Evaluation of Sotagliflozin in the Management of Post-Bariatric Hypoglycemia: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

The primary objective of the study is to evaluate the effect of **sotagliflozin** on hypoglycemia and glycemic excursions in individuals who have undergone Roux-en-Y gastric bypass (RYGB) surgery and are experiencing confirmed biochemical post-bariatric hypoglycemia. This is clinically relevant as post-bariatric hypoglycemia can significantly impact the quality of life and metabolic stability of affected individuals. The study is designed as an interventional, randomized, double-blind, placebo-controlled crossover trial, where participants will receive sotagliflozin 400 mg once daily and a placebo in random order over two four-week periods.

The clinical trial involves participants diagnosed with **post-bariatric hypoglycaemia**, specifically those who have undergone Roux-en-Y gastric bypass (RYGB) surgery more than 18 months prior. The study population includes both male and female subjects, aged between 18 and 74 years, who are in general good health with no history of cardiac arrhythmias or cardiac ischaemia. Participants must have a history of postprandial neuroglycopenia and documented episodes of level 2 hypoglycaemia. The trial does not involve a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **sotagliflozin** in managing **postbariatric hypoglycaemia**. This is a randomized, double-blind, placebo-controlled crossover study involving participants who have undergone Roux-en-Y gastric bypass (RYGB) surgery and are experiencing confirmed biochemical post-bariatric hypoglycaemia. The trial will involve two intervention periods, each lasting four weeks, where participants will receive either sotagliflozin 400 mg once daily or a placebo, administered orally in a random sequence. The primary objective is to assess the time spent in level 2 hypoglycaemia, with secondary endpoints including various measures of glycaemic control and variability.

Participants will be involved in the study for a total duration of approximately five weeks, including a screening visit, two treatment periods, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, history of postprandial neuroglycopenia, and specific glucose concentration thresholds. Follow-up visits will occur at the end of each treatment period to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all study endpoints.

Inclusion criteria require participants to be aged 18-74 years, have undergone RYGB surgery more than 18 months prior, and have documented episodes of hypoglycaemia. Exclusion criteria include any history of cardiac arrhythmias or ischaemia, and for women, a negative urine human chorionic gonadotropin (hCG) test is required. Participants may be withdrawn from the study if they experience adverse events or if they do not adhere to the study protocol. The trial is expected to start recruitment in September 2024 and conclude by March 2026.

The clinical trial involves the administration of **Sotagliflozin**, an experimental medication, in the form of a film-coated tablet. The active substance, **Sotagliflozin**, is a small molecule of chemical origin. Participants will receive a dosage of 400 mg once daily (QD) via the oral route. The maximum daily dose is set at 400 mg, with a total maximum dose of 14,000 mg over the treatment period. The treatment duration is limited to a maximum of five weeks. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** will be used as a comparator in this double-blind, placebo-controlled crossover study. The placebo is also administered as a film-coated tablet, matching the pharmaceutical form of the experimental medication. The placebo will be given orally at a dosage of 400 mg once daily, mirroring the administration schedule of **Sotagliflozin**. The placebo serves as a control to evaluate the efficacy and safety of the experimental treatment. The study design ensures that each participant receives both the experimental medication and the placebo in a randomized order, allowing for a comprehensive assessment of the treatment's impact on post-bariatric hypoglycaemia.

The efficacy of **sotagliflozin** in the treatment of post-bariatric hypoglycaemia will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the time spent in level 2 hypoglycaemia, defined as interstitial glucose (IG) levels below 3.0 mmol/l, measured using continuous glucose monitoring (CGM) during the outpatient phase of the study. This will compare the effects of sotagliflozin 400 mg once daily (QD) against a placebo.

Secondary endpoints include various measures of glycaemic control and variability. These encompass the time spent in level 1 hypoglycaemia (IG 3.0–3.9 mmol/l), time below range (IG < 3.9 mmol/l), time within the target range (IG 3.9–10.0 mmol/l), and time above specified glucose thresholds (>7.8, >10.0, and >13.9 mmol/l). Additionally, the frequency of hypoglycaemic and hyperglycaemic events, glycaemic variability assessed by coefficient of variation (CV), standard deviation (SD), and low blood glucose index (LBGI) will be evaluated. Patient-reported outcomes will be measured using the Edinburgh Hypoglycaemia Symptom Scale (EHSS), Hypoglycaemia Fear Scale (HFS-II), and the 36-item Short Form health survey (SF-36).

In the inpatient part of the study, nadir plasma glucose levels, time spent in hypoglycaemia, and changes in plasma/serum concentrations of various hormones and metabolites will be assessed. The rate of gastric emptying will be evaluated using acetaminophen concentration metrics. These assessments will provide a comprehensive evaluation of the efficacy of sotagliflozin in managing post-bariatric hypoglycaemia.