Notes Adnexectomy for Benign Pathology Compared to Laparoscopic Excision
Condition: Natural Orifice Endoscopic Surgery; Disease, Adnexal; Laparoscopic Surgery
MeSH terms: Adnexal Diseases
Study type: Interventional

Summary: 
      Objective: To compare vNOTES (vaginal Natural Orifice Transluminal Endoscopic Surgery) and
      established laparoscopic removal of benign adnexal masses Study design: Randomized
      controlled/single center/single-blinded/parallel-group/non-inferiority/efficacy trial.

      Study population: Women aged 18 to 70 years with symptomatic or persistent benign adnexal
      masses detected by clinical examination and ultrasound.

      Randomization: Women will be randomly allocated to undergo one of two techniques for removal
      of the benign adnexal mass immediately before surgery by using a computer generated
      randomization list. The investigators will use stratified randomization according to the cyst
      diameter.

      Intervention: Women will be treated by a surgeon who is not blinded to the treatment
      allocation and who is equally skilled in performing both techniques. In the intervention
      group a vNOTES technique will be used.

      Control: In the control group surgery will be done by a classical laparoscopic technique.

      Participants, nursing staff and outcome assessors will be blinded.

      Main study parameters/endpoints:

      Primary outcomes: successful removal of a benign adnexal mass without spill. Secondary
      outcomes: the proportion of women discharged the same day based on their own preference;
      postoperative pain scores using a VAS (Visual Analogue Scale) measured between day 1 till 7
      by the participating women following surgery and the total amount of analgesics used as
      described in the standardized pain treatment protocol between day 1 till 7; 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 detected 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 (Short Sexual Functioning Scale);
      direct costs associated up to 6 weeks after the surgical intervention with both procedures.
    

Detailed description: 
      1. Objectives of the NOTABLE Trial

      The primary research questions of this IDEAL stage 2b efficacy trial are as follows: is a
      vNOTES adnexectomy at least as effective compared to the standard transabdominal laparoscopic
      approach (LSC) for removing a benign adnexal mass without spill? (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 benign adnexal mass by vNOTES faster compared to LSC?

        -  Does a vNOTES cause more pelvic infection or other complications compared to LSC?

        -  Does a vNOTES cause more hospital readmissions within 6 weeks following surgery compared
           to LSC?

        -  Does a vNOTES approach result in more women reporting dyspareunia, less sexual wellbeing
           or less health-related quality of life at 3 or 6 months after surgery when compared to
           women treated by LSC?

        -  What are the direct and indirect costs up to 6 weeks of a vNOTES compared to LSC?

      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 2.3. Time schedule Based upon the
      mean number of laparoscopic adnexectomies performed annually at the department of Obstetrics
      and Gynecology of the participating center (36) the investigators estimate that the duration
      of recruitment will be 21 months. Based upon the follow up (6 months) and the period of
      analysis/reporting (3 months) the total study period will be 2.5 years.

      2.4. Participating center Department of Obstetrics and Gynecology Imeldahospital Imeldalaan 9
      2820 Bonheiden Belgium

      3. ELIGIBILITY, CONSENT AND RANDOMIZATION 3.1. Screening and consent prior to surgery All
      women aged 18 to 70 years regardless of parity presenting with a symptomatic or asymptomatic
      persistent benign adnexal mass on clinical examination confirmed by ultrasound are eligible
      for inclusion. The diagnosis of benign adnexal mass will be based upon the prospectively
      validated IOTA classification(International Ovarian Tumour Analysis Group) simple ultrasound
      rules to distinguish between benign and malignant adnexal masses.

      3.2. Determining eligibility All women aged 18 to 70 years regardless of parity presenting
      with a symptomatic or asymptomatic persistent benign adnexal mass on clinical examination who
      provide consent to participation are eligible in the NOTABLE trial based on the findings of
      the ultrasound findings and will be randomized before the procedure.

      3.3. Randomization If the woman is eligible for the NOTABLE 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 before the surgical intervention for logistic reasons. The investigators
      will use stratified randomization in this small pilot RCT (randomized controlled trial)
      according to the cyst diameter.

      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 NOTABLE trial. A formal non-randomized follow-up of these
      women will not be done for simple logistical reasons.

      3.5. Stratification of randomization A blocked randomization procedure will be used to avoid
      chance imbalances for the parameter 'cyst diameter'.

      To avoid any possibility of foreknowledge, the randomized allocation will not be given until
      all eligibility and stratification data have been given.

