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

A Phase 2 Randomized Double-blind, Placebo-controlled Clinical Trial of Intravenous Citrulline for Vaso-occlusive Pain Episode in Hospitalized Patients With Sickle Cell Disease (CONQUER SCD Pain Trial)

The goal of this clinical trial is to learn if intravenous citrulline works to treat acute pain in hospitalized patients with sickle cell disease. It will also learn about the safety of intravenous citrulline. The main questions it aims to answer are:

• Does intravenous citrulline decrease the duration of sickle cell pain during hospitalization
• What medical problems do participants have when taking intravenous citrulline? Researchers will compare intravenous citrulline to a placebo (a look-alike substance that contains no drug) to see if intravenous citrulline works to treat acute pain.

Participants will:

• Receive baseline tests and intravenous citrulline for 16 hours during the hospital stay
• After hospital discharge, visit the clinic in about 30 days for checkup and tests

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease; Vaso-occlusive Pain Episode
• Intervention / Treatment: Drug: L-citrulline; Drug: L-citrulline; Other: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jillian Baker, RN; Phone Number: 202-476-1311; Email: jbaker5@childrensnational.org

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Recruiting
      • Children's National Hospital
      • Principal Investigator: Suvankar Majumdar, MD
      • Contact: Jillian Baker, RN; Phone Number: 202-476-1311; Email: jbaker5@childrensnational.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Isotonic normal saline
Experimental: Low dose intravenous L-citrulline	Drug: L-citrulline; Intravenous L-citrulline (50 mg/kg + 9mg/kg/hr.) for 16 hours; Drug: L-citrulline; Intravenous L-citrulline (25 mg/kg + 9mg/kg/hr.) for 16 hours
Experimental: High dose intravenous L-citrulline	Drug: L-citrulline; Intravenous L-citrulline (50 mg/kg + 9mg/kg/hr.) for 16 hours; Drug: L-citrulline; Intravenous L-citrulline (25 mg/kg + 9mg/kg/hr.) for 16 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-crisis resolution	Change in time-to-crisis resolution as defined by the time (in hours) from first dose of intravenous study drug or placebo to the time of last dose of intravenous opioid during hospitalization	Baseline to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0	Baseline to 30 days
Opioid consumption	Change in cumulative opioid consumption (calculated in morphine equivalents) from time of study drug administration to last dose of IV/oral opioid during hospitalization	Baseline to 30 days
Pain scores	Change in baseline pain scores will be recorded from a 0-10 scale, 10 is worst pain	Baseline to 30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Citrulline and arginine bioavailability	Change in baseline citrulline and arginine concentration during hospitalization and 30 day follow up/	Baseline to 30 days
Nitric oxide	Change in baseline nitric oxide concentration during hospitalization and 30 day follow up	Baseline to 30 days
Cytokine interleukin IL-1ß	Change in baseline plasmatic levels of IL-1ß concentration during hospitalization and 30 day follow up	Baseline to 30 days
Mitochondrial function	Mitochondrial respiratory complex activities will be measured to estimate mitochondrial function. Change in baseline mitochondrial respiratory complex activity during hospitalization and 30 day follow up	Baseline to 30 days
Genetic	DNA to test specific genetic polymorphisms related to nitric oxide pathway	Baseline

Collaborators and Investigators

• Sponsor: Suvankar Majumdar
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Suvankar Majumdar, MD, Children's National Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: October 7, 2024
• First Submitted That Met QC Criteria: October 9, 2024
• First Posted (Actual): October 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: sickle cell disease; citrulline; sickle cell pain crisis
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Amino Acids, Peptides, and Proteins; Amino Acids; Amino Acids, Diamino; Citrulline
• Other Study ID Numbers: 00000880; 1R61HL167806 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication will be shared
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years after the publication of results
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP). For more information or to submit a request, please contact smajumdar@childrensnational.org
• IPD Sharing Supporting Information Type: ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No