A Phase 3, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Multicenter Trial to Confirm the Efficacy and Safety of Glepaglutide 10 mg Twice-Weekly, Followed by a Long-Term, Open-Label Safety Evaluation in Patients with Short Bowel Syndrome–Intestinal Failure (SBS-IF)

The primary objective is to confirm the efficacy of glepaglutide 10 mg administered twice weekly in patients with short bowel syndrome with intestinal failure (SBS-IF). This addresses a critical clinical need in managing patients who require parenteral support due to inadequate intestinal absorption capacity following extensive bowel resection or disease. The secondary objectives include: evaluation of the efficacy of glepaglutide on additional efficacy endpoints in patients with SBS-IF, and assessment of the safety and tolerability of glepaglutide in this patient population.

The clinical trial enrolled a total of **24 participants** diagnosed with **Short Bowel Syndrome** requiring **parenteral support**. The study population comprised both **male** and **female** subjects aged between **18 and 90 years**. Participants were selected based on specific clinical characteristics, including a diagnosis of Short Bowel Syndrome defined by an estimated **small bowel length of less than 200 cm** in continuity, with the most recent intestinal resection having occurred at least 6 months prior to screening. Eligible individuals demonstrated a stable parenteral support requirement of at least **3 days per week** and had either a **stoma** or **colon in continuity**. Participants with planned restorative surgery during the trial period were not included in the study population. All enrolled subjects provided **signed informed consent** prior to participation. The trial included a **vulnerable population**.

This is a Phase 3, double-blind, randomized, parallel-group, placebo-controlled, multicenter clinical trial designed to confirm the efficacy and safety of glepaglutide 10 mg administered twice weekly in patients with Short Bowel Syndrome with intestinal failure (SBS-IF), followed by a long-term, open-label safety evaluation. The trial investigates glepaglutide, a synthetic peptide available as a 20.0 mg/mL solution for injection, administered via subcutaneous route. The maximum daily dose is 10 mg, with a maximum total dose of 10 mg and a maximum treatment period of 48 weeks. The control group receives a matching placebo. The study is estimated to commence recruitment in January 2026 and is expected to conclude in February 2032.

The primary objective of the trial is to confirm the efficacy of glepaglutide 10 mg twice weekly in patients with SBS-IF. The primary endpoint is the change in weekly parenteral support (PS) volume from baseline to Week 24. Secondary endpoints include clinical response defined as achieving at least a 20% reduction in weekly PS volume from baseline to Week 52, reduction in days on PS by at least 1 day per week from baseline to Week 52, complete weaning off PS (100% reduction in weekly PS volume) from baseline to Week 52, achieving 'much better' Patient Global Impression of Change (PGIC) status at Week 24, clinical response at both Week 20 and Week 24, reduction in days on PS from baseline to Week 24, complete weaning off PS from baseline to Week 24, changes in weekly PS volume from baseline to Week 12 and Week 8, and treatment-emergent adverse events (TEAEs) from baseline to Week 52.

Eligible participants must meet the following principal inclusion criteria: signed informed consent; age between 18 and 90 years; a diagnosis of SBS defined as having a small bowel with an estimated length of less than 200 cm in continuity with the latest intestinal resection having occurred at least 6 months before screening; stable PS need of at least 3 days per week; no restorative surgery planned during the trial period; and having a stoma or colon in continuity. The screening visit serves to assess eligibility and establish baseline measurements. Participants will attend scheduled follow-up visits throughout the treatment period to monitor efficacy and safety parameters, with key assessment points at Week 8, Week 12, Week 20, Week 24, and Week 52. The end-of-study visit will occur at Week 52 for the controlled phase, followed by continuation into the long-term open-label safety evaluation phase.

The expected length of participant involvement extends through the 52-week controlled phase and continues into the long-term open-label extension phase. Early termination from the study may occur under conditions such as withdrawal of consent, significant protocol violations, safety concerns, adverse events requiring discontinuation, or at the discretion of the investigator if continued participation is not in the best interest of the participant.

The experimental medication **glepaglutide** is administered as a **solution for injection** at a concentration of 20.0 mg/mL. Glepaglutide is a **synthetic peptide** with the active substance classified as a protein. The **pharmaceutical form** is supplied as a solution for injection intended for **subcutaneous use**. The **dosage** consists of 10 mg administered **twice weekly**, with a **maximum daily dose** of 10 mg and a **maximum total dose** of 10 mg per administration. The **treatment period** extends up to **48 weeks**. The product is manufactured by Zealand Pharma and identified by the sponsor product code ZP1848 20.0 mg/mL. Administration is facilitated using a medical device that bears the CE mark, ensuring compliance with regulatory standards for safety and quality.

A **placebo** for glepaglutide is utilized as the **comparator treatment** in this **double-blind, randomized, parallel-group, placebo-controlled** clinical trial. The placebo is designed to match the experimental medication in appearance and administration method to maintain blinding throughout the study. Participants receiving placebo undergo the same dosing schedule and route of administration as those receiving the active treatment, ensuring consistency in study procedures and enabling valid comparison of efficacy and safety outcomes between treatment groups.

Efficacy will be assessed using **parenteral support (PS)** volume and frequency as the primary measures in patients with **short bowel syndrome-intestinal failure**. The primary endpoint is the change in weekly PS volume from baseline to Week 24. Secondary efficacy endpoints include clinical response defined as achieving at least a 20% reduction in weekly PS volume from baseline to Week 52, reduction in days on PS by at least 1 day per week from baseline to Week 52, and complete weaning off PS (100% reduction in weekly PS volume) from baseline to Week 52. Additional secondary endpoints assess Patient Global Impression of Change (PGIC) status at Week 24, clinical response defined as achieving at least a 20% reduction in weekly PS volume from baseline to both Week 20 and Week 24, reduction in days on PS by at least 1 day per week from baseline to Week 24, complete weaning off PS from baseline to Week 24, and changes in weekly PS volume from baseline to Week 12 and Week 8. Safety will be evaluated through treatment-emergent adverse events from baseline to Week 52. The trial includes a double-blind, placebo-controlled phase followed by a long-term open-label safety evaluation period extending up to 48 weeks of treatment.