This study is sponsored by Children's Hospital of Philadelphia Department of Radiology. The purpose of this research is to study 18F-L-Fluoro-DOPA (F-DOPA), a tracer, which is used to take pictures of the pancreas. This imaging test is called an F-DOPA PET scan. The F-DOPA tracer is used to highlight areas of the pancreas that make too much insulin on the PET scan images. The test includes a CT scan (computerized tomography) done at the same time on the same machine, to help define exactly where the highlighted area is located within the pancreas and determine the location of blood vessels and other vital structures. Who can participate:

• Infants, children and adults with hyperinsulinemic hypoglycemia, diagnosed by a fasting test and/or response to glucagon stimulation
• Any age, from birth on
• Requiring surgery to remove part or all of the pancreas

The purpose of this study is to look at the safety and tolerability (how well you will react) of the study drug (HM15136) and to determine if it is effective for the treatment of Congenital Hyperinsulinism (HI). HM15136 is an experimental drug which is not approved by the FDA for the treatment of HI. HM15136 is stable and has a long effect in the body, only requiring it to be given (by injection) once a week. HM15136 is designed to act like glucagon, a hormone produced by the pancreas that helps the body maintain normal blood sugar levels by increasing the glucose produced in the liver and breaking down glycogen (a form of stored glucose) into the usable glucose form.

Participation lasts for up to 22 weeks and will involve up to 13 study visits. Study procedures include taking the study drug for 8 weeks, having electrocardiograms, wearing a continuous glucose monitor (CGM) and using a handheld glucose meter, having blood and urine tests, and completing an electronic diary.

The main risks of this study include: nausea, vomiting, diarrhea, abdominal pain, injection site reactions (swelling, itching, bleeding, or pain), loss of appetite, weight loss, high blood sugar. You may benefit if the study drug proves to be more effective than your current treatment plan in treating low blood sugar.

The purpose of this study is to understand how cognitive function changes over time in children with hyperinsulinism (HI) compared to children who are healthy volunteers. Participants will be asked to complete cognitive function tasks and questionnaires three times over the course of two years: at the start of the study, one year later, and one year after that. Each visit is approximately 2 hours. If you like, you can receive a summary of the results from the tasks. Compensation is provided for your time and effort.

The Congenital Hyperinsulinism Center at the Childrens Hospital of Philadelphia is working on a research study to better understand how people with hyperinsulinism may have different blood sugar responses to certain tests (like fasting or drinking a high-protein shake) when compared to people without hyperinsulinism. This study will involve a screening visit where we will ask you about your medical history and any known episodes of low blood sugar. Depending on your responses during the interview, you will be asked to complete up to five tests at our outpatient research center. These tests include fasting, drinking a high-protein shake, drinking a high-sugar drink, eating a regular meal, and exercising on a stationary bike. We will collect blood samples from an IV throughout the tests to measure certain blood levels like glucose and insulin. You will be compensated for some or all of your travel costs and you will receive payment for your time. If you are interested in learning more, please contact us at HIResearch@chop.edu.

Our team is working on a study to better understand neurological problems, including seizures and developmental delays, that occur in children with hyperinsulinism, including HI/HA syndrome, and type 1 diabetes mellitus. The study involves a one-day visit to The Children's Hospital of Philadelphia and The University of Pennsylvania for a specialized magnetic resonance imaging scan (MRI) of the brain, an electroencephalogram (EEG), blood draw, and completion of questionnaires to evaluate development and behavior. The entire study visit is expected to take about five hours. If you are interested in learning more, please contact us at HIResearch@email.chop.edu.

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.