Assessment of Women's Sexual Quality of Life After Benign Adnexal Surgery Using vNOTES Approach in Comparison to Conventional Laparoscopy: a Randomized Controlled Trial
Phase: NA
Conditions: Gynecologic Disease, Adnexal Mass, Adnexal Cyst, Sexuality, Adnexal Diseases, Sexual Dysfunction, Quality of Life, Pathology, Dyspareunia, Pelvic Pain, Complication
Sponsor: Jean Dubuisson

Study vNOTES CCER n°2022-00407 
Version 8.3, 24/07/2022 
Protocol Title 
 
 
 
 
Assessment  of women’s sexual  quality  of life  after  
benign  adnexal  surgery  using  vNOTES approach  in 
comparison  to conventional  laparoscopy:  a 
randomized  controlled  trial  
 
 
 
 
 
Study Type: 
Other Clinical Trial according to ClinO, Chapter 4 
 
Risk Categorisation:  
A 
 
Study Registration: 
 
Intended to be statement of study registration: ClinicalTrials.gov  
 
Registration number from the FOPH portal SNCTP (Swiss 
National Clinical Trial Portal): CCER 2022-00407 
 
Sponsor: 
Dr. Jean Dubuisson, MD 
Hôpitaux Universitaires de Genève 
Service de gynécologie 
Unité de Chirurgie Gynécologique 
Bd de la Cluse 30, 1205 Genève 
 
Jean.Dubuisson@hcuge.ch 
+41 (0)79 55 35 018  
 
Principal Investigator: 
Same as Sponsor 
 
Investigated Intervention: 
Benign adnexal surgery using vNOTES approach in comparison to 
conventional abdominal laparoscopy.  
 
Protocol ID: 
 
 
Study vNOTES CCER n°2022-00407 
 
Version and Date: 
 
Version 8.3 (dated 24.07.2022) 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of Sponsor-Principal 
Investigator, Dr Jean Dubuisson. The information may not - in full or in part - be transmitted, 
reproduced, published, or disclosed to others than the applicable Competent Ethics Committee(s) 
and Regulatory Authority(ies) without prior written authorisation from the sponsor except to the 
extent necessary to obtain informed consent from those who will participate in the study. 
 
 

 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
2 
GLOSSARY OF ABBREVATIONS 
3 
1 STUDY SYNOPSIS 
4 
2 BACKGROUND AND RATIONALE 
7 
3 STUDY OBJECTIVES AND DESIGN 
9 
3.1 Hypothesis and primary objective 
9 
3.2 Primary and secondary endpoints 
9 
3.3 Study design 
11 
3.4. Study intervention 
11 
4 STUDY POPULATION AND STUDY PROCEDURES 
13 
4.1 Inclusion and exclusion criteria, justification of study population 
13 
4.2 Recruitment, screening and informed consent procedure 
14 
4.3 Study procedures 
16 
4.4 Withdrawal and discontinuation 
21 
5 STATISTICS AND METHODOLOGY 
22 
5.1. Statistical analysis plan and sample size calculation 
22 
5.2. Handling of missing data and drop-outs 
23 
6 REGULATORY ASPECTS AND SAFETY 
24 
6.1 Local regulations / Declaration of Helsinki 
24 
6.2 (Serious) Adverse Events and notification of safety and protective measures 
24 
6.3 (Periodic) safety reporting 
25 
6.4 Radiation (not applicable) 
25 
6.5 Pregnancy (not applicable) 
25 
6.6 Amendments 
25 
6.7 Notification and reporting upon completion, discontinuation or interruption of the study
 
25 
6.8 Insurance 
26 
7 FURTHER ASPECTS 
27 
7.1 Overall ethical considerations 
27 
7.2 Risk-benefit assessment 
27 
8 QUALITY CONTROL AND DATA PROTECTION 
28 
8.1 Quality measures 
28 
8.2 Data recording and source data 
28 
8.3 Confidentiality and coding 
28 
8.4 Retention and destruction of study data 
29 
9  MONITORIMG AND REGISTRATION 
30 
10. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
30 
11. REFERENCES 
31 
 
 

 
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GLOSSARY OF ABBREVATIONS 
 
AE 
Adverse Event 
ASR 
Annual Safety Repot 
BASEC 
Business Administration System for Ethical Committees 
CAL 
Conventional Abdominal Laparoscopy 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
electronic Case Report Form 
FADP 
Federal Act on Data Protection (in German: DSG, in French: LPD, in Italian: LPD) 
FOPH 
Federal Office of Public Health 
GCP 
Good Clinical Practice 
HRA 
Human Research Act (in German: HFG, in French: LRH, in Italian: LRUm) 
ICH 
International Conference on Harmonisation  
POD 
Pouch Of Douglas 
RCT 
Randomised Controlled Trial 
SAE 
Serious Adverse Event 
vNOTES  
Transvaginal Natural Orifice Transluminal Endoscopic Surgery 
 
 
 
 
 

 
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1 
STUDY SYNOPSIS 
Sponsor-
Investigator 
Dr. Jean Dubuisson, MD 
Hôpitaux Universitaires de Genève 
Service de gynécologie 
Unité de Chirurgie Gynécologique 
Bd de la Cluse 30, 1205 Genève 
Jean.Dubuisson@hcuge.ch 
+41 (0)79 55 35 018 
Study Title 
Assessment of women’s sexual quality of life after benign adnexal surgery using vNOTES 
approach in comparison to conventional laparoscopy: a randomized controlled trial. 
Short Title / 
Study ID 
Study vNOTES CCER n°2022-00407  
Protocol Version 
and Date 
Version 8.3 (dated 24/07/2022) 
Study 
Registration 
Intended to be statement of study registration: ClinicalTrials.gov 
Study Category 
and Rationale 
A, used in accordance with the prescribing information. 
Background and 
Rationale  
Transvaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES), a recent 
innovation in minimally invasive surgery, has already demonstrated its potential superiority to 
conventional abdominal laparoscopy (CAL) for hysterectomy in terms of effectiveness and 
safety and its absence of impairment on women’s sexuality. However, we note a lack of 
medical literature and no specific randomized controlled trial (RCT) assessing women’s 
sexual function after vNOTES for benign adnexal surgery.   
Risk / Benefit 
Assessment 
Risk: any. Both surgical techniques are used in routine and have proven their effectiveness 
and safety for benign adnexal surgery.  
Benefit: by contributing to the general and sexual well-being research and by aiming to 
promote a more effective and safer surgical technique. 
Objective(s) 
Primary objective: confirm non-inferiority of vNOTES on women’s sexual function.  
Secondary objective: confirm vNOTES technique’s equivalency in terms of efficiency, 
morbidity and complications compared to CAL. 
Endpoint(s) 
Primary outcome: women’s quality of sexual life evaluation after benign adnexal surgery by 
vNOTES compared to CAL using FSFI, CSI-16 questionnaires and a self-reported 
questionnaire on dyspareunia.   
 
Secondary outcomes: compare vNOTES with CAL in terms of effectiveness (operation 
duration and length of stay, need to specimen morcellation for extraction), recovery 
(postoperative pain and pain medication consumption) and complications up to 30 days 
postoperative (rate of entry failure, complications during laparoscopic entry, vaginal or 
parietal complications, re-hospitalization and reoperation). 
Study Design 
Open label; randomized (1:1 ratio); active control; parallel groups. 
Statistical 
Considerations 
Analyses will be carried out according to the intention-to-treat principle. Sensitivity analyses 
will be conducted to verify whether the exclusion of participants who no longer conform to the 
protocol may alter the study’s final results.  
 
