{"paper_id":"beb294b5-6fb4-4145-9ddb-adc3f0777bc9","body_text":"Mackenzie et al. Trials          (2023) 24:425  \nhttps://doi.org/10.1186/s13063-023-07386-x\nSTUDY PROTOCOL Open Access\n© The Author(s) 2023. Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nTrials\nEffectiveness of laparoscopic removal \nof isolated superficial peritoneal endometriosis \nfor the management of chronic pelvic pain \nin women (ESPriT2): protocol for a multi-centre \nrandomised controlled trial\nScott C. Mackenzie1  , Jacqueline Stephen2  , Linda Williams2  , Jane Daniels3  , John Norrie2  , \nChristian M. Becker4  , Dominic Byrne5, Ying Cheong6  , T. Justin Clark7  , Kevin G. Cooper8  , Emma Cox9, \nAnn M. Doust1  , Priscilla Fernandez1, Jeremy Hawe10, Tom Holland11  , Lone Hummelshoj12  , \nLouise J. Jackson13  , Kathleen King14, Abha Maheshwari15  , Dan C. Martin16,17,18, Lauren Sutherland1  , \nJim Thornton19  , Katy Vincent4  , Sanjay Vyas20, Andrew W. Horne1   and Lucy H. R. Whitaker1*   \nAbstract \nBackground Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it \nis associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic \nlaparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometrio-\nsis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically \nremove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the \nmanagement of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to \ndetermine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain.\nMethods We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and \ncost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health \nService Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected \nendometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or \novarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by exci-\nsion or ablation or both, according to surgeons’ preference) versus diagnostic laparoscopy alone. Randomisation with \nblock-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they \nreceived until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to \nparticipants’ preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, \n6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Pro-\nfile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard \n*Correspondence:\nLucy H. R. Whitaker\nlucy.whitaker@ed.ac.uk\nFull list of author information is available at the end of the article\n\nPage 2 of 15Mackenzie et al. Trials          (2023) 24:425 \ndeviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are \nrequired to be randomised to detect an 8-point pain score difference.\nDiscussion This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal \nof isolated SPE.\nTrial registration ISRCTN registry ISRCTN27244948. Registered 6 April 2021.\nKeywords Endometriosis, Pelvic pain, Laparoscopy, Surgical ablation, Surgical excision, Randomised controlled trial\nAdministrative information\nNote: the numbers in curly brackets in this protocol refer \nto SPIRIT checklist item numbers. The order of the items \nhas been modified to group similar items (see http:// \nwww. equat or- netwo rk. org/ repor ting- guide lines/ spirit- \n2013- state ment- defin ing- stand ard- proto col- items- for- \nclini cal- trials/).\nTitle {1} Effectiveness of laparoscopic removal of \nisolated superficial peritoneal endometrio-\nsis for the management of chronic pelvic \npain in women (ESPriT2): protocol for a \nmulti-centre randomised controlled trial\nTrial registration {2a and \n2b}.\nISRCTN registry ISRCTN27244948. Regis-\ntered 6th April 2021.\nProtocol version {3} Version 4.0\nFunding {4} This study is funded by the NIHR Health \nTechnology Assessment programme \n(NIHR129801). The views expressed are \nthose of the author(s) and not necessarily \nthose of the NIHR or the Department of \nHealth and Social Care.\nAuthor details {5a} SCM, AMD, PF, LS, AWH, LHRW: MRC \nCentre for Reproductive Health, University \nof Edinburgh, Edinburgh, EH16 4TJ, UK\nJS, LW, JN: Usher Institute, Edinburgh \nClinical Trials Unit, University of Edinburgh, \nNINE, Edinburgh BioQuarter, Edinburgh, \nEH16 4UX, UK\nJD: Nottingham Clinical Trials Unit, Uni-\nversity of Nottingham, Nottingham, NG7 \n2RD, UK\nKV, CMB: Endometriosis CaRe, Nuffield \nDepartment of Women’s and Reproductive \nHealth, University of Oxford, Oxford, OX3 \n9DU, UK\nDB: Royal Cornwall Hospitals NHS Trust, \nTruro, UK\nYC: Faculty of Medicine, Human Develop-\nment and Health, University of Southamp-\nton, Southampton, UK\nTJC: Birmingham Women’s and Children \nHospital, Birmingham, B15 2TG, UK\nKGC: NHS Grampian, Aberdeen Royal Infir-\nmary, Foresterhill, Aberdeen, AB25 2ZN, UK\nEC: Endometriosis UK\nJH: Corniche Hospital, Abu Dhabi, United \nArab Emirates.\nTH: Guys and St Thomas NHS Trust, London, \nUK\nLH: Endometriosis.org\nLJJ: University of Birmingham, Birmingham, \nUK\nKK: Independent endometriosis advocate, \nIreland.\nAM: Aberdeen Fertility Centre, NHS Gram-\npian, Aberdeen, UK\nDCM: University of Tennessee Health \nScience Center, Department of Obstetrics \nand Gynecology, Memphis, Tennessee, \nUSA; Virginia Commonwealth University, \nInstitutional Review Board, Richmond, Vir-\nginia, USA; Scientific and Medical Director \nof EndoFound (Endometriosis Foundation \nof America)\nJT: University of Nottingham, Nottingham, \nUK\nSV: Southmead Hospital, North Bristol NHS \nTrust, Bristol BS10 5NB\nName and contact infor-\nmation for the trial sponsor \n{5b}\nUniversity of Edinburgh & NHS Lothian \nACCORD Research Governance & QA Office, \nThe Queen’s Medical Research Institute, 47 \nLittle France Crescent Edinburgh, EH16 4TJ, \nEmail:\nresgov@accord.scot\n\nPage 3 of 15\nMackenzie et al. Trials          (2023) 24:425 \n \nRole of sponsor {5c} The sponsor is the individual, organisa-\ntion or partnership that takes on overall \nresponsibility for proportionate, effective \narrangements being in place to set up, run \nand report a research project.\nIntroduction\nBackground and rationale {6a}\nEndometriosis is a chronic oestrogen-dependent, neuro-\ninflammatory condition that affects approximately 10% of \nwomen and those assigned female at birth of reproduc -\ntive age worldwide [1]. It is characterized by the growth \nof endometrial-like tissue (‘lesions’) outside of the uterus, \nmost commonly on the peritoneum and ovaries. Symp -\ntoms can include chronic pelvic pain, painful periods, \npainful sex, infertility and fatigue [2]. Endometriosis-\nassociated pain can be disabling and worsen quality of \nlife; the societal economic cost is estimated at £8500 per \nwoman per year globally [3].\nThree subtypes of endometriosis have been described: \nsuperficial peritoneal endometriosis (SPE), ovarian endo -\nmetriosis and deep endometriosis [2]. Around 80% of \nthose with endometriosis have SPE. A lack of non-inva -\nsive endometriosis tests mean definitive diagnosis is usu -\nally achieved by visualisation of the lesions at diagnostic \nlaparoscopy [2]. During laparoscopy, if SPE is found, \ngynaecologists usually remove it surgically (by excision \nor ablation) [4, 5]. Investigation and surgical removal \nrequire gynaecological surgical expertise and form a \nsignificant proportion of the gynaecological workload. \nHowever, around 50% of patients who have undergone \nsurgical treatment for endometriosis re-present with \npersistent, or recurrent, pain within 5 years and surgical \nreintervention rates are high [6, 7].\nLimited evidence exists to support current endometri -\nosis guidelines, showing whether or not surgical removal \nof isolated SPE improves (or worsens) symptoms and \nquality of life [4, 5]. A 2014 Cochrane systematic review \nand meta-analysis of laparoscopic surgery for endome -\ntriosis concluded that laparoscopic treatment leads to \nimproved condition-associated pain (cited as ‘better’ or \n‘improved’) when compared to diagnostic laparoscopy \nalone at 6 months (OR 6.58, 95% CI 3.31–13.10) [8]. How-\never, this conclusion is drawn from three randomised \ncontrolled trials (RCT), comprising 171 participants with \nmultiple endometriosis subtypes. Furthermore, only one \nsmall RCT included in the analysis (69 participants) has \nfollow-up data to 12 months showing benefit of surgery \n(OR 10.00, 95% CI 3.21–31.17). This led the authors \nof the systematic review to define the strength of the \nevidence, based on GRADE criteria, as of moderate and \nlow quality at six and 12 months respectively.\nThis Cochrane review was updated in 2020, but despite \nreviewing 1175 articles, the authors reduced the num -\nber of included trials examining the effect of laparo -\nscopic treatment of endometriosis on pain to one study \nof 16 participants with mixed disease type [9]. This was \na consequence of altered methodology including appli -\ncation the core outcome set for trial reporting in endo -\nmetriosis studies [10]. Whilst the authors noted that \nsurgery improved pain at 12 months, the study was con -\nsidered ‘very low-quality’ evidence. This led the authors \nto conclude that they were ‘uncertain of the effect of \nlaparoscopic excision on overall pain scores compared \nto diagnostic laparoscopy only and that further trials \nare needed’ . The paucity of evidence and need for addi -\ntional studies was further echoed by an additional sys -\ntematic review and meta-analysis of the effectiveness of \nlaparoscopic surgery for endometriosis, also published in \n2020 [11]. Furthermore, the uncertainty surrounding the \neffectiveness of laparoscopic management of SPE is com -\npounded by the limited evidence to allow an informed \nselection of specific surgical modalities to remove SPE \n(ablation versus excision) [12].\nConsequently, both the 2017 National Institute of Clin-\nical Excellence (NICE) Endometriosis Guideline and the \nrecent Endometriosis Guideline by the European Soci -\nety of Human Reproduction and Embryology (ESHRE) \nrecommend further research is needed to determine the \neffectiveness of laparoscopic removal of isolated SPE to \nmanage endometriosis-associated pain [4, 5]. This call \nfor research was further supported by the outcome of the \n2017 James Lind Alliance Endometriosis Priority Setting \nPartnership that established key research questions most \nimportant to those with endometriosis and healthcare \npractitioners [13].\nWe, therefore, plan to undertake a multi-centre trial \nacross the UK (called ESPriT2) where women who have \nonly SPE found at diagnostic laparoscopy are randomly \nallocated to have surgical removal of SPE or diagnostic \nlaparoscopy alone. Surgical removal of SPE in the context \nof this trial means excision, ablation, or a combination \nof both. We aim to determine whether surgical removal \nof endometriotic lesions improves overall endometrio -\nsis-associated symptoms and quality of life or whether \nsurgery is of no benefit, exacerbates symptoms or even \ncauses harm.\nIn this protocol, from now on we use the terms ‘woman’ \nand ‘women. ’ However, it is important to note that endo-\nmetriosis can affect all people assigned female at birth, all \nof whom are eligible to participate in this trial.\n\nPage 4 of 15Mackenzie et al. Trials          (2023) 24:425 \nObjectives {7}\nThe primary objective of this trial is to compare laparo -\nscopic removal of isolated SPE versus diagnostic laparos -\ncopy alone in terms of participants’ pain at 12  months \npost-randomisation.\nThe secondary objectives of this trial are to compare \nlaparoscopic removal of isolated SPE versus diagnostic \nlaparoscopy alone in terms of:\n• Physical and emotional functioning\n• Requirement for future intervention\n• Occupational outcomes\n• Post-operative pain scores\n• Surgical complications\n• Pregnancy events\n• Cost-effectiveness\n• Adverse events\nFig. 1 Schematic diagram of ESPriT2 trial design\n\nPage 5 of 15\nMackenzie et al. Trials          (2023) 24:425 \n \nTrial design {8}\nESPriT2 is a multi-centre participant-blind parallel-\ngroup, superiority randomised (1:1) controlled clinical \nand cost-effectiveness trial with internal pilot. Figure  1 \nprovides a schematic diagram of the ESPriT2 trial design. \nThe trial design and development of patient facing mate -\nrials was informed by an ESPriT2 patient and public \ninvolvement panel consisting of individuals with lived \nexperience of endometriosis and representatives from \npatient support organisations.\nMethods: participants, interventions and outcomes\nStudy setting {9}\nThis trial will take place in National Health Service \n(NHS) hospitals in the UK including both British Society \nfor Gynaecological Endoscopy (BSGE) centres and gen -\neral gynaecology units. We aim to recruit in up to 70 hos-\npital sites.\nEligibility criteria {10}\nInclusion and exclusion criteria for trial participants are \ndetailed in Table 1.\nWho will take informed consent? {26a}\nPotentially eligible participants who are referred or self-\nrefer will be provided with a patient information sheet by \na member of the clinical research team at their trial site. \nInitial contact may be face-to-face during a routine clinic \nappointment or may be via a telephone/video call via an \napproved NHS platform by a member of the research \nteam.\nInformed consent to participate in the trial will only to \nbe taken by a member of the clinic research team once \nthe patient has had sufficient time to read the patient \ninformation sheet, have their questions answered and \nconsider whether they wish to participate in the trial. At \nleast 24 h will be provided for potentially eligible partici -\npants to consider participation. All participants who are \napproached via a call will have the option to attend the \nhospital to discuss the trial and provide written informed \nconsent in person or provide informed consent verbally \nover the call. Those who give verbal consent will have the \nconsent form signed by the researcher and a copy of this \nsigned form will be sent to the participant with contact \ndetails of the research team should they decide to with -\ndraw consent. At the time of consent, the participant \nwill be reminded that they will be given a diagnosis post-\noperatively of the findings at the time of laparoscopy but \nwill not be told if surgical removal was carried out. All \nparticipants will be asked to re-confirm consent at the \ntime of their laparoscopy and will be asked to wet ink \nsign the trial consent form before any further research \nactivities are carried out although questionnaires may be \ncompleted before this signature is obtained.