First Line Surgery or First Line Fertility Treatment Using Assisted Reproductive Technologies in Patients With Advanced Endometriosis

WHY THIS TRIAL IS NEEDED

BACKGROUND

Endometriosis Endometriosis is a prevalent condition affecting 10% of female population of reproductive age, leading to pain and sub-fertility. An earlier systematic literature reviews and meta-analysis suggests that women with advanced endometriosis (revised American Society for Reproductive Medicine classification of endometriosis (rASRM) stage III-IV) have a lower likelihood of achieving clinical pregnancy/live birth compared to women without endometriosis, while this difference has not been observed for mild disease (stage I-II).

Gynaecological Ultrasound and staging The prevalence of endometrioma and deep endometriosis found through systematic transvaginal ultrasound on women referred for ART treatment in Sweden has been estimated at 21.8%. Additionally, 75.8% of those with endometriosis were unaware of their condition prior to diagnosis. In recent years, two staging systems, namely the American Association of Gynecologic Laparoscopists (AAGL) Endometriosis classification and #ENZIAN have gained prominence owing to their accuracy when juxtaposed with surgical findings.

Surgical Treatment Women with endometriosis seem to experience pain relief after bowel surgery due to endometriosis. Consensus from the European Society of Human Reproduction and Embryology (ESHRE) indicates that surgery can be performed prior to treatment with assisted reproductive technologies (ART). Additionally, the number of spontaneous pregnancies is high after surgery on patients with deep endometriosis. Furthermore, in patients with endometriosis stage I-II or in infertile patients with endometriomas, surgery can in some cases be considered to improve fertility. However, the risk of severe complications in patients undergoing rectal surgery is up to 10% including anastomosis leakage and fistulas.

Fertility treatment An earlier meta-analysis found that the number of oocytes and fertilization rates are lower in women with endometriosis as compared to those without, although not necessarily impacting the live birth rate. Still, some previous studies have shown lower likelihood of live birth and pregnancy after in vitro fertilisation (IVF) in women with endometriosis compared to women with unexplained or tubal infertility. Even though there is some controversy when it comes to the evidence of association between endometriosis and adverse reproductive outcome after IVF, there is biological plausibility for this type of association, especially in women with advanced endometriosis (chronic inflammation affecting folliculogenesis, technical difficulties at oocyte retrieval due to endometriomas or adhesions, increased risk of pelvic infection after oocyte pick-up).

RATIONALE FOR STUDY

Only a few comparative retrospective studies on first-line surgery versus first-line ART have been performed, with no available randomised controlled trials (RCTs). In two retrospective register studies, first-line surgery in patients with deep endometriosis (DE) in the anterior compartment or colorectal DE showed improved live birth rates (LBR) and pregnancy rates (PR) compared to first-line ART. An important limitation in the previous studies on patients with endometriosis has been the challenge of staging and characterizing the disease consistently using preoperative imaging techniques. Currently, the decision regarding the choice between surgery and IVF is collaborative and individualised, considering various factors such as the patient's medical and surgical history, presence of pain symptoms, age, results of ovarian reserve testing, and semen analysis. Lack of randomised RCTs or at least robust prospective cohort studies comparing these two approaches is noteworthy. Hence, there is an obvious need for a randomised controlled trial to address the impact of surgery prior to ART on the reproductive outcomes in women with endometriosis AAGL stage III-IV, to help patients and health-care workers with decision-making, with the overall aim to improve patient-outcomes.

STUDY OBJECTIVES

HYPOTHESIS First line surgery (prior to ART treatment) in women with endometriosis AAGL stage III-IV will result in improved cumulative live birth rate (CLBR) as compared to first line ART.

PRIMARY OBJECTIVE To assess whether surgery conducted prior to ART treatments in women with endometriosis AAGL stage III-IV increases chances of CLBR as compared to first line ART.

SECONDARY OBJECTIVES

To evaluate whether surgery prior to ART treatments in women with endometriosis AAGL stage III-IV will result in:

* improved cumulative pregnancy rate (CPR) and lower miscarriage rate as compared to first line ART. * shorter time to live birth or pregnancy as compared to first line ART. * better reproductive outcomes per IVF cycle and a lower rate of recurrent implantation failure (RIF). * lower rate of infections after oocyte pick-up requiring treatment with antibiotics as compared to first line ART. * higher Quality of life and less pain measured with Endometriosis Health Profile (EHP-30) and Numeric Rating Scale (NRS) before ART, i) at the time of oocyte retrieval, ii) two months after ART and iii) at the three-year follow-up visit as compared to first line ART. * reduced pregnancy and delivery complications, as well as fewer complications within 8 weeks postpartum.

To explore whether surgery prior to ART treatments in women with endometriosis AAGL stage III-IV will be cost effective compared with first line ART.

To investigate whether serum progesterone level on the day of frozen embryotransfer in hormone replacement cycles in patients with severe endometriosis is associated with reproductive outcomes (LBR, pregnancy rate, miscarriage rate) and to determine if there is any difference in p-progesterone level between the two different study groups first line ART vs first line surgery in women with endometriosis AAGL stage III-IV.

PRIMARY OUTCOME MEASURE Cumulative live-birth rate within three years from first treatment (surgery or ART treatment).

SECONDARY OUTCOME MEASURES (see below in the protocol)

STUDY ENROLLMENT

SCREENING PROCEDURE AND PARTICIPANT IDENTIFICATION

All women with stage III-IV AAGL endometriosis with infertility referred and/or eligible for surgery and/or ART-treatment such as IVF or ICSI will undergo screening for this trial. The results of this screening will be documented in a screening log. After obtaining oral and written informed consent, patients will be registered and randomised. Registration data will be entered to an electronic Case Report Form (eCRF).

