Hysterectomy for Benign Gynaecological Disease by Natural Orifice Transluminal Endoscopic Surgery or Laparoscopy
Phase: NA
Conditions: Uterine Diseases
Sponsor: Imelda Hospital, Bonheiden

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RESEARCH PROTOCOL 
HALON trial 
 
 
 
(Hysterectomy by transAbdominal Laparoscopy Or Notes) 
 
UNIQUE PROTOCOL ID: B689201526261 
ClinicalTrials.gov ID: NCT02631837 
 
 
 
 
 
 
 
 

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Protocol ID                                        B689201526261 
                                                            NCT02631837 
Short title                                          HALON 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: jan.baekelandt@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, 
Gynecologist 
 
 
 
 
Coordinating Investigator: 
 
Dr. Jan Bosteels, MD, PhD, 
Gynecologist 
 
 
 
 
Principal investigator/project 
leader: 
 
Dr. Jan Baekelandt, MD, 
Gynecologist 
 
 
 
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 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
 
 
7-8 
 
SUMMARY 
 
 
 
 
 
 
 
 
 
9-10 
1. BACKGROUND 
 
 
 
 
 
 
 
 
11-22 
1.1. Disease: benign gynecological disease treated by hysterectomy 
 
 
11 
 
1.1.1 Population to be studied  
 
 
 
 
 
 
11 
 
1.2. Current therapy for hysterectomy  
 
 
 
 
 
11-13  
1.3. New therapy for hysterectomy 
 
 
 
 
 
 
13 
1.4. Literature review  
 
 
 
 
 
 
 
13-18  
1.4.1 Systematic Review 
 
 
 
 
 
 
 
13-18  
1.4.2 Current clinical practice   
 
 
 
 
 
 
18 
 
1.4.3 Pilot studies 
 
 
 
 
 
 
 
 
18-20  
1.5. The need for a pilot trial of vNOTES versus LSK hysterectomy 
 
 
20-21 
1.6. Objectives of the HALON Trial 
 
 
 
 
 
 
22 
2. TRIAL DESIGN 
 
 
 
 
 
 
 
 
23 
 
2.1. Design 
 
 
 
 
 
 
 
 
 
23 
 
2.2. Simple pilot randomized trial: minimal extra workload  
 
 
 
23 
 
2.3. Time schedule 
 
 
 
 
 
 
 
 
23 
 
2.4. Participating center 
 
 
 
 
 
 
 
23 
3. ELIGIBILITY, CONSENT AND RANDOMIZATION  
 
 
 
 
24-26  
3.1. Screening and consent prior to surgery 
 
 
 
 
 
24 
3.2. Determining eligibility 
 
 
 
 
 
 
 
24-25  
3.3. Randomization 
 
 
 
 
 
 
 
 
25 
 
3.4. Patients with strong preference for treatment  
 
 
 
 
25 
 
3.5. Stratification of randomization 
 
 
 
 
 
 
25-26 
4. TREATMENT ALLOCATIONS  
 
 
 
 
 
 
27-34  
4.1. Surgical procedures 
 
 
 
 
 
 
 
27-33  
4.1.1 vNOTES hysterectomy 
 
 
 
 
 
 
 
27-30  
4.1.2 LSK hysterectomy  
 
 
 
 
 
 
 
30-33  
4.1.3 Failure of procedure 
 
 
 
 
 
 
 
33 
 

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4.2. Concomitant interventions and treatments  
 
 
 
 
33 
 
4.3. Withdrawal from the HALON trial  
 
 
 
 
 
33-34 
4.4. Serious and unexpected adverse events  
 
 
 
 
 
34 
 
5. FOLLOW-UP AND OUTCOME MEASURES 
    
 
 
 
 
35-38  
5.1. Clinical assessments 
 
 
 
 
 
 
 
35 
 
5.1.1 Format 
 
 
 
 
 
 
 
 
 
35 
 
5.1.2 Timing of assessments 
 
 
 
 
 
 
 
35 
 
5.2. Primary clinical outcome measure  
 
 
 
 
 
35 
 
5.3. Secondary clinical outcome measures 
 
 
 
 
 
35-36 
5.4. Health economic outcomes 
 
 
 
 
 
 
37-38  
5.5. Data management and validation  
 
 
 
 
 
38 
 
5.5.1 Confidentiality of personal data  
 
 
 
 
 
38 
 
5.5.2 Long-term storage of data 
 
 
 
 
 
 
38 
 
5.6. Withdrawal from follow-up 
 
 
 
 
 
 
38 
 
6. ACCRUAL AND ANALYSIS 
 
 
 
 
 
 
 
39-42  
6.1. Sample size 
 
 
 
 
 
 
 
 
39 
 
6.2. Projected accrual and attrition rates 
 
 
 
 
 
39 
6.3. Statistical Analysis  
 
 
 
 
 
 
 
39-40  
6.3.1 Subgroup analyses 
 
 
 
 
 
 
 
40 
 
6.3.2 Proposed frequency of analyses  
 
 
 
 
 
40 
 
6.3.3 Handling missing data  
 
 
 
 
 
 
 
40-41  
6.4. Health Economic Analysis  
 
 
 
 
 
 
41-42  
6.4.1 Form of the economic evaluation  
 
 
 
 
 
41 
 
6.4.2 Economic analysis 
 
 
 
 
 
 
 
41-42  
6.5. Definition of the end of trial 
 
 
 
 
 
 
42 
 
7. ASSESSMENT OF PATIENT ACCEPTABILITY 
 
 
 
 
 
43-44  
7.1. Measurements for Patient Acceptability  
 
 
 
 
 
43 
 
7.1.1 Sampling of Participants for In-depth Interview 
 
 
 
 
43 
7.2. Evaluation of Patient Acceptability   
 
 
 
 
 
43-44  
8. DATA ACCESS AND QUALITY ASSURANCE 
 
 
 
 
 
45-46  
8.1. In-house Data Quality Assurance 
 
 
 
 
 
 
45 
 
8.2. Independent Trial Steering Committee 
 
 
 
 
 
45 
 
8.3. Data Monitoring and Ethics Committee 
 
 
 
 
 
45-46   
9. ORGANIZATION AND RESPONSIBILITIES 
 
 
 
 
 
47-49  
9.1. Centre eligibility 
 
 
 
 
 
 
 
 
47 
 

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9.2. Local Coordinator at each center 
 
 
 
 
 
 
47 
 
9.3. Nursing Coordinator at each center  
 
 
 
 
 
47 
 
9.4. The HALON Trial Office 
 
 
 
 
 
 
 
47 
 
9.5. Research Governance  
 
 
 
 
 
 
 
47-48  
9.6. Research Governance and Ethical Approval  
 
 
 
 
48-49 
9.7. Funding and Cost implications 
 
 
 
 
 
 
49 
9.8. Indemnity  
 
 
 
 
 
 
 
 
49 
 
9.9. Publication  
 
 
 
 
 
 
 
 
49 
 
9.10. Ancillary studies  
 
 
 
 
 
 
 
49-50  
10. REFERENCES  
 
 
 
 
 
 
 
 
51-52 
APPENDIX I: Table I Overview of patient and perioperative characteristics 
 
53 
APPENDIX II: Table II Patient and perioperative data 
 
 
 
 
53 
APPENDIX III: Clavien- Dindo classification 
 
 
 
 
 
54 
APPENDIX IV: CONSORT 2010 Flow Diagram 
 
 
 
 
 
