EfficAcy of In-vitro Fertilisation add-ons in improvINg the reproductive outcomes of couples with inferTilitY (AFFINITY): A development programme for a Bayesian multi-stage multi-arm adaptive randomised trial.

Background: Several supplementary fertility treatments (commonly called IVF add-ons) are offered in addition to standard assisted reproductive technology treatment with the aim of maximising chances of pregnancy and live birth, often at significant added cost to patients. Evidence to support the safety and efficacy of many of these IVF add-ons is limited raising concerns of exposing vulnerable patients to expensive and potentially harmful unproven interventions. There is an urgent need for a comprehensive, robust, and adequately powered randomised trial to evaluate the efficacy of available IVF add-ons and inform responsible and ethical use of these add-ons across NHS and private fertility clinics in the UK. Research question: What is the optimal design of a multi-stage multi-arm adaptive randomised trial that could efficiently evaluate the safety and efficacy of various IVF add-ons with sufficient proof-of-concept to improve the reproductive outcomes of couples undergoing assisted conception. Aims and objectives: To co-produce and design a Bayesian multi-stage multi-arm ‘drop the loser’ adaptive randomised trial to evaluate the efficacy of various IVF add-ons while considering the treatment preferences of patients with infertility and potential methodological challenges to recruiting patients from fertility clinics in the UK. Methods: The proposed development programme will comprise of five Work Packages. First, we will conduct a literature review and a network meta-analysis to identify IVF add-ons with sufficient proof-of-concept and rank them for their perceived efficacy. We will then conduct a focus group with lay patient representatives to refine and prioritise shortlisted add-ons for their perceived acceptability, safety, importance, preferred reported outcomes and willingness to pay. The third work package will conduct an elicitation process of multi-disciplinary fertility experts leveraging the findings of the two proceeding work packages to forge consensus on key trial design aspects including priors of effect estimate, outcomes selection and correlation, and utility/futility margin to drop underperforming add-ons in the full-scale trial. Given the varied use of IVF add-ons across fertility clinics in the UK, the 4th work package will survey licensed fertility clinics and aim to produce standardised protocols of shortlisted IVF add-ons to be used consistently across recruiting sites in the full-scale trial. Finally, we will run simulations to assess trial power and sample size exploring different assumptions to co-produce the trial protocol with input from lay patient representatives and multi-disciplinary stakeholders. Timelines for delivery: We forecast 12 months to complete the project as follows: Review of systematic reviews and network meta-analysis (Months 1-4), PPI focus groups and expert elicitation process (Months 2-8), survey of used add-ons in the UK (Months 2-4), full trial simulation, protocol development, and write up (Months 8-12). Anticipated impact and dissemination: We will co-produce a draft protocol and a post-development grant application to secure funding to execute the full-scale randomised trial. The findings of each Work Package will be disseminated to both the scientific and lay community. We will rally support in the fertility community to maximise the trial’s success and its impact to invoke a radical change in the practice of assisted conception in the UK and worldwide.