PINC2: A pragmatic, multi-centre, parallel-arm, double-blind, placebo-controlled, randomised controlled trial to evaluate the clinical effectiveness, cost effectiveness and safety of exogenous luteal phase progesterone support in natural menstrual cycles in couples with unexplained infertility.

Research question Does exogenous progesterone support during the luteal phase of natural menstrual cycles improve the live birth rate compared to no support in couples with unexplained infertility, providing a safe and cost-effective fertility treatment option? Background Infertility is a common issue that affects 1 in 6 adults in their lifetime. In up to half of these cases, no specific cause can be identified; a condition known as Unexplained Infertility (UI). Treatment options for UI are limited, mainly consisting of two approaches: waiting and trying to conceive naturally or undergoing In-Vitro Fertilisation (IVF). Unfortunately, neither option has strong support from clinical or cost-effectiveness evidence, and IVF may not be accessible to everyone. There are multiple possible causes of UI; some of which are related to the embryo and endometrium but are rarely diagnosed. Progesterone has a crucial physiological role in optimising endometrial receptivity and supporting embryo implantation. For some couples, a decrease in progesterone-mediated endometrial receptivity can be an important cause contributing to infertility. There is emerging evidence that prescribing progesterone in an appropriate phase of the menstrual cycle may enhance fertility. Our published feasibility randomised controlled trial (RCT) demonstrates that this approach is both feasible and acceptable to patients and provides an effect size estimate for a larger trial. Aim To determine if exogenous progesterone support during the luteal phase of natural menstrual cycles improves the live birth rate compared to no support in women with UI. Objective To conduct an RCT with nested qualitative research and a health economic evaluation to assess the clinical effectiveness, cost-effectiveness, and safety of exogenous luteal phase progesterone support during natural menstrual cycles in couples with UI. Methods This study is a pragmatic, multi-centre, parallel-group, placebo-controlled, double-blind RCT with an internal pilot phase. It will be conducted across 10 sites recruiting 1,136 couples who have a diagnosis of UI. The trial will take place at fertility clinics in secondary and tertiary care. Eligible participants will be randomly assigned in a 1:1 ratio to receive either luteal phase progesterone support or a placebo during natural menstrual cycles for up to 6 cycles. We will use micronized vaginal progesterone (Cyclogest pessaries) at a dosage of 400 mg twice daily, following the British National Formulary guidance. The primary outcome of the study is the live birth rate. Additionally, we will assess several secondary outcomes related to clinical effectiveness and safety, conduct a health economic evaluation and a nested qualitative research. Timelines for delivery The trial will be conducted over 60 months in four phases: set-up, recruitment, follow up and analysis. Anticipated impact and dissemination The trial will provide high-quality evidence for the clinical effectiveness and safety of a new alternative intervention. If effective, an economic evaluation will provide data for the NHS and policymakers to inform their decision on whether to incorporate this intervention into routine practice. The Chief Investigator will coordinate the dissemination of results from this trial. A core team consisting of the co-applicants, the clinical trials unit and an advisory committee will plan and implement effective communication of the research findings to all stakeholders.