Pudendal Nerve Block in Patient Treated for Hemorrhoidectomy Under Spinal Anaesthesia: Prospective Randomized Double-blind Controlled Trial
Phase: NA
Conditions: Hemorrhoids, Postoperative Pain
Sponsor: Francesco Mongelli

2017-00769, Version 1.2, 8.10.2018 
 
Page 1 of 35 
Pudendal nerve block in patient treated for 
hemorrhoidectomy under spinal anaesthesia: prospective 
randomized single blind controlled trial 
 
 
 
 
Clinical Study Protocol 
 
 
 
Pudendal nerve block in patient treated for hemorrhoidectomy under spinal anaesthesia: 
prospective randomized single blind controlled trial 
 
 
Pudendal nerve block for hemorrhoidectomy 
 
 
 
Study Type: 
Prospective randomized single blind controlled trial 
Study Categorisation: 
altre sperimentazioni cliniche secondo OSRUm cap. 4 
Study Registration: 
2017-00769 
Study Identifier: 
CE TI 3222 
Sponsor, Sponsor-Investigator or 
Principal Investigator: 
Dr. Med Davide La Regina, viceprimario Chirurgia 
ORBV, Bellinzona (GPC statement levels I and II done) 
Investigational Product: 
None 
Protocol Version and Date: 
Version 1.2, 8.10.2018 
 
 

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Signature Page(s)  
 
Study number 
2017-00769 
Study Title 
Pudendal 
nerve 
block 
in 
patient 
treated 
for 
hemorrhoidectomy under spinal anaesthesia: prospective 
randomized single blind controlled trial 
 
The Sponsor-Investigator and trial statistician have approved the protocol version 1.2, 8.10.2018, and 
confirm hereby to conduct the study according to the protocol, current version of the World Medical 
Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and the local 
legally applicable requirements. 
 
Sponsor-Investigator: 
Dr. Med Davide La Regina, Viceprimario chirurgia ORBV, Bellinzona 
 
 
Bellinzona 8.10.2018 
Place/Date 
 
Signature 
 
 

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Table of Contents 
STUDY SYNOPSIS ................................................................................................................................. 6 
ABBREVIATIONS ................................................................................................................................. 11 
STUDY SCHEDULE .............................................................................................................................. 12 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 13 
1.1 
Sponsor, Sponsor-Investigator .................................................................................................... 13 
1.2 
Principal Investigator(s) ................................................................................................................ 13 
1.3 
Statistician ("Biostatistician") ........................................................................................................ 13 
1.4 
Monitoring institution .................................................................................................................... 13 
1.5 
Data Safety Monitoring Committee .............................................................................................. 13 
1.6 
Any other relevant Committee, Person, Organisation, Institution ................................................ 13 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 14 
2.1 
Study registration ....................................................................................................................... 144 
2.2 
Categorisation of study ................................................................................................................ 14 
2.3 
Competent Ethics Committee (CEC) ........................................................................................... 14 
2.4 
Competent Authorities (CA) ......................................................................................................... 14 
2.5 
Ethical Conduct of the Study ........................................................................................................ 14 
2.6 
Declaration of interest .................................................................................................................. 14 
2.7 
Patient Information and Informed Consent .................................................................................. 14 
2.8 
Participant privacy and confidentiality .......................................................................................... 15 
2.9 
Early termination of the study....................................................................................................... 15 
2.10 Protocol amendments ................................................................................................................. 15 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 16 
3.1 
Background and Rationale ........................................................................................................... 16 
3.2 
Clinical Evidence to Date ............................................................................................................. 16 
3.3 
Rationale for the intended purpose in study ................................................................................ 16 
3.4 
Explanation for choice of comparator (or placebo) ...................................................................... 17 
3.5 
Risks / Benefits ............................................................................................................................ 17 
3.6 
Justification of choice of study population .................................................................................... 17 
4. 
STUDY OBJECTIVES ................................................................................................................... 18 
4.1 
Overall Objective .......................................................................................................................... 18 
4.2 
Primary Objective ......................................................................................................................... 18 
4.3 
Secondary Objectives .................................................................................................................. 18 
4.4 
Safety Objectives ......................................................................................................................... 18 
5. 
STUDY OUTCOMES ..................................................................................................................... 19 
5.1 
Primary Outcome ......................................................................................................................... 19 
5.2 
Secondary Outcomes ................................................................................................................... 19 
5.3 
Safety Outcomes .......................................................................................................................... 19 
6. 
STUDY DESIGN ............................................................................................................................ 20 
6.1 
General study design and justification of design.......................................................................... 20 
6.2 
Methods of minimising bias .......................................................................................................... 20 
6.2.1 Randomisation .................................................................................................................... 20 
6.2.2 Blinding procedures ............................................................................................................ 20 
6.3 
Unblinding Procedures (Code break) ........................................................................................... 20 
7. 
STUDY POPULATION .................................................................................................................. 20 
7.1 
Eligibility criteria ........................................................................................................................... 20 

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7.2 
Recruitment and screening .......................................................................................................... 21 
7.3 
Assignment to study groups ......................................................................................................... 21 
7.4 
Criteria for withdrawal / discontinuation of participants ................................................................ 21 
8. 
STUDY INTERVENTION ............................................................................................................... 22 
8.1 
Identity of Investigational Products .............................................................................................. 22 
8.1.1 Experimental Intervention ................................................................................................... 22 
8.1.2 Control Intervention ............................................................................................................. 22 
8.2 
Administration of experimental and control interventions ............................................................ 22 
8.2.1 Experimental Intervention ................................................................................................... 22 
8.2.2 Control Intervention ............................................................................................................. 23 
8.3 
Dose / Device modifications ......................................................................................................... 23 
8.4 
Data Collection and Follow-up for withdrawn participants ........................................................... 23 
8.5 
Concomitant Interventions (treatments) ....................................................................................... 23 
9. 
STUDY ASSESSMENTS ............................................................................................................... 24 
9.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 24 
9.2 
Assessments of outcomes ........................................................................................................... 24 
9.2.1 Assessment of primary outcome ......................................................................................... 24 
9.2.2 Assessment of secondary outcomes .................................................................................. 25 
9.2.3 Assessment of safety outcomes ......................................................................................... 25 
9.2.5 Assessments in participants who prematurely stop the study ............................................ 25 
9.3 
Procedures at each visit ............................................................................................................... 25 
10. SAFETY ......................................................................................................................................... 26 
10.1 Drug studies ................................................................................................................................ 26 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events .. 26 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events ..................... 27 
10.1.3 Follow up of (Serious) Adverse Events ............................................................................... 28 
11. STATISTICAL METHODS ............................................................................................................. 29 
11.1 Hypothesis ................................................................................................................................... 29 
11.2 Determination of Sample Size ..................................................................................................... 29 
11.3 Planned Analyses ........................................................................................................................ 29 
11.3.1 Datasets to be analysed, analysis populations ................................................................... 29 
11.3.2 Primary Analysis ................................................................................................................. 29 
11.3.3 Safety analysis .................................................................................................................... 29 
11.4 Handling of missing data and drop-outs...................................................................................... 29 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 30 
12.1 Data handling and record keeping / archiving ............................................................................. 30 
12.1.1 Case Report Forms ............................................................................................................. 30 
12.1.2 Specification of source documents ..................................................................................... 30 
12.1.3 Record keeping / archiving ................................................................................................. 30 
12.2 Data management ....................................................................................................................... 30 
12.2.1 Data Management System ................................................................................................. 30 
12.2.2 Data security, access and back-up ..................................................................................... 30 
12.2.3 Analysis and archiving ........................................................................................................ 31 
12.3 Monitoring .................................................................................................................................... 31 
12.4 Audits and Inspections ................................................................................................................ 31 
12.5 Confidentiality, Data Protection ................................................................................................... 31 

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13. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 31 
14. FUNDING AND SUPPORT ............................................................................................................ 32 
14.1 Funding ....................................................................................................................................... 32 
14.2 Other Support .............................................................................................................................. 32 
15. INSURANCE .................................................................................................................................. 32 
16. REFERENCES ............................................................................................................................... 33 
17. APPENDICES ................................................................................................................................ 35 
 
 

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STUDY SYNOPSIS 
Sponsor / Sponsor-
Investigator 
Dr. Med Davide La Regina, Viceprimario chirurgia ORBV, 
Bellinzona 
Study Title: 
Pudendal nerve block in patient treated for hemorrhoidectomy 
under spinal anaesthesia: prospective randomized single blind 
controlled trial 
Short Title / Study ID: Pudendal nerve block for hemorrhoidectomy 
Protocol Version and 
Date: 
Version 1.2, 8.10.2018 
Trial registration: 
CE TI 3222, BASEC 2017-00769 
Study category and 
Rationale 
Prospective randomized single blind controlled trial 
Clinical Phase: 
Study Phase 3 
Background 
and 
Rationale: 
Haemorrhoids are common disease in the population and the 
surgical treatment is among the most frequently performed surgical 
procedures in the world1. The post-operative pain is an important 
issue. A.Medina-Gallardo and coll2 published a study showing that 
the Milligan-Morgan hemorrhoidectomy is a procedure in which 
severe pain and demand for opiates are comparable to major 
surgery. 
The evidence-based recommendations of 2016 (PROSPECT 
Working 
Group)3 
for 
the 
management 
of 
pain 
after 
hemorrhoidectomy include: topical application of lidocaine 2% and 
nitro-glycerine 0.2% (Grade A), administration of metronidazole 
(Grade A) and laxatives (Grade A), NSAID (Grade B), 
acetaminophen (Grade B), strong and weak opioids (Grade B). It is 
preferable the perianal infiltration of local anaesthetics rather than 
the peripheral nerve blocks (perineal, pudendal or ischiorectal), due 
to the simplicity of the procedure3. Although the recommendations 
do not suggest the peripheral nerve block, the level of evidence is 
weak and there are no recommendations regarding a type of 
anaesthesia rather than another.  
Imbelloni LE and coll4 have published a randomized study for the 
pudendal nerve block evaluation, reporting a high rate of efficacy 
and a lower use of opioids compared to the control group. Tepetes 
K and al5 demonstrated in a randomized prospective trial that 
anaesthesia with the pudendal nerve block is more effective than 
the 
perianal 
infiltration 
of 
local 
anaesthetic 
during 
the 
hemorrhoidectomy procedures. Z. Naja and coll6 published a study 
that compares the pudendal nerve block driven by neurostimulation 
and sedation with general anaesthesia in patients undergoing 
hemorrhoidectomy. They have demonstrated a benefit in terms of 
prolonged postoperative analgesia, a reduced use of opioids, 
NSAIDs and a reduced length of hospital stay. Similarly, C.Rubod 
and coll7 in a prospective single-centre randomized trial have 
shown that the pudendal nerve block driven by neurostimulation is 
a simple and a useful technique that reduce the postoperative drugs 
intake. 

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The pudendal nerve block with local anaesthetic is effective to 
reduce the postoperative pain for up to 24 hours8. Currently no 
randomized study compares the effectiveness of perianal nerve 
blocks as adjuvant to spinal anaesthesia in the management of 
postoperative pain in patients undergoing hemorrhoidectomy. On 
the other hand, the pudendal nerve block procedure is safe, 
economic and simple. Complications related to the procedure such 
as intravenous injection of the anaesthetic, the formation of a 
retroperitoneal hematoma or abscess of the psoas muscle are 
described, although extremely rare9. 
The aim of this prospective randomized double-blind study is to 
compare the postoperative pain in patients undergoing Milligan 
Morgan hemorrhoidectomy under spinal anaesthesia with or 
without the pudendal nerve block. 
Objective(s): 
The objective is to assess the efficacy of the pudendal nerve block 
in patients treated by hemorrhoidectomy under spinal anaesthesia 
Outcome(s): 
Primary outcome:  
• 
Postoperative pain measured on VAS scale at 6, 12, 24, 48 
hours 
Secondary outcomes: 
• 
Antalgic drugs as needed (opioids needed) 
• 
Length of hospital stay 
• 
Safety of the pudendal nerve block 
Study design: 
Randomized control single-blind trial 
Inclusion / Exclusion 
criteria: 
Inclusion criteria: 
• 
Patients affected by haemorrhoids (grade III and IV) and 
treated with Milligan-Morgan hemorrhoidectomy under 
spinal anaesthesia  
• 
Signed informed consent  
Exclusion criteria: 
• 
Age < 18 year-old  
• 
Pregnancy 
• 
Allergy to local anaesthetics 
Measurements 
and 
procedures: 
Patients’ clinical data and operative time will be collected 
Patients selected will be randomized in two groups. 
• 
Group A will undergo Milligan-Morgan hemorrhoidectomy 
under pudendal nerve block plus spinal anaesthesia  
• 
Group B will undergo Milligan-Morgan hemorrhoidectomy 
under spinal anaesthesia 
The randomization list will be created by the CTU-EOC and the 
randomization will be performed by the authorized personnel 
(physician responsible for the study, the anaesthetist and the 
surgeons) of the participating centre via RedCap®. Only the 
physician responsible for the study, the anaesthetist and the 
surgeons will be informed about the treatment arm. 