\nAdditional consent provisions for collection and use \nof participant data and biological specimens {26b}\nParticipants consented to ESPriT2 will be offered the \noption to participate in related biomarker (venous blood \nsample prior to surgery) and imaging (pelvic ultrasound) \nstudies (ESPriT +) for future analysis. In addition, con -\nsent will be obtained for longer-term follow-up at two \nand five years and data linkage for fertility outcomes and \nsurgical reintervention.\nTable 1 Inclusion and exclusion criteria for trial participants\n* Women includes those assigned female at birth\nInclusion criteria Exclusion criteria\n• Women* aged over 16\n• Undergoing laparoscopy for the investigation of chronic pelvic pain\n• In order to be randomised, isolated superficial peritoneal endometriosis \n(SPE) must be identified at laparoscopy (macroscopically)\n• Able to give informed consent\n• Previous surgical diagnosis of endometriosis\n• Pregnant\n• Women* who have undergone hysterectomy and/or bilateral oophorec-\ntomy\n• Women* who are undergoing the following concurrent procedures at the \ntime of laparoscopy\n o Salpingectomy\n o Ovarian cystectomy\n o Oophorectomy\n o Division of dense adhesions\n o Endometrial ablation\n• Ovarian cyst on imaging that is the indication for surgery\n• Deep endometriosis on imaging or at time of laparoscopy\n• Endometrioma observed at the time of laparoscopy\n• Peritoneal ‘pockets’ only noted at laparoscopy\n\nPage 6 of 15Mackenzie et al. Trials          (2023) 24:425 \nInterventions\nExplanation for the choice of comparators {6b}\nDiagnostic laparoscopy is required to diagnose SPE, com-\npared to other endometriosis subtypes (ovarian or deep) \nthat can sometimes be diagnosed using ultrasound by a \nskilled operator. When SPE is identified, management \noptions include surgical removal (including surgical exci-\nsion or surgical ablation or both) or no operative treat -\nment. The term surgical removal of SPE in the context \nof this trial means excision, ablation or a combination of \nboth.\nIntervention description {11a}\nAt the time of diagnostic laparoscopy, participants will \nbe randomised to diagnostic laparoscopy with surgical \nremoval of SPE or diagnostic laparoscopy alone. For par -\nticipants allocated to surgical removal of SPE, excision \nand/or ablation of SPE will be dependent on the operat -\ning surgeon’s preference/usual practice. To maintain par-\nticipant blinding, all participants will have two accessory \nports sited in addition to the optical (usually umbilical) \nport. All participants will be informed of a diagnosis \npost-operatively but will not be informed whether surgi -\ncal removal of SPE occurred.\nCriteria for discontinuing or modifying allocated \ninterventions {11b}\nAllocation will occur during diagnostic laparoscopy once \neligibility (see Table 1) has been confirmed. Perioperative \ncomplications or surgical complexity may lead to discon -\ntinuation of the allocated intervention, and this is at the \ndiscretion of the operating surgeon. Reasons for incom -\nplete removal of disease in those randomised to removal \nare documented at the end of the procedure if applicable.\nStrategies to improve adherence to interventions {11c}\nNot applicable. The trial intervention will occur whilst \nthe patient is anaesthetised.\nRelevant concomitant care permitted or prohibited \nduring the trial {11d}\nAll participants will be offered routine NHS gynaeco -\nlogical care during the trial, which includes the option \nof taking any of the current recommended treatment \noptions for endometriosis, such as oral analgesia or \nhormones (including concurrent levonorgestrel-intra -\nuterine system insertion at surgery). Participants will \nbe permitted to take part in non-interventional stud -\nies such as questionnaire studies and bio banking (with \nthe exception of peritoneal biopsies). Participants will \nbe discouraged from co-enrolling in other drug, treat -\nment of pain or surgical trials. If participants co-enrol \nin another drug, treatment of pain or surgical trial their \nsubsequently collected ESPriT2 data will be excluded \nfrom our analysis. Similarly, those enrolled in active \nintervention phase of another gynaecological trial will \nbe excluded but eligible for inclusion if in long term fol -\nlow-up phase of other gynaecological trials.\nProvisions for post‑trial care {30}\nAt the end of 12  months of post-randomisation fol -\nlow-up, participants will be given the option to be told \nwhich group they were randomised to. If they were \nallocated to the diagnostic laparoscopy alone group, \nthey will have the opportunity to discuss whether they \nwish to have surgical removal of SPE as a component of \ntheir routine NHS gynaecological follow-up.\nOutcomes {12}\nThe primary outcome in this trial is the ‘pain domain’ \nof the Endometriosis Health Profile-30 (EHP-30) ques -\ntionnaire at 12 months post-randomisation.\nEHP-30 is a commonly used, condition-specific, \npatient reported outcome questionnaire that assesses \nhealth-related quality of life in endometriosis across five \nkey domains (pain, control and powerlessness, emo -\ntional well-being, social support, and self-image) [14]. \nEvaluation of EHP-30 has shown consistent acceptabil -\nity, validity, reliability and sensitivity to change suitable \nfor use within endometriosis research and clinical trials \nof endometriosis interventions [15, 16].\nSecondary clinical outcomes will include measures of \nuse of hormones and analgesics, occupational impact, \npost-operative pain and reproductive outcomes. Second -\nary outcomes are detailed as follows:\n• Time off work and presenteeism defined by the Work \nProductivity and Activity Impairment Questionnaire \n(WPAIQ) at 12 months\n• Need for hormonal medication for endometriosis-\nrelated symptoms at 3, 6 and 12 months\n• Need for analgesics for endometriosis-related symp -\ntoms at 3, 6 and 12 months\n• Pain domain of the EHP-30 at 3 and 6 months\n• Total score of EHP-30 at 3, 6 and 12 months\n• Fatigue symptoms defined by the Brief Pain Inven -\ntory (BFI) at 12 months\n• Neuropathic pain features identified by PainDE -\nTECT™ at 12 months\n• Urinary symptoms defined by Pelvic Pain and Urinary \nFrequency (PUF) Patient Symptom Scale at 12 months\n• Irritable bowel symptoms defined by the ROME IV \nCriteria at 12 months\n\nPage 7 of 15\nMackenzie et al. Trials          (2023) 24:425 \n \n• Pain catastrophizing measured by Pain Catastrophiz-\ning Questionnaire (PCQ) at 12 months\n• Fibromyalgia defined by Fibromyalgia Scale (FS) at \n12 months\n• Specific patient reported symptoms defined by Meas-\nure Yourself Medical Outcome Profile 2 (MYMOP2)\n• Post-operative (up to 7  days after surgery) pain and \nanalgesic requirements by patient reported diary\n• Length of hospital stay\n• Adverse events related to surgery at 30 days\n• Surgical complications at 30 days\n• Surgical operating time\n• Need for further surgery for endometriosis related \nsymptoms at 12 months\n• Pregnancy events at 3, 6 and 12 months\nOutcomes used for the economic evaluation will \ninclude:\n• Utility values, derived from EQ-5D-5L health-related \nquality of life score at 3, 6, and 12 months\n• General wellbeing defined by Capability Question -\nnaire (ICECAP-A) at 3, 6, and 12 months\n• Costs and resource use at 3, 6 and 12  months (pri -\nmary and secondary care use)\n• Impacts on employment, caregiving, and other usual \nactivities (e.g. education)\nFor those allocated to surgical removal, we will also report \nthe operative technique for removal of endometriosis (exci-\nsion, ablation, or combination) and adequacy of removal \nof endometriosis (subjective and independent). Subject to \nfurther funding we aim to compare future fertility and need \nfor further surgery using data linkage and assess EHP-30, \nROME IV, PUF, EQ-5D-5L, PainDETECT™, hormonal and \nanalgesic use, fertility interventions and pregnancy events \nmeasured at 2 and 5 years post-randomisation.