Title: Recurrence of Endometriosis: a randomised controlled trial of clinical and cost effectiveness of Gonadotrophin Releasing Hormone Analogues with add back hormone replacement therapy versus repeat Laparoscopic surgery (REGAL trial)
Funder: Chief Scientist Office, Scotland

Abstract: Endometriosis is a common condition which affects one in ten women from puberty to menopause. It causes pelvic pain, poor quality of life and reduced work productivity. It occurs when cells similar to those lining the womb grow outside it, generally within the pelvis. These cells behave like the cells lining the womb, causing internal bleeding at the time of periods, scarring and pain. Endometriosis depends on the female hormone oestrogen (produced by the ovaries) for growth, and symptoms improve after menopause due to lack of oestrogen._x000D_ The condition is diagnosed by laparoscopy (key hole surgery) to identify areas of endometriosis which can be destroyed or removed to treat pain. Surgery may not provide lasting relief and pain can return in up to half of treated women within five years. To reduce the chance of regrowth of endometriosis and recurrence of pain, following surgery women who are not trying to get pregnant are offered the combined oral contraceptive pill or other contraceptives containing hormones called progestogens._x000D_ Despite surgery and hormonal contraceptives, about two in three women will require further surgery to treat pain due to endometriosis that has come back. Repeat surgery is invasive, expensive and risky, without guaranteeing a cure. Removing the ovaries (often along with the womb) provides the best chance of pain relief and least chance of more operations but is not an option for many premenopausal women with endometriosis. _x000D_ Taking away the ovaries switches off the supply of oestrogen necessary for endometriosis tissue growth. A less invasive way of shrinking endometriosis is to use a drug called gonadotrophin releasing hormone analogue (GnRHa) which temporarily stops the ovaries from producing oestrogen. While very effective in terms of reducing pain, this treatment is generally only used for 6 months to a year because of side effects such as hot flushes and night sweats caused by the lack of oestrogen, and concerns about osteoporosis (thinning of the bones). Recent research has shown that adding small doses of hormone replacement therapy (HRT) in women on GnRHa reduces the risk of side effects and osteoporosis whilst controlling the pain. An effective long-term non-surgical treatment for endometriosis has been identified as a research priority by patients and clinicians, but to date there have been no attempts to compare long-term use (more than 1 year) of GnRHa with HRT to further key hole surgery to treat endometriosis. _x000D_ We therefore propose a trial comparing long-term (2 years) GnRHa with added HRT to key hole surgery to destroy or remove endometriosis in women who experience recurrence of pain after endometriosis surgery but wish to preserve their fertility. We have assembled a team of experts including surgeons, trialists, statisticians, health economists and patient representatives to plan the research. _x000D_ Involvement of patients and the public, a key element of our proposal, has been achieved in partnership with the University of Aberdeen Public Interest Research Group, Endometriosis UK and an online survey of women with endometriosis. We have also developed a clear plan to share the results of this trial with GPs, hospital doctors, professional societies, patient support groups, NHS policy makers and patients. Our findings will be made available to stakeholders through national and international presentations, publication in medical journals and the website of the Bristish Society of Gynaecology Endoscopy and the national charity, Endometriosis UK.

Lay abstract: Research Question: Are long-term gonadotrophin releasing hormone analogues (GnRHa) with add back hormone replacement therapy (HRT) superior to repeat laparoscopic surgery for treatment of recurrent pain following previous surgical treatment of endometriosis? _x000D_ Background: Endometriosis is a chronic oestrogen dependent condition that affects 10% of women of reproductive age. It causes pelvic pain, psychological morbidity, poor quality of life and reduced work productivity. Women with pain due to suspected endometriosis are initially treated empirically with hormonal contraception (combined oral contraceptive pill, long acting reversible progestogen only contraceptives or progestogen tablets) but the diagnosis is confirmed by laparoscopy – generally combined with surgical ablation or excision of endometriotic lesions to treat pain. Following surgery, pain can recur in up to 50% of women, two thirds of whom have one or more further surgery including repeat laparoscopic surgery to excise or ablate endometriosis. In 20%, this involves removal of the ovaries (often along with the uterus) which reduces circulating oestrogen levels. This causes endometriotic lesions to shrink and appears to be the most effective way of treating pain. Removal of ovaries and/or hysterectomy is not an acceptable option for many women with endometriosis._x000D_ A non-surgical alternative is the use of GnRHa (drugs which reduce oestrogen to postmenopausal levels), which have been shown to control endometriosis associated pain and are currently used only for six to 12 months. Addition of a small amount of concomitant HRT can reduce side effects (vasomotor symptoms, osteoporosis) without reactivating pain. _x000D_ Aims and objectives: To evaluate clinical and cost-effectiveness of long-term GnRHa with add back HRT compared to repeat laparoscopic surgery in women with recurrence of pain after previous surgical treatment of endometriosis._x000D_ Methods: A randomised trial comparing GnRHa with add back HRT for two years versus repeat laparoscopic surgery to ablate or excise endometriosis (200 in each arm). Women aged 21-49 years with recurrence of pain after a previous laparoscopic surgery to treat endometriosis will be eligible. We will recruit from British Society of Gynaecology Endoscopy (BSGE) accredited endometriosis centres in the UK. _x000D_ Our primary patient outcome is the pain domain of Endometriosis Health Profile -30 questionnaire at 24 months. Primary economic outcome is incremental cost per QALY gained from a health service perspective. Secondary outcomes include safety, persistent symptoms, bone density (baseline, 12 and 24 months), need for further gynaecological medical or surgical intervention in the 2-year follow-up and modelled long-term cost effectiveness. _x000D_ A qualitative evaluation is embedded within the RCT to inform the delivery of the trial and facilitate problem solving. Analysis of audio-recordings from trial consultations, interviews with trial participants and site staff, and analysis of participant flow at sites will be integrated together to provide site directed feedback to help improve recruitment and retention across the trial._x000D_ Timelines for delivery: Trial set-up, 6 months, recruitment, 18 months, follow-up for 2 years (up to month 50), analysis, writing and dissemination 6 months (total 54 months). _x000D_ Anticipated impact and dissemination: If GnRHa are proven to be more effective and safer than repeat surgery, clinical uptake will be rapid as the intervention is inexpensive and less invasive. Results will be disseminated via Endometriosis UK, professional bodies (Royal College, BSGE) NHS and university websites, open access journals, clinical practice guidelines and presentations in relevant conferences.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH