Two-part Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia in Patients Scheduled for Hip Replacement Surgery
Phase: PHASE1
Conditions: Phase 1: Pain Management, Phase 2: Pain Management
Sponsor: Sintetica SA

CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
 
 
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  
 
Prospective, single centre, randomised, parallel-group, double-blind, placebo-controlled, 
three doses of intrathecal paracetamol, 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, 01DEC15 
 
 
 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
 
 
 
 
This document comprises 74 pages 
CROSS Research S.A. 
Page 1 

CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS 
 
Title: Dose-finding study of intrathecal paracetamol administered immediately before spinal anaesthesia in 
patients scheduled for hip replacement surgery 
 
Protocol number: CRO-15-126 - Sponsor code PAR.3/02-2015 
 
Clinical phase: Phase II 
 
Study design: Prospective, single centre, randomised, parallel-group, double-blind, placebo-controlled, three 
doses of intrathecal paracetamol, 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 medicinal product (IMP):  
Paracetamol 3% (30 mg/mL), solution for injection, Sintetica S.A., Switzerland. Three doses of the paracetamol 
solution, administered by intrathecal injection, will be investigated in the study. A fourth treatment group will 
only receive a placebo solution. 
 
D1: 60 mg Paracetamol 3% (2 mL) 
 
D2: 90 mg Paracetamol 3% (3 mL) 
 
D3: 120 mg Paracetamol 3% (4 mL) 
 
P: Placebo (0.9% saline solution) (2 mL, 3 mL and 4 mL) 
 
Other products (Non-investigational medicinal product, NIMP) 
Hyperbaric Bupivacaine HCl 0.5% (5 mg/mL), injectable solution, Sintetica S.A., Switzerland, will be 
administered by intrathecal injection to all patients in the 4 treatment groups, at the dose of either 12.5 mg (2.5 
mL, patient’s height ≤160 cm) or 15 mg (3 mL, patient height > 160 cm). The anaesthetic will be administered 
immediately after intrathecal paracetamol administration (maximal interval between administrations: 2 min).  
 
Dose regimen: Patients scheduled for hip replacement surgery 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 placebo 
solution (P) by intrathecal (IT) injection. Immediately after paracetamol or placebo IT administration, all patients 
will receive a single IT dose of Hyperbaric Bupivacaine HCl 0.5% (12.5 mg for ≤ 160 cm-tall patients and 15 
mg for > 160 cm-tall patients). The time interval between paracetamol IT and bupivacaine IT administrations 
should not exceed 2 min. Administrations’ times will be recorded. 
Postoperatively all patients will have access to morphine via a patient controlled analgesia (PCA) pump with a 
standard programme (1-mg bolus, 5-min lock-out interval, no 4-h dose limit). 
 
Objective:  
The objective of the 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 solution, for post-operative 
analgesia of hip replacement surgery performed under spinal anaesthesia. 
 
End-points:  
Primary end-point:  
 
Pain intensity at rest at 1, 2, 3 h and then every 3 h up to 48 h after anaesthetic IT injection (time 0h), using 
a 0-100 mm VAS.  
Secondary end-points:  
 
Total morphine use in the first 24 h, in the first 48 h and in the entire study period 
 
Time to first morphine use 
 
Need for supplementary analgesia, other than the planned morphine PCA (i.e. other narcotic or analgesic)  
 
Time to first supplementary analgesia, other than the planned morphine PCA  
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS (cont.) 
 
Secondary end-points, continued:  
 
Functional assessment reflecting post-operative recovery status, in terms of: Nocturnal awakenings due to 
pain; Time to gastro-intestinal (GI) motility (return of bowel sounds, flatulence or bowel movement); Need 
for postoperative urinary indwelling catheter after initial removal of surgical catheter; Resumption of 
ambulation; Resumption of liquid intake and solid diet; Length of hospital stay 
 
Morphine-related adverse events (Diffuse pruritus, overt respiratory depression requiring treatment, Post-
operative vomiting or need for anti-emetic medication, Sedation and combined safety assessment) 
 
Onset of spinal block (i.e. readiness for surgery) 
 
Maximum level of sensory block 
 
Time to maximum level of sensory block 
 
Regression of spinal block 
Safety monitoring 
Safety will be monitored throughout the study as follows: 
 
Treatment-emergent adverse events, including morphine-related adverse events (see above) and transient 
neurological symptoms (TNS);  
 
Routine monitoring (vital signs, SpO2 and ECG) 
 
Concomitant medications 
 
Transfusion monitoring  
 
Routine safety laboratory tests at screening and final visit. Blood cell count on Day 2 
 
Study variables: 
Primary efficacy variable:  
 
Pain at rest VAS scores at screening, baseline (0 h), 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 
45 and 48 h after anaesthetic IT injection and at discharge, using a 0-100 mm VAS.  
Secondary efficacy and safety variables: 
 
Pain at rest VAS scores AUCt1-t2 (0-12h, 12-24h, 24-48h [if applicable] intervals), where AUCt1-t2 is defined 
as the area under the pain intensity curve at the specified time-intervals 
 
Total morphine use in the first 24 h, in the first 48 h and in the entire study period 
 
Time to first morphine use 
 
Proportion of patients requiring supplementary analgesia  
 
Time to first supplementary analgesia 
 
Functional assessment variables (reflecting post-operation recovery status): 
o 
Nocturnal awakenings due to pain (number of events, proportion of patients) 
o 
Time to GI motility (every 6 h; return of bowel sounds, flatulence or bowel movement) 
o 
Need for postoperative urinary indwelling catheter after initial removal of surgical catheter 
(proportion of patients) 
o 
Time to resumption of ambulation 
o 
Time to resumption of liquid intake and solid diet 
o 
Time to home discharge (Length of hospital stay) 
 
Morphine-related adverse events:  
o 
Diffuse pruritus,  
o 
Overt respiratory depression requiring treatment,  
o 
Post-operative vomiting or need for anti-emetic medication,  
o 
Sedation, defined as score ≤ -3 on the Richmond Agitation Sedation Scale (RASS) 
o 
Combined Safety Assessment (defined as the summary of the binary occurrences of any of the events 
listed above during the first 48 h) 
 
Treatment-emergent adverse events, including morphine-related adverse events (see above) throughout the 
study 
 
Incidence of transient neurologic symptoms (TNS) at day 6±1 
 
Vital signs (blood pressure, heart rate and peripheral oxygen saturation [SpO2]) and ECG 
 
Concomitant medications 
 
Time to onset of spinal block (i.e. time to readiness for surgery) 
 
Maximum level of sensory block 
 
Time to maximum level of sensory block 
 
Time to regression of spinal block 
 
Safety laboratory tests parameters 
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS (cont.) 
 
Sample size:  
At least sixty (60) male/female patients (15 patients per dose group), aged 18-80 years, scheduled for hip 
replacement surgery under spinal anaesthesia with anticipated need for post-operative narcotic analgesia, who 
have adequate i.v. access and anticipated hospital stay > 48 hours will be enrolled in order to have 15 treated 
patients per treatment group. 
 
The sample size for the study is not based on any formal sample size calculation. The number of 15 treated 
patients/treatment group 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 18-80 years (inclusive) old patients, scheduled for hip replacement 
surgery, with anticipated need for post-operative narcotic analgesia, adequate i.v. access and anticipated 
hospital stay > 48 hours. 
3. Body Mass Index (BMI): 18 - 34 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. Pain assessment: anticipated to be unable to make a reliable self-report of pain intensity 
5. Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol and/or amide type 
anaesthetics) and/or formulations’ ingredients or related drugs, opioids, non-steroidal anti-inflammatory 
drugs; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers could 
affect the outcome of the study 
6. 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 asthma or 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. 
7. Liver function: Impaired liver function (transaminases > twice upper limit) 
8. Renal function: Renal dysfunction (creatinine > 2.0 mg/dL) 
9. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study, calculated from the first day of the month following the last visit of the previous study 
10. Drug, alcohol: history of drug or alcohol abuse. Pre-existing dependence on narcotics or known tolerance to 
opioids 
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)] 
12. Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, anticonvulsant agents or 
chronic analgesic therapy). 
13. 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 1 week before the start of the 
study and during the study. Hormonal contraceptives for females are allowed.  
 
Study schedule: 
The study will include a screening phase (Visit 1, Days -21/1), a treatment phase (paracetamol IT administration, 
anaesthesia and surgical procedure: Visit 2, Day 1) and a follow-up phase including an observation period (Visit 
3, from Day 1 after surgery until discharge, a final visit (at discharge) and a follow-up (day 6±1). 
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS (cont.) 
 
Study schedule, continued: 
Screening Phase (Visit 1, Day -21/-1): Patients scheduled for hip replacement surgery will be informed about 
the aims, procedures and possible risks of the study and will be asked to sign the informed consent form for the 
inclusion in the trial. Routine pre-surgery assessments, including safety laboratory tests, 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, lifestyle, physical abnormalities, body weight, height, vital signs, peripheral oxygen 
saturation (SpO2) and ECG, medical/surgical history and previous/concomitant medications. Pain history and 
pain intensity at rest (measured using a 100 mm VAS) will also be recorded at screening. 
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 the placebo solution by IT injection. 
Blood pressure, heart rate, SpO2 and ECG (if foreseen by the hospital procedures) will be monitored at baseline 
and during block placement using standard monitors. Before any procedure, patients will be pre-medicated with 
propofol (1-2 mg/kg/h); in addition, an antibiotic will be administered. Ringer’s solution will be infused from the 
beginning of surgery until patient’s discharge from the recovery room. Pain intensity will be measured at 
baseline using a 100 mm VAS (see Efficacy assessments below). 
Paracetamol or placebo will be administered intrathecally (IT) just before spinal anaesthesia.  
For the intrathecal injection of the analgesic/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 Reganesth or Nizell needle; caudocranial direction of 
the bevel) 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 
in the lateral decubitus position (or sitting, if more appropriate) using a midline approach at the L3/L4 or L4/L5 
interspaces. After the lumbar puncture and after verifying the spontaneous flow of liquor at the beginning and at 
the end of the procedure, two short aspirations will be done to verify the proper positioning of the needle. 
Barbotage must be avoided. 
After intrathecal administration of the paracetamol dose or placebo, the anaesthetic (Hyperbaric bupivacaine HCl 
0.5%) will be administered. Time interval between the 2 administrations should not exceed 2 min. The time of 
paracetamol/placebo IT administration and the time of bupivacaine IT administration will be recorded in the case 
report form (CRF). Before the block (pre-dose assessment), as already reported above, and during the spinal 
block every 10 min until the end of anaesthesia, hemodynamic variables (HR, BP, SpO2; ECG if available) will 
be monitored according to the hospital standard procedures. 
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 discharge) 
Postoperatively all patients will have access to morphine via a PCA device with a standardised programme (1 
mg/mL, 1-mg bolus, 5-min lock out time interval, no 4-h dose limit). If adequate pain relief is not achieved with 
the i.v. PCA device alone, supplemental rescue boluses of i.v. morphine or another analgesic (according to the 
Investigator’s opinion) will be administered as needed, according to the standard hospital procedures.  
In the morning of the first postoperative day (24 h post-dose), laboratory tests (blood cell count) will be 
performed.  
 
Efficacy and safety assessments 
In the morning of the first postoperative day (24 h post-dose) after completion of the routine nursing activities, 
the PCA device will be temporarily discontinued and the total amount of morphine administered to the patient 
recorded. Total amount of administered morphine via the PCA device will also be recorded at 48 h and for the 
entire study period. Details on rescue medication and time to rescue medication (i.v. morphine or another 
analgesic) will also be recorded. 
 
Pain intensity at rest will be recorded, using a 0-100 mm VAS, at pre-specified time points, i.e. at baseline (0), 1, 
2, 3 h and then every 3 h up to 48 h after anaesthetic IT injection. 
 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS (cont.) 
 
Study schedule, continued 
Efficacy and safety assessments, continued 
Treatment-emergent adverse events will be recorded and treated according to the standard procedures of the 
hospital. Particular attention will be given to the occurrence of nausea, vomiting, sedation, pruritus and 
respiratory depression as well as to the occurrence of paraesthesia, headache, miction/defecation difficulties, 
tiredness, vertigo and TNS.  
To measure the agitation/sedation status of patients, the Richmond agitation-sedation scale will be used (Curtis 
N et al. American Journal of Respiratory and Critical Care Medicine 2002;166(10):1338-44).  
GI motility will be assessed every 6 h until return of bowel sounds, flatulence or bowel movement, and recorded 
in the CRF. All primary and secondary study variables will be recorded.  
 
Follow-up Phase - Discharge (final visit) 
Patients will stay in the hospital until the criteria for discharge are met according to the investigator’s opinion 
and the hospitals’ standard procedures. Before discharge they will undergo a final visit (or early termination visit 
[ETV] in case of premature discontinuation from the study). Day and time of discharge from the hospital will be 
recorded. 
 
Follow-up Phase - Follow-up: On Day 6±1 (i.e. 5±1 days after analgesic/anaesthetic IT injection and surgery), 
the investigator or his deputy will question patients about symptoms of TNS and unusual sensations not 
associated with the operation area (buttock, thigh posterior, thigh anterior, lower limb, sacrum, calves, other 
areas) following prepared questions. 
 
Data analysis:  
Statistical analyses will be done using SAS® version 9.3 (TS1M1) or higher for Windows.  
Definition of analysis sets:  
Enrolled Set: all enrolled subjects. This analysis set will be used for demographic, baseline and background 
characteristics. 
Full Analysis Set (FAS): all randomised patients who fulfil the study protocol requirements in terms of 
investigational product (i.e. paracetamol/placebo) and anaesthetic administration and have at least one post-
baseline assessment of the primary efficacy evaluation (i.e. 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. 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. 
Efficacy analysis 
All study data will be listed by patient, treatment group and assessment time point/evaluation interval (if 
applicable) and will be summarised by treatment group and assessment time point/evaluation interval (if 
applicable) using classic descriptive statistics (i.e. mean, SD, CV%, min, median and max) for quantitative 
variables and tables of frequencies for qualitative variables. Summarisation 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 will be analysed using a 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 (120 mg) 
2. P vs. D2 (90 mg) 
3. P vs. D1 (60 mg) 
4. D1 (60 mg) vs. D3 (120 mg) 
5. D2 (90 mg) vs. D3 (120 mg) 
6. D1 (60 mg) vs. D2 (90 mg) 
 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS (cont.) 
 
Data analysis, continued:  
Primary efficacy analysis, continued 
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 
 
All the analyses on the secondary variables will be performed with a nominal two-sided type I error α = 0.05.  
The same pairwise comparisons foreseen for the primary variable will be performed. 
As secondary efficacy analysis, pain at rest will be analysed using a repeated measures ANCOVA with baseline 
pain at rest as covariate and treatment, assessment time point and treatment*assessment time point as fixed 
effect. 
Pain at rest VAS scores AUCt1-t2 (0-12h, 12-24h, 24-48h intervals) will be analysed using a rank-transformed 
ANOVA with treatment as fixed effect. Different analyses will be performed for the AUCt1-t2 (0-12h), AUCt1-t2 
(12-24h) and AUCt1-t2 (24-48h). 
Pain at rest VAS scores AUCt1-t2 (0-12h, 12-24h, 24-48h intervals) will be analysed using an ANOVA with 
treatment as fixed effect. Different analyses will be performed for the AUCt1-t2 (0-12h), AUCt1-t2 (12-24h) and 
AUCt1-t2 (24-48h) 
Total amount of morphine used in the first 24 h, in the first 48 h and in the entire study period will be analysed 
using a rank-transformed ANOVA with treatment as fixed effect. Different analyses will be performed for the 
amount used in the first 24 h, in the first 48 h and in the entire study period. 
Total amount of morphine used in the first 24 h, in the first 48 h and in the entire study period will be analysed 
using an ANOVA with treatment as fixed effect. Different analyses will be performed for the amount used in the 
first 24 h, in the first 48 h and in the entire study period. 
Time to first morphine use will be presented using Kaplan-Meier curves and will be compared between 
treatment groups by log-rank test. 
Proportion of patients in need of narcotics other than morphine or in need of other rescue analgesics will be 
compared between treatment groups by Fisher's exact test. 
Time to first subsequent analgesia (narcotic or NSAIDs) will be presented using Kaplan-Meier curves and will 
be compared between treatment groups by log-rank test. 
Proportion of patients with nocturnal awakenings due to pain will be compared between treatment groups by 
Fisher's exact test. The same pairwise comparisons foreseen for the primary variable will be performed. 
Number of nocturnal awakenings due to pain will be compared between treatment groups by Wilcoxon rank-sum 
test. 
Time to GI motility will be presented using Kaplan-Meier curves and will be compared between treatment 
groups by log-rank test. 
Proportion of patients who need postoperative urinary indwelling catheter after initial removal of surgical 
catheter will be compared between treatment groups by Fisher's exact test. 
Time to resumption of ambulation will be presented using Kaplan-Meier curves and will be compared between 
treatment groups by log-rank test. 
Time to resumption of liquid intake and solid diet will be presented using Kaplan-Meier curves and will be 
compared between treatment groups by log-rank test. 
 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
STUDY SYNOPSIS (cont.) 
 
Data analysis, continued:  
 
Secondary efficacy analysis, continued 
Time to home discharge will be presented using Kaplan-Meier curves and will be compared between treatment 
groups by log-rank test. 
Proportion of patients with morphine-related adverse events will be compared between treatment groups by 
Fisher's exact test. 
Time to onset of spinal block will be presented using Kaplan-Meier curves and will be compared between 
treatment groups by log-rank test.  
The maximum level of sensory block will be compared between treatment groups by Wilcoxon rank-sum test. 
Time to maximum level of sensory block will be presented using Kaplan-Meier curves and will be compared 
between treatment groups by log-rank test. 
Time to regression of spinal block will be presented using Kaplan-Meier curves and will be compared between 
treatment groups by log-rank test. 
 
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 tables of 
frequencies for qualitative variables.  
 
 
 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
 
STUDY SCHEDULE 
 
Visit 
Visit 1 
Day -21/-1 
Visit 2 
Day 1 
Follow-up phase 
Observation 
period 
From end of 
surgery to 
discharge* 
Final 
visit/ETV5 
Day 6±1 
Informed consent 
x 
 
 
 
 
Demography and lifestyle 
x 
 
 
 
 
Medical/surgical history 
x 
 
 
 
 
Physical examination 
x 
 
 
 
 
Pain history and pain intensity 
x 
 
 
 
 
Previous and concomitant 
medication 
x 
x 
x 
 
x 
Height 
x 
 
 
 
 
Body weight 
x 
 
 
 
 
Vital signs (blood pressure, heart 
rate)1 
x 
x 
x 
x 
 
SpO2
1 
x 
x 
x 
x 
 
ECG1 
x 
x 
x 
x 
 
Laboratory tests2 
x 
 
x 
x 
 
Pregnancy test (urine)3 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
Enrolment and Randomisation 
 
x 
 
 
 
Propofol premedication 
 
x 
 
 
 
Antibiotic 
 
x 
 
 
 
Ringer’s solution infusion - 
premedication 
 
x 
 
 
 
Paracetamol IT administration 
 
x 
 
 
 
Bupivacaine IT administration 
 
x 
 
 
 
Blocks assessment 
 
x 
x 
 
 
Hip replacement surgery 
 
x 
 
 
 
Pain intensity (VAS) 
 
x4 
x4 
x4 
 
Morphine use assessment 
 
x 
x 
 
 
TNS questionnaire 
 
 
 
x 
x 
Adverse events monitoring 
x 
x 
x 
x 
x 
Morphine-related AEs6 
 
 
x 
x 
x 
Functional assessment7 
 
x 
x 
x 
 
Transfusion monitoring8 
 
x 
x 
 
 
 
*Observation period from the end of surgery to home discharge.  
The minimum duration of the observation period will be 48 h. During the observation period, efficacy 
assessments and safety monitoring according to the protocol and standard safety monitoring procedures of the 
hospital. Home discharge according to the investigator’s opinion and standard hospital procedures 
 
1. 
Vital signs, SpO2 and ECG (as foreseen by the standard hospital procedures) at screening, at baseline 
(before the spinal injection, then every 10 min from spinal injection until the end of the anaesthesia, 
according to the hospital standard procedures  
2. 
Laboratory tests at screening and before discharge (final visit) according to the hospital procedures. In the 
morning of the post-operative day (day 2) complete blood cell count according to the hospital procedures. 
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Study protocol CRO-15-126 
Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
3. 
Pregnancy test performed only for patients who cannot exclude a pregnancy 
4. 
Pain intensity at rest will be recorded using a 0-100 mm VAS at baseline (0 h), 1, 2, 3, 6, 9, 12, 15, 18, 21, 
24, 27, 30, 33, 36, 39, 42, 45 and 48 h after anaesthetic IT injection and at discharge 
5. 
Patients will be discharged after the hospital criteria for discharge are met (final visit) and according to 
the hospital’s standard procedures. In case of discontinuation, subjects will undergo an early termination 
visit (ETV) 
6. 
Assessment of morphine-related side effects: diffuse pruritus, overt respiratory depression, post-operative 
vomiting or need for anti-emetic medication, sedation (defined as score ≤-3 on the RASS) 
7. 
Functional assessment (post-operative recovery status): Nocturnal awakenings due to pain (number of 
events, proportion of patients), Time to GI motility (every 6 h; return of bowel sounds, flatulence or bowel 
movement), Need for postoperative urinary indwelling catheter after initial removal of surgical catheter, 
Resumption of ambulation, Resumption of liquid intake and solid diet, Home discharge time (Length of 
hospital stay) 
8. 
According to the standard hospital’s procedures 
 
