A Study of Oral L-citrulline in Sickle Cell Disease

Study Overview
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Brief Summary
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Sickle cell disease is a genetic red blood cell disorder that can result in blocking of the small blood vessels from sickle shaped red blood cells. This causes pain, the main feature of sickle cell disease. Also, low amounts of nitric oxide can occur in sickle cell disease, a substance important for widening the blood vessel wall and therefore preventing blockage of the small blood vessels. Citrulline is a drug that is known to increase nitric oxide. This is a phase I study of citrulline given by mouth to evaluate the safety, tolerability and appropriate dosing of this medication for individuals with sickle cell disease.

Official Title
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A Phase I Dose-Ranging Study of Oral L-citrulline in Steady-State Sickle Cell

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Oral L-citrulline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sickle cell disease genotypes (HbSS, HbS/β-thalassemia HbS/β+thalassemia, HbSC) Patients with sickle cell disease aged 10 to 25 years old Patients ages 10 through 17 years of age, whose parents have signed permission, and who provide signed patient assent themselves Patients 18 through 25 years of age who provide signed consent. Exclusion Criteria: Presence of any acute illness defined by fever >100.4°F within the past 48 hours Presence of sickle cell pain crisis defined by the presence of pain requiring oral or parental opioid therapy. Presence of acute chest syndrome or 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, and patients with diabetes etc. Severe anemia (hemoglobin < 5g/dL) History of red blood cell transfusion within the last 14 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. Elevated 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 assent (ages 10 to 17 years) or consent (ages 18 through 25 years) will be excluded History of diabetes due to risk of electrolyte imbalance

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 25 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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral citrulline<br> | Drug: Oral L-citrulline<br>* There will be a total of 16 patients divided into 4 equal cohorts. The first 4 cohorts will be started on a 7 day oral regimen of twice daily L-citrulline. They will return to clinic on day #7 to evaluate nitric oxide metabolite levels and pharmacokinetic (PK) profile of citrulline. After PK analysis, the next cohort of patients will be given a higher or lower dose based on their weight and also based safety and tolerability. Of note, a PK analysis will be performed for each 4 patient cohort prior to starting citrulline for the subsequent cohort. Assessment for adverse events will be done at specified times throughout the study duration via both phone and clinic encounters.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma citrulline concentration (Cmax) |  | 7 days | 
| Rate of citrulline appearance (Rapp) |  | 7 days | 
| Constant of citrulline removal (krem) |  | 7 days | 
| Volume of distribution |  | 7 days | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of nitric oxide |  | 7 days |