Adnexectomy for Benign Gynaecological Pathology by Natural Orifice Transluminal Endoscopy or Laparoscopy
Phase: NA
Conditions: Natural Orifice Endoscopic Surgery, Disease, Adnexal, Laparoscopic Surgery
Sponsor: Imelda Hospital, Bonheiden

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RESEARCH PROTOCOL 
NOTABLE trial 
 
 
 
(NOTes Adnexectomy for Benign pathology compared 
to Laparoscopic Excision) 
 
UNIQUE PROTOCOL ID: B689201526268 
 
ClinicalTrials.govID: NCT02630329 
 
 
 
 
 
 

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Protocol ID                                        B689201526268 
                                                            NCT02630329 
Short title                                          NOTABLE trial 
Version                                               5 
Date                                                    28-12-2015 
Coordinating investigator               Dr. J. Bosteels 
                                                             Imeldaziekenhuis  
                                                             Department of Obstetrics and Gynaecology 
                                                             Imeldalaan 9, 2820 Bonheiden, Belgium 
                                                             T: + 32 15 505205 
                                                             M: jan.bosteels@imelda.be 
Principal investigator                       Dr. J. Baekelandt 
                                                             Imeldaziekenhuis  
                                                             Department of Obstetrics and Gynaecology 
                                                             Imeldalaan 9, 2820 Bonheiden, Belgium 
                                                             T: + 32 15 505208 
                                                             M: jbaekelandt@imelda.be 
Sponsor                                               Investigator driven trial  
Independent physician                     Not applicable 
Laboratory sites                                 Clinical laboratory 
                                                              Imeldaziekenhuis  
                                                              Imeldalaan 9, 2820 Bonheiden, Belgium 
                                                             T: + 32 15 505460                                                              
Pharmacy                                            Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
Name 
Signature 
Date 
 
For non-commercial research, Head 
of Department: 
 
Dr. Philippe Delattin, MD, 
Gynaecologist 
 
 
 
 
Coordinating Investigator: 
 
Dr. Jan Bosteels, MD, PhD, 
Gynaecologist 
 
 
 
 
Principal investigator/project leader: 
 
Dr. Jan Baekelandt, MD, Gynaecologist 
 
 
 
Assistant study investigators: 
 
Dr Jona Vercammen, MD 
 
Dr Sylvie De Rijdt, MD 
 
Dr. Siel Olbrecht, MD 
 
Dr. Judith De Coene, MD 
 
Dr. Maja Van Goitsenhoven, MD 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL ID  
 
 
 
 
 
 
 
 
2 
PROTOCOL SIGNATURE SHEET  
 
 
 
 
 
 
3 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
4-6 
LISTS OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
 
 
7 
SUMMARY 
 
 
 
 
 
 
 
 
 
8-9 
1. BACKGROUND 
 
 
 
 
 
 
 
 
10-16 
1.1. Disease: benign adnexal mass 
 
 
 
 
 
 
10 
1.1.1 Population to be studied  
 
 
 
 
 
 
10 
1.2. Current therapy for removal of a benign adnexal mass 
 
 
 
10-11 
1.3. New therapy for removal of a benign adnexal mass  
 
 
 
11 
1.4. Literature review  
 
 
 
 
 
 
 
11-13 
1.4.1 Systematic Review 
 
 
 
 
 
 
 
11-13 
1.4.2 Current clinical practice   
 
 
 
 
 
 
13 
1.4.3 Pilot studies 
 
 
 
 
 
 
 
 
14-15 
1.5. The need for a pilot trial of vNOTES versus LSK adnexectomy 
 
 
15-16 
1.6. Objectives of the NOTABLE Trial 
 
 
 
 
 
 
16 
2. TRIAL DESIGN 
 
 
 
 
 
 
 
 
17 
2.1. Design 
 
 
 
 
 
 
 
 
 
17 
2.2. Simple pilot randomised trial: minimal extra workload  
 
 
 
17 
2.3. Time schedule 
 
 
 
 
 
 
 
 
17 
2.4. Participating center 
 
 
 
 
 
 
 
17 
3. ELIGIBILITY, CONSENT AND RANDOMISATION  
 
 
 
 
18-20  
3.1. Screening and consent prior to surgery 
 
 
 
 
 
18 
3.2. Determining eligibility 
 
 
 
 
 
 
 
18-19 
3.3. Randomization 
 
 
 
 
 
 
 
 
19 
3.4. Patients with strong preference for treatment  
 
 
 
 
20 
3.5. Stratification of randomisation 
 
 
 
 
 
 
20 
4. TREATMENT ALLOCATIONS  
 
 
 
 
 
 
21-25 
4.1. Surgical procedures 
 
 
 
 
 
 
 
21-25 
4.1.1 vNOTES adnexectomy 
 
 
 
 
 
 
 
21-22 
4.1.2 LSK adnexectomy  
 
 
 
 
 
 
 
23-24 
4.1.3 Failure of procedure 
 
 
 
 
 
 
 
24 
 
4.2. Concomitant interventions and treatments  
 
 
 
 
24-25 

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4.3. Withdrawal from the NOTABLE trial 
 
 
 
 
 
25 
4.4. Serious and unexpected adverse events  
 
 
 
 
 
25 
5. FOLLOW-UP AND OUTCOME MEASURES 
 
 
 
 
 
26-30 
5.1. Clinical assessments 
 
 
 
 
 
 
 
26 
5.1.1 Format 
 
 
 
 
 
 
 
 
 
26 
5.1.2 Timing of assessments 
 
 
 
 
 
 
 
26 
5.2. Primary clinical outcome measure  
 
 
 
 
 
26 
5.3. Secondary clinical outcome measures 
 
 
 
 
 
26-28 
5.4. Health economic outcomes 
 
 
 
 
 
 
28-29 
5.5. Data management and validation  
 
 
 
 
 
29 
5.5.1 Confidentiality of personal data  
 
 
 
 
 
29 
5.5.2 Long-term storage of data 
 
 
 
 
 
 
29 
5.6. Withdrawal from follow-up 
 
 
 
 
 
 
29-30 
6. ACCRUAL AND ANALYSIS 
 
 
 
 
 
 
 
30-33 
6.1. Sample size 
 
 
 
 
 
 
 
 
30 
6.2. Projected accrual and attrition rates 
 
 
 
 
 
30 
6.3. Statistical Analysis  
 
 
 
 
 
 
 
30-31 
6.3.1 Subgroup analyses 
 
 
 
 
 
 
 
31 
6.3.2 Proposed frequency of analyses  
 
 
 
 
 
31 
6.3.3 Handling missing data  
 
 
 
 
 
 
 
31-32 
6.4. Health Economic Analysis  
 
 
 
 
 
 
32 
6.4.1 Form of the economic evaluation  
 
 
 
 
 
32 
6.4.2 Economic analysis 
 
 
 
 
 
 
 
32-33 
6.5. Definition of the end of trial 
 
 
 
 
 
 
33 
7. ASSESSMENT OF PATIENT ACCEPTABILITY 
 
 
 
 
 
34-35 
7.1. Measurements for Patient Acceptability  
 
 
 
 
 
34 
7.1.1 Sampling of Participants for In-depth Interview 
 
 
 
 
34 
7.2. Evaluation of Patient Acceptability   
 
 
 
 
 
34-35 
8. DATA ACCESS AND QUALITY ASSURANCE 
 
 
 
 
 
36-37 
8.1. In-house Data Quality Assurance 
 
 
 
 
 
 
36 
8.2. Independent Trial Steering Committee 
 
 
 
 
 
36 
8.3. Data Monitoring and Ethics Committee 
 
 
 
 
 
36-37  
9. ORGANIZATION AND RESPONSIBILITIES 
 
 
 
 
 
38-41 
9.1. Centre eligibility 
 
 
 
 
 
 
 
 
38 
9.2. Local Coordinator at each centre 
 
 
 
 
 
 
38 

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9.3. Nursing Coordinator at each centre  
 
 
 
 
 
38 
9.4. The NOTABLE Trial Office  
 
 
 
 
 
 
38 
9.5. Research Governance  
 
 
 
 
 
 
 
38-39 
9.6. Research Governance and Ethical Approval  
 
 
 
 
39-40 
9.7. Funding and Cost implications 
 
 
 
 
 
 
40 
9.8. Indemnity  
 
 
 
 
 
 
 
 
40 
9.9. Publication  
 
 
 
 
 
 
 
 
40 
 
9.10. Ancillary studies  
 
 
 
 
 
 
 
40-41  
10. REFERENCES  
 
 
 
 
 
 
 
 
42-43  
APPENDIX I: Table I Overview of patient and perioperative characteristics 
 
44 
APPENDIX II: Table II Patient and perioperative characteristics  
 
 
44 
APPENDIX III: Clavien- Dindo classification 
 
 
 
 
 
45 
APPENDIX IV: CONSORT 2010 Flow Diagram 
 
 
 
 
 
46 
APPENDIX V: Pain protocol 
 
 
 
 
 
 
 
47 
APPENDIX VI: VAS Scale 
 
 
 
 
 
 
 
48 
APPENDIX VII: Participant’s pain log book 
 
 
 
 
 
49-52  
APPENDIX VIII: Dyspareunia questionnaire  
 
 
 
 
 
53 
 
APPENDIX IX: Short Sexual Functioning Scale 
 
 
 
 
 
54-58  
APPENDIX X: EQ-5D-3L Health questionnaire 
 
 
 
 
 
59-61 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
ACOG  
American College of Obstetricians and Gynecologists 
AE 
  
Adverse Event 
CAT 
 
Computerized Axial Tomography 
CONSORT 
Consolidated Standards of Reporting Trials 
DMEC   
Data Monitoring and Ethics Committee  
EuroQoL 
EQ-5D Health Questionnaire  
GMT 
 
Greenwich Mean Time 
GP 
 
General Practitioner 
HTA 
 
Health Technology Assessment 
IOTA 
 
International Ovarian Tumour Analysis  
IV 
 
intravenous 
LSK 
 
laparoscopy 
MID 
 
Minimally Important Difference 
NHS 
 
National Health Service 
NOTABLE 
NOTES Adnexectomy for Benign pathology compared to Laparoscopic Excision 
NOTES  
natural orifice transluminal endoscopy 
vNOTES 
vaginal natural orifice transluminal endoscopy 
PROM  
Patient Reported Outcome Measure 
RCT 
Randomised Controlled Trial 
(S)AE   
(Serious) Adverse Event 
SD 
 
Standard Deviation 
SSFS 
 
Short Sexual Functioning Scale 
SILS 
 
Single Incision Laparoscopic Surgery 
SUSAR   
Suspected Unexpected Serious Adverse Reaction 
TSC 
 
Trial Steering Committee 
TU 
 
Trans Umbilical 
TV 
 
Trans Vaginal 
VAS 
 
Visual analogue scale 
QALY  
Quality adjusted life year 
 
 

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SUMMARY 
Rationale: Driven by the desire to minimalise surgical morbidity, the evolution from laparotomy to 
laparoscopic surgery has now extended to less invasive surgery such as robotics, mini- laparoscopy, 
single incision laparoscopic surgery (SILS), and natural orifice transluminal endoscopic surgery 
(NOTES). Minimally invasive surgery not only improves cosmetic outcome, it has the potential to 
restrict the magnitude of the surgical injury, which in turn can attenuate the inflammatory and 
neuroendocrine response resulting in less postoperative pain and quicker recovery (1, 2). 
NOTES attempts to reach the abdominal cavity through an invisible scar, i.e. the surgical intervention 
is performed via a natural body orifice. Its popularity amongst general surgeons, urologists and 
gastroenterologist has increased over the past few years and its feasibility and safety has been 
reported in the medical literature (3). 
NOTES can be done by various approaches including access via the stomach, oesophagus, bladder or 
rectum. The majority of NOTES procedures in women are done by the vagina as this site provides 
direct access to the lower abdominal cavity (4). Colpotomy has been used widely for several surgical 
procedures (by gynaecologists as well as general surgeons for the extraction of large specimens) and 
it has been reported as a safe access that is easy to close afterwards (5, 6). 
In hybrid NOTES the surgical procedure is performed through a natural body orifice with 
transabdominal assistance, whereas the term pure NOTES refers to procedures that involve only 
transluminal access.  
Given its potential benefits, including no visible scars, fewer port-related complications, and less 
painful and faster post-operative recovery, we have introduced transvaginal pure NOTES (vNOTES) 
for the treatment of benign adnexal masses in our surgical practice since November 2013.  A case-
series by our group describing the technical feasibility of removing benign adnexal masses by vNOTES 
in 20 women has been published recently (7). Most women reported a low postoperative pain score 
(range 0 to 2) measured at day 1 following surgery by a visual analogue scale (VAS). Based on these 
preliminary observational findings we decided to design a pilot randomized trial to study the 
effectiveness of the new vNOTES approach based on the hypothesis that the new technique is at 
least as effective for removing a benign adnexal mass without cyst rupture compared to the classical 
laparoscopic technique. 
Objective: To compare vNOTES and established laparoscopic removal of benign adnexal masses  
Study design: Randomised controlled/single centre/single-blinded/parallel-group/non-
inferiority/efficacy trial.  

