Effectiveness of ClOmipheNe CitRate for the management of mEn wiTh infErtility (CONCRETE): A randomised double-blind placebo-controlled trial.

Background: Male factor infertility defined by abnormal semen parameters affects >50% of infertile couples. In most cases no clear cause can be identified for (idiopathic), which may be associated with a mild reduction in Testosterone (secondary hypogonadism). While a common health condition, effective medical treatments for men with hypogonadism or idiopathic male infertility remain limited with an over reliance on using expensive and invasive assisted reproductive technology treatments. Clomiphene is a selective oestrogen receptor modulator that could stimulate testosterone secretion from the testes and boost spermatogenesis. Data from small randomised trials and observational studies suggest some benefit of using it to improve semen parameters in affected men. However, evidence of its efficacy and safety for use in this cohort remains heterogenous due to poor study quality. Research question: What is the efficacy and safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility to improve semen parameters and reproductive outcomes compared to placebo. Aims and objectives: to evaluate the efficacy and safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility. Objectives -To determine the efficacy of clomiphene in improving semen parameters in this group of men. -To determine the efficacy of clomiphene in improving clinical, reproductive and pregnancy outcomes in this group of men -To determine the safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility -To explore the feasibility and acceptability of using Clomiphene as a primary treatment in this group of men Methods: A multicentre two-arm parallel group double-blind placebo controlled randomised trial with an internal pilot and qualitative process evaluation. Men who meet the eligibility criteria from five NHS fertility clinics will be randomised in a 1:1 ratio to either Clomiphene (25mg/day) or identical placebo for 12 months. Both groups will receive standard lifestyle advice as per national guidelines. We will primarily report on change in sperm concentration at 6 months in addition to other semen parameters, biochemical, reproductive, pregnancy, clinical, and quality of life outcomes. Couples seeking to start any assisted conception treatment during the trial will be enabled without delay. An increase of 5 million/ml in sperm concentration can significantly increase the chances of spontaneous conception in men with oligozoospermia. To detect a 5 million/ml improvement in sperm concentration between groups, assuming a 0.5 correlation coefficient and a SD of 10, we need 160 participants to achieve 90% power, and 5% type-1 error rate and allowing 20% loss to follow-up. Timelines for delivery: We forecast 48 months to execute the trial including: trial set up (Months 1-9), recruitment and intervention delivery (Months 9-21), follow-up (Months 21-33), site close down and capturing pregnancy outcomes (Months 33-42), and statistical analysis and dissemination (Months 42-48). Anticipated impact and dissemination: The findings will be published in medical journals and international conferences. The results will be shared with the NHS repurposing programme to review Clomiphene licence. We devised a PPIE strategy, lay communication strategy, and established strong links with relevant charities to promote the voice of lay men with infertility.