 
9.3 
Safety assessments 
46 
10 
STATISTICAL METHODS 
47 
10.1 
Analysis Sets 
47 
10.1.1 
Definitions 
47 
10.1.2 
Reasons for exclusion from the Full Analysis Set 
48 
10.1.3 
Reasons for exclusion from the Per Protocol set 
48 
10.2 
Sample size and power considerations 
48 
10.3 
Demographic, baseline and background characteristics 
48 
10.4 
Analysis of efficacy parameters 
48 
10.4.1 
Primary efficacy analysis 
48 
10.4.2 
Sensitivity analysis 
49 
10.4.3 
Secondary efficacy analysis 
49 
10.5 
Safety and tolerability evaluation 
49 
11 
DEFINITION AND HANDLING OF AEs AND SAEs 
51 
11.1 
Applicable SOPs 
51 
11.2 
Definitions 
51 
11.3 
AEs monitoring window 
52 
11.4 
AEs recording 
52 
11.5 
SAEs reporting 
54 
11.6 
SUSARs management 
54 
11.7 
Other events qualified for expedited reporting 
55 
11.8 
SAEs: contacts 
55 
12 
DATA MANAGEMENT PROCEDURES 
56 
12.1 
Data collection – CRFs 
56 
12.2 
Unique subject identifier 
56 
12.3 
Database management 
56 
12.3.1 
Coding dictionaries 
56 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
57 
13.1 
Monitoring 
57 
13.2 
Quality Control and Quality Assurance 
57 
13.3 
Applicable SOPs 
58 
13.4 
Data access 
58 
13.5 
Audits and inspections 
58 
14 
ETHICAL CONSIDERATIONS 
59 
14.1 
Ethics and Good Clinical Practice (GCP) 
59 
14.2 
Informed consent 
59 
14.3 
Insurance policy 
60 
14.4 
Withdrawal of subjects 
60 
14.4.1 
Discontinuation type 
60 
14.4.2 
Primary reason for discontinuation 
60 
14.4.3 
Discontinuation procedures 
61 
14.5 
Study termination 
61 
15 
ADMINISTRATIVE PROCEDURES 
62 
15.1 
Material supplied to the clinical centre 
62 
15.2 
Protocol amendments 
62 
15.3 
Study documentation and record keeping 
62 
15.4 
Study subjects’ recruitment 
63 
15.5 
Confidentiality and data protection 
63 
15.6 
Publication policy 
63 
16 
STUDY RESPONSIBLE PERSONS 
65 
16.1 
Sponsor 
65 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
16.2 
Institutes performing the study 
65 
16.2.1 
Clinical centre 
65 
16.3 
Co-ordination, monitoring, data analysis & reporting 
65 
17 
REFERENCES 
67 
18 
APPENDICES 
69 
18.1 
Neurological complications (including TNS) questionnaires 
69 
 
 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
TABLES 
Page 
 
Table 3.1.2.1 
Dose groups 
26 
Table 7.2.2.1 
Differential diagnosis criteria for neurological complications including TNS and other 
events following intrathecal injection 
39 
Table 7.3.1 
Recommended tolerance ranges for the scheduled VAS assessment times 
40 
 
 
FIGURES 
Page 
 
Figure 1.1.1.1 
Paracetamol molecular structure 
18 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
LIST OF ABBREVIATIONS 
 
γ-GT 
γ-Glutamyl transpeptidase 
β-HCG 
human chorionic gonadotropin β 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
AUCt1-t2 
Area under the curve (AUC) over the interval from T1 to T2 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CA 
Competent Authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CSF 
Cerebrospinal Fluid 
CI 
Confidence Interval 
CMS 
Clinical Medical Service 
CNS 
Central Nervous System 
CPL 
Clinical Project Leader 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CRS 
Clinical Study Report 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
D1 
30 mg Paracetamol 3% (1 mL) 
D2 
60 mg Paracetamol 3% (2 mL) 
D3 
90 mg Paracetamol 3% (3 mL) 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GI 
Gastro-intestinal 
GLP 
Good Laboratory Practice 
HBs Ag 
Hepatitis B virus surface antigen 
HCV Ab 
Hepatitis C virus antibodies 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IT 
intrathecal 
IUD 
Intra-Uterine Device 
i.v. 
Intravenous 
LSLV 
Last Subject Last Visit 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
MW 
Molecular Weight 
N 
Normal 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
NA 
Not Applicable 
NCS 
Not clinically significant 
NIMP 
Non Investigational Medicinal Product 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over The Counter 
P 
Placebo solution (0.9% saline solution) 
PDPH 
Post-Dural-Puncture Headache 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
RASS 
Richmond Agitation Sedation Scale 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Peripheral oxygen saturation 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
THC 
delta-9-tetrahydrocannabinol 
TNS 
Transient Neurological Symptoms 
USDA 
United States Department of Agriculture 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cells 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
1 
INTRODUCTION 
 
1.1 
Background 
 
1.1.1 
Paracetamol 
 
Paracetamol (acetyl-p-aminophenol; Figure 1.1.1.1), also commonly known as acetaminophen 
in USA, is an active ingredient possessing analgesic and antipyretic activity, widely used in 
the medical practice to alleviate acute and chronic pain and to reduce the body temperature 
when this exceeds physiological values (1). 
 
 
 
Figure 1.1.1.1 
Paracetamol molecular structure 
Paracetamol is almost devoid of antiaggregant and anti-inflammatory activity. To date, its 
mechanism of action remains little known, although the molecule was synthesised for the first 
time in 1878 and its use in the medical field has been established for more than 100 years (2). 
 
In the clinical field, paracetamol is used as analgesic in the treatment of mild and medium 
pain (3) and as an antipyretic in the treatment of febrile states in adults and in children (2). 
The most common pharmaceutical form for this active ingredient is the solid form. The most 
typical paracetamol-based pharmaceutical formulations are those in solid tablet form, in 
granule form or in the form of suppositories (4).  
Formulations containing paracetamol in the form of a solution for intravenous (i.v.) infusion 
are also present on the market (5, 6, 7, 8). These are formulations indicated for the short-term 
treatment of pain of medium intensity, in particular of the type experienced following a 
surgical intervention. Intravenous (i.v.) administration is reserved for cases in which, from a 
clinical viewpoint, there is the need to treat the pain and/or hyperthermia with urgency or in 
cases in which it is impossible to implement the other administration methods. 
 
Paracetamol can be effective even against severe pain if i.v. administered. In a repeated-dose, 
randomized, double-blind, placebo-controlled, 3-parallel group study in orthopaedic surgery 
patients comparing 1000 mg i.v. paracetamol (given at 6-h intervals over 24 h) and placebo, 
pain intensity, pain relief and rescue i.v. patient-controlled morphine use (time to use and 
amount used) were significantly decreased in the paracetamol group compared with the 
placebo group (9). 
 
1.1.2 
Spinal anesthesia 
 
Since paracetamol is devoid of anaesthetic action, it has never been used in the field of 
general, local or loco-regional anaesthesia, such as spinal anaesthesia. Spinal anaesthesia is an 
anaesthesia technique in which an injectable solution containing an active ingredient 
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CONFIDENTIAL 
 
Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
possessing local anaesthetic activity is injected through the dura mater, i.e. the outer 
meningeal membrane protecting the spinal cord, into the medullary canal. The spinal injection 
is usually carried out by highly qualified medical personnel between the spinous processes of 
two vertebrae, usually in the lumbar zone, using specific needles, which are long and slender 
(10). 
During the spinal injection, the risks of causing neurological damage are limited by the fact 
that the spinal column is protected by the pia mater, the innermost of the meningeal 
membranes. 
During the infusion process, the solution containing the local anaesthetic mixes with the 
cerebrospinal fluid, thus blocking impulse conduction via the nervous system to the brain and 
causing a reversible loss of sensitivity, which may be accompanied by motor paralysis. 
Generally, spinal anaesthesia is used for interventions on organs of the small pelvis and on the 
lower limbs. Typical examples where spinal anaesthesia is used are appendectomy, 
hernioplasty, caesarean section, arthroscopy, orthopaedic surgery of the lower limbs, etc. 
 
Among the spinal anaesthesia techniques, it is possible to distinguish between epidural 
injection and intrathecal (IT) injection. In the latter case, the solution containing local 
anaesthetic is injected into the subarachnoid space. 
 
Whereas the intrathecal technique is more invasive than the epidural technique since the 
injection is performed in a deeper zone of the spine, it has the advantage of requiring 
comparably lower doses of local anaesthetic. 
 
Depending on the local anaesthetic used, the spinal anaesthesia can last from one to three 
hours approximately. Once this action ceases, the patient progressively regains mobility and 
sensitivity and the perception of pain increases as time passes due to the effects of the surgical 
procedure. The analgesic action of local anaesthetics therefore remains limited to the period 
of the surgical intervention, for which reason it is essential to establish suitable analgesic 
therapy in the immediate post-surgical period.  
 
1.1.3 
Paracetamol for post-operative pain 
 
Paracetamol is frequently used as an analgesic in postoperative pain, alone or in combination 
with NSAIDs or opioids. Clinical pharmacology, safety and analgesic efficacy of paracetamol 
are well established by various routes of administration. A Cochrane review on 51 studies for 
a total of 5762 patients (3277 treated with a single oral dose of paracetamol and 2425 with 
placebo) concluded that a single dose of oral paracetamol provides effective analgesia for 
about half of the patients with acute postoperative pain, for a period of about 4 – 6 hours, and 
is associated with few, mainly mild, adverse events (3). Several studies available in the 
published literature show the efficacy of paracetamol administered intravenously either as 
paracetamol or as its pro-drug, propacetamol (9, 11-15). Alternative paracetamol 
administration routes in postoperative pain management have recently started to be explored 
in humans.  
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
1.1.4 
Paracetamol solution for spinal administration 
 
Sintetica S.A. has recently developed and patented a supersaturated Paracetamol 3% 
injectable solution for spinal administration to be administered intrathecally alone or before 
loco-regional anaesthesia for the treatment of postsurgical pain (10).  
 