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Study population: Women with symptomatic or persistent benign adnexal masses detected by 
clinical examination and ultrasound.  
Randomisation: After assessment of eligibility/ informed consent women will be randomly allocated 
to undergo one of two techniques for removal of the benign adnexal mass before surgery by using a 
computer generated randomisation list. We will use stratified randomisation according to the cyst 
diameter. 
Intervention: Women will be treated by a surgeon who is not blinded to the treatment allocation and 
who is equally skilled in performing both techniques. In the intervention group a vNOTES technique 
will be used. 
Control: In the control group surgery will be done by a classical laparoscopic technique. 
Participants, nursing staff and outcome assessors will be blinded by the use of mock surgical skin 
incisions. Pre- and postoperative treatment will be provided by staff blinded for the allocated 
intervention using a standardized protocol that is identical for both techniques. All women will be 
advised not to work during a 4-week period and to abstain from sexual intercourse until their 6-week 
booked appointment for a postoperative assessment. 
Main study parameters/endpoints:  
Primary outcomes: successful removal of a benign adnexal mass without spill. 
Secondary outcomes: the proportion of women discharged the same day based on their own 
preference; postoperative pain scores using a VAS scale measured between day 1 till 7 by the 
participating women following surgery and the total use of analgesics as described in the 
standardized pain treatment protocol; postoperative infection defined by lower abdominal pain with 
fever > 38°C and positive clinical signs or laboratory findings; per- or postoperative complications 
according to the Clavien- Dindo classification (8) detected during the first six weeks of surgery; 
hospital readmission during the first six weeks of surgery; duration of the surgical procedure; 
incidence and intensity of dyspareunia recorded by the participants at 3 and 6 months by self-
reporting using a simple questionnaire and VAS scale; sexual wellbeing recorded by the participants  
at 3 and 6 months by SSFS; quality of life by self-reporting the EQ-5D-3L questionnaire at 3 and 6 
months; direct costs associated with both procedures. 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: The burden and risks associated with the participation in the study are comparable with 
the risks related to the established technique of laparoscopic adnexectomy. 

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1. BACKGROUND 
1.1. Disease: adnexal mass 
An adnexal mass (mass of the ovary, fallopian tube, or surrounding connective tissues) is a common 
gynaecological problem. In the United States, it is estimated that there is a 5 to 10 percent lifetime 
risk for women undergoing surgery for a suspected ovarian neoplasm (9). Adnexal masses may be 
found in females of all ages, foetuses to the elderly, and there is a wide variety of types of masses. 
The management of an adnexal mass depends upon the type of mass, urgency of the presentation 
(e.g. ectopic pregnancy or ovarian torsion require immediate intervention), and degree of suspicion 
that the mass might be malignant. 
1.1.1 
Population to be studied 
All women with a benign adnexal mass will be eligible for inclusion provided that they have no 
exclusion criteria and after giving fully informed consent.  
The diagnosis of a benign adnexal mass will be based upon the prospectively IOTA validated simple 
ultrasound rules to distinguish between benign and malignant adnexal masses before surgery (10).  
All the ultrasound examinations will be reviewed before the randomisation by a named operator 
with competence in gynaecological ultrasound and experience in applying the simple rules. The need 
for additional examinations (CAT scan or CA-125) is based upon good clinical practice. 
1.2. Current therapy for removal of an adnexal mass 
Surgical exploration for an adnexal mass may be performed laparoscopically (conventional or 
robotic) or by laparotomy. The choice of surgical approach depends upon the degree of suspicion of 
malignancy and surgeon and patient preference. Ovarian cancer staging can be performed using an 
open or laparoscopic approach, although the majority of surgeons in current practice prefer 
laparotomy if there is a high degree of suspicion of malignancy. If there is a low or moderate 
suspicion of malignancy, a laparoscopic approach is typically used. Laparoscopy is associated with a 
shorter recovery and decreased perioperative morbidity compared with laparotomy.  
The surgical technique used must minimise the potential for tumour disruption or dissemination. If 
malignancy is suspected, oophorectomy is required rather than ovarian cystectomy. Women with 
early stage ovarian cancer (i.e. no malignant cells in ascites or peritoneal cytology) benefit from 
removal of the adnexal mass intact, since opening the mass results in a more advanced stage and 
adversely affects prognosis (11, 12). In addition, every attempt must be made to provide the 
pathologist with an ovarian specimen with an intact cortex. If a laparoscopic approach is used, the 
ovary can be placed in a tissue recovery bag. If the specimen is too large to remove through the 
existing incisions, cyst fluid may be aspirated (but the collapsed cyst should not be disrupted) or the 
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because it may compromise pathology evaluation. In general, aspiration of cyst contents is not 
advisable as the sole surgical intervention because no tissue is obtained for histopathology and 
cytology of cyst fluid is not reliable for exclusion of malignancy, and there is a high rate of recurrence. 
Recent years have witnessed the use of a posterior colpotomy to retrieve large benign ovarian 
lesions since removal through the umbilicus may not be straightforward (13). 
1.3. New therapy for removal of a benign adnexal mass 
Natural orifice transluminal endoscopic surgery (NOTES) is a surgical technique whereby "scarless" 
abdominal operations can be performed with an endoscope passed through a natural orifice (mouth, 
urethra, anus, etc.) then through an internal incision in the stomach, vagina, bladder or colon, thus 
avoiding any external incisions or scars. NOTES was originally described in animals by researchers at 
Johns Hopkins University (Dr. Anthony Kalloo et al.), and was once upon a time used for transgastric 
appendectomy in humans in India (by Drs. G.V. Rao and N. Reddy). On June 25, 2007 Swanstrom and 
colleagues reported the first human transgastric cholecystectomy. The transvaginal access to NOTES 
seems to be the safest and most feasible approach for clinical application.  
1.4. Literature review 
1.4.1 Systematic Review 
Health technology assessment (HTA) of surgical interventions requires an initial evaluation of the 
safety and feasibility followed by randomised controlled trials of effectiveness. We conducted a 
comprehensive systematic review on the efficacy of colpotomy in the treatment of benign adnexal 
mass. After searching three electronic databases (MEDLINE, EMBASE and The Cochrane Library) from 
inception to 1 August 2015 using ‘colpotomy’ and ‘adnexal diseases’ or ‘adnexal mass’ as MeSH 
terms or key words, ten citations were identified, of which a total of four studies were eligible for 
inclusion. Two studies were observational including one very small case series (7 women) and one 
prospective cohort study (257 women); two studies were randomised controlled trials (66 women 
and 79 women respectively).  
A summary of the evidence is given below: 
We retrieved one observational study from Korea (14). The authors performed transvaginal NOTES in 
seven women with adnexal masses through a 2-cm incision in the posterior vaginal fornix. A 
transvaginal NOTES system comprising a wound protractor and a surgical glove with sheaths was 
used. Resection was performed according to the method of standard laparoscopic adnexal surgery. 
The adnexal mass was removed via the incision of the posterior vaginal fornix after complete 
resection. Since June 2011, seven women have undergone transvaginal NOTES for adnexal masses. 
All cases were completed successfully without conversion to standard laparoscopic approach. The 
median age of the women was 48 years (range: 36–60 years) and the median body mass index was 
23.6 (range: 20.4–25.3). The median tumour size was 6 cm (range: 3.7–6.7 cm). The median 

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operative time was 45 min (range: 40–80 min). The estimated blood loss was minimal (range: 5–
300 mL). The median postoperative hospital stay was 2 days (range: 1–3 days). No postoperative 
complications were observed at follow-up. All women were very satisfied with the cosmetic result. 
The authors conclude that transvaginal NOTES may be a feasible, safe and effective surgical 
technique that results in excellent cosmetic results. It may be an alternative technique for the 
treatment of properly selected patients with adnexal masses. The authors stress the need for further 
clinical research.  
We retrieved a prospective cohort study from the United States (15). This descriptive study was 
conducted on women treated by a private gynaecological surgery practice in a community hospital 
setting from January 1, 2004 through April 30, 2011. Two-hundred fifty-seven consecutive women 
with adnexal masses of 8 cm to 13 cm on preoperative ultrasound examination not meeting triage 
criteria set forth in ACOG Committee Opinion 280 for referral to gynaecological oncologists were 
treated with operative laparoscopy, adnexal removal, bagging, and colpotomy. Laparoscopic surgery 
combined with posterior colpotomy has a low incidence of significant complications. Outcome data 
show that by observing the principals of minimally invasive surgery, 97% of women were successfully 
treated as outpatients: 98% of surgeries lasted <136 minutes; 97% had blood loss <200mL, and there 
were few consequential postoperative complications. Intraoperative rupture of the ovarian capsule 
was extremely uncommon: capsular rupture was noted in just 1.2% of cases. The most common 
lesions were cystadenomas, endometriotic cysts and mature teratomas accounting for 85% of all 
cases. Borderline tumours accounted for 5% of lesions, while invasive ovarian malignancy 
represented 3.7% of the specimens. 
We retrieved one RCT from Italy (16). Women scheduled for a laparoscopic resection of an adnexal 
mass were randomised to have their surgical specimen removed either through a posterior 
colpotomy (n = 34) or the umbilical port site (n = 32). Group allocation was concealed from study 
participants and bedside clinicians. The primary outcome was postoperative incisional pain assessed 
by a 10-cm visual analogue scale at 1, 3, and 24 hours after surgery. Transvaginal retrieval caused less 
postoperative pain than transumbilical specimen extraction at each time point (visual analogue scale 
score at 1 hour: 2.6 ± 2.9 vs 1.2 ± 2.0, P = 0.03; at 3 hours: 2.4 ± 2.0 vs 1.4 ± 2.0, P = 0.02; and at 24 
hours: 1.1 ± 1.5 vs 0.5 ± 1.4, P = 0.02). A higher proportion of women in the transumbilical group than 
in the transvaginal group indicated the umbilicus as the most painful area at 1 and 3 hours 
postoperatively. Two months after surgery, the participants scored similarly as to their overall 
satisfaction, cosmetic outcome, and dyspareunia upon resumption of intercourse. The authors 
conclude that a transvaginal approach for specimen removal after laparoscopic resection of adnexal 
masses may offer the advantage of less postoperative pain than the classical umbilical retrieval. 

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We retrieved one RCT from Taiwan (17). Seventy-nine women with mature teratomas identified by 
ultrasound examination and biochemical markers were randomly assigned to have their cysts 
removed via vaginal cystectomy without laparoscopy (n= 37, group A) or laparoscopic cystectomy via 
culdotomy (n=42, group B). Inclusion criteria were history of vaginal delivery, no previous abdominal 
surgery, no history of pelvic inflammatory disease, no medical illness, and no presenting symptoms. 
Eight women randomised to group A withdrew before surgery. The laparoscopically resected 
tumours were each put into a cellulose bag, and tumours without laparoscopic- assistance were 
removed directly via the vagina. Blood loss in group A (88± 37 ml) was significantly more than that in 
group B (64± 20 ml, P= 0.000). The post-operative recovery times were 20 and 17 hours, respectively 
(P= 0.030). The rates of successful surgery were 58.6 and 97.6%, respectively (P= 0.002). The spillage 
rates were 44.8% and 19.0%, respectively (P= 0.006). There were no significant differences in tumour 
size, patient age, and operative time between groups. The authors concluded that cystectomy 
without assistance of laparoscopy could be applied to manage mature teratoma of the ovary; 
however, because of the difficulty of this technique, there were high percentages of tumour spillage 
and more blood loss during operation and a high percentage of patients who required conversion to 
laparotomy compared with laparoscopic cystectomy. The authors favour laparoscopically assisted 
cystectomy to manage mature teratoma. 
1.4.2 Current clinical practice 
At the present the laparoscopic route is considered to be the gold standard for removing a benign 
adnexal mass compared to laparotomy. According to a Cochrane review (18), in women undergoing 
surgery for benign ovarian tumors, laparoscopy was associated with a reduction in fever, urinary 
tract infection, postoperative complications, postoperative pain, number of days in hospital, and 
total cost. These findings should be interpreted with caution since only a small number of studies 
(nine) were identified. These included a total of only 769 women and not all of the important 
outcomes were reported in each study.  
In the days prior to widespread availability of laparoscopy, skilled gynaecological surgeons frequently 
used colpotomy for ready access to the pelvis (15). Unlike episiotomy that can cause dyspareunia, 
colpotomy does not transect muscles and, therefore, has less bleeding and negligible postoperative 
pain. Some surgeons may point out the potential disadvantages of colpotomy, including incisional 
infection, peritonitis, and technical complexity, particularly in patients after hysterectomy. Many 
gynaecologists seem reluctant to perform transvaginal surgery because this approach can be difficult 
for inexperienced surgeons and is occasionally unsuccessful. Moreover, conversion to conventional 
laparoscopy because of unsuccessful transvaginal approach is not acceptable to women who are 
expecting a minimally invasive surgery with no abdominal surgical scars. Therefore colpotomy is not 
used as the standard clinical practice in Belgium for removal of the adnexa.  

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1.4.3 Pilot studies 
Given its apparent benefits, including no visible scars, fewer port-related complications, and less 
painful and faster post-operative recovery, we introduced transvaginal pure NOTES (vNOTES) for 
benign adnexal masses in our surgical practice since November 2013.  Our group has recently 
published a case-series describing the feasibility of adnexectomy by vNOTES in 20 women for benign 
adnexal masses (7). 
The purpose of the observational case-series was to describe the new technique as well as to 
demonstrate the feasibility of adnexectomy by transvaginal natural orifice transluminal endoscopic 
surgery (vNOTES) for the removal of benign adnexal masses. Conventional, reusable laparoscopic 
instruments were used, inserted through an inexpensive, self-designed single port device. Between 
November 2013 and November 2014, 20 adnexectomies by vNOTES were performed by a single 
surgeon (Dr. Jan Baekelandt).  
We selected each participant based on the following inclusion criteria: no contraindication for 
general anaesthesia, pneumoperitoneum or Trendelenburg position; no fixed uterus, strong pelvic 
adhesions or nodularity in the pouch of Douglas on clinical examination; no history of pelvic 
inflammatory disease or moderate to severe endometriosis and mass not suspicious for malignancy. 
We excluded women with large fibroid uteri as these may impair visualization. Virginity and 
concomitant pregnancy were predefined as exclusion criteria whereas obesity (BMI ≥ 30) and 
nulliparity were not. 
The self-designed single port device was made by assembling a surgical glove, a wound protector, 
one reusable 10 mm trocar, and four reusable 5 mm trocars. The adnexectomy was performed 
according to the technique for standard laparoscopic surgery and the specimen was removed 
through the colpotomy incision. 
The following patient and perioperative data were collected and retrospectively analysed: patient 
age, body mass index (BMI), parity, history of vaginal delivery, previous pelvic surgery, type of 
surgery, total operating time, serum haemoglobin (Hb) drop (change between the preoperative Hb 
and postoperative Hb one day after surgery), (peri-) operative complications, postoperative pain 
score and size of the adnexal mass. The duration of surgery was defined as the time from the start of 
colpotomy to the end of vaginal closure. Bowel, bladder, ureteral or vascular injuries, as well as blood 
loss > 300 ml, were considered as intraoperative complications. Short-term postoperative 
complications were classified as urinary tract infection, postoperative ileus, vaginal vault bleeding or 
infection, or haematuria. Postoperative pain was assessed using the visual analogue pain scale (VAS) 
(scoring from 0 = no pain to 10 = worst imaginable pain). The VAS score was evaluated at 6 and 24 
hours postoperatively. All women received the same intraoperative analgesia: intravenous 

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paracetamol 1000 mg and ketorolac trometamol 20 mg. Postoperative pain was managed by 
paracetamol 1000 mg and ketorolac trometamol was administered on patient’s demand. 
No bowel preparation was done prior to surgery. A Foley catheter was placed just before surgery and 
removed the morning after surgery (range 12-22 hours). Prophylactic intravenous antibiotic therapy, 
cefazoline 2 g and metronidazol 500 mg, was administrated during surgery. As this was a new 
technique the first patients were closely monitored post operatively. No vaginal intercourse was 
allowed for 6 weeks after the procedure. Each patient was re-assessed at the post-operative 
consultation 6 weeks after surgery. 
Between November 2013 and November 2014, twenty procedures were successfully performed by 
Poor Man’s vNOTES using conventional, reusable laparoscopic instruments. No conversion to 
standard multi incision laparoscopy or laparotomy was necessary. Fourteen women underwent a 
unilateral adnexectomy. In six women a bilateral salpingo-oophorectomy was performed. 
Table 1 (Appendix I) gives a cumulative overview of patient characteristics and relevant perioperative 
data. Individual patient data are presented in Table 2 (Appendix II). Mean operation time was 32 
minutes (range 20 to 50 minutes). Five women had had previous pelvic surgery. There were no 
intraoperative complications and only one patient had a postoperative cystitis for which oral 
antibiotic therapy was administered. The mean drop in haemoglobin level was 0.9 g/dl (range 0 to 
2.1 g/dl). Most women reported a low postoperative pain score (range 0 to 2) measured at day 1 
following surgery by a visual analogue scale (VAS).  The mean size of the removed adnexal mass was 
51.8 mm (35-110 mm). Each patient was examined six weeks after surgery. There was no vaginal 
wound infection nor dehiscence, and no patient complained of pain during pelvic examination. All 
women were in good health and were all satisfied with the result.  
Based on this observational case-series we concluded that adnexectomy by vNOTES is feasible for 
masses up to 110 mm even when performed with reusable, conventional laparoscopic instruments. 
The potential benefits with vNOTES are better cosmetics, low postoperative pain scores, and easy 
removal of the specimen without spillage. We stated that this new technique may enable surgeons in 
low resource settings to perform procedures by vNOTES since no expensive devices or instruments 
are needed. 
1.5. The need for a pilot trial of vNOTES versus LSK adnexectomy 
Surgical innovation is an important part of surgical practice. Its assessment is complex because of 
idiosyncrasies related to surgical practice, but necessary so that introduction and adoption of surgical 
innovations can derive from evidence-based principles rather than trial and error. We decided to 
follow the principles and guidelines established by IDEAL. On four occasions between 2007 and 
2009, invited international experts gathered at Balliol College, Oxford, to explore potential solutions 
concerning quality, innovation and evaluation in surgical practice and research. The conclusions and 

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guiding principles were published in The Lancet in 2009. Surgery lacks regulatory authorities that 
require studies of efficacy before a new procedure can be offered to patients. Nevertheless there is 
little difference between operations and other complex treatments delivered by individuals within 
teams. In each instance, the skill, experience, and judgment of the operator should be recognized, 
and outcomes are affected by the patient and the team. There was agreement between the experts 
that none of these factors is beyond the design of a clinical trial. The rationale for the resulting IDEAL 
framework (Idea–Development–Exploration–Assessment–Longterm study) for surgical research has 
been presented in a three article series in The Lancet (19, 20, 21). The central concept is that 
surgeons are regularly innovating and improving their skills. Because the point at which an 
innovation evolves into a novel procedure might not be obvious at the time, prospective open 
registration of new procedures and early ethical approval are encouraged. Evolution and evaluation 
can then occur simultaneously. The framework recognizes that at different stages of innovation, 
different study designs will be appropriate. According to the IDEAL framework the vNOTES approach 
has entered stage 2b (exploration) given that the technique of vNOTES has been described and the 
main technical aspects have been worked out. Even at this early stage a small efficacy RCT may be 
appropriate for the evaluation of the innovative surgical technique. The learning curve is likely to 
affect which surgeons participate in RCTs trials and when they become involved. We decided to use 
an RCT as the appropriate study design: the principal investigator had achieved his learning curve.  
1.6. Objectives of the NOTABLE Trial 
Is a vNOTES adnexectomy at least as effective compared to the standard transabdominal 
laparoscopic approach (LSC) for removing a benign adnexal mass without spill? 
Secondary research questions are:  
• 
Do more women treated by vNOTES prefer to leave the hospital on the day of surgery 
compared to LSC?  
• 
Do women treated by vNOTES suffer from less pain compared to women treated by LSC in 
the first postoperative week?  
• 
Is the removal of a benign adnexal mass by vNOTES faster compared to LSC? 
• 
 Does a vNOTES cause more pelvic infection or other complications compared to LSC?  
• 
Does a vNOTES result in more hospital readmissions during the first six weeks following 
surgery compared to LSC? 
• 
Does a vNOTES approach result in more women reporting dyspareunia, less quality of life or 
less sexual wellbeing at 3 or 6 months after surgery when compared to women treated by 
LSC?  
• 
What are the costs of a vNOTES compared to LSC? 

