Safety and potential efficacy of DM199, a tissue kallikrein-1 analogue, for treating pre-eclampsia and fetal growth restriction: study protocol for a South African, hospital-based phase I/II open-label trial.

introductionPre-eclampsia and fetal growth restriction are leading causes of perinatal morbidity and mortality. A therapy that enhances maternal vascular function and promotes vasodilation to increase placental perfusion could treat both conditions.Tissue kallikrein-1 is an endogenous enzyme that releases bradykinin to activate the bradykinin 2 receptor on endothelial cells. This induces potent vasodilation and pro-angiogenic, anti-oxidant and anti-inflammatory effects.DM199 is a recombinant form of tissue kallikrein which can be administered intravenously or subcutaneously. Clinical trials in non-pregnant populations have demonstrated its safety. Being a protein, it is unlikely to cross the placenta. This protocol describes an early-phase trial for DM199 for pre-eclampsia and fetal growth restriction. METHODS AND ANALYSIS: This phase IB/IIA open-label trial at Tygerberg Hospital, Western Cape Province, South Africa, will determine the safety and effective dose of DM199 for pre-eclampsia and/or fetal growth restriction. The trial consists of two parts. Part 1 will be an ascending dose finding study, treating women with pre-eclampsia and severe hypertension who are for planned birth within 72 hours. This will search for doses that safely lower blood pressure (n=3/dose, recruiting up to 42 participants). Part 2 is a safety and efficacy study of three cohorts of pregnant women (n=30/cohort): (1) with pre-eclampsia and severe hypertension requiring delivery within 72 hours, (2) with preterm pre-eclampsia (<33 weeks' gestation) undergoing expectant management and (3) with preterm fetal growth restriction. Primary outcomes will include adverse events and umbilical cord concentrations of DM199. DM199 pharmacokinetics will be described and exploratory outcomes assessed to evaluate preliminary evidence of efficacy. ETHICS AND DISSEMINATION: The trial has ethical approval (Health Research Ethics Committee, Stellenbosch University, Protocol number M24/04/009) and is registered (Pan African Clinical Trial Registry, PACTR202404895013782) and approved by the South African Health Products Regulatory Authority (20240801). Data will be presented at international conferences and published in peer-reviewed journals.