In preclinical studies performed in mice and rats, the spinal administration of the novel 
supersaturated solution at the doses of 200-500 µg resulted in effective analgesia against 
carrageen-induced inflammatory pain and in post-surgical pain, for at least 24 h (10). Four 
studies conducted in a rat model of mechanical hyperalgesia showed that the analgesic effect 
of the Paracetamol solution increased with increasing dose: in particular, treatment with 200 
and 300 µg Paracetamol resulted in a statistically significant decrease from baseline in 
nociceptive pain, starting at the first time-point (i.e. 2 h) up to 48 h after spinal injection. With 
500 µg paracetamol, the effect was still present at 72 h post-dose (4, 16-19). 
In the studies, the administration of IT Paracetamol with IT chloroprocaine resulted in a 
significant effect up to 48 h after spinal injection when paracetamol was injected before 
chloroprocaine. The effect was evident at all investigated doses. No response was present 
when chloroprocaine was injected before paracetamol. Interestingly, the analgesic action of 
paracetamol appeared to have an additive effect with respect to the anaesthesia produced by 
the local anaesthetic. A clinical study is presently being conducted in patients undergoing hip 
replacement surgery under spinal anaesthesia to investigate the safety and efficacy of the 
newly developed paracetamol solution intrathecally administered at the three doses of 60, 90 
and 120 mg, before the intrathecal administration of the anaesthetic (20). 
 
1.2 
Rationale 
 
Results of the preclinical studies described above indicate that the newly developed 
Paracetamol 3% solution administered by intrathecal injection just before spinal anaesthesia 
has an analgesic effect on postoperative pain, with a long-lasting action which is maintained 
after the effect of the anaesthetic has ended. Preclinical data showed that IT administration of 
paracetamol supersaturated (5%) aqueous solution to rats was not associated to any 
neurotoxic effect (21). 
 
The present study is being conducted to investigate the effectiveness and the safety of the 
supersaturated aqueous solution of paracetamol (Paracetamol 3% Sintetica), administered at 3 
different doses, in patients undergoing short duration (up to 40 min) knee procedures under 
spinal anaesthesia.  
 
The present study will evaluate the efficacy of the treatment in reducing post-operative pain in 
comparison to placebo. Spinal anaesthesia will be performed according to the standard 
hospital procedures using Chloroprocaine hydrochloride (HCl) 1%, a short-acting local 
anaesthetic belonging to the amino-ester class (22, 23), which is characterized by a rapid 
onset of action and spinal anaesthesia average duration of 80-100 min, depending on the 
amount used (23). This anaesthetic was approved in 2012 in Europe and is presently on the 
market in several European Countries, at the recommended doses of 40 and 50 mg, for spinal 
anaesthesia in adults where the planned surgical procedure should not exceed 40 min (23). 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
Chloroprocaine HCl 1% Sintetica has been on the Swiss market since 2002 for local 
anaesthesia and peripheral nerve block (22). 
 
The safety of three doses of the Paracetamol 3% solution administered by IT injection, i.e 60, 
90 and 120 mg, are presently being investigated in a two-part study performed in patients 
undergoing hip replacement surgery under spinal anaesthesia (20). Preliminary results 
confirm the safety of the administered doses (24). 
The 60 mg, 90 mg and 120 mg doses of intrathecal Paracetamol 3% investigated in the above 
mentioned study were derived by an evaluation of the doses found to be efficacious in the 
preclinical studies (i.e. 200 – 500 µg; rat body weight: 175-199 g) and are 8 – 17 times lower 
than the doses normally administered in humans by the oral or i.v. route for post-operative 
pain control.  
In the present study, lower doses of the Paracetamol 3% solution, i.e. 30 mg, 60 mg and 90 
mg, will be investigated considering that the surgical procedures (i.e. knee procedures up to 
40 min duration) are shorter, less invasive and possibly associated to a lower post-operative 
pain than the hip replacement surgery investigated in the previous study. 
 
1.3 
Risks and benefits 
 
There are no direct benefits to the patients participating in the study. 
 
The risks for the study patients are anticipated to be low, considering that systemic adverse 
reactions following appropriate use of intrathecal paracetamol and intrathecal chloroprocaine 
are unlikely, due to the small dose absorbed. 
Systemic toxicity is rarely associated with spinal anaesthesia but might occur after accidental 
intravascular injection. 
 
The following undesirable effects have been reported following the oral and i.v. use of 
paracetamol: blood dyscrasias including thrombocytopenia and agranulocytosis, but these 
were not necessarily causally related to paracetamol. Hypersensitivity, including skin rash, 
and pain at the i.v. injection site have also been reported. 
 
The possible undesirable effects due to the use of Chloroprocaine HCl 1% are generally 
similar to the undesirable effects of other local anaesthetics for spinal anaesthesia from the 
ester group. The undesirable effects induced by the medicinal product are difficult to 
distinguish from the physiological effects of the nerve block (e.g. reduction in arterial 
pressure, bradycardia, temporary urine retention), from direct effects (e.g. spinal hematoma) 
or the indirect effects (e.g. meningitis) of the injection or from the effects due to the loss of 
cerebrospinal liquid (e.g. post-spinal headache). Common effects reported on Chloroprocaine 
HCl 1% SmPC (23) are hypotension, anxiety, restlessness, paresthesia, dizziness, vomiting. 
 
The intrathecal injection is quite an invasive administration technique. However, the 
technique is well-established and routinely used in all hospital anaesthesiology settings and is 
undertaken by clinicians with the necessary knowledge and experience. Even if in the study 
two products will be administered by intrathecal injection, only one injection in the 
subarachnoid space will be performed. In fact an introducer needle will be used. The syringe 
of paracetamol will be attached to a second needle, the intrathecal needle, and the paracetamol 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
will be injected. Then the syringe of the anaesthetic will be attached to the same intrathecal 
needle and the anaesthetic injected, thus reducing the discomfort and risk for the patients.  
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
2 
STUDY OBJECTIVES 
 
The objective of this study is to investigate the efficacy and safety of a single intrathecal 
injection of paracetamol, administered at 3 doses to 3 active treatment groups, as compared to 
placebo, for post-operative analgesia in knee procedures up to 40 min duration performed 
under spinal anaesthesia. 
 
2.1 
Primary endpoint 
 
 Pain intensity at rest evaluated using a 0-100 mm VAS at baseline (within 30 min before 
NIMP IT injection, 0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, then every 30 min 
(i.e. 2.5, 3 h, etc.) after NIMP IT injection until eligibility for home discharge. Punctual 
VAS scores at the pre-specified time-points will be compared between treatments. 
 
2.2 
Secondary endpoints 
 
2.2.1 
Secondary efficacy endpoints 
 
 Pain at rest VAS scores AUCt1-t2, where AUCt1-t2 is defined as the area under the pain 
intensity curve at the specified time-intervals (intervals: 0-2h, 0-4h) 
 Pain at rest VAS scores AUClast, where AUClast is defined as the area under the pain 
intensity curve from 0 h up to the last assessment time 
 Time to first postoperative analgesia (level 1 or 2) (Tpa) 
 Time to level 1 analgesia (TA1) 
 Time to level 2 analgesia (TA2) 
 Total amount of analgesic 1 consumption (A1) 
 Total amount of analgesic 2 consumption (A2) 
 Proportion of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery 
end (π2h)  
 Proportion of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery 
end (π4h) 
 Proportion of patients requiring analgesia (level 1 or level 2) from surgery end until 
eligibility for home discharge (πed) 
 Proportion of patients requiring level 1 analgesia (πA1) from surgery end until eligibility for 
home discharge 
 Proportion of patients requiring level 2 analgesia (πA2) from surgery end until eligibility for 
home discharge 
 Time to first supplementary analgesia, other than the planned level 1 or 2 analgesia (Tao) 
 Proportion of patients requiring supplementary analgesia, other than the planned level 1 or 
2 analgesia (πao) 
 Time to rescue anaesthesia (Tras) 
 Proportion of patients requiring rescue anaesthesia (πras) 
 Time to onset of spinal block (i.e. time to readiness for surgery) (Trs) 
 Maximum level of sensory block (SBmax) 
 Time to maximum level of sensory block (TSBmax) 
 Time to regression of spinal block (Treg) (defined as complete regression of sensory block 
to S1) 
 Time to unassisted ambulation (Tua) 
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Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 Time to first spontaneous urine voiding (Tuv) 
 Time to eligibility for home discharge (Ted) 
 
2.2.2 
Secondary safety end-points 
 
 Treatment-emergent adverse events throughout the study 
 Incidence of neurological complications including transient neurologic symptoms (TNS) at 
24 h post-dose and at day 7±1 
 Vital signs (blood pressure, heart rate), peripheral oxygen saturation (SpO2) 
 Concomitant medications 
 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of products 
 
3.1.1.1 
Test product 
 
TEST IMP 
Paracetamol 3% solution (30 mg/mL)  
Manufacturer and Supplier 
Sintetica S.A., Switzerland 
Pharmaceutical form 
Solution for injection (5-mL ampoule, filled with 4 mL of 
solution) 
Dose 
D1: 1 mL corresponding to 30 mg paracetamol 
D2: 2 mL corresponding to 60 mg paracetamol 
D3: 3 mL corresponding to 90 mg paracetamol 
Administration route 
Intrathecal 
 
3.1.1.2 
Reference product 
 
CONTROL (P) 
Placebo, 0.9% saline solution 
Manufacturer and Supplier 
Sintetica S.A., Switzerland 
Pharmaceutical form 
Solution for injection (5-mL ampoule) 
Dose 
1, 2 or 3 mL 
Administration route 
Intrathecal 
 
3.1.1.3 
NIMP (Non investigational medicinal product)  
 
Product name 
Chloroprocaine HCl 1% (10 mg/mL)  
Manufacturer and Supplier 
Sintetica S.A., Switzerland 
Pharmaceutical form 
Solution for injection (5-mL ampoule) 
Dose 
According to the Summary of Product Characteristics 
indications 
Administration route 
Intrathecal 
 
3.1.2 
Dose regimen 
 
Eligible patients undergoing elective short-duration knee procedures up to 40 min duration 
(e.g. diagnostic knee arthroscopy and meniscectomy not requiring the micro-fracture 
technique) will be randomised into four treatment groups (15 patients/group) to receive either 
one of the three single doses of Paracetamol 3% (D1, D2 or D3) or placebo solution (P) by 
intrathecal injection (IT), according to the randomised, parallel-group design.  
 
In detail: 
 
Patients in D1 group will receive a single dose of 1 mL Paracetamol 3% (corresponding 
to 30 mg paracetamol).  
 
Patients in D2 group will receive a single dose of 2 mL Paracetamol 3% (corresponding 
to 60 mg paracetamol). 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
Patients in D3 group will receive a single dose of 3 mL Paracetamol 3% (corresponding 
to 90 mg paracetamol). 
 
Patients in P group will receive a single dose of the placebo solution, as follows: 5 
patients will receive 1 mL, 5 patients will receive 2 mL and 5 patients will receive 3 mL. 
 
Immediately after paracetamol or placebo IT administration, all patients will receive a single 
IT dose of Chloroprocaine HCl 1%, according to the SmPC indications. The time interval 
between paracetamol IT and chloroprocaine IT administrations should not exceed 2 min.  
The doses are summarised in the following scheme: 
 
Table 3.1.2.1 Dose groups 
Dose group 
N of patients 
IMP 
Dose 
All patients 
(within 2 min from 
paracetamol/placebo IT) 
D1 
15 
Paracetamol 
3% IT 
30 mg (1 mL) 
Chloroprocaine HCl 1% 
(according to SmPC) 
D2 
15 
60 mg (2 mL) 
D3 
15 
90 mg (3 mL) 
P 
15 
5 
Placebo IT 
1 mL 
5 
2 mL 
5 
3 mL 
 
3.1.2.1 
General remarks 
 
The investigational product Paracetamol 3% will be provided in 5-mL ampoules, filled with 4 
mL of solution, the placebo will be provided in 5-mL ampoules and the non-investigational 
product Chloroprocaine HCl 1% will be provided in 5-mL ampoules. The volume 
corresponding to the dose of paracetamol or placebo solution and the volume of the 
anaesthetic will be taken from the corresponding ampoule using a graduated syringe. The 
residual amount of paracetamol/placebo will be collected from the ampoule using another 
graduated syringe, completely sealable, and retained for drug accountability together with the 
empty ampoule. 
 
3.1.3 
Route and method of administration 
 
An antibiotic will be administered, if necessary, according to the standard hospital procedures. 
Before surgery, patients will be pre-medicated with propofol (1-2 mg/kg/h), if needed. In 
addition, if needed, Ringer’s solution will be infused from the beginning until the end of 
surgery.  
 
Paracetamol or placebo will be administered intrathecally (IT) just before spinal anaesthesia. 
Syringes for injection will be prepared by a person not involved in any other study-related 
activity. Paracetamol or placebo individual ampoules (one ampoule per patient) will be 
opened just before the administration. Details on the procedure for the preparation of the 
paracetamol/placebo syringes and on the injection procedure will be given in the study 
manual. 
 
After intrathecal administration of the paracetamol dose or placebo, the anaesthetic 
(Chloroprocaine HCl 1%) will be administered. Time interval between the 2 administrations 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
should not exceed 2 min. The time of paracetamol/placebo IT administration and the time of 
chloroprocaine IT administration will be recorded in the case report form (CRF). 
 
The injections will be performed according to the hospital procedures. For the intrathecal 
injection of paracetamol/placebo followed by the intrathecal injection of the anaesthetic, two 
needles will be used: one introducer needle, which will serve to introduce the second needle 
through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or 
Nizell needle) to which the first syringe containing paracetamol will be attached first, 
followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture 
will be performed. Lumbar puncture will be done according to the standard hospital 
procedures. 
 
Postoperatively, patients will be administered an analgesic as needed (see § 7.3 and 7.4). Post-
operative analgesia will include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or 
Tramadol i.v. 1 mg/kg (level 2 analgesia). 
The administered analgesic (level 1 or 2), analgesic dose and intake frequency will be decided 
by the investigator according to the reported surgery-related pain intensity. Time of analgesic 
administration and details on the administered analgesic (name, dose, frequency) will be 
recorded on the CRF. 
 
In case of incomplete anaesthesia during surgery or incomplete analgesia during surgery or 
postoperatively, either sedative, analgesics or anaesthetics will be administered according to 
the standard hospital’s procedures. Details will be recorded in the CRF. 
 
3.1.4 
Investigational product distribution 
 
The investigational products and the anaesthetic 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 of the investigational products (Paracetamol 3% and Placebo 
solution) will be carried out by the Sponsor. The primary packaging of the investigational 
products will be a 5-mL glass ampoule packed in individual carton packages (patients’ kits).  
 
Labelling in local language will report all the information requested according to the Annex 
13 to the Good Manufacturing Practice (published by the Commission in “The rules 
governing medicinal products in the European Community”, Volume 4; 25). 
 
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.;  
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
e) 
The study subject identification number/treatment number;  
f) 
Expiry in month/year format and in a manner that avoids any ambiguity;  
g) 
Investigator's name;  
h) 
Directions for use;  
i) 
“For clinical trial use only” wording;  
j) 
The storage conditions. 
 
Labels of the individual syringes of the investigational products (paracetamol/placebo) will 
report only the patient’s randomisation number and the kit number. 
Further details on the products packaging will be given in the study manual. 
 
Packaging of the anaesthetic (Chloroprocaine HCl 1%) will be the commercial packaging. 
 
3.3 
Storage conditions 
 
The investigational products (Paracetamol and Placebo) and the non-investigational product 
(Chloroprocaine HCl 1%) must be stored at 15-25°C. The products will be stored in a dry 
locked place, sheltered from light. The products will not be refrigerated or frozen. 
 
3.4 
Drug accountability 
 
The 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 investigator will confirm in writing by 
signing and dating standard drug delivery forms. 
 
At the end of the study, used, unused and partially used supplies of the investigational product 
provided by the sponsor/manufacturer will be either destroyed on site (upon written 
authorisation) or returned to the sponsor/manufacturer (upon written authorization), after 
assessment of drug accountability. 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
This is a phase II, single centre, randomised, parallel-group, double-blind, three doses, 
placebo-controlled, exploratory efficacy and safety study. 
 
4.2 
Discussion of design 
 
This study has been designed to evaluate the effectiveness of a novel aqueous solution of 
Paracetamol (Paracetamol Sintetica 3%) administered by intrathecal injection before spinal 
anesthesia in patients undergoing elective short-duration knee procedures up to 40 min 
duration (e.g. diagnostic knee arthroscopy and meniscectomy not requiring the micro-fracture 
technique) under spinal anaesthesia. In particular the study will investigate the effectiveness 
of the three paracetamol doses, administered by intrathecal injection before spinal anaesthesia, 
in reducing postoperative pain.  
 
Administration of paracetamol for postoperative pain management using methods alternative 
to the traditional oral or i.v. routes is being explored in humans. Results of preclinical studies 
conducted in rat models of mechanical hyperalgesia indicated that the newly developed 
Paracetamol 3% solution administered by intrathecal injection just before spinal anaesthesia 
has an analgesic effect on postoperative pain, with a long-lasting action which is maintained 
after the effect of the anaesthetic has ended.  
 
The study will be placebo-controlled. Each patient will be allocated to a treatment arm (one of 
the three paracetamol doses or one of the three volumes of the placebo solution) according to 
a computer-generated randomisation list. 
 
The doses of intrathecal Paracetamol 3% investigated in a previous study, i.e. 60, 90 and 120 
(24), were derived by an evaluation of the doses found to be safe and efficacious in the 
preclinical studies (i.e. 200 – 500 µg; rat body weight: 175-199 g) and were 8 – 17 times 
lower than the doses normally administered in humans by the oral or i.v. route for post-
operative pain control. These doses, intrathecally administered, have been shown to be safe in 
patients undergoing hip replacement surgery (24). In the present study, lower doses of the 
Paracetamol 3% solution, i.e. 30 mg, 60 mg and 90 mg, will be investigated considering that 
the surgical procedures (i.e. knee procedures up to 40 min duration) are shorter, less invasive 
and possibly associated to a lower post-operative pain than the hip replacement surgery 
investigated in the previous study. 
 
Two products [1-Paracetamol (or placebo); 2-Anaesthetic] will be administered to each 
patient by intrathecal injection. However, only one injection in the subarachnoid space will be 
performed. For the procedure two needles, an introducer needle and a Pencil point intrathecal 
needle will be used. First, the syringe of paracetamol will be attached to the intrathecal needle 
and the paracetamol will be injected. Then the paracetamol syringe will be detached from the 
needle, the anaesthetic syringe will be attached to the same intrathecal needle and the 
anaesthetic injected, thus reducing the discomfort and risk for the patients.  
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
The study will be double-blind. Neither the Investigator/co-investigators/study nurses 
involved in the clinical study procedures, nor will the patients be aware of the administered 
treatment. Syringes for injection will be prepared by a person not involved in any study-
related activities where a bias is possible.  
 
Spinal anaesthesia will be performed according to the standard hospital procedures using 
Chloroprocaine HCl 1%, a short-acting local anaesthetic characterized by a rapid onset of 
action and spinal anaesthesia average duration of 80-100 min, depending on the amount used 
(23).  
 
In the present study the occurrence of neurological complications including TNS, which have 
been reported after spinal anaesthesia, will be carefully monitored. In addition, for all 
intrathecal injections a 27- or 25-Gauge Pencil point needle will be used in order to decrease 
the risk of Post-Dural-Puncture Headache (PDPH) occurrence.  
 
Occurrence of clinically relevant hypotension and bradycardia) will be monitored throughout 
the study and if observed appropriately treated, according to the standard hospital procedures. 
 
Pre-medication with propofol will be performed, if needed, to reduce possible anxiety before 
the operation. This is common clinical practice. Propofol at the indicated doses will not 
influence the patient pain perception. 
 
 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
5 
STUDY POPULATION 
 
5.1 
Target population 
 
Patients aged 18-80 years, scheduled for elective knee procedures up to 40 min duration (e.g. 
diagnostic knee arthroscopy and meniscectomy not requiring the micro-fracture technique) 
under spinal anaesthesia. 
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all of these criteria: 
1. Informed consent: signed written informed consent before inclusion in the study 
2. Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for 
short duration (up to 40 min) knee procedures 
3. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive  
4. ASA physical status: I-III 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study. 
 
5.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
1. Physical findings: clinically significant abnormal physical findings which could interfere 
with the objectives of the study. Contraindications to spinal anaesthesia. History of 
neuromuscular diseases to the lower extremities  
2. ASA physical status: IV-V 
3. Further anaesthesia: patients expected to require further anaesthesia  
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol 
and/or ester type anaesthetics) and/or formulations’ ingredients or related drugs, non-
steroidal anti-inflammatory drugs and/or opioid derivatives; history of anaphylaxis to 
drugs or allergic reactions in general, which the investigator considers could affect the 
outcome of the study 
5. Chronic pain syndromes: patients with chronic pain syndromes taking opioids, 
anticonvulsant agents or chronic analgesic therapy 
6. Pain assessment: patients anticipated to be unable to make a reliable self-report of pain 
intensity 
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 and neurological diseases, sepsis, blood coagulation 
disorders, severe cardiopulmonary disease, thyroid disease, diabetes, other neuropathies, 
history or evidence of heart failure. History of severe head trauma that required 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
hospitalisation, intracranial surgery or stroke within the previous 30 days, or any history 
of intracerebral arteriovenous malformation, cerebral aneurism or CNS mass lesion 
8. Medications: medication known to interfere with the extent of spinal blocks for 2 weeks 
before the start of the study. Paracetamol formulations, other than the investigational 
product, for 2 weeks before the start of the study and during the study. Hormonal 
contraceptives for females are allowed. Anti-hypotensive, anti-bradycardia (e.g. 
ephedrine, atropine, Ringer’s solution), anti-haemetic and anti-nausea medications will be 
allowed 
9. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study. The 3-month interval is calculated as the time between the 
first calendar day of the month that follows the last visit of the previous study and the first 
day of the present study 
10. Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion 
11. Pregnancy and lactation: positive pregnancy test at screening (if applicable), pregnant or 
lactating women [The pregnancy test will be performed to all fertile women and to all 
women up to 55 years old, if not in proven menopause (available laboratory test 
confirming menopause or surgically sterilised)] 
 
5.3.1 
Not allowed treatments and other treatments 
 
No medication known to interfere with the extent of spinal block will be allowed for 2 weeks 
before the start of the study and during the whole study duration (except for medications 
administered as part of the study).  
Paracetamol formulations, other than the investigational product, will not be allowed for 2 
week before the start of the study and during the study.  
Hormonal contraceptives for females are allowed.  
 
Anti-hypotensive, anti-bradycardia (e.g. ephedrine, atropine, Ringer’s solution), anti-haemetic 
and anti-nausea medications will be allowed. 
 
The area to be operated will be aseptically prepared with iodine-based disinfectants, e.g. 
chlorhexidine.  
 
An antibiotic will be administered, if needed, according to the standard hospital procedures. 
Before surgery, patients will be pre-medicated with propofol (1-2 mg/kg/h), if needed. In 
addition, if needed, Ringer’s solution will be infused from the beginning to the end of surgery.  
 
Postoperatively, patients will be administered an analgesic as needed (see § 7.3 and 7.4). Post-
operative analgesia will include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or 
Tramadol i.v. 1 mg/kg (level 2 analgesia).  
 
In case of incomplete anaesthesia during surgery or incomplete analgesia during surgery or 
postoperatively, either a sedative, analgesic or anaesthetic will be administered according to 
the standard hospital’s procedures. Details will be recorded in the CRF. 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
6.1 
Study visits and procedures 
 
The study will include a screening visit, one treatment phase, followed by a follow-up phase 
with an observation period, a final visit and two follow-ups. A written informed consent will 
be obtained before enrolment in the study. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened patient. The last subject last visit (LSLV) is defined as the last follow-up 
performed by the last patient, i.e. the last visit foreseen by the study protocol, independently 
of the fact that the patient is a completer or a withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening - visit 1: between Day -21 and Day -1 
 
 Treatment phase 
 Visit 2 - Day 1: paracetamol/placebo IT administration, anaesthesia and surgery 
 
 Follow-up phase  
 Visit 3 (Observation period) – from Day 1 after surgery until final visit/ETV:  
• Efficacy and safety assessments 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 Follow-up at 24 h after analgesic and anaesthetic IT injection and surgery (Day 2) 
 Follow-up on Day 7±1 (i.e. 6±1 days after analgesic/anaesthetic IT injection and 
surgery) 
 
Study visits and procedures are detailed below: 
 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
Study schedule 
 
 
Day 
Procedures/Assessments 
Notes 
Screening Phase 
Visit 1 
From day -21 
 to day -1 
 Explanation to the patient of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data  
 Previous/concomitant medications 
 Routine pre-surgery assessments according to the 
hospital 
standard 
procedures, 
including 
medical/surgical history, pain history, physical 
examination, height, weight, vital signs (blood 
pressure, heart rate), SpO2 
 ECG for patients > 60 years old 
 Urine pregnancy test for women, if applicable 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 AE monitoring 
 
Treatment Phase 
Visit 2 
Day 1 
 Concomitant medications 
 Adverse events 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Subject randomisation 
 Vital signs, SpO2 and ECG monitoring (if 
applicable) until at least the end of anaesthesia, or 
longer if necessary, according to the standard 
hospital procedures 
 Baseline pain assessment at rest using a 0-100 mm 
visual analogue scale (VAS) 
 Premedication:  
• Antibiotic, if needed, according to the hospital 
practice 
• Propofol (before surgery), if needed 
• Ringer’s solution (from surgery start to surgery 
end), if needed 
 Paracetamol/placebo intrathecal injection 
 Anaesthesic intrathecal injection 
 Blocks assessment 
 Surgery (up to 40 min duration) 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
Day 
Procedures/Assessments 
Notes 
Follow-up Phase 
Observation period – Visit 3 
Day 1 after 
surgery until 
final visit/ETV 
 Concomitant medications 
 Adverse events 
 Vital signs, SpO2 and ECG monitoring (if 
applicable) until at least the end of anaesthesia, or 
longer if necessary, according to the standard 
hospital procedures 
 Pain assessment at rest at 1, 1.25, 1.5, 1.75, 2 h after 
NIMP IT injection, then every 30 min (i.e. 2.5, 3 h, 
etc.) after NIMP IT injection until eligibility for 
home discharge using a 0-100 mm VAS 
 Additional post-operative analgesia, only if needed 
 Blocks assessment, if applicable  
Standardised meals will 
be served according to 
the hospital procedures. 
Follow-up Phase  
Final Visit/ETV 
At the end of 
the observation 
period or upon 
discontinuation 
for ETV  
 Final assessments, including surgery-related pain 
assessment at rest (0-100 VAS), according to the 
hospital’s standard procedures  
 Vital signs (BP, HR), SpO2 
 Concomitant medications  
 Adverse events 
 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator until 
the normalisation of the concerned clinical parameter(s) 
Patients will be eligible 
for home discharge when 
criteria for discharge are 
met. Patients will be 
actually discharged from 
the hospital according to 
the 
standard 
hospital 
procedures 
Follow-up Phase 
Follow-ups 
Day 2, 24 h 
post-dose 
 Adverse 
events, 
including 
neurological 
complications and TNS (questionnaire) 
 Pain at the injection site and surgery-related pain 
 Concomitant medications 
Follow-ups 
will 
be 
performed by telephone 
if the patient has left the 
hospital 
Day 7±1 
 Adverse 
events, 
including 
neurological 
complications and TNS (questionnaire) 
 Pain at the injection site and surgery-related pain 
 Concomitant medications 
 
6.2 
Diet and lifestyle 
 
Study participants will follow the study procedures 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 after meeting the hospital criteria for discharge (eligibility for home discharge) 
and according to the hospital procedures.  
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
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 according 
to the investigator’s opinion. Meals will be served according to the hospital’s standard 
procedures. 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Full physical examinations, including body weight and evaluation of the physical status 
according to ASA general relative values, will be performed at the pre-surgery (screening) 
visit.  
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. 
 
7.1.1 
Vital signs and peripheral oxygen saturation (SpO2) 
 
Patients’ blood pressure (BP), heart rate (HR) and peripheral oxygen saturation (SpO2) will be 
measured by the investigator or his/her deputy after 5 min at rest according to the hospital 
procedures.  
 
Vital signs (blood pressure, heart rate) and SpO2 will be checked at screening and monitored 
starting at baseline (before the spinal injection) then every 10 min from spinal injection until 
at least the end of the anaesthesia, or longer if necessary, according to the standard hospital 
procedures. Standard monitors will be used according to ASA recommendations.  
 
Blood pressure, heart rate and SpO2 will be monitored also before discharge at final 
visit/ETV.  
 
Monitoring after spinal injection will be performed for safety reasons and results will not be 
reported in the CRF, unless clinical significant values are observed. Screening, baseline and 
before discharge assessments of haemodynamic variables and any other assessment after the 
surgery judged clinical significant will be reported in the CRF.  
 
Occurrence of clinically relevant hypotension and bradycardia will be monitored throughout 
the study and, if observed, appropriately treated, according to the Investigator's opinion. 
 
7.1.2 
ECGs 
 
ECG will be performed at screening for patients > 60 years old. ECG will be monitored in all 
patients using standard monitors at baseline (before the spinal injection), during the block 
(every 10 min) until at least the end of anaesthesia, or longer if necessary, according to the 
standard hospital procedures.  
 
Monitoring will be performed for safety reasons. Results will be assessed by the 
Investigator/his deputies and not recorded in the CRF unless clinically significant. 
 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
7.2 
Assessment of treatment-emergent adverse events 
 
7.2.1 
Treatment-emergent adverse events (TEAEs) 
 
For the definition of adverse events (AEs) and treatment-emergent adverse events (TEAEs) 
please refer to § 11. 
 
AEs will be assessed throughout the study from the signature of the informed consent up to 
the second follow-up (day 7±1).  
 
Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.  
 
Any complication during anaesthesia will be recorded (and treated according to the standard 
hospital procedures). Pain at the site of injection and any other pain not related to surgery will 
be recorded as adverse event. 
Surgery-related pain at the site of surgery will not be recorded as an adverse event (see § 7.3, 
Pain intensity). 
 
Particular attention will be given to systemic and local toxicity symptoms, neurological 
symptoms and allergic reactions. The occurrence of headache and of lower limbs and gluteus 
paraesthesia, as well as nausea and vomiting will be carefully checked. Patients will also be 
instructed to report any signs of systemic (central nervous system) toxicity. 
 
7.2.2 
Neurological complications and transient neurological symptoms 
 
Attention will be given to the possible occurrence of neurological complications including 
transient neurological symptoms (TNS). In particular the incidence of neurological 
complications including TNS and unusual sensations not associated to the operation area will 
be assessed at 24 h and at day 7±1 (i.e. 6±1 days) after analgesic/anaesthetic IT injection and 
surgery, directly or through a telephonic interview (if the patient has already left the hospital). 
A specific questionnaire will be filled-in and the following symptoms will be questioned (see 
Appendix 18.1): 
 
 Well being 
 fatigue 
 nausea/vomiting 
 dizziness 
 urination/defecation difficulty 
 pain at the site of injection and surgery-related pain 
 unusual sensations (burning, tingling, dull, aching, numbness, hypoesthesia or other 
sensations) 
 location of the symptoms (buttocks, thighs anterior, thighs posterior, lower limbs, 
sacrum, calves or back)  
 laterality of the symptoms (one sided or bilateral) 
 previous experience of such symptoms 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
Symptoms reported through the questionnaires will also be recorded as adverse events (see § 
7.2.1). 
The questionnaire will be reviewed by the investigator who will judge whether the reported 
symptoms could be classified as neurological complications or TNS (this information will be 
reported in the CRF) on the basis of the available evidence and referring to the diagnosis 
criteria reported by Pollock et al. (26) and ASA, and summarised in the table below: 
 
Table 7.2.2.1 Differential diagnosis criteria for neurological complications including TNS and other events 
following intrathecal injection 
Event 
Onset – Duration 
Symptoms 
Treatment 
TNS 
6-36 h after spinal or 
epidural 
anaesthesia/1-7 
days 
Unilateral or bilateral 
pain in the anterior or 
posterior thigh ± 
extension into legs ± back 
pain 
No motor weakness 
No neurological 
abnormalities 
NSAIDs, opioids, warm 
heat, trigger-point 
injections 
Epidural haematoma 
0 - 2 days 
Muscle weakness, 
radicular back pain, 
sensory deficit 
CT scan, neurological 
consult, surgical 
decompressive 
laminectomy 
Epidural abscess 
2 - 7 days 
Backache, progressive 
neurological symptoms ± 
fever 
Antibiotics, possible 
surgical drainage 
Spinal nerve injury 
0 - 2 days/1 - 12 weeks 
Pain during insertion of 
needle or catheter, pain 
on injection, paraesthesia, 
pain and numbness over 
distribution of nerve root 
May need EMG to assess 
baseline neurological 
status 
Anterior 
spinal 
artery 
syndrome 
Immediate 
Postoperative painless 
paraplegia 
If secondary to 
vasospasm may respond 
to vasodilating drugs and 
hypertensive therapy 
Adhesive arachnoiditis 
0 months 
Pain on injection, variable 
degree of neurological 
deficit, often progressive, 
with pain and paraplegia 
Diagnosis by CT, MRI or 
myelography. No 
effective treatment 
Cauda equine syndrome 
0 days 
Loss of bowel and 
bladder function, 
paraplegia, motor 
weakness, sensory loss 
No effective treatment 
 
7.3 
Pain intensity at rest 
 
Surgery-related pain intensity at rest will be assessed by the patients using a 0-100 mm visual 
analogue scale (VAS) at the following time-points: 
 
 Baseline (within 30 min before NIMP IT injection, 0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP 
IT injection, then every 30 min (i.e. 2.5, 3 h, etc.) after NIMP IT injection until eligibility 
for home discharge. 
 
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Study protocol CRO-17-133 
Sponsor code PAR.3-01-2017 
Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
Surgery-related pain intensity will also be assessed before discharge (at final visit/ETV) using 
a 0-100 mm VAS. 
 
Additional pain assessments could be performed if the patient spontaneously report pain 
outside the pre-specified time-points. Also in this case, the patient will report surgery-related 
pain intensity on the 0-100 mm VAS scale. 
If the score on the VAS scale is ≥ 4 at the pre-specified or additional assessment times, an 
analgesic will be administered as detailed in § 7.4.  
VAS scores will be measured and reported in the CRF by the Investigator or his/her deputy.  
 
The study primary efficacy measures will be the VAS scores at each predefined time-point 
after the NIMP IT injection until eligibility for home discharge whilst the additional 
assessments and the assessment before discharge will not be taken into account for the 
primary efficacy analysis. 
 
VAS assessment times should not deviate more than the recommended tolerance ranges 
summarised in the following table. 
 
Table 7.3.1 
Recommended tolerance ranges for the scheduled VAS assessment times 
VAS assessment times 
Tolerance ranges 
Baseline (0 h) 
Within 30 min before the IT injection 
1, 1.25, 1.5, 1.75, 2, 2.5 hours after NIMP injection 
± 5 min 
3 hours after NIMP injection and all other assessments 
until eligibility for home discharge 
± 10 min 
Before discharge (at final visit/ETV) 
Not applicable 
 
Any deviations from the scheduled VAS assessment times outside the tolerance ranges will be 
verified through Data Clarification Forms. 
 
 
Pain at the injection site will be recorded independently of surgery-related pain and will be 
reported as AE. Surgery-related pain will not be reported as AE (see § 7.2.1). 
 
Pain at the injection site will also be assessed at the two follow-ups (24 h post-dose and day 
7±1) using a questionnaire (see § 7.2.2). The following grading system will be used for pain at 
the site of injection: 
 
Scores 0, 1, 2 
=> 
No adverse event 
Scores 3, 4, 5 
=> 
Adverse event with severity 'Mild' 
Scores 6, 7, 8 
=> 
Adverse event with severity 'Moderate' 
Scores 9, 10 
=> 
Adverse event with severity 'Severe' 
 
7.4 
Post-operative pain control 
 
Postoperatively, patients will be administered an analgesic as needed (see § 7.3). Post-
operative analgesia could include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or 
Tramadol i.v. 1 mg/kg (level 2 analgesia). 
 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
The administered analgesic (level 1 or 2), analgesic dose and intake frequency will be decided 
according to the reported surgery-related pain intensity.  
 
Time of analgesic administration and details on the administered analgesic (name, dose, 
frequency) will be recorded on the CRF. 
 
7.5 
Rescue analgesia/anaesthesia 
 
In case of incomplete anaesthesia during surgery or incomplete analgesia during surgery or 
postoperatively, either a sedative, analgesic or anaesthetic will be administered according to 
the standard hospital’s procedures. Details will be recorded in the CRF. 
 
7.6 
Block assessment 
 
The evolution of both sensory and motor blocks, including sensory block metameric level, 
will be evaluated every 5 min until readiness for surgery (see definition below), then every 10 
min until the maximum level is reached (two consecutive observations with the same level of 
sensory block only if applicable or if possible, otherwise one observation) and then every 15 
min until complete regression of sensory block to S1.  
 
Sensory block will be verified by bilateral Pinprick test using a 20-G hypodermic needle and 
will be recorded. Pinprick sensation will be scored as being present (score 1) or absent (score 
0). Onset of sensory block is defined as an absent touch sensation (score 0). 
 
Motor block will be verified using a modified Bromage scale (0=no block; 1=hip blocked; 
2=hip and knee blocked; 3=hip, knee and ankle blocked). Onset of motor block is defined as a 
motor block score ≥ 2.  
 
Time to onset of sensory block and time to onset of motor block are defined as the time period 
from the spinal injection (time 0 h) to the achievement of sensory block and motor block, 
respectively. 
 
Spinal block/Readiness for surgery is defined as the presence of an adequate motor block 
(Bromage’s score ≥ 2) and loss of Pinprick sensation, according to the Investigator's opinion. 
Time to readiness for surgery is defined as the time from the spinal injection (time 0 h) to 
achievement of readiness for surgery. 
Regression (offset) of sensory block will be deemed to have occurred when sensitive 
sensation has returned (score 1). Regression (offset) of motor block will be deemed to have 
occurred when motor score returns to 0.  
 
Time of onset of spinal block (i.e. time to readiness for surgery), Maximum level of sensory 
block, Time of maximum level of sensory block and Time of regression of spinal block 
(defined as time to complete regression of sensory block to S1), will be reported in the CRF. 
Start time and end time of surgery will also be recorded.  
 
 
 
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7.7 
Procedures for assessing eligibility for home discharge 
 
Patients will stay in the hospital after surgery until at least they are considered eligible for 
home discharge.   
Patients will be eligible for home discharge when the criteria for discharge are met, according 
to the standard hospital procedures (generally: autonomous ambulation, absence of surgical 
pain, ability to take food).  
 
At final visit/ETV, patients will be asked about any adverse events, with particular attention 
to local toxicity and neurological symptoms, such as paraesthesia of the gluteus and of the 
lower limb, and to possible allergic reactions (e.g. urticarial). Pain will be assessed as 
specified in § 7.3. Vital signs and SpO2 will be checked. 
The patients will be actually discharged according to the hospital’s standard procedures. 
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Paracetamol/Chloroprocaine IT 
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8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomisation 
 
The randomisation list will be computer generated by the Biometry Unit of the Clinical 
Contract Research Organization (CRO), using the PLAN procedure of the SAS® system 
version 9.3 (TS1M1) (27) or higher for Windows (the version will be stated in the final 
clinical study report). The randomisation list will be attached to the final clinical study report. 
 
8.2 
Treatment allocation 
 
The patients will be allocated to D1, D2, D3 or one of the P volumes according to the study 
randomisation list.  
 
Randomisation number will be given to the patients on study Day 1 and will be used to 
allocate each patient to a dose group, as detailed above. 
 
The 5-mL ampoules with the investigational products will be numbered. Each patient will be 
allocated the product ampoule corresponding to his/her randomisation number. 
 
All patients will receive Chloroprocaine HCl 1% as spinal anaesthetic after intrathecal 
injection of the IMP and before the surgical procedure (see § 3.1.2). 
 
8.3 
Blinding 
 
The study is double-blind, i.e. the Investigator and the patients will not be aware of the 
administered investigational product. 
 
Three (3) copies of the list will be generated and sealed in individual envelopes: 
 one copy will be sent to the manufacturer for the preparation of the individual treatment 
boxes 
 one copy will be kept at the CRO Quality Assurance Unit 
 one copy will be stored in the CROSS Metrics Project File 
 
Neither the members of the clinical staff nor the CPL or the CRA/monitor, monitoring the 
study evaluations and procedures, will have access to the randomisation code.  
Only the person preparing the syringe (and not involved in any other study-related procedure) 
and the CRA/monitor who performs the drug accountability will be aware of the administered 
investigational product. 
The CRO will open the envelope containing the randomisation list only when data-entry is 
complete and decisions to be made in blinding, before data analysis, are final.  
 
The CRO will notify breaking of the randomisation list to the sponsor. 
 
Syringes for injection will be prepared by a person not involved in any study-related activities 
where a bias is possible.  
 
 
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Final version 1.0, 16OCT17 
8.3.1 
Emergency code and unblinding procedures 
 
Unblinding of the code for specific patients, if applicable, will be fully documented in the 
source documents, in the CRFs and in the clinical study report. 
 
8.3.2 
Emergency individual envelopes 
 
The emergency envelopes containing the individual randomisation codes will be sent to the 
clinical centre. 
 
The randomisation code will be filed in the investigator’s study file in a sealed envelope for 
each patient, with the key for its identification. Copies of the individual emergency envelopes 
will be sent to the pharmacovigilance representative and to the sponsor representative (if not 
coinciding). 
 
Inside each envelope, the individual randomisation code must be clearly indicated, reporting 
the allocated treatment. 
 
Breaking of an individual randomisation code during the study is allowed only when 
knowledge of the code is essential for the patient's health. In this case, only the envelope 
related to the concerned subject will be opened. Individual code breaking will be clearly 
reported in the patient CRF and on the envelope; the latter is sealed again. 
 
In any case, the monitor must be informed within 24 h from code breaking. 
 
The date and the reason for breaking the code must be recorded in the CRF and on the 
envelope. All envelope sets containing the randomisation code of each patient must be kept 
closed even after database lock. At the end of the study, all envelope sets will be sent to the 
sponsor. 
 
8.3.3 
Individual kit replacement envelopes 
 
The clinical centre will also receive individual kit replacement envelopes. If a reserve kit 
needs to be used, the kit replacement envelope will be opened and the injectable solution will 
be prepared out of the operating room by a person not involved in any other study activity in 
such a way that the double-blind condition of the study is maintained. The date and the reason 
for opening the kit replacement envelope will be recorded on the envelope and then the 
envelope will be sealed again. 
 
All kit replacement envelope sets must be kept closed even after database lock. At the end of 
the study, all envelope sets will be sent to the sponsor. 
 
 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary efficacy variables 
 
The primary efficacy variables will be the VAS scores at each predefined time-point. 
 
Pain intensity at rest (as VAS scores) will be evaluated using a 0-100 mm VAS at baseline 
(within 30 min before NIMP IT injection, 0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, 
then every 30 min (i.e. 2.5, 3 h, etc.) after NIMP IT injection until eligibility for home 
discharge.  
 
9.1.2 
Secondary efficacy variables 
 
 Pain at rest VAS scores AUCt1-t2, where AUCt1-t2 is defined as the area under the pain 
intensity curve at the specified time-intervals (intervals: 0-2h, 0-4h) 
 Pain at rest VAS scores AUClast, where AUClast is defined as the area under the pain 
intensity curve from 0 h up to the last assessment time 
 Time to first postoperative analgesia (level 1 or 2, see below) (Tpa) 
 Time to level 1 analgesia (TA1) 
 Time to level 2 analgesia (TA2) 
 Total amount of analgesic 1 consumption (A1) 
 Total amount of analgesic 2 consumption (A2) 
 Proportion of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery 
end (π2h)  
 Proportion of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery 
end (π4h) 
 Proportion of patients requiring analgesia (level 1 or level 2) from surgery end until 
eligibility for home discharge (πed) 
 Proportion of patients requiring level 1 analgesia (πA1) from surgery end until eligibility for 
home discharge 
 Proportion of patients requiring level 2 analgesia (πA2) from surgery end until eligibility for 
home discharge 
 Time to first supplementary analgesia, other than the planned level 1 or 2 analgesia (Tao) 
 Proportion of patients requiring supplementary analgesia, other than the planned level 1 or 
2 analgesia (πao) 
 Time to rescue anaesthesia (Tras) 
 Proportion of patients requiring rescue anaesthesia (πras) 
 Time to onset of spinal block (i.e. time to readiness for surgery) (Trs) 
 Maximum level of sensory block (SBmax) 
 Time to maximum level of sensory block (TSBmax) 
 Time to regression of spinal block (Treg) (defined as complete regression of sensory block 
to S1) 
 Time to unassisted ambulation (Tua) 
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 Time to first spontaneous urine voiding (Tuv) 
 Time to eligibility for home discharge (Ted) 
 
9.1.3 
Safety variables 
 
 Treatment-emergent adverse events throughout the study 
 Incidence of neurological complications including TNS at 24 h post-dose and at day 7±1 
 Vital signs (blood pressure, heart rate), SpO2 
 Concomitant medications 
 
9.2 
Efficacy assessments 
 
9.2.1 
Efficacy parameters 
 
Efficacy assessments are based on the primary and secondary efficacy variables listed in § 9.1 
above. Assessment procedures are detailed in § 7. 
 
9.3 
Safety assessments 
 
Patients will be questioned about the occurrence of treatment-emergent adverse events 
(TEAEs) throughout the study. Particular attention will be given to neurological 
complications including TNS symptoms. Further details on the AE assessments are given in § 
7.2.  
 
ECG at screening will be recorded only for patients > 60 years old. ECG, blood pressure, 
heart rate and SpO2 will be monitored and assessed as detailed in § 7.1.1 and 7.1.2.  
Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.  
Concomitant medication intake will be recorded. 
 
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10 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. arithmetic mean, SD, CV (%), minimum, 
median and maximum values for quantitative variables, and frequencies for qualitative 
variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis will be 
performed using SAS® system version 9.3 (TS1M1) (27) or higher for Windows (the actual 
version will be stated in the final clinical study report). Pain intensity AUCs will be calculated 
and analysed using WinNonlin® version 6.3 (28) or higher (the actual version will be stated in 
the final report). 
 
10.1 
Analysis Sets 
 
10.1.1 
Definitions 
 
A patient will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A patient will be defined as eligible if he/she respects all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A patient will be defined as enrolled in the study if he/she is included into the treatment phase 
of the study. The enrolment will be performed through randomised allocation to a dose group. 
 
A patient will be defined as randomised in the study when he/she is assigned to a randomised 
dose group. 
 
 Enrolled set: all enrolled patients. This analysis set will be used for demographic and 
baseline characteristics. 
 Full Analysis Set (FAS): all randomised patients who fulfil the study protocol 
requirements in terms of investigational product (i.e. paracetamol/placebo) administration 
and anaesthetic administration and have at least one post-baseline assessment of the 
primary efficacy evaluation (i.e. surgery-related pain at rest). This analysis set will be 
used for the sensitivity analysis and for the secondary efficacy analysis. 
 Per Protocol set (PP): all randomised patients who fulfil the study protocol requirements 
in terms of investigational product administration, anaesthetic administration and primary 
efficacy evaluation (i.e. surgery-related pain at rest), with no major deviations that could 
affect the primary efficacy results. This analysis set will be used for the primary efficacy 
analysis and for the secondary efficacy analysis. 
 Safety set: all patients who receive at least one dose of the investigational product and/or 
anaesthetic. 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 
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actually receive (Enrolled set, PP set and Safety set) and to the treatment they are assigned to 
(FAS). 
 
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 IMP or the NIMP 
 
lack of any primary efficacy data post enrolment 
 
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 or to the NIMP (i.e. whole scheduled dose not 
administered) 
 
exposure to an IMP or NIMP different from the one assigned to the subject 
 
missing primary efficacy data 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
 
10.2 
Sample size and power considerations 
 
At least sixty (60) male/female patients (at least 15 patients per dose group), aged 18-80 
years, scheduled for elective knee procedures up to 40 min duration (e.g. diagnostic knee 
arthroscopy and meniscectomy not requiring the micro-fracture technique) under spinal 
anaesthesia will be enrolled in order to have at least 15 treated patients per treatment group 
included in the Per Protocol Set. The sample size for the study is not based on any formal 
sample size calculation. The number of at least 15 treated patients/treatment group included in 
the Per Protocol Set is deemed appropriate considering the exploratory and descriptive nature 
of the study. 
 
10.3 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarised in contingency tables. Quantitative data will be 
summarised using classic descriptive statistics.  
 
10.4 
Analysis of efficacy parameters 
 
All study data will be listed by patient, treatment group and assessment time point/interval (if 
applicable) and will be summarised by treatment group and assessment time point/interval (if 
applicable) using classic descriptive statistics (i.e. mean, SD, CV%, min, median and max) for 
quantitative variables and frequencies for qualitative variables. Summary statistics will be 
performed on the Per Protocol Set and on the Full Analysis Set.  
 
10.4.1 
Primary efficacy analysis 
 
The primary efficacy analysis will be performed on the Per Protocol Set. 
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Final version 1.0, 16OCT17 
Pain at rest (VAS scores at each pre-defined time point) will be analysed using rank-
transformed repeated measures ANCOVA with rank-transformed baseline pain at rest as 
covariate, and treatment, assessment time point and treatment*assessment time point as fixed 
effect. Pairwise comparisons between treatment groups for pain at rest will be performed at a 
two-sided type I error α = 0.05 according to the following hierarchical order: 
 
1. P vs. D3 (90 mg) 
2. P vs. D2 (60 mg) 
3. P vs. D1 (30 mg) 
4. D1 (30 mg) vs. D3 (90 mg) 
5. D2 (60 mg) vs. D3 (90 mg) 
6. D1 (30 mg) vs. D2 (60 mg) 
 
Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary 
for the primary endpoint (CPMP/EWP/908/99 guideline, 19SEP02). However, if a null 
hypothesis of a comparison cannot be rejected all the null hypotheses of the subsequent 
comparisons cannot be rejected. 
 
10.4.2 
Sensitivity analysis 
 
The primary efficacy analysis will be repeated on the Full Analysis Set. The same pairwise 
comparisons foreseen for the primary variable will be performed at a two-sided type I error α 
= 0.05 according to the same hierarchical order. 
 
10.4.3 
Secondary efficacy analysis 
 
Due to the small sample size, collected data will be compared using nonparametric tests. 
Tpa, TA1, TA2, Tao, Tras, Trs, TSBmax, Treg, Tua, Tuv and Ted will be presented using Kaplan-Meier 
curves and will be compared between treatment groups by log rank test. 
A1, A2, AUCt1-t2 (AUC0-2h, AUC0-4h) and AUClast will be summarised by treatment group 
using classic descriptive statistics (i.e. mean, SD, CV%, min, median and max). 
SBmax, π2h, π4h, πed, πA1, πA2, πao and πras will be summarised by treatment group using 
frequency tables.  
SBmax, A1 and A2 will be compared between treatment groups by Wilcoxon rank sum test. 
π2h, π4h, πed, πA1, πA2, πao and πras will be compared between treatment groups using the Fisher 
exact test. 
VAS scores for pain at rest AUCt1-t2 (AUC0-2h, AUC0-4h) and AUClast will be analysed by 
rank-transformed ANOVA with treatment as fixed effect, and by ANOVA with treatment as 
fixed effect.  
 
10.5 
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:  
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Final version 1.0, 16OCT17 
 PTAEs: all AEs occurring before the first dose of IMP and not worsening after the 
first dose of IMP 
 TEAEs: all AEs occurring or worsening after the first dose of IMP 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC 
and PT, seriousness, relationship to treatment and severity. For TEAEs that change severity 
during the study (e.g. from mild to moderate or from moderate to mild), the more severe 
intensity will be reported in the summary tables. 
The Investigator will evaluate the reasonable possibility of a causal relationship with the study 
drug and any other causal relationship as follows: 
 
• Relationship to investigational product (IMP) 
• Other causal relationship 
 Not applicable 
 Relationship to study anaesthetic (NIMP) 
 Other 
 
 Physical examination 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
 Vital signs and SpO2 
Screening, baseline and final/early termination assessments of haemodynamic variables and 
any other assessment judged clinical significant will be reported in the CRF and listed in the 
clinical study report. Screening, baseline and before-discharge values of vital signs and SpO2 
will be summarised by descriptive statistics.  
 
 Body weight  
Values of body weight will be listed and summarised by descriptive statistics. 
 
 ECG 
ECG results at screening (when applicable) will be listed. ECG results during monitoring 
judged clinical significant will be reported in the CRF and listed in the clinical study report. 
 
 Incidence of neurological complications including TNS  
The incidence of neurological complications including TNS at 24 h post-dose and at day 7±1 
(i.e. 6±1 days after analgesic/anaesthetic IT injection and surgery) will be summarised by 
treatment group and overall using tables of frequency. 
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11 
DEFINITION AND HANDLING OF AES AND SAES 
 
11.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the CRO SOPs, based upon 
applicable local and international regulations. The full SOP or an operative summary will be 
made available to the clinical centre. 
 
A brief summary of AE definition, classification and management is reported below. 
 
11.2 
Definitions 
 
 Adverse event (AE) 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with treatment. 
 
 Adverse Drug Reaction (ADR) 
Any noxious and unintended response to a medicinal product (i.e. a causal relationship 
between a medicinal product and an AE is at least reasonably possible in the investigator's or 
sponsor's opinion, the relationship cannot be ruled out) resulting not only from the authorised 
use of a medicinal product at normal doses, but also from medication errors and uses outside 
the terms of the marketing authorisation, including the misuse and abuse of the medicinal 
product. 
 
 Pre-treatment AE (PTAE) 
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) of the investigational product and the 
information leaflet of the NIMP 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 in 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 starts before or after the first intake of the study drug or 
whether the adverse event has worsened or not after the first intake of the study drug 
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 causes the subject to be discontinued from 
the study 
16. 
Other Action Taken: other actions taken as a result of the event that are unrelated to 
dose adjustments of study drug 
17. 
Outcome: Outcome of the event 
• 
1 Recovered/Resolved 
• 
2 Recovered/Resolved With Sequelae 
• 
3 Recovering/Resolving 
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• 
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 in the report. 
The sponsor will evaluate the SAE expectedness on the basis of the RSI. 
 
11.6 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the sponsor (day 0).  
For fatal and life-threatening SUSARs the EC and Competent Authority (CA) should be 
informed as soon as possible and in any case within 7 days. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days. 
 
The minimum information to be reported includes: 
 Sponsor study number 
 One identifiable coded subject 
 One identifiable reporter 
 One SUSAR 
 One suspect IMP (including active substance name, code) 
 A causality assessment (a reasonable possibility of a causal relationship with the study 
drug can be excluded only if there is information supporting this decision, otherwise it 
cannot be excluded). 
 
 
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11.7 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting when they might materially alter the 
current benefit-risk assessment of a medicinal product or would be sufficient to consider 
changes in the medicinal product administration or in the overall conduct of the trial, for 
instance: 
 single case reports of an expected serious adverse reaction with an unexpected 
outcome (e.g.: a fatal outcome) 
 an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
 post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the investigator by the subject. 
 new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
− a SAE which could be associated with the trial procedures and which could modify 
the conduct of the trial 
− a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) or from other clinical trials. 
 
11.8 
SAEs: contacts 
 
SAEs must be reported on SAE reporting forms and faxed/emailed within 24 H to Corporate 
Drug Safety Unit of the sponsor - contact details below: 
 
 
 
 
 
 
 
Fax: 
+41(0)91.646.85.61 
Phone: +41(0)91.640.42.50 
Email:  corporate_drug_safety@sintetica.com 
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Paracetamol/Chloroprocaine IT 
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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. PAR.3-01-2017), the 3-digit centre number (i.e. 001), the 4-digit screening number (e.g. 
S001, S002, etc.) and, if applicable, the 3-digit subject randomisation number (i.e. 001, 002 .., 
060). 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, clinically significant physical examination 
abnormalities and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™). 
Previous and concomitant medications will be coded using the WHO Drug Dictionary 
Enhanced (WHODDE). The version of the coding dictionaries will be stated in the study 
report. 
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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
13.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff of CROSS Research S.A. (see § 
16.3) and of the Sponsor. Two monitors will be involved: one monitor will perform the 
checks of the study evaluations and procedures and will not be involved in the drug 
accountability. A second monitor will be defined before the start of the study and will be 
responsible for performing the drug accountability. He/she will not be involved in other 
monitoring activities. This will be done to safeguard the double-blind. Due care will be 
applied in order to avoid any disclosure of unblinded information to blind staff. 
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures and monitoring reports will comply 
with ICH-GCP chapter 5.18 requirements. Monitoring activities will be detailed in the 
monitoring plan. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorised individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOAC principles (Attributable-Legible-
Contemporaneous-Original-Accurate-Complete). 
 
The clinical centre is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirement(s). 
 
The CRO and the sponsor will be responsible for their respective activities. 
 
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The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a 
CRO, but the ultimate responsibility for the quality and integrity of the trial data always 
resides with the sponsor. 
 
13.3 
Applicable SOPs 
 
The sponsor, the clinical 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 inspections. 
 
13.5 
Audits and inspections 
 
The sponsor and 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 investigator(s) agree, by written consent to this protocol, to fully co-operate and support 
audits and inspections compliance checks by allowing authorised individuals to have access to 
all the study documentation. 
 
 
 
 
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14 
ETHICAL CONSIDERATIONS 
 
14.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the local (Canton Ticino) IEC and by the Federal 
Health Authorities (Swissmedic) will be obtained before the start of the study.  
 
The present clinical study will be carried out according to the general principles of the current 
revision of Good Clinical Practice (GCP), ICH Topic E6 (R2), and the applicable local law 
requirements. 
 
14.2 
Informed consent 
 
Before being enrolled in the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
It will include all the elements required by law according to the ICH-GCP recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment 
 any potential negative effects attributable to the study treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of subject insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms 
to be used. The forms will be signed and dated by both the investigator and the subject. A 
copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements (see § 15.3). 
The investigator will allow inspection of the forms by authorised representatives of the 
sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 
 
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14.3 
Insurance policy 
 
An insurance cover has been issued in favour of the subjects participating in this clinical 
study. The insurance is in compliance with the local regulations 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 endpoints 
 Discontinuation from interventions and data collection: the subject discontinues from 
the intake of the IMP(s) and/or NIMP and from the collection of primary and secondary 
endpoints 
 
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 
 site terminated by sponsor: an indication that a clinical study was stopped at a particular 
site by its sponsor 
 study terminated by sponsor: an indication that a clinical study was stopped by its 
sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
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 other: different than the ones previously specified 
 
14.4.3 
Discontinuation procedures 
 
For any subject discontinuing from 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 
 
Subjects discontinued after paracetamol and anaesthetic spinal injection will not be replaced, 
whilst subjects discontinued before paracetamol and anaesthetic spinal injection can be 
replaced in order to have 15 administered patients per dose group. 
 
14.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation.  
 
Reasons for discontinuation have to be documented appropriately. 
 
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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical centre 
 
Beside IMPs and NIMP, the following study material will be supplied to the clinical centre: 
 final version of the study protocol 
 CRF for each subject plus some spare copies 
 copy of the investigator’s brochure (IB) and Summary of Products Characteristics relative 
to the IMP and NIMP, respectively 
 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 Swissmedic, as applicable. 
 
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 and the original signed informed consent forms. 
 
Data reported in the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 
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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects, insurance contracts, certificate of analysis of the IMP(s), drug accountability records, 
signed informed consent forms, confidential subjects identification code, CRFs, curricula 
vitae of the investigator and other participants in the study, study staff lists and 
responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the sponsor agree to adhere to these requirements. 
 
15.4 
Study subjects’ recruitment 
 
Study participants will be recruited at the clinical centre among the patients attending the 
clinic for knee procedures up to 40 min duration (e.g. diagnostic knee arthroscopy and 
meniscectomy not requiring the micro-fracture technique).  
 
15.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator and the CRO agree to keep all the information 
provided by the sponsor in strict confidentiality and to request the same confidentiality from 
their staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected in the CRFs during the study will be documented in an anonymous 
way (see § 12.2). If, as an exception, for safety or regulatory reasons identification of a 
subject becomes necessary, the monitor, the sponsor and the investigator will be bound to 
keep this information confidential. 
 
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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Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual 
property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 
 
According to The Federal Act on Research involving Human Beings and the Ordinance on 
Clinical Trials in Human Research, the study will be registered and published in a WHO 
primary register or clinicaltrials.gov as well as in the supplementary federal database. 
 
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Paracetamol/Chloroprocaine IT 
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16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Sintetica S.A., Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: 
+41.91.640.42.50 
Fax: 
+41.91.646.85.61 
 
Sponsor representatives  
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 the complete address and contact details, please see clinical centre below) 
 
16.2 
Institutes performing the study 
 
16.2.1 
Clinical centre 
 
Department of Anaesthesiology, Clinica Ars Medica, Via Cantonale, CH-6929 Gravesano, 
Switzerland  
Phone: 
+41.91.611.6211 
Fax: 
+41.91.605.1559 
 
Principal investigator 
Claudio Camponovo, MD. Chairman of the Department of Anaesthesiology  
Email: 
ccamponovo@arsmedica.ch 
 
16.3 
Co-ordination, monitoring, data analysis & reporting 
 
CROSS Research S.A. and CROSS Metrics S.A., Switzerland, sister companies, share the 
same standard operating procedures and quality assurance system 
 
CROSS Research 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 Representative 
Chiara Leuratti, Clinical Projects Unit Head 
Email: 
medicalwriting@croalliance.com 
 
 
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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 
 
Monitoring 
Chiara Castiglioni, Clinical Research Associate and Clinical Trial Assistant 
Email: 
projectmanagement@croalliance.com 
 
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17 
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S.A., Switzerland. March 2013 
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acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery. Br J Anaesth 
2005;94:642-648.  
13. Juhl GI, Norholt SE, Tonnesen E, Hiesse-Provost O, Jensen TS. Analgesic efficacy and safety of 
intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery. 
Eur J Pain 2006;10:371-377.  
14. Pettersson HP, Jakobsson J, Öwall A. Plasma concentrations following repeated rectal or intravenous 
administration of paracetamol after heart surgery. Acta Anaesthesiol Scand 2006;50:673-677.  
15. Lahtinen P, Kokki H, Hendolin H, Hakala T, Hynynen M. Propacetamol as adjunctive treatment for 
postoperative pain after cardiac surgery. Anesth Analg 2002;95:813-819.  
16. Report on file. Dose-effect of Sintetico following spinal administration in a post-operative pain model. 
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17. Report on file. Effect of spinal co-administration of Sintetico and Chloroprocaine in a post-operative pain 
model. Russo R and Calignano C. Pharmacy Dept, University of Naples “Federico II”, Napoli, Italy. 
17FEB2014 
18. Report on file. Effect of spinal sequential administration of Sintetico and Chloroprocaine in a post-operative 
pain model. Russo R and Calignano C. Pharmacy Dept, University of Naples “Federico II”, Napoli, Italy. 
17DEC2014 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
19. Report on file. Effect of co-administration of oral acetaminophen and spinal Sintetico in a post-operative 
pain model. Russo R and Calignano C. Pharmacy Dept, University of Naples “Federico II”, Napoli, Italy. 
07NOV2014 
20. Study CRO-15-126 / Sponsor code PAR.3/02-2015. Dose-finding study of intrathecal paracetamol 
administered immediately before spinal anaesthesia in patients scheduled for hip replacement surgery. 
Principal investigator: Claudio Camponovo MD, Switzerland 
21. Report on file. Histopathological evaluation of spinal cord by 5% Sintetico single and repeated 
administrations in rats. Russo R and Calignano C. Pharmacy Dept, University of Naples “Federico II”, 
Napoli, Italy. 12OCT2015 
22. Chloroprocaine HCl Sintetica 1%. Information professionnelle du Compendium Suisse des Médicaments®. 
Sintetica S.A., Switzerland. March 2013 
23. Ampres solution for injection. Summary of Product Characteristics. Mercury Pharmaceuticals Ltd, UK. 19 
April 2012 
24. Preliminary safety report - Study part 1 - Study CRO-15-126 / Sponsor code PAR.3/02-2015. Dose-finding 
study of intrathecal paracetamol administered immediately before spinal anaesthesia in patients scheduled 
for hip replacement surgery. Principal investigator: Claudio Camponovo MD, Switzerland 
25. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the 
European Community, Volume 4 
26. Pollock JE, Mulroy MF, Bent E, Polissar NL. A comparison of two regional anesthetic techniques for 
outpatient knee arthroscopy. Anesth Analg 2003;97:397-401 
27. SAS/STAT® User’s Guide 
28. Phoenix WinNonlin® version 6.3 Getting Started Guide, Pharsight Corporation 
 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
18 
APPENDICES 
 
18.1 
Neurological complications (including TNS) questionnaires 
 
 
 
 
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Paracetamol/Chloroprocaine IT 
Final version 1.0, 16OCT17 
 
 
 
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