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Final version 1.0, 01DEC15 
TABLE OF CONTENTS 
 
Page 
PROTOCOL APPROVAL 
2 
STUDY SYNOPSIS 
5 
STUDY SCHEDULE 
12 
TABLE OF CONTENTS 
14 
LIST OF ABBREVIATIONS 
18 
1 
INTRODUCTION 
20 
1.1 
Background 
20 
1.1.1 
Paracetamol 
20 
1.1.2 
Spinal anesthesia 
21 
1.1.3 
Analgesia for post-operative pain in combination with spinal anaesthesia 
21 
1.1.4 
Paracetamol solution for spinal administration 
22 
1.2 
Rationale 
22 
1.3 
Risks and benefits 
23 
2 
STUDY OBJECTIVES 
24 
2.1 
Primary end-point 
24 
2.2 
Secondary end-points 
24 
3 
CLINICAL SUPPLIES 
25 
3.1 
Treatment 
25 
3.1.1 
Description of products 
25 
3.1.1.1 
Test product 
25 
3.1.1.2 
Reference product 
25 
3.1.1.3 
NIMP (Non investigational medicinal product) 
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 
36 
7.1 
Physical examination 
36 
7.1.1 
Vital signs 
36 
7.1.2 
ECGs 
36 
7.2 
Clinical laboratory assays 
37 
7.2.1 
Transfusion monitoring 
37 
7.2.2 
Assessment of treatment-emergent adverse events 
37 
7.2.2.1 
Treatment-emergent adverse events (TEAEs) 
37 
7.2.2.2 
Morphine-related adverse events 
38 
7.2.2.3 
Transient neurological symptoms 
38 
7.3 
Functional assessment 
39 
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7.4 
Block assessment 
40 
7.5 
Post-operative pain control 
40 
7.5.1 
Morphine administration 
40 
7.5.2 
Additional post-operative pain control 
41 
7.6 
Pain intensity at rest 
41 
7.7 
Procedures for discharge 
41 
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 
Individual emergency envelopes 
44 
8.3.3 
Individual kit replacement envelopes 
44 
9 
EVALUATION PARAMETERS 
45 
9.1 
Study variables 
45 
9.1.1 
Primary efficacy variable 
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 
49 
10.4.2 
Sensitivity analysis 
49 
10.4.3 
Secondary efficacy analysis 
49 
10.5 
Safety and tolerability evaluation 
50 
11 
DEFINITION AND HANDLING OF AES AND SAES 
53 
11.1 
Applicable SOPs 
53 
11.2 
Definitions 
53 
11.3 
AEs monitoring window 
54 
11.4 
AEs recording 
54 
11.5 
SAEs reporting 
56 
11.6 
SUSARs management 
56 
11.7 
Other events qualified for expedited reporting 
57 
11.8 
SAEs: contacts 
57 
12 
DATA MANAGEMENT PROCEDURES 
58 
12.1 
Data collection – CRFs 
58 
12.2 
Unique subject identifier 
58 
12.3 
Database management 
58 
12.3.1 
Coding dictionaries 
58 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
59 
13.1 
Monitoring 
59 
13.2 
Quality Control and Quality Assurance 
59 
13.3 
Applicable SOPs 
60 
13.4 
Data access 
60 
13.5 
Audits and inspections 
60 
14 
ETHICAL CONSIDERATIONS 
61 
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14.1 
Ethics and Good Clinical Practice (GCP) 
61 
14.2 
Informed consent 
61 
14.3 
Insurance policy 
62 
14.4 
Withdrawal of subjects 
62 
14.4.1 
Discontinuation type 
62 
14.4.2 
Primary reason for discontinuation 
62 
14.4.3 
Discontinuation procedures 
63 
14.5 
Study termination 
63 
15 
ADMINISTRATIVE PROCEDURES 
64 
15.1 
Material supplied to the clinical centre 
64 
15.2 
Protocol amendments 
64 
15.3 
Study documentation and record keeping 
64 
15.4 
Study subjects’ recruitment 
65 
15.5 
Confidentiality and data protection 
65 
15.6 
Publication policy 
65 
16 
STUDY RESPONSIBLE PERSONS 
67 
16.1 
Sponsor 
67 
16.2 
Institutes performing the study 
67 
16.2.1 
Clinical centre 
67 
16.3 
Clinical laboratory 
67 
16.4 
Co-ordination, monitoring, data analysis & reporting 
67 
17 
REFERENCES 
69 
18 
APPENDICES 
71 
18.1 
TNA questionnaires 
71 
18.2 
Modified Aldrete score scale 
73 
18.3 
Richmond Agitation-Sedation Scale 
74 
 
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Final version 1.0, 01DEC15 
TABLES 
Page 
 
Table 3.1.2.1 
Dose groups 
26 
Table 7.2.2.1 
Differential diagnosis criteria for TNS and other events following intrathecal injection 
39 
Table 7.6.1 
Recommended tolerance ranges for the scheduled VAS assessment times 
41 
 
 
 
FIGURES 
Page 
 
Figure 1.1.1.1 
Paracetamol molecular structure 
20 
 
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Paracetamol IT 
Final version 1.0, 01DEC15 
LIST OF ABBREVIATIONS 
 
β-HCG 
human chorionic gonadotropin β 
γ-GT 
γ-Glutamyl transpeptidase 
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 
60 mg Paracetamol 3% (2 mL) 
D2 
90 mg Paracetamol 3% (3 mL) 
D3 
120 mg Paracetamol 3% (4 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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Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
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) 
PCA 
Patient-controlled analgesia 
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 
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-15-126 
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Paracetamol IT 
Final version 1.0, 01DEC15 
1 
INTRODUCTION 
 
1.1 
Background 
 
1.1.1 
Paracetamol 
 
Paracetamol (acetyl-p-aminophenol), also commonly known as acetaminophen in USA, is an 
active ingredient possessing analgesic and antipyretic activity used widely in 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, conversely to the majority of commonly used analgesic drugs, is not an NSAID 
(non-steroidal anti-inflammatory drug), since it is almost devoid of antiaggregant and anti-
inflammatory activity. To date, its mechanism of action remains little known, although this 
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. 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). 
 
 
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Paracetamol IT 
Final version 1.0, 01DEC15 
 
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 
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 
Analgesia for post-operative pain in combination with spinal anaesthesia 
 
In medical practice, it has been observed that, in order to obtain a suitable post-surgical 
analgesic effect, it is necessary to administer analgesics in high quantities or, alternatively, to 
resort to the administration of opioid drugs (3,11).  
Both of these therapeutic approaches expose patients to a series of possible side effects 
varying in accordance with the type and quantity of drug administered. Using opioids alone 
intensifies their side-effect profile that includes respiratory depression, postoperative nausea 
and vomiting, over-sedation, and pruritus.  
 
Recently, there has been increased interest towards multimodal analgesia for postoperative 
pain control in order to reduce opioid related side effects and provide better patient 
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Paracetamol IT 
Final version 1.0, 01DEC15 
satisfaction (12). Maund et al. found that there is a decrease in 24 h morphine consumption 
when paracetamol, NSAIDs or COX-2 inhibitors are given in addition to morphine patient-
controlled analgesia (PCA) after surgery (13, 14). 
 
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 for the treatment of postsurgical pain (10). The 
formulation intrathecally injected alone or before loco-regional anaesthesia is intended to give 
an effective analgesia for post-surgical pain. 
 
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, 15-18). 
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. 
 
1.2 
Rationale 
 
Administration of paracetamol for postoperative pain management using methods alternative 
to the traditional oral or iv routes is still to be explored in humans.  
 
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. 
 
The present study is being conducted to investigate the effectiveness of the novel 
supersaturated aqueous solution of paracetamol (Paracetamol 3% Sintetica), administered at 3 
different doses, in reducing the post-operative pain in patients undergoing hip replacement 
surgery under spinal anaesthesia. Spinal anaesthesia will be performed according to the 
standard hospital procedures using Hyperbaric Bupivacaine (19). Bupivacaine is a well-
known long-acting anaesthetic agent of the amide type for intrathecal (subarachnoid) 
anaesthesia, commonly used for urological and lower limb surgery lasting 1.5 - 3 hours and 
for abdominal surgery lasting 1.5 – 2 hours (20).  
 
The doses of intrathecal Paracetamol 3% investigated in the present study, i.e. 60 mg, 90 mg 
and 120 mg, 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). The paracetamol doses of 
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Paracetamol IT 
Final version 1.0, 01DEC15 
the present study are 8 – 17 times lower than the doses normally administered in humans by 
the oral or i.v. route for post-operative pain control. 
 
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 bupivacaine 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. 
 
Bupivacaine has been on the market under different brand names in Switzerland, EU and 
USA for many years for the proposed indication and is routinely used as loco-regional 
anaesthetic in the surgical procedure performed in the study. Adverse reactions following 
Bupivacaine intrathecal injection could be caused by the drug or by the physiological effects 
of the nerve block (e.g. decrease in blood pressure, bradycardia, temporary urinary retention), 
events caused directly (e.g. spinal haematoma) or indirectly (e.g. meningitis, epidural abscess) 
by needle puncture or events associated to cerebrospinal leakage (e.g. postdural puntural 
headache). Bupivacaine systemic adverse reactions are numbness of tongue, light-headedness, 
dizziness and tremors, followed by convulsions and cardiovascular disorders. 
 
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 
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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Final version 1.0, 01DEC15 
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 of hip replacement surgery performed under spinal 
anaesthesia. 
 
2.1 
Primary end-point 
 
 
Pain intensity at rest at 1, 2, 3 h and then every 3 h up to 48 h after anaesthetic IT 
injection (time 0h), using a 0-100 mm VAS.  
 
2.2 
Secondary end-points 
 
 
Total morphine use in the first 24 h, in the first 48 h and in the entire study period 
 
Time to first morphine use 
 
Need for supplementary analgesia, other than the planned morphine PCA (i.e. other 
narcotic or analgesic)  
 
Time to first supplementary analgesia, other than the planned morphine PCA  
 
Functional assessment reflecting post-operative recovery status, in terms of: 
o 
Nocturnal awakenings due to pain 
o 
Time to gastro-intestinal (GI) motility (return of bowel sounds, flatulence or bowel 
movement)  
o 
Need for postoperative urinary indwelling catheter after initial removal of surgical 
catheter 
o 
Resumption of ambulation 
o 
Resumption of liquid intake and solid diet 
o 
Length of hospital stay 
 Morphine-related adverse events: Diffuse pruritus, Overt respiratory depression requiring 
treatment, Post-operative vomiting or need for anti-emetic medication, Sedation 
(Richmond Agitation Sedation Scale [score ≤ -3]) and Combined safety assessment. 
 Onset of spinal block (i.e. readiness for surgery) 
 Maximum level of sensory block 
 Time to maximum level of sensory block 
 Regression of spinal block 
 
Safety monitoring 
Safety will be monitored throughout the study as follows: 
 Treatment-emergent adverse events, including morphine-related adverse events (see 
above) and transient neurological symptoms (TNS);  
 Routine monitoring (vital signs, SpO2 and ECG) 
 Concomitant medications 
 Transfusion monitoring  
 Routine safety laboratory tests at screening and final visit. Blood cell count on Day 2 
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Final version 1.0, 01DEC15 
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) 
Dose 
D1: 2 mL corresponding to 60 mg paracetamol 
D2: 3 mL corresponding to 90 mg paracetamol 
D3: 4 mL corresponding to 120 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 
2, 3 or 4 mL 
Administration route 
Intrathecal 
 
3.1.1.3 
NIMP (Non investigational medicinal product)  
 
Product name 
Hyperbaric Bupivacaine HCl 0.5% (5 mg/mL)  
Manufacturer and Supplier 
Sintetica S.A., Switzerland 
Pharmaceutical form 
Solution for injection (4-mL ampoule) 
Dose 
Patient height ≤ 160 cm: 12.5 mg (2.5 mL) 
Patient height > 160 cm: 15 mg (3 mL) 
Administration route 
Intrathecal 
 
3.1.2 
Dose regimen 
 
Patients scheduled for hip replacement surgery will be randomised into four treatment groups 
(15 patients/group) to receive either one of 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 of the study.  
 
In detail: 
 
Patients in D1 group will receive a single dose of 2 mL Paracetamol 3% (corresponding 
to 60 mg paracetamol).  
 
Patients in D2 group will receive a single dose of 3 mL Paracetamol 3% (corresponding 
to 90 mg paracetamol). 
 
Patients in D3 group will receive a single dose of 4 mL Paracetamol 3% (corresponding 
to 120 mg paracetamol). 
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Final version 1.0, 01DEC15 
 
Patients in P group will receive a single dose of the placebo solution, as follows: 5 
patients will receive 2 mL, 5 patients will receive 3 mL and 5 patients will receive 4 mL. 
 
Immediately after paracetamol or placebo IT administration, all patients will receive a single 
IT dose of either 12.5 mg (patient’s height ≤ 160 cm) or 15 mg (patient’s height > 160 cm) 
Hyperbaric Bupivacaine HCl 0.5%. The time interval between paracetamol IT and 
bupivacaine 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 
60 mg (2 mL) 
Hyperbaric bupivacaine HCl 0.5% - 
Height ≤160 cm: 12.5 mg (2.5 mL) 
Height >160 cm: 15 mg (3 mL) 
D2 
15 
90 mg (3 mL) 
D3 
15 
120 mg (4 mL) 
P 
15 
5 
Placebo IT 
2 mL 
5 
3 mL 
5 
4 mL 
 
The investigational product Paracetamol 3% and placebo will be provided in 5-mL ampoules, 
the non-investigational product Hyperbaric bupivacaine HCl 0.5% will be in 4-mL ampoules 
(commercial packaging). 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 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 
 
Paracetamol or placebo will be administered intrathecally (IT) just before spinal anaesthesia. 
Syringes for injection will be prepared inside a curtain cubicle space within the operating 
room by a person not involved in any other study activity. The syringe preparation area will 
not be visible from the outside. All the clinical staff (Investigator/co-investigators/study 
nurses) involved in investigational product administration, anaesthesia, surgery or patient’s 
care will be blind with respect to the administered treatment. Test and 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 for injection and on the 
transfer of the syringes from the preparation to the operating room will be given in the study 
manual. 
 
For the intrathecal injection of the analgesic/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 Reganesth or Nizell needle; caudocranial direction of the bevel) 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 in the lateral decubitus position (or sitting, if more appropriate) using a midline 
approach at the L3/L4 or L4/L5 interspaces. After the lumbar puncture and after verifying the 
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Final version 1.0, 01DEC15 
spontaneous flow of liquor at the beginning and at the end of the procedure, two short 
aspirations will be done to verify the proper positioning of the needle. Barbotage must be 
avoided. 
After intrathecal administration of the paracetamol dose or placebo, the anaesthetic 
(Hyperbaric bupivacaine HCl 0.5%) will be administered. Time interval between the 2 
administrations should not exceed 2 min. The time of paracetamol/placebo IT administration 
and the time of bupivacaine IT administration will be recorded in the case report form (CRF). 
 
Postoperatively all patients will have access to morphine via a PCA device with a 
standardised programme (1 mg/mL, 1-mg bolus, 5-min lock out time interval, no 4-h dose 
limit). If adequate pain relief is not achieved with the i.v. PCA device alone, supplemental 
rescue boluses of i.v. morphine or another analgesic (according to the Investigator’s opinion) 
will be administered as needed, according to standard hospital procedures.  
 
3.1.4 
Investigational product distribution 
 
The investigational products and the anaesthetic will be administered by the investigator or by 
his/her deputy. The person administering the investigational product will also administer the 
anaesthetic. 
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 according to the randomisation list. The primary 
packaging of the investigational products will be a 5-mL glass ampoule packed in individual 
carton packages (patients’ kits). Each patient kit will contain the glass ampoule with the 
product and a sealable graduated syringe for the collection of the residual product after 
administration. 
 
Labelling in local language will report all the information requested according to the Annex 
13 to the Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4). 
 
Labelling on packages will report: 
a) 
Name, address and telephone number of the sponsor and CRO;  
b) 
Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency;  
c) 
Batch number;  
d) 
Study Nr.;  
e) 
The study subject identification number/treatment number;  
f) 
Expiry in month/year format and in a manner that avoids any ambiguity;  
g) 
Investigator's name;  
h) 
Directions for use;  
i) 
“For clinical trial use only” wording;  
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Paracetamol IT 
Final version 1.0, 01DEC15 
j) 
The storage conditions. 
 
Labels of the individual syringes of the investigational products (paracetamol/placebo), 
prepared outside the operating room by a person not involved in any study activity, 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 (Hyperbaric Bupivacaine HCl 0.5%) will be the commercial 
packaging. 
 
3.3 
Storage conditions 
 
The investigational products (Paracetamol and Placebo) and the non-investigational product 
(Bupivacaine) 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 product will be provided directly to the investigator by the sponsor, in 
excess of the amount necessary for the study (at least 25% excess). 
 
The non-investigational product will be directly purchased by the clinical centre, 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 study products 
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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Paracetamol IT 
Final version 1.0, 01DEC15 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
This is a prospective, single centre, randomised, parallel-group, double-blind, placebo-
controlled, three doses of intrathecal paracetamol, exploratory efficacy and safety study 
 
4.2 
Discussion of design 
 
The study has been designed to evaluate the effectiveness in reducing postoperative pain of a 
novel aqueous solution of Paracetamol (Paracetamol Sintetica 3%) administered by 
intrathecal injection in patients undergoing hip replacement surgery under spinal block.  
 
Administration of paracetamol for postoperative pain management using methods alternative 
to the traditional oral or i.v. routes is still to be 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 doses of intrathecal Paracetamol 3% investigated in the present study, i.e. 60 mg, 90 mg 
and 120 mg, 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). The paracetamol doses of 
the present study are 8 – 17 times lower than the doses normally administered in humans by 
the oral or i.v. route for post-operative pain control. 
 
The study will be placebo-controlled.  
In the study two products (1. paracetamol/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.  
 
Each patient will be allocated to a treatment arm (one of the three paracetamol doses or 
placebo) according to a computer-generated randomisation list. 
 
The study will be double-blind. Neither the Investigator/co-investigators/study nurses 
involved in the clinical study procedures, nor will the patients be aware of the administered 
treatment. Syringes for injection will be prepared out of the operating room (in a curtain 
cubicle space) by a person not involved in any other study activity.  
 
Spinal anaesthesia will be performed according to the standard hospital procedures using 
Hyperbaric Bupivacaine (19). Bupivacaine is a well-known long-acting anaesthetic agent of 
the amide type for intrathecal (subarachnoid) anaesthesia, commonly used for urological and 
lower limb surgery lasting 1.5 - 3 hours and for abdominal surgery lasting 1.5 – 2 hours (20).  
 
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Paracetamol IT 
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In the present study the occurrence of 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 (defined as a decrease in systolic arterial blood 
pressure by approximately 30% or more from baseline values) and bradycardia (defined as 
heart rate decrease below 45 beats per minute) will be monitored throughout the study and if 
observed appropriately treated. 
 
Pre-medication with propofol will be performed in all patients to reduce possible anxiety 
before the operation. This is common clinical practice. 
 
 
 
 
 
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Paracetamol IT 
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5 
STUDY POPULATION 
 
5.1 
Target population 
 
Patients aged 18-80 years, scheduled for hip replacement surgery under spinal anaesthesia 
with anticipated need for post-operative narcotic analgesia, who have adequate i.v. access and 
anticipated hospital stay > 48 hours. 
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, patients must fulfil all these criteria: 
 
1. Informed consent: signed written informed consent before inclusion in the study 
2. Sex, age and surgery: male/female 18-80 years (inclusive) old patients, scheduled for hip 
replacement surgery, with anticipated need for post-operative narcotic analgesia, adequate 
i.v. access and anticipated hospital stay > 48 hours. 
3. Body Mass Index (BMI): 18 - 34 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 
 
Patients 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. Pain assessment: anticipated to be unable to make a reliable self-report of pain intensity 
5. Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol 
and/or amide type anaesthetics) and/or formulations’ ingredients or related drugs, opioids, 
non-steroidal anti-inflammatory drugs (NSAIDs); history of anaphylaxis to drugs or 
allergic reactions in general, which the investigator considers could affect the outcome of 
the study 
6. 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 asthma or 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. 
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7. Liver function: Impaired liver function (transaminases > twice upper limit) 
8. Renal function: Renal dysfunction (creatinine > 2.0 mg/dL) 
9. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study, calculated from the first day of the month following the 
last visit of the previous study 
10. Drug, alcohol: history of drug or alcohol abuse. Pre-existing dependence on narcotics or 
known tolerance to opioids 
11. Pregnancy and lactation: positive pregnancy test at screening, 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)] 
12. Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, 
anticonvulsant agents or chronic analgesic therapy). 
13. Medications: medication known to interfere with the extent of spinal block for 2 weeks 
before the start of the study. Paracetamol formulations, other than the investigational 
product, for 1 week before the start of the study and during the study. Hormonal 
contraceptives for females are allowed.  
 
5.3.1 
Not allowed treatments and other treatments 
 
No medication known to interfere with the extent of spinal block, in particular no therapeutic 
use of opioids, will be allowed for 2 weeks before the start of the study and during the whole 
study duration (except for those administered as part of the study).  
Paracetamol formulations, other than the investigational product, will not be allowed for 1 
week before the start of the study and during the study.  
Hormonal contraceptives for females are allowed.  
 
The area to be operated will be aseptically prepared with disinfectants, e.g. chlorhexidine, 
iodine-based disinfectants.  
 
After admission to the operating theatre and before the spinal punctures, patients will be pre-
medicated with propofol (1-2 mg/kg/h); in addition, an antibiotic will be administered. 
Ringer’s solution will be infused from the beginning of surgery until patient’s discharge from 
the recovery room. 
 
Post-operatively all patients will receive morphine via a PCA device with a standardised 
programme (1 mg/mL, 1-mg bolus, 5-min lock out time interval, no 4-h dose limit). If 
adequate pain relief is not achieved with the i.v. PCA device alone, supplemental rescue 
boluses of i.v. morphine or another analgesic (according to the Investigator’s opinion) will be 
administered as needed, according to the standard hospital procedures.  
 
 
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Final version 1.0, 01DEC15 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 12. 
 
6.1 
Study visits and procedures 
 
The study protocol foresees a screening visit, one study treatment for each patient, followed 
by a follow-up phase including an observation period, a final visit and a follow-up. A written 
informed consent will be obtained before any study assessment or procedure. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened 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 IT administration, anaesthesia and surgery 
 
 Follow-up phase  
 Visit 3 (Observation period) – from Day 1 after surgery 4 until eligibility for 
discharge: Efficacy and safety assessments 
 Final visit/early termination visit (ETV) and discharge. In case of early 
discontinuation, discontinued subjects will undergo an early termination visit (ETV) 
 Day 6±1 (i.e. 5±1 days after analgesic/anaesthetic IT injection and surgery) - Follow-
up 
 
 
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Paracetamol IT 
Final version 1.0, 01DEC15 
 
Day 
Procedures/Assessments 
Notes 
Screening - Visit 1 
From day -21 
 to day -1 
 
Explanation to the subject of study aims, 
procedures and possible risks 
 
Informed consent signature 
 
Screening number (as S001, S002, etc.) 
 
Demographic data and life style recording 
 
Previous/concomitant medications 
 
Routine pre-surgery assessments according to the 
hospital 
standard 
procedures, 
including 
medical/surgical history, pai history and intensity, 
physical examination, height, weight, vital signs 
(blood pressure, heart rate), ECG, SpO2 
 
Laboratory tests 
 
Urine pregnancy test for women, if applicable 
 
Inclusion/exclusion criteria evaluation 
 
AE monitoring 
 
Treatment - Visit 2 
Day 1 
 Concomitant medications 
 Adverse events (before, during and after block 
placement and surgery) 
 Inclusion/exclusion criteria evaluation 
 Subject randomisation 
 Vital signs, SpO2 and ECG (if foreseen by the 
standard hospital procedures) 
 Baseline pain assessment at rest using a 0-100 mm 
visual analogue scale (VAS) 
 Premedication:  
• Propofol 
• Antibiotic 
• Ringer’s solution (from surgery start to 
discharge from recovery room) 
 Paracetamol intrathecal injection 
 Anaesthesic intrathecal injection 
 Surgery 
Transfusion monitoring 
Follow-up Phase - Observation period – 
Visit 3 
Day 1 after 
surgery until 
eligibility for 
discharge 
 Post-recovery and hospital stay 
 Concomitant medications 
 Adverse events, including morphine related adverse 
events 
 Blood cell count (Day 2, morning)  
 Vital signs, SpO2 and ECG (if foreseen by the 
standard hospital procedures) 
 Pain assessment at rest at 1, 2, 3 h and every 3 h up 
to 48 h after anaesthetic IT injection 
 Morphine administration by PCA 
 Total amount of administered morphine recorded at 
24 h and 48 h 
 Additional post-operative analgesia, only if needed, 
according to the hospital standard procedures  
 Functional assessment (see § 7.3) 
 Blocks assessment (see § 7.4)  
Transfusion monitoring  
Standardised meals will 
be served according to 
the hospital procedures. 
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Paracetamol IT 
Final version 1.0, 01DEC15 
 
Day 
Procedures/Assessments 
Notes 
Follow-up Phase - Final Visit/ETV 
At discharge or 
upon 
discontinuation 
for ETV  
 Final assessments, including pain assessment at rest 
(0-100 VAS), before discharge according to the 
hospital’s standard procedures  
 Aldrete’s scoring scale 
 Vital signs (BP, HR, SpO2) and ECG (if foreseen 
by the standard hospital procedures) 
 Laboratory tests 
 Concomitant medications  
 Adverse events, including TNS (questionnaire)  
 Discharge (when criteria for discharge are met and 
according to the hospital’s standard procedures) 
 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator until 
the normalisation of the concerned clinical parameter(s) 
 
Follow-up Phase 
- Follow-up 
Day 6±1 
 Adverse events, including TNS (questionnaire)  
 Concomitant medications 
 
 
6.2 
Diet and lifestyle 
 
Study participants will follow 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 criteria for discharge, according to the hospital procedures.  
 
On Day 1, patients will be under fasting conditions before surgery. Clear fluids intake is 
allowed until 2 h before surgery. The patients will remain under fasting conditions according 
to the investigator’s opinion. Meals will be served according to the hospital’s standard 
procedures. 
 
 
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Final version 1.0, 01DEC15 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
Full physical examinations, including body weight and evaluation of the physical status 
according to ASA general relative values, will be performed at the pre-surgery (screening) 
visit.  
 
7.1.1 
Vital signs 
 
Patients’ blood pressure (BP), heart rate (HR) and peripheral oxygen saturation (SpO2) will be 
measured by the investigator or his/her deputy after 5 min at rest (sitting position) according 
to the hospital procedures.  
The following normal ranges for haemodynamic variables will be used: 
 
• 
Systolic Blood Pressure: 100-139 mmHg 
• 
Diastolic Blood Pressure: 50-89 mmHg 
• 
Heart Rate: 50-90 beats/min 
• 
Peripheral Oxygen Saturation: ≥ 95% 
 
SpO2 values < 95% but ≥ 92% will be considered not clinically significant. 
 
Haemodynamic variables (BP, HR and SpO2), will be recorded at screening, at baseline 
(before the spinal injection) then every 10 min from spinal injection until the end of the 
anaesthesia. Standard monitors will be used according to ASA recommendations. SpO2 
should be ≥ 92% during the monitoring period. 
Blood pressure, heart rate and SpO2 will be monitored also at post-operative recovery and 
final visit. To meet criteria for discharge, the patients’ haemodynamic variables must be stable 
and SpO2 must be acceptable (> 92%). 
 
Screening, baseline and final/early termination assessments of haemodynamic variables and 
any other assessment judged clinical significant will be reported into the CRF. 
 
Occurrence of clinically relevant hypotension (defined as a decrease in systolic arterial blood 
pressure by approximately 30% or more from baseline values) and bradycardia (defined as 
heart rate decrease below 45 beats per minute) will be monitored throughout the study and if 
observed appropriately treated. 
 
7.1.2 
ECGs 
 
ECG will be performed at screening and, if foreseen by standard hospital procedures, will be 
monitored using standard monitors at baseline (before block placement), during the block 
(every 10 min) and at post-operative recovery / final visit  
 
The following normal ranges for ECG parameters will be used: 
 
• 
Heart Rate: 50-90 beats/min 
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Final version 1.0, 01DEC15 
• 
PR Interval: 100-220 msec 
• 
QRS Duration: ≤ 120 msec 
• 
QT Interval: ≤ 500 msec 
 
Any assessment judged as clinical significant will be reported in the CRF. 
 
7.2 
Clinical laboratory assays 
 
Samples of blood will be collected. The following laboratory analyses will be performed at 
screening and before discharge (final visit). 
 
HAEMATOLOGY 
Leukocytes, erythrocytes, haemoglobin (conv. units), haemoglobin (IS units), haematocrit, 
MCV, MCH, MCHC, thrombocytes. 
 
BLOOD CHEMISTRY 
Electrolytes: sodium, potassium 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: creatinine, fasting glucose 
 
At screening, a urine pregnancy test will be performed, if applicable (see § 5.3).  
 
In the morning of the post-operative day (day 2), blood cell count will be repeated. 
 
7.2.1 
Transfusion monitoring 
 
If the surgeon/investigator determines that a patient’s operation may require a blood 
transfusion, the transfusion will be performed and monitored according to the standard 
hospital procedures. 
Blood transfusion and transfused blood volume will be recorded in the patient’s source 
documents. 
 
7.2.2 
Assessment of treatment-emergent adverse events 
 
7.2.2.1 
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 follow-up (day 6±1).  
 
Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.  
 
Any complication during anaesthesia, e.g. paraesthesia and micturition disorders, will be 
recorded. Pain at the site of injection will be recorded as adverse event. 
Pain at the site of surgery will not be recorded as an adverse event (see § 7.6, Pain intensity). 
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Paracetamol IT 
Final version 1.0, 01DEC15 
 
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 signs of systemic (central nervous system) toxicity. 
 
7.2.2.2 
Morphine-related adverse events 
 
The following morphine-related adverse events will be carefully monitored: 
 
 
Diffuse pruritus,  
 
Overt respiratory depression requiring treatment,  
 
Post-operative vomiting or need for anti-emetic medication,  
 
Sedation, defined as score ≤ -3 on the Richmond Agitation Sedation Scale score (RASS) 
(23, 24) 
 
A Combined Safety Assessment (defined as the summary of the binary occurrences of any of 
the events listed above during the first 48 h) will be computed. 
 
7.2.2.3 
Transient neurological symptoms 
 
Attention will be given to the possible occurrence of transient neurological symptoms (TNS). 
In particular the incidence of TNS and unusual sensations not associated to the operation area 
will be assessed at day 6±1 (i.e. 5±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 
 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 
 
The questionnaire will be reviewed by the investigator who will judge whether the reported 
symptoms could be classified as TNS on the basis of the available evidence and referring to 
the diagnosis criteria reported by Pollock et al. (25) and ASA, and summarised in the table 
below: 
 
 
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Paracetamol IT 
Final version 1.0, 01DEC15 
 
Table 7.2.2.1 
Differential diagnosis criteria for TNS and other events following intrathecal injection 
Event 
Onset – Duration 
Symptoms 
Treatment 
TNS 
6-36 h after spinal or 
epidural 
anaesthesia/1-7 
days 
Unilateral or bilateral 
pain in the anterior or 
posterior thigh ± 
extension into legs ± back 
pain 
No motor weakness 
No neurological 
abnormalities 
NSAIDs, opioids, warm 
heat, trigger-point 
injections 
Epidural haematoma 
0 - 2 days 
Muscle weakness, 
radicular back pain, 
sensory deficit 
CT scan, neurological 
consult, surgical 
decompressive 
laminectomy 
Epidural abscess 
2 - 7 days 
Backache, progressive 
neurological symptoms ± 
fever 
Antibiotics, possible 
surgical drainage 
Spinal nerve injury 
0 - 2 days/1 - 12 weeks 
Pain during insertion of 
needle or catheter, pain 
on injection, paraesthesia, 
pain and numbness over 
distribution of nerve root 
May need EMG to assess 
baseline neurological 
status 
Anterior 
spinal 
artery 
syndrome 
Immediate 
Postoperative painless 
paraplegia 
If secondary to 
vasospasm may respond 
to vasodilating drugs and 
hypertensive therapy 
Adhesive arachnoiditis 
0 months 
Pain on injection, variable 
degree of neurological 
deficit, often progressive, 
with pain and paraplegia 
Diagnosis by CT, MRI or 
myelography. No 
effective treatment 
Cauda equine syndrome 
0 days 
Loss of bowel and 
bladder function, 
paraplegia, motor 
weakness, sensory loss 
No effective treatment 
 
7.3 
Functional assessment 
 
The following functional assessment parameters, reflecting post-operation recovery status, 
will be verified: 
 
 Nocturnal awakenings due to pain (number of events, proportion of patients): 
spontaneously reported by the patient or reported by the patient upon investigator’s 
questioning each morning 
 Time to GI motility (return of bowel sounds, flatulence or bowel movement): assessed by 
the Investigator every 6 h starting from the end of surgery 
 Need for postoperative urinary indwelling catheter after initial removal of surgical 
catheter (proportion of patients) 
 Time to resumption of ambulation (from the end of surgery) 
 Time to resumption of liquid intake and solid diet (from the end of surgery) 
 Time to home discharge (Length of hospital stay) (from the end of surgery) 
 
Results of the assessments will be recorded on the individual CRF. 
 
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7.4 
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) (15 min when the patient is in the recovery room) and then every 30 min until 
regression of spinal block and complete regression of sensory block to S1.  
 
Sensorial block will be verified by bilateral Pinprick test using a 20-G hypodermic needle and 
will be recorded. Pinprick sensation will be scored as being present (score 1) or absent (score 
0). 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. 
 
Readiness for surgery is defined as the presence of an adequate motor block (Bromage’s 
score ≥ 2) and loss of Pinprick sensation. 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 the time when Bromage score returns to 0 and sensitive perception returns to S1), 
will be reported in the CRF. Start time and end time of surgery will also be recorded.  
 
7.5 
Post-operative pain control 
 
7.5.1 
Morphine administration 
 
Postoperatively, all patients will have access to morphine via a PCA device with a 
standardised programme (1 mg/mL, 1-mg bolus, 5-min lock out time interval, no 4-h dose 
limit).  
Time of first morphine use will be recorded.  
In the morning of the first postoperative day (24 h post-dose) after completion of the routine 
nursing activities, the PCA device will be temporarily discontinued and the total amount of 
morphine administered to the patient recorded. Total amount of administered morphine via 
the PCA device will also be recorded at 48 h and for the entire study period. 
Morphine administration through the PCA device will be disconnected at 48 h after spinal 
administration only if pain VAS score is ≤30 mm. 
 
 
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7.5.2 
Additional post-operative pain control 
 
If adequate pain relief is not achieved with the i.v. PCA device alone, supplemental rescue 
boluses of i.v. morphine or another analgesic (according to the Investigator’s opinion) will be 
administered as needed, according to standard hospital procedures.  
 
Time when additional analgesia is required will be noted. The analgesic used and its dosage 
will be recorded in the CRF.  
 
7.6 
Pain intensity at rest 
 
Pain intensity at rest, at the site of surgery, will be assessed by the patients using a 0-100 mm 
visual analogue scale (VAS) at the following time-points: 
 
 Screening, baseline (0 h), 1, 2, 3 h and then every 3 h up to 48 h after anaesthetic IT 
injection and at discharge. 
 
VAS scores will be measured and reported in the CRF by the Investigator or his/her deputy.  
The primary efficacy measures will be the VAS scores at each predefined time-point. 
 
VAS assessment times should not deviate more than the recommended tolerance ranges 
summarised in the following table. 
 
Table 7.6.1 
Recommended tolerance ranges for the scheduled VAS assessment times 
VAS assessment times 
Tolerance ranges 
Screening 
Not applicable 
Baseline (0 h) 
Within 30 min before the anaesthetic IT injection 
1, 2, 3 hours after anaesthetic IT injection 
± 5 min 
6, 9, 12 hours after anaesthetic IT injection 
± 10 min 
15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45 and 48 hours 
after anaesthetic IT injection 
± 30 min 
Discharge 
Not applicable 
 
Any deviations from the scheduled VAS assessment times outside the tolerance ranges will be 
verified through Data Clarification Forms. 
 
7.7 
Procedures for discharge 
 
At the end of the surgical procedure, patients will be moved to the post-operative recovery 
room, where they will be monitored.  
 
Patients will then be moved from the recovery room to a hospital room when the following 
criteria are met (internal hospital procedure): 
a) Blood pressure and heart rate: ± 20% baseline values 
b) SpO2: > 92% 
c) No bleeding 
d) No pain (evaluated on a 0-100 mm VAS) 
e) No nausea or vomiting 
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f) Patient must be conscious 
 
Patients typically stay in the hospital for 4-5 days after surgery but this will vary depending 
on how quickly they progress. Patients will be discharged according to the investigator’s 
opinion and standard hospital procedures. A score ≥ 18 on the modified Aldrete’s scoring 
scale (26; Appendix 18.2) is generally required. Haemodynamic variables must be stable and 
SpO2 must be acceptable (> 92%) without oxygen therapy.  
Patients will be asked about any adverse events, with particular attention to local toxicity and 
neurological symptoms, such as paraesthesia of the gluteus and of the lower limb, and to 
possible allergic reactions (e.g. urticarial). If all the criteria are met and no adverse reactions 
occur, the patient will be discharged according to the hospital’s standard procedures. 
 
 
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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 
 
Patients will be allocated to D1, D2, D3 or P dose group in a 1:1:1:1 ratio according to the 
study randomisation list.  
 
Randomisation number will be given to the patients on study Day 1 and will be used to 
allocate each patient to a dose group, as detailed above. 
 
The 5-mL ampoules with the investigational products will be numbered. Each patient will be 
allocated the product ampoule corresponding to his/her randomisation number. 
 
All patients will receive Hyperbaric Bupivacaine HCl 0.5% as spinal anaesthetic before the 
surgical procedure (§ 3.1.1.3) 
 
8.3 
Blinding 
 
This is a double-blind study. Both the Investigator and the patients will not be aware of the 
treatment administered. 
 
Three (3) copies of the list will be generated and sealed in individual envelopes: 
 one copy is sent to the manufacturer for the preparation of the individual treatment boxes 
 one copy is kept at the CRO Quality Assurance Unit 
 one copy is stored in the statistical study file 
 
Neither the members of the clinical staff nor the CPL or the CRA/monitor, monitoring the 
study evaluations and procedures, will have access to the randomisation code.  
Only the person preparing the syringe (and not involved in any other study procedure) and the 
CRA/monitor who performs the drug accountability will be aware of the administered 
treatments. 
The CRO will open the envelope containing the randomisation list only when data-entry is 
complete and decisions to be made in blinding, before data analysis, are final.  
 
The CRO will notify breaking of the randomisation list to the sponsor. 
 
Syringes for injection will be prepared out of the operating room by a person not involved in 
any other study activity.  
 
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8.3.1 
Emergency code and unblinding procedures 
 
Unblinding of the code for specific patients will be fully documented in the source 
documents, in the CRFs and in the clinical study report. 
 
8.3.2 
Individual emergency envelopes 
 
The emergency envelopes containing the individual randomisation codes will be sent to the 
clinical 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 on the CRF and on the 
envelope. All envelope sets containing the randomisation code of each patient must be kept 
closed even after database lock. At the end of the study, all envelope sets will be sent to the 
sponsor. 
 
8.3.3 
Individual kit replacement envelopes 
 
The clinical centres will also receive individual kit replacement envelopes. If a reserve kit 
needs to be used, the kit replacement envelope will be opened and the injectable solution will 
be prepared out of the 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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9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary efficacy variable 
 
The primary efficacy variables will be the VAS scores at each predefined time-point. 
 
Pain at rest VAS scores will be recorded at screening, baseline (0 h), 1, 2, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, 33, 36, 39, 42, 45 and 48 h after anaesthetic IT injection and at discharge, 
using a 0-100 mm VAS.  
 
9.1.2 
Secondary efficacy variables 
 
 
Pain at rest VAS scores AUCt1-t2 (0-12h, 12-24h, 24-48h [if applicable] intervals), where 
AUCt1-t2 is defined as the area under the pain intensity curve at the specified time-
intervals 
 
Total morphine use in the first 24 h, in the first 48 h and in the entire study period 
 
Time to first morphine use 
 
Proportion of patients requiring supplementary analgesia, i.e. analgesia other than the 
planned morphine PCA (i.e. other narcotic or analgesic)   
 
Time to first supplementary analgesia, i.e. analgesia other than the planned morphine 
PCA (i.e. other narcotic or analgesic)   
 
Functional assessment variables (reflecting post-operation recovery status): 
o 
Nocturnal awakenings due to pain (number of events, proportion of patients) 
o 
Time to GI motility (every 6 h; return of bowel sounds, flatulence or bowel 
movement) 
o 
Need for postoperative urinary indwelling catheter after initial removal of surgical 
catheter (proportion of patients) 
o 
Time to resumption of ambulation 
o 
Time to resumption of liquid intake and solid diet 
o 
Time to home discharge (Length of hospital stay) 
 
Morphine-related adverse events:  
o 
Diffuse pruritus,  
o 
Overt respiratory depression requiring treatment,  
o 
Post-operative vomiting or need for anti-emetic medication,  
o 
Sedation, defined as score ≤ -3 on the Richmond Agitation Sedation Scale (RASS) 
(see Appendix 18.3) 
o 
Combined Safety Assessment (defined as the summary of the binary occurrences of 
any of the events listed above during the first 48 h) 
 
Time to onset of spinal block (i.e. time to readiness for surgery) 
 
Maximum level of sensory block 
 
Time to maximum level of sensory block 
 
Time to regression of spinal block 
 
 
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9.1.3 
Safety variables 
 
 
Treatment-emergent adverse events including morphine-related adverse events (see 
efficacy variables) 
 
Incidence of transient neurologic symptoms (TNS) at day 6±1 (i.e. 5±1 days after 
analgesic/anaesthetic IT injection and surgery) 
 
Vital signs (blood pressure [BP], heart rate [HR] and peripheral oxygen saturation 
[SpO2]) and ECG 
 
Concomitant medications 
 
Laboratory tests parameters 
 
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 morphine-related TEAEs 
and to TNS symptoms. Further details on the AE assessments are given in § 7.2.2.  
 
