Endometrial receptivity enhancement through induced injury and repair during ovarian stimulation: the Receptivity Enhancement by Follicular-phase Renewal after Endometrial ScratcHing (REFRESH) trial protocol.

study questionDoes intentional endometrial injury (i.e. endometrial scratching) during ART enhance pregnancy rates? SUMMARY ANSWER: We propose a randomized controlled clinical trial in women performing ART in which the intervention group will undergo an additional endometrial biopsy during exogenous ovarian stimulation. WHAT IS KNOWN ALREADY: Although endometrial receptivity has been extensively studied, the mechanisms behind the implantation of an embryo remain largely a mystery. Intentional endometrial injury has been put forward by many researchers as an inexpensive clinical tool capable of enhancing endometrial receptivity. However, despite its widespread use, the benefit of endometrial scratching is still a contentious and unresolved issue. STUDY DESIGN SIZE DURATION: Pragmatic two-arm randomized, single-centre, controlled open-label trial in women undergoing exogenous gonadotropin ovarian stimulation for ART followed by a fresh embryo transfer in a gonadotropin-releasing hormone antagonist suppressed cycle. The trial will include 360 women in total with a 1:1 allocation ratio and an expected total duration of up to 45 months. PARTICIPANTS/MATERIALS SETTING

methodsSubjects in the intervention group will undergo an endometrial biopsy during the follicular phase, on the sixth to eighth day of exogenous stimulation. Furthermore, nested within this clinical trial, we will also evaluate whether the transcriptomic signatures of the material collected during the biopsy may accurately distinguish women who become pregnant from those who do not. These endometrial transcriptomic signatures will be assessed both immediately after the biopsy and following MAIN RESULTS AND THE ROLE OF CHANCE: Our primary objective is to assess the effect of endometrial injury during exogenous gonadotropin ovarian stimulation on clinical pregnancy rates after ART. Secondary efficacy and safety outcomes include: live-birth delivery after 24 weeks, the endometrial transcriptomic profile among women in the intervention group, short-term safety (e.g. procedure intolerance due to pain, post-procedure bleeding) and long-term safety (e.g. cancelled transfers, miscarriage) outcomes. LIMITATIONS REASONS FOR CAUTION: Owing to its pragmatic design, this study may have limited power to determine one or more of our secondary outcomes and whether there are specific subgroups of women who may benefit significantly from performing endometrial scratching and endometrial transcriptomic profiling. WIDER IMPLICATIONS OF THE

findingsDespite the weak biological plausibility, heterogeneity in the existing randomized controlled trials and lack of evaluation of any potential risks associated with endometrial scratching, this procedure is still widely applied in current clinical practice. This clinical trial aims to pragmatically assess the potential benefits and harms of the generalized use of this strategy. STUDY FUNDING/COMPETING INTERESTS: this study has received a grant from the Research Foundation-Flanders (FWO, 1524417N). This organization has no further role in the study, namely with regards to protocol development, study conduction and evaluation of results. TRIAL REGISTRATION NUMBER: NCT02061228. TRIAL REGISTRATION DATE: 10 February 2014. DATE OF FIRST PATIENT’S ENROLMENT: 3 April 2014. PROTOCOL VERSION: 2.0.