A novel, efficient and seamless Phase 2A‐2B design to test varoglutamstat in early AD: the VIVA‐MIND study

Abstract

AbstractBackgroundImproved Phase 2 study designs may increase success rates in late stage AD trials. Varoglutamstat (PQ912) is an oral small molecule glutaminyl cyclase inhibitor designed to address several key disease mechanisms. A Phase 2A study (NCT02389413) of 120 early AD patients treated for 12 weeks provided preliminary evidence of safety and tolerability, and effects on working memory, CSF biomarkers, and synaptic function (EEG theta‐power).ObjectiveTo design a well‐powered, safe, and efficient study of varoglutamstat in early AD incorporating adaptive dose selection in Phase 2A, a futility analysis testing pharmacological, biological and cognitive criteria, and a seamless transition to a larger Phase 2B study investigating longer‐term efficacy and safety.MethodsAn efficient and safe selection rule across 3 descending doses (600mg, 300mg, 150 mg BID) was established using a continuously monitored Pocock safety boundary targeting a set of treatment emergent AE’s of interest. Well‐powered stage‐gate criteria at a planned interim futility analysis included thresholds for target occupancy in plasma, and would detect negative effects on a cognitive composite or absence of benefit on EEG theta‐power. The Phase 2B study was powered to detect an effect size of 0.7 points on the Clinical Dementia Rating – Sum of Boxes score at 18 months, an established approvable endpoint.ResultsThe on‐going Phase 2A adaptive dose‐finding trial (NCT03919162) is randomizing 180 subjects with MCI or mild probable AD, initially to 24+ weeks of 600mg varoglutamstat dose or placebo, BID. If the safety boundary is hit, the dose will be discontinued and all subjects titrated down, with similar sequential testing of lower doses as needed. The interim futility analysis will occur when the first 180 randomized subjects have been on study for at least 24 weeks. If this stage‐gate is passed, Phase 2B will enroll 234 additional patients to achieve 414 total patients treated for 72 weeks at full dose of varoglutamstat or placebo.ConclusionThis novel study design enables adaptive dose selection, an early interim futility analysis, and longer‐term determination of cognitive and functional efficacy, and should support robust proof‐of‐concept for varoglutamstat using a total sample of 414 subjects treated for 72 weeks.