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2. TRIAL DESIGN 
2.1. Design 
A single centre, single-blinded, parallel group randomised, non-inferiority efficacy trial. 
2.2. Simple pilot randomised trial: minimal extra workload  
This is a pilot randomised trial aiming to demonstrate that vNOTES is at least as effective compared 
to the classical gold standard approach of laparoscopy for successfully removing benign adnexal 
masses without spill (non-inferiority design). In this phase of HTA the trial will need the participation 
of only one centre. To make this practicable, trial procedures are kept simple, with the minimal extra 
workload placed on participating clinicians, beyond that required to treat their patients. This will be 
achieved by simple entry procedures, the use of standard local diagnostic and surgical regimens, 
routine follow-up of patients (with few additional hospital visits or tests to be performed above 
those done as part of standard care), minimising documentation and largely patient-based evaluation 
of outcome (PROM). 
2.3. Time schedule 
Based upon the mean number of laparoscopic adnexectomies performed annually at the department 
of Obstetrics and Gynaecology of the participating centre (36) we estimate that the duration of 
recruitment will be 21 months. Based upon the follow up (6 months) and the period of 
analysis/reporting (3 months) the total study period will be 2.5 years.  
2.4. Participating centre 
Department of Obstetrics and Gynaecology  
Imelda Hospital 
Imeldalaan 9 
2820 Bonheiden 
Belgium 
 
 

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3. ELIGIBILITY, CONSENT AND RANDOMISATION  
3.1. Screening and consent prior to surgery 
All women regardless of age and parity presenting with a symptomatic or asymptomatic persistent 
benign adnexal mass on clinical examination confirmed by ultrasound are eligible for inclusion. The 
diagnosis of benign adnexal mass will be based upon the prospectively IOTA validated simple 
ultrasound rules to distinguish between benign and malignant adnexal masses (10).  All the 
ultrasound examinations will be reviewed before the randomisation by a named operator with 
competence in gynaecological ultrasound and experience in applying the simple rules. The need for 
additional examinations (CAT scan or CA-125) is based upon good clinical practice. 
The trial will be introduced to the eligible women in the outpatient clinic and a comprehensive, 
evidence-based patient information sheet will be provided at the clinic visit. Participant information 
sheets and consent form will be provided in Dutch. 
Before the procedure, the women will be given a chance to discuss the risks and benefits of vNOTES 
or laparoscopy for removing the adnexal mass, the process of randomisation and the follow-up 
requirements with the consultant gynaecologist. It will be carefully explained that the final decision 
about eligibility will be taken during the surgical procedure and is dependent on the findings; 
therefore consent will be required before the procedure, in every instance.  
Over the past 4 years 145 laparoscopic adnexectomies were performed at the department of 
Obstetrics and Gynaecology of the participating centre. The mean number of procedures per year 
(SD) is 36 (± 13). About 69 % of the eligible women should be willing to participate in the proposed 
study to include the required amount of participants within 2.5 years (see: Section 6.1. Sample size 
on pages 31-32). 
3.2. Determining eligibility 
All women regardless of age and parity presenting with a symptomatic or asymptomatic persistent 
benign adnexal mass on clinical examination who provide consent to participation are eligible in the 
NOTABLE trial based on the findings of the ultrasound findings and will be randomised before the 
procedure. 
The following inclusion/exclusion criteria will be applied to assess eligibility: 
Inclusion criteria: 
• 
All women regardless of age and parity with a symptomatic adnexal mass presumed to be 
benign based on ultrasound examination by applying the IOTA simple rules 
• 
All women regardless of age and parity with an asymptomatic persistent adnexal mass 
presumed to be benign based on ultrasound examination by applying the IOTA simple rules 

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• 
Written informed consent obtained prior to surgery 
Exclusion criteria: 
• 
History of hysterectomy by any technique 
• 
History of rectal surgery 
• 
Suspected rectovaginal endometriosis 
• 
Suspected endometriotic cyst 
• 
Solid adnexal mass 
• 
High suspicion of adnexal malignancy based on clinical, ultrasound or biochemical findings 
• 
History of pelvic inflammatory disease, especially prior tubo-ovarian or pouch of Douglas 
abscess  
• 
Active lower genital tract infection e.g. Chlamydia, N. gonorrhoeae 
• 
Virginity 
• 
Pregnancy 
• 
Need for other uterine surgical intervention (i.e. endometrial ablation, resection, 
myomectomy or hysterectomy) 
• 
Additional pathology necessitating hysterectomy 
• 
Failure to provide written informed consent prior to surgery 
 
Obesity (Body Mass Index or BMI > 30), nulliparity or large diameter of the cyst are not 
considered to be an exclusion criterion per se. We will only stratify for the diameter of the cyst 
because this parameter was perceived by the gynaecological surgeon as the most important one 
to influence the difficulty of the procedure. Stratification for three parameters in a small pilot 
randomised trial with a limited number of participants is not sensible. 
3.3. Randomisation 
If the woman is eligible for the NOTABLE trial, the trial secretary will obtain a randomised allocation 
the day before surgery. This will be done using a randomisation list generated by a free computer 
software program offered by Research Randomizer (https://www.randomizer.org). The random 
sequence generation will be concealed using sequentially numbered opaque sealed envelopes. The 
envelope will be opened by the nurse assistant on the day of surgery for practical logistic reasons. 
We will use stratified randomisation according to the cyst diameter. See 3.5 Stratification of 
randomisation.  
 
 
 

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3.4. Patients with strong preference for treatment  
A minority of women will express a clear preference for one of both treatments (e.g. strong desire to 
have no scar) and for this reason will not wish to be randomised between surgical treatments. To 
investigate how outcomes vary by choice, these women could be followed up in exactly the same 
way as for those women randomised into the NOTABLE trial. We will however not do any formal non-
randomised follow-up of these women for simple logistical reasons. 
3.5. Stratification of randomisation 
A blocked randomisation procedure will be used to avoid chance imbalances for the parameter ‘cyst 
diameter’. We preferred not to use minimisation because this trial was not funded and we therefore 
could not afford to buy licenses for a computer-based algorithm for minimisation. Although parity 
and BMI may be prognostic parameters influencing the chances of the successful removal of the 
adnexal mass, we preferred to limit the stratification to one parameter for reasons of simplicity 
based on what is affordable to conduct the present research. It was not considered appropriate to 
use three strata in a small pilot study including a small number of participants. 
To avoid any possibility of foreknowledge, the randomised allocation will not be given until all 
eligibility and stratification data have been given.  
 
 

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4. TREATMENT ALLOCATIONS 
4.1. Surgical procedures 
The principal investigator, who has training and experience in both laparoscopy and NOTES, will 
perform all surgical procedures. He is therefore not blinded. All vNOTES participants will be blinded 
by three superficial “mock” skin incisions similar to those routinely done with the laparoscopic 
technique. The wound bandages will be left in place until the day 7 postoperative control to be 
removed by the coordinating investigator who will state at that moment that the wound healing has 
left an almost invisible scar as expected. This procedure aims to blind the participants, personnel and 
outcome assessors. The practice of performing “mock” incisions should not be considered as 
unethical: it is a procedure that has already been used in some surgical trials to minimise 
performance and detection bias whenever a subjective outcome is measured (22). The decision to 
use “mock” surgery is based on the clinical equipoise regarding the balance between benefits and 
adverse events for the two interventions under comparison (23). 
4.1.1 vNOTES adnexectomy  
This is the surgical procedure done in the intervention arm of the NOTABLE trial. 
Clindamycin vaginal cream is administered on admission of the study participant to the outpatient 
ward.  
The patient is placed in lithotomy position in a vacuum mattress. The abdomen, the vulva and the 
vagina are disinfected with an alcoholic betadine solution and draped. A Foley catheter is inserted 
into the bladder. 
Three superficial skin incisions are made, one deep in the umbilicus and one in the left and right iliac 
fossa lateral of the epigastric vessels, and in the suprapubic region. The small vertical intraumbilical 
skin incision is closed with a monocryl 3/0 intradermal suture. Wound bandages are applied to all 
three skin incisions. 
A 2.5 cm posterior colpotomy is made using a cold knife. The pouch of Douglas is opened using cold 
scissors.  A Gelpoint Mini (Applied Medical) is used as vNOTES port and is inserted into the pouch of 
Douglas.  CO2 is insufflated until a maximal intraperitoneal pressure of 15mmHg. An optic is inserted 
and the peritoneal cavity is inspected. The patient is now placed in Trendelenburg position. The small 
intestine is lifted out of the pelvis. 
The ureter is identified, but not routinely dissected. It is only dissected if it cannot be identified 
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using a reusable bipolar grasping forceps before being cut using cold scissors. The ovarian ligament is 
coagulated and cut.  The infundibulopelvic ligament is coagulated and cut.   The adnexa is resected. If 
necessary, the same procedure is repeated for the contralateral side.  The peritoneal cavity is rinsed 
and haemostasis is checked. 
Small and benign adnexa will be removed directly through the wound protector part of the NOTES 
port. Large adnexa or adnexa that are macroscopically suspicious, will be placed in an endobag 
(Memobag, Teleflex).  The purse string of the endobag is pulled through the wound protector and 
the purse string is released. The content of the cyst is aspirated to reduce the volume of the adnexa. 
The endobag is now removed with the adnexa inside it. The vNOTES port is removed. 
The colpotomy is closed using three interrupted figure-of-eight Vicryl 2/0 sutures. A vaginal plug 
(betadine gauze 10cmx5m) is placed to be removed after 3 hours together with the Foley catheter. 
Antibiotic administration: 
Cefazolin 2g and metronidazol 1.5g are administered IV during the procedure. 
Analgesia at the recovery room and the nursing ward: The pain management for both groups was 
discussed with two senior staff members of the department of anaesthesiology of the hospital, who 
are co-investigators. The protocol will be standard for both comparison groups and is presented in 
appendix V. 
The vaginal plug and the Foley catheter are removed 3 hours after the surgery. The bandages are left 
in place and not changed unless soaked by blood with a need to change. The personnel of the 
recovery room will be asked to replace bandages only for hygienic reasons and immediately to apply 
a new wound dressing without revealing any information to the participant or personnel on the 
outpatient or hospitalization ward.  
The decision to discharge or to admit to hospital for the night will be based solely on the choice of 
the woman to return home the same day or stay overnight. The outcome assessor will report this 
decision in the patient record without consulting the results of the pain scoring or whether or not 
additional analgesics were administered. Every woman leaving the hospital will be given a standard 
list with instructions not to have intercourse during six weeks and not to work for a period of four 
weeks. Telephone numbers will be provided for contacting the staff members on call in case urgent 
medical care for treating any adverse event is needed. Cefazolin 2g is administered IV before 
discharge. 
 

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4.1.2 LSC adnexectomy 
This is the surgical procedure done in the control arm of the NOTABLE trial. 
Clindamycin vaginal cream is administered on admission of the study participant to the outpatient 
ward.  
The woman is placed in lithotomy position in a vacuum mattress. The abdomen, the vulva and the 
vagina are disinfected with an alcoholic betadine solution and draped. A Foley catheter is inserted 
into the bladder. 
A small vertical intra-umbilical skin incision is made. A Verress needle is inserted into the peritoneal 
cavity; the correct position of the needle tip is checked with Semm test. CO2 is insufflated until a 
maximal intraperitoneal pressure of 15mmHg. The Verress needle is removed and replaced by a 
10mm reusable trocar. An optic is inserted through the 10mm trocar and the peritoneal cavity is 
inspected.  The patient is now placed in Trendelenburg position. Two reusable 5mm trocars are 
placed under direct vision in the left and right iliac fossa lateral of the epigastric vessels.  The small 
intestine is lifted out of the pelvis. 
The ureter is identified, but not routinely dissected. It is only dissected if it cannot be identified 
transperitoneally.  The proximal end of the Fallopian tube is coagulated at its origin into the uterus 
using a reusable bipolar grasper and cut using cold scissors. The ovarian ligament is coagulated and 
cut.  The infundibulopelvic ligament is coagulated and cut.   The adnexa are resected and placed in an 
endobag (Memobag, Teleflex).  If necessary, the same procedure is repeated for the contralateral 
side. 
The peritoneal cavity is rinsed and haemostasis is checked.  No drains are left in the peritoneal cavity 
except when there might be any uncertainty concerning the haemostasis.  The 5 mm trocars are 
removed under direct vision.  The purse string of the endobag is pulled through the 10 mm trocar 
upon removal of the optic.  The umbilical incision is extended vertically in caudal direction, the size 
being not more than 2.5 cm. The fascia and peritoneum are opened and the proximal end of the 
endobag is pulled through the incision without causing any rupture if possible. If not possible, the 
endobag should be opened and the content of the cyst should be aspirated to reduce the volume of 
the adnexa.  The aspirated fluid should be send for cytological examination. The endobag is now 
removed with the adnexa inside it. 
The fascia is closed using a Vicryl-1 running suture. The umbilicus and the other incisions are 
disinfected with Betadine solution. The skin incisions are closed with a monocryl 3/0 intradermal 

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suture and steri-strips. The wound sites are covered with a standard bandage. A vaginal plug 
(betadine gauze 10 cm x 5 m) is placed to be removed after 3 hours together with the Foley catheter. 
Antibiotic administration: 
Cefazolin 2g and metronidazol 1.5g are administered IV during the procedure. 
Analgesia at the recovery room and the nursing ward: The pain management for both groups was 
discussed with two senior staff member of the department of anaesthesiology of the hospital, who 
are co-investigators. The protocol will be standard for both comparison groups and is presented in 
appendix V. 
The vaginal plug and the Foley catheter are removed 3 hours after the surgery. The bandages are left 
in place and not changed unless soaked by blood with a need to change. The personnel of the 
recovery room will be asked to replace bandages only for hygienic reasons and immediately to apply 
a new wound dressing without revealing any information to the participant or personnel on the day 
care unit or hospitalisation ward.  
The decision to discharge or to admit to hospital for the night will be based solely on the choice of 
the woman to return home the same day or stay overnight. The outcome assessor will report this 
decision in the patient record without consulting the results of the pain scoring or whether or not 
additional analgesics were administered. Every woman leaving the hospital will be given a standard 
list with instructions not to have intercourse during six weeks and not to work for a period of four 
weeks. Telephone numbers will be provided for contacting the staff members on call in case urgent 
medical care for treating any adverse event is needed. Cefazolin 2g is administered IV before 
discharge. 
4.1.3 Failure of procedure 
Occasionally, surgical removal of a benign adnexal mass by any of the two techniques may not be 
completed according to the random sequence generation because of technical limitations or 
unexpected findings such as extensive adhesions or unexpected malignancy. Successful vNOTES or 
laparoscopic removal of a benign adnexal mass is possible in the majority of women, but the 
probability of success is not readily predictable. In cases where the intended procedure has to be 
abandoned, the appropriate technique (e.g. staging laparotomy for ovarian cancer) or a second 
procedure (e.g. laparoscopy or laparotomy after bowel preparation) under general anaesthesia 
should be scheduled as soon as possible. Women who require an alternative more appropriate 
intervention or a second procedure are not excluded or withdrawn from the NOTABLE trial. The 
investigators will sensitively explain to them that follow-up information is still very important, 

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despite the change in treatment, and unless they wish to withdrawn completely from the trial, they 
will be followed up. 
4.2. Concomitant interventions and treatments 
It is anticipated that most women presenting with a suspected benign adnexal mass will require no 
further intervention other that removal of the adnexa. However, in some circumstances additional 
treatments may be considered necessary by the responsible clinician at the time of adnexal removal 
or subsequently. Surgical interventions in the form of endometrial ablation or hysterectomy may 
subsequently be necessary and the need for such interventions will be recorded. However, if the 
need for additional surgery at the time of surgery is indicated, then such patients are excluded for 
recruitment to the NOTABLE trial. All therapeutic interventions additional to removal of one or both 
adnexa will be recorded and as the trial is randomised we anticipate that these further interventions 
will be symmetrically applicable. 
4.3. Withdrawal from the NOTABLE trial 
All women who consent to the randomised NOTABLE trial, should be followed up and asked to 
complete postal questionnaires, regardless of actual treatment received. 
If a woman specifically requests a treatment setting after randomisation, then her choices should be 
respected. This does not necessitate withdrawal from the trial. Similarly, if one of both procedures 
fails, she will require subsequent treatment. In both circumstances, it should be sensitively explained 
to them that follow-up information is still very important, and unless they wish to withdrawn 
completely from the trial, they will be followed up. Any request to withdraw from follow-up should 
be notified to the NOTABLE study nurse. 
4.4. Serious and unexpected adverse events  
There may be mortality and morbidity associated with either procedure, therefore all serious adverse 
events (SAE) should be reported by fax to the NOTABLE Trial Office as soon as possible. This report 
should be followed within 2 days by a completed SAE form to the Ethics Committee and the Federal 
Agency for Medicines and Health Products (FAMHP). For the purposes of this study, “serious” 
adverse events are those which are fatal, life-threatening, disabling or prolong hospitalisation and 
have resulted from the surgical procedure, the anaesthetic or post-operative recovery e.g. deep vein 
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5. FOLLOW-UP AND OUTCOME MEASURES 
5.1. Clinical assessments 
5.1.1 Format 
PROMs will be collected using a postal questionnaire at baseline, at three and six months. 
The postal questionnaires will be sent from the NOTABLE Trial Office with postage paid envelopes 
two weeks before the due date. Reminders will be sent to the participants if the questionnaire is not 
returned within one week of the due date and attempts will be made to contact the women by 
phone if the questionnaire is not returned by two weeks after the due date.  
5.1.2 Timing of assessments 
The primary outcome will be measured clinically at the end of the surgical procedure. In addition 
PROMs will take place the evening of the surgical intervention (return home), during the first 
postoperative week (pain by VAS scores and medication) and at 3 and 6 months (dyspareunia and 
sexual wellbeing). Clinical physician assessment will take place the evening of the surgical 
intervention (return home) and during the first six weeks following surgery (pelvic infection, surgical 
complications). 
5.2. Primary clinical outcome measure 
The proportion of women successfully treated by removing the adnexal mass without spill, using a 
dichotomous outcome measure, will be used as a measure of efficacy. An important consideration in 
adnexal mass surgery is the inadvertent opening of the ovarian capsule. The likelihood of cyst 
rupture during removal by laparotomy or laparoscopy ranges from 10.5% to 41.8% in published 
studies (15). We will consider any spontaneous rupture of the cyst or any need to aspirate the cyst to 
allow removal from the abdominal cavity as treatment failures, even if the content of the ruptured 
cyst does not spill freely inside the cavity but remains within the endobag. By avoiding any subjective 
interpretations this rigorous definition allows an objective measure of success. As the risk of rupture 
may be associated to the cyst size, due to the stratified random sequence generation we anticipate 
that the risk of rupture due to the cyst size rather than the technique used will be symmetrically 
applicable. 
5.3. Secondary clinical outcome measures 
We will measure the following secondary outcomes: 
• 
The proportion of women discharged the same day based on their own preference, as a 
dichotomous outcome. The decision to discharge from the day care unit or to admit to 
hospital for the night will be based solely on the choice of the woman to return home the 
same day or stay overnight. The outcome assessor will report this decision in the patient 
record without consulting the results of the pain scoring or whether or not additional 

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analgesics were administered. In case of conflict (women wishing to return home against 
outcome assessor’s advice based on clinical suspicion of possible complications for instance) 
the study participant is not excluded from further follow-up. Data will be analysed using a 
sensitivity analysis by imputing that the index participant would have agreed to stay 
overnight as dictated by the clinical judgement of the outcome assessor versus the available 
data analysis. 
• 
Postoperative pain scores, as an ordinal outcome, measured using a VAS scale twice daily 
from day 1 till 7 self-reported by the participating women: one measurement will be done in 
the morning after bed rest at night (rest) and the other will be done in the evening before 
going to bed after physical activity (active). The participants should place the cursor of the 
VAS scale device available at the day care unit of the participating centre on the picture 
indicating the expression of pain sensation that according to their own experience best 
describes how they feel pain at the time point of measurement. By looking at the back of the 
scale they can measure the level of pain by recording the numbers immediately to the left 
and right of the red line: e.g. pain level 0 to 1, or pain level 5 to 6. The lowest number will be 
recorded by the outcome assessor for data analysis. The reliability of VAS has been 
established in the assessment of chronic gynaecological conditions like pain. 
• 
Postoperative pain defined by the total use of analgesics during the first week following 
surgery as described in the standardized pain treatment protocol, as an ordinal outcome. 
The use of pain medication following surgery should be reported in the nursing file. At home 
the participants should note in their participant log book the name, dosage, route of 
administration of any analgesic drug that was taken from the moment they are at home 
until the assessment on day 7 irrespective of whether this was done on their own initiative 
or after consulting a family physician or any other medical specialist. The assessment of the 
total use of analgesics will be done on day 7 by the outcome assessor (the coordinating 
investigator), who is blinded for the intervention done by the principal investigator.  
• 
Postoperative infection defined by lower abdominal pain with fever > 38°C and positive 
clinical signs or laboratory findings, detected during the first six weeks of surgery, as a 
dichotomous outcome. 
• 
Per- or postoperative complications according to the Clavien- Dindo classification detected 
during the first six weeks of surgery, as a dichotomous outcome (Appendix III). 
• 
Hospital readmission during the first six weeks of surgery, as a dichotomous outcome. 
• 
Incidence and intensity of dyspareunia recorded by the participants at 3 and 6 months by 
self-reporting using a simple questionnaire and VAS scale, as a dichotomous and ordinal 

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outcome. A measurement of the prevalence and the intensity of dyspareunia will be done at 
baseline assessment. 
• 
Sexual wellbeing at baseline, at 3 and 6 months by self-reporting the SSFS. 
• 
Quality of life at baseline, at 3 and 6 months by self-reporting the EQ-5D-3L questionnaire. 
• 
Duration of surgery measured as the time in minutes from the insertion of the bladder 
catheter to the end of vaginal/abdominal wound closure, as a continuous outcome. 
5.4. Health economic outcomes 
Costs and consequences of the treatment pathways will be collected from health care providers at 
the time of the procedure and at follow up in order to conduct the cost-effectiveness analyses. 
Resource use data will include: 
• Surgical treatment of benign adnexal mass 
• Tests and investigations received 
• The frequency and duration of out-patient visits and primary care consultations 
• Inpatient stays 
• Type and volume of medications received 
• The number and duration of hospital readmissions and re-treatments. 
These data will be collected prospectively from health care providers using a post-operative case 
report form and patient-completed questionnaires that assess patient health service utilisation at the 
follow-up time points throughout the trial. Costs incurred by patients will also be collected to 
conduct an evaluation from a wider societal perspective. Therefore, a patient cost questionnaire will 
be administered to all trial patients in order to consider the wider cost implications of the 
interventions which will contain questions to determine out of pocket expenses incurred when 
attending for treatment and private time costs including time lost from work. 
Unit costs obtained from published sources and the trial centre will be used to estimate costs 
associated with resource use. Responses to the EuroQol EQ-5D-3L questionnaire will inform the 
effectiveness in terms of QALYs and clinical effectiveness will be measured in cured cases at six 
months. We obtained full approval of EUROQoL to use the questionnaire for free. 
Data collection will be undertaken prospectively for all trial patients so that a stochastic cost analysis 
can be undertaken. The process of collecting resource use data will be undertaken separately from 
data collection on unit costs. 
The main resource use to be monitored include the following: 
1) Consultation time required prior for each procedure for explanation and consent. 
2) Costs involved with each procedure including level of health care professional involvement in the 
procedure, equipment required, overheads, consumables and drugs including anaesthesia. 