STAGING

At baseline, a specialised transvaginal and abdominal ultrasound examination, supplemented with transabdominal ultrasound if indicated will be performed according to the International Deep Endometriosis Analysis (IDEA) group recommendations to identify endometriosis lesions. Ultrasound and, if needed, magnetic resonance imaging (MRI) findings will be classified using the #ENZIAN and AAGL classification system.

The presence of adenomyosis will also be documented and characterized according to the Morphological Uterus Sonographic Assessment (MUSA) group recommendation. Women with and without suspected adenomyosis will receive the same treatment protocols. Presence of adenomyosis will not influence allocation but will be considered during the discussion of the final analysis of study results.

The use of hormonal treatment for endometriosis, prior to the surgery/ first ART-treatment or between the surgery and ART-treatment, will be documented and considered in the discussion of the outcomes.

RANDOMISATION

After verification of eligibility, signed informed written consent participants will be randomly assigned to either undergo first-line ART or first-line surgery, followed by ART by equal allocation, 1:1. The randomisation procedure will be stratified for participating center (permuted block design). Randomisation will be performed at each site using the web-based instrument Red Cap. All inclusion criteria and no exclusion criteria must be met. One month before first treatment (IVF or surgery), inclusion and exclusion criteria are entered into the randomisation/registration application RedCap. Patients withdrawn from the study after randomisation but before treatment will be substituted by newly enrolled patients. Patients withdrawn from the study after first treatment will not be substituted. Username and password are required to log in; each investigator authorised to register patients has a personal login username and password. If all criteria are met, patients are registered, and the allocated patient number is recorded in the patients' medical file.

There could be some uncertainty surrounding participants' willingness to engage in a Randomised Controlled Trial (RCT) comparing two fundamentally distinct approaches. Therefore, we intend to offer women who fullfill eligibility criteria but decline randomisation. the opportunity to take part in a parallel study - a prospective cohort study, that would provide valuable real-world outcomes of two different approaches to treatment of endometriosis -associated infertility. This parallel study will evaluate identical outcomes to those in the randomised trial. However, instead of random assignment, participation decisions will be made by the patients themselves, resulting in what is commonly referred to as a patient preference trial.

DEFINITION START OF TRIAL

Start of trial will be defined as start of first treatment which will be either surgery or first ART cycle (e.g. start of FSH injections).

DEFINITION END OF TRIAL

The study will end when all patients enrolled in trial have been followed for 3 years after first treatment, withdrawn consent, or are lost to follow-up. Data from study participants that are lost to follow will be included in the final analysis. The trial steering committee may end enrolment at any time if it is deemed that this is in the best interest of the patients.

STUDY TREATMENT

Time from randomization to first treatment (surgery or first ART cycle) should be minimized with a goal of three months and should preferably not exceed six months. Complications due to treatments (IVF or surgery) will be register in the eCRF and treated according to clinical routine at each hospital.

EXPERIMENTAL TREATMENT

First line endometriosis surgery followed by ART such as IVF or ICSI.

STANDARD/CONTROL TREATMENT

First line ART such as IVF or ICSI.

QUALITY ASSURANCE OF SURGERY AND FERTILITY TREATMENT PARTICIPATING CENTERS

All participating surgical centers have been selected by the National Board of Health and Welfare following an application process to perform highly specialised advanced endometriosis surgery at a national level. A quality assessment form including institutional experience with endometriosis surgery and ART, annual volume of benign gynaecological complex cases must be completed. Moreover, surgical variables (e.g. operation time, blood loss) and complications within 30 days after surgery according to Clavien Dindo (22) must be reported . Furthermore, the infrastructure to participate in the trial must be satisfactory. In addition, the institution's ability to perform staging of endometriosis is considered. All ART-clinics authorised to provide publicly funded fertility care report their results continuously to the National Quality Registry for Assisted Reproduction (Q-IVF).

• Cumulative Pregnancy Rate (CPR) [Time frame: From first treatment (surgery or ART) until three years of follow up]
• Time to pregnancy and live birth [Time frame: Time is measured up to three years after first treatment]
• Spontaneous Pregnancy Rate [Time frame: between first treatment and end of follow-up (three years)]
• Miscarriage rate and/or extrauterine pregnancies [Time frame: occurring between first treatment and end of follow-up (three years)]
• Number of oocytes per IVF/ICSI cycle [Time frame: At the day of oocyte retrieval for each IVF/ICSI cycle]
• Fertilisation rate [Time frame: The day after oocyte pick-up in each IVF/ICSI-cycle]
• Fresh embryo transfer per IVF/ICSI cycle [Time frame: At the time of transfer or at the end of embryo culture (up to Day 6), per IVF/ICSI cycle]
• Blastocysts cryopreserved per cycle [Time frame: at the end of embryo culture (Day 6 after oocyte pick-up)]
• Pregnancy outcomes per embryo transfer (ET) [Time frame: From ET until delivery (up to 10 months)]
• Cumulative reproductive outcomes per IVF/ICSI cycle [Time frame: From the start of each IVF/ICSI cycle until completion of all embryo transfers from that cycle (up to 12 months)]
• Rate of recurrent implantation failure (RIF), (20) evaluated at the end of the study period [Time frame: Assessed at the end of the study period ( 3 years after randomisation)]
• Infections after oocyte retrieval [Time frame: From each oocyte retrieval and within 2 following months]