ECG (if foreseen by the standard hospital procedures), blood pressure, heart rate and SpO2 
will be monitored as detailed in § 7.1.1 and 7.1.2.  
Occurrence of clinically relevant hypotension or bradycardia will be monitored throughout the 
study and, if observed, treated according to the hospitals’ standard procedures.  
 
Safety laboratory tests will be performed at screening, on the post-operative day (blood cell 
count) and at final visit according to the standard hospital procedures. 
Concomitant medication intake will be recorded. 
 
In addition to the assessments listed above, patients will be monitored for transfusion need, as 
detailed in § 7.2.1. 
 
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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, 
baseline and background characteristics. 
 Full Analysis Set (FAS): all randomised patients who fulfil the study protocol 
requirements in terms of investigational product (i.e. paracetamol/placebo) and 
anaesthetic administration and have at least one post-baseline assessment of the primary 
efficacy evaluation (i.e. pain at rest). This analysis set will be used for 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, anaesthetic administration and primary efficacy 
evaluation (i.e. 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. 
 
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Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Enrolled 
set, FAS, PP set and Safety set. Subjects will be evaluated according to the treatment they 
actually receive (Enrolled set, FAS, PP set and Safety set). 
 
10.1.2 
Reasons for exclusion from the Full Analysis Set  
 
Reasons for the exclusion from the Full Analysis Set are the following: 
 
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 (15 patients per dose group), aged 18-80 years, 
scheduled for hip replacement surgery under spinal anaesthesia with anticipated need for post-
operative narcotic analgesia, who have adequate i.v. access and anticipated hospital stay > 48 
hours will be enrolled in order to have 15 treated patients per treatment group. 
 
The sample size for the study is not based on any formal sample size calculation. The number 
of 15 treated patients/treatment group 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/evaluation 
interval (if applicable) and will be summarised by treatment group and assessment time 
point/evaluation interval (if applicable) using classic descriptive statistics (i.e. mean, SD, 
CV%, min, median and max) for quantitative variables and tables of frequencies for 
qualitative variables. Summarisation will be performed on the Per Protocol Set and on the 
Full Analysis Set. 
 
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10.4.1 
Primary efficacy analysis 
 
The primary efficacy analysis will be performed on the Per Protocol Set. 
Pain at rest will be analysed using a 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 (120 mg) 
2. P vs. D2 (90 mg) 
3. P vs. D1 (60 mg) 
4. D1 (60 mg) vs. D3 (120 mg) 
5. D2 (90 mg) vs. D3 (120 mg) 
6. D1 (60 mg) vs. D2 (90 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 
 
All the analyses on the secondary variables will be performed with a nominal two-sided type I 
error α = 0.05.  
 
The same pairwise comparisons foreseen for the primary variable will be performed. 
 
 
Pain at rest will be analysed using a repeated measures ANCOVA with baseline pain at 
rest as covariate and treatment, assessment time point and treatment*assessment time 
point as fixed effect. 
 
Pain at rest VAS scores AUCt1-t2 (0-12h, 12-24h, 24-48h intervals) will be analysed 
using a rank-transformed ANOVA with treatment as fixed effect. Different analyses 
will be performed for the AUCt1-t2 (0-12h), AUCt1-t2 (12-24h) and AUCt1-t2 (24-48h). 
 
Pain at rest VAS scores AUCt1-t2 (0-12h, 12-24h, 24-48h intervals) will be analysed 
using an ANOVA with treatment as fixed effect. Different analyses will be performed 
for the AUCt1-t2 (0-12h), AUCt1-t2 (12-24h) and AUCt1-t2 (24-48h) 
 
Total amount of morphine used in the first 24 h, in the first 48 h and in the entire study 
period will be analysed using a rank-transformed ANOVA with treatment as fixed 
effect. Different analyses will be performed for the amount used in the first 24 h, in the 
first 48 h and in the entire study period. 
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 
Total amount of morphine used in the first 24 h, in the first 48 h and in the entire study 
period will be analysed using an ANOVA with treatment as fixed effect. Different 
analyses will be performed for the amount used in the first 24 h, in the first 48 h and in 
the entire study period. 
 
Time to first morphine use will be presented using Kaplan-Meier curves and will be 
compared between treatment groups by log-rank test. 
 
Proportion of patients in need of narcotics other than morphine or in need of other 
rescue analgesics will be compared between treatment groups by Fisher's exact test. 
 
Time to first subsequent analgesia (narcotic or NSAIDs) will be presented using 
Kaplan-Meier curves and will be compared between treatment groups by log-rank test. 
 
Proportion of patients with nocturnal awakenings due to pain will be compared between 
treatment groups by Fisher's exact test. The same pairwise comparisons foreseen for the 
primary variable will be performed. 
 
Number of nocturnal awakenings due to pain will be compared between treatment 
groups by Wilcoxon rank-sum test. 
 
Time to GI motility will be presented using Kaplan-Meier curves and will be compared 
between treatment groups by log-rank test. 
 
Proportion of patients who need postoperative urinary indwelling catheter after initial 
removal of surgical catheter will be compared between treatment groups by Fisher's 
exact test. 
 
Time to resumption of ambulation will be presented using Kaplan-Meier curves and 
will be compared between treatment groups by log-rank test. 
 
Time to resumption of liquid intake and solid diet will be presented using Kaplan-Meier 
curves and will be compared between treatment groups by log-rank test. 
 
Time to home discharge will be presented using Kaplan-Meier curves and will be 
compared between treatment groups by log-rank test. 
 
Proportion of patients with morphine-related adverse events will be compared between 
treatment groups by Fisher's exact test. 
 
Time to onset of spinal block will be presented using Kaplan-Meier curves and will be 
compared between treatment groups by log-rank test.  
 
The maximum level of sensory block will be compared between treatment groups by 
Wilcoxon rank-sum test. 
 
Time to maximum level of sensory block will be presented using Kaplan-Meier curves 
and will be compared between treatment groups by log-rank test. 
 
Time to regression of spinal block will be presented using Kaplan-Meier curves and will 
be compared between treatment groups by log-rank test. 
 
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:  
• 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 
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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 study drug (IMP) 
• Other causal relationship 
 Not applicable 
 Relationship to study anaesthetic (NIMP) 
 Relationship to morphine 
 Other 
 
 Morphine-related adverse events 
The occurrence of diffuse pruritus, overt respiratory depression requiring treatment, post-
operative vomiting and need for anti-emetic medication or sedation will be summarised by 
treatment group and overall using tables of frequency. 
The scores of the combined safety assessment (0, 1, 2, 3 and 4) will be summarised by 
treatment group and overall using tables of frequency. 
 
 Physical examination 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see § 11), will be recorded in the subject source documents. Overall investigator’s 
interpretation (as normal, abnormal not clinically significant [NCS] or abnormal clinically 
significant [CS]) will be reported in the CRF. 
 
 Vital signs 
Screening, baseline and final/early termination assessments of haemodynamic variables and 
any other assessment judged clinical significant will be reported in the CRF and listed in the 
clinical study report. Screening, baseline and final/early termination values of vital signs will 
be summarised by descriptive statistics.  
 
 Body weight  
Values of body weight will be listed and summarised by descriptive statistics. 
 
 ECG 
Any ECG assessment judged clinical significant will be reported into the CRF. 
Date/time of ECG recording, overall investigator’s interpretation (as normal, abnormal not 
clinically significant [NCS] or abnormal clinically significant [CS]) and HR, PR, QRS and 
QT parameters will be reported in the CRF and listed in the clinical study report. Hard copies 
of the ECGs will be attached to the CRF. All clinically significant abnormalities after the 
screening visit will be recorded as AEs.  
 
 
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 Laboratory data  
Date/time of samples collection and overall investigator’s interpretation (N, NCS, CS) will be 
recorded in the CRF and listed in the final report. Hard copies of the laboratory printouts will 
be attached to the CRF. 
Laboratory data will be inserted into the clinical database and listed in the final report. 
 
 Incidence of TNS at day 6±1 
The incidence of TNS at day 6±1 (i.e. 5±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 and of morphine will be used. 
 
 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An ADR that is both unexpected (not consistent with the RSI) and also meets the definition of 
a SAE. 
 
11.3 
AEs monitoring window 
 
 Start of monitoring: from immediately after the signature of the informed consent 
 End of monitoring: last follow-up visit/ETV  
An AE occurring after the last follow-up visit/ETV and coming to knowledge of the 
investigator (e.g. by spontaneous reporting by study subjects) must be recorded only if it is an 
ADR, according to the investigator’s judgment. 
 
11.4 
AEs recording 
 
All AEs derived by spontaneous, unsolicited reports of the subjects, by observation and by 
routine open questioning should be collected and reported. 
The following minimal information will be recorded for an AE (detailed explanation for each 
element is available in the SOP or in the operative summary made available to the clinical 
centre) in the source documents and later transcribed into the CRF: 
 
1. 
Adverse Event: progressive number of the adverse event  
2. 
Description: verbatim description of the adverse event or  
 
Follow-up: progressive number of follow-up of the adverse event  
3. 
Start Date/Time: start date/time of the adverse event or  
 
Follow-up Date/Time: follow-up date/time of the adverse event  
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4. 
End Date/Time: end date/time of the adverse event  
5. 
Affected Body Area: anatomical location relevant for the event 
6. 
Whether the adverse event start before or after the first intake of the study drug or 
whether the adverse event has worsened or not after the first intake of the study drug 
7. 
Last Study Drug Administration Date/Time Before Onset: if the adverse event started 
after the first administration of the study drug, the date/time of last administration of the 
study drug before the onset of the adverse event or 
Last Study Drug Administration Date/Time Before Worsening: In case of treatment 
emergent adverse event, the date/time of the last administration of the study drug(s) 
before the worsening of the adverse event.  
8. 
Investigator's opinion about the reasonable possibility of a causal relationship with the 
study drug.  
9. 
Investigator's opinion about other causal relationship (e.g. non study drug, concomitant 
therapy, study device, etc.).  
10. 
Severity: the severity or intensity of the event 
• 
1 Mild  
• 
2 Moderate 
• 
3 Severe 
11. 
Pattern: Used to indicate the pattern of the event over time 
• 
1 Single Event 
• 
2 Continuous 
• 
3 Intermittent 
12. 
Serious Adverse Event  
13. 
Action Taken with Study Drug: describes changes to the study drug as a result of the 
event. It is specifically for actions taken with the study drug 
• 
1 Dose Not Changed 
• 
2 Dose Increased 
• 
3 Dose Reduced 
• 
4 Drug Interrupted (i.e. temporary stop) 
• 
5 Drug Withdrawn (i.e. definitive stop) 
• 
6 Not Applicable (e.g. drug administration not started yet or completed) 
• 
7 Unknown 
14. 
Concomitant Therapy: if a concomitant therapy is given, it must be reported in the 
specific CRF forms 
15. 
Study Discontinuation: if the adverse event cause the subject to be discontinued from 
the study 
16. 
Other Action Taken: other actions taken as a result of the event that are unrelated to 
dose adjustments of study drug 
17. 
Outcome: Outcome of the event 
• 
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 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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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.3/02-2015), 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 § 
16.4).  
 
