A Study of Oral L-citrulline in Sickle Cell Disease

NCT02659644 | Withdrawn Phase 1 DMC

• 1 other identifier: 2015-0191
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Sickle Cell Disease

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (1)

• Level of nitric oxide

  7 days

Study Arms (1)

Oral citrulline

EXPERIMENTAL

Drug: Oral L-citrulline

Interventions

Oral L-citrulline DRUG

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.

Oral citrulline

Eligibility Criteria

• Age: 10 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Mississippi Medical Center: lead

Study Sites (1)

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Related Publications (2)

• 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.

  PMID: 17662090 BACKGROUND

• 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.

  PMID: 17953788 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Citrulline

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 29, 2015
• First Posted: January 20, 2016
• Study Start: December 1, 2015
• Primary Completion: December 31, 2017
• Study Completion: December 31, 2017
• Last Updated: June 21, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)