55 
APPENDIX V: Pain protocol 
 
 
 
 
 
 
 
56 
APPENDIX VI: VAS Scale 
 
 
 
 
 
 
 
57 
APPENDIX VII: Participant’s pain log book 
 
 
 
 
 
58-61  
APPENDIX VIII: Dyspareunia questionnaire  
 
 
 
 
 
62 
 
APPENDIX IX: Short Sexual Functioning Scale 
 
 
 
 
 
63-67  
APPENDIX X: EQ-5D-3L Health questionnaire 
 
 
 
 
 
68-70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
AH 
 
Abdominal hysterectomy 
BMI 
 
Body Mass Index 
CDSR  
Cochrane Database of Systematic Reviews 
CI 
 
Confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
DMEC   
Data Monitoring and Ethics Committee  
DUB 
 
Dysfunctional uterine bleeding 
EMBASE 
Excerpta Medica dataBASE 
EuroQoL 
EQ-5D Health Questionnaire  
GMT 
 
Greenwich Mean Time 
GP 
 
General Practitioner 
HTA 
 
Health Technology Assessment 
IDEAL  
acronym: Idea, Development, Exploration, Assessment, Long-term follow-up 
IV 
 
Intravenous 
LAVH  
Laparoscopy assisted vaginal hysterectomy 
LSK 
 
Laparoscopy 
MEDLINE 
Medical Literature Analysis and Retrieval System Online 
MeSH  
Medical Subject Heading 
NAVH  
NOTES-assisted vaginal hysterectomy 
NHS 
 
National Health Service 
NIHDI  
National Institute for Health and Disability Insurance (Belgium: RIZIV/INAMI) 
NOTES  
natural orifice transluminal endoscopy 
vNOTES 
vaginal natural orifice transluminal endoscopy 
OR 
 
Odds ratio 
PROM  
Patient Reported Outcome Measure 
RCT 
Randomized Controlled Trial 
SEM 
Standard error of the mean 
(S)AE   
(Serious) Adverse Event 

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SD 
 
Standard Deviation 
SILS 
 
Single Incision Laparoscopic Surgery 
SSFS 
 
Short Sexual Functioning Scale 
TLH 
 
Total laparoscopic hysterectomy 
TMG 
 
Trial management group 
TSC 
 
Trial Steering Committee 
TV-NOTES 
Transvaginal NOTES 
tVNOTEH 
Transvaginal natural orifice transluminal endoscopic hysterectomy 
VAMIS  
Vaginal access minimally invasive surgery 
VAS 
 
Visual analog scale 
VH 
 
Vaginal hysterectomy 
QALY  
Quality adjusted life year 
 
 

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SUMMARY 
Rationale: Driven by the desire to minimize surgical morbidity, the evolution from laparotomy to 
laparoscopic surgery has now extended to the era of even less invasive surgery such as robotics, 
mini- laparoscopy, single incision laparoscopic surgery (SILS), and natural orifice transluminal 
endoscopy (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 procedure is 
performed via a natural body orifice. It has gained popularity amongst general surgeons, urologists 
and gastroenterologists over the past few years and its feasibility and safety has been embraced. (3) 
NOTES can be performed through various entry approaches including stomach, esophagus, bladder 
and rectum. The vast majority of NOTES procedures in women have been performed through the 
vagina (4). Colpotomy has been used widely for several surgical procedures (by gynecologists but also 
by general surgeons for 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 introduced transvaginal pure NOTES (vNOTES) in our 
surgical practice since November 2013.  A first case series describing the feasibility of vNOTES 
Hysterectomy in 16 women was published in 2012 (7). A case series of 137 women reporting the 
feasibility and safety of vNOTES hysterectomy was published in 2015 (8). A first case describing 10 
cases of total vaginal NOTES hysterectomy in our department was published in 2015 (9).  Most 
women reported a low postoperative pain score (range 0 to 2) measured at day 1 following surgery 
by a visual analogue scale (VAS). 
Objective: To compare vNOTES and laparoscopic hysterectomy for successful removal of the uterus 
for benign gynecological pathology.  
Study design: Randomized controlled/single center/single-blinded/parallel-group/non-
inferiority/efficacy trial.  

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Study population: All women aged 18 to 70 years regardless of parity with benign indication for 
hysterectomy.  
Randomization: After assessment of eligibility/ informed consent women will be randomly allocated 
to either technique  before surgery by using a computer generated randomization list. We will use 
stratified randomization according to the estimated uterine size on clinical examination. 
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 6-week period and to abstain from sexual intercourse until their 6-week 
booked appointment for a postoperative assessment. 
Main study parameters/endpoints:  
Primary study outcome parameters: successful removal of the uterus with the intended approach 
without conversion to an alternative approach. 
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 (10) 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 up to 6 weeks 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 hysterectomy. 

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1. BACKGROUND  
 
 
 
 
 
 
 
 
1.1. Disease: benign gynecological disease treated by hysterectomy 
Hysterectomy is the most commonly performed major gynecological surgical procedure in the United 
States of America. Over 400,000 hysterectomies are performed annually and it is estimated that 1 in 
3 women will have had a hysterectomy by age 60 years. Of the benign hysterectomies performed in 
the United States, 68% are done for the primary indication of abnormal uterine bleeding (AUB), 
uterine fibroids, and endometriosis (11). Fibroids account for approximately 30 percent of 
hysterectomies (12). Dysfunctional uterine bleeding accounts for approximately 20 percent of 
hysterectomies (12). Genital prolapse is the reason for about 15 percent of hysterectomies (12). 
Approximately 20 percent of hysterectomies are performed because of endometriosis and/or 
adenomyosis (12). Chronic pelvic pain has been the principal preoperative indication for 
approximately 10 percent of hysterectomies (12). Endometrial hyperplasia accounts for 
approximately 6 percent of hysterectomies (12).  
 
1.1.1 
Population to be studied 
 
All women aged 18 to 70 years regardless of parity with an indication for hysterectomy for benign 
gynecological pathology will be eligible for inclusion provided that they have no exclusion criteria and 
after giving fully informed consent.  
1.2. Current therapy for hysterectomy (13) 
Hysterectomy is the surgical removal of the uterus. The first reported elective hysterectomy was 
performed by Conrad Langenbeck in 1813 who used a vaginal approach. The first elective abdominal 
hysterectomy, a subtotal operation (where the cervix was conserved), was performed by Charles Clay 
of Manchester in 1863. These approaches remained the only two options until the latter part of the 
20th century. The first laparoscopic-assisted vaginal hysterectomy was performed by Harry Reich in 
1989. He also reported the first total laparoscopic hysterectomy in 1993. The approaches to 
hysterectomy may be broadly categorized into three: abdominal hysterectomy (AH); vaginal 
hysterectomy (VH); laparoscopic hysterectomy where at least some of the operation is conducted 
laparoscopically. 
The abdominal approach (AH) has traditionally been the surgical approach for gynecological 
malignancy, when other pelvic pathology is present such as endometriosis or adhesions, and in the 
context of an enlarged uterus. It remains the 'fallback option' if the uterus cannot be removed by 
another approach. 