Sample size was calculated considering truly no difference in the preoperative and 
postoperative FSFI score between women treated with laparoscopy and with the vNOTES 
approach. 80% sure that the lower limit of a one-sided 95% confidence interval will be above 
the non-inferiority limit of -2, with a significance level of 5%. Standard deviation of the 
outcome equal to 3. 
 
 

 
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Inclusion- / 
Exclusion 
Criteria 
Inclusion criteria: Women aged from 18 to 70 years; Discernment capacity with oral and 
written consent signed; Heterosexual intercourse (with vaginal penetration) within four weeks 
prior to inclusion in the study.  
 
Exclusion criteria: History of rectal surgery; Suspected rectovaginal/retrocervical 
endometriosis; History of brachytherapy or pelvic radiation; Suspected ovarian malignancy; 
History of severe pelvic inflammatory disease; Active lower genital tract infection; Pregnancy; 
Women who do not speak fluent French or English (language of surveys); Patients under 
tutelage. 
Number of 
Participants with 
Rationale 
Total of participants: 62.  
31 participants per treatment group.  
 
Study 
Intervention 
Benign adnexal surgery using transvaginal Natural Orifice Transluminal Endoscopic Surgery 
Control 
Intervention 
Benign adnexal surgery using Conventional Abdominal Laparoscopy.  
Study 
procedures 
Women aged 18–70 years with a benign adnexal surgery planed (elective 
cystectomy/oophorectomy for presumed benign adnexal pathology, elective salpingectomy 
or tubal sterilization) at Geneva University Hospitals will be eligible and randomized to one of 
the two intervention groups.  
Participants will complete the FSFI, the CSI-16 and a self-reported questionnaire on 
dyspareunia within 4 weeks prior to randomization and at 3 + 6 months after surgery. 
General and clinical data will be collected when the patient is enrolled in the study, during 
hospitalization and at 1 month postoperative to assess secondary outcomes.  
Study Duration 
and Schedule 
Pilot phase: 6 months  
Total estimated duration: 2 years 
First-Participant-In: 10.2022 
Last-Participant-Out: 04.2023 (pilot phase) / 10.2024 
Investigator(s) 
Doctorate- Co-Investigator:  
Med. Pract. Eloïse Krull 
Université de Genève, Faculté de Médecine 
eloise.krull@bluewin.ch  
 
Co-Investigator:  
Dr. Shahzia Lambat Emery  
Hôpitaux universitaires de Genève 
Services de gynécologie et obstétrique  
Shahzia.LambatEmery@hcuge.ch  
 
Statistician:  
Dr. Manuela Viviano 
Hôpitaux universitaires de Genève 
Services de gynécologie et obstétrique  
Manuela.Viviano@hcuge.ch  
 
Co-Investigator:  
Dr. Leen Aerts 
Hôpitaux universitaires de Genève 
Service de gynécologie  
Leen.Aerts@hcuge.ch  
 
Co-Investigator:  
Prof. Patrick Petignat  
Hôpitaux universitaires de Genève 
Service de gynécologie  
Patrick.Petignat@hcuge.ch  
 
Research nurse : not yet known 

 
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Study Centre(s) 
Hôpitaux Universitaires de Genève  
Service de gynécologie 
30 Bd de la Cluse  
 
1211 Genève 
Data privacy 
Access to data by authorised persons only; Anonymization by using study numbers; 
Documents locked in a secure place; Care maps for traceability; Use of secure generated 
computer program and online research platform; Use of opaque envelope.  
Ethical 
consideration 
Contribution to clinical research; Improvement of women’s quality of life; Safety of care; Valid 
clinical and scientific results; Favourable Risk-Benefit ratio; Fair study; Voluntary consent; 
Respect for participants.  
GCP Statement 
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, the ICH-GCP, the HRA as well as other locally relevant legal and 
regulatory requirements.  
 
 
 

 
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BACKGROUND AND RATIONALE  
By the end of the twentieth century, conventional abdominal laparoscopy (CAL) has become the 
gold standard and the technique of choice for minimally invasive surgery in many gynaecological 
indications, especially to treat benign adnexal pathologies. Nevertheless, surgical techniques are 
constantly evolving with the aim of being ever less invasive and improving surgical efficiency. 
NOTES (Natural Orifice Transluminal Endoscopic Surgery) is the latest evolution in minimally 
invasive surgery. This surgical technique uses natural orifices of the human body for surgical 
approach (for instance oropharynx, rectum or vagina).  
 
vNOTES is a surgical technique in full expansion in Switzerland. Its use requires specific and 
additional training compared to CAL. This explains why vNOTES is currently only used in certain 
centres and more widely in university hospitals. 
 
Vagina as a surgical route has a long medical history. It has been described and spread since 
the 19th century for hysterectomy (1). Today vaginal route is recommended by international 
societies as the approach of choice for hysterectomy when feasible (2). As demonstrated by two 
medical literature reviews of randomized trials comparing surgical approaches to hysterectomy  
for benign pathology, vaginal hysterectomy has proven its superiority and should be preferred to 
abdominal open hysterectomy for its lower rate of pain and complications, its shorter procedure 
duration and its shorter recovery time (3,4).  
 
The first randomized clinical trial available in the medical literature compares transvaginal NOTES 
(vNOTES) and CAL hysterectomy for a benign pathology (5). Not only does this study prove that 
vNOTES is not inferior to CAL in achieving a successful hysterectomy, without the need for 
conversion, but it also proves that vNOTES is superior to CAL with a shorter procedure duration 
and length of stay, a lower pain Visual Analog Scale (VAS), a diminished use of pain medication 
the week following surgery and a lower rate of postoperative complications.  
 
Although vNOTES for adnexal surgery is also considered effective in the medical literature 
(shorter procedure and length of stay, lower rate of conversion to CAL) and safe (lower rate of 
postoperative complications) (6–12), there is little evidence available. Up to now, there is only 
one recent randomized controlled clinical trial comparing the effectiveness and safety of vNOTES 
technique to CAL for benign adnexal surgery in the medical literature  (13). This NOTABLE trial 
demonstrates non-inferiority of vNOTES approach in terms of effectiveness (success of the 
allocated intervention without the need for conversion to another technique). It also demonstrates 
shorter procedure time, lower pain VAS and diminished use of pain medication during the first 
postoperative week with the vNOTES approach. However, the study shows a trend for more 
adverse effects with vNOTES approach (one case of intraperitoneal spilling, four cases of 
postoperative bleeding) but no statistically significance between the two approaches for 
intraoperative and postoperative complications.  
 
vNOTES adnexal surgery is particularity attractive to women (14,15) because it does not involve 
any parietal scarring and thus represents a reduced risk of parietal complications. These 
complications include trocar-site hematoma (mainly due to injury of the lower epigastric vessels), 
trocar-site infection, trocar-site neuralgia (due to iliohypogastric or iliolinguinal nerves injury during 
fascial closure of the trocar incisions), trocar-site dehiscence, trocar-site hernia, leading to re-
hospitalization and re-operation (14–17). Intraoperatively, the laparoscopic entry and the creation 
of the pneumoperitoneum during CAL can lead to vessel or bowel injuries as well as failure to 
enter the peritoneal cavity, particularly in case of severe intraabdominal adhesions. The 
transvaginal approach bypasses these intraabdominal adhesions by using a direct route and thus 
represents less risk.  
 
 
 

 
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vNOTES for adnexal pathology seems to be a promising technique but the consequences of a 
transvaginal approach, including a vaginal scar, on women’s sexual quality of life are not well 
established yet.   
Studies looking at women's perceptions towards vNOTES showed that young nulliparous women, 
although more concerned than older women about vNOTES’s cosmetic benefits, were less likely 
to accept it because they feared for their future sexual function (including dyspareunia) and fertility 
(14,15,18). Bucher et al. detailed patients fears and showed that 76% of their participants had 
concerns regarding postoperative intercourse abstinence after vNOTES, including: feeling less 
attractive (40%), less feminine (40%), tension with their intimate (35%), lover non-acceptation 
(20%), possible abortion of new relationship (26%) and feeling less comfortable socially (16%).  
 
Assessment of women's sexual function before and after vNOTES has already been studied for 
non-gynaecological surgical procedures (cholecystectomy, anterior gastrointestinal resection, 
appendectomy, bariatric surgery, adrenalectomy and nephrectomy with or without renal 
transplantation). Although a 2016 review of the medical literature (19) concluded that there was 
no risk of sexual dysfunction after vNOTES gynaecological surgeries, we note a lack of data 
assessing women’s sexual function. 
 
Therefore, we propose a randomized controlled trial comparing vNOTES with CAL for benign 
adnexal surgery (risk category: A, used in accordance with indication). The primary objective of 
this study is to confirm non-inferiority of vNOTES on women’s sexual function. The secondary 
objective is to compare vNOTES with CAL in terms of effectiveness (operation duration and length 
of stay, need to specimen morcellation for extraction), recovery (postoperative pain and pain 
medication consumption) and complications (rate of entry failure, complications during 
laparoscopic entry, vaginal or parietal complications, re-hospitalization and reoperation). 
 
By proving the absence of statistically significant alteration of the vNOTES technique on women's 
sexual quality of life compared to CAL, associated with the confirmation of this technique's 
equivalency in terms of its efficiency, we hope to increase the acceptance of the vNOTES 
technique for benign adnexal surgery in the female general population and more specifically in 
the younger women, who are presently more reticent to this technique.    
 
 

 
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3 
STUDY OBJECTIVES AND DESIGN  
3.1 Hypothesis and primary objective 
The primary objective of this study is women’s quality of sexual life evaluation after benign 
adnexal surgery (cystectomy, oophorectomy, tubal sterilization, salpingectomy) by vNOTES 
compared to CAL using FSFI, CSI-16 questionnaires and a self-reported questionnaire on 
dyspareunia.   
Based on the data available, our hypothesis is that vNOTES does not alter women’s sexual 
function after benign adnexal surgery, with similar outcomes to CAL. 
 
The secondary objective of this study is to confirm the vNOTES technique’s equivalency in terms 
of efficiency, morbidity and complications compared to CAL.  
3.2 Primary and secondary endpoints 
 
Primary outcome:  
 
Sexual function is a complex and multidimensional issue. It interacts closely with emotional well-
being, quality of life, relationship with partner and health status (20). In order to evaluate sexual 
quality of life of patients after benign adnexal surgery, it is important to consider these close links.  
In our study, emotional well-being is assessed asking the presence of any anxiety or depressive 
disorder during the medical preoperative consultation. No specific questionnaire to identify the 
anxiety-depressive state is added in order to avoid overloading patients with questions. 
Information about the patient's health status will also be collected during the preoperative medical 
consultation. The FSFI questionnaire precisely assesses each domain of sexuality and includes 
questions about the intimate relationship with the partner. CSI-16 asks questions related more 
generally to the love relationship with the partner. We added a self-developed questionnaire on 
dyspareunia. The presence of superficial and/or deep dyspareunia will be assessed together with 
pain intensity.    
 
FSFI 
The FSFI questionnaire, created in 2000 by Raymond Rosen, is a reliable and complete 
multidimensional self-reported instrument for the measurement of female sexual function. It is 
validated in English and assesses 19 items divided into six domains of sexual function: (a) desire 
(2 items), (b) subjective arousal (4 items), (c) lubrication (4 items), (d) orgasm (3 items), (e) 
satisfaction (3 items) and (f) pain/discomfort (3 items). Each item focuses on the situation during 
the last 4 weeks. FSFI is a good instrument as it addresses both cognitive and functional 
dimensions of sexual function (21). Moreover, it is available in a validated French version (22).  
The total score is the sum of answers provided for each of the 6 domains. The scores for items 
1, 2, 15 and 16 range from 1 to 5 while the others range from 0 to 5. Lower is the score, worse is 
the patient's sexual function. A total score below 26 defines impaired sexual function (23). 
 
CSI-16 
The Couple Satisfaction Index (CSI) is a precise, consistent and validated scale that evaluates 
the quality of a couple’s relationship satisfaction (24). A longer version (CSI-32) and a shorter 
version exist (CSI-4). We chose the 16-items version because it provides enough information for 
the assessment of relationship satisfaction (24) and reduces the number of questions to be 
answered, a significant aspect in our study, which includes several questionnaires for a 
multidimensional assessment. Limitation of this questionnaire is the insufficient evidence of good 
reliability over short periods of time (25). Each item is scored from 0 to 5 with different answer 
formats. The total score can range from 0 to 81. Higher is the total score, better is the relationship 
satisfaction. A relationship dissatisfaction is suggested when the total score is bellow 51,5 (25). 

 
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The French available version of CSI-16 has unfortunately not been translated and validated by 
the developers.  
 
Primary Outcome: Sexual Function 
The primary outcome regarding the absence of impairment on sexual function, after elective 
benign adnexal surgery by vNOTES in comparison with CAL, refers to the stability or improvement 
of FSFI total scores in each group at 3 and 6 months after surgery compared with the preoperative 
score and the absence of a statistically significant difference in FSFI total postoperative scores 
between the two groups.  
The results of preoperative CSI-16 and self-reported questionnaire on dyspareunia provide an 
indication of the patient's baseline status. Results and evolution of these questionnaires scores 
at 3 and 6 months postoperatively allow us to specify, in the case of a de novo postoperative 
sexual dysfunction, whether it is solely related to the surgical technique used, in which case CSI-
16 and self-reported questionnaire on superficial dyspareunia scores are the same as baseline 
values or below the diagnostic cut-off point, or whether it is associated with a relationship issue 
or superficial dyspareunia, in which case such scores are statistically increased in comparison 
with baseline values. 
 
 
Secondary outcomes:  
 
Comparison on effectiveness, morbidity, complications rate  
Evaluation of the success rate (removal of the specimen without the need of conversion to 
laparoscopy or open-surgery), the procedure duration including the need for adhesiolysis, 
recovery (length of stay, pain scores) and perioperative complications up to 30 days 
postoperatively: 
− 
Intraoperative complications: failure to enter the peritoneal cavity, need for conversion, 
intraoperative complication during peritoneal cavity access, intraoperative blood loss, bowel 
or vessel injury.  
− 
Postoperative complications: delayed vaginal or parietal healing (abscess, hematoma, 
dehiscence), trocar-site hernia, trocar-site nerve injury, re-hospitalization and re-operation. 
 
