Long-term Safety and Efficacy Evaluation of Subcutaneous Dasiglucagon Infusion in Pediatric Congenital Hyperinsulinism: An Extension Study

The primary objective of this study is to evaluate the long-term **safety** of dasiglucagon when administered as a subcutaneous infusion in children with congenital hyperinsulinism (CHI). This is clinically relevant as ensuring the safety of dasiglucagon is crucial for its potential use in managing CHI, a condition characterized by excessive insulin production leading to hypoglycemia.

Secondary objectives include:

• Evaluating the long-term efficacy of dasiglucagon in reducing hypoglycemia.
• Assessing the long-term efficacy of dasiglucagon in reducing glucose requirements.
• Evaluating the long-term tolerability of dasiglucagon administered as a subcutaneous infusion in children with CHI.
• Investigating quality of life (QoL) and resource utilization.

The clinical trial involves a total of **35 participants** who are children diagnosed with **congenital hyperinsulinism**. The study population includes both male and female subjects, with an age range that falls under the pediatric category. Participants were selected based on their completion of prior treatment in either Trial ZP4207-17103 or ZP4207-17109 and are expected to continue to have a positive benefit-risk assessment for treatment with dasiglucagon. The trial does not specifically target a vulnerable population. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The selection criteria include the ability and willingness to comply with trial procedures, and for females of child-bearing potential, a negative serum pregnancy test at baseline is required. Additionally, sexually active female participants and their partners must adhere to strict contraception guidelines or abstain from sexual activity during the trial period. The trial aims to evaluate the long-term safety of dasiglucagon administered as a subcutaneous infusion in this specific pediatric population.

The clinical trial is designed to evaluate the long-term safety and efficacy of **dasiglucagon** for the treatment of children with **congenital hyperinsulinism** (CHI). This is a Phase 3, randomized, double-blind, controlled trial. The trial is expected to run until November 30, 2026, with recruitment having started on May 2, 2019. Participants will be involved in the study for a maximum treatment period of 57 days, during which they will receive dasiglucagon administered as a subcutaneous infusion. The trial will include several key visits: an inclusion (screening) visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will assess eligibility based on criteria such as completion of prior related trials and a positive benefit-risk assessment for dasiglucagon treatment. Follow-up visits will monitor adverse events, the primary endpoint, and secondary endpoints such as the total amount of gastric carbohydrates administered to treat hypoglycemia and the time to removal of nasogastric tubes. The end-of-study visit will conclude the participant's involvement, assessing overall safety and efficacy outcomes. Participants may be terminated early from the study if they experience significant adverse events or if they no longer meet the inclusion criteria. The trial aims to provide comprehensive data on the safety profile of dasiglucagon in the pediatric population with CHI, contributing to the understanding of its long-term use in managing this rare metabolic disorder.

The clinical trial involves the administration of **Dasiglucagon**, a pharmaceutical product developed by Zealand Pharma. Dasiglucagon is formulated as a **solution for injection** with a concentration of 4 mg/ml. The active substance, dasiglucagon, is a protein of other origin. The medication is administered via **subcutaneous use**. The maximum daily dose is 1.68 mg, with the same amount being the maximum total dose allowed per day. The treatment period extends up to 57 days. Dasiglucagon is delivered using the Accu-Chek® Spirit Combo insulin pump system, which is designed for the subcutaneous infusion of insulin units. The pump system includes the Accu-Chek® FlexLink infusion set, which consists of a cannula and tubing for precise delivery.

In addition to the experimental treatment, the trial utilizes several devices to ensure accurate administration and monitoring. The Accu-Chek® Spirit Combo Pump, including the Accu-Chek® FlexLink Infusion set, is employed for the subcutaneous infusion of dasiglucagon. The Accu-Chek® LinkAssist insertion device is used to facilitate the insertion of the infusion set. Furthermore, the Accu-Chek® Rapid-D Link Infusion set is also available for use in the trial. All devices have been certified with a CE mark, ensuring compliance with safety and performance standards. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of **Dasiglucagon** in the treatment of children with Congenital Hyperinsulinism (CHI) will be assessed through a series of secondary endpoints. These endpoints include the total amount of gastric carbohydrates administered via nasogastric (NG) tube or gastrostomy to treat hypoglycemia, the time to removal of the NG tube or gastrostomy, and the time to pancreatic surgery, whether sub-total or total pancreatectomy. Additionally, continuous glucose monitoring (CGM) will be utilized to evaluate the percent time blood glucose levels are below 70 mg/dL (3.9 mmol/L), the rate of CGM-detected hypoglycemia episodes below 70 mg/dL (3.9 mmol/L) lasting 15 minutes or more, and the rate of clinically significant CGM-detected hypoglycemia episodes below 54 mg/dL (3.0 mmol/L) for 15 minutes or more.

The collection and analysis of these efficacy parameters will be conducted using validated methods and tools, including CGM devices, to ensure accurate and reliable data. The schedule for measuring these parameters will be aligned with the trial's protocol, ensuring consistent and systematic data collection throughout the study period. The trial is designed to provide comprehensive insights into the long-term efficacy of Dasiglucagon in managing CHI, contributing valuable information to the understanding of its therapeutic potential in this patient population.