Title: A Multicentre Randomised Controlled Trial of Induced Endometrial Trauma In Women Undergoing First Time In Vitro Fertilisation (IVF)
Funder: Department of Health and Social Care

Abstract: DESIGN:Multi-Centre,Parallel Group,RCT SETTING:10 NHS Assisted Conception Units(ACUs) POPULATION:Women attending ACUs for 1st time IVF treatment. Inclusion Criteria: Women <=37 years;Expected to receive IVF treatment using antagonist protocol;1st time IVF/ICSI treatment;Ovulatory menstrual cycle;No endometrial abnormalities;Blastocyst transfer expected. Exclusion Criteria: Single embryo transfer not anticipated;BMI= 35 kg/m2;Known grade 4 endometriosis;Significant medical condition/abnormality;Participating in study involving medical/surgical intervention/deviation from standard IVF/ICSI. INTERVENTIONS:Participants allocated on ratio of 1:1 using web-based randomisation system,stratified by site to 1)Endometrial scratch(ES)in the midluteal phase of the cycle prior to starting IVF treatment(n=522); 2)Treatment as Usual(n=522). INTERNAL PILOT: Set up and recruit at 4 centres for 6 mths to assess feasibility of recruitment. Progression Criteria, min 108 randomised (75% of target, 1-2 per week per site, max expected 144) OUTCOMES: Primary Outcome:Live birth rate(LBR)-birth of a living fetus after completed 20wks gestation Secondary outcomes: Implanation rate Clinical pregnancy rate,observation of viable intrauterine pregnancy with a positive heart pulsation seen on ultrasound at/after 8wks gestation Ectopic pregnancy rate-visualisation of pregnancy sac outside endometrial cavity on ultrasound or laparoscopy. Miscarriage rates,spontaneous pregnancy loss prior to 20wks gestation Preterm delivery rate,live birth after 20wks before 37wks gestation Still birth rate,delivery of a still born fetus showing no signs of life after 20wk gestation Multiple birth rate-birth of more than one living foetus after completed 20 weeks gestation Health & Wellbeing assessed at baseline, 9/10 months Resource use,cost effectiveness Adverse Events SAMPLE SIZE:Assuming 30% LBR in the control group and that an absolute increase of 10%,to 40% LBR in the intervention groups is of clinical & practical importance. Then to have a 90% power of detecting this difference or more,in LBR rates between the groups,as statistically significant at the 5% two-sided level, will require 496 women per group (992 total).Adjusting for predicted drop-out rate of 5%(due to anticipated difficulties of follow-up for patients referred from other NHS Trusts)we will require 1044 participants. ANALYSIS:The statistical analysis will be performed on an intention-to-treat basis & reported according to CONSORT guidelines. The primary binary outcome,the LBR,will be compared between the 2 groups(Endometrial scratch treatment and treatment as usual) using a Chi-squared test.A 95% confidence interval for the difference in LBR between the groups will also be calculated.The health economic analysis will present costs per extra live birth of endometrial scratch versus treatment as usual from an NHS and social care perspective. TIMETABLE: 58 mth project,Dec 2015-Sep 2020: 7mths set-up;30mths recruitment(including 6mth internal pilot);3mth intervention;12mth follow-up;6mth close-out,analysis & write-up.Recruitment window based on availability of eligible participants at 10 ACUs & adjusted for capacity to perform ES procedure/likely refusal rate(assuming achievable consent rate of 2pts/week in large units, 1 in small units) EXPERTISE:Multi-disciplinary team including clinical experts from ACUs,methodological expertise in Statistics,Health Ec & Registered CTRU

Lay abstract: Taking a small amount of tissue from the lining of the womb (endometrium) can sometimes improve the chance of achieving a pregnancy in women who have previously had several unsuccessful attempts at In Vitro Fertilisation (IVF). This procedure has been named “endometrial scratch”(ES). It is not known exactly why performing an Endometrial Scratch may be beneficial, but it is thought that the process of “scratching” the lining of the womb may release certain chemicals that are important in helping the fertilised egg (embryo) stick to the lining of the womb (implantation). The use of Endometrial Scratch has not yet been fully tried in women who are about to have IVF for the first time. If found to be beneficial then it could be used to improve the chance of achieving a pregnancy for a large group of women without the need for repeated IVF attempts. Our study aims to explore the use of performing an Endoemtrial Scratch in younger women (37yrs of age or younger) about to start their first IVF treatment cycle. The study will involve 1044 participants over the course of two & half years. Women taking part in the study will be selected to have either the scratch or not in a random way (like a tossing a coin) so each woman would have a 50/50 chance of having the scratch procedure. Those having the scratch would be known as the “study group” and those who do not the “control group”. Both groups would then have their IVF treatment in the usual way and would be followed up to see whether or not they get pregnant and have a healthy baby. Except for one extra visit when the scratch is performed, the study does not involve any other visits or treatments above normal routine care. Participation in this study will be entirely voluntary and the choice not to participate would not have any impact on the woman’s care. Performing the emdometrial scratch is a very simple routine outpatient procedure that does not require any anaesthetic. Women are advised to take some simple painkillers beforehand (such as paracetamol) as these should lessen the chance of any discomfort as the procedure can sometimes cause period like cramps. The procedure involves placing a small tube (about the size of a small drinking straw) through the neck of the womb and then the lining of the uterus (the endometrium) is gently ‘scratched’. There will be a small sub-study performed in only in Sheffield where consent will be sought to remove a small amount of tissue from the lining of the womb. This tissue will be stored and later examined in the laboratory which could provide helpful information to tell us why some women may respond better than others to the scratch procedure. Performing the Endometrial Scratch has no clear risks although, in theory, inserting any instrument into the womb could carry a risk of infection. However all women having IVF are routinely screened for important vaginal infections before starting their IVF treatment. The Endometrial Scratch procedure is performed about a week before starting IVF treatment. The study will involve collaboration with 10 units across the UK. Each Unit will have a designated person responsible for the safe running of the study(Principle Investigator) but the overall conduct of the study will lie with the Chief Investigator at the lead site. By the end of the study we hope to be able to tell whether or not endometrial scratch should be offered routinely to women having their first IVF treatment cycle.

Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH