Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism

Study Overview
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Brief Summary
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The objective of the trial is to evaluate the efficacy of dasiglucagon in reducing glucose requirements in children with persistent congenital hyperinsulinism (CHI) requiring continuous intravenous (IV) glucose administration to prevent/manage hypoglycemia.

Official Title
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A Randomized Trial in 2 Parts: Double-Blind, Placebo-Controlled, Crossover Part 1 and Open-label Part 2, Evaluating the Efficacy and Safety of Dasiglucagon for the Treatment of Children With Congenital Hyperinsulinism

Conditions
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Congenital Hyperinsulinism

Intervention / Treatment
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* Drug: dasiglucagon
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CHI diagnosis established based on the following: Hyperinsulinemia: plasma insulin above the limit of detection of the assay documented during an event of hypoglycemia, and/or Hypofattyacidemia: plasma free fatty acid <1.7 mmol/L, and/or Hypoketonemia: Beta-hydroxybutyrate <1.8 mmol/L, and/or Glycemic response: an increase in PG of >30 mg/dL (1.7 mmol/L) after 1 mg IV or intramuscular (IM) glucagon administration Male or female, age ≥7 days and <12 months at screening Body weight of ≥2.0 kg (4.4 lbs.) Continuous IV glucose requirement to prevent hypoglycemia Exclusion Criteria: Is suspected of having a transient form of CHI (e.g., transient hyperinsulinism due to maternal diabetes or perinatal stress) Was born preterm below 34 weeks of gestational age Presence of hypertension or hypotension, including circulatory instability requiring supportive medication or presence of pheochromocytoma Known or suspected presence of severe brain damage Evidence of metabolic, endocrine, or syndromic causes of hypoglycemia not due to hyperinsulinism Use of systemic corticosteroids, e.g., hydrocortisone >20 mg/m2 body surface area or equivalent within 5 days before screening Prior use of lanreotide, sirolimus (mechanistic target of rapamycin (mTOR) inhibitors), anti inflammatory biological agents, or other immune modulating agents. Prior use of octreotide is allowed after a minimum of 48 hour washout before randomization. Any clinically significant abnormality identified on echocardiogram that in the opinion of the investigator would affect the subject's ability to participate in the trial Any recognized clotting or bleeding disorder The use of prescription or non-prescription medications known to cause QT prolongation

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 364 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dasiglucagon first then placebo<br>48 hours of dasiglucagon subcutaneous (sc) infusion starting at 10 µg/hour with crossover to 48 hours placebo sc infusion (part 1) followed by 21 days of dasiglucagon sc infusion (part 2). | Drug: dasiglucagon<br>* Glucagon analogue<br>* Other names: ZP4207;Drug: Placebo<br>* Placebo for dasiglucagon<br>|
| Experimental: placebo first then dasiglucagon<br>48 hours of placebo sc infusion with crossover to 48 hours dasiglucagon sc infusion starting at 10 µg/hour (part 1) followed by 21 days of dasiglucagon sc infusion (part 2). | Drug: dasiglucagon<br>* Glucagon analogue<br>* Other names: ZP4207;Drug: Placebo<br>* Placebo for dasiglucagon<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean intravenous glucose infusion rate | Mean intravenous glucose infusion rate in the last 12 hours of each treatment period during the crossover part of the trial (dasiglucagon or placebo administration) | 36-48 hours after initiation of trial drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carbohydrates administered | Total amount (g) of carbohydrates administered during the crossover part of the trial (dasiglucagon or placebo administration) per day | 0-48 hours after initiation of trial drug | 
| Carbohydrates administered | Mean intravenous glucose infusion rate for each 48-hour treatment period during the crossover part of the trial (dasiglucagon or placebo administration) | 0-48 hours after initiation of trial drug | 
| Carbohydrates administered | Mean intravenous glucose infusion rate below 10 mg/kg/min in the last 12 hours of each treatment period during the crossover part of the trial (yes/no) (dasiglucagon or placebo administration) | 36-48 hours after initiation of trial drug | 
| Time to complete weaning off intravenous glucose | Time to complete weaning off intravenous glucose administration during part 2 | Day 5-25 | 
| Hypoglycemia event rate in part 2 | Hypoglycemia event rate, defined as number of hypoglycemic events (PG <70 mg/dL or 3.9 mmol/L), as detected by self-monitored plasma glucose | Day 5-25 | 
| Clinically significant hypoglycemia events in part 2 | Clinically significant hypoglycemia event rate, defined as number of events <54 mg/dL (3.0 mmol/L), as detected by self-monitored plasma glucose | Day 5-25 | 
| Time to actual hospital discharge | Time (days) from start of part 2 until the patient is discharged from the hospital | Day 5-25 | 
| Time to pancreatic surgery | Time (days) to pancreatic surgery (sub-total or total pancreatectomy) | Day 5-25 | 
| Carbohydrates administered | Total amount (g) of carbohydrates administered (regardless of the route) per day | Day 5-25 | 
| Carbohydrates administered intravenously | Amount (g) of carbohydrates administered via IV glucose infusion or bolus (not as part of total parental nutrition) | Day 5-25 | 
| Carbohydrates administered parenterally | Amount (g) of carbohydrates administered as part of total parenteral nutrition | Day 5-25 | 
| Carbohydrates administered orally | Amount (g) of carbohydrates administered via oral route | Day 5-25 | 
| Carbohydrates administered via gastric feed | Amount (g) of carbohydrates administered via nasogastric tube or gastrostomy | Day 5-25 | 
| Time in range in part 2 | Percent time in range 70-180 mg/dL (3.9-10.0 mmol/L) as measured by continuous glucose monitoring | Day 5-25 | 
| Time in hypoglycemia in part 2 | Percent time in hypoglycemia (<70 mg/dL or 3.9 mmol/L) as measured by continuous glucose monitoring | Day 5-25 | 
| Time in clinically significant hypoglycemia in part 2 | Percent time in clinically significant hypoglycemia (<54 mg/dL or 3.0 mmol/L) as measured by continuous glucose monitoring | Day 5-25 | 
| Hypoglycemia episodes in part 2 | Rate of hypoglycemia episodes, defined as number of episodes <70 mg/dL (3.9 mmol/L) for 15 min or more, as measured by continuous glucose monitoring | Day 5-25 | 
| Clinically significant hypoglycemia episodes in part 2 | Rate of clinically significant hypoglycemia episodes, defined as number of episodes <54 mg/dL (3.0 mmol/L) for 15 min or more, as measured by continuous glucose monitoring | Day 5-25 | 
| Extent of hypoglycemia in part 2 | Extent of hypoglycemia (area over the glucose curve [AOCglucose] below 70 mg/dL [3.9 mmol/L]) as measured by continuous glucose monitoring | Day 5-25 | 
| Extent of clinically significant hypoglycemia in part 2 | Extent of clinically significant hypoglycemia (area over the glucose curve [AOCglucose] below 54 mg/dL [3.0 mmol/L]) as measured by continuous glucose monitoring | Day 5-25 | 
| Time in hyperglycemia in part 2 | Percent time in hyperglycemia (>180 mg/dL or 10.0 mmol/L), as measured by continuous glucose monitoring | Day 5-25 |