      4. TREATMENT ALLOCATIONS 4.1. Surgical procedures The principal investigator, who has
      training and experience in both laparoscopy and NOTES, will perform all surgical procedures.
      He is therefore not blinded. All vNOTES participants will be blinded by three superficial
      "mock" skin incisions similar to those routinely done with the laparoscopic technique.

      4.1.1 vNOTES adnexectomy This is the surgical procedure done in the intervention arm of the
      NOTABLE trial.

      4.1.2 LSC adnexectomy This is the surgical procedure done in the control arm of the NOTABLE
      trial. 5. FOLLOW-UP AND OUTCOME MEASURES 5.1. Clinical assessments 5.1.1 Format PROMs will be
      collected using a postal questionnaire, which will include a combination of disease specific
      and generic measurement instruments.

      The postal questionnaires will be sent from the NOTABLE Trial Office with postage paid
      envelopes two weeks before the due date. Reminders will be sent to the participants if the
      questionnaire is not returned within one week of the due date and attempts will be made to
      contact the women by phone if the questionnaire is not returned by two weeks after the due
      date.

      5.1.2 Timing of assessments The primary outcome will be measured clinically at the end of the
      surgical procedure. In addition patient reported outcome measures (PROMs) will take place the
      evening of the surgical intervention (return home), during the first postoperative week (pain
      by Visual Analogue (VAS)scores and analgetic drugs) and at 3 and 6 months (dyspareunia/
      sexual well being/ health related quality of life). 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, hospital readmission rate).

      5.2. Primary clinical outcome measure The proportion of women successfully treated by
      removing the adnexal mass without spill, using a dichotomous outcome measure, will be used as
      a measure of efficacy.

      5.3. Secondary clinical outcome measures

      The following secondary outcomes will be measured:

        -  The proportion of women admitted in-hospital for at least one night observation based on
           their own preference, as a dichotomous outcome.

        -  Postoperative pain scores, as an ordinal outcome, measured using a Visual Analogue Scale
           (VAS) scale twice daily from day 1 till 7 self-reported by the participating women. VAS
           scores range from 0=no pain to 10= worst imaginable pain.

        -  Postoperative pain defined by the total amount of analgesics used as described in the
           standardized pain treatment protocol, as a continuous outcome.

        -  Postoperative infection 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.

        -  Hospital readmission within 6 weeks following 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 Visual Analogue Scale (VAS) scale, as a
           dichotomous and ordinal outcome. VAS scores range from 0=no pain to 10= worst imaginable
           pain.

        -  Sexual wellbeing at baseline, at 3 and 6 months by self-reporting the Short Sexual
           Functioning Scale (SSFS). The SSFS is a questionnaire with 7 open ended questions on
           sexual wellbeing.

        -  Health-related quality of life, at baseline, at 3 and 6 months by self-reporting the
           EQ-5D-3L tool consisting of a questionnaire on 5 domains and a scale ranging from
           0=worst possible health-related quality of life to 100 = best possible health-related
           quality of life.

        -  Duration of surgery measured as the time in minutes from the insertion of the bladder
           catheter to the end of vaginal/abdominal wound closure, as a continuous outcome.

      5.4. Health economic outcomes The direct and indirect costs of both techniques up to 6 weeks
      after the surgical intervention will be calculated.

      6. ACCRUAL AND ANALYSIS 6.1. Sample size The sample size for this trial has been chosen to
      give good statistical power to preclude any clinically important inferiority of vNOTES
      compared to laparoscopy and is based on evidence retrieved from a systematic review of the
      literature and a RCT comparing the excision of mature teratoma using culdotomy with and
      without laparoscopy. Based on the power calculations for the primary outcome and two
      secondary outcomes and assuming a loss-to-follow-up rate of 10% the investigators decided to
      include 66 study participants in the NOTABLE trial.

      6.2. Projected accrual and attrition rates It is anticipated that recruitment of participants
      will take two years. Based upon the mean number of laparoscopic adnexectomies performed
      annually at the department of Obstetrics and Gynecology of the participating center (36) the
      investigators estimate that the duration of recruitment will be 21 months. Based upon the
      follow up (6 months) and the period of analysis/reporting (3 months) the total study period
      will be 2.5 years. First publication will be possible within four years of trial
      commencement.
    

Intervention name(s): vNOTES adnexectomy; Laparoscopic adnexectomy
Intervention type(s): Procedure; Procedure
Intervention description(s): Surgical removal of one or both adnexa by a natural orifice transluminal endoscopic surgical technique using a colpotomy (transvaginal incision); Surgical removal of one or both adnexa by transabdominal laparoscopy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: NOTES; Benign adnexal disease; Laparoscopy