Morcellation/aspiration and histological analysis  
Although our study focuses on presumed benign adnexal masses, the risk of unexpected 
malignancy needs to be taken into consideration during the specimen extraction in order to avoid 
any tumoral cell spillage. Only postoperative histological analysis can determine the definitive 
diagnosis. The Swiss Society of Gynaecology and Obstetrics practice guide for the discovery of 
an adnexal mass recommends that a suspicious diagnosis of a mass should be established on 
the basis of the information provided by clinical and paraclinical examinations, including mass 
size and ultrasound morphological criteria (26). This type of information allows scoring and 
facilitates the distinction between benignity and malignancy and thus the subsequent 
management (26).  
Morcellation or aspiration of an adnexal mass is not recommended (26). However, it is performed 
in case of a large mass to provide its extraction during CAL in order to limit the cosmetic sequelae 
and possible parietal consequences of enlarging the incision. If morcellation or aspiration is 
required, it is done in an endoscopic bag in order to limit cell spillage. 
To the best of our knowledge, there is no data in the literature investigating the relationship 
between adnexal mass morcellation/aspiration and histological analysis quality of the surgical 
specimen.  In fact, histological analysis is always possible even on a fragmented specimen. 
However, the ability to obtain an accurate malignancy diagnosis seems to be compromised since 
TNM Classification of malignant tumors requires macroscopic information such as ovary's surface 
invasion for instance.  
We believe that the elastic vaginal incision offered by vNOTES reduces the need for operative 
morcellation or aspiration during the specimen extraction in comparison with transparietal 
removal. 

 
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3.3 Study design  
This is a single-centre, parallel-group, unblinded, balanced randomization study (1:1 matching for 
vNOTES and CAL) conducted in the Department of Paediatrics, Gynaecology and Obstetrics at 
the Geneva University Hospitals, Switzerland. We will be using a non-inferiority study design to 
address primary outcome of vNOTES versus CAL for elective benign adnexal surgery. 
Methods of minimising bias include: randomisation and use of validated questionnaires.  
3.4. Study intervention 
 
Intervention description: vNOTES interventional group  
 
First common steps: 
General anaesthesia, prophylactic antibiotic, 0° Trendelenburg position. Bladder catheterization.  
The bladder is catheterized during the whole procedure.  
 
1. Clinical examination 
A pelvic examination is performed to confirm the absence of nodularity infiltrating the 
rectouterine (RU) pouch, to assess the mobility of the uterus. 
Vaginal retractors help to well expose the operative field. 
 
2. Vaginal infiltration 
Vaginal mucosa in the posterior fornix is infiltrated with diluted adrenaline solution 
according to patient comorbidities. 
 
3. Posterior colpotomy  
A cold scalpel is used for the colpotomy. 
A 2.5 – 3 cm «smile-like» incision is performed, 2cm away from the cervix. 
Dissection is then performed with scissors, pushing away dorsally the rectal fibres until 
seeing the pouch of Douglas (POD) by transparency. 
Peritoneal incision is performed to access to the entire POD, stretching the opened 
peritoneum. 
 
4. Insertion of the Alexis wound retractor  
The Alexis retractor-protector is inserted into the created spaces by squeezing the inner 
ring.  
The tenaculum is removed.  
 
The outer ring of the Alexis is then rolled up  
 
5. Attachment of the GelPoint cap 
The GelPOINT access platform is connected to the Alexis retractor. 
A 7cm vNOTES port is chosen. 
The GelPOINT has 3 port access: 1 for the endoscope and two for the accessory trocars.  
Concerning the trocar placement, the optic trocar is placed at 6 o’clock and 2 accessory 
trocars at 10 and 2 o’clock. 
 
6. CO2 insufflation 
A pneumoperitoneum is created with CO2 insufflation as in conventional abdominal 
laparoscopic surgery. Low intraabdominal pressures are used (10-12 mmHg).  
7. Endoscopic part of the vNOTES procedure:  
The patient is then put in a 20° Trendelenburg position. 
A 0° or 30° 10mm endoscope is inserted with standard laparoscopic instruments.  
The entire abdominal cavity is inspected. 

 
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Peritoneal washing is performed at this time. 
The specific procedures include the same steps as during CAL.  
 
An endoscopic bag is inserted to remove the specimen. 
 
Common final steps: 
the vNOTES GelPoint platform and the Alexis retractor are removed 
The posterior colpotomy, including vaginal mucosa and peritoneum, is closed using a running 
absorbable suture. 
 
No packing, no Foley catheter is needed in the postoperative period, following the principles of 
FAST TRACK surgery  
 
 
Intervention description: CAL control group   
 
First common steps: 
General anaesthesia, prophylactic antibiotic, 0° Trendelenburg position. Bladder catheterization.  
The bladder is catheterized during the whole procedure.  
Clinical examination. 
 
1. Laparoscopic entry using a Veres needle, either at the Palmer point or in the umbilicus.  
2. 3 or 4 trocars are inserted with a high pressure pneumoperitoneum (20 mmHg). In a 
second step the pressure is decreased to 12 mmHg after the trocar placement. A 0° 5mm 
or 10mm endoscope is used.   
3. 20 to 25° Trendelenburg position.  
4. Inspection of the entire abdominal cavity 
5. Peritoneal washing. Identify the ureters. Inspect the entire abdominal cavity (liver, 
stomach, peritoneum).  
 
The specific procedures include the same steps as during vNOTES.  
 
An endoscopic bag is inserted for the removal of the specimen.  
Most of time, the parietal incision of the left accessory trocar is enlarged to remove the specimen. 
Depending on its size and its components, using in-bag cold morcellation and/or intracystic liquid 
aspiration may be necessary.   
 
The Foley catheter is removed at the end of the surgery. 
 
 
 
 

 
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4 
STUDY POPULATION AND STUDY PROCEDURES 
4.1 Inclusion and exclusion criteria, justification of study population 
All women aged from 18 to 70 years regardless of parity in whom a benign adnexal surgery 
(elective cystectomy/oophorectomy for presumed benign adnexal pathology, elective 
salpingectomy or tubal sterilization) is planned in the division of Gynaecology of the Geneva 
University Hospitals will be proposed this study, if they do not meet exclusion criteria.  
The study needs a total number of participants of 62 (31 in each group) to achieve sufficient 
power.  
 
Inclusion criteria are the following:  
1. Women aged from 18 to 70 years. 
2. Discernment capacity with oral and written consent signed. 
3. Heterosexual intercourse (with vaginal penetration) within four weeks prior to inclusion in 
the study. 
 
Exclusion criteria are the following:  
• 
History of rectal surgery 
• 
Suspected rectovaginal/retrocervical endometriosis 
• 
History of brachytherapy or pelvic radiation 
• 
Suspected ovarian malignancy 
• 
History of severe pelvic inflammatory disease 
• 
Active lower genital tract infection  
• 
Pregnancy  
• 
Women who do not speak fluent French or English 
• 
Patients under tutelage 
 
Patients under tutelage, with or without capacity of judgement, will be excluded from the study 
because of assessment modalities including the intrusive nature of the questionnaires.  
 
 

 
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4.2 Recruitment, screening and informed consent procedure 
 
The surgeon will give eligible patients who agree to participate all the information specific to the 
two surgery approaches in order to have the surgical consent form signed in a free and informed 
manner during the medical preoperative consultation.  
 
Right after the medical preoperative consultation, the research nurse will give to those patients 
all the information (nature, purpose, procedures, expected duration, potential risks and benefits 
and any discomfort it may entail) about the study to get the information sheet and consent form 
describing the study signed in a free and informed manner. Each patient is informed that the 
participation is voluntary and that she may withdraw from the study at any time and that withdrawal 
of consent will not affect her subsequent medical assistance and treatment. The patient is also 
informed that authorised individuals other than their treating physician may examine their medical 
records. The patient is informed that she can ask any question, and consult with family members, 
friends, their treating physicians or other experts before deciding about their participation in the 
study. Enough time is given to the subjects. A subsequent consultation appointment with the 
research nurse can be arranged few days to one week later if necessary.  
 
If the patient agrees to participate in the study, a copy of the consent form signed by the patient, 
the surgeon and/or the research nurse will be given to the patient and the original will be kept as 
part of the survey records. The informed consent process will be documented in the patient file 
and any discrepancy to the process described in the protocol will be explained. 
 
The formal consent of a participant, using the approved consent form, will be obtained before the 
participant is submitted to any study procedure.   
 
 
 

 
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Figure 1. CONSORT (Consolidated Standards of Reporting Trials) 2010 flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed for eligibility 
(n = ) 
Women 18-70 years with elective 
benign adnexal surgery planed 
 
 
Excluded (n = )  
- With exclusion criteria (n = ) 
- Not meeting inclusion criteria (n = ) 
- Decline to participate (n = ) 
 
Allocated to CAL (n = 31) 
 
Allocated to vNOTES 
(n = 31) 
 
Received intervention (n = ) 
 
Did not receive 
intervention  
(give reasons) (n = ) 
 
Randomized (n = 62) 
 
 
Did not receive 
intervention  
(give reasons) (n = ) 
 
Follow -up (n = ) 
 
Discontinued intervention 
 
(give reasons) (n = ) 
 
Lost to follow -up  
(give reasons) (n = ) 
 
Received intervention (n = ) 
 
Discontinued intervention 
 
(give reasons) (n = ) 
 
Lost to follow -up  
(give reasons) (n = ) 
 
Follow -up (n = ) 
 
Analyzed  (n = ) 
 
Not analyzed  (n = ) 
 
Analyzed  (n = ) 
 
Not analyzed  (n = ) 
 
Enrollment  
 
 
Allocation  
 
 
Follow -up 
 
 
Analysis  
 

 
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4.3 Study procedures 
If the patient accepts to participate in the study, the surgeon will get the surgery informed consent 
form signed and collect clinical and demographic information on the medical-logbook during the 
preoperative medical consultation. Right after, the research nurse will complete general 
information and will get the study informed consent form signed.  
The FSFI and CSI-16 questionnaires will be provided in French or English depending on the 
patient’s preference and self-completed by the patient within 4 weeks prior to randomization and 
3 + 6 months postoperatively on a secure online platform. If patients do not respond on time, the 
online response platform will send them up to three reminders.   
Patients with pre-existing sexual dysfunction can be included in the study. The type of sexual 
dysfunction must be documented and the evolution of sexual function can still be assessed by 
comparing preoperative and postoperative questionnaires scores.  
The diagnosis of rectovaginal or retrocervical endometriosis is strong anatomical exclusion 
criteria for vNOTES approach.  
We have deliberately not given a latency postoperative period before resuming sexual activity to 
avoid biasing women according to the surgical technique used. We trust that they will resume 
sexual activity based on the sensations of their body. We do not fear more vaginal infectious 
complications or vaginal cuff dehiscence when resuming sexual activity early after using the 
vNOTES approach.  
 
Instruments: 
1) Care maps will be used as a step-by-step procedure for all medical providers (surgeons, 
residents, anaesthetists, nurses and the research nurse) for each group.  
2) A medical-logbook containing general and clinical information will follow the patient at 
each stage of her medical pathway (preoperative, intraoperative, during hospitalization 
and at 1 month postoperatively) and will be filled in by each medical provider.  
3) All three questionnaires will be self-completed by the patient within 4 weeks prior to 
randomization and at 3 + 6 months postoperative on a secure online platform. A 
satisfaction enquiry will be self-completed by the patient on the last day of her 
hospitalization. 
 
General information collected preoperatively are the following:  
1) Age 
2) BMI 
3) Parity/gestity 
4) Number of vaginal deliveries 
5) Menopausal status (pre-menopause, post-menopause) 
6) Marital status (single, in couple) 
7) Employment status (employed part-time, employed full-time, unemployed but looking for 
work, unemployed and not looking for work, self-employed, student) 
8) Level of education (high school, college or equivalent, university or other higher studies)  
9) Habits (smoking, alcohol, drugs) 
10) Infertility: primary or secondary 
11) Non-gynaecological comorbidities 
12) Gynaecological comorbidities 
13) Active follow-up for sexual function disorder: if yes, which type? 
14) History of abdominal or pelvic surgery 
15) History of pelvic radiation 
16) Diagnosis of anxiety-depressive disorder 
17) History of sexual abuse 
18) Treatments (hormonal, potentially sexual impacting drugs such as antidepressants or 
antipsychotics) 

 
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The research nurse will be trained by the HUG's UIMPV (Interdisciplinary Unit for Medicine and 
Prevention of Violence) to ask about a history of sexual abuse. In this way, she will be able to 
receive the information and to refer the patient to the HUG's UIMPV in a more or less urgent 
manner depending on the situation. If the patient refuses help, the research nurse will give her 
contact details in case she changes her mind, as well as emergency numbers and places for help 
in case such a situation occurs again. The research nurse will obviously explain to the patient 
how this information will be used to interpret the data.  
 
Clinical information collected include: 
1) Preoperative:  
a) Clinical examination:  
i) 
Pain (0-1), intensity (VAS scale 0-10), location of the pain 
b) Paraclinical examination: ultrasound +/- MRI 
i) 
Uterus: size, morphology (anteverted/ retroverted/ lateralized)  
ii) Ovaries and adnexal mass: size, type (cystic (functional, organic), solid, mix), O-RADS 
and/or IOTA classification. 
iii) Other findings  
c) Tumoral markers: CA 125, others 
d) Urine pregnancy test 
 
2) Intraoperative:  
a) Surgery:  
i) 
Type: unilateral cystectomy (1), bilateral cystectomy (2) unilateral oophorectomy (3), 
bilateral oophorectomy (4), tubal sterilization (5), unilateral salpingectomy (6), bilateral 
salpingectomy (7) 
ii) Interventional group: vNOTES arm vs CAL arm  
iii) vNOTES intraoperative complications:  
(1) Entry failure 
(2) Need for CAL/open surgery conversion 
(3) Blood loss (ml), localization (vessel injured) need for blood transfusion (number of 
erythrocyte concentrate (EC)) 
(4) Bowel injury  
(5) Other 
iv) CAL intraoperative complications:  
(1) Entry failure 
(2) Need for conversion to open surgery  
(3) Bleeding at trocar site  
(4) Blood loss (ml), localization (vessel injured), need for blood transfusion (number 
of EC) 
(5) Bowel injury  
(6) Other 
v) Intraabdominal parietal adhesions: yes/no, Need for adhesiolysis: yes/no 
vi) Procedure duration 
b) Surgical specimen extraction method:  
i) 
Transvaginal / transparietal 
ii) Use of endoscopic bag: yes/no  
iii) Need to enlarge the incision: yes/no, if yes how many millimetres (mm) more? 
iv) Need for morcellation or aspiration: yes/no, if morcellation: number of fragments (1-5; 
5-10; >10) 
 
 

 
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3) During hospital stay: 
a) Postoperative complications during hospital stay: type according to Clavien-Dindo 
classification 
i) 
Vaginal hematoma (hematic collection confirmed on ultrasound or CT scan associated 
with clinical signs (pelvic or vaginal pain)). 
ii) Parietal hematoma (hematic collection confirmed on ultrasound or CT scan associated 
with clinical signs (pain at the site of the hematoma). 
iii) Vaginal bleeding (ml). 
iv) Intraperitoneal haemorrhage (hematic fluid confirmed on ultrasound or CT scan 
associated with abdominal pain and or hypotension / tachycardia). 
v) Need for blood transfusion (number of EC) 
vi) Other 
b) Need for an intervention procedure/ reoperation: rate and reason 
c) Length of stay in hours 
d) Postoperative pain:  
i) 
Mean VAS 
ii) Pain relief: total number and level  
 
