An Open-Label Multiple Dose Study of RZ358 in Patients With Congenital Hyperinsulinism

Study Overview
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Brief Summary
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The objective of this trial is to evaluate the safety, tolerability and glucose-raising effects of RZ358 in patients with Congenital Hyperinsulinism (HI).

Detailed Description
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There is a significant unmet medical need to develop new therapies aimed at preventing chronic recurrent hypoglycemia in congenital HI, the most common cause of persistent hypoglycemia in children. RZ358 is a human mAb that allosterically attenuates excessive insulin action on target cells. Therefore, RZ358 is ideally suited as a potential therapy for hyperinsulinism, and it is being developed to treat the hypoglycemia associated with diseases such as congenital HI. This is a Phase 2, multicenter, open label clinical study designed to assess the safety and efficacy of four progressively higher doses of RZ358 in separate groups of patients with hyperinsulinemic hypoglycemia due to Congenital HI, not adequately controlled with or without current standard of care. A screening period of up to 5 weeks will evaluate eligibility. Once enrolled, RZ358 will be administered bi-weekly over 8 weeks, and then patients will complete a post-treatment follow-up period of 13 weeks.

Official Title
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An Open-Label Multiple-Dose Study of RZ358 in Patients With Congenital Hyperinsulinism

Conditions
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Congenital Hyperinsulinism

Intervention / Treatment
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* Drug: RZ358 Sequential Group Cohort 1
* Drug: RZ358 Sequential Group Cohort 2
* Drug: RZ358 Sequential Group Cohort 3
* Drug: RZ358 Sequential Group Cohort 4


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age 2-45 years old (except age 12-45 in US) with an established clinical diagnosis of congenital hyperinsulinism Able to provide written informed consent or, as applicable, assent Confirmed hypoglycemia as assessed by CGM, SMBG, and clinical evaluation, during Screening Willingness to use contraception if of child-bearing potential Exclusion Criteria: Out of range blood work for study entry Body Mass index outside of study entry criteria History of malignancy Clinically significant diseases, seropositivity for HIV, hepatitis B or C antibody Use of systemic corticosteroids within 30 days before Screening Known or suspected allergy to the study drug Recent use of an investigational drug or treatment, or participation in an investigational study Pregnant or lactating women History of drug abuse or excessive alcohol use

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 45 Years

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RZ358 Cohort 1<br> | Drug: RZ358 Sequential Group Cohort 1<br>* IV infusion for 8 weeks (3 mg/kg bi-weekly for 8 weeks)<br>|
| Experimental: RZ358 Cohort 2<br> | Drug: RZ358 Sequential Group Cohort 2<br>* IV infusion for 8 weeks (6 mg/kg bi-weekly for 8 weeks)<br>|
| Experimental: RZ358 Cohort 3<br> | Drug: RZ358 Sequential Group Cohort 3<br>* IV infusion for 8 weeks (9 mg/kg bi-weekly for 8 weeks)<br>|
| Experimental: RZ358 Cohort 4<br> | Drug: RZ358 Sequential Group Cohort 4<br>* IV infusion for 8 weeks (bi-weekly fixed dose-titration from 3 to 9 mg/kg for the first 4 weeks, followed by a fixed 9 mg/kg dose amount thereafter for the remaining 4 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic efficacy: Target glucose control | Change from Baseline in Percent Time in Glucose Target Range by Continuous Glucose Monitor (CGM) | 8 weeks | 
| Repeat dose safety and tolerability of RZ358 | Occurrence of a safety signal as assessed by the incidence of treatment-emergent AEs, SAEs, and AEs leading to study drug discontinuation. | Through 21 Weeks | 
| Repeat dose pharmacokinetics of RZ358 | Change from baseline in RZ358 drug exposure as assessed by Population-PK modeling of maximum concentrations (Cmax) and Area under the Concentration-Time Curve (AUC). | Through 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic efficacy: Occurrence of hypoglycemia | Change from Baseline in the Incidence of Hypoglycemia by Self-Monitored Blood Glucose (SMBG) | 8 weeks | 
| Glycemic efficacy: Duration of Hypoglycemia | Change from Baseline in the Absolute (minutes) and Percent Time with Hypoglycemia by CGM | 8 weeks | 
| Glycemic efficacy: Occurrence of Hypoglycemia | Change from Baseline in the Incidence of Hypoglycemia by CGM | 8 weeks | 
| Overnight Target Glucose Control | Change from Baseline in Percent Time in Overnight (midnight to 8 am) Glucose Target Range by CGM | 8 weeks | 
| Glycemic Efficacy: Ability to Complete a Fast without Hypoglycemia | Change from Baseline in Incidence of Hypoglycemia by SMBG, During a 12-hour Fasting Challenge | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Digestive System Diseases, Hyperinsulinism, Hypoglycemia, Congenital Hyperinsulinism, Glucose Metabolism Disorders, Metabolic Diseases, Pancreatic Diseases