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The vaginal approach (VH) was originally used for prolapse only, but has become more widely used 
for menstrual abnormalities such as dysfunctional uterine bleeding (DUB) when the uterus is fairly 
normal size. Compared to AH, VH was (and still is) regarded as less invasive and seemed to have the 
advantages of fewer blood transfusions, less febrile morbidity (fever) and less risk of injury to the 
ureter, but the disadvantages of more bleeding complications and greater risk of bladder injury. 
The term 'laparoscopic hysterectomy' usually refers to a hysterectomy where at least part of the 
operation is undertaken laparoscopically and these approaches require greater surgical expertise. 
The proportion of hysterectomies performed by LH has gradually increased and, although the surgery 
tends to take longer, its proponents have argued that the main advantages are the possibility to 
diagnose and treat other pelvic diseases such as endometriosis, to carry out adnexal surgery 
including the removal of the ovaries, the ability to secure thorough intraperitoneal hemostasis (direct 
laparoscopic vision enables careful sealing of bleeding vessels at the end of the procedure) and a 
more rapid recovery time from surgery compared to AH. More recently, three sub-categorizations of 
LH have been described as follows.  
(i) Laparoscopic assisted vaginal hysterectomy (LAVH) is where part of the hysterectomy is performed 
by laparoscopic surgery and part vaginally, but the laparoscopic component of the operation does 
not involve division of the uterine vessels.  
(ii) Laparoscopic hysterectomy (LH) is where the uterine vessels are ligated laparoscopically but part 
of the operation is performed vaginally.  
(iii) Total laparoscopic hysterectomy (TLH) is where the entire operation (including suturing of the 
vaginal vault) is performed laparoscopically and there is no vaginal component. This operation 
requires the highest degree of surgical skill and currently only a very small proportion of 
gynecologists are able to perform this type of surgery. It has been unclear whether TLH offers any 
benefit over other forms of hysterectomy. 
A total hysterectomy is the removal of the entire uterus including the cervix. When the cervix is not 
removed, this is known as a subtotal or supracervical hysterectomy. Subtotal hysterectomies are 
most easily performed abdominally or laparoscopically, although it is possible to conserve the cervix 
in a VH or LAVH. 
In common with the overall hysterectomy rate, the proportion of hysterectomies currently being 
performed by each of the above approaches varies markedly across countries, within the same 
country and even between individual surgeons working within the same unit. Women's expectations 
and individual surgeons' training and experience are factors underlying this. Even though VH has 
been widely considered to be the operation of choice for dysfunctional uterine bleeding (DUB), the 

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VALUE study showed that 74% of the hysterectomies performed in 1995 for this indication in the UK 
were AHs. The surgical approach taken at hysterectomy continues to depend upon the experience 
and biases of the surgeon. It was interesting to note in 1998 that there was not a single randomized 
controlled trial (RCT) comparing AH versus VH. The introduction of the newer approaches to 
hysterectomy (LAVH, LH and TLH) has stimulated a much greater interest in the proper scientific 
evaluation of all forms of hysterectomy. 
Apart from the surgical approach to hysterectomy, other aspects of the surgical technique may have 
an effect on the outcome of surgery. Examples of this include total versus subtotal (where the cervix 
is not removed) hysterectomy; Döderlein VH or LAVH versus standard VH or LAVH; techniques to 
support the vaginal vault; bilateral elective oophorectomy versus ovarian conservation; other 
strategies, used mainly by those conducting laparoscopic surgery with the aim of reducing the 
likelihood of complications, including the use of vaginal delineators, rectal probes and illuminated 
ureteric stents.  
 
 
1.3. New therapy for hysterectomy 
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 randomized controlled trials of effectiveness. We conducted a 
comprehensive systematic review on the efficacy of NOTES for hysterectomy for benign 
gynecological pathology. After searching three electronic databases (MEDLINE, EMBASE and The 
Cochrane Library) from inception to 25 August 2015 using ‘Natural Orifice Endoscopic Surgery’ and 
‘hysterectomy’ as MeSH terms or key words, 58 records were identified, of which a total of ten were 
eligible for inclusion.  
 
 

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DATABASE 
SEARCH STRING 
STUDIES 
MEDLINE (PubMed) 
(inception to 25 August 2015) 
"Natural Orifice Endoscopic Surgery" 
[Majr] AND "Hysterectomy"[Mesh] 
(8 records) 
 
• 
Lee 201 
• 
Su 2012 
• 
Wang 2015 
• 
Yang 2014 
EMBASE (Embase.com) 
(inception to 25 August 2015) 
'natural orifice endoscopic surgery'/exp 
OR 'natural orifice endoscopic surgery' 
AND 'hysterectomy' 
(50 records) 
• 
Wang 2015 
• 
Atallah 2015 
• 
Wu 2014 
• 
Yang 2014 
• 
Lee 2013 
• 
Su 2012 
• 
Chen 2012 
• 
Su 2012 abstract 
• 
Lee 2012 
CDSR (The Cochrane Library) 
(inception to 25 August 2015) 
"Natural Orifice Endoscopic Surgery" 
AND hysterectomy 
(0 records) 
 
 
After looking for duplications of study reports, seven studies including 731 study participants were 
identified for inclusion. None of the included studies was a randomized controlled trial. One study 
was a preclinical study describing the technical feasibility of transvaginal NOTES hysterectomy on a 
female cadaver (Atallah 2015). One study was a prospective cohort study (Lee 2013; Lee 2014; Wu 
2014). Two studies were retrospective comparative studies (Wang 2015 and Yang 2014). Three 
studies were case series (Chen 2012; Lee 2012; Su 2012).   
The main study characteristics are presented in the table below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY 
N  
POPULATION 
INTERVENTION 
COMPARISON 
OUTCOME 
Atallah 2015 (14) 
1  
Female cadaver 
VAMIS(1) 
None 
None 
Chen 2012 (15) 
8 women 
5 female-to-male 
transsexuals 
TV NOTES (2) 
hysterectomy 
None 
Operating time 
Blood loss 
Complications 
Lee 2012 (16) 
10 women 
15 women with 
benign adnexal/  
uterine disease 
TV NOTES (2) 
hysterectomy 
None 
Operating time 
Blood loss 
Complications 
Lee 2013 
+ Lee 2014 (8) 
+ Wu 2014  
137 women 
Women who 
were scheduled 
to undergo lap. 
hysterectomy 
(exclusion: 
virginity or 
suspected pelvic 
inflammation or 
cul-de-sac 
obliteration) 
TV NOTES (2) 
hysterectomy 
None 
Successful 
procedure 
Operating time 
Blood loss 
Complications 
Su 2012 (7) 
+ Su 2012 abstr. 
16 women 
Women with 
benign disease of 
the uterus 
TV NOTES (2) 
hysterectomy 
None 
Operating time 
Blood loss 
Hospital stay 
Complications 
Wang 2015 (17) 
512 women 
Women with 
benign disease of 
the uterus and 
no genital 
prolapse 
tVNOTEH (3) 
(n=147) 
LAVH (5) 
(n=365) 
Operating time 
Blood loss 
Hospital stay 
Costs 
Complications 
Yang 2014 (18) 
48 women 
Women with 
benign disease of 
the uterus 
NAVH (4) 
(n=16) 
LAVH (5) 
(n=32) 
Operating time 
Blood loss 
Pain 
Hospital stay 
Complications 
 
(1) VAMIS: vaginal access minimally invasive surgery 
(2) TV-NOTES: transvaginal natural orifice transluminal endoscopic surgery 
(3) tVNOTEH: transvaginal natural orifice transluminal endoscopic hysterectomy 
(4) NAVH: NOTES-assisted vaginal hysterectomy 
(5) LAVH: laparoscopy-assisted vaginal hysterectomy 
 
A summary of the evidence of the individual studies is briefly presented. We did not do a critical 
appraisal of the retrieved evidence by a formal risk of bias assessment: the focus was to retrieve 
background information before designing a RCT rather than writing a systematic review with critical 
appraisal. 

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Atallah 2015 is a preclinical study describing the technique of VAMIS (vaginal access minimally 
invasive surgery) in a female cadaver.  
Chen 2012 is a case series describing 8 women that underwent transvaginal NOTES of hysterectomy. 
Five were identified as female-to-male transsexuals. The transsexuals were younger (22-45 years, 
median 27 years), with no parity (P0).The operating times were 70-120 minutes (median 80 minutes). 
Blood loss during surgery (100-650 mL, median 200 mL). There were no complications after surgery. 
The authors conclude that transvaginal natural orifice transluminal endoscopic surgery 
(NOTES) hysterectomy and bilateral salpingo- oophorectomy for female-to-male transsexuals seems 
a safe and feasible procedure. 
Lee 2012 is a case series. Transvaginal NOTES was successfully completed in five adnexal surgeries 
and 10 hysterectomies without complications, an ancillary port on the abdomen, or conversion to 
conventional laparoscopy or laparotomy. For the 10 hysterectomies, the surgical time was 93.4 ± 6.3 
minutes (mean ± standard) deviation), intraoperative estimated blood loss 245 ± 54.0 mL, uterine 
weight 440.1 ± 76.5 g, and the postoperative hospital stay 2.7 ± 0.3 days. No patients required 
intraoperative blood transfusion. The authors concluded that transvaginal NOTES for adnexal surgery 
and hysterectomy is feasible and safe.  
Lee 2013/2014 + Wu 2014 are three published reports of a single prospective cohort study. The main 
study report is identified as Lee 2014. The study included 137 patients, with mean (SEM) age 46.0 
(0.4) years and body mass index 24.7 (0.4). Transvaginal NOTES was successfully performed in 130 
women (94.9%). Fifteen women underwent concurrent adhesiolysis and 17 underwent adnexal 
procedures. Mean (SEM) uterine weight was 450.0 (24.1) g; in 45 women (34.6%) the uterine weight 
was > 500 g, and in 7 (5.4%) it was >1000 g. Operative time was 88.2 (SEM 4.1) minutes, with blood 
loss of 257.7 (SEM 23.9) mL. In 2 patients there was intraoperative hemorrhage or unintended 
cystotomy, and in another 5 transvaginal colpotomy failed because of a narrow vagina, cul-de-sac 
obliteration by bowel adhesions, or mass obstruction. All complications in these seven patients 
(5.1%) were successfully managed via transabdominal laparoscopy. Five patients (3.6%) experienced 
postoperative urinary retention or febrile morbidity, and recovered uneventfully with conservative 
treatment. The authors concluded that transvaginal NOTES is a feasible technique for performance of 
hysterectomy and can be used in procedures that are difficult to complete via conventional vaginal 
surgery because posterior colpotomy is achievable. This procedure was not impeded by uterine 
volume, and had the advantage of no abdominal incision. 
Su 2012 + abstract is a case series to evaluate the feasibility and safety of performing a hysterectomy 
using the transvaginal natural orifice transluminal endoscopic surgery (NOTES). From May through 
December 2010, 16 women with benign uterine disease who were eligible for laparoscopic 

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hysterectomy were recruited to undergo transvaginal NOTES at a tertiary referral medical center. 
Intraoperative and postoperative surgical outcomes were measured. All of the included 
hysterectomies were completed via transvaginal NOTES without conversion to conventional 
laparoscopy. The mean ± standard error of mean (SEM) uterine weight was 538.8 ± 102.9 g, the 
mean operative time was 122.7 ± 17.6 minutes, and the mean blood loss was 379.4 ± 95.4 mL. The 
mean postoperative hospital stay was 2.8 ± 0.2 days. No intraoperative or postoperative 
complications were noted in this series. The authors concluded that hysterectomy for the treatment 
of benign diseases can be feasibly carried out via transvaginal NOTES but prospective studies are 
needed to determine its full clinical application. 
Wang 2015 is a retrospective comparative study that aimed to examine the safety and feasibility of 
transvaginal natural orifice transluminal endoscopic hysterectomy (tVNOTEH) for non-prolapsed uteri 
in the management of benign gynecological disease. Records were reviewed for the 147 consecutive 
tVNOTEH procedures between April 2011 and October 2013. Age, body mass index, number of 
vaginal deliveries, and specimen weight were used to select comparable patients who had 
undergone laparoscopically assisted vaginal hysterectomy (LAVH).  A total of 512 women were 
recruited in this study (147 tVNOTEHs and 365 LAVHs, respectively). The participants were stratified 
into six subgroups according to the uterine weight and type of hysterectomy. There was no case of 
conversion to abdominal laparotomy. Length of operation, estimated blood loss (EBL), requirement 
of blood transfusion, and length of postoperative stay were significantly greater in the LAVH group 
than in the tVNOTEH group but total hospital charges were higher in the tVNOTEH group (p<0.001). 
There was no difference in overall incidence of operative complications between the two groups but 
more complications in LAVH for uterine weight more than 500 g (4.3 vs. 0 %, p<0.001); this likely 
reflects higher hospital charges in this subgroup. Significant linear correlations of uterine weight with 
operating time and EBL existed in both groups. The authors concluded that tVNOTEH can be safely 
performed for large and non-prolapsed uterus. Besides, as uterine weight increased, the operative 
efficiency of tVNOTEH increased compared with LAVH. 
Yang 2014 is a retrospective comparative study for the assessment of NAVH using a novel 
homemade NOTES system comprised of a glove-wound retractor NOTES port versus LAVH using 
conventional laparoscopic instruments and an umbilical glove port. From July 2012, 16 women with 
benign uterine disease were treated by NAVH. Another 32 paired, AVH patients from the registered 
database were used to compare these two modalities of laparoscopy-assisted techniques for vaginal 
hysterectomy. All NAVHs were completed successfully without the need of an additional port or 
conversion to the standard laparoscopic approach. Intraoperative and postoperative surgical 
outcomes were assessed in both comparison groups. There were no significant differences between 
both groups in perioperative outcomes such as estimated blood loss, decrease in hemoglobin on 

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postoperative day 1, amount of analgesic drugs used, postoperative visual analog scale pain score, 
and febrile complications, except for operative time and length of postoperative hospital stay. The 
mean operative time was 70.6 ± 12.8 minutes for NAVH and 93.2 ± 21.4 minutes for SP-LAVH (p < 
0.001). The median postoperative hospital stay was 3.5 days (range, 3–5) for NAVH and 4 days 
(range, 3–6) for SP-LAVH (p<0.001). The authors concluded that NAVH is a feasible and safe surgical 
technique and has a short operative time and postoperative hospital stay compared with LAVH. 
Prospective studies are needed to determine its full clinical application. 
1.4.2 Current clinical practice   
Based on data from 111161 hysterectomies registered between 2000 and 2013 by the Health care 
department of the National Institute for Health and Disability Insurance (NIHDI) of Belgium, the 
proportion of LAVH (RR 1.26, 95% CI 1.19 to 1.33, P<0.00001) and total laparoscopic hysterectomy 
has increased significantly (RR  69, 95% CI 51 to 94, P<0.00001) at the expense of the proportion of 
abdominal hysterectomies, which has dropped significantly (RR 0.50 , 95%CI 0.49 to 0.52, 
P<0.00001). There is a significant uptake in Belgium of the minimally invasive approach by 
laparoscopy for hysterectomy for benign gynecological disease, as reported by others (19).  
 
