A Study of Oral L-citrulline in Sickle Cell Disease

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Oral L-citrulline

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Sickle cell disease genotypes (HbSS, HbS/β-thalassemia
2. HbS/β+thalassemia, HbSC)
3. Patients with sickle cell disease aged 10 to 25 years old
4. Patients ages 10 through 17 years of age, whose parents have signed permission, and who provide signed patient assent themselves
5. Patients 18 through 25 years of age who provide signed consent.

Exclusion Criteria:

1. Presence of any acute illness defined by fever >100.4°F within the past 48 hours
2. Presence of sickle cell pain crisis defined by the presence of pain requiring oral or parental opioid therapy.
3. 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.
4. Severe anemia (hemoglobin < 5g/dL)
5. History of red blood cell transfusion within the last 14 days
6. Systemic steroid therapy within the last 48 hours
7. Pregnant (as confirmed by a negative urine pregnancy test) or lactating female
8. Alanine/aspartate transferase >2x upper limit of normal laboratory range for age.
9. 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
10. Patients with an inability to give assent (ages 10 to 17 years) or consent (ages 18 through 25 years) will be excluded
11. History of diabetes due to risk of electrolyte imbalance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Oral citrulline

Drug: Oral L-citrulline; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	Time Frame
Level of nitric oxide	7 days

Collaborators and Investigators

• Sponsor: University of Mississippi Medical Center

Publications and helpful links

General Publications

• Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Boger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51-9. doi: 10.1111/j.1365-2125.2007.02990.x. Epub 2007 Jul 27.
• Moinard C, Nicolis I, Neveux N, Darquy S, Benazeth S, Cynober L. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr. 2008 Apr;99(4):855-62. doi: 10.1017/S0007114507841110. Epub 2007 Oct 22.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Anticipated): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: December 29, 2015
• First Submitted That Met QC Criteria: January 19, 2016
• First Posted (Estimate): January 20, 2016

Study Record Updates

• Last Update Posted (Actual): June 21, 2018
• Last Update Submitted That Met QC Criteria: June 19, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: 2015-0191

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No