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3) Any additional procedures required where initial treatment is unsuccessful or incomplete. 
4) Duration of inpatient stay when women opt to stay overnight. 
Information on any additional related primary or secondary care contacts will also be collected from 
all women to ensure any resulting resource use from additional complications is recorded. Unit costs 
will be obtained and attached to resource items in order that a cost can be calculated for each trial 
patient. Unit costs will be obtained from published sources and the centre participating in the trial.  
In addition, the set-up costs of NOTABLE will be estimated and additional analyses will be undertaken 
including these costs.  
5.5. Data management and validation 
5.5.1 Confidentiality of personal data 
Personal data and sensitive information required for the NOTABLE Trial will be collected directly from 
participants, who will be informed about the transfer of this information to the trial office at the 
department of Obstetrics and Gynaecology of the participating centre and will be asked to consent to 
this. The data will be entered onto a secure computer database, either by staff or directly via a 
secure internet connection. Any data to be processed outside the trial office will be anonymised. All 
personal information obtained for the study will be held securely and treated as (strictly) 
confidential. All staff involved in the NOTABLE Trial (clinical, paramedical, administration) share the 
same duty of care to prevent unauthorized disclosure of personal information. No data that could be 
used to identify an individual will be published. We will handle all data confidentially in accordance 
with the Belgian law of 8 December 1992 on the protection of privacy with respect to the handling of 
individual personal data. 
5.5.2 Long-term storage of data 
In line with existing guidelines and Belgian legislation, all data will be stored for up to 15 years after 
the last participant has reached the 2.5 year follow-up to allow adequate time for review, reappraisal 
or further research, and to allow any queries or concerns about the data, conduct or conclusions of 
the study to be resolved.  
5.6. Withdrawal from follow-up 
Withdrawal from follow-up is the decision of the participant. However, withdrawn patients can bias 
clinical trial results and reduce the power of the study to detect important differences, so women 
should be encouraged to complete all follow-up questionnaires. Methods to reduce the burden of 
follow-up will be explored e.g. online data entry for participants. If the reason for withdrawal is 
known, it should be communicated to the NOTABLE Trial Office. To reduce loss to follow-up, we shall 
record patient’s social security number, which allows us to track patients changing GP practice. With 
postal and telephone reminders we anticipate that, the completeness of data should surpass 90% 
although, as set out below incomplete follow-up is incorporated into the power calculations. 

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6. ACCRUAL AND ANALYSIS 
6.1. Sample size 
The sample size for the primary outcome of this trial has been chosen to give good statistical power 
to preclude any clinically important inferiority of vNOTES compared to laparoscopy and is based on 
evidence retrieved from a systematic review of the literature (15) and a RCT comparing the excision 
of mature teratoma using culdotomy with and without laparoscopy (17). An important consideration 
in adnexal mass surgery is the inadvertent opening of the ovarian capsule. The likelihood of cyst 
rupture during removal by laparotomy or laparoscopy ranges from 10.5% to 41.8% in published 
studies (15). Based on a low failure rate to remove dermoid cysts by colpotomy using laparoscopy 
(2.4%), according to the findings from a RCT (17) we assumed a successful removal of adnexal cysts 
without spill to be feasible in 95% of all cases. We calculated the sample size with a one-sided test for 
non-inferiority studies for the primary outcome. The vNOTES approach may be more convenient for 
women in that no scar in the abdominal wall is required. We believe, therefore, that vNOTES would 
be the treatment of choice even if 15% less women had successful removal of a benign adnexal mass 
by using the vNOTES approach. Non inferiority will be concluded when 15% lies above the upper limit 
of the 95% confidence interval calculated for the difference in the proportion of women successfully 
treated with either of both techniques. To achieve 80% power to demonstrate non-inferiority under 
the assumption of similar success rates of 95% in both groups a sample size of 54 participants (27 
women per group) will be required. The target sample size was increased to 64 participants (32 
women per group) to account for a drop-out rate of 15%.  
 (https://www.sealedenvelope.com/power/binary-noninferior/). Based on the power calculations for 
the primary outcome, the use of three strata for the randomisation and assuming a loss-to-follow-up 
rate of 15 % we decided to include 66 study participants in the NOTABLE trial. 
6.2. Projected accrual and attrition rates 
It is anticipated that recruitment of participants will take two years. Based upon the mean number of 
laparoscopic adnexectomies performed annually at the department of Obstetrics and Gynecology of 
the participating centre (36) we estimate that the duration of recruitment will be 21 months. Based 
upon the follow up (6 months) and the period of analysis/reporting (3 months) the total study period 
will be 2.5 years. First publication will be possible within four years of trial commencement. 
Our sample size calculation has allowed for a 15% loss to follow up rate. In order to minimise rates of 
attrition we will employ a dedicated research secretary to optimize recruitment and follow up. 
6.3. Statistical Analysis 
We will calculate a 95% confidence interval of the difference in the proportions of women with a 
successful removal of an adnexal cyst.  Non inferiority of the intervention (vNOTES) will be concluded 

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when 15% lies above the upper limit of this confidence interval. For this primary analysis, 
adjustments for prognostic factors will not be made in the first instance; the effect of the variables 
listed in Section 3.5 (Stratification of randomisation) will be explored as a secondary analysis.  
Continuous measures (VAS scores) will be analysed using analysis of covariance (adjusting for 
baseline value). Multilevel models for repeated measurements will also be used to compare the 
mean differences in VAS pain scores between groups overall at all time points, thereby maximising 
the power of the data available.  
Analysis will be performed on an ‘intention to treat’ basis in the first instance as recommended in the 
CONSORT statement. A ‘per protocol’ analysis will also be performed to test the robustness of the 
results obtained. As a conservative measure, estimates of effect sizes between the two arms will be 
presented as point estimates with two-sided 95% confidence intervals. The trial can only conclude 
non-inferiority if 15% lies out of the upper band of the confidence interval (i.e. vNOTES 15% less 
successful than laparoscopic treatment). 
Baseline characteristics of the patients enrolled in the two groups will be compared to ensure that 
randomisation has produced comparable groups of participants, and will be covariates in the 
modelling procedure.  
6.3.1 Subgroup analyses 
Subgroup analyses are limited by statistical power and can produce spurious results particularly if 
many are undertaken. We will not undertake any subgroup analyses in this pilot study. 
6.3.2 Proposed frequency of analyses 
1. Twice yearly review of recruitment, compliance and loss to follow-up for NOTABLE Trial 
Steering Committee. 
2. Annual interim analyses of effectiveness for confidential review by Ethics Committee to 
determine whether the principal question has been answered and to monitor adverse 
events. 
3. Main analyses of effectiveness of NOTABLE once all participants have reached 6-month 
follow up of the total study sample. 
4. Additional analysis of longer term effects (completion of one and two years of follow-up). 
6.3.3 Handling missing data  
The interpretation of missing values in the analysis of clinical trials can be fraught with danger. The 
methods used to allow for missing data make assumptions about the reasons for data not being 
present, such as in the “observed case” analysis, where the presence or absence of data is viewed as 
unrelated to outcome, or in the “Last Observation Carried Forward” analysis where the assumption is 
that the condition does not improve or worsen following withdrawal from follow-up. To minimise 
possible biases, participants will continue to be followed up even after protocol treatment violation. 

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Missing data items will be imputed from given values if limited to a single item response. If a form is 
missing entirely or greater than one item imputation will not be attempted. Sensitivity analyses will 
be carried out to determine whether or not the results obtained are robust to the methods used to 
handle missing data. These approaches are in line with the recent recommendations from the 
European Agency for the Evaluation of Medicinal Products. 
Questionnaires will only be treated as late if they are returned after the subsequent questionnaire 
has been sent to the participant. However if this form is the only form available at the later time 
point it will be included at the subsequent time. 
6.4. Health Economic Analysis 
6.4.1 Form of the economic evaluation 
If vNOTES is found to be an effective treatment for the removal of benign adnexal mass, then it is 
likely that there can be cost implications for the health care sector. For example, as the woman will 
be treated as an outpatient, thus avoiding an inpatient stay, resources may be saved. However, 
vNOTES may incur costs due to equipment required and the specialist nature of health care 
professionals to perform this procedure. Therefore all costs incurred by both procedures need to be 
assessed in conjunction with measures of effectiveness. 
The aim of the economic evaluation is to determine the cost-effectiveness of vNOTES compared with 
standard laparoscopic treatment. Although the trial has been designed as a non-inferiority trial, we 
feel the most appropriate type of analysis is a cost-effectiveness analysis. Cost-effectiveness will be 
determined in two ways. A cost-effectiveness analysis will be undertaken to calculate the cost per 
additional cured case adnexal removal at six months, utilizing the clinical outcome data collected 
within the trial. In addition, a cost-utility analysis will be undertaken to calculate the cost per 
additional quality-adjusted life year (QALY) gained. The utility values required to calculate QALYs will 
be obtained by administering the EuroQol EQ-5D-3L questionnaire to all study patients at baseline, 
three months and six months. In the first instance, the evaluation will consider costs incurred by the 
health service in the delivery of both treatment pathways. However, information on costs incurred 
by patients will also be collected in order that an evaluation from a wider societal perspective can 
also be undertaken. 
6.4.2 Economic analysis 
Given the objective of the trial and limited available evidence in support of the NOTABLE strategy, 
only a within trial economic analysis will be carried out. The analysis will adopt an incremental 
approach in that data collection will concentrate on resource use and outcome differences between 
trial arms. As the majority of cost data are skewed, and the mean cost of each procedure is of 
importance, a bootstrapping approach will be undertaken in order to calculate confidence intervals 

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around the mean costs. As the time frame of the economic evaluation is not greater than one year, 
discounting is not required. 
Uncertainty in the confidence to be placed on the results of the economic analysis will be explored by 
estimating cost-effectiveness acceptability curves. These plot the probability that the intervention is 
cost-effective against threshold values for cost-effectiveness. The robustness of the results will be 
explored using sensitivity analysis. This will explore uncertainties in the trial based data itself, the 
methods employed to analyse the data and the generalizability of the results to other settings. 
We will seek the assistance of an expert in health economics at the University of Ghent, Belgium. 
6.5. Definition of the end of trial 
The end of the NOTABLE trial will be defined as the time when the last participant recruited has 
completed 6 months of follow up. 
 
 

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7. ASSESSMENT OF PATIENT ACCEPTABILITY 
 
7.1. Measurements for Patient Acceptability  
The acceptability of vNOTES will principally be assessed using a questionnaire designed specifically 
for the study and administered within 24 hours of treatment to limit recall bias. Pilot testing will be 
carried out to make certain the questionnaire is usable. In addition to the questionnaire, data will be 
collected on the women who do not give consent to randomization (state a preference and agree to 
be registered for the NOTABLE study), and requested from those who decline to participate. 
In order to aid interpretation and understanding of the questionnaire data, and to gain greater depth 
of experience, the acceptability of NOTABLE will further be assessed using a qualitative methodology. 
Interviewing after discharge will allow the woman time to reflect on her experience, and will also 
minimise the chance that gratitude to doctors and other hospital staff results in unduly positive 
responses. Honesty is also more likely to occur on neutral or the patient’s home ground. Interviews 
will be recorded with patients’ permission and transcribed verbatim. The interview schedule will be 
designed following a literature search on patient acceptability of surgical procedures, and from the 
focus group discussions. From these, a set of items will be derived which will seem relevant to the 
participants and cover all the areas thought to be important by participants. The latter will also 
ensure that the questionnaire is as discriminatory as possible. The interview schedule will be piloted 
with five women. These procedures will ensure face and content validity, and sending each woman 
the transcript of her interview with the opportunity to amend any inaccuracy will assess fair and 
accurate representation. 
7.1.1 Sampling of Participants for In-depth Interview 
We propose to select a 20% random sample (6 women) from each arm of the research for interview 
within one week of discharge either face to face, or by telephone. 
7.2. Evaluation of Patient Acceptability  
Analysis of data will be by content analysis with the development of analytical themes. The initial 
process will be the intensive reading and re-reading of interview transcripts, and a search for 
regularities, contradictions, patterns and themes by comparing the participants’ statements using a 
coding frame. Inter-rater reliability on the coding of transcripts will be undertaken. A percentage of 
the transcripts will be coded independently by two members of the qualitative research team and 
discrepancies discussed and resolved. Emergent themes obtained by this process will be refined until 
final themes are agreed by all applicants as reflective of the data. ‘Researcher triangulation’ will offer 
the first step to verification of the findings. This will be achieved through the independent analysis of 
20% of transcripts from the sample by the researchers. Verification occurs through discussion of their 
analyses, comparison and subsequent consensus. ‘Respondent validation’ will also be sought by 

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taking the tentative findings back to a sample of participants in order to be verified as reflective of 
their experience. A final form of verification is the comparison of findings with, and their 
embeddedness in the available literature. 
It is anticipated that the questionnaire and the subsequent in depth interviews will measure and 
provide insight into acceptability and satisfaction in the following areas: the procedure(s) for 
diagnosis; the information provided when consent is obtained; procedures to protect confidentiality; 
preference for one arm of the trial over the other; experience of the procedure and the immediate 
post-operative phase; overall satisfaction with the process; acceptability for the same procedure if 
adnexal masses are diagnosed in the future; perceptions of being involved in an RCT. 
 
