MON-617 - Participant-Informed Design Considerations in Phase 3 LUCIDITY Trial of Avexitide for Post-Bariatric Hypoglycemia

Background:
Post-bariatric hypoglycemia (PBH) is an increasingly recognized chronic metabolic condition characterized by hyperinsulinemic hypoglycemia after bariatric surgery. PBH is thought to be driven by an exaggerated glucagon-like peptide-1 (GLP-1) response, leading to excessive insulin secretion. PBH can lead to debilitating neuroglycopenic events, significantly impacting quality of life. Despite its clinical burden, there are currently no approved pharmacologic treatments. Avexitide is an investigational, first-in-class inhibitor of GLP-1 receptor activity (iGLP-1R) that competitively inhibits GLP-1–mediated insulin secretion to stabilize glucose levels. In earlier-phase studies, avexitide showed clinical benefit and was well tolerated, with no treatment-related serious adverse events or discontinuations.

Objective:
To describe the LUCIDITY trial design with emphasis on participant-informed design considerations and the endpoint strategy selected to capture PBH clinical and participant-reported burden.

Methods:
LUCIDITY (NCT06747468) is a Phase 3, randomized, placebo-controlled trial evaluating the efficacy and safety of avexitide in ~75 adults with PBH inadequately controlled by dietary management across ~20 U.S. sites. Eligible participants are adults ≥18 years, ≥12 months post-Roux-en-Y gastric bypass, with confirmed PBH and ≥3 discrete hypoglycemic episodes during a 3-week run-in period. Following screening, participants enter a 16-week double-blind treatment phase, randomized in a 3:2 ratio to receive avexitide 90 mg subcutaneously once daily or placebo. After completion of this phase, participants enter a 32-week open-label extension. Continuous glucose monitoring (CGM), self-monitoring of blood glucose (SMBG), and electronic diaries are used to collect data on Level 2 and 3 hypoglycemic events. The primary efficacy endpoint is the composite rate of Level 2 (SMBG) and Level 3 (independent Event Adjudication Committee) hypoglycemic events during the double-blind period. Disease burden and participant quality of life are assessed as exploratory endpoints using a variety of participant-reported outcomes and surveys. During protocol development, input from individuals with PBH was used to identify meaningful outcomes and practical considerations. The final design balances comprehensive measurement with participant feedback.

Results &

Conclusions:
The detailed study design will be presented at the meeting, focusing on participant-informed considerations and the endpoint strategy developed to capture PBH disease burden. This trial aims to address a critical unmet need among individuals living with post-bariatric hypoglycemia. Topline clinical trial data are expected in Q3 2026.

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