4) At 1 month postoperative:  
a) Surgery recommendation to surroundings (reasons) 
b) Pain  
i) 
Mean VAS  
ii) Location 
iii) Pain relief: level 
 
c) Complications: type, Clavien-Dindo classification 
i) 
Delayed vaginal healing 
Secondary to:  
(1) Abscess: a fluid-like collection seen on ultrasound or CT scan with clinical (pain, 
leucorrhoea, fever) and/or biological (leucocytosis, increased CRP) infectious 
signs +/- presence of a germ on culture. 
(2) Hematoma: a hematic collection seen on ultrasound or CT scan with clinical signs 
(pelvic or vaginal pain). 
 
ii) Delayed parietal healing 
Secondary to:  
(1) Abscess: a fluid-like collection seen on ultrasound or CT scan with clinical (pain at 
the site of the hematoma, fever) and/or biological (leucocytosis, increased CRP) 
infectious signs +/- presence of a germ on culture. 
(2) Hematoma: a hematic collection seen on ultrasound or CT scan with clinical 
 
signs (parietal pain). 
 
iii) Trocar-site dehiscence  
(1) Superficial dehiscence limited to the skin and clinically evident. 
(2) Incisional hernia including peritoneal tissue which must be confirmed on 
ultrasound or CT scan.  
 
iv) Vaginal scar dehiscence: opening of the vaginal mucosa confirmed at the clinical 
examination  
 
 

 
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v) Trocar-site neuralgia: iliohypogastric or iliolinguinal nerves injury during fascial closure 
of the trocar incisions or introduction of the trocars. It is characterized by a persistent pain 
at 4 weeks postoperative or appearing after surgery, such as electric discharge/burning 
or painful cold sensation, respecting the territory of the nerve affected (with irradiation 
towards the pubis for the iliohypogastric nerve and towards the labia majora with or without 
presence of dyspareunia for the ilioinguinal nerve) and which may be associated with 
dysesthesia (tingling, prickling, itchiness, numbing)(27). 
 
vi) Others 
 
d) Rehospitalisation: rate and reason 
e) Need for an interventional procedure/ reoperation: rate and reason 
 
f) Sexuality: 
i) 
Latency to resume sexual activity (vaginal penetration) 
ii) Frequency of sexual intercourse in the last month (vaginal penetration) 
 
g) Histology: complete/limited, diagnosis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Patient  completes all three questionnaires on secure online platform 
If there is no response, up to three reminders sent automatically by the online response platform 
 
3 + 6 
months  
postop  
Figure 2. Study protocol; preop = preoperative; postop = postoperative 
 
 
 
 
 
18-70y eligible patients who agree to participate in the study 
 
Medical preop consultation
 
Surgery indication 
Surgeon:  
- Gets the intervention informed consent form signed 
- Completes medical logbook (general + clinical information) 
 
Research nurse:  
- Address a study number to the patient  
- Completes medical-logbook (general + clinical information) 
- Gives study’s objectives and protocol, get the study informed consent form signed 
 
1. Research nurse  sends study numbers to the research assistant  
2. Research assistant  randomizes study numbers with a computer generated program 
3. Research assistant  sends allocation to research nurse  
4. Research nurse  inserts allocation in an opaque envelope containing patient’s name 
 
 
Randomization  
Surgeon:  
- Opens the opaque envelope and takes note of the allocation 
 
The day before or 
The day of surgery  
Allocation 
 
CAL arm  
 
vNOTES arm 
Anesthetic  consultation 
Hospitalization on day of surgery: 
Solids stopped 6 hours prior to surgery, drinking encouraged up to 2 hours prior to surgery, urine 
pregnancy test 
 
Common steps during specific surgery:  
Bladder catheterizing; anti-infectious prophylaxis, anesthesia via IV propofol/remifentanil; anti-nausea 
prophylaxis; pain control based on limited systemic opioid use 
 
Immediate postoperative:   
Surgeon  completes the “intraoperative” part of the medical-logbook  
Surgeon informs the patient about her allocation 
 
 
 
Surgery  
 
Resident and nurses complete the “hospital stay” part of the medical-logbook 
Patient completes the satisfaction enquiry 
 
Postop 
hospital 
stay 
 
Follow-up medical consultation: 
Surgeon  completes the “1 month postoperative” part of the medical-logbook 
 
1 month 
postop  
 
Patient  completes all three questionnaires within 4 weeks prior to randomization on secure online platform 

 
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4.4 Withdrawal and discontinuation 
The participant is withdrawn from the study if she requests it, if exclusion criteria are identified 
during the course of the study, if the disease progresses and requires different medical 
management. Upon premature patient withdrawal from the study, all patient data collected up 
until her drop out will be analysed. Data will be kept anonymous. Reasons for patient drop-out 
will be explained in the final manuscript.  
 

 
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5 
STATISTICS AND METHODOLOGY 
5.1. Statistical analysis plan and sample size calculation 
Statistician: Dr Manuela Viviano, Hôpitaux Universitaires de Genève, Services de Gynécologie et 
Obstétrique 
Role: Participation in the creation of the study design, creation of the statistical analysis plan, 
calculation of the sample size, help with analysis of the statistical data. 
 
Sample size  
Sample size was calculated considering the mean difference in the preoperative and 
postoperative FSFI score, and comparing such difference between women treated with 
abdominal laparoscopy and with the vNOTES approach. If there is truly no difference between 
abdominal laparoscopy and vNOTES in terms of FSFI score, then a sample size of 56 patients, 
corresponding to 28 women in each of the two groups, is needed to be 80% sure that the lower 
limit of a one-sided 95% confidence interval will be above the non-inferiority limit of -2, with a 
significance level of 5%.  We considered a standard deviation of the outcome to be equal to 3. 
We selected the non-inferiority margin based on previously published literature, according to 
which a mean difference of FSFI score by as much as 2 was not statistically significant between 
the abdominal laparoscopic and vaginal approach for hysterectomy (28). Similarly, a study 
evaluating the FSFI after surgery for endometriosis found a statistically significant difference 
between the pre-operative score of 19.1 and the post-operative score of 22.7 (29). Sample size 
was calculated using the online software available at www.sealedenvelope.com. 
We expect a drop-out rate of 10% over the study period, which makes it reasonable to increase 
the total sample size to 62 patients, corresponding to 31 patients per group. Analyses will be 
carried out according to the intention-to-treat principle. Sensitivity analyses will be conducted to 
verify whether the exclusion of participants who no longer conform to the protocol may alter the 
study’s final results, so as to show non-inferiority in both the intention-to-treat and the per-protocol 
populations (30). Reasons of non-conformity may include, among others, the patient’s personal 
decision to drop out of the study after initial inclusion and surgical complications affecting the 
woman’s intra- and post-operative course.  
 
The Department of Paediatrics, Gynaecology and Obstetrics at the Geneva University Hospitals 
surgically treat an average of 100 benign adnexal surgeries per year. We expect a recruitment 
rate of 31%. Thus, we believe that our study will take two years to be completed. This recruitment 
rate may seem high. To test our recruitment rate. We will conduct a 6-month pilot phase.  In case 
the recruitment is lower than expected, the study duration will be extended proportionally to obtain 
the desired sample size. If recruitment at 6 months is greater than or equal to 16 patients, then 
the study will continue for a total duration of 2 years. 
 