 
 
 
 
 
 
 
 
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 

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benign adnexal masses in our surgical practice in 2014.  A first case describing 10 cases of total 
vaginal NOTES Hysterectomy in our department was published in 2015. (9)   
The purpose of the observational case-series was to describe the present technique as well as to 
demonstrate the feasibility of a hysterectomy by transvaginal natural orifice transluminal endoscopic 
surgery (vNOTES) for the removal of benign uteri both in parous and nulliparous women. 
Conventional, reusable laparoscopic instruments were used, inserted through an inexpensive, self-
designed single port device. All vNOTES hysterectomies were performed by a single surgeon (Jan 
Baekelandt).  
Patients were selected based on the following criteria: no contraindication for general anesthesia, 
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; no 
suspicion for malignancy. Obesity (BMI > 30) was not considered to be an exclusion criterion. 
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 hysterectomy was performed 
according to the technique for standard vaginal hysterectomy but performed with laparoscopic 
instruments. The uterus was removed through the colpotomy incision. 
The following patient and perioperative data were collected and retrospectively analyzed: patient 
age, body mass index (BMI), parity, history of vaginal delivery, previous pelvic surgery, type of 
surgery, total operating time, serum hemoglobin (Hb) drop (change between the preoperative Hb 
and postoperative Hb one day after surgery), peri-operative complications, and postoperative pain 
score. The duration of surgery was defined as the time from the insertion of the Foley catheter 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 
identified to be urinary tract infection, postoperative ileus, vaginal vault bleeding or infection, or 
hematuria. 
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 
patients received the same intraoperative analgesia: intravenous 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. Prophylactic intravenous antibiotic 
therapy, cefazoline 2 g and metronidazol 500 mg, was administrated during surgery. No vaginal 
intercourse was allowed for 6 weeks after the procedure. Each patient was re-assessed at the post-
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Between January 2013 and March 2015, ten TVNH’s were successfully performed by Poor Man’s 
vNOTES using conventional, reusable laparoscopic instruments. No conversion to standard multi-
incision laparoscopy or laparotomy was necessary. In four patients one or both adnexa were also 
removed; one of them had an 8 cm mucinous cystadenoma.  
Table 1 (Appendix 1) presents an overview of patient and perioperative data. Individual patient 
details are presented in Table 2 (Appendix 2). Mean operation time was 97 minutes. Five patients 
had had previous pelvic surgery. There were no intraoperative complications. One patient had a 
postoperative cystitis for which oral antibiotic therapy was administered; and one patient had a small 
vault hematoma that was managed conservatively under antibiotic cover. The mean drop in 
hemoglobin level was 1.5 g/dl. Most patients scored a low postoperative pain score (range 1-2) 24 
hours after surgery. All uteri were benign upon pathological examination (specimen weight 51-353g). 
As these were the first 10 patients to be operated by a new surgical technique, we requested all 
patients to remain hospitalized for 72 hours for comprehensive follow up. Each patient was 
examined six weeks after surgery. There was no vaginal wound infection nor dehiscence, and none of 
the patients complained of pain during pelvic examination. All patients were in good health and were 
back at work.  
Based on this observational case-series we concluded that total hysterectomy by vNOTES is feasible, 
even in nulliparous women, and even when performed with reusable, conventional laparoscopic 
instruments. The potential benefits with vNOTES are better cosmetics, low postoperative pain scores, 
and a quicker recovery. This innovative technique may enable surgeons in low resource settings to 
perform adnexectomies by vNOTES since no expensive devices or instruments are needed. 
 
 
 
 
 
 
 
 
 
1.5. The need for a pilot trial of vNOTES versus LSK hysterectomy 
 
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 
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, 

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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 (20, 21, 22). The central concept is that 
surgeons are regularly innovating and improving their craft. 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 because the principal investigator had achieved his learning curve.  
 
 

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1.6. Objectives of the HALON Trial 
 
The primary research question of this IDEAL stage 2b efficacy trial is as follows: is a vNOTES 
hysterectomy at least as effective compared to the standard transabdominal laparoscopic approach 
(LSC) for removing a uterus without the need for conversion to an alternative approach? (non- 
inferiority design) 
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 uterus 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 direct costs up to 6 weeks of a vNOTES compared to LSC? 
 
 

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2. TRIAL DESIGN 
2.1. Design 
A single center, single-blinded, parallel group randomized, non-inferiority efficacy trial. 
2.2. Simple pilot randomized trial: minimal extra workload  
This is a pilot randomized trial aiming to demonstrate that vNOTES is at least as effective compared 
to the classical gold standard approach of laparoscopy for successfully removing benign diseased 
uteri by the intended approach without conversion to an alternative approach (non-inferiority 
design). In this phase of HTA the trial will need the participation of only one center. 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), minimizing documentation and largely patient-based evaluation of outcome (PROM). 
2.3. Time schedule 
Based upon the mean number of hysterectomies performed annually for benign gynecological 
disease at the department of Obstetrics and Gynecology of the participating center (168) we 
estimate that the duration of recruitment will be 12 months. Based upon the follow up (6 months) 
and the period of analysis/reporting (3 months) the total study period will be 2 years.  
2.4. Participating center 
Department of Obstetrics and Gynecology  
Imeldahospital 
Imeldalaan 9 
2820 Bonheiden 
Belgium 
 
 

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3. ELIGIBILITY, CONSENT AND RANDOMIZATION   
 
 
 
 
3.1. Screening and consent prior to surgery 
 
All women aged 18 to 70 years, regardless of parity, in need of a hysterectomy for benign indication 
are eligible for inclusion. 
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 uterus, the process of randomization and the follow-up 
requirements with the consultant gynecologist. 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 3 years 504 hysterectomies were performed at the department of Obstetrics and 
Gynecology of the participating center. The mean number of procedures per year is 168 (±SD 19). 
About 40 % of the eligible women should be willing to participate in the proposed study to recruit the 
required amount of participants within one year (see: Section 6.1. Sample size on pages 31-32). 
3.2. Determining eligibility 
All women aged 18 to 70 years, regardless of parity, in need of a hysterectomy for benign indication 
who provide consent to participation are eligible in the HALON trial and will be randomized before 
the procedure. 
The following inclusion/exclusion criteria will be applied to assess eligibility: 
Inclusion criteria: 
• 
All women aged 18 to 70 years, regardless of parity, in need of a hysterectomy for benign 
indication 
• 
Written informed consent obtained prior to surgery 
Exclusion criteria: 
• 
History of rectal surgery 
• 
Suspected rectovaginal endometriosis 
• 
Suspected malignancy 
• 
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 

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• 
Pregnancy 
• 
Failure to provide written informed consent prior to surgery 
Body Mass Index or BMI > 35, age > 65, uterine weight 200-500g or uterine weight > 500 g are not 
considered to be an exclusion criterion per se but are characteristics that may increase the risk of 
conversion: the risk of conversion was increased at BMI >35 (OR 6.5, p < 0.001), age >65 years (OR 
7.0, p =0.007), and uterus weight 200 to 500 g (OR 4.1, p < 0.001) and especially >500 g (OR 31, p < 
0.001) based on the findings of a Dutch multicenter prospective cohort study in 42 hospitals 
including 1534 laparoscopic hysterectomies between 2008 and 2010 (23). We decided to stratify for 
uterine weight only because this is the most important variable in clinical practice and it is not 
practical to use four strata in this small pilot RCT. 
3.3. Randomization 
 
If the woman is eligible for the HALON trial, the trial secretary will obtain a randomized allocation the 
day before surgery. This will be done using a randomization 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 randomization in this small pilot RCT according to the estimated uterine size on 
clinical examination. See 3.5 Stratification of randomization.  
 
 
 
 
 
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 randomized 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 randomized into the HALON trial. We will however not do any formal non-
randomized follow-up of these women for logistical reasons. 
3.5. Stratification of randomization 
 
A blocked randomization procedure will be used to avoid chance imbalances for the parameter 
‘uterine size’. We preferred not to use minimization because this trial was not funded and we 
therefore could not afford to buy licenses for a computer-based algorithm for minimization. 
Although BMI and age are also prognostic parameters influencing the chances of the successful 
removal of the uterus, 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 only a limited number of participants. 
We therefore decided to stratify for uterine size only because this is the most important variable in 
clinical practice. 

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We used the following three strata: 
 
• 
Stratum A: uterine size < 10 weeks 
• 
Stratum B: uterine weight 10-16 weeks 
• 
Stratum C: uterine size > 16 weeks 
 
To avoid any possibility of foreknowledge, the randomized 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 non therapeutic or mock incisions in the skin 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 principal 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 
minimize performance and detection bias whenever a subjective outcome is measured (24). 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 (25). 
4.1.1 vNOTES hysterectomy 
 
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 suprapubically. The small vertical intraumbilical skin 
incision is closed with a monocryl 3/0 intradermal suture. Wound bandages are applied to all three 
skin incisions. 
The assessments whether the anterior and posterior colpotomy and the transection of both sacro-
uterine ligaments are best performed with laparoscopic instruments (TVNH) or with classical 
instruments for vaginal surgery (VANH). 
For VANH: 
A circular incision is made around the cervix using a cold knife. The pouch of Douglas is opened using 
cold scissors.  The vesico-uterine peritoneum is opened using cold scissors. Both sacro-uterine 
ligaments are transected using cold scissors and tied off using a Vicryl-1 suture. A Gelpoint (Applied 
Medical) is used as vNOTES port and is inserted into peritoneal cavity.  CO2 is insufflated until a 
maximal intraperitoneal pressure of 15mmHg. An optic is inserted and the peritoneal cavity is 

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inspected. The patient is now placed in Trendelenburg position. The small intestine is lifted out of the 
pelvis. 
For TVNH: 
A Gelpoint mini (Applied Medical) is used as vNOTES port and is inserted into the vagina. CO2 is 
insufflated until a maximal pressure of 15 mmHg. An optic is inserted into the pneumovagina. A 
circular incision is made around the cervix using a monopolar laparoscopic hook. The pouch of 
Douglas is opened using a laparoscopic scissors. The vesico-uterine peritoneum is opened using 
laparoscopic scissors.  Both sacro-uterine ligaments are coagulated using a laparoscopic bipolar 
grasper before being cut. 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 rest of the procedure is identical for VANH and TVNH: 
The ureter is identified, but not routinely dissected. It is only dissected if it cannot be identified 
transperitoneally. The uterine artery is coagulated using a bipolar grasper and cut. The ovarian artery 
is coagulated using a bipolar grasper and cut. The meso of the Falopian tube is coagulated using a 
bipolar grasper and cut. In patients requiring an adnexectomy, the infundibulopelvic ligament is 
coagulated using a bipolar grasper and is transected. Hemostasis is checked and the peritoneal cavity 
is rinsed. The NOTES port and the uterus are removed trans-vaginally and the pneumoperitoneum is 
deflated.   
The colpotomy is closed using a running Vicryl-1 suture. 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. 
Postoperative care 
Recovery room 
Analgesia: The pain management for both groups was discussed with two senior staff members of 
the department of anesthesiology of the hospital. The protocol will be standard for both comparison 
groups and is presented in appendix V. 
 
 
 

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Outpatient ward 
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.  
Cefazolin 2g is administered IV before discharge. 
Analgesia: see appendix V.  
Any additional pain medication should be reported in the nursing file which will be consulted by the 
outcome assessor (the coordinating investigator) who is blinded for the intervention done by the 
principal investigator. The assessment of whether or not additional analgesics were administered will 
be done on day 7 by the outcome assessor (the coordinating investigator). 
VAS scores See appendix VI. 
The women will be asked to use a VAS scale for measuring postoperative pain. They should place the 
cursor of the device 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 the nurse can measure the level of pain (range 0 to 10). The use of the VAS scale 
will be explained by a nurse from day care unit to ensure that women understand how the 
assessment of this subjective outcome is done in a clinical research setting. The measurements on 
the evening of the surgical procedure are noted in the patient record that will be assessed by the 
outcome assessor on day 7. The number to the left and right of the red line of the cursor will be 
recorded: e.g. pain level 0 to 1, or pain level 5 to 6. 
The decision to discharge the patient 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. If the patient decides to stay in 
the hospital, the same procedure regarding decision to discharge will be used the following days. 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 six 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. 
 

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At home 
Analgesia 
The participants should note in their participant log book the name, dosage, route of administration 
of any additional 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. These data are assessed on day 7 by the outcome 
assessor (the coordinating investigator). 
VAS scores 
The women will be asked to measure postoperative pain using a VAS scale twice daily during 7 days. 
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). They should place the cursor 
of the device 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. 
4.1.2 LSK hysterectomy 
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 reusable Hohl uterus manipulator is inserted transvaginally. 
A small vertical intra-umbilical skin incision is made. A Verress needle is inserted into the peritoneal 
cavity; correct position 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. Three reusable 5mm trocars are placed under direct vision in the 
left and right iliac fossa lateral of the epigastric vessels, and in the suprapubic region.  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 meso of the Fallopian tube is coagulated from lateral to medial using a 
reusable bipolar grasper and is cut using cold scissors. In case of hysterectomy without ovariectomy, 
the ovarian ligament is coagulated and cut. In case of hysterectomy with ovariectomy, the 

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infundibulopelvic ligament is coagulated and cut.   The round ligament is coagulated using a bipolar 
grasper and cut using cold scissors. The ligamentum latum is opened and the bladder is dissected 
from the cervix and cranial part of the vagina. The uterine artery is coagulated using a bipolar grasper 
and cut using cold scissors. The rest of the parametrium is coagulated using a bipolar grasper and cut 
using cold scissors. The same procedure is performed on the contralateral side. The vagina is then 
opened over the cup of the Hohl manipulator using a reusable monopolar hook. The cervix is excised 
circularly over the vaginal cup and the uterus is extracted transvaginally. Hemostasis is obtained 
using a bipolar grasper. The vaginal vault is closed laparoscopically using three figure of eight Vicryl-1 
sutures.  
The peritoneal cavity is rinsed and hemostasis is checked.  No drains are left in the peritoneal cavity 
except when there might be any uncertainty concerning the hemostasis.  The 5 mm trocars are 
removed under direct vision.  The 10 mm trocar is removed. The fascia is not sutured. The umbilicus 
and the other incisions are disinfected with Betadine solution. The skin incisions are closed using a 
monocryl 3/0 intradermal suture and steri-strips. The wound sites are covered with a standard 
bandage. A vaginal plug (betadine gauze 10cmx5m) is placed to be removed after 3 hours together 
with the Foley catheter. The operating time is defined as the time from insertion of the Foley 
catheter until the time of placement of the vaginal plug. 
Antibiotic administration: 
Cefazolin 2g and metronidazol 1.5g are administered IV during the procedure. 
Postoperative care 
Recovery room 
Analgesia: The pain management for both groups was discussed with two senior staff members of 
the department of anesthesiology of the hospital. The protocol will be standard for both comparison 
groups and is presented in appendix V. 
Outpatient ward 
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.  
Cefazolin 2g is administered IV before discharge. 
Analgesia: see appendix V.  