\nParticipant timeline {13}\nA schedule of events for participants is detailed in \nTable 2.\nSample size {14}\nAn 8-point difference of the EHP-30 pain domain is \nequivalent to a standardized difference of 0.36 (assuming \na standard deviation of 22) and reduction in pain of this \nmagnitude is considered clinically significant. Data from \na UK endometriosis trial (PRE-EMPT ISRCTN97865475) \nshows a standard deviation (SD) of 19 (95% CI 16–22) in \nbaseline EHP-30 scores  [17]. Assuming an 8-point dif -\nference and a SD of 22, 160 participants are required in \neach treatment arm to detect that difference with 90% \npower and a two-sided 5% significance level. Assuming a \nmaximum of 20% loss of primary outcome data, 400 ran -\ndomised participants will be required. We acknowledge \nthat the variability in our outcome may be different to \nthat observed in the PRE-EMPT trial due to differences \nin the intervention; therefore, the ESPriT2 trial steering \ncommittee (TSC) will review blinded pooled EHP-30 \ndata and advise whether the sample size should be recon-\nsidered, if necessary.\nTable 2 Trial composite questionnaires can be completed in person, via telephone, via post or via online link (*). Follow-up outcome \nquestions are completed via a telephone call (**). Consent confirmed if initial consent was via telephone (***). NB: Longer term \nfollow-up not shown in this table as not funded at time of writing\nPhase Baseline Randomisation \n(day of surgery)\nDays 1–7 post‑\noperatively \n(± 1 week)\n30 days post‑\noperatively \n(± 1 week)\n3 months post‑\noperatively \n(± 2 weeks)\n6 months post‑\noperatively \n(± 2 weeks)\n12 months \npost‑operatively \n(± 2 weeks)\nConsent to trial x x***\nEligibility x x\nMedical history x\nPost-operative \npain diary\nx\nPost-operative \nphone call (com-\nplications)\nx\nTrial composite \nquestionnaires*\nx x x x\nFollow-up out-\ncome form**\nx x x\nAdverse events x\n\nPage 8 of 15Mackenzie et al. Trials          (2023) 24:425 \nRecruitment {15}\nWe will randomise 400 participants (200 per trial group). \nTo achieve this, we estimate we will need to consent \n1000–1200 participants (based on our experience of \nrecruiting to similar surgical endometriosis trials). Iden -\ntification of potentially eligible ESPriT2 participants will \noccur via three pathways. Potentially eligible participants \ncan be identified via gynaecology out-patient depart -\nments following a clinical decision to perform a diag -\nnostic laparoscopy for the investigation of chronic pelvic \npain. Alternatively, potentially eligible participants can be \nidentified from diagnostic laparoscopy waiting lists and \ninvited to participate, or individuals can self-refer after \nseeing trial promotional material.\nAssignment of interventions: allocation\nSequence generation {16a}\nEligibility will be confirmed at the time of laparoscopy \nfollowing a finding of SPE only. Participants will be ran -\ndomised in 1:1 ratio to either diagnostic laparoscopy \nalone or to concurrent surgical removal (ablation/exci -\nsion/combination of both) using a remote randomisation \nsystem provided independently by Edinburgh Clinical \nTrials Unit (ECTU). Randomisation will use a computer-\nbased randomisation system stratified using permuted \nblocks by the following important prognostic variables:\n• Presence of dysmenorrhoea (yes/no)\n• Pre-operative hormone treatment (yes/no)\n• Presence of dyspareunia (yes/no)\nConcealment mechanism {16b}\nThe participant’s intraoperative data will be entered into \na 24-h computerised central randomisation service by \nmeans of a secure web interface or by a telephone call to \nthe trial management team.\nImplementation {16c}\nThe ECTU randomisation service determines the treat -\nment allocation and will be given to the operating \nsurgeon. If the database is not available, emergency ran -\ndomisations will be performed by simple randomisation \nusing a computer-generated random number list pro -\nvided independently by ECTU. The allocation sequence \nwill be enclosed in sequentially numbered, opaque, \nsealed envelopes. Envelopes are opened by the research \nteam only after the enrolled participant has eligibility \nconfirmed, and the treatment allocation will be given to \nthe operating surgeon.\nAssignment of interventions: blinding\nWho will be blinded {17a}\nThis is a participant blind trial. Participants will be \ninformed of a diagnosis post-operatively but will not be \ninformed if surgical removal was carried out. All attempts \nwill be made to minimise the inadvertent unblinding of \nall trial participants. This will include providing tem -\nplates for operative findings and standardised discharge \nletters. The operation note will include only the operative \nfindings but not treatment allocation or details of surgi -\ncal removal (if applicable). These will be recorded within \nthe surgical case report form (SCRF) and will be added to \nthe individuals NHS records at the end of participation. \nParticipants’ general practitioners will not be informed \nof whether surgical removal of SPE occurred during the \ntrial period but will be informed when a diagnosis of SPE \nis made. Where feasible, the onward clinical management \nwithin secondary care will not be those who performed \nsurgery. The importance of maintaining blinding will be \nemphasised to all members of the surgical care team, e.g. \nanaesthetic staff, theatre, and recovery staff, etc.\nProcedure for unblinding if needed {17b}\nAt the end of 12  months of post-randomisation follow-\nup, participants will be given the option to be unblinded. \nAn unblinding facility will be available on the database. \nIf it becomes necessary to unblind a participant prior \n(e.g. at the participant’s request or for emergency pur -\nposes), they will need to contact the local principal \ninvestigator (PI) and local research team who will fol -\nlow the unblinding procedure on the trial database. \nThis will be documented on the database with the rea -\nson why the unblinding has taken place as well as the \ndate of the unblinding. Participants unblinded prior to \n12  months will still be requested to complete trial out -\ncome measures.\nData collection and management\nPlans for assessment and collection of outcomes {18a}\nTrial composite questionnaire\nThe trial composite questionnaire contains a range of \nvalidated patient-reported outcome measures. Responses \nto this questionnaire will be collected pre-operatively and \nthen at 3, 6 and 12 months post-operatively (see Table 2). \nIt can be completed in person, via telephone, via post or \nvia online link. The baseline and follow-up trial compos -\nite questionnaire will include:\n• Endometriosis Health Profile-30 (EHP-30) [14]\n\nPage 9 of 15\nMackenzie et al. Trials          (2023) 24:425 \n \no 30 question and five scale endometriosis ques -\ntionnaire (explained above)\n• Rome IV Criteria [18]\no Three questions to identify irritable bowel syn -\ndrome\n• Pelvic Pain and Urinary Frequency (PUF) Patient \nSymptom Scale [19]\no Eight-point scale about urinary patterns and \npain\n• PainDETECT.