Randomization 
Randomization of included patients will be computer-generated with a 1 to 1 ratio, in randomly 
alternating blocks of 4, 6 and 8. After having signed the study and intervention informed consent 
form, patients will be allocated to one of the two treatment arms (vNOTES vs CAL) by means of 
consecutive, numbered, sealed and opaque envelopes.  
Randomization will be performed using an automatically-generated computer program 
(www.randomization.com).  
 
 
 

 
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Sequence design  
A research nurse will be responsible of inserting the randomized pairing choice into a sequentially 
numbered opaque envelope. To avoid the risk of switching the allocation sequence, the 
participant's name and date of birth will be written on the envelope in addition to the allocated 
number. To avoid selection bias, the research assistant will not be allowed to see the patient’s 
file and will not be involved in the data collection. The research nurse will place the sealed 
envelope in the patient's file. 
The surgeon will open the opaque envelope and read the patients assignment to one of the two 
treatment arms on the day before surgery or on the day of surgery and inform the patient about 
her allocation after the surgery. In case the patient decides to withdraw from the study, it should 
be documented in the patient's record. 
 
Blinding 
This is an unblinded study where neither the surgeon, nor the patient is blinded to treatment arm 
assignment.  
 
Statistical analysis  
As recommended by the Consolidated Standards of Reporting Trials (CONSORT) statement, 
analysis will be performed in an intention-to-treat principle. Continuous variables will be reported 
as means with the relative standard deviation (SD). Non-normally distributed continuous variables 
will be reported as medians with the relative inter-quartile range (IQR). Categorical variables will 
be reported as absolute numbers and percentages. The Student T-test will be used to compare 
continuous variables when reported as means, whereas the χ2 test will be used to compare 
categorical variables. The alfa value will be set at 5%, with a probability (p) less than 0.05 to be 
considered as statistically significant. 
5.2. Handling of missing data and drop-outs 
Patient’s data will be analysed until their withdrawal from the study, as in the intention-to-treat 
principle. Reasons for dropping out from the study will be explained in the study’s final manuscript. 
Sensitivity analyses will be carried out in order to evaluate whether the participants who have 
dropped out of the study may alter its final results. The handling of drop-outs is further explained 
in the paragraph “Sample size”.  
 
 

 
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6 
REGULATORY ASPECTS AND SAFETY 
6.1 Local regulations / Declaration of Helsinki 
This study is conducted in compliance with the protocol, the current version of the Declaration of 
Helsinki, the ICH-GCP, the HRA as well as other locally relevant legal and regulatory 
requirements.  
6.2 (Serious) Adverse Events and notification of safety and protective measures 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
subject which does not necessarily have a causal relationship with the trial procedure. An AE can 
therefore be any unfavourable or unintended finding, symptom, or disease temporally associated 
with a trial procedure, whether or not related to it. 
 
A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that 
- 
Results in death or is life-threatening, 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization, 
- 
Results in persistent or significant disability or incapacity, or 
- 
Causes a congenital anomaly or birth defect  
 
Adverse effects are reported by the operators themselves. Indeed, as with many surgical 
specialties, the surgeon must be able to identify and manage such complications.  
In order to reduce the risk of measurement bias as much as possible, we will include in our 
database the diagnoses and management of perioperative complications carried out by the 
gynaecological emergency service at the HUG or at other external hospital centres.   
 
Both Investigator and Sponsor-Investigator make a causality assessment of the event to the trial 
intervention, (see table below based on the terms given in ICH E2A guidelines). Any event 
assessed as possibly, probably or definitely related is classified as related to the trial intervention. 
 
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 
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 
 
Both Investigator and Sponsor-Investigator make a severity assessment of the event as mild, 
moderate or severe. Mild means the complication is tolerable, moderate means it interferes with 
daily activities and severe means it renders daily activities impossible.  
 

 
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Reporting of SAEs (see ClinO, Art. 63) 
All SAEs are documented and reported immediately (within a maximum of 24 hours) to the 
Sponsor-Investigator of the study. 
If it cannot be excluded that the SAE occurring in Switzerland is attributable to the intervention 
under investigation, the Investigator reports it to the Ethics Committee via BASEC within 15 days. 
 
Follow up of (Serious) Adverse Events 
Participants terminating the study with reported ongoing (S)AEs will be followed up in specialized 
medical consultations respecting the general guidelines of the gynaecology department until 
resolution or stabilisation.  
 
Notification of safety and protective measures (see ClinO, Art 62, b) 
If immediate safety and protective measures have to be taken during the conduct of the study, 
the investigator notifies the Ethics committee of these measures, and of the circumstances 
necessitating them, within 7 days. 
6.3 (Periodic) safety reporting 
An annual safety report (ASR) is submitted once a year to the local Ethics Committee by the 
Investigator (ClinO, Art. 43 Abs 1). 
6.4 Radiation 
Not applicable. 
6.5 Pregnancy  
Not applicable. 
6.6 Amendments 
Substantial changes to the study setup and study organization, the protocol and relevant study 
documents are submitted to the Ethics Committee for approval before implementation. 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 Ethics Committee. Such deviations 
shall be documented and reported to the Ethics Committee as soon as possible. 
Substantial amendments are changes that affect the safety, health, rights and obligations of 
participants, changes in the protocol that affect study objective(s) or central research topic, 
changes of study site(s) or of study leader and sponsor (ClinO, Art. 29). 
A list of substantial changes is also available on www.swissethics.ch. 
A list of all non-substantial amendments will be submitted once a year to the competent EC 
together with the ASR. 
6.7 Notification and reporting upon completion, discontinuation or interruption of the 
study 
Upon regular study completion, the Ethics Committee is notified via BASEC within 90 days (ClinO, 
Art. 38).  
Provide a statement that the Sponsor-Investigator and any other competent authority may 
terminate the study prematurely according to certain circumstances, e.g.:  
- 
Ethical concerns, 
- 
Insufficient participant recruitment, 

 
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- 
When the safety of the participants is doubtful or at risk (e.g. when the benefit-risk 
assessment is no longer positive), 
- 
Alterations in accepted clinical practice that make the continuation of the study unwise, or 
- 
Early evidence of harm or benefit of the experimental intervention 
 
Upon premature study termination or study interruption, the Ethics Committee is notified via 
BASEC within 15 days (ClinO, Art. 38). 
 
A final report is submitted to the Ethics Committee via BASEC within a year after completion or 
discontinuation of the study, unless a longer period is specified in the protocol (ClinO, Art. 38). 
6.8 Insurance 
In the event of study-related damage or injuries, the liability of the institution Hôpitaux 
Universitaires de Genève; Département de la Femme, de L’Enfant et de l’Adolescent; Service de 
Gynécologie provides compensation, except for claims that arise from misconduct or gross 
negligence.  
 
 
 

 
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7 
FURTHER ASPECTS 
7.1 Overall ethical considerations 
 
By providing new knowledge, this study contributes to clinical research. Improving the quality of 
life of women in gynaecological surgery, while ensuring safety of care, is our priority.  The rigorous 
methodology of this study, and the resulting valid clinical and scientific evidence, could lead to a 
change in recommendations for a better surgical experience for the patient. 
 
By using two types of surgery already used routinely and considered safe and valid for the 
indication of benign adnexal disease, this study represents potential benefits to society that 
outweigh the risks involved. 
 
