Intravenous L-Citrulline for Vaso-occlusive Pain Episode in Sickle Cell Disease

This is a single-center phase 2 randomized double-blind, placebo-controlled trial of intravenous L-citrulline for sickle cell patients ages 4 to 21 years experiencing a vaso-occlusive pain crisis episode (VOE). Eligible subjects will have a documented history of sickle cell disease and inpatient hospitalization for treatment of acute pain with parenteral opioid. Subjects will be randomized to receive high dose intravenous L-citrulline, low dose intravenous L-citrulline or placebo in addition to standard of care. Subjects will be followed closely to evaluate time-to-crisis resolution as the primary outcome defined by time from first dose of intravenous study drug/placebo to the last dose of parenteral opioid prior to hospital discharge. Participants will be monitored for any adverse events including 30-day re-hospitalization rates. Total opioid consumption during the time-to-crisis resolution will be compared between the three arms. In addition, exploratory outcomes will be evaluated for pain score, tissue blood flow, genetic and candidate biomarkers related to vaso-occlusion.

Objectives Primary Objective

• To demonstrate the efficacy of intravenous L-citrulline in reducing the time-to-crisis resolution in sickle cell subjects experiencing a vaso-occlusive pain crisis episode (VOE).

Secondary Objectives

• To evaluate the safety of intravenous L-citrulline in the treatment of VOE
• To determine if intravenous L-citrulline improves cumulative opioid consumption during the treatment of VOE Exploratory Objectives
• To determine if intravenous L-citrulline improves pain scores during the hospitalization
• To determine if intravenous L-citrulline improves 30-day re-hospitalization rates
• To determine the pharmacokinetic (PK) profile of intravenous L-citrulline
• To evaluate whether intravenous L-citrulline improves tissue blood flow and candidate biomarkers related to vaso-occlusion.
• To assess whether genetic single nucleotide polymorphisms related to the nitric oxide pathway influence study outcomes

Inclusion criteria

• Sickle cell disease (all genotypes)
• Patients with sickle cell disease ages 4 to 21 years old
• Presence of sickle cell vaso-occlusive pain episode requiring hospitalization and parenteral opioid therapy
• Able to randomize to study drug/placebo within 12 hours of first dose of parenteral opioid in the Emergency Department

Exclusion criteria

• Current pain lasting >3 days.
• >9 hospitalizations in the prior year
• Presence of any other complication related to sickle cell disease requiring the hospitalization such as splenic sequestration, hepatic sequestration, stroke, transient ischemic attack, etc.
• History of opioid use disorder, chronic pain or medical regimen requiring daily opioid use.
• Severe anemia (hemoglobin <6g/dL)
• Pregnant (as confirmed by a positive 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 4 to 13 years > 0.9 mg/dL
• Age 14 to 17 years 1.0 mg/dL
• Age ≥18 years >1.5mg/dL
• Presence of acute chest syndrome, sepsis, bacterial infection, hemodynamic instability
• Use of L-glutamine
• History of allergic reaction to L-citrulline products