Two monitors will be involved at each centre: one monitor will perform the checks of the 
study evaluations and procedures and will not be involved in the drug accountability. 
A second independent monitor will be defined before the start of the study and will be 
responsible of performing the drug accountability. He/she will not be involved in other 
monitoring activities. This will be done to safeguard the double-blind. Due care will be 
applied in order to avoid any disclosure of unblind 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.  
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorised individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOA principles (Attributable-Legible-
Contemporaneous-Original-Accurate). 
 
The clinical centre is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirement(s). 
 
The CRO and the sponsor will be responsible 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 inspection. 
 
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 investigators agree, by written consent to this protocol, to fully co-operate and support 
audits and inspections compliance checks by allowing authorised individuals to have access to 
all the study documentation. 
 
 
 
 
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14 
ETHICAL CONSIDERATIONS 
 
14.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the relevant Ethics Committee and by the Federal 
Health Authority (Swissmedic) will be obtained before the start of the study.  
 
The present clinical study will be carried out according to the general principles of “ICH 
Topic E6, CPMP/ICH/135/95”, July 1996 including post Step 4 errata, status September 1997 
and post Step errata (linguistic corrections), July 2002. 
 
14.2 
Informed consent 
 
Before being enrolled 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 regulation and with the requirements of 
the Health Authorities. 
 
14.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a 
subject, study treatment or observations are discontinued, the type of discontinuation and the 
primary reason for discontinuation will be recorded. 
 
14.4.1 
Discontinuation type 
 
 Discontinuation from data collection: the subject discontinues from the collection of 
primary and secondary end-points 
 discontinuation from interventions and data collection: the subject discontinues from 
the intake of the IMP(s) and/or NIMP and from the collection of primary and secondary 
end-points 
 
14.4.2 
Primary reason for discontinuation 
 
 Adverse event: Any significant adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 11.2. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by sponsor: an indication that a clinical study was stopped by its 
sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
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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 information leaflet 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 concerned Competent Authority, according to the 
current regulations in Switzerland. 
 
The amendment will be applicable only when it is approved by the concerned authorities, 
unless the changes consist of urgent safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
15.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 
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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects including lab tests and ECG tracing, insurance contracts, certificate of analysis of the 
IMP(s), drug accountability records, signed informed consent forms, confidential subjects 
identification code, CRFs, curricula vitae of the investigator and other participants in the 
study, study staff lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the sponsor agree to adhere to these requirements. 
 
15.4 
Study subjects’ recruitment 
 
Study participants will be recruited at the clinical centre among the patients attending the 
clinic for hip replacement surgery.  
 
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 
his/her staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected 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. 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
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As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual 
property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 
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16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Sintetica SA, Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: 
+41.91.640.42.50 
Fax: 
+41.91.646.85.61 
 
Sponsor representatives  
Clinical Project Leader 
Elisabetta Donati, Corporate Director Scientific Affairs 
Email: 
edonati@sintetica.com 
 
Medical Expert 
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 and coordinating investigator in Switzerland 
Claudio Camponovo, MD. Chairman of the Department of Anaesthesiology  
Email: 
ccamponovo@arsmedica.ch 
 
16.3 
Clinical laboratory 
 
Synlab Suisse, Via Vira 1, 6942 Savosa, Switzerland 
Phone: 
+41.91.9735620 
Fax: 
+41.91.9711706 
Email: 
info.ticino@synlab.com 
 
Synlab Savosa has an operative laboratory within Clinica Ars Medica, and all analyses will be 
performed at the clinic. 
 
16.4 
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 Reserach S.A., Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.6300510 
Fax: 
+41.91.6300511 
 
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Coordination 
Angelo Vaccani, Clinical Project Leader 
Email: 
projectmanagement@croalliance.com 
 
Medical Writing Unit Representative 
Chiara Leuratti, Medical Writing Manager, Unit Head 
Email: 
medicalwriting@croalliance.com 
 
Biometry Unit Representative 
Matteo Rossini, Biometry Manager, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Mario Corrado, Quality Assurance Manager, Unit Head 
Email: 
qau@croalliance.com 
 
Monitoring 
Chiara Castiglioni, Clinical Research Associate and Clinical Trial Assistant 
Email: 
projectmanagement@croalliance.com 
 
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17 
REFERENCES 
1. Toussaint K, Yang XC, Zielinski MA, Reigle KL, Sacavage SD, Nagar S, Raffa RB. What do we (not) 
know about how paracetamol (acetaminophen) works? J Clin Pharm Ther. 2010 Dec;35(6):617-38. doi: 
10.1111/j.1365-2710.2009.01143.x. 
2. Prescott LF. Paracetamol: past, present, and future. Am J Ther 7, 143-147, 2000 
3. Toms L, McQuay HJ, Derry S, Moore RA.. Single dose oral paracetamol (acetaminophen) for postoperative 
pain 
in 
adults. 
Cochrane 
Database 
Syst 
Rev. 
2008 
Oct 
8;(4):CD004602. 
doi: 
10.1002/14651858.CD004602.pub2. 
4. Investigator’s Brochure. Paracetamol 3% solution. First Edition, Final version 1.0, December 2015 
5. Paracetamol Sintetica. Information professionnelle du Compendium Suisse des Médicaments®. Sintetica 
S.A., Switzerland. March 2013 
6. PERFALGAN 10 mg/ml, solution for infusion. Bristol-Myers Squibb Pharmaceuticals Ltd, UK. 21 
November 2013 
7. Flouvat B, Leneveu A, Fitoussi S, Delhotal-Landes B, Gendron A. Bioequivalence study comparing a new 
paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects. Int 
J Clin Pharmacol Ther 42, 50-57, 2004 
8. Chiam E, Weinberg L, Bellomo R. Paracetamol: a review with specific focus on the haemodynamic effects 
of intravenous administration. Heart Lung Vessel. 2015;7(2):121-32. 
9. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of 
single and repeated administration of 1 g intravenous acetaminophen injection (paracetamol) for pain 
management after major orthopaedic surgery. Anesthesiology 102, 822-831, 2005 
10. Sintetica S.A. Injectable supersaturated acetaminophen solution for spinal administration. Patent 
WO2014002042 A1, Filing date 27 June 2013; Publication date 03 January 2014. Also published as 
CA2876801A1, CN104487051A, EP2874602A1, US20150148379.  
11. Machino M1, Yukawa Y, Hida T, Oka Y, Terashima T, Kinoshita S, Kato F. A prospective randomized 
study for postoperative pain relief of lower extremity fractures: efficacy of intrathecal morphine 
administration. Nagoya J Med Sci. 2010 Aug;72(3-4):145-50. 
12. Gandhi K and Viscusi E. Multimodal pain management techniques in hip and knee arthroplasty. J NY 
School Reg Anaest 2009;13:1-10. 
13. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-
selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after 
major surgery: a systematic review. Br J Anaesth. 2011 Mar;106(3):292-7. doi: 10.1093/bja/aeq406. 
14. Apfel CC, Turan A, Souza K, Pergolizzi J, Hornuss C. Intravenous acetaminophen reduces postoperative 
nausea and vomiting: a systematic review and meta-analysis. Pain. 2013 May;154(5):677-89. doi: 
10.1016/j.pain.2012.12.025. Epub 2013 Jan 11. 
15. Report on file. Dose-effect of Sintetico following spinal administration in a post-operative pain model. 
Russo R and Calignano C. Pharmacy Dept, University of Naples “Federico II”, Napoli, Italy. 18NOV2013 
16. 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 
17. 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 
18. 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 
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Sponsor code PAR.3/02-2015 
Paracetamol IT 
Final version 1.0, 01DEC15 
19. BUPIVACAIN 0.5 % hyperbar Sintetica. Information professionnelle du Compendium Suisse des 
Médicaments®. Sintetica S.A., Switzerland. June 2012 
20. Sintetica S.A., Switzerland.Marcain Heavy, 0.5% solution for injection. Summary of Product 
Characteristics. AstraZeneca UK Limited. Updated 23 March 2015 
21. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the 
European Community, Volume 4 
22. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: Dietary Guidelines for Americans, 2010 
23. Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, 
Margolin R, Sessler CN, Dittus RS, Bernard GR. Monitoring sedation status over time in ICU patients: 
reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003 Jun 
11;289(22):2983-91. 
24. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The 
Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J 
Respir Crit Care Med. 2002 Nov 15;166(10):1338-44. 
25. 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 
26. Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth. 1995 Feb;7(1):89-91. 
27. SAS/STAT® User’s Guide 
28. Phoenix WinNonlin® version 6.3 Getting Started Guide, Pharsight Corporation 
 
 
 
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Paracetamol IT 
Final version 1.0, 01DEC15 
18 
APPENDICES 
 
18.1 
TNA questionnaires 
 
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18.2 
Modified Aldrete score scale 
 
 
 
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18.3 
Richmond Agitation-Sedation Scale 
 
Score 
Classification 
(RASS) 
4 
Combative 
Overtly combative or violent; immediate danger to staff 
3 
Very agitated 
Pulls on or removes tube(s) or catheter(s) or has aggressive 
behavior toward staff 
2 
Agitated 
Frequent nonpurposeful movement or patient–ventilator 
dyssynchrony 
1 
Restless 
Anxious or apprehensive but movements not aggressive or 
vigorous 
0 
Alert and calm 
 
-1 
Drowsy 
Not fully alert, but has sustained (more than 10 seconds) 
awakening, with eye contact, to voice 
-2 
Light sedation 
Briefly (less than 10 seconds) awakens with eye contact to 
voice 
-3 
Moderate sedation 
Any movement (but no eye contact) to voice 
-4 
Deep sedation 
No response to voice, but any movement to physical 
stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
From: Sessler CN et al. Am J Resp Crit Care Med. 2002;166(10):1338-1344.  
Ely EW et al.. JAMA. 2003;289(22):2983-91. 
 
 
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