The study is designed to be as fair as possible. The target population for this study is chosen to 
correspond to the population most commonly affected by benign adnexal disease that may 
require surgical management. The exclusion criteria for this study correspond mainly to the 
exclusion criteria for the vNOTES surgical technique. The limitation of this study to the French or 
English speaking population only, thus excluding a major part of the Geneva foreign population, 
is explained by the limited availability of the questionnaires in a validated translated version. 
Indeed, the validity of a randomized controlled trial study depends on the validity of its 
measurement instruments. The validity of the study also relies on the review of non-affiliated 
parties.  
 
Participation is voluntary and withdrawal from the study can be made at any time, without 
justification. The free and informed signature of the consent form, after having received all the 
necessary information and having benefited from a period of reflection if needed, is mandatory.  
 
Respect for the participant is a key point of the study and this is reflected in the respect for privacy, 
attention to the participant's well-being and absence of judgment. 
7.2 Risk-benefit assessment  
This study does not present any risk for patients who will undergo elective adnexal surgery for 
benign pathology by CAL or by vNOTES. Both surgical techniques are used in routine and have 
proven their effectiveness and safety for benign adnexal surgery. The objectives of this study are 
in accordance with the principle of beneficence for the patients by contributing to their general 
and sexual well-being and by aiming to promote a more effective and safer surgical technique.  
As the study progresses, patients will be informed of new findings, which may influence their 
decision to participate or not. A patient who presents more risks than benefits from such a 
randomized allocation will be withdrawn from the study for safety reasons. Adverse effects will be 
managed by following the standard protocols of the Geneva University Hospitals. In the event 
that significant side effects are observed and attributed to the study, the study will be stopped. 
The results will be shared with the patients at the end of the study. 
 
 

 
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8 
QUALITY CONTROL AND DATA PROTECTION 
8.1 Quality measures  
Measures taken for quality assurance and quality control: double data entry, study personnel 
trained on all important study related aspects, planned quality visits, data management from a 
specialized team. 
For quality assurance the sponsor, the Ethics Committee or an independent trial monitor may visit 
the research sites. Direct access to the source data and all study related files is granted on such 
occasions. All involved parties keep the participant data strictly confidential.  
8.2 Data recording and source data 
Clinical data management will be carried out with the help of the Geneva University Hospitals 
Clinical Research Centre (CRC) in accordance with all laws and regulations relating to Good 
Clinical Trial Practice. We have chosen the REDCap® platform as our data collection (CRF) and 
online questionnaire response platform. It is a platform that provides secure and anonymous data 
collection, analysis and storage. Patients will receive an invitation to complete the questionnaires 
by email or SMS. They will register to the online questionnaire platform using their study number. 
The platform will automatically send them up to 3 reminders if they do not respond in time. 
 
The source data used in the study are listed under the following headings above: general and 
clinical information which will be found in the patient’s file (personal information, medical history, 
laboratory and radiological results) and transferred to the patient’s CRF. More detailed clinical 
information designed specifically for the study will be collected directly from the CRFs. The same 
applies to the response to the questionnaires.  
8.3 Confidentiality and coding 
Trial and participant data will be handled with uttermost discretion and is only accessible to 
authorised personnel who require the data to fulfil their duties within the scope of the study. On 
the CRFs and other study specific documents, participants are only identified by a unique 
participant number.  
 
To ensure patient confidentiality, all patient data will be anonymized. Patients included in the 
study will immediately receive a study number on a first-come, first-served basis, which will follow 
them on all study documents (care maps and logbooks) according to the "main courante" 
principle. For instance, the third participant included in the study will be known under patient 3 
and she will keep this number throughout the study, regardless of the allocation. 
 
Only the investigators and the research nurse will have access to patient’s names assigned to 
the study numbers. All study documents will be locked in the Gynaecology division of the Geneva 
University Hospitals. The person responsible for data analysis (statistician) will only have access 
to the study numbers and data will be collected in a computerized file. Care maps will be used as 
a step-by-step procedure for all medical providers but also to ensure traceability.  
 
Study numbers will be randomized to one of the two interventional arms using an automatically-
generated computer program. The allocation of the study number to the intervention arm will be 
inserted in an opaque envelope and place in the patient’s file by the research nurse. This envelope 
will also include the patient's name to avoid the risk of exchange.  
The surgeon will open the envelope on the day before or on the day of surgery and informs the 
patient about her allocation after the surgery.  
 

 
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Access to the Geneva University Hospital's computerised medical file is limited to persons 
authorised by an identifier and a password. The history of the individuals who opened the file is 
recorded. The same applies to access to the online research platform REDCap®. 
 
Only non-genetic data are used.  
8.4 Retention and destruction of study data  
All study data are archived in Geneva University Hospitals for 10 years after study termination or 
premature termination of the study. 
 
 

 
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9  MONITORING AND REGISTRATION 
The Sponsor-Principal Investigator is fulfilling the monitoring duties. The monitoring visits will take 
place on site, in the gynaecology department of the Geneva University Hospital. The visits will 
involve the Sponsor-Principal investigator, the research nurse and the principal co-investigators. 
The monitor must ensure that the clinical study is being conducted in accordance with the protocol 
and that data are being collected and processed correctly. The monitor will also ensure that the 
study is conducted in accordance with standard operating procedures, good clinical practice and 
the legislative and regulatory provisions in force. The monitoring will include the 4 key stages: 
pre-visit, study initiation visit, intermediate visits (per semester), closing visit.  
As the monitor is the principal investigator, he has access to all the data of the study and can 
communicate with his working team through a professional email address. 
The study is intended to be registered on ClinicalTrials.gov (database of privately and publicly 
funded clinical studies conducted around the world). The study is already registered on SNCTP 
vis BASEC.  
10. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
Funds were allocated as follows:  
• 
A research nurse at 20% for 6 months (pilot phase), statistical analysis, data management 
through Geneva University Hospitals Clinical Research Centre, and spell checking will be covered 
by the medical direction, Geneva University Hospitals (Public, 50'000 CHF, 83,3%). 
• 
Computing resources, office equipment, premises, request to the ethics committee and 
publication costs will be covered by the Geneva University Hospitals (Public, 10’000CHF, 16,7%). 
 
A request for additional funds will be applied to continue the study after the pilot phase. 
 
The members of the study intend to publish the study protocol, as well as the study results, once 
obtained. Each investigator and co-investigator, including the statistician, will be included in the 
list of authors. This study is also part of a MD thesis under the direction of the Principal-
Investigator and will be presented to a jury for validation.  In any case, no personal data identifying 
any of the participants of the study will be revealed. The principles of confidentiality and anonymity 
will always be respected. 
 
The authors declare no conflict of interest.  
 
 

 
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11. ETHICAL REFERENCES 
• 
Common Terminology Criteria for Adverse Events (CTCAE) 
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
• 
Declaration of Helsinki 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects/ 
• 
Federal Act on Data Protection (FADP) 
https://www.admin.ch/opc/en/classified-compilation/19920153/index.html 
• 
Human Research Act (HRA) 
https://www.admin.ch/opc/de/classified-compilation/20061313/index.html 
• 
International Conference on Harmonization (ICH) E6(R2) Guideline for Good Clinical 
Practice 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_
_Step_4_2016_1109.pdf 
• 
International Conference on Harmonization (ICH) E2A Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002749.pdf 
• 
Ordinance on Clinical Trials in Human Research (ClinO) 
https://www.admin.ch/opc/de/classified-compilation/20121176/index.html 
 
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