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After the operation all the patient will receive Metronidazole 500 mg 
x3 + Paracetamol 1 gr x4 + NSAID + opioids as needed for at least 
48 hours. The postoperative pain will be evaluated at 6, 12, 24, 48 
hours with VAS scale both as in-patients or out-patients on specific 
formularies. In-patients will be then controlled after 1 months, while 
out-patients after 1 and 4 weeks. 
Results will be collected on specific printed Case report form. The 
Principal Investigator will preserve the sensitive data in his office in 
a closed cabinet key. Results will be then collected on a Redcap® 
electronic database. The access to the database will require 
username and password. Only the authorized personnel 
(physicians responsible for the study) will have the access rights 
and all changes on the database are trackable. 
Study 
Product 
/ 
Intervention: 
The pudendal nerve block will be done after the spinal anaesthesia: 
Ultrasonography allows the visualization of important landmarks: 
the ischial spine, pudendal artery, sacrospinous ligament, sacro-
tuberous ligament and pudendal nerve. It also allows real-time 
needle advancement and confirmation of injectate spread within the 
interligamentous plane. A low frequency 2-5 MHz curved array 
ultrasound 
probe 
is 
used. 
After 
skin 
preparation 
with 
Povidoneiodine and sterile probe preparation within a transparent 
plastic sheath, scanning is performed in transverse planes to 
visualize the ischium forming the lateral border of the sciatic notch. 
By moving the ultrasound probe in a cephalad-caudal direction, the 
ischium appears as a progressively lengthening hyperechoic line 
that is widest at the ischial spine level. The ischium is initially seen 
as a curved line as it forms the posterior aspect of the acetabulum. 
When the probe is at the ischial spine level, the ischium will appear 
as a straight line. At this level, a colour Doppler is used to localize 
the internal pudendal artery pulsations in close proximity to the 
ischial spine. Another arterial pulsation is often seen lateral to the 
tip of the ischial spine and is accompanied by the sciatic nerve. This 
is the inferior gluteal artery. Mistaking this artery for the pudendal 
artery will result in sciatic nerve block. The sacrospinous ligament 
appears as a hyperechoic line in continuity with the ischial spine, 
with lower echogenicity than bone. Similarly, the sacrotuberous 
ligament is seen as a light hyperechoic line deep within gluteus 
maximus muscle and appears parallel and superior to the 
sacrospinous ligament in ultrasound images. Localization of the 
pudendal nerve is targeted in the plane between these 2 ligaments. 
Under ultrasound guidance, a peripheral nerve stimulating needle 
is inserted from the medial aspect of the probe. It is advanced in 
line with the ultrasound probe to the medial aspect of the internal 
pudendal 
artery. 
Once 
the 
needle 
passes 
through 
the 
sacrotuberous ligament, a “click” is usually felt and a small volume 
(1 – 2 mL) of local anaesthetic is injected. The solution appears as 
a hypoechoic collection, in order to identify the plane between the 
sacrotuberous and the sacro-spinous ligaments and to accentuate 
the pudendal nerve appearance (pudendal nerve however is not 
always visible). The needle is inserted medially toward the 
pudendal artery as the pudendal nerve is principally located medial 
to this artery. 10 mls of ropivacaine 0.75% are injected within this 
fascial plane, after negative aspiration. The procedure is than 
repeated identically on the contralateral side10.  

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This procedure is usually a quite painful technique; thus, it is 
important to perform it after the spinal anaesthesia. It would be 
necessary to do it before the spinal anaesthesia just in case the 
pain would be associated to a nerve lesion. In this study the 
infiltration is not done on the nerve but in a muscular plane, thus is 
not needed the patient’s sensibility11. 
The procedure will be performed at our institution by one of the 
three expert anaesthesiologists in the peripheral nerves’ blockage. 
Those anaesthesiologists are: 
• 
Dr. Med. Luciano Anselmi, Primario di Anestesia ORBV 
• 
Dr. Med. Andrea Saporito, Caposervizio Anestesia ORBV, 
board member of the Swiss Society of Loco-regional 
Anaesthesia 
• 
Dr. Med. Fabrizio Beretta, Caposervizio Anestesia e 
responsabile terapia del dolore ORBV 
Control Intervention 
(if applicable): 
None 
Number 
of 
Participants 
with 
Rationale: 
Based on previous studies we will expect a 33% reduction in VAS 
scale. To detect a clinically relevant difference between groups with 
a type I error of 0.05 and a power of 0.80 we determined a sample 
size of 18 subjects per group. Taken into account a possible drop 
out for different reasons of 10% we calculated the definitive sample 
size in 20 patients per group. 
Study Duration: 
According to the volume of the Milligan-Morgan hemorrhoidectomy 
performed every year in our centre, the estimated duration of the 
study is 2 years. 
Study Schedule: 
First-Participant-In planned: 01.01.2018 
Last-Participant-Out planned: 31.12.2019 
Investigator(s): 
Dr. Med Davide La Regina, Viceprimario Chirurgia ORBV, 
Bellinzona, davide.laregina@eoc.ch 
 
Dr. Med Andrea Saporito, Caposervizio di Anestesia ORBV, 
Bellinzona, andrea.saporito@eoc.ch  
 
Dr. Med Di Giuseppe Matteo, Capoclinica Chirurgia ORBV, 
Bellinzona, matteo.digiuseppe@eoc.ch  
 
Dr. Med Francesco Mongelli, Medico Assistente Chirurgia ORBV, 
Bellinzona, francesco.mongelli@eoc.ch  
Study Centre(s): 
Single-centre 

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Statistical 
Considerations: 
Descriptive statistics will be presented as mean with standard 
deviation (SD) or as median with interquartile range (IQR) for 
quantitative data. Qualitative data will be presented as absolute 
numbers with percentages. Comparisons of postoperative pain 
measured on VAS scale at 6, 12 and 24 h after surgery between 
group A and group B will be performed with the non-parametric 
repeated measures analysis of variance (Friedman test). By 
statistically significant p-value, post-hoc tests will be performed 
taken into account the multiple comparisons. Qualitative data 
between groups of patients will be compared with the Chi-Square 
test, or the Fisher exact test as appropriate. By statistically 
significant result post-hoc comparisons were made with the 
appropriate critical level adjustment. Comparisons of quantitative 
data between groups will performed with the Student’s t-test or with 
the Mann-Whitney test as appropriate. All tests will be conducted 
two-sided, and p-values < 0.05 will be considered statistically 
significant. Stata version 12.1 (StatCorp. LP, College Station, TX, 
USA) will be used for all statistical analysis. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, the ICH-GCP or ISO 
EN 14155 (as far as applicable) as well as all national legal and 
regulatory requirements. 
The Principal Investigator Dr. med Davide La Regina has obtained 
the GPC statement I and II level in June 2017 
 
 

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ABBREVIATIONS 
Provide a list of abbreviations used on the protocol - to be completed 
 
