Luteal Phase Support in MOH-IUI treatment (LUMO study)

The primary objective of the LUMO study is to evaluate the **clinical efficacy** of adding luteal phase support (LPS) in the treatment of unexplained subfertility using mild ovarian hyperstimulation with intra-uterine insemination (MOH-IUI). This is assessed by measuring the improvement in cumulative live birth rates. The clinical relevance of this objective lies in its potential to enhance fertility treatment outcomes for couples experiencing unexplained infertility, thereby increasing the likelihood of achieving a successful pregnancy.

Secondary objectives include:

• Determining the total budget impact of incorporating LPS in MOH-IUI treatment, specifically in terms of reducing overall expenditure on infertility care for patients with a low prognosis for spontaneous pregnancy.
• Assessing the safety and feasibility of LPS in MOH-IUI treatment by evaluating side effects, quality-of-life measures, and pregnancy and neonatal outcomes.

The clinical trial focuses on a population of **female** participants aged 18 to 43 years, diagnosed with **unexplained subfertility**. The study does not provide the total number of participants, as this information was not disclosed by the sponsor. Participants were selected based on specific criteria, including a body mass index (BMI) of less than 45 kg/m², regular menstrual cycles, and a total mobile sperm count (TMC) greater than 10 million. The trial targets individuals experiencing primary or secondary subfertility for at least one year, with a calculated prognosis for pregnancy leading to a live birth in the year ahead being less than 30%, or 30% or more after an expectant management period of at least six additional months. The trial involves the first MOH-IUI cycle with gonadotropins, with the intent to continue this treatment for at least six months. The study population is considered vulnerable, and lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **progesterone** luteal phase support in women undergoing intra-uterine insemination (IUI) with mild ovarian hyperstimulation. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is expected to run from March 2023 to March 2027, with participant involvement lasting up to 12 months, including follow-up assessments.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as a diagnosis of unexplained subfertility, female age between 18-43 years, and regular menstrual cycles. Following randomization, participants will receive either the active treatment, Utrogestan 300 mg vaginal capsules, or a matching placebo. The primary endpoint is the occurrence of pregnancy leading to a live birth within six months post-randomization. Secondary endpoints include clinical pregnancy rates, miscarriage rates, and quality of life assessments.

Study visits will include regular follow-ups to monitor treatment compliance, side effects, and pregnancy outcomes. The end-of-study visit will assess the overall health of the participants and any pregnancies achieved during the trial. Participants may be withdrawn from the study if they experience significant adverse effects, choose to discontinue, or if the study is terminated early for any reason. The trial aims to provide valuable insights into the cost-effectiveness and clinical benefits of adding progesterone luteal support to IUI treatment protocols.

The clinical trial involves the administration of **Utrogestan 300 mg soft vaginal capsules**, which contain **micronised progesterone** as the active substance. The pharmaceutical form is a soft vaginal capsule, designed for **vaginal use**. The maximum daily dose is 600 mg, with a total maximum dose of 25,000 mg over a treatment period of up to 5 days. The medication is classified under sex hormones and modulators of the genital system, specifically progestogens. The product is manufactured by Besins Healthcare Ireland Limited and is identified by the marketing authorization number 60954. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

The trial also includes a **placebo** treatment, which is a 300 mg soft capsule designed to match the active product in appearance and administration. The placebo is an oblong, slightly yellow capsule containing a whitish oily solution, manufactured to mimic the active product for blinding purposes. The manufacturing and control processes for the placebo are similar to those of the active product, but without the inclusion of the progesterone drug substance. The placebo is produced at the same manufacturing site as the active capsules, ensuring consistency in the trial's blinding protocol.

The clinical trial aims to assess the efficacy of **Luteal Phase Support (LPS)** in Modified Ovarian Hyperstimulation-Intrauterine Insemination (MOH-IUI) treatment, specifically focusing on the improvement of cumulative live birth rates. The primary endpoint for evaluating efficacy is the occurrence of pregnancy within six months after randomization, leading to a live birth. Secondary endpoints include clinical pregnancy rates, ongoing pregnancy rates, biochemical pregnancy loss, miscarriage rates, and other pregnancy-related outcomes within the same timeframe. Additionally, the trial will assess the number of MOH-IUI cycles initiated, completed, and canceled, as well as side effects and compliance to therapy using a medication diary and a questionnaire sent out six months post-randomization.

Quality of life will be evaluated at the time of randomization and at six and eighteen months after randomization using the FertiQoL questionnaire. The trial will also monitor progression to IVF/ICSI within six months post-randomization and the use of Assisted Reproductive Technology (ART) and ongoing pregnancies achieved after the six-month study period within a twelve-month follow-up. Budget impact and cost-effectiveness analyses will be conducted using live birth rates, costs, and quality of life as parameters. The trial is designed as a low-intervention study, utilizing **progesterone** (Utrogestan) 300 mg vaginal capsules and placebo capsules, with Utrogestan being registered in the EU for use in ART cycles. The trial is expected to conclude by March 2027.