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)

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? 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. 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. 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. 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. 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. 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. 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). 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.