Canakinumab for the treatment of postprandial hypoglycaemia: study protocol for a randomised, placebo-controlled, parallel-group, double-blind, multicentric, superiority trial-the CanpHy study.

introductionPostbariatric hypoglycaemia (PBH) is a complex medical condition with a significant impact on patients' quality of life. The underlying mechanisms remain to be elucidated. We have shown that food ingestion increases IL-1β and subsequently stimulates insulin secretion. We therefore hypothesised that overactivation of the IL-1β pathway could lead to PBH by promoting excessive insulin secretion after a meal. In a proof-of-concept study, we have shown that acute treatment with the IL-1 receptor antagonist anakinra can attenuate PBH after a single liquid mixed meal. This study aims to validate this therapeutic approach over a longer period of time using the long-acting anti-IL-1β antibody canakinumab. METHODS AND ANALYSIS: In this prospective, randomised, double-blind, placebo-controlled, multicentre trial, we plan to enrol 62 adult patients after bariatric surgery with frequent, postprandial hypoglycaemia (ie, <3.0 mmol/L and at least five hypoglycaemic episodes per week). Eligible subjects will be randomised to receive either single-dose 150 mg canakinumab (Ilaris, Novartis) subcutaneously (s.c.) or matched placebo (1.0 mL physiologic saline). For 28 days, patients are required to wear a blinded continuous glucose monitoring device (CGMS, Dexcom G6) and use a diary to track their hypoglycaemic episodes. Primary outcomes include health-related quality of life, measured by the SF-36, as well as postprandial hypoglycaemic events (glucose <3.0 mmol/L). A significant improvement in any one of these outcomes will be considered sufficient to demonstrate the clinical superiority of canakinumab over placebo. Secondary outcomes include patient-oriented measures such as postprandial hypoglycaemic symptoms, hypoglycaemia unawareness, fear of hypoglycaemia, as well as metabolic measures and safety assessments. ETHICS AND DISSEMINATION: The trial was approved by the Cantonal Ethics Committee 'Ethikkommission Nordwest- und Zentralschweiz' in January 2022 (#2021-02325), as well as by Swissmedic in April 2022 (#701280). Current, approved protocol version 1.3 of 28.03.2023. The study is actively recruiting. Results will be published in a relevant scientific journal and communicated to participants and relevant institutions through dissemination activities. Individual data are accessible on request.

trial registrationThe study is registered with the www. CLINICALTRIALS: gov registry (NCT05401578) and the Swiss National Clinical Trials Portal (SNCTP) on www.kofam.ch (SNCTP000004838).