A Study of Intravenous L-Citrulline in Patients Aged 6-21 Years Old With Sickle Cell Disease Presenting to Emergency Departments in Acute Vaso-Occlusive Crisis

NCT06989567 | Not Yet Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: CIT-SCD-003-01
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 6

Brief Summary

This study is being done to learn more about a possible new treatment for pain episodes (called vaso-occlusive crises or VOCs) in children, teens, and young adults with sickle cell disease (SCD). The study will include about 120 participants between the ages of 6 and 21 who come to the emergency department (ED) with a VOC. A VOC is a painful episode that happens with no clear cause and no signs of infection or major problems with organs like the liver or kidneys. Before joining the study, patients and their families may be asked to learn about it and give permission (called consent or assent) while at a regular clinic visit. If that hasn't happened yet, the consent/assent process will happen at the emergency department when the patient comes in for care. If the patient meets all the study requirements, they can join the treatment part of the study. Participants will be randomly assigned (like flipping a coin) to receive either: L-citrulline, the study drug, or A placebo, which looks the same but has no active ingredients. Everyone has an equal chance of getting either one. The study drug is given through an IV. It starts with one larger dose, followed by a steady infusion for up to 12 hours. All patients in the study will still receive the usual pain treatment (called standard of care), which may include opioids. However, some patients may need fewer opioids if the study treatment helps with their pain. If any medicines are not allowed during the study, the doctor will explain this during the consent process. Patients can go home once: Their pain is controlled with oral (by mouth) pain medicine, They're eating and drinking well, and They've been given a personal pain management plan to use at home. After leaving the hospital, the study team will follow up with patients by phone about 2 days later (within a 12-hour window), again around Day 7, and again around Day 30 to check how they're doing.

Conditions

Sickle Cell Disease

Keywords

sickle cell disease; citrulline; Vaso-Occlusive Crisis; Pain Crisis Relief in Sickle Cell Disease; Children and Adolescents with Sickle Cell

Outcome Measures

Primary Outcomes (2)

• Change in pain score from baseline to discharge

  This outcome measures the change in self-reported pain using either the Numeric Rating Scale (NRS) or the Faces Pain Scale. Participants will rate their pain at baseline (prior to study treatment) and again at the time of hospital discharge. The pain scale used depends on the participant's age and cognitive ability. A clinically meaningful improvement is defined as a reduction of ≥2 points or ≥30% from baseline.

  From enrollment to hospital discharge (typically within 12 to 72 hours), up to max of 30 day study duration

• Time to pain crisis resolution

  Time (in hours) from administration of the initial bolus dose of study drug (L-citrulline or placebo) to the end of the last IV opioid dose required during the hospitalization. This endpoint reflects how quickly the participant's vaso-occlusive crisis resolves to a degree that no longer requires intravenous opioid pain medication.

  From start of study drug infusion to discontinuation of IV opioids (within the index hospitalization), up to max of 30 day study duration

Secondary Outcomes (5)

• Duration of hospital stay

  From study drug administration to hospital discharge (typically within 12 to 72 hours), up to max of 30 day study duration up to max of 30 day study duration

• Total opioid use during hospitalization

  From ED registration to hospital discharge, up to max of 30 day study duration

• Proportion of patients with ≥30% reduction in opioid use

  From start of study drug administration to hospital discharge, up to max of 30 day study duration

• Change in Patient-Reported Outcomes Measurement Information System Pain Interference Score

  From baseline to Day 7 (+2) post-enrollment

• Hospital admission rate

  From ED presentation through hospital discharge or decision not to admit, up to max of 30 day study duration

Other Outcomes (10)

• Healthcare resource utilization

  From emergency department (ED) presentation through hospital discharge, up to max of 30 day study duration

• Cost utility and cost benefit

  From ED presentation through Day 30 follow-up

• Change from baseline in hemoglobin concentration

  From baseline to discharge and at 48 hours post-bolus dose

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Participants randomized to this arm will receive a placebo intravenous (IV) treatment designed to match the appearance and administration schedule of L-citrulline. The placebo will be given as a single bolus dose followed by a continuous infusion for up to 12 hours. All participants will continue to receive standard of care pain management for sickle cell disease, consistent with the treating site's protocol and adjusted as needed based on the patient's clinical condition.

Other: Placebo

L-citrulline Intravenous Treatment Arm

EXPERIMENTAL

Participants randomized to this arm will receive intravenous (IV) L-citrulline, a naturally occurring amino acid being investigated for its potential to treat vaso-occlusive crises (VOCs) in sickle cell disease. The study drug will be administered as a 50 mg/kg IV bolus, followed by a continuous infusion at 9 mg/kg/hour for up to 12 hours. The investigational product is provided as an isotonic solution in vials containing L-citrulline 50 mg/mL. Treatment will begin within 120 minutes of informed consent/assent and following the initial dose of opioid or ketamine, but prior to any subsequent doses. All participants will continue to receive standard-of-care (SoC) pain management per site protocol, which may be adjusted based on clinical response to study treatment.

Drug: L-citrulline

Interventions

L-citrulline DRUG

This intervention uses intravenous L-citrulline as an acute treatment for vaso-occlusive crisis (VOC) in sickle cell disease, administered as a 50 mg/kg IV bolus followed by a 9 mg/kg/hr continuous infusion. Unlike other studies that evaluate oral citrulline or chronic VOC prevention, this study focuses on real-time symptom resolution in the emergency department setting by targeting impaired nitric oxide production and vasoconstriction. The selected dosing regimen was optimized in prior studies to achieve a therapeutic plasma concentration associated with improved pain scores and reduced opioid use, distinguishing it mechanistically and clinically from other interventions.

L-citrulline Intