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

Rezolute23 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Congenital Hyperinsulinism

Interventions

RZ358 Sequential Group Cohort 1DRUG

IV infusion for 8 weeks (3 mg/kg bi-weekly for 8 weeks)

RZ358 Sequential Group Cohort 2DRUG

IV infusion for 8 weeks (6 mg/kg bi-weekly for 8 weeks)

RZ358 Sequential Group Cohort 3DRUG

IV infusion for 8 weeks (9 mg/kg bi-weekly for 8 weeks)

Eligibility

Sex: ALLMin age: 2 YearsMax age: 45 Years

Medical Language ↔ Plain English

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

Locations (17)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Outcomes

Primary Outcomes

Median of Average Daily Percent Time Within a Glucose Target Range of 70-180 mg/dL (3.9-10 mmol/L) by CGM at Baseline (BL) and End of Treatment (EOT)

The median of average daily percent time within the glucose target range 70-180 mg/dL (3.9-10 mmol/L) by CGM at Baseline and End of Treatment (EOT) is reported.

Time frame: 8 weeks

Median Percent Change of Average Daily Percent Time Within a Glucose Target Range of 70-180 mg/dL (3.9-10 mmol/L) by CGM From Baseline (BL)

The average daily percent time within the glucose target range (70-180 mg/dL) is compared from baseline to end of treatment (EOT) and the median percent change of that difference is reported.

Time frame: 8 weeks

Repeat Dose Pharmacokinetics of RZ358

All patients who received RZ358 and for whom the primary PK data was considered to be sufficient and interpretable were to be included in the PK analyses. Individual and mean plasma concentration data is summarized descriptively at the specified timepoints. The results of this study may be combined with those of other studies for analysis and modeling (e.g., population PK and PK-PD), and therefore the PK parameters are reported separately, as part of an iterative population PK approach.

Time frame: Pre dose Weeks 1,3,5,7, 1-hr post dose Week 1 and Week 7, and Follow up on Days 14, Day 28, Day 42, and Day 105

Secondary Outcomes

Median of Average Weekly Overall, Moderate, and Severe Hypoglycemia Events by SMBG at Baseline (BL) and End of Treatment (EOT)

The median of average weekly number of overall hypoglycemia events (\<70 mg/dL \[3.9mmol/L\], moderate hypoglycemia events (\<60 mg/dL \[3.3 mmol/L\] and severe hypoglycemia events (\<50 mg/dL \[2.8mmol/L\]) by SMBG at baseline (BL) and end of treatment (EOT) is reported.

Time frame: 8 weeks

Median Percent Change of Average Weekly Overall, Moderate, and Severe Hypoglycemia Events by SMBG From Baseline (BL)

Data from ClinicalTrials.gov

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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)

SHAT Children diseases "Prof. Dr. Ivan Mitov"

Sofia, Bulgaria

Medical University of Varna UMHAT "St. Marina"

Varna, Bulgaria

Research Institute of the McGill University Health Centre

Monteral, Qubec, Canada

Odense University Hospital

Odense, Denmark

LTD "Pediatric Surgery Centre"

Tbilisi, Georgia

Magdeburg University Clinic Center (Otto-von-Guericke Universität)

Magdeburg, Germany

Edmond & Lilly Safra's Children Hospital

Ramat Gan, Tel-Hashomer, Israel

Hadassah Har Hazofim MC - Division of Pediatric Endocrinology

Jerusalem, Israel

...and 7 more locations

The average weekly number overall hypoglycemia events (\<70 mg/dL \[3.9mmol/L\], moderate hypoglycemia events (\<60 mg/dL \[3.3 mmol/L\] and severe hypoglycemia events (\<50 mg/dL \[2.8mmol/L\]) by SMBG is compared from baseline (BL) to end of treatment (EOT) and the median percent changes of those differences are reported.

Median of Average Daily Percent Time With Overall, Moderate, and Severe Hypoglycemia by CGM at Baseline (BL) and End of Treatment (EOT)

The median of average daily percent time in overall (\<70 mg/dL \[\<3.9 mmol/L\]), moderate (\<60 mg/dL \[3.3 mmol/L\]), and severe (\<50 mg/dL \[2.8 mmol/L\]) hypoglycemia at baseline (BL) and end of treatment (EOT) is reported.

Time frame: 8 weeks

Median Percent Change of Average Daily Percent Time With Overall, Moderate, and Severe Hypoglycemia by CGM From Baseline (BL)

The average daily percent time in overall (\<70 mg/dL \[\<3.9 mmol/L\]), moderate (\<60 mg/dL \[3.3 mmol/L\]), and severe (\<50 mg/dL \[2.8 mmol/L\]) hypoglycemia is compared from baseline (BL) to end of treatment (EOT) and the median percent changes of those differences are reported.

Time frame: 8 weeks

Median of Average Daily Duration (Minutes) With Overall, Moderate, and Severe Hypoglycemia by CGM at Baseline (BL) and End of Treatment (EOT)

The median of average duration (minutes) in overall (\<70 mg/dL \[\<3.9 mmol/L\]), moderate (\<60 mg/dL \[3.3 mmol/L\] ), and severe (\<50 mg/dL \[2.8 mmol/L\]) hypoglycemia by CGM at baseline (BL) and end of treatment (EOT) is reported.

Time frame: 8 weeks

Median Percent Change of Average Daily Duration (Minutes) With Overall, Moderate, and Severe Hypoglycemia by CGM From Baseline (BL)

The average duration (minutes) in overall (\<70 mg/dL \[\<3.9 mmol/L\]), moderate (\<60 mg/dL \[3.3 mmol/L\] ), and severe (\<50 mg/dL \[2.8 mmol/L\]) hypoglycemia by CGM is compared from baseline (BL) to end of treatment (EOT) and the median percent changes of those differences are reported.

Time frame: 8 weeks

Occurrence of Hypoglycemia During Fasting Challenge

The occurrence of hypoglycemia during a 12 Hour fasting challenge.

Time frame: 8 Weeks

Median of Average Hypoglycemia Events Per Day at Each of the Specified Glucose Thresholds by CGM at Baseline (BL) and End of Treatment (EOT)

The median of average hypoglycemia events per day at each of the specified glucose thresholds \[\<70, \<60, and \<50 mg/dL (3.9, 3.3, and 2.8 mmol/L)\], by CGM at baseline (BL) and end of treatment (EOT) is reported.

Time frame: 8 weeks

Median Net Change of Average Hypoglycemia Events Per Day at Each of the Specified Glucose Thresholds by CGM From Baseline (BL)

The average hypoglycemia events per day at each of the specified glucose thresholds \[\<70, \<60, and \<50 mg/dL (3.9, 3.3, and 2.8 mmol/L)\], by CGM is compared from baseline (BL) to end of treatment (EOT) and the median net changes of those differences are reported.

Time frame: 8 weeks

Median of Average 8-hour Overnight Percent Time in Glucose Target Range of 70-180mg/dL by CGM at Baseline (BL) and End of Treatment (EOT)

The median of average 8-hour overnight (12am-8am) percent time within the glucose target range (70-180 mg/dL) at baseline (BL) and end of treatment (EOT) is reported.

Time frame: 8 weeks

Median Percent Change of Average 8-hour Overnight Percent Time in Glucose Target Range of 70-180mg/dL by CGM From Baseline (BL)

The average 8-hour overnight (12am-8am) percent time within the glucose target range (70-180 mg/dL) is compared from baseline (BL) to end of treeatment (EOT) and the median percent change of that difference is reported.

Time frame: 8 weeks