™ [20]\no 14-item questionnaire to identify neuropathic \npain\n• Brief Fatigue Inventory (BFI) [21]\no Six-item questionnaire correlated with stand -\nard quality of life measures assessing severity \nof fatigue and impact of fatigue on functioning \nover the previous 24 h\n• Pain Catastrophizing Questionnaire (PCQ) [22]\no 13-item scale, with each item rated on a 5-point \nscale. The PCQ is broken into three subscales \nbeing magnification, rumination, and helpless -\nness. The scale was developed as a self-report \nmeasurement tool that provided a valid index \nof catastrophising\n• Fibromyalgia Scale [23]\no Seven questions related to fibromyalgia symp -\ntoms\n• Measure Yourself Medical Outcome Profile 2 \n(MYMOP2) [24]\no Patient-generated outcome questionnaire\n• Work Productivity and Activity Impairment Ques -\ntionnaire (WPAIQ) [25]\no Questions related to the effect your health \nissues have on work and regular activities\n• EuroQol 5 Dimensions 5 Level Questionnaire (EQ-\n5D-5L) [26]\no Two-part questionnaire with the EQ-5D \ndescriptive system and the EQ visual analogue \nscale to assess patients’ health state in five \ndimensions: mobility, self-care, usual activities, \npain/discomfort and anxiety/depression\n• Capability Questionnaire (ICECAP-A) [27]\no Capability instrument for adults\nThe baseline and follow-up questionnaire differ \nwhere:\n1. The baseline questionnaire contains text prior to the \nEHP-30 as follows “This questionnaire asks about \n‘symptoms due to endometriosis. ’ We realise that you \ndo not know whether or not you have endometriosis \nso please try and ignore the references to endometri -\nosis and simply answer the questions focusing on the \nsymptoms. ”\n2. The questions in the MYMOP2 questionnaire are \nadapted in the follow-up questionnaires to account \nfor the fact that the participant needs to remember \nhow they answered this questionnaire at baseline.\nTrial follow‑up outcome form\nThe trial follow-up outcome form documenting analgesic \nuse, hormonal medication, pregnancy events and use of \nhealthcare services will be collected at 3, 6 and 12 months \npost-operatively via telephone by the research team. Par -\nticipants will also be asked about any impacts associated \nwith their condition on their work, caring responsibilities \nor other usual activities (e.g. education).\nSurgical case report form\nFollowing laparoscopy, the surgeon will complete a surgi-\ncal case report form (SCRF) detailing information about \nthe operation. For all participants this will be:\n• Grade of surgeon and whether they self-identify as an \nadvanced laparoscopic surgeon\n• Diagnosis of endometriosis subtype (SPE, ovarian \nendometrioma, deep)\n• Ovarian cyst present that requires removal\n• Confirmation of eligibility to be randomised\n• Details of SPE (location, number and appearance of \nlesions)\n• Details of other findings (fibroids, adhesions, perito -\nneal pockets)\n• Hysteroscopy/cystoscopy taking place during lapa -\nroscopy (yes/no)\n• Pathology results if endometriosis is removed or \ndeep disease or endometrioma found\nFor all randomised participants:\n• Details of any tubal dye tests performed\n• Duration of surgery\n• Concurrent intrauterine system/device insertion\n\nPage 10 of 15Mackenzie et al. Trials          (2023) 24:425 \n• Number and location of accessory ports, not includ -\ning optical port.\n• Intraoperative complications (e.g. uterine perfora -\ntion, anaesthetic complication, injury to surrounding \nanatomy, haemorrhage, and laparotomy)\n• Details of images captured for diagnosis\nFor randomised participants allocated to surgical \nremoval of SPE:\n• Type of removal will be recorded (excision, ablation \nor combined)\n• Details of images captured showing any removal\n• Subjective assessment of whether or not complete \nremoval was achieved (and reasons for this)\n• Histological result if SPE excised and sent for histo -\nlogical assessment\nThe SCRF includes a specific set of pre-determined \nimages. For the diagnostic laparoscopy, this is a stand -\nard panel of images of the pelvis which include the uter -\novesical fold, pouch of Douglas and right and left ovarian \nfossa. If allocated to surgical removal, the type of surgi -\ncal removal will be documented, and an assessment of \nthe adequacy of removal and images of treated areas will \nbe performed. Three independent clinicians will assess \nthese images, blind to operating surgeon’s classification, \nto reduce the likelihood of misclassification and complete \nan electronic surgical verification form detailing extent of \nendometriosis and adequacy of removal (if carried out).\nPost‑operative diary\nParticipants will be asked to complete a diary of analgesic \nuse and numerical rating score for worst and average pel-\nvic pain on days 1 to 7 post-operatively.\nPost‑operative form\nA post-operative form (part of the electronic data col -\nlection form (DCF) will be completed detailing com -\nplications up to 30  days post-operatively. This will be \ncompleted by the clinical research team, utilising infor -\nmation gained by a phone-call to the patient and cor -\nrelated with the participant’s hospital record. Specific \ncomplications include urinary retention, unintended \novernight stay, haemorrhage, transfusion, pelvic haema -\ntoma, visceral injury (bowel, bladder, ureteric), infection \n(urinary, chest, wound, pelvic abscess, other), venous \nthromboembolism, fistula, hernia, return to theatre, \nreadmission, ITU admission and death. Any report -\nable adverse events (AE) will be collected up to 30 days \npost-operatively.\nData collection form\nAt baseline, the following personal data will be collected \nfrom trial participants in the data collection form (paper \nor electronic via a secure web interface to the trial data -\nbase): name, NHS number or community health index \nnumber (Scotland only), unique hospital number, email \naddress, telephone number, home address, ethnicity and \nyear of birth. On the day of randomisation, an electronic \nDCF will be completed by a member of trial team and \nwill include current analgesic use, current hormone use, \nvisits to primary and secondary care providers, postcode \nto determine deprivation index, clinical pregnancy test \nresult, future fertility intent, occupation and education, \npresence of dysmenorrhea (yes/no), presence of dyspare -\nunia (yes/no) and presence of cyclical pain without men -\nses (yes/no).\nPlans to promote participant retention and complete \nfollow‑up {18b}\nParticipant retention strategies include flexibility in data \ncollection method and timing. Participants can provide \ndata in person or using telephone, online or postal meth -\nods with a 2–4-week window provided around each point \nof follow-up. Support is available from a clinical research \nnurse via telephone if a participant may experience dis -\ntress when completing the trial questionnaires.\nData management {19}\nElectronic data will be stored on University of Edinburgh \nsecure server which is password protected and access \nis limited according to trial role. The participant’s email \naddress will be kept securely on the trial database for \nthe purposes of follow-up. Data from the trial composite \nquestionnaire, trial follow-up outcome form (DCF), post-\noperative form, and SCRF will be uploaded and stored on \na secure database. Personal data will be stored for a mini-\nmum of 5 years by the research team in a locked cabinet \nwith limited access in research offices in all centres. Sur -\ngical digital images will be anonymised and uploaded. If \nprint out images are only available, these will be scanned \nand then uploaded via the secure web interface.\nThe University of Edinburgh and NHS Lothian are joint \ndata controllers. Any data breaches will be reported to the \nUniversity of Edinburgh and NHS Lothian Data Protection \nOfficers who will onward report to the relevant authority \naccording to the appropriate timelines if required.\n\nPage 11 of 15\nMackenzie et al. Trials          (2023) 24:425 \n \nConfidentiality {27}\nAll evaluation forms, reports and other records will be \nidentified in a manner designed to maintain participant \nconfidentiality. All records will be kept in a secure storage \narea with limited access. Clinical information will not be \nreleased without the written consent of the participant. \nThe investigator and trial site staff involved with this trial \nmay not disclose or use for any purpose other than per -\nformance of the trial, any data, record or other unpub -\nlished information, which is confidential or identifiable, \nand has been disclosed to those individuals for the pur -\npose of the trial. Prior written agreement from the spon -\nsor or its designee must be obtained for the disclosure of \nany said confidential information to other parties.\nPlans for collection, laboratory evaluation and storage \nof biological specimens for genetic or molecular analysis \nin this trial/future use {33}\nParticipants consented to ESPriT2 will be offered \nthe option of providing a venous blood sample \n(approximately 55  ml) for a separate biomarker study \n(ESPriT +). Standard processes regarding collection \nand processing of the samples will used by each partici -\npating site. Blood samples (serum and plasma) will be \nfrozen and stored locally and then sent via a specialised \ncourier to the trial management team within the Uni -\nversity of Edinburgh. Part of the blood samples will be \nsent with consent to Roche Diagnostics, Penzberg, Ger -\nmany, and part of the blood samples will be retained \nby the University of Edinburgh for future ethically \napproved studies. All samples will be coded and will \nonly be identifiable via a unique participant number.\nStatistical methods\nStatistical methods for primary and secondary outcomes \n{20a}\nAnalyses will primarily be intention-to-treat where all \nrandomised participants will be included in the analysis \nretained in the group to which they were allocated and \nfor whom outcome data are available. All results will be \npresented as point estimates, 95% confidence intervals \nwith associated p -values. We will specify all analyses to \nbe undertaken in a statistical analysis plan to be final -\nised before database lock.\nPrimary outcome analysis\nThe primary outcome, pain domain of the EHP-30 at \n12  months, will be compared using a linear regression \nmodel to estimate the mean difference in outcome, includ-\ning fixed effect terms for surgical removal group, baseline \npain score and stratification variables. Unadjusted results \nwill also be presented to support the findings of the pri -\nmary analysis. Secondary analyses will include using \nrepeated-measures (multi-level) models incorporating \noutcome data from other follow-up time points.\nSecondary outcome analysis\nA similar approach to the primary analysis will be used for \nanalyses of the other secondary outcomes, using an appro-\npriate (depending on outcome type) regression model.\nEconomic analysis\nAn economic evaluation will be conducted using trial \ndata based on the primary economic outcome of cost \nper quality-adjusted life year (QALY) gained, with a \nsecondary analysis of cost per clinically significant \nchange in symptom score at 12 months (using EHP-30). \nThe primary perspective adopted will be an NHS and \npersonal social services perspective, but a wider soci -\netal perspective will also be pursued using trial data \nabout impact on work productivity. The NHS resource \nuse collected will include secondary care costs related \nto surgery, length of stay and complications/readmis -\nsions as well as primary care and other healthcare costs. \nIf the trial demonstrates that laparoscopic removal is \neffective in the management of SPE, longer term costs \nand outcomes will be assessed as part of a decision-\nanalytic model.\nThe primary analysis will be in the form of a cost-\nutility analysis using the EQ-5D-5L instrument (col -\nlected at baseline, 3 months, 6 months and 12 months) \nplus data on costs and resource use collected in the \ntrial. For the cost-utility analysis, we will evaluate the \ncost per QALY gained at 12 months. A secondary anal -\nysis will use the EHP-30 (using the same approach as \nadopted for the clinical analysis) and evaluate the cost \nper clinically significant change in symptom scores at \n12 months. For those allocated to surgical removal, the \nprimary outcome data will be summarised by the surgi -\ncal approach (excision, ablation, or combined). A range \nof sensitivity analyses will be conducted to explore the \nimpact of uncertainty on the results.\nInterim analyses {21b}\nFor the internal pilot, we will use stop–go criteria based \non a Green-Amber-Red statistical approach includ -\ning sites recruiting over the first 18 months. Assuming \neach centre month follows an independent identically \ndistributed Poisson distribution with mean 0.33 and an \nexpected randomisation of 54 participants by the end \nof month 18, we will use the following stop–go criteria.\n• ‘Green’ will be within 1 standard deviations of 54, \ni.e. if we have randomised 46 or more with an aver -\n\nPage 12 of 15Mackenzie et al. Trials          (2023) 24:425 \nage rate per centre per month of 0.28 we will con -\ntinue unchanged.\n• ‘ Amber’ will be within 1–4 standard deviations, i.e. \nif we randomise between 24 and 46 with an aver -\nage rate per centre per month of 0.12, then we will \nmodify (export identified best practice from best \nrecruiting sites; and/or more sites; and/or more \nrecruitment time).\n• ‘Red’ will be if we randomise less than 24 then con -\nsideration will be given to stopping the trial, includ -\ning discussions with the funder (NIHR/HTA).\nMethods for additional analyses (e.g. subgroup \nanalyses) {20b}\nSubgroup analyses\nWe will perform the following sub-group analysis of the \nprimary outcome, and test for sub-group interactions if \nappropriate:\n• Dysmenorrhoea (yes/no)\n• Dyspareunia (yes/no)\n• Use of hormones (yes/no)\n• Extent of disease (< 1  cm2, 1–3  cm2 and > 3 cm.2)\n• Neuropathic pain (PainDETECT. ™) defined by a \nscore of ≥ 19\nExploratory analyses\nIn addition, for those allocated to surgical removal, the \nprimary outcome data will be summarised descriptively \nby the surgical approach (excision, ablation, or com -\nbined). These analyses will be exploratory only, reflect -\ning that the modality of SPE removal is the choice of \nthe operating surgeon rather than randomised. Con -\nsequently, the three groups (excision, ablation or com -\nbined) are likely to be imbalanced with regard to size, \npatient characteristics and other confounding factors. \nThey will also be of insufficient size to draw conclusions \nof relative efficacy between excision and ablation.