A Study of Intravenous L-Citrulline in Patients Aged 6-21 Years Old With Sickle Cell Disease Presenting to Emergency Departments in Acute Vaso-Occlusive Crisis

Overview

This study is being done to learn more about a possible new treatment for pain episodes (called vaso-occlusive crises or VOCs) in children, teens, and young adults with sickle cell disease (SCD). The study will include about 120 participants between the ages of 6 and 21 who come to the emergency department (ED) with a VOC. A VOC is a painful episode that happens with no clear cause and no signs of infection or major problems with organs like the liver or kidneys. Before joining the study, patients and their families may be asked to learn about it and give permission (called consent or assent) while at a regular clinic visit. If that hasn't happened yet, the consent/assent process will happen at the emergency department when the patient comes in for care. If the patient meets all the study requirements, they can join the treatment part of the study. Participants will be randomly assigned (like flipping a coin) to receive either: L-citrulline, the study drug, or A placebo, which looks the same but has no active ingredients. Everyone has an equal chance of getting either one. The study drug is given through an IV. It starts with one larger dose, followed by a steady infusion for up to 12 hours. All patients in the study will still receive the usual pain treatment (called standard of care), which may include opioids. However, some patients may need fewer opioids if the study treatment helps with their pain. If any medicines are not allowed during the study, the doctor will explain this during the consent process. Patients can go home once: Their pain is controlled with oral (by mouth) pain medicine, They're eating and drinking well, and They've been given a personal pain management plan to use at home. After leaving the hospital, the study team will follow up with patients by phone about 2 days later (within a 12-hour window), again around Day 7, and again around Day 30 to check how they're doing.

What is Sickle Cell Disease (SCD)? Sickle cell disease is a genetic blood condition that affects red blood cells. People with SCD have a different kind of hemoglobin (called hemoglobin S) that can make red blood cells change shape. These sickle-shaped cells can block blood flow and cause painful episodes, organ damage, and other serious complications. In the U.S., about 100,000 people live with SCD, and it affects millions worldwide. What is a VOC? A vaso-occlusive crisis (VOC) is one of the most common and painful problems in SCD. It happens when sickled red blood cells get stuck in small blood vessels, causing pain and damage. VOC is the main reason why people with SCD go to the emergency department or hospital. Why is This Study Being Done? While there are medicines to help prevent VOCs, there are no treatments that work well to stop a VOC once it starts. That's what this study is trying to change. Researchers are testing L-citrulline, a natural substance found in the body and in some foods, to see if it can help stop a VOC in progress and reduce the need for pain medicine. What is L-citrulline? L-citrulline is an amino acid that helps the body make nitric oxide, a substance that opens up blood vessels and improves blood flow. People with SCD often have low levels of nitric oxide, which can make VOCs worse. By giving L-citrulline through an IV, researchers hope to increase nitric oxide and relieve pain faster. What Did Earlier Studies Show? Earlier studies in children and teens with SCD showed that L-citrulline was: Safe and well tolerated Most helpful at a specific dose (50 mg/kg followed by an infusion) Effective at reducing pain and lowering the need for opioid medications in some patients The studies also showed that very high doses might not work as well. That's why the current study uses the best dose found in earlier research. How Will This Study Work? This study will test how well L-citrulline works in the emergency room when a patient comes in with a VOC. Everyone in the study will still receive standard pain care, including opioids if needed. Some patients will also receive L-citrulline through an IV, and others will receive a placebo (a treatment that looks the same but has no active medicine). Researchers will compare how quickly the pain improves, how much medicine is needed, and how long patients stay in the hospital. Is L-citrulline Safe? Yes, L-citrulline has been studied in many children, including those with heart conditions and SCD. It has not caused serious side effects in these studies. In fact, children with other medical problems safely take even higher doses. The most common side effect seen was temporary low blood pressure, which happened rarely and was not serious. Why Is This Important? People with SCD deserve better options to treat pain quickly and safely. If this study shows that L-citrulline can help shorten or ease a VOC, it could lead to better care and fewer hospital stays in the future. What is this study testing? This study is testing whether L-citrulline, given through an IV, can help treat a pain crisis (VOC) in people with sickle cell disease (SCD) more quickly and safely than standard treatment alone. The goal is to see if it reduces pain, lowers the need for pain medications like opioids, and shortens hospital stays. Who can join? The study includes: Children, teens, and young adults ages 6 to 21 years Who come to the emergency department (ED) with a VOC Who do not have other causes of pain, serious infection, or organ problems How does the study work? About 120 patients will take part in this study. Each person will be randomly placed (like flipping a coin) into one of two groups: One group gets L-citrulline The other group gets a placebo (a treatment that looks the same but has no active medicine) This process is double-blinded, meaning neither the patient nor the care team will know which treatment is being given. What is the treatment? Patients receive a dose of the study drug (or placebo) within 2 hours of giving consent and before getting more IV pain medicine. The treatment starts with a bolus dose (a quick push of medicine) followed by a continuous IV infusion for up to 12 hours. All patients will still receive standard sickle cell pain care, but it may be adjusted depending on how well the study treatment works. When can patients go home? Patients may be discharged from the hospital once: Their pain is controlled with oral pain medicine They are eating and drinking normally They have been given a personalized pain plan to manage symptoms at home What happens after the hospital? Patients will be followed by the study team: At discharge About 2 days later Around Day 7 Around Day 30 Follow-up may happen by phone. The team will ask how the patient is feeling and whether they needed more care. What will the researchers look at? To understand how well the treatment works, the study will measure: Pain scores How quickly the pain crisis gets better How much pain medication is used How long the hospital stay lasts How much pain interferes with daily life (using a short survey) Blood markers of inflammation and red blood cell damage Who is watching the safety? An independent group of experts, including doctors and a statistician, will regularly review the study's progress and safety results. This group can recommend changes or even stop the study if needed to protect patients. Why was this dose chosen? Earlier studies in children with SCD showed that this dose of L-citrulline (50 mg/kg + 9 mg/kg/hr infusion) was: Well tolerated (no serious side effects) Helpful in improving pain Safe, even at higher doses in other groups of children This dose was chosen based on those positive results. When does a patient finish the study? A patient is considered to have finished the study once they complete the final visit (about 30 days after treatment). When would the study stop early? A patient may be taken off the study if they have a serious or unexpected reaction that may be related to the treatment. The whole study may be paused or stopped if two patients have serious reactions that the study doctor and sponsor believe may be related to the treatment.