438. Integrating basic science with clinical data to inform the design of RCT’s for preeclampsia

Abstract

Preeclampsia is associated with increased placental release of anti-angiogenic factors (such as sFlt1 and soluble endoglin) that cause endothelial dysfunction, hypertension and maternal end organ injury. In recent years, our research team have developed a laboratory based drug screening pipeline to identify drugs that 1) decrease placental release of sFlt1 and soluble endoglin 2) decrease endothelial dysfunction in multiple assays and 3) promote vasodilation in whole maternal vessels. We also test an animal model of preeclampsia. Using this drug screening pipeline in our laboratory we have identified a number of agents that have most - or all - of these properties. They are drugs that are currently used for varying indications and are quite unrelated. They include proton pump inhibitors (used for gastric reflux), metformin (used to treat diabetes), statins (used to treat high cholesterol [we published data validating this concept that was first proposed by others]) sulfasalazine (used for inflammatory bowel disease), resveratrol, and others. We now currently have a list of drug candidates that may have efficacy in treating or preventing preeclampsia. Importantly, we have progressed to successive RCTs to evaluate whether some of them may indeed be effective in treating preterm preeclampsia (being run in a close collaborative partnership with academics at Tygerberg Hospital). We are also implementing large multi-centre trials to test whether drugs can prevent preeclampsia. In this presentation, we will discuss our strategic reasoning to decide what order to test these drugs in RCTs, and our approach to designing RCTs. To make these decisions, we have been integrating data from our laboratory studies with clinical reasoning (taking into account any prior published clinical data, pharmacokinetics, known drug side effects, and safety concerns).