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Any additional pain medication should be reported in the nursing file which will be consulted by the 
outcome assessor (the coordinating investigator) who is blinded for the intervention done by the 
principal investigator. The assessment of whether or not additional analgesics were administered will 
be done on day 7 by the outcome assessor (the coordinating investigator). 
VAS scores See appendix VI. 
The women will be asked to use a VAS scale for measuring postoperative pain. They should place the 
cursor of the device 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 the nurse can measure the level of pain (range 0 to 10). The use of the VAS scale 
will be explained by a nurse from the day care unit to ensure that women understand how the 
assessment of this subjective outcome is done in a clinical research setting. The measurements on 
the evening of the surgical procedure are noted in the patient record that will be assessed by the 
outcome assessor on day 7. The number to the left and right of the red line of the cursor will be 
recorded: e.g. pain level 0 to 1, or pain level 5 to 6. 
The decision to discharge the patient 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. If the patient decides to stay in 
the hospital, the same procedure regarding decision to discharge will be used the following days. 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 six 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. 
At home 
Analgesia 
The participants should note in their participant log book the name, dosage, route of administration 
of any additional 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. These data are assessed on day 7 by the outcome 
assessor (the coordinating investigator). 
VAS scores 
The women will be asked to measure postoperative pain using a VAS scale twice daily during 7 days. 
One measurement will be done in the morning after bed rest at night (rest) and the other will be 

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done in the evening before going to bed after physical activity (active). They should place the cursor 
of the device 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.  
 
 
4.1.3 Failure of procedure 
Occasionally, surgical removal of a benign diseased uterus 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 hysterectomy is feasible 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 anesthetic 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 HALON trial. The investigators will sensitively explain to 
them that follow-up information is still very important, 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 diseased uterus will require no 
further intervention other than removal of the uterus with or without the adnexa. However, in some 
circumstances additional medical treatments may be considered necessary by the responsible 
clinician at the time of surgery or subsequently. This 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 HALON trial. All therapeutic interventions additional to removal of the uterus with one or both 
adnexa will be recorded and as the trial is randomized we anticipate that these further interventions 
will be symmetrically applicable. 
4.3. Withdrawal from the HALON trial 
All women who consent to the randomized HALON 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 randomization, 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 

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completely from the trial, they will be followed up. Any request to withdraw from follow-up should 
be notified to the HALON 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 HALON Trial Office as soon as possible. This report 
should be followed within 2 days by a completed SAE form to be sent 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 
hospitalization and have resulted from the surgical procedure, the anesthetic or post-operative 
recovery e.g. deep vein thrombosis, hospital acquired infections. 
 
 

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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, sent at three and six months after the surgical 
intervention. 
The postal questionnaires will be sent from the HALON Trial Office with postage paid envelopes two 
weeks before the due date. Reminders will be sent to patient if the questionnaire is not returned 
within one week of the due date and attempts will be made to contact the patient 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 uterus by the intended approach 
without conversion to another approach, using a dichotomous outcome measure, will be used as a 
measure of efficacy.  
 
 
 
 
 
 
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 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. In 
exceptional 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 analyzed 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 
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• 
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 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 gynecological 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 
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 
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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 
• 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 utilization 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 trial centers 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 anesthesia. 
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 centers participating in the trial. 
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Primary cost data will be collected from a representative sample of participating hospitals. In 
addition, the set-up costs of HALON 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 HALON 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 Gynecology 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 anonymized. All personal information 
obtained for the study will be held securely and treated as (strictly) confidential. All staff involved in 
the HALON 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. Limited data on the participants and records of any adverse events may be 
kept for longer if so recommended by an independent advisory board.  
 
 
 
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 HALON 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 Dutch prospective cohort study (23). An important consideration in the 
approach for hysterectomy is the rate of conversion to an alternative approach: the intended 
technique cannot be successfully completed for technical reasons or concerns for patient safety. The 
literature reports a mean conversion rate for laparoscopic hysterectomy of 3.5% (range 0% to 19%); 
the findings of the prospective cohort study including 1534 procedures demonstrate a conversion 
rate of 4.6%. We calculated the sample size with a one-sided test for non-inferiority for the primary 
outcome. The vNOTES approach may be more convenient for women in that no scar in the 
abdominal wall is required. 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 conversion rates of 5% 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%.  
Based on the power calculations for the primary outcome, the use of three strata for randomization 
and assuming a loss-to-follow-up rate of 15% we decided to include 66 study participants in the 
HALON trial (https://www.sealedenvelope.com/power/binary-noninferior/). 
6.2. Projected accrual and attrition rates 
 
It is anticipated that recruitment of patients will take one year. Based upon the mean number of 
hysterectomies performed annually at the department of Obstetrics and Gynecology of the 
participating center (168) we estimate that the duration of recruitment will be 12 months. Based 
upon the follow up (6 months) and the period of analysis/reporting (3 months) the total study period 
will be 2 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 minimize 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 a benign diseased uterus. Non inferiority of the intervention (vNOTES) will be 
concluded 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 randomization) will be explored as a secondary analysis.  

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Continuous measures (VAS scores) will be analyzed 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 maximizing 
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 2-sided 95% confidence intervals.  
Baseline characteristics of the patients enrolled in the two groups will be compared to ensure that 
randomization 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 HALON 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 HALON once all study entrants 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 minimize 
possible biases, participants will continue to be followed up even after protocol treatment violation. 
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 
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Questionnaires will only be treated as late if they are returned after the subsequent questionnaire 
has been sent to the patient. 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 diseased uterus, then it is 
likely that there can be cost implications for the health care sector. For example, as the patient can 
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 hysterectomy 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 HALON 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 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 

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explored using sensitivity analysis. This will explore uncertainties in the trial based data itself, the 
methods employed to analyze 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 HALON 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 HALON 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 HALON will further be assessed using a qualitative methodology. 
Interviewing after discharge will allow the woman time to reflect on her experience, and will also 
minimize 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 
when giving advice to family members or friends bound to undergo an hysterectomy; 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 and the Sponsor 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 
 
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 randomized 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 HALON is a single center pilot 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 HALON 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 HALON Trial Office 
 
The Trial Office at department of Obstetrics and Gynecology of the participating center is responsible 
for providing all trial materials, including the trial folders containing center specific trial 
documentation, standard operating procedures and training materials. Additional supplies of any 
printed material can be obtained on request or downloaded from the HALON 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 center.  
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 (AE) 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 translumenal 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. Su H, Yen CF, Wu KY, Han CM, Lee CL. Hysterectomy by transvaginal natural orifice transluminal 
endoscopic surgery (NOTES): Feasibility of an innovative approach. TJOG 2012; 51: 217-21. 
8. Lee CL, Wu KY, Su H, Wu PJ, Han CM, Yen CF. Hysterectomy by transvaginal natural orifice 
transluminal endoscopic surgery (NOTES): a series of 137 patients. J Minim Invasive Gynecol. 2014; 1: 
818-24. 
9. Baekelandt J. Total Vaginal NOTES Hysterectomy: A New Approach to Hysterectomy. J Minim 
Invasive Gynecol 2015; 22:1088-94. 
10. Dindo D, Demartines N, Clavien PA. Classification 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. 
11. Corona LE, Swenson CW, Sheetz KH, Shelby G, Berger MB, Pearlman MD, Campbell DA, DeLancey 
JO, Morgan DM. Use of other treatments before hysterectomy for benign conditions in a statewide 
hospital collaborative. American Journal of Obstetrics & Gynecology 2015; 212(3): 304.e1-304.e7. 
12. Carlson KJ, Nichols DH, Schiff I. Indications for Hysterectomy. N Engl J Med 1993; 328:856-60. 
 