AE 
Adverse Event  
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
CRF 
Case Report Form  
GCP 
Good Clinical Practice  
ISO 
International Organisation for Standardisation 
IQR 
Interquartile Range 
NSAID 
Nonsteroidal anti-inflammatory drug 
PI 
Principal Investigator  
SD 
Standard Deviation 
 
 
 

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STUDY SCHEDULE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients selection 
(History taking, physical examination, anaesthesiologist 
evaluation, inclusion and exclusion criteria) 
Randomization 
Group A: Milligan-Morgan 
hemorrhoidectomy under 
pudendal nerve block plus spinal 
anaesthesia 
Group B: Milligan-Morgan 
hemorrhoidectomy under spinal 
anaesthesia 
Metronidazole 500 mg x3 Paracetamol 1 
gr x4 + NSAID + opioids as needed for at 
least 24 hours. 
Postoperative pain evaluation at 6, 12, 24 
and 48 hours with VAS scale. 
In-patients will be then controlled after 1 
months. Out-patients after 1 and 4 weeks. 
Results collection 
(Postoperative pain measurement, 
antalgic drugs demanded, length of 
hospital stay). CRF and e-database. 
Results analysis 

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1. STUDY ADMINISTRATIVE STRUCTURE  
Sponsor/PI: 
Dr. Med Davide La Regina, Viceprimario Chirurgia ORBV, Bellinzona, 
davide.laregina@eoc.ch. 091 811 9106 
Coordinator: 
Dr. Med Andrea Saporito, Caposervizio di Anestesia ORBV, Bellinzona, 
andrea.saporito@eoc.ch  
 
Dr. Med Di Giuseppe Matteo, Capoclinica Chirurgia ORBV, Bellinzona, 
matteo.digiuseppe@eoc.ch  
 
Data collector: 
Dr. Med Francesco Mongelli, Medico Assistente Chirurgia ORBV, 
Bellinzona, francesco.mongelli@meoc.ch. 091 811 9465 
 
1.1 Sponsor, Sponsor-Investigator  
Sponsor/PI: 
Dr. Med Davide La Regina, Viceprimario Chirurgia ORBV, via Ospedale, 
Bellinzona, davide.laregina@eoc.ch. 091 811 9106 
The role in the study is to provide the rationale of the study, the study design and has the 
overall responsibility for it. 
 
1.2 Principal Investigator(s)  
For this study the sponsor and the PI are the same person, as mention above 
1.3 Statistician ("Biostatistician")  
Dr. Med Pagnamenta Alberto, OBV 
 
1.4 Monitoring institution 
The Monitor of the study will be: 
• 
Dr. Med. Stephan Engelberger, Caposervizio Chirurgia Vascolare OCL Lugano. GCP 
statement I and II level 
 
1.5 Data Safety Monitoring Committee  
The monitor will perform 2 inspections / year and will send to the Local Ethical Committee 1 
report / year about safety data. 
 
1.6 Any other relevant Committee, Person, Organisation, Institution 
None 
 
 

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2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the protocol, the proposed patient information and consent 
form as well as other study-specific documents shall be submitted to a properly constituted 
Competent Ethics Committee (CEC) and/or competent authorities  
 
2.1 Study registration  
2017-00769 
 
2.2 Categorisation of study  
The risk categorization for this study is A.  
The treatment option proposed for group A and B are both widely used in the current clinical 
practice. Risks related to the pudendal nerve block are extremely rare9. 
 
2.3 Competent Ethics Committee (CEC)  
The competent ethics committee is the Comitato etico cantonale, c/o Ufficio di sanità, Via Orico 
5, 6501 Bellinzona  
No changes are made to the protocol without prior Sponsor and CEC approval, except where 
necessary to eliminate apparent immediate hazards to study participants. 
 
2.4 Competent Authorities (CA)  
The Sponsor will obtain approval from the competent authority before the start of the clinical 
trial.  
 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in 
the current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice 
(GCP) issued by ICH, in case of medical device: the European Directive on medical devices 
93/42/EEC and the ISO Norm 14155 and ISO 14971, the Swiss Law and Swiss regulatory 
authority’s requirements. The CEC and regulatory authorities will receive annual safety and 
interim reports and be informed about study stop/end in agreement with local requirements.  
 
2.6 Declaration of interest  
We declare no conflicts of interest 
 
2.7 Patient Information and Informed Consent 
All patient will receive an informed consent to participate to the study. 
The investigators will explain to each participant the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and any discomfort 
it may entail. Each participant will be informed that the participation in the study is voluntary 
and that he/she may withdraw from the study at any time and that withdrawal of consent will 
not affect his/her subsequent medical assistance and treatment.  
The participant must be informed that his/her medical records may be examined by authorised 
individuals other than their treating physician. 

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All participants for the study will be provided a participant information sheet and a consent form 
describing the study and providing sufficient information for participant to make an informed 
decision about their participation in the study.  
The patient information sheet and the consent form will be submitted to the CEC and to the 
competent authority to be reviewed and approved. The formal consent of a participant, using 
the approved consent form, must be obtained before the participant is submitted to any study 
procedure.   
The participant should read and consider the statement before signing and dating the informed 
consent form, and should be given a copy of the signed document. The consent form must 
also be signed and dated by the investigator (or his designee) and it will be retained as part of 
the study records. 
 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that 
they shall comply with applicable privacy laws. Especially, anonymity of the participants shall 
be guaranteed when presenting the data at scientific meetings or publishing them in scientific 
journals.  
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Subject confidentiality will be further 
ensured by utilising subject identification code numbers to correspond to treatment data in the 
computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), the 
monitor, a competent authority or an ethics committee may require direct access to parts of 
the medical records relevant to the study, including participants’ medical history. 
 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain 
circumstances, for example: 
• 
ethical concerns, 
• 
insufficient participant recruitment, 
• 
when the safety of the participants is doubtful or at risk, respectively, 
• 
alterations in accepted clinical practice that make the continuation of a clinical trial 
unwise,  
• 
early evidence of benefit or harm of the experimental intervention  
 
2.10 Protocol amendments 
Substantial amendments are only implemented after approval of the CEC and CA respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and 
well-being of human subjects may proceed without prior approval of the sponsor and the 
CEC/CA. Such deviations shall be documented and reported to the sponsor and the CEC/CA 
as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if applicable 
and to the CEC within the Annual Safety Report (ASR).  
 
 

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3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
Haemorrhoids are common disease in the population and the surgical treatment is among the 
most frequently performed surgical procedures in the world1. The post-operative pain is an 
important issue. A.Medina-Gallardo and coll2 published a study showing that the Milligan-
Morgan hemorrhoidectomy is a procedure in which severe pain and demand for opiates are 
comparable to major surgery. 
The evidence-based recommendations of 2016 (PROSPECT Working Group)3 for the 
management of pain after hemorrhoidectomy include: topical application of lidocaine 2% and 
nitro-glycerine 0.2% (Grade A), administration of metronidazole (Grade A) and laxatives 
(Grade A), NSAID (Grade B), acetaminophen (Grade B), strong and weak opioids (Grade B). 
It is preferable the perianal infiltration of local anaesthetics rather than the peripheral nerve 
blocks (perineal, pudendal or ischiorectal), due to the simplicity of the procedure3. Although 
the recommendations do not suggest the peripheral nerve block, the level of evidence is weak 
and there are no recommendations regarding a type of anaesthesia rather than another.  
Imbelloni LE and coll4 have published a randomized study for the pudendal nerve block 
evaluation, reporting a high rate of efficacy and a lower use of opioids compared to the control 
group. Tepetes K and al5 demonstrated in a randomized prospective trial that anaesthesia with 
the pudendal nerve block is more effective than the perianal infiltration of local anaesthetic 
during the hemorrhoidectomy procedures. Z.Naja and coll6 published a study that compares 
the pudendal nerve block driven by neurostimulation and sedation with general anaesthesia in 
patients undergoing hemorrhoidectomy. They have demonstrated a benefit in terms of 
prolonged postoperative analgesia, a reduced use of opioids, NSAIDs and a reduced length 
of hospital stay. Similarly, C.Rubod and coll7 in a prospective single-centre randomized trial 
have shown that the pudendal nerve block driven by neurostimulation is a simple and a useful 
technique that reduce the postoperative drugs intake. 
The aim of this prospective randomized single-blind study is to compare the postoperative pain 
in patients undergoing Milligan Morgan hemorrhoidectomy under spinal anaesthesia with or 
without the pudendal nerve block. 
 
3.2 Clinical Evidence to Date  
The pudendal nerve block with local anaesthetic is effective to reduce the postoperative pain 
for up to 24 hours8. Currently no randomized study compares the effectiveness of perianal 
nerve blocks as adjuvant to spinal anaesthesia in the management of postoperative pain in 
patients undergoing hemorrhoidectomy. On the other hand, the pudendal nerve block 
procedure is safe, economic and simple. Complications related to the procedure such as 
intravenous injection of the anaesthetic, the formation of a retroperitoneal hematoma or 
abscess of the psoas muscle are described, although extremely rare9. 
 
3.3 Rationale for the intended purpose in study 
The pudendal nerve block will be done as follow before the spinal anaesthesia: 
Ultrasonography allows the visualization of important landmarks: the ischial spine, pudendal 
artery, sacrospinous ligament, sacrotuberous ligament and pudendal nerve. It also allows real-
time needle advancement and confirmation of injectate spread within the interligamentous 
plane. A low frequency 2-5 MHz curved array ultrasound probe is used. After skin preparation 
with Povidoneiodine and sterile probe preparation within a transparent plastic sheath, scanning 
is performed in transverse planes to visualize the ischium forming the lateral border of the 
sciatic notch. By moving the ultrasound probe in a cephalad-caudal direction, the ischium 
appears as a progressively lengthening hyperechoic line that is widest at the ischial spine level. 
The ischium is initially seen as a curved line as it forms the posterior aspect of the acetabulum. 

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When the probe is at the ischial spine level, the ischium will appear as a straight line. At this 
level, a colour Doppler is used to localize the internal pudendal artery pulsations in close 
proximity to the ischial spine. Another arterial pulsation is often seen lateral to the tip of the 
ischial spine and is accompanied by the sciatic nerve. This is the inferior gluteal artery. 
Mistaking this artery for the pudendal artery will result in sciatic nerve block. The sacrospinous 
ligament appears as a hyperechoic line in continuity with the ischial spine, with lower 
echogenicity than bone. Similarly, the sacrotuberous ligament is seen as a light hyperechoic 
line deep within gluteus maximus muscle and appears parallel and superior to the 
sacrospinous ligament in ultrasound images. Localization of the pudendal nerve is targeted in 
the plane between these 2 ligaments. Under ultrasound guidance, a peripheral nerve 
stimulating needle is inserted from the medial aspect of the probe. It is advanced in line with 
the ultrasound probe to the medial aspect of the internal pudendal artery. Once the needle 
passes through the sacrotuberous ligament, a “click” is usually felt and a small volume (1 – 2 
mL) of local anaesthetic is injected. The solution appears as a hypoechoic collection, in order 
to identify the plane between the sacrotuberous and the sacrospinous ligaments and to 
accentuate the pudendal nerve appearance (pudendal nerve however is not always visible). 
The needle is inserted medially toward the pudendal artery as the pudendal nerve is principally 
located medial to this artery. 10 mls of ropivacaine 0.75% are injected within this fascial plane, 
after negative aspiration. The procedure is than repeated identically on the contralateral side10. 
This procedure is usually a quite painful technique; thus, it is important to perform it after the 
spinal anaesthesia. It would be necessary to do it before the spinal anaesthesia just in case 
the pain would be associated to a nerve lesion. In this study the infiltration is not done on the 
nerve but in a muscular plane, thus is not needed the patient’s sensibility11. 
The procedure will be performed at our institution by one of the three expert anaesthesiologists 
in the peripheral nerves’ blockage. Those anaesthesiologists are: 
• 
Dr. Med. Luciano Anselmi, Primario di Anestesia ORBV 
• 
Dr. Med. Andrea Saporito, Caposervizio Anestesia ORBV, board member of the Swiss 
Society of Loco-regional Anaesthesia 
• 
Dr. Med. Fabrizio Beretta, Caposervizio Anestesia e responsabile terapia del dolore 
ORBV 
3.4 Explanation for choice of comparator (or placebo)  
Since the efficacy of the pudendal nerve block in patient operated for hemorrhoidectomy under 
spinal anaesthesia is not well established, the purpose is to evaluate differences in the 
postoperative pain if the nerve block is performed or not. 
3.5 Risks / Benefits  
The risks related to the pudendal nerve block are extremely rare9. Complications include the 
intravenous injection of the anaesthetic, the formation of a retroperitoneal hematoma or 
abscess of the psoas muscle. In case such complications occur, a multidisciplinary team 
composed by anaesthesiologist, surgeons and interventional radiologist will be promptly 
available.  
 
3.6 Justification of choice of study population  
Patients affected by haemorrhoids (grade III and IV) and treated with Milligan-Morgan 
hemorrhoidectomy  
 
 

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4. STUDY OBJECTIVES  
4.1 Overall Objective 
The purpose is to evaluate differences in the postoperative pain if the pudendal nerve block is 
performed or not in patients treated for hemorrhoidectomy under spinal anaesthesia.  
 
