Study design and participants
dyslipidemias, TG, hepatic steatosis, SAD
MAY, DYSLIPIDEMIAS, HEPATIC STEATOSIS
This phase 1, multicenter, randomized, double-blind, placebo-controlled, open-label single and multiple dose-escalating study (The study was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained from all participants. Sex and race were self-reported by all participants. All participants were reimbursed for their time and travel in accordance with local regulations.The first patient to be consented was consented on 10 December 2018, and the first patient was randomized on 4 January 2019. The last patient was consented on 24 January 2020, and the last patient visit was on 17 May 2021. All cohorts, including those not reported here, have completed the study.The study comprised six double-blind cohorts and eight open-label cohorts, with SAD and MAD designs. The aim of the study was to determine the safety and efficacy of ARO-ANG3 using escalating single doses of ARO-ANG3 in HPs and multiple doses in participants with hepatic steatosis. Eligible HPs in double-blind cohorts were allocated a unique randomization number, in accordance with the randomization schedule. In each cohort, the first two participants (sentinels) were randomized separately, one to active treatment and one to placebo. Each participant was assigned to either active (ARO-ANG3) or placebo treatment. The allocation of active treatment or placebo was determined by a computer-generated randomization schedule provided to the clinical site pharmacies by Novotech. The randomization schedule specified the treatment allocated to each randomization number. Sites enrolled the participants per the randomization schedule prepared by the pharmacists. After completion of the double-blind cohorts, the sponsor was unblinded, but the principal investigator and study participants remained blinded. This could occur after all participants in a cohort had completed the final planned study visit on day 113. The study schema is shown in Extended Data Fig. Cohorts 1–4 included eligible HP participants aged 18–65 years at screening who were on a stable diet for at least 4 weeks with no plans to meaningfully alter diet or body mass index (BMI) during the study. Placebo-controlled HP cohorts 1–4 were required to have a fasting screening TG >100 mg dlA basket trial approach was taken to evaluate early proof of concept, and four cohorts of participants with diverse dyslipidemias were enrolled. These cohorts included participants with hepatic steatosis (defined as baseline MRI-PDFF ≥10%) in cohort 5; participants with LDL-C >70 mg dlFull details of eligibility and exclusion criteria are described in the Study Protocol.