The iSEARCH Trials of oral Sildenafil in labour: Protocol for a randomised trial in 3,200 Australian women and Rationale for an Individual Participant Data Prospective Meta-Analysis of trials in 14,000 women in high-income countries and a mega-trial of 50,000 women in low or middle-income countries.

Introduction: We showed in a Phase 2 RCT that oral Sildenafil during term labour halves the need for operative birth for suspected fetal distress. To assess if Sildenafil reduces adverse perinatal outcomes, we describe a Phase 3 RCT ( iSEARCH ) and the rationale for an individual participant data prospective meta-analysis (IPD PMA) of RCTs in high-income countries and a mega-trial in low- and middle-income countries. Methods: and analysis iSEARCH will enrol 3200 women in term labour, yielding >80% power to determine whether oral administration of up to three 50 mg doses of Sildenafil versus placebo reduces the relative risk of intrapartum hypoxia, determined as a primary composite endpoint of ten perinatal outcomes, by 35% (from 7% to 4.55%). We also outline the rationale for (i) an IPD PMA of RCTs in about 14,000 women in Australia and other countries with low perinatal mortality rates which would yield 90% power to test if oral Sildenafil achieves a more moderate and realistic reduction of 20% in the relative risk of this composite endpoint and (ii) a mega-trial in about 50,000 women in countries with moderate or high perinatal mortality rates to test if oral Sildenafil achieves a similarly moderate and realistic 20% reduction in the relative risk of a composite endpoint comprising intrapartum stillbirth or 7-day neonatal mortality. Secondary aims will be to evaluate the rate of operative birth for fetal distress, its cost-effectiveness, and developmental and educational outcomes.