A Phase 1 Study of Continuous Intravenous L-citrulline During Sickle Cell Pain Crisis or Acute Chest Syndrome

Study Overview
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Brief Summary
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Sickle cell disease is a genetic red blood cell disorder characterized by vaso-occlusion from sickling of red blood cells, that can lead to pain or organ complications such as acute chest syndrome. Sickle cell disease is associated with low amounts of nitric oxide, a compound important for dilating the blood vessel wall. Citrulline is a substance that is known to increase nitric oxide. The goal of this Phase I study are to find the highest safe dose of continuous IV citrulline that can be given to individuals with sickle cell disease experiencing a sickle cell pain crisis or acute chest syndrome without causing severe side effects.

Official Title
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A Phase 1 Dose Escalation Study of Continuous Intravenous L-citrulline During Sickle Cell Pain Crisis or Acute Chest Syndrome

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Intravenous citrulline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sickle cell disease genotypes (HbSS, HbS/β0-thalassemia, HbS/β+-thalassemia, HbSC) Ages 6 to 50 years old Patients with sickle cell disease aged 6 to 50 years old Presence of sickle cell pain crisis defined by the presence of pain requiring hospitalization and parental opioid therapy Presence of acute chest syndrome defined by the presence of a new CXR infiltrate and any one of the following respiratory symptoms of fever, shortness of breath, wheezing, chest pain, cough or new onset hypoxia. Exclusion Criteria: Presence of any other complication related to sickle cell disease requiring hospitalization such as splenic sequestration, hepatic sequestration, stroke, avascular necrosis of the hip/shoulder, acute priapism, etc. Severe anemia (hemoglobin < 5g/dL) History of red blood cell transfusion within the last 30 days Systemic steroid therapy within the last 48 hours Pregnant (as confirmed by a negative urine pregnancy test) or lactating female Alanine/aspartate transferase >2x upper limit of normal laboratory range for age. Subject has the following serum creatinine: Age 6 to 13 years > 0.9 mg/dL Age 14-17 years 1.0 mg/dL Age 18 years >1.5mg/dL Patients with an inability to give consent will be excluded

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 50 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous citrulline<br>Intravenous citrulline at a bolus dose over 5 minutes and then a continuous rate for the next 23 hours. | Drug: Intravenous citrulline<br>* Intravenous citrulline at a bolus dose of 20 mg/kg over 5 minutes and then continuous at a rate of 7 mg/kg/hour for the next 23 hours for the first 7 participants, and depending on safety and pharmacokinetic profile, increase or decrease the continuous rate to 9 or 5 mg/kg/hour for the next 7 participants.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | The number and severity of adverse event will be determined according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) | 30 days | 
| Plasma Citrulline Level |  | Plasma citrulline levels will be evaluated at the following time points: trough level, 10 minutes (peak level), 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours, to evaluate the pharmacokinetic profile | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease, citrulline