Letrozole Co-treatment During Ovarian Stimulation for IVF/ICSI in Women with Endometriosis: A Randomised Multicentre Trial

The primary objective is to evaluate whether letrozole co-administration during ovarian stimulation for IVF/ICSI improves cumulative live birth per stimulation cycle in women with endometriosis, including fresh and frozen embryo transfers derived from the same oocyte aspiration within 1 year of randomization. This outcome is clinically relevant because it directly measures the likelihood of achieving a live birth after treatment. Secondary objectives are to compare other reproductive outcomes, including implantation, clinical pregnancy, ectopic pregnancy, and miscarriage rates; pregnancy-related complications, neonatal outcomes, and congenital abnormalities in pregnancies beyond 24 weeks; treatment exposure and stimulation burden, including total recFSH dose and number of stimulation days; laboratory and cycle parameters, including endometrial thickness, estradiol and progesterone levels, cumulus oocyte complexes, mature M2 oocytes, fertilization rates, and the number of good-quality blastocysts; pain scores after oocyte pick-up; patient quality of life at 5 days post oocyte pick-up compared with baseline; and the occurrence of side effects and tolerability related to letrozole.

The sponsor did not provide the total number of participants. The trial population consisted of women with endometriosis undergoing IVF/ICSI, with or without concomitant adenomyosis. Eligible participants were subfertile or infertile women aged 18 to less than 40 years, with BMI below 35 kg/m², capable of giving informed consent, and planned for fresh embryo transfer after oocyte retrieval. Selection was based on a diagnosis of endometriosis established by transvaginal ultrasound, MRI, or surgery, and on an indication for IVF/ICSI according to existing guidelines. Participants had not undergone more than three consecutive unsuccessful IVF/ICSI cycles since the last ongoing pregnancy, and each participant could enroll only once. No information was provided regarding lifestyle factors such as diet, physical activity, or habits.

The study is a randomized, multicentre, parallel-group, pragmatic clinical trial evaluating letrozole co-administration during ovarian stimulation for IVF/ICSI in women with endometriosis, with or without adenomyosis. The overall trial duration is planned from June 2026 to June 2031. Study participation begins with a screening visit to confirm eligibility, including diagnosis, age, BMI, treatment indication, prior IVF/ICSI history, and informed consent. Eligible participants are then randomized and undergo ovarian stimulation followed by oocyte retrieval and planned fresh embryo transfer. Follow-up continues after transfer and includes assessment of pregnancy outcomes, with frozen embryo transfers from the same oocyte aspiration included within 1 year of randomization. An end-of-study assessment is completed after the final required outcome evaluation or after the 1-year follow-up window. Expected participant involvement is up to 52 weeks from randomization. Early termination may occur if eligibility criteria are no longer met, consent is withdrawn, the participant does not proceed with the planned treatment pathway, or the participant is otherwise unable to continue study procedures.

The experimental treatment was letrozole, administered as film-coated tablets for oral use. The source product was Letrozole Teva 2.5 mg film-coated tablets. The stated dose was 5 mg per administration, given during ovarian stimulation as co-treatment in the IVF/ICSI cycle. The frequency of administration was not specified in the source data.

No non-experimental treatment, placebo, or comparator regimen was specified in the source data. The trial evaluated letrozole co-administration during ovarian stimulation, with outcomes assessed over the stimulation cycle and subsequent embryo transfers. Information on dosing schedules beyond the stated dose and on compliance monitoring was not provided.

Efficacy will be assessed by cumulative live birth per stimulation cycle, including fresh and frozen embryo transfers resulting from the same oocyte aspiration and transferred within 1 year of randomization. Additional efficacy outcomes will include live birth rate per fresh embryo transfer cycle, number of embryo transfers needed for successful pregnancy, miscarriage rate, implantation rate, clinical pregnancy rate, and the rate of ectopic pregnancy or pregnancy of unknown location. For pregnancies beyond 24 weeks, assessment will also include pregnancy-related complications, extreme preterm birth, still birth and termination of pregnancy, gestational age at delivery, birthweight, neonatal admission and mortality, and major congenital abnormalities. Pain score will be measured using an NRS 1-10 one to four hours after oocyte pick-up. Patient quality of life will be assessed at the day of fresh embryo transfer, corresponding to oocyte pick-up plus 5 days, and compared with baseline using FertiQOL.