\nMethods in analysis to handle protocol non‑adherence \nand any statistical methods to handle missing data {20c}\nThe trial sample size calculation accounts for a loss of \n20% of primary outcome data. A sensitivity analysis \nusing imputation of missing values will be considered \nonly if the proportion of cases with missing values is \nsufficiently large.\nPlans to give access to the full protocol, participant‑level \ndata and statistical code {31c}\nThe datasets, including participant-level data gener -\nated during the current trial, will available via the \ncorresponding authors 6 months following publication \nof the trial results.\nOversight and monitoring\nComposition of the coordinating centre and trial steering \ncommittee {5d}\nDuring development of the trial, a trial management \ngroup (TMG) was established to oversee and lead the \ntrial. The TMG includes academic gynaecologists, \nresearch nurses, a clinical trials manager, a methodolo -\ngist and a blinded and unblinded statistician. The TMG \nmeets monthly. An independent TSC was established \nto provide oversight of trial conduct and progress. The \ntrial steering committee meets 12 monthly and includes \nsix members (gynaecologists, trialists and a patient and \npublic involvement representative).\nComposition of the data monitoring committee, its role \nand reporting structure {21a}\nAn independent data monitoring and ethics commit -\ntee (DMEC) of three experienced trialists and stat -\nisticians has been established to oversee the safety \nof participants in the trial. The DMEC will regularly \nreview data on the outcomes and adverse events along \nwith updates on results of other related studies and \nany other analyses that the DMEC may request. If the \nopinion of the DMEC is that one treatment is defi -\nnitely more or less effective that the other, they will \nadvise the chair of the TSC. The Trial office will for -\nward DMEC open meeting minutes to the sponsor and \nfunder.\nAdverse event reporting and harms {22}\nParticipants will be asked about the occurrence of AEs \nrelated to their surgery or related to any new medical \ntherapies taken for treatment of their pelvic pain started \nfrom the day of laparoscopy. These will be recorded by \nthe research teams during the 30-day follow-up phone \ncall. No adverse events will be recorded for any pre-exist-\ning or unrelated conditions. No adverse events will be \ncollected after 30  days post-operatively. No serious AEs \nwill be reported to the sponsor. Any common anticipated \nevents, e.g. surgical complications, which are collected as \ndata on the DCF do not need to be recorded as AEs to \nreduce duplication of data.\nFrequency and plans for auditing trial conduct {23}\nThis trial is co-sponsored by The University of Edinburgh \nand NHS Lothian. The Academic and Clinical Central \nOffice for Research & Development (ACCORD) spon -\nsor representative risk assessment, if required, will deter -\nmine if audit by the ACCORD quality assurance group is \n\nPage 13 of 15\nMackenzie et al. Trials          (2023) 24:425 \n \nrequired. Should audit be required, details will be cap -\ntured in an audit plan. Audit of investigator sites, trial \nmanagement activities and trial collaborative units, facili-\nties and third parties may be performed.\nPlans for communicating important protocol amendments \nto relevant parties (e.g. trial participants, ethical \ncommittees) {25}\nAny changes in research activity, except those necessary \nto remove an apparent, immediate hazard to the par -\nticipant in the case of an urgent safety measure, will be \nreviewed and approved by the chief investigator. Amend-\nments will be submitted to a sponsor representative for \nreview and authorisation before being submitted in writ -\ning to the appropriate research ethics committee and \nlocal R&D offices for approval prior to participants being \nenrolled into an amended protocol.\nDissemination plans {31a}\nResults from this trial will be shared through publica -\ntion in a high-impact open access peer-reviewed journal \npublication and presented at international conferences. \nResults will be shared through professional bodies, such \nas the British Society for Gynaecological Endoscopy. \nFindings will be disseminated to the public via organisa -\ntions such as Endometriosis.org and Endometriosis UK \nand published on the Chief Investigators institutional \nwebpages (www. exppe ctedi nburgh. co. uk).\nDiscussion\nThis trial aims to generate high-quality data to inform \nclinical practice on the clinical and cost-effectiveness of \nsurgically removing isolated SPE in women with chronic \npelvic pain. Regardless of trial outcome, we believe the \ndata collected will contribute significantly to support -\ning women in informed decision-making regarding their \nindividual endometriosis treatment options.\nWe appreciate that there may be recruitment difficulties \nencountered in this trial, due to preconceived ideas about \nsurgical outcomes amongst both patients and clinicians fol-\nlowing surgical management of SPE, e.g. that ‘excisional’ \nlaparoscopic surgery is curative. Similar preconceived ideas \nregarding treatment outcomes have been observed to act \nas barriers to recruitment in other surgical RCTs with pla-\ncebo arms, even when evidence supporting existing surgical \npractice is poor [28]. However, we were reassured, during \nthe trial planning, that most UK endometriosis surgeons \nrecognized the poor evidence base for ablation or excision \nof SPE for the treatment of pelvic pain [29]. Of the surgeons \nwho responded to our survey (n = 88), 81% considered a trial \nto be required, and 73% were willing to participate. When \nwomen with chronic pelvic pain (n = 1218; 98.8% of whom \nhad endometriosis) were surveyed: 20% said they ‘definitely \nwould’ and 26% said that they ‘would likely participate’ in our \nclinical trial.\nWe also acknowledge that we will need to recruit and \nconsent between 2- and threefold more women (esti -\nmated to be 1000–1200) to facilitate our randomisation \ntarget of 400 women. In addition, we appreciate that we \ncannot control the time between consent and date of sur-\ngery (day of randomisation). Most notably, restructuring \nof service provision and de-prioritisation of non-emer -\ngency gynaecological operating in the UK following the \nCOVID-19 pandemic has seen waiting times for diagnos -\ntic laparoscopy grow significantly [30, 31].\nIn summary, this multi-centre participant-blind par -\nallel-group randomised controlled trial represents an \nimportant step towards the improved understanding of \nthe role of surgical removal of SPE in the management of \nendometriosis-associated pain.\nTrial status\nRecruitment began on 1 April 2021 and is estimated to \ncomplete on 30 January 2024. At the time of initial man -\nuscript submission, 45 sites are recruiting, 382 partici -\npants have been consented and 89 participants have been \nrandomised. Current protocol version is 4.0.