Title: PRE-EMPT: Preventing Recurrence of Endometriosis by Means of long acting Progestogen Therapy
Funder: Chief Scientist Office, Scotland

Abstract: DESIGN: A randomised, pragmatic multicentre trial with integrated economic evaluation and investigation of patient experience with an internal pilot phase. SETTING: 20 NHS hospitals within the United Kingdom. TARGET POPULATION: Women of reproductive age, who are undergoing a laparoscopy to investigate whether their pelvic pain is due to endometriosis. Exclusion criteria: infertility, plans to conceive in the next 3 years. HEALTH TECHNOLOGIES ASSESSED: Randomisation to one of a) no hormonal treatment b) LNG-IUS (fitted by gynaecologist); c) 3 monthly depot medroxyprogesterone acetate (DMPA) injection (administered by the patient’s general practitioner); d) any combined oral contraceptive (COC) OUTCOMES: The primary outcome is the recurrence of symptoms as evaluated by the pain domain of the EHP-30 questionnaire at 36 months post-randomisation. The EHP-30 is a validated, responsive HRQOL measure for endometriosis. It will also be assessed prior to randomisation and at 6, 12 and 24 months. Secondary outcomes: -All other symptom and QoL domains of the EHP-30 -Non-menstrual pelvic pain and dysmenorrhea measured by 0-100 visual analogue (VAS) pain scale -Fatigue, as measured by Fatigue Severity Score11 -Menstrual regularity -Generic QoL (EQ-5D) and capabilities, as measure of wellbeing (ICE-CAP) -Further diagnostic and therapeutic surgery for endometriosis (as a proxy for recurrence) -Discontinuation rates of randomised treatment, with reasons for change, serious adverse events -Cost per QALY and cost per change in symptom score. -An increased knowledge of issues identified as important by the participants regarding their treatment and its impact on their lives PILOT: A pilot phase over the first nine months will be built into the study to fine-tune study procedures and case report forms and to assess the assumptions around the sample size calculation and recruitment rates. Flexible entry will be used during this period to assess women’s and clinicians acceptability to the four proposed treatment options. ANALYSIS: We will have up to six primary comparisons: DMPA, LNG-IUS and COC versus no treatment and each of DMPA, LNG-IUS and COC compared with each other. Analysis of the primary outcome for each comparison will be performed by analysis of covariance adjusting for baseline score. Standard statistical methods will be used for other outcomes. Effect sizes will be presented as point estimates and 95% confidence intervals. All analysis will be by intention to treat. SAMPLE SIZE: The study will be powered to detect 10 points difference between four groups for the pain domain of the EHP-30 with 80% power, or between three groups at 90% power. This would require 100-133 per group but to allow for multiple testing - as we have potentially six primary comparisons - this has been inflated to 148-188 per group (type I error reduced to 0.01 from 0.05). To also allow for up to 20% loss to follow-up at 3 years, our overall recruitment target will be 750 women in total. 750 women would be enough to detect similar size differences in other secondary outcomes measured on a continuous scale.

Lay abstract: Endometriosis is a common condition where cells similar to those within the lining of the womb are found in abnormal locations elsewhere in the body, commonly within the pelvis. Like the lining of the womb itself, these cells respond to oestrogen produced by the ovaries and go through a phase of growth followed by breakdown and bleeding. This internal bleeding within the pelvis causes inflammation, the formation of scar tissue (adhesions) and is associated with pain. Endometriosis occurs in 6-10% of women of reproductive age. The condition is painful and can have a serious impact on their lives. Many will need surgery to remove areas of endometriosis in order to relieve pain. However, symptoms of endometriosis tend to return and women need to go through repeated surgery including removal of their womb and ovaries. Endometriosis costs the UK >£2.8 billion/year in loss of productivity mainly due to associated pelvic pain symptoms. Drugs which reduce levels of oestrogen can prevent the re-growth of endometriosis. Previous research has suggested that medicines containing other hormones such as progestogens can reduce the chances of symptoms returning. However, these studies were done with small numbers of participants and were unable to provide definitive results. We now wish to carry out a large randomised controlled clinical trial in which women undergoing surgery for endometriosis will be randomly allocated to take long acting progestogens (either as three monthly injections or as an intra-uterine device (coil), or long term treatment with the oral contraceptive pill or no treatment. The trial will provide information on which treatment is the most effective in terms of symptom relief, side-effects, acceptability and costs. This information will be vital in terms of future clinical decision making in an area of uncertainty.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH