This clinical trial is for patients with congenital hyperinsulinism (HI) who are experiencing low blood sugar on their current treatment. The purpose of this study is to find out if the study drug, named RZ358, helps improve blood sugar levels compared to current HI treatments. RZ358 is an experimental drug which the FDA has approved for use in this clinical trial, but it has not approved the study drug to be given outside of clinical research testing. The study drug is a specialized protein (called a monoclonal antibody) meant to decrease the effect insulin has on lowering blood sugar.

Participation will last for up to 33 weeks or up to 3 years overall for subjects who would like to join the open-label extension phase. This includes a 5-week Screening Period, a Treatment Period that lasts 24 weeks, and then either an 8-week Follow-up Period or a 2-year Extension Period where participants can continue to receive the study drug. Individuals do not need to participate in the 2-year extension part of the study to take part in the treatment and monitoring period. During the treatment period, participants will be given the study drug or a placebo. A placebo is an inactive substance used to compare how well the study drug works. Only study drug and not placebo is given during the extension period.

Participants in this trial will:

• Receive the study drug or a placebo 7 times during the treatment period
• Receive the study drug for up to 2 years in the optional extension period
• Have electrocardiograms (ECGs)
• Have ultrasounds of their liver
• Wear a continuous glucose monitor (CGM) and take fingerstick glucose checks
• Have research blood tests
• Complete study diaries and surveys

The main risks of this study are from the study drug. These include infusion reactions (redness, tenderness, irritation at the infusion site), headaches, dizziness, hypoglycemia (low blood sugar), upper respiratory infections (colds), and excess body hair growth. Participants may benefit if the study drug proves to be more effective than current HI medications.

Our team is working on a study to see if children with HI/HA Syndrome tolerate Vitamin E supplementation. This is an experimental, non-FDA approved use of Vitamin E which will lead to further studies to evaluate if Vitamin E can be used as a treatment for HI/HA. The study involves taking Vitamin E once a day for two weeks at home, completing a tolerability questionnaires, and two, one-day visits to the CHOP outpatient Center for Human Phenomic Science (one visit before and one visit after taking the Vitamin E supplement for two weeks). During each study visit, fasting oral protein tolerance will be performed and blood samples will be drawn.