\nAbbreviations\nACCORD  Academic and Clinical Central Office for Research and \nDevelopment\nCI  Confidence interval\nBFI  Brief Pain Inventory\nDCF  Data collection form\nDMEC  Data monitoring and ethics committee\nECTU   Edinburgh Clinical Trials Unit\nEHP-30  Endometriosis Health Profile-30\nESHRE  European Society of Human Reproduction and Embryology\nESPriT2  Effectiveness of laparoscopic removal of isolated superficial peri-\ntoneal endometriosis for the management of chronic pelvic pain \nin women\nEQ-5D-5L  EuroQol 5 Dimensions 5 Level Questionnaire\nHTA  Health Technology Assessment\nITT  Intention-to-treat\nMYMOP2   Measure Yourself Medical Outcome Profile 2\nNICE  National Institute of Health and Care Excellence\nNIHR  National Institute of Health and Care Research\nNHS  National Health Service\nPCS   Pain Catastrophizing Scale\nPI  Principal investigator\nPUF  Pelvic Pain and Urinary Frequency (Patient Symptom Scale)\nSPE  Superficial peritoneal endometriosis\nTMG  Trial management group\nTSC  Trial steering committee\nQALY  Quality-adjusted life year\nWPAIQ  Work Productivity and Activity Impairment Questionnaire\nAcknowledgements\nWe wish to acknowledge patient and public involvement group who contrib-\nuted to trial design, development and delivery and the TSC and DMEC for their \ncontribution to trial oversight. Medical Research Council (MRC) Centre grant \nto the Centre for Reproductive Health (CRH) (MR/N022556/1) is also gratefully \nacknowledged.\n\nPage 14 of 15Mackenzie et al. Trials          (2023) 24:425 \nAuthors’ contributions {31b}\nSCM drafted the manuscript. All authors contributed to the trial design. JS, \nLW and JN wrote the statistical plan for the trial. All authors read, critically \nreviewed and approved the final manuscript.\nAuthors’ information (optional)\nCMB is the Chair of the ESHRE Endometriosis Guideline Group and a member of \nthe NICE Endometriosis Guideline Group and a medical advisor to Endome-\ntriosis UK. DB was a member of the NICE endometriosis guideline group. YC \nwas a member of ESHRE endometriosis guideline group. EC is an employee of \nEndometriosis UK. JH was a member of the NICE endometriosis guideline group. \nLH is the EPHect programme manager for the World Endometriosis Research \nFoundation and acts as an advisor for the Horizon 2020 funded FEMaLe project. \nKK is the former chair of the Endometriosis Association of Ireland. DCM is a \nretired gynaecologic surgeon; the volunteer Scientific and Medical Director \nof EndoFound (Endometriosis Foundation of America), a 501(c) (3) non-profit \nthat funds research of endometriosis; an otherwise non-affiliated community \nmember of the Institutional Review Board of the Virginia Commonwealth Uni-\nversity; Professor Emeritus, the University of Tennessee Health Science Center; \nan unpaid medical advisor to SLBST Pharmaceuticals and Genomic Profiling \nLLC; and on the editorial board of five medical journals. KV is a Medical Advisor \nto Endometriosis UK. AWH is Trustee and Medical Advisor to Endometriosis UK. \nAWH was a member of the NICE and ESHRE Endometriosis Guideline Groups. \nLHRW is a member of the Early Career Board, World Endometriosis Society.\nFunding {4}\nThis study is funded by the NIHR Health Technology Assessment programme \n(NIHR129801). The views expressed are those of the author(s) and not neces-\nsarily those of the NIHR or the Department of Health and Social Care.\nAvailability of data and materials {29}\nThe datasets, including anonymised patient-level data generated during the cur-\nrent trial, will be available via the corresponding authors 6 months following publi-\ncation of the trial results. Requests will be assessed for scientific rigor prior to secure \ndata transfer and a data sharing agreement may be required. Further requests for \naccess to the blood sample biobank will be considered by the sponsor.\nDeclarations\nEthics approval and consent to participate {24}\nEthical approval for this trial was obtained on 27 January 2021 from the East \nof Scotland Research Ethics Committee (NHREC 20/ES/0127). Written or verbal \n(where participants are consented via telephone/video call) informed consent \nto participate will be obtained from all participants.\nConsent for publication {32}\nThe model consent form for this trial is available from the corresponding \nauthor upon reasonable request.\nCompeting interests {28}\nCMB has received research funding from Bayer Healthcare and has done con-\nsultancy for Myovant, ObsEva, Gedeon Richter and Theramex. YC has received \nhonoraria for medical advisory from Merck, Ferring, Nordic Pharma and Abbot \nand research funding from Merck and Geurbet. AM has received funding to \nattend meetings and honoraria for speaking at educational events by Ferring, \nMerck, Cook Medical, Geodeon Ricter and Pharmasure. DCM has received \nlegal expert witness fees from Lowenthal & Abrams, P .C. (Bala Cynwyd, PA) and \nfunding to attend annual scientific meetings by EndoFound (Endometriosis \nFoundation of America) and the American Society of Reproductive Medicine \n(ASRM) as the 2022 recipient of the Society of Reproductive Surgeons (SRS) \naward recipient (a monetary award by the ASRM accompanied the SRS \naward). KV has received research funding from Bayer Healthcare and honoraria \nfor consultancy for Bayer Healthcare, AbbVie, Eli Lilly and Reckitts. AWH has \nreceived honoraria for consultancy for Roche Diagnostics and Gesynta. AWH \nand LHRW have received research funding from Roche Diagnostics. SCM, \nKV, AWH and LHRW are listed as co-inventors on a UK Patent Application \n(No. 2217921.2) relating to the use of a genetic test to determine efficacy of \ngabapentin for chronic pelvic pain treatment. The other authors declare no \nconflict of interest pertaining to this manuscript.\nAuthor details\n1 MRC Centre for Reproductive Health, University of Edinburgh, Edin-\nburgh EH16 4TJ, UK. 2 Edinburgh Clinical Trials Unit, Usher Institute, University \nof Edinburgh, NINE, Edinburgh BioQuarter, Edinburgh EH16 4UX, UK. 3 Not-\ntingham Clinical Trials Unit, University of Nottingham, Nottingham NG7 2RD, \nUK. 4 Endometriosis CaRe, Nuffield Department of Women’s and Reproductive \nHealth, University of Oxford, Oxford OX3 9DU, UK. 5 Royal Cornwall Hospitals \nNHS Trust, Truro, UK. 6 Faculty of Medicine, Human Development and Health, \nUniversity of Southampton, Southampton, UK. 7 Birmingham Women’s \nand Children Hospital, Birmingham B15 2TG, UK. 8 NHS Grampian, Aberdeen \nRoyal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK. 9 Endometriosis UK, Lon-\ndon, UK. 10 Corniche Hospital, Abu Dhabi, United Arab Emirates. 11 Guys and St \nThomas NHS Trust, London, UK. 12 Endometriosis.org, London, UK. 13 University \nof Birmingham, Birmingham, UK. 14 Letterkenny, Ireland. 15 Aberdeen Fertility \nCentre, NHS Grampian, Aberdeen, UK. 16 Department of Obstetrics and Gyne-\ncology, University of Tennessee Health Science Center, Memphis, TN, USA. \n17 Virginia Commonwealth University, Institutional Review Board, Richmond, \nVA, USA. 18 EndoFound (Endometriosis Foundation of America), New York, USA. \n19 University of Nottingham, Nottingham, UK. 20 Southmead Hospital, North \nBristol NHS Trust, Bristol BS10 5NB, UK. \nReceived: 21 April 2023   Accepted: 18 May 2023\nReferences\n 1. 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