13. Nieboer TE, Johnson N, Barlow D, Lethaby A, Tavender E, Curr E, Garry R, van Voorst S, Mol BWJ, 
Kluivers K. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database 
of Systematic Reviews 2006, Issue 2. Art. No.: CD003677. 

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Page 52 of 71 
 
14. Atallah S, Martin-Perez B, Albert M, Schoonyoung H, Quinteros F, Hunter L, Larach S.  
Vaginal Access Minimally Invasive Surgery (VAMIS): A New Approach to Hysterectomy. Surgical 
Innovation 2015; 22(4): 344–7. 
15. Chen YJ, Yen MS, Tsai HW, Wang PH, Twu NF,Chao KC.Transvaginal Natural Orifice Transluminal 
Endoscopic Surgery (NOTES) Hysterectomy and Bilateral Salpingoovariectomy for Female-to-Male 
Transsexuals. Abstracts / Journal of Minimally Invasive Gynecology 2012; 19: S123–S150. 
16. Chyi-Long Lee, Kai-Yun Wu, Hsuan Su, Pei-Ju Wu, Chien-Min Han, Chin-Jung Wang, 
Chih-Feng Yen. Natural orifice transluminal endoscopic surgery in gynecology. Gynecology and 
Minimally Invasive Therapy 1 (2012) 23e26. 
17. Chin-Jung Wang, Hui-Yu Huang, Chen-Ying Huang, Hsuan Su. Hysterectomy via transvaginal 
natural orifice transluminal endoscopic surgery for nonprolapsed uteri. Surg Endosc 2015; 29:100–7. 
18. Yun Seok Yang, Soo Young Kim, Myung Haeng Hur, Kwoan Young Oh. Natural Orifice Transluminal 
Endoscopic Surgery-assisted Versus Single-port Laparoscopic-assisted Vaginal Hysterectomy: 
A Case-matched Study. Journal of Minimally Invasive Gynecology 2014; 21: 624–31. 
19. Donnez O, Jadoul P, Squifflet J, Donnez J. A series of 3190 laparoscopic hysterectomies for benign 
disease from 1990 to 2006: evaluation of complications compared with vaginal and abdominal 
procedures. BJOG 2008; 116:492-500. 
20. 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. 
21. 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. 
22. Mc Culloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, Nicholl J, for the Balliol 
Collaboration. No surgical innovation without evaluation: the IDEAL recommendations. The Lancet 
2009; 374:1105-12. 
23. Twijnstra AR, Blikkendaal MD, van Zwet EW, Jansen FW. Clinical relevance of conversion rate and 
its evaluation in laparoscopic hysterectomy. J Minim Invasive Gynecol 2013; 20(1):64-72. 
24. 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. 
25. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141-5. 
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.  Harkki-Siren 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 
 
Table 1 Overview of patient and perioperative characteristics 
 
 
 
 
 
 
 
APPENDIX II: TABLE II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data 
Mean 
Range 
Age (years) 
48.4 
34 - 61 
BMI (kg/m2) 
25.1 
19.7 – 33.3 
Total operating time (min) 
97 
60 - 120 
Serum hemoglobine drop (g/dl) 
1.5 
0.5 – 2.4 
Postoperative pain score 
6h 
24h 
 
2.5 
1.7 
 
1 – 6 
1 – 2 
Table 2 Patient and perioperative data 
Pati
ent 
no. 
Age 
(years) 
BMI 
(kg/m2) 
Parity 
Hist
ory 
of 
vagi
nal 
deliv
ery 
Previous 
pelvic 
surgery 
 
 
Indication 
Type of 
surgery 
 
 
Port Type 
Total 
oper
ating 
time 
(min
) 
Seru
m 
hem
o-
globi
ne 
drop 
(g/dl
) 
(Peri-) 
operative 
complication
s 
 
Specim
en 
Weight  
(grams
) 
Postoperativ
e pain score 
 
6h 
24h 
1 
46 
33.3 
A1P1G2 
yes 
AE EUG 
menorrhagia 
TVNH 
LMA 
120 
0.7 
cystitis 
83 
2 
1 
2 
46 
24.8 
A0P1G1 
no 
LLETZ CS 
menorrhagia 
TVNH 
Wound 
Protector 
115 
1.5 
3cm vault 
haematoma 
126 
2 
2 
3 
61 
22.1 
A0P3G3 
yes 
- 
Ovarian cyst 
TVNH+BSO 
LMA 
105 
1.5 
- 
224 
2 
2 
4 
61 
24.7 
A0P0G0 
no 
AE 
PMB 
TVNH+BSO 
Wound 
Protector 
120 
1.9 
- 
107 
2 
2 
5 
34 
23.8 
A1P2G3 
yes 
LLETZ 
 cervical 
dysplasia 
TVNH 
LMA 
65 
1.0 
- 
39 
1 
1 
6 
36 
20.3 
A0P0G0 
no 
LLETZ LS 
endometrio
sis 
adhaesiolys
is 
 
dysmenorrhe
a 
TVNH 
Wound 
Protector 
110 
1.8 
- 
 
51 
3 
2 
7 
45 
23.7 
A0P0G0 
no 
- 
myomatous 
uterus 
TVNH 
Wound 
Protector 
115 
2.0 
- 
353 
2 
1 
8 
52 
31.6 
A0P1G1 
yes 
Hemicolect
omy 
USO 
 
adenomyosis 
TVNH+USO 
LMA 
 
70 
0.5 
- 
62 
6 
2 
9 
52 
19.7 
A0P3G3 
no 
CS x 3 
LLETZ 
AE 
cervical 
dysplasia 
TVNH 
 
Wound 
Protector 
60 
1.5 
- 
 
55 
3 
2 
10 
51 
26.4 
A0P1G1 
yes 
- 
myomatous 
uterus 
TVNH+USO 
LMA 
90 
2.4 
- 
223 
2 
2 
 
AE = appendectomy; EUG = laparoscopic salpingectomy for ectopic pregnancy; CS = caesarean section; LLETZ = large loop excision of transformation zone; LS = laparoscopic 
sterilisation; endometriosis = laparoscopy for pelvic endometriosis; adhaesiolysis = laparoscopy for adhaesiolysis; USO = unilateral salpingo-oophorectomy; TVNH= total vaginal 
NOTES hysterectomy; BSO= bilateral salpingo-oophorectomy; LMA= self-constructed NOTES port using laryngeal mask airway ; PMB = persistent postmenopausal bleeding 
 

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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 
 
HALON 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  

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2. A mild problem 
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 

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4. A severe or extreme problem 
 
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 

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3. A moderate problem 
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 
 
 
 
 

Version 5, 28-12-2015 
 
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Version 5, 28-12-2015 
 
HALON trial 
Page 70 of 71 
 
 
 
 

Version 5, 28-12-2015 
 
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Page 71 of 71