 

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8. DATA ACCESS AND QUALITY ASSURANCE 
8.1. In-house Data Quality Assurance 
The study will adopt a centralized approach to monitoring data quality and compliance. A computer 
database will be constructed specifically for the study data and will include range and logic checks to 
prevent erroneous data entry. Independent checking of data entry of paper questionnaires will be 
periodically undertaken on small sub-samples. The trial statistician will regularly check the balance of 
allocations by the stratification variables. Source data verification will only be employed if there is 
reason to believe data quality has been compromised. 
8.2. Independent Trial Steering Committee 
The Trial Steering Committee (TSC) provides independent supervision for the trial, providing advice 
to the Chief and Co- Investigators on all aspects of the trial and affording protection for patients by 
ensuring the trial is conducted according to the MRC Guidelines for Good Clinical Practice in Clinical 
Trials. 
If the Chief and Co-Investigators are unable to resolve any concern satisfactorily, Principal 
Investigators, and all others associated with the study, may write through the Trial Office to the 
chairman of the TSC, drawing attention to any concerns they may have about the possibility of 
particular side-effects, or of particular categories of patient requiring special study, or about any 
other matters thought relevant. 
8.3. Data Monitoring and Ethics Committee: Determining when clear answers have emerged  
If vNOTES is clearly inferior to standard laparoscopic treatment, with respect to the primary 
endpoint, then this may become apparent before the target recruitment has been reached. 
Alternatively, new evidence might emerge from other sources that vNOTES definitely more, or less, 
effective than laparoscopy. To protect against this, during the period of recruitment to the study, 
interim analyses of major endpoints will be supplied, in strict confidence, to an independent Data 
Monitoring and Ethics Committee (DMEC) along with updates on results of other related studies, and 
any other analyses that the DMEC may request. The DMEC will advise the chair of the Trial Steering 
Committee if, in their view, any of the randomised comparisons in the trial have provided both (a) 
“proof beyond reasonable doubt” that for all, or some, women that vNOTES is so inferior from 
laparoscopy that non-inferiority can never be demonstrated, and (b) evidence that might reasonably 
be expected to influence the patient management of many clinicians who are already aware of the 
other main trial results (b) evidence that might reasonably be expected to influence the patient 
management of many clinicians who are already aware of the other main trial results. The TSC can 
then decide whether to close or modify any part of the trial. Unless this happens, however, the Trial 

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management group (TMG), TSC, the investigators and all of the central administrative staff (except 
the statisticians who supply the confidential analyses) will remain unaware of the interim results. 
 
 

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9. ORGANIZATION AND RESPONSIBILITIES 
All investigators are responsible for ensuring that any research they undertake follows the agreed 
protocol, for helping care professionals to ensure that participants receive appropriate care while 
involved in research, for protecting the integrity and confidentiality of clinical and other records and 
data generated by the research, and for reporting any failures in these respects, surgical 
complications and other events or suspected misconduct through the appropriate systems. 
9.1. Centre eligibility 
Not applicable since NOTABLE is a single centre RCT. 
9.2. Local Coordinator 
The responsibilities of the local Principal Investigator will be to ensure that all medical and nursing 
staff involved in the care of NOTABLE are well informed about the study and trained in trial 
procedures, including obtaining informed consent. The local Principal Investigator should liaise with 
the Trial Coordinator on logistic and administrative matters connected with the trial. 
9.3. Nursing Coordinator 
One nurse will be designated as local Nursing Coordinator. This person would be responsible for 
ensuring that all eligible patients are considered for the trial, that patients are provided with patient 
information sheets, and have an opportunity to discuss the study if required. The nurse may be 
responsible for collecting the baseline patient data and will act as a contact for obtaining missing 
follow-up evaluations. Again, this person would be sent updates and newsletters, and would be 
invited to training and progress meetings. 
9.4. The NOTABLE Trial Office 
The Trial Office at department of Obstetrics and Gynaecology of the participating centre is 
responsible for providing all trial materials, including the trial folders containing centre specific trial 
documentation, standard operating procedures and training materials. Additional supplies of any 
printed material can be obtained on request or downloaded from the NOTABLE trial website. The 
Trial Office is responsible for collection and checking of data (including reports of serious surgical 
complications), for reporting of serious adverse events to the sponsor and/ or regulatory authorities 
and for analyses. The Trial Office will help resolve any local problems that may be encountered in 
trial participation. 
9.5. Research Governance  
The study will be conducted according to the principles of the Declaration of Helsinki (Adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 52nd WMA General 
Assembly, Edinburgh, Scotland, October 2000) and in accordance with the Belgian law of 7 May 2004 
that regulates human experiments in Belgium.  

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All Principal Investigators will be required to sign an Investigator’s Agreement, detailing their 
commitment to accrual, compliance, Good Clinical Practice, confidentiality and publication. 
Deviations from the agreement will be monitored and the TSC will decide whether any action needs 
to be taken, e.g. withdrawal of funding, suspension of centre.  
9.6. Research Governance and Ethical Approval 
As the trial does not involve an investigational medicinal product, clinical trial authorization from the 
Medicines and Healthcare products Regulatory Authority is not required. 
In accordance to the Belgian law of 7 May 2004 that regulates human experiments, the investigator 
will inform the study participants and the medical ethical committee if anything occurs, on the basis 
of which it appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal. The study will be suspended pending further review, except 
insofar as suspension would jeopardize the subjects’ health. The investigator will take care that all 
subjects are kept informed. 
The principal investigator will report all adverse and serious events to the medical ethical committee.  
Adverse events are defined as any undesirable experience occurring to a participant during the study, 
whether or not considered to be related to the intervention. 
All adverse events reported spontaneously by the participant or observed by the investigator or his 
staff will be recorded. 
A serious adverse event is any untoward medical occurrence or effect that: 
o results in death; 
o is life threatening (at the time of the event); 
o requires hospitalization or prolongation of existing inpatients’ hospitalization; 
o results in persistent or significant disability or incapacity; 
o is a congenital anomaly or birth defect; 
o is a new event of the trial likely to affect the safety of the subjects, such as an 
unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the  
treatment of a life threatening disease, major safety finding from a newly completed 
animal study, etc. 
All SAEs will be reported to medical ethical committee that approved the protocol, within 15 days 
after the investigator has first knowledge of the serious adverse reactions. 

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SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur no later than 7 days after the responsible investigator has first knowledge of the 
adverse reaction. This is for a preliminary report with another 8 days for completion of the report. 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
9.7. Funding and Cost implications 
The research costs of this non-commercial trial are funded by the investigating team. 
9.8. Indemnity 
No additional preoperative examinations are needed when compared to the situation where the 
woman would not have given informed consent for study participation. One additional postoperative 
examination is needed for study participants compared to routine clinical practice: no risks or side 
effects are associated with this additional assessment. The risks and side effects for both types of 
surgical interventions have been extensively described in the consent form. According to two large 
prospective studies the incidence of complications associated with minimally invasive surgery are 
less than 1%. (26, 27) The benefit is an, as of yet, unknown increase in the chance of being 
discharged the same day as the surgical procedure with less postoperative pain. 
The investigators have a ‘no fault’ liability insurance which is in accordance to the Belgian law of 7 
May 2004 that regulates human experiments. The insurance aims to cover the financial 
consequences of the civil liability that the investigators may incur even when no fault has occurred as 
a result of the organization of medical experiments on the human person. All physical and material 
damage sustained by the participant in the experiment and/or his/her assignees and arising from the 
insured experiment are covered for an amount of 2 500 000 € per experiment. The insurance applies 
to the damage that becomes apparent during the study or within 36 months after the end of the 
study. 
9.9. Publication 
A meeting will be held after the end of the study to allow discussion of the main results among the 
collaborators prior to publication. The success of the study depends entirely on the wholehearted 
collaboration of a dedicated team of doctors, nurses and others. 
. 
9.10. Ancillary studies 
It is requested that any proposals for formal additional studies of the effects of the trial treatments 
on some participants (e.g. special investigations in selected hospitals) be referred to the Trial 

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Management Committee for consideration. In general, it would be preferable for the trial to be kept 
as simple as possible, and add-on studies will need to be fully justified. 
 
 

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10. REFERENCES 
(1) Burpee SE, Kurian M, Murakame Y, Benevides S, Gagner M. The metabolic and immune 
response to laparoscopic versus open liver resection. Surg Endosc. 2002; 16(6):899 –904. 
(2) Grande M, Tucci GF, Adorisio O, et al. Systemic acute-phase response after laparoscopic and 
open cholecystectomy. Surg Endosc. 2002; 16(2):313–6. 
(3) Rattner D, Kalloo A. ASGE/SAGES working group on natural Orifice transluminal endoscopic 
surgery. October 2005. Surg Endosc. 2006; 20:329-33. 
(4) Santos BF, Hungness ES. Natural orifice transluminal endoscopic surgery: progress in humans 
since white paper. World J Gastroenterol. 2011; 17:1655–65. 
(5) Tolcher MC, Kalogera E, Hopkins MR, Weaver AL, Bingener J, Dowdy SC. Safety of Culdotomy 
as a Surgical Approach: Implications for Natural Orifice Transluminal. JSLS. 2012; 16:413–20 
(6) Uccella S, Cromi A, Bogani G, Casarin J, Serati M, Ghezzi F. Transvaginal specimen extraction at 
laparoscopy without concomitant hysterectomy: our experience and systematic review of the 
literature. J Minim Invasive Gynecol. 2013; 20:583-90. 
(7) Reynders A, Baekelandt J. Adnexectomy by Poor Man’s Transvaginal NOTES. Gynecological 
Surgery 2015; 12(3): 207-11.  
(8) Dindo D, Demartines N, Clavien PA. Classifi cation of surgical complications: a new proposal 
with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: 205–
13. 
(9) Mc Williams GD, Hill MJ, Dietrich CS. Gynecologic emergencies. Surg Clin North Am 2008; 
88(2): 265-83. 
(10) Timmerman D,  Ameye L, Fischerova D, Epstein E,  Melis GB, Guerriero S,  Van Holsbeke C,  
Savelli L, Fruscio R, Lissoni AA, Testa AC, Veldman J, Vergote I, Van Huffel S, Bourne T, Valentin 
L. Simple ultrasound rules to distinguish between benign and malignant adnexal masses 
before surgery: prospective validation by IOTA group. BMJ 2010; 341:c6839 
doi:10.1136/bmj.c6839.  
(11) Sainz de la Cuesta R, Goff BA, Fuller AF Jr, Nikrui N, Eichhorn JH, Rice LW. Prognostic 
importance of intraoperative rupture of malignant ovarian epithelial neoplasms. Obstet 
Gynecol. 1994;84(1):1. 
(12) Webb MJ, Decker DG, Mussey E, Williams TJ. Factor influencing survival in Stage I ovarian 
cancer. Am J Obstet Gynecol. 1973;116(2):222. 
(13) Pillai R, Yoong W. Posterior colpotomy revisited: a forgotten route for retrieving larger benign 
ovarian lesions following laparoscopic excision. Arch Gynecol Obstet. 2010; 281(4):609-11.  

