Evaluation of Letrozole Versus Gonadotropins for Ovulation Induction in Polycystic Ovary Syndrome: A Randomized Clinical Trial

The primary objective of this study is to evaluate the **clinical efficacy** of continuing ovulation induction with **letrozole** versus switching to ovarian stimulation with **gonadotropins** in women with **polycystic ovary syndrome (PCOS)**. This is assessed in terms of improvement in the cumulative live birth rate, which is a critical measure of treatment success in infertility management.

Secondary objectives include:

• Determining the safety and feasibility of continuing ovulation induction with letrozole versus switching to ovarian stimulation with gonadotropins, focusing on side-effects, pregnancy, and neonatal outcomes.
• Assessing the impact on quality-of-life and mental health measures when continuing with letrozole compared to switching to gonadotropins.
• Evaluating the total budget impact of the two treatment strategies, specifically the reduction in total budget spent on infertility care in women with PCOS who ovulate on letrozole but have not conceived after six ovulatory cycles.
• Determining the environmental impact of continuing ovulation induction with letrozole versus switching to ovarian stimulation with gonadotropins.

The clinical trial focuses on evaluating treatments for **polycystic ovary syndrome (PCOS)**, specifically comparing the efficacy of continuing ovulation induction with letrozole versus switching to ovarian stimulation with gonadotropins. The study population comprises females aged 18 to 43 years, who have been diagnosed with PCOS characterized by normogonadotropic anovulation with hyperandrogenaemia or polycystic ovaries as confirmed by ultrasound. Participants include both couples and single women with a desire for children, who have been ovulatory for six cycles on letrozole treatment. The trial does not involve a vulnerable population, and the sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **clinical efficacy** of continuing ovulation induction with **letrozole** versus switching to ovarian stimulation with **gonadotropins** in women diagnosed with **polycystic ovary syndrome (PCOS)**. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The estimated duration of the trial is from June 2025 to June 2030, with participant recruitment beginning in June 2025. The primary endpoint is the achievement of pregnancy within eight months after randomization, leading to a live birth. Secondary endpoints include clinical pregnancy rates, miscarriage rates, and quality of life assessments, among others.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-43 years), a diagnosis of PCOS, and previous ovulatory response to letrozole. Following randomization, participants will attend follow-up visits at three and six months to monitor treatment compliance, side effects, and quality of life using standardized questionnaires. The end-of-study visit will occur at eight months post-randomization to assess the primary and secondary endpoints. The expected length of participant involvement is approximately eight months, with conditions for early termination including non-compliance with the study protocol or adverse events that compromise participant safety.

The trial involves the administration of **letrozole** as an oral film-coated tablet with a maximum daily dose of 7.5 mg, and **gonadotropins** (either **human menopausal gonadotrophins** or **follitropin alfa**) as subcutaneous injections with a maximum daily dose of 225 mg or IU, respectively. The maximum treatment period for letrozole is five days, while for gonadotropins, it is 14 days. The trial is categorized as low-intervention, as the interventions align with current standard practices, with the primary difference being the extended duration of letrozole treatment. The trial aims to provide valuable insights into the most effective treatment strategy for improving live birth rates in women with PCOS.

The clinical trial involves the use of three distinct treatments to evaluate their efficacy in women with **polycystic ovary syndrome**. The first treatment is **LETROZOLE**, a chemically derived active substance administered in the form of a film-coated tablet. The dosage for LETROZOLE is set at a maximum of 7.5 mg per day, with a total maximum dose of 37.5 mg over a treatment period of up to 5 days. The route of administration is oral. LETROZOLE serves as a comparator in the trial, and participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

The second treatment involves **HUMAN MENOPAUSAL GONADOTROPHINS**, which are urinary-derived and provided as a solution for injection. The maximum daily dose is 225 mg, with a cumulative maximum dose of 3150 mg over a 14-day treatment period. The administration route is subcutaneous. This treatment is part of the test group in the trial, and compliance is monitored through scheduled follow-ups and participant logs to track adherence to the injection schedule.

The third treatment is **FOLLITROPIN ALFA**, also urinary-derived, and is administered as a solution for injection in a pre-filled pen. The dosing regimen mirrors that of HUMAN MENOPAUSAL GONADOTROPHINS, with a maximum daily dose of 225 IU and a total maximum dose of 3150 IU over 14 days. The administration is subcutaneous. FOLLITROPIN ALFA is included in the test group, and participant compliance is ensured through regular monitoring and documentation of injection adherence.

The clinical trial aims to assess the efficacy of continuing ovulation induction with **letrozole** versus switching to ovarian stimulation with gonadotropins in women with polycystic ovary syndrome (PCOS). The primary endpoint for evaluating efficacy is the achievement of pregnancy within 8 months after randomization, leading to a live birth. Secondary endpoints include clinical pregnancy, ongoing pregnancy, biochemical pregnancy loss, and miscarriage rates within the same timeframe. Additionally, the trial will evaluate the number of treatment cycles initiated, completed, and cancelled, as well as multiple pregnancy rates, time to pregnancy, pregnancy complications, perinatal outcomes, type of delivery, and outcomes for all achieved pregnancies, including spontaneous ones.

Side effects and compliance to therapy will be assessed using a medication diary and a questionnaire, administered at 3 months and 8 months after randomization. Quality of life and mental health will be evaluated at the time of randomization, and at 3 months and 6 months after randomization, using the FertiQoL questionnaire and the HADS questionnaire. The trial will also monitor progression to IVF/ICSI within 8 months after randomization. Budget impact and cost-effectiveness analyses will be conducted using live birth rates, costs, and quality of life as parameters.