Long-Term Safety and Efficacy Evaluation of Glepaglutide in Patients with Short Bowel Syndrome: A Phase 3 Double-Blind Extension Trial

Trial ID: 2024-513374-22-00
Protocol: ZP1848-17127
Sponsor: Zealand Pharma A/S

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Diseases & Conditions

Short-bowel syndrome

Objectives

The primary objective of this study is to evaluate the long-term **safety** of glepaglutide treatment in patients with **Short Bowel Syndrome (SBS)**. This is clinically relevant as ensuring the safety of long-term treatment options is crucial for managing chronic conditions like SBS, where patients often require ongoing therapy to maintain nutritional status and quality of life.

Secondary objectives include:

Evaluating the long-term efficacy of glepaglutide treatment in SBS patients, which is important for understanding the sustained therapeutic benefits of the drug.
Assessing the long-term immunogenicity of glepaglutide and its impact on pharmacokinetics (PK), efficacy, and safety in SBS patients, which is essential for determining the potential for immune response and its effects on drug performance and patient safety.
Evaluating the quality of life for SBS patients treated with glepaglutide, providing insights into the broader impacts of treatment on patient well-being and daily functioning.

Participants

The clinical trial involves a total of **36 participants** diagnosed with **Short Bowel Syndrome**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on their previous involvement in a lead-in trial, with eligibility contingent upon either completion of the full treatment phase of the prior trial or meeting the same inclusion and exclusion criteria as the lead-in trial. The trial does not include a vulnerable population. No specific lifestyle considerations such as diet, physical activity, or habits have been highlighted for this study. The primary objective is to evaluate the long-term safety of glepaglutide treatment in this patient population.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the long-term safety and efficacy of **glepaglutide** in patients with **Short Bowel Syndrome**. The trial is a Phase 3 extension, following a lead-in trial, and aims to assess both safety and efficacy endpoints. The study involves the administration of **glepaglutide** as a **solution for injection** via **subcutaneous use**. Participants will be randomly assigned to receive either the active treatment or a placebo. The trial is expected to last until November 2026, with participant involvement potentially extending up to 104 weeks, depending on individual response and adherence to the protocol.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as completion of the lead-in trial or meeting specific inclusion/exclusion criteria. Follow-up visits will occur at regular intervals to monitor safety endpoints, including the incidence of adverse events, changes in vital signs, and laboratory assessments such as hematology and biochemistry. Efficacy will be evaluated through endpoints like the reduction in parenteral support volume and the number of days on parenteral support per week. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or choose to withdraw consent. The trial's primary objective is to ensure the long-term safety of **glepaglutide** treatment, with secondary objectives focusing on efficacy measures. The study's design and procedures are meticulously planned to provide robust data on the treatment's impact on **Short Bowel Syndrome**, contributing valuable insights into its potential as a therapeutic option.

Treatment

The clinical trial involves the administration of **Glepaglutide**, a synthetic peptide, as the experimental medication. Glepaglutide is provided in a **solution for injection** form, with a concentration of 20.0 mg/mL. The medication is administered subcutaneously, with a maximum daily dose of 10 mg. The treatment period extends up to 104 weeks. The active substance, glepaglutide, is classified as a protein of other origin. The pharmaceutical product is developed by Zealand Pharma and is identified by the sponsor product code ZP1848 20.0 mg/mL. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group, which receives a placebo treatment designed to match the experimental medication in appearance but contains no active substance. The placebo is used to provide a comparator for assessing the efficacy and safety of glepaglutide in patients with short bowel syndrome. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The use of a placebo control is essential for evaluating the true therapeutic effects of the experimental medication.

Efficacy

The clinical trial aims to assess the efficacy of **glepaglutide** in patients with Short Bowel Syndrome (SBS) through a series of predefined endpoints. Efficacy will be primarily evaluated by measuring the reduction in weekly parenteral support (PS) volume from baseline. Specific efficacy endpoints include a reduction of at least 20% in weekly PS volume, a reduction in days on PS by at least one day per week from baseline, and a complete reduction in weekly PS volume, indicating weaning off PS.

Secondary efficacy endpoints will include changes in fluid composite effect (FCE) from baseline, reduction in the calculated energy content of parenteral macronutrients, reduction in the number of days on PS per week, a reduction of at least 40% in weekly PS volume, and changes in weight from baseline. These parameters will be collected and analyzed at various timepoints throughout the trial to determine the long-term efficacy of glepaglutide treatment in the target population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients rolling over from the lead-in trial: Signed informed consent
Patients rolling over from the lead-in trial: A) Completed the full Treatment Phase of the lead-in trial (ZP1848-17111), regardless of treatment adherence OR B) Eligible based on the same inclusion/exclusion criteria as in the lead-in trial (patients may be directly screened into this trial)

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Exclusion Criteria

Patients rolling over from the lead-in trial: Withdrew consent from lead-in trial.
Patients rolling over from the lead-in trial: Any condition, disease, or circumstance that in the Investigator's opinion would put the patient at any undue risk, prevent completion of the trial, or confounds planned assessments of the trial.
Patients rolling over from the lead-in trial: Use of GLP-1, GLP-2, human growth hormone (HGH), dipeptidyl peptidase-4 (DPP-4) inhibitors, citrulline, somatostatin, or analogs thereof within 3 months. Note: Prior glepaglutide trial drug is allowed.
Patients rolling over from the lead-in trial: Females of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant, or are not using highly effective contraceptive methods. Highly effective contraception methods and definition of child-bearing potential are described in Section 11.4.4.
Patients rolling over from the lead-in trial: Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
Patients rolling over from the lead-in trial: An employee of the sponsor or Investigator or otherwise dependent on them.
Patients screened directly to the Extension Trial: More than More than 2 SBS-related or PS-related hospitalizations (e.g., catheter related bacteremia/sepsis, bowel obstruction, severe water-electrolytes disturbances, etc.) within 6 months prior to Screening.
Patients screened directly to the Extension Trial: Poorly controlled inflammatory bowel disease (IBD) that is moderately or severely active or fistula interfering with measurements or examinations required in the trial.
Patients screened directly to the Extension Trial: Bowel obstruction.
Patients screened directly to the Extension Trial: Known radiation enteritis or significant villous atrophy, e.g., due to active celiac disease.
Patients screened directly to the Extension Trial: Cardiac disease defined as: decompensated heart failure (New York Heart Association [NYHA] Class III-IV), unstable angina pectoris, and.
Patients screened directly to the Extension Trial: Clinically significant abnormal ECG as judged by the Investigator.
Patients screened directly to the Extension Trial: Repeated (2 or more consecutive measurements separated by at least 15 minutes) systolic blood pressure measurements > 180 mm Hg.
Patients screened directly to the Extension Trial: Human immunodeficiency virus (HIV) positive, acute liver disease, or unstable chronic liver disease.
Patients screened directly to the Extension Trial: Any history of colon cancer. History of any other cancers (except margin-free resected cutaneous basal or squamous cell carcinoma or adequately treated in situ cervical cancer) unless disease-free state for at least 5 years.
Patients screened directly to the Extension Trial: Estimated creatinine clearance (CrCL; by the Cockcroft-Gault formula) < 30 mL/min.
Patients screened directly to the Extension Trial: Hepatic impairment defined as: a. Total bilirubin ≥ 2 × the upper limit of normal (ULN), or b. Aspartate aminotransferase (AST) ≥ 5 × ULN, or c. Alanine aminotransferase (ALT) ≥ 5× ULN
Patients screened directly to the Extension Trial: Use of GLP-1, GLP-2, HGH, somatostatin, or analogs thereof, within 3 months prior to Screening.
Patients screened directly to the Extension Trial: Use of DPP-4 inhibitors within 3 months prior to Screening.
Patients screened directly to the Extension Trial: Systemic immunosuppressive therapy that has been introduced or has been unstable within 3 months prior to Screening.
Patients screened directly to the Extension Trial: Unstable biological therapy (e.g. anti-tumor necrosis factor alpha [TNF-α], natalizumab, etc.) within 6 months prior to Screening, including significant changes in doses or switch of drug.
Patients screened directly to the Extension Trial: Females of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant or are not using highly effective contraceptive methods. Highly effective contraception methods and definition of child-bearing potential are described in Section 11.4.4.
Patients screened directly to the Extension Trial: Known or suspected hypersensitivity to glepaglutide or related products.
Patients screened directly to the Extension Trial: Previous exposure to glepaglutide.
Patients screened directly to the Extension Trial: Previous participation (randomization) in this trial.
Patients screened directly to the Extension Trial: Current, or within 30 days prior to Screening, participation in another interventional clinical trial that includes administration of an active compound.
Patients screened directly to the Extension Trial: Mental incapacity or language barriers which preclude adequate understanding or cooperation, or unwillingness to comply with trial requirements.
Patients screened directly to the Extension Trial: Any condition or disease or circumstance that in the Investigator's opinion would put the patient at any undue risk, prevent completion of the trial, or interfere with the analysis of the trial results.
Patients screened directly to the Extension Trial: Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
Patients screened directly to the Extension Trial: An employee of the Sponsor or Investigator or otherwise dependent on them.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	07 May 2019	10
France	Not Recruiting	07 May 2019	8
Germany	Not Recruiting	07 May 2019	24
The Netherlands	Not Recruiting	07 May 2019	—
Poland	Not Recruiting	07 May 2019	32
Netherlands	—	—	3