4.2 Primary Objective 
Postoperative pain evaluation 
 
4.3 Secondary Objectives 
Antalgic drugs as needed (opioids needed) 
Length of hospital stay 
 
4.4 Safety Objectives 
The safety of the pudendal nerve block will be assessed. The assessment will be evaluated 
recording complications (type and severity according to CTCAE Version 4.03 - June 14, 
201012) after the nerve block during the hospital stay. In-patients will be then controlled 1 
months after the operation, out-patients after 1 and 4 weeks. 
 
 

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5. STUDY OUTCOMES  
5.1 Primary Outcome 
Postoperative pain measured on VAS scale at 6, 12, 24, 48 hours 
 
5.2 Secondary Outcomes 
Antalgic drugs as needed (type of drug and number of administrations) 
Length of hospital stay (days) 
 
5.3 Safety Outcomes 
The type and the severity of AEs related to the pudendal nerve block will be recorded according 
to CTCAE Version 4.03 - June 14, 201012. The evaluation will be done after the nerve block, 
during the hospital stay and 1 months after the operation for in-patients or after 1 and 4 weeks 
for out-patients. 
 
 

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6. STUDY DESIGN  
6.1 General study design and justification of design  
This study is a randomized control single blind trial.  
Patient will be randomized: Group A will undergo the pudendal nerve block under 
ultrasonographic control with injection of 10 mls of ropivacaine 0.75% before the spinal 
anaesthesia. 
The population include patients with haemorrhoids (grade III and IV) 
The study is single blind: an expert from the anaesthesiology team will perform the nerve block, 
the surgeon will be informed about the group of randomization. The nursing personnel 
(blinded) or the patient itself on specific formularies will evaluate the VAS scale at 6, 12, 24, 
48 hours. 
The comparator is no treatment 
The method of randomization will be created by the CTU-EOC and the randomization will be 
performed by the authorized personnel (physician responsible for the study, the anaesthetist 
and the surgeons) of the participating centre via RedCap®. Only the physician responsible for 
the study, the anaesthetist and the surgeons will be informed about the treatment arm. 
The expected duration of the study is 2 years, 100 patients. 
 
6.2 Methods of minimising bias  
6.2.1 
Randomisation  
The randomization list will be created by the CTU-EOC and the randomization will be 
performed by the authorized personnel (physician responsible for the study, the anaesthetist 
and the surgeons) of the participating centre via RedCap®. Only the physician responsible for 
the study, the anaesthetist and the surgeons will be informed about the treatment arm. 
6.2.2 
Blinding procedures  
The study is single blind: an expert from the anaesthesiology team will perform the nerve block, 
the surgeon will be informed about the group of randomization. The nursing personnel and 
patients that will fulfil the VAS scale formularies at 6, 12, 24, 48 hours are blinded, they will not 
know the arm of treatment. 
6.3 Unblinding Procedures (Code break)  
The Principal Investigator will be informed on the randomization and will be available 24/24 
hours, 365 days/year in case of complications related to the pudendal nerve block occur. In 
case of serious complications also the authorized personnel (physician responsible for the 
study, the anaesthetist and the surgeons) will have the possibility to access to the 
randomization, the principal investigator will be always get informed. 
7. STUDY POPULATION  
7.1 Eligibility criteria  
Inclusion criteria: 
• 
Patients affected by haemorrhoids (grade III and IV) and treated with Milligan-Morgan 
hemorrhoidectomy under spinal anaesthesia  
• 
Signed informed consent  
Exclusion criteria: 
• 
Age < 18 years old  

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• 
Pregnancy 
• 
Allergy to local anaesthetics 
 
7.2 Recruitment and screening  
The population recruitment will be at the Proctology Consulting Room, ORBV Bellinzona. 
 
7.3 Assignment to study groups  
The randomization list will be created by the CTU-EOC and the randomization will be 
performed by the authorized personnel (physician responsible for the study, the anaesthetist 
and the surgeons) of the participating centre via RedCap®. Only the physician responsible for 
the study, the anaesthetist and the surgeons will be informed about the treatment arm. 
 
7.4 Criteria for withdrawal / discontinuation of participants  
Participants are withdrawn from the study in case of informed consent not signed or non-
compliance to the treatments. 
 
 

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8. STUDY INTERVENTION  
8.1 Identity of Investigational Products 
8.1.1 
Experimental Intervention 
After patients select and randomization: 
Group A will undergo pudendal nerve block under ultrasonographic control with injection of 10 
mls of ropivacaine 0.75. Group B will receive no treatment. 
 
8.1.2 
Control Intervention 
In the postoperative period all the patients will receive metronidazole 500 mg x3 + paracetamol 
1 gr x4 + NSAID + opioids as needed for at least 24 hours. Opioids used will be “strong opioids” 
(Pethidine 50 mg sc or Oxycodone Kaps 5 mg) 
 
8.2 Administration of experimental and control interventions  
8.2.1 
Experimental Intervention  
The pudendal nerve block will be done as follow before the spinal anaesthesia: 
Ultrasonography allows the visualization of important landmarks: the ischial spine, pudendal 
artery, sacrospinous ligament, sacrotuberous ligament and pudendal nerve. It also allows real-
time needle advancement and confirmation of injectate spread within the interligamentous 
plane. A low frequency 2-5 MHz curved array ultrasound probe is used. After skin preparation 
with Povidoneiodine and sterile probe preparation within a transparent plastic sheath, scanning 
is performed in transverse planes to visualize the ischium forming the lateral border of the 
sciatic notch. By moving the ultrasound probe in a cephalad-caudal direction, the ischium 
appears as a progressively lengthening hyperechoic line that is widest at the ischial spine level. 
The ischium is initially seen as a curved line as it forms the posterior aspect of the acetabulum. 
When the probe is at the ischial spine level, the ischium will appear as a straight line. At this 
level, a colour Doppler is used to localize the internal pudendal artery pulsations in close 
proximity to the ischial spine. Another arterial pulsation is often seen lateral to the tip of the 
ischial spine and is accompanied by the sciatic nerve. This is the inferior gluteal artery. 
Mistaking this artery for the pudendal artery will result in sciatic nerve block. The sacrospinous 
ligament appears as a hyperechoic line in continuity with the ischial spine, with lower 
echogenicity than bone. Similarly, the sacrotuberous ligament is seen as a light hyperechoic 
line deep within gluteus maximus muscle and appears parallel and superior to the 
sacrospinous ligament in ultrasound images. Localization of the pudendal nerve is targeted in 
the plane between these 2 ligaments. Under ultrasound guidance, a peripheral nerve 
stimulating needle is inserted from the medial aspect of the probe. It is advanced in line with 
the ultrasound probe to the medial aspect of the internal pudendal artery. Once the needle 
passes through the sacrotuberous ligament, a “click” is usually felt and a small volume (1 – 2 
mL) of local anaesthetic is injected. The solution appears as a hypoechoic collection, in order 
to identify the plane between the sacrotuberous and the sacrospinous ligaments and to 
accentuate the pudendal nerve appearance (pudendal nerve however is not always visible). 
The needle is inserted medially toward the pudendal artery as the pudendal nerve is principally 
located medial to this artery. 10 mls of ropivacaine 0.75% are injected within this fascial plane, 
after negative aspiration. The procedure is than repeated identically on the contralateral side10. 
This procedure is usually a quite painful technique; thus, it is important to perform it after the 
spinal anaesthesia. It would be necessary to do it before the spinal anaesthesia just in case 
the pain would be associated to a nerve lesion. In this study the infiltration is not done on the 
nerve but in a muscular plane, thus is not needed the patient’s sensibility11. 
The procedure will be performed at our institution by one of the three expert anaesthesiologists 
in the peripheral nerves’ blockage. Those anaesthesiologists are: 

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• 
Dr. Med. Luciano Anselmi, Primario di Anestesia ORBV 
• 
Dr. Med. Andrea Saporito, Caposervizio Anestesia ORBV, board member of the Swiss 
Society of Loco-regional Anaesthesia 
• 
Dr. Med. Fabrizio Beretta, Caposervizio Anestesia e responsabile terapia del dolore 
ORBV 
 
8.2.2 
Control Intervention 
The control group will not undergo the pudendal nerve block. 
 
8.3 Dose / Device modifications  
No dose modification are planned 
 
8.4 Data Collection and Follow-up for withdrawn participants  
Results will be collected on specific printed formularies (CRFs). The Principal Investigator will 
preserve the sensitive data in his office in a closed cabinet key. Results will be then collected 
on a Redcap® electronic database. The access to the database will require username and 
password. Only the authorized personnel (physicians responsible for the study) will have the 
access rights and all changes on the database are trackable. 
In-patients will be then controlled after 1 months and out-patients will be controlled after 1 and 
4 weeks. 
 
8.5 Concomitant Interventions (treatments)  
No specific or relevant concomitant care or treatment are allowed. 
 
 

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9. STUDY ASSESSMENTS  
9.1 Study flow chart(s) / table of study procedures and assessments 
 
 
 
9.2 Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
Postoperative pain measured on VAS scale at 6, 12, 24, 48 hours. The data will be registered 
by the nursing personnel in the postoperative period on printed formularies (CRFs) or by the 
patient itself on a specific formulary.  
 

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9.2.2 
Assessment of secondary outcomes 
Opioids drugs as needed, length of hospital stay and complications data will be registered by 
the care providers in the postoperative period on specific printed formularies. 
 
9.2.3 
Assessment of safety outcomes 
The type and the severity of AEs related to the pudendal nerve block will be recorded according 
to CTCAE Version 4.03 - June 14, 201012. The evaluation will be done after the nerve block, 
during the hospital stay and 1 months (in-patients) or 1 and 4 weeks (out-patients) after the 
operation. 
 
9.2.3.1 
Adverse events  
For adverse event the information collected are: time of onset, duration, resolution, action to 
be taken, assessment of intensity, relationship with study treatment. The evaluations will be 
done during the hospital stay and during the further planned clinical evaluations. 
 
9.2.4 
Assessments in participants who prematurely stop the study 
Participants can be withdrawn from the study prematurely in case of adverse events after the 
pudendal nerve block. 
 
9.3 Procedures at each visit 
One pre-operatory visit is planned: history taking, physical examination, anaesthesiologist 
evaluation will be assessed.  
All patients will be then controlled (history taking and clinical examination) after 1 months or 1 
and 4 weeks (in- or out patients respectively). 
 
 

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10. SAFETY  
10.1 Drug studies 
During the entire duration of the study, all adverse events (AE) and all serious adverse events 
(SAEs) are collected, fully investigated and documented in source documents and case report 
forms (CRF). Study duration encompassed the time from when the participant signs the 
informed consent until the last protocol-specific procedure has been completed, including a 
safety follow-up period. For adverse event the information collected are: time of onset, 
duration, resolution, action to be taken, assessment of intensity, relationship with study 
treatment. The evaluations will be done during the hospital stay and the further planned clinical 
evaluations. 
 
10.1.1 Definition and assessment of (serious) adverse events and other safety related 
events 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have a causal relationship with the study procedure. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product. 
 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
• 
results in death, 
• 
is life-threatening, 
• 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in 
death, or require hospitalisation, but may jeopardise the patient or may require intervention to 
prevent one of the other outcomes listed above should also usually be considered serious. 
SAEs will be followed until stabilisation. Participants with ongoing SAEs at study termination 
(including safety visit) will be further followed up until stabilisation of the disease after 
termination.  
The Principal Investigator will be informed on the randomization and will be available 24/24 
hours, 365 days/year in case of complications related to the pudendal nerve block occur.  
 
Assessment of Causality 
The Sponsor-investigator make a causality assessment of the event to the study drug, based 
on the criteria listed in the ICH E2A guidelines: 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 

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Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which 
is not consistent with the applicable product information (e.g. Investigator’s Brochure for drugs 
that are not yet approved and Product Information for approved drugs, respectively).  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, 
causality and expectedness. If the event is related to the investigational product and is both 
serious and unexpected, it is classified as a SUSAR. 
 
Assessment of Severity 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical 
descriptions of severity for each AE based on this general guideline: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activity day living. 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activity 
day living. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
For a detailed description of EAs, we follow the CTCAE Version 4.03 - June 14, 201012. 
 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events  
Reporting of SAEs 
All SAEs will be reported immediately and within a maximum of 24 hours to the Sponsor-
Investigator of the study. SAEs resulting in death are reported to the local Ethics Committee 
(via local Investigator) within 7 days. 
Reporting of SUSARs 
A SUSAR needs to be reported to the local Ethics Committee (local event via local Investigator) 
and to Swissmedic for category B and C studies (via Sponsor-Investigator) within 7 days, if the 
event is fatal, or within 15 days (all other events). 
Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known adverse reactions that require 
safety-related measures, i.e. so-called safety signals, must be reported to the Sponsor-
Investigator within 24 hours. The Sponsor-Investigator must report the safety signals within 7 
days to the local Ethics Committee 
Periodic reporting of safety 

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An annual safety report is submitted once a year to the local Ethics Committee via local 
Investigator 
 
10.1.3 Follow up of (Serious) Adverse Events 
In case of SAE the patient will be followed up according the type and the severity of the 
complication developed, at least until stabilization. 
 
 

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11. STATISTICAL METHODS  
11.1 Hypothesis 
The hypothesis to be tested is that the spinal anaesthesia + pudendal nerve block is superior 
to the spinal anaesthesia alone in terms of postoperative pain. 
 
11.2 Determination of Sample Size  
Based on previous studies we will expect a 33% reduction in VAS scale. To detect a clinically 
relevant difference between groups with a type I error of 0.05 and a power of 0.80 we 
determined a sample size of 18 subjects per group. Taken into account a possible drop out for 
different reasons of 10% we calculated the definitive sample size in 20 patients per group. 
 
11.3 Planned Analyses  
Descriptive statistics will be presented as mean with standard deviation (SD) or as median with 
interquartile range (IQR) for quantitative data. Qualitative data will be presented as absolute 
numbers with percentages. Comparisons of postoperative pain measured on VAS scale at 6, 
12 and 24 h after surgery between group A and group B will be performed with the non-
parametric repeated measures analysis of variance (Friedman test). By statistically significant 
p-value, post-hoc tests will be performed taken into account the multiple comparisons. 
Qualitative data between groups of patients will be compared with the Chi-Square test, or the 
Fisher exact test as appropriate. By statistically significant result post-hoc comparisons were 
made with the appropriate critical level adjustment. Comparisons of quantitative data between 
groups will performed with the Student’s t-test or with the Mann-Whitney test as appropriate. 
All tests will be conducted two-sided, and p-values < 0.05 will be considered statistically 
significant. Stata version 12.1 (StatCorp. LP, College Station, TX, USA) will be used for all 
statistical analysis. 
 
11.3.1 Datasets to be analysed, analysis populations 
All randomized subject will be included in the analyses 
 
11.3.2 Primary Analysis 
The primary analyses will be conducted at the end of the study by Dr. Med Pagnamenta 
Alberto, OBV (Chief of the EOC Biostatistic Service) 
 
11.3.3 Safety analysis 
The analysis of the safety will be conducted at the end of the study by Dr. Med Pagnamenta 
Alberto, OBV (Chief of the EOC Biostatistic Service). Parameters analysed will be the type and 
severity of AEs, treatment and resolution or stabilization (according to CTCAE Version 4.03 - 
June 14, 201012). 
 
11.4 Handling of missing data and drop-outs  
In case of missing data, the patient will be dropped-out. 2 drop-outs each arm is planned  
 
 

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12. QUALITY ASSURANCE AND CONTROL  
The Principal investigator is responsible for maintaining quality assurance and quality control, 
he is also responsible for proper training of all involved study personnel. 
 
12.1 Data handling and record keeping / archiving  
All the data will be collected on specific printed Case report form for each patient. The Principal 
Investigator will preserve the sensitive data in his office in a closed cabinet key. 
 
12.1.1 Case Report Forms  
A paper Case Report Forms will be used. Participants will not be identified in the CRF by name 
or initials and birth date. Appropriate coded identification will be used and managed by the 
Principal Investigator. 
The Principal Investigator, Coordinators, data collector, authorised representatives of the 
Sponsor (-Investigator), the monitor, a competent authority or an ethics committee may have 
direct access to parts of the medical records relevant to the study. They are authorized to CRF 
access.  
Results will be then collected on a Redcap® electronic database. The access to the database 
will require username and password. Only the authorized personnel (physicians responsible 
for the study) will have the access rights and all changes on the database are trackable. 
 
12.1.2 Specification of source documents  
Source data on the CRF include the original documents relating to the study, as well as the 
medical treatment and medical history of the participant (demographic data, clinical data, 
participation in study and Informed Consent, VAS scale at 6, 12, 24, 48, drugs taken, length of 
hospital stay, complications).  
 
12.1.3 Record keeping / archiving  
The Principal Investigator will preserve the sensitive data in his office in a closed cabinet key, 
archiving for 10 years. The e-database Redcap® grants security standard according to the 
EOC sensible data system storage and security. 
 
12.2 Data management  
The Principal Investigator has the overall responsibility for the data management.  
 
12.2.1 Data Management System  
CRF paper will be used and secured by the principal investigator in his office in a closed 
cabinet key. Results will be then collected on a Redcap® electronic database. The access to 
the database will require username and password. Only the authorized personnel (physicians 
responsible for the study) will have the access rights and all changes on the database are 
trackable (double data entry).  
 
12.2.2 Data security, access and back-up  
CRF paper will be used and secured by the principal investigator in his office in a closed 
cabinet key. Results will be then collected on a Redcap® electronic database. The access to 
the database will require username and password. Only the authorized personnel (physicians 

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responsible for the study) will have the access rights and all changes on the database are 
trackable (double data entry).  
CRFs and the electronic database will be accessible only by authorized personnel (physicians 
responsible for the study). Authorised representatives of the Sponsor/Investigator, the monitor, 
a competent authority or an ethics committee will have the access to sensible data. 
 
12.2.3 Analysis and archiving 
Results will be then collected on a Redcap® electronic database. The access to the database 
will require username and password. Only the authorized personnel (physicians responsible 
for the study) will have the access rights and all changes on the database are trackable. 
Sensitive data will be archived for 10 years. 
 
12.3 Monitoring  
The Monitor of the study will be: 
• 
Dr. Med. Stephan Engelberger, Caposervizio Chirurgia Vascolare OCL Lugano. GCP 
statement I and II level 
 
12.4 Audits and Inspections  
The monitor will perform 2 inspections / year and will send to the Local Ethical Committee 1 
report / year about safety data. 
 
12.5 Confidentiality, Data Protection  
The Principal Investigator has the overall responsibility for the data management. Data will be 
accessible only by authorized personnel (physicians responsible for the study). Authorised 
representatives of the Sponsor/Investigator, the monitor, a competent authority or an ethics 
committee may have direct access to parts of the medical records relevant to the study. They 
are authorized to CRF access.  
 
13. PUBLICATION AND DISSEMINATION POLICY  
The trial results will be communicated to the healthcare professionals, the public and other 
relevant groups via publication 
 
 

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14. FUNDING AND SUPPORT  
None 
 
14.1 Funding  
None 
 
14.2 Other Support  
None. 
 
15. INSURANCE  
Not needed 
 
 

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16. REFERENCES  
1. Simillis C, Thoukididou SN, Slesser AA, Rasheed S, Tan E, Tekkis PP. Systematic review and 
network meta-analysis comparing clinical outcomes and effectiveness of surgical treatments for 
haemorrhoids. Br J Surg. 2015 Dec;102(13):1603-18. 
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12. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, Published: May 28, 2009 

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17. APPENDICES 
Other documents needed are listed:  
 
1. Informed consent 
2. Patient’s formulary (CRF include all the clinical information to be collected in the trial) 
3. Protocollo per pazienti ambulanti