PravastatIn tO preveNt prEtErm biRth (PIONEER): a parallel group randomised placebo-controlled trial

Research question:1)Is Pravastatin better than placebo at extending gestational length of pregnancy?2)If so, does Pravastatin have this effect through changes to the cervico-vaginal inflammatory profile, vaginal and gut microbiota or serum lipids? Background:Preterm birth (PTB) is a global concern. In 2019, nearly one million children under 5 years died due to complications of prematurity. Risk for poor outcome is inversely proportional to gestational age at birth. Rates of PTB have not significantly altered over recent decades. Aims and objectives:1)Evaluate the efficacy of Pravastatin versus placebo in reducing PTB in those at risk:a)Assess difference between groups in mean gestational age (GA) (days) at birth;b)Estimate difference between groups with respect to a range of secondary outcomes.2)Investigate mechanisms via which Pravastatin prevents PTB by assessing the effect of Pravastatin vs placebo on maternal: a)Cervicovaginal inflammatory profile;b)Vaginal and gut microbiota;c)Serum lipid profile Design:Multi-site parallel group placebo-controlled RCT with blinding and internal pilot, with integrated monitoring and feedback to maximise recruitment and adherence to study medication, with an embedded mechanistic investigation, and a Quintet Recruitment Intervention to optimise recruitment and safeguard informed consent. Population:Pregnant people referred to PTB prevention clinics across the UK. Intervention:20mg Pravastatin every day, from the 2nd trimester until 37+0 weeks or birth. Comparator:Placebo, taken as intervention. Primary outcome:Gestational age at birth. Secondary outcomes: Defined maternal and neonatal core set for evaluation of PTB prevention interventions; childhood assessment at 2 years corrected age via PARCA-R questionnaire. Mechanistic sub-study:For 250 participants, mechanistic studies will assess maternal: 1. Cervicovaginal fluid inflammatory profile; 2. Vaginal microbiota profile; 3. Serum lipid profile; 4. Stool microbiota profile. Sample size:A difference of one week in GA is the minimum clinicians require to consider interventions as effective in PTB prevention, and used here. The estimated standard deviation (4.2 weeks) was taken from the OPPTIMUM trial of Progesterone prophylaxis for PTB. A sample size of 750 participants (375 per group), allows an effect size of 0.24 to be detected with 90% power at the 5% 2-tailed significance level, assuming complete data for primary outcome and treatment compliance. Analyses:Conducted according to intention-to-treat, following CONSORT reporting guidelines. Randomised participants who do not complete treatment will be included in the primary analysis. All models will compare treatment groups and adjust for site and previous PTB. Sensitivity analyses, restricted to participants who take at least 80% of the study medication will be conducted. Subgroup analysis to investigate whether prior LLETZ procedure affects Pravastatin efficacy will be performed. Timelines for delivery:Total duration 60 months (m), comprising: set up (8m); internal pilot (12m); main trial recruitment (24m); follow-up (8m), analysis, reporting and archiving (8m). An internal pilot phase will include the first 12m of recruitment, and progression criteria will need to have been met to ensure continuation to the main study. Impact:If this study shows that low-cost Pravastatin increases GA at birth when compared with placebo, this study could change management of PTB and reduce PTB rates globally.