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(14) Yang YS, Hur MH, Oh KY, Kim SY. Transvaginal natural orifice transluminal endoscopic surgery 
for adnexal masses. J Obstet Gynaecol Res. 2013 Dec; 39(12):1604-9. 
(15) Demir RH, Marchand GJ. Adnexal masses suspected to be benign treated with laparoscopy. 
JSLS JSLS. 2012 Jan-Mar; 16(1): 71–84. 
(16) Ghezzi F, Cromi A, Uccella S, Bogani G, Serati M, Bolis PF. Transumbilical versus transvaginal 
retrieval of surgical specimens at laparoscopy: a randomized trial. Am J Obstet Gynecol 2012; 
207(2): 112.e1-112.e6. 
(17) Wang PH, Lee WL, Juang CM, Tsai WY, Chao HT, Yuan CC. Excision of mature teratoma using 
culdotomy, with and without laparoscopy: A prospective randomized trial. BJOG 2001; 108: 
91-4. 
(18) Medeiros LR, Rosa DD, Bozzetti MC, Fachel JM, Furness S, Garry R, Rosa MI, Stein AT. 
Laparoscopy versus laparotomy for benign ovarian tumour. Cochrane Database Syst Rev. 2009 
Apr 15; (2):CD004751. 
(19) Barkun JS, Aronson JK, Feldman LS, Maddern GJ, Strasberg SM, for the Balliol Collaboration. 
Evaluation and stages of surgical innovations. The Lancet 2009; 374:1089-96. 
(20) Ergina PL, Cook JA, Blazeby JM, Boutron I, Clavien PA, Reeves BC, Seiler CM, for the Balliol 
Collaboration. Challenges in evaluating surgical innovation. The Lancet 2009; 374:1097-1104. 
(21) Mc Culloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, Nicholl J, for the 
Balliol Collaboration. No surgical intervention without evaluation: the IDEAL 
recommendations. The Lancet 2009; 374: 1105-12. 
(22) Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, 
Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. 
N Engl J Med. 2002 Jul 11; 347(2):81-8. 
(23) Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141-145. 
(24) Bird SB, Dickson EW. Clinically significant changes in pain along the visual analog scale. Ann 
Emerg Med 2001;38: 639-43. 
(25) Todd KH, Funk KG, Funk JP, Bonacci R. Clinical significance of reported changes in pain 
severity. Ann Emerg Med 1996; 27: 485-9. 
(26) Jansen FW, Kapiteyn K, Trimbos-Kemper T, Hermans J, Trimbos-Kemper JB. Complications of 
laparoscopy: a prospective multicenter observational study. Br J Obstet Gynaeco 1997; 104: 
595-600. 
(27) Harrki-Sirén P, Sjoberg J, Kurki T. Major complications of laparoscopy: a follow-up Finnish 
study. Obstet Gynecol 1999; 94: 94-8. 
 
 

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APPENDIX I: TABLE I 
 
 
 
APPENDIX II: TABLE II 
 
 
 
 
 
 
 
 

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APPENDIX III 
 
CLAVIEN-DINDO CLASSIFICATION 
 
 
 
 
 

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APPENDIX IV 
CONSORT 2010 Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed for eligibility (n=  ) 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
   Other reasons (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Allocation 
Analysis 
Follow-Up 
Randomized (n=  ) 
Enrollment 

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APPENDIX V Pain protocol 
PROTOCOL ADNEXECTOMY – DR. BAEKELANDT 
ASA I & ASA II PATIENTS 
 
1. INDUCTION ANEASTHESIA 
• 
Propolipid 2,5mg/kg 
• 
Sufentanil 0,15µg/kg 
• 
Rocurorium 0,6mg/kg 
• 
Dexamethasone 5mg 
• 
 
2. MAINTENANCE ANESTHESIA 
 
• 
O2/ room air  50/50 
DES   1 MAC 
• 
Need be  Alfentanil 5mg/kg one shot 
• 
30min. before end surgery IV shot 
o 1g Paracetamol 
o 
Ketorolac 0,5mg/kg (maximum dose 30mg) 
 
3. POSTOPERATIVE PHASE 
 
RECOVERY 
• 
If VAS >4: 1g Paracetamol IV 
• 
Reevaluation after 30min.  
o 
If VAS >4: 2,5mg Piritramide IV 
 
 

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APPENDIX VI VAS scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX VII: Participant’s pain log book 
 
NOTABLE trial 
First & last name: 
 
Date of surgical procedure: 
 
 
 
Arrival at home:  
Time of arrival at home: …………………….. 
Pain score: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
Day 1 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
 

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Day 2 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
 
 
Day 3 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
 
 

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Day 4 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
 
Day 5 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
 
 
 
 

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Day 6 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
Day 7 after surgery:  
Pain score morning: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain score evening: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
Pain medication: 
 
Dose in mg 
Number of tablets 
Time intake  
Paracetamol 
 
 
 
Ibuprofen  
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX VIII: Dyspareunia questionnaire 
 
PAIN 
LOCATION AND INTENSITY 
   
1) Do you experience pain during sexual activity?  Yes / No   
  
2) If yes, where do you experience pain during sexual activity? Is there a specific place? 
     
a) at the vaginal opening     
b) at the labia majora (major lips)   
c) in the vagina  
d) in the pelvic or abdominal region  
  
3) Please classify the intensity of the pain at the entrance and/or the first part of the vagina on the 
scale below from 0 to 10?.  
___________________________________________________________________ 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
No  
 
 
 
 
 
 
 
 
 
worst  
pain  
 
 
 
 
 
 
 
 
 
pain ever   
  
  
3) Please classify the intensity of the pain in the pelvic or abdominal region on the scale below from 0 
to 10?  
 
___________________________________________________________________ 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
No  
 
 
 
 
 
 
 
 
 
worst  
pain  
 
 
 
 
 
 
 
 
 
pain ever   

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APPENDIX IX: Short Sexual Functioning Scale 
Short Sexual Functioning scale – female version 
 
SHORT SEXUAL FUNCTION SCALE – FEMALE VERSION 
 
We would like to know whether you experienced certain sexual difficulties over the past three months. 
We ask about physical reactions and feelings that may occur during sexual activity. If a sexual difficulty 
occurred, we also ask whether you and your partner experienced this as a problem and whether this 
had a negative effect on your relationship with your partner.  
 
Please indicate for each item the degree to which you experienced difficulties during the past three 
months with the following aspects of sexual functioning. Sometimes it is indicated that you can skip 
the rest of the question; then continue to the next questions. There are no right or wrong answers. 
Please be careful and do not leave questions open! 
 
 
1. During the past 3 months, did you have too little desire for sex, too little desire for sexual 
activities, too little sexual fantasies or erotic thoughts (=too little sexual desire)? 
0. 
I did not have too little desire ➔ go to question 2   
1. 
I had mildly too little desire  
2. 
I had moderately too little desire  
3. 
I had severely or  extremely too little desire 
 
If I have too little desire, I experience this as: 
1. 
Not a problem  
2. 
A mild problem 
3. 
A moderate problem 
4. 
A severe or extreme problem 
 
If I have too little desire, my partner experiences this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have too little desire, I experience this in my relationship as: 
1. 
Not a problem  
2. 
A mild problem 
3. 
A moderate problem 
4. 
A severe or extreme problem 
 
2. During the past 3 months, if your partner initiated sex and you began the sexual encounter 
with no sexual desire, did you then have difficulties to get sexual desire? 
0. 
I then did not have difficulties to get sexual desire  ➔ go to question 3   

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1. 
I then had mild difficulties to get sexual desire  
 
2. 
I then had moderate difficulties to get sexual desire 
 
 
3. 
I then had severe or extreme difficulties to get sexual desire 
 
 
 
If I have difficulties to get sexual desire when my partner initiates sex, I experience this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have difficulty to get sexual desire when my partner initiates sex, my partner experiences 
this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have difficulty to get sexual desire when my partner initiates sex, I experience this in my 
relationship as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
3. During the past 3 months, when having pleasurable sex with your partner, did you 
experience difficulties with becoming lubricated (wet) during sex? 
0. 
I did not experience difficulties becoming lubricated (wet) ➔ go to question 4  
1. 
I had mild difficulties becoming lubricated (wet) 
 
2. 
I had moderate difficulties becoming  lubricated (wet)  
3. 
I had severe or extreme difficulties becoming lubricated (wet)  
 
If I have difficulties to become lubricated, I experience this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have difficulties to become lubricated, my partner experiences this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have difficulties to become lubricated, I experience this in my relationship as: 
1. Not a problem  
2. A mild problem 

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3. A moderate problem 
4. A severe or extreme problem 
 
4. During the past 3 months, when you were having pleasurable sex with your partner, did 
you experience little or no feelings of (emotional/subjective) arousal? 
0. 
I did not have difficulties experiencing subjective arousal ➔ go to question 5 
1. 
I  had mild difficulties experiencing subjective arousal  
2. 
I had moderate difficulties experiencing subjective arousal  
3. 
I had severe or extreme difficulties experiencing subjective arousal  
 
If I experience little or no feelings of arousal, I experience this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I experience little or no feelings of arousal, my partner experiences this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I experience little or no feelings of arousal, I experience this in my relationship as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
5. During the past 3 months, when you were having pleasurable sex with your partner, did 
you have difficulty reaching orgasm? 
0. 
I did not have difficulties reaching orgasm ➔ go to question 6 
1. 
I had mild difficulties reaching orgasm  
 
2. 
I had moderate difficulties reaching orgasm 
3. 
I had extreme difficulties reaching orgasm 
 
If I have difficulties reaching orgasm, I experience this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have difficulties reaching  orgasm, my partner experiences this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 

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If I have difficulties reaching orgasm, I experience this in my relationship as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
6. 
During the past 3 months, did you have difficulty reaching orgasm during masturbation? 
0. I did not masturbate over the past 3 months. ➔ go to question 7  
1. I did not have difficulties reaching orgasm during masturbation 
2. I had mild difficulties reaching orgasm during masturbation 
3. I clearly had moderate difficulties reaching orgasm during masturbation 
4. I had severe or extreme difficulties reaching orgasm during masturbation 
 
 
If I have difficulties reaching orgasm during masturbation, I experience this as: 
1. 
No or a mild problem 
2. 
A moderate problem 
3. 
A severe or extreme problem 
 
7. Please select which one of the following options best reflects your experience over the past 
3 months (please select only one option). 
0. Vaginal penetration (= insertion of penis, finger or dildo into the vagina) was possible 
and not painful  ➔ end of the questionnaire 
1. Vaginal penetration was possible, but painful ➔ go to question 7a.  
 
2. Vaginal penetration (with my current partner) was possible in the past, but not 
anymore ➔ end of the questionnaire 
 
 
 
 
 
3. Vaginal penetration (with my current partner) has never succeeded   
➔ end of the questionnaire 
  
 
 
 
 
 
 
7a. During the past 3 months, did you have pain before, during, or after (attempting) vaginal 
penetration? 
0. 
I had no pain before, during or after (attempted vaginal) penetration 
1. 
I had mild pain before, during or after (attempting) vaginal penetration 
2. 
I had moderate pain before, during or after (attempting) vaginal penetration 
3. 
I  had severe or extreme pain before, during or after (attempting) vaginal penetration 
 
If I have pain before, during or after vaginal penetration, I experience this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
If I have pain before, during or after vaginal penetration, my partner experiences this as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 

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4. A severe or extreme problem 
 
If I have pain before, during or after vaginal penetration, I experience this in my relationship 
as: 
1. Not a problem  
2. A mild problem 
3. A moderate problem 
4. A severe or extreme problem 
 
 
 
Thank you very much for completing this questionnaire !! 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX X: EQ-5D-3L Health questionnaire 
 
 
 
 

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