Efficacy and Safety of Follitropin Delta in Men with Idiopathic Infertility: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **FE 999049** (follitropin delta) on the likelihood of achieving spontaneous pregnancy in female partners of men diagnosed with **idiopathic male infertility**, including conditions such as oligoasthenozoospermia. This objective is clinically significant as it addresses the potential of follitropin delta to improve fertility outcomes in cases where the cause of infertility is unexplained, thereby offering a therapeutic option for affected couples. No secondary objectives are specified for this trial.

The clinical trial involves a total of **203 male participants** diagnosed with **idiopathic male infertility**, including conditions such as oligoasthenozoospermia. The study population consists exclusively of men aged between **18 and 50 years**, with no female subjects included. Participants were selected based on specific criteria, including a history of infertility with their current partner for 12 to 60 months and specific sperm parameters such as a total sperm count of 5-39 million and total sperm motility of at least 10%, confirmed by two consecutive samples. Additionally, participants are required to have serum follicle-stimulating hormone (FSH) levels of 1.5-8.0 IU/L, luteinising hormone (LH) levels of 1.2-7.5 IU/L, and total testosterone levels of at least 300 ng/dL. The trial does not include a vulnerable population, and participants are expected to maintain regular intercourse with their current female partner, who must be a pre-menopausal woman aged 18 to 35 years with regular menstrual cycles, and agree not to seek infertility treatment outside the trial for nine months. The selection process ensures that participants meet these criteria to assess the effect of FE 999049 treatment on the chance of spontaneous pregnancy in their female partners.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **follitropin delta** in the treatment of men with idiopathic infertility. The trial aims to assess the impact of the treatment on the likelihood of spontaneous pregnancy in the female partners of the male participants. The study is expected to span approximately three years, with an estimated recruitment start date of July 13, 2023, and an anticipated end date of July 15, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a history of infertility for 12-60 months, sperm count, motility, and hormone levels. Following randomization, participants will receive either the active treatment or a placebo via **subcutaneous injection** using a pre-filled pen. The treatment period is set for a maximum of six months, with a daily dose not exceeding 12 micrograms and a total dose not surpassing 2190 micrograms.

Throughout the trial, participants will attend regular follow-up visits to monitor treatment effects and ensure adherence to the protocol. These visits will include assessments of sperm parameters and hormone levels, as well as the collection of information regarding the female partner's pregnancy status. The primary endpoint is the occurrence of a spontaneous pregnancy, defined as a vital pregnancy with documentation of at least one intrauterine gestational sac with a fetal heartbeat by ultrasound, within nine months after the male subject's randomization.

The expected length of participant involvement is up to nine months from randomization, with conditions for early termination including non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **REKOVELLE**, a solution for injection containing **follitropin delta** as the active substance. This medication is provided in a pre-filled pen, with a concentration of 72 micrograms per 2.16 mL. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous injection. The maximum daily dose is 12 micrograms, with a total maximum dose of 2190 micrograms over a treatment period of up to 6 weeks. The medication is manufactured by Ferring Pharmaceuticals A/S and is classified under the ATC code G03GA10. The active substance, follitropin delta, is a protein of non-human origin, specifically categorized as "Protein - Other." Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** treatment, which is administered in a similar pre-filled pen containing a 2.16 mL solution for subcutaneous injection. The placebo is designed to match the experimental medication in appearance and administration method to maintain the double-blind nature of the trial. The placebo does not contain any active pharmaceutical ingredients. The administration schedule for the placebo will mirror that of the experimental treatment to ensure consistency in the trial protocol.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the occurrence of **spontaneous pregnancy** in the female partners of male subjects with idiopathic infertility. Spontaneous pregnancy is defined as a vital pregnancy, documented by the presence of at least one intrauterine gestational sac with a fetal heartbeat confirmed via ultrasound. This assessment will be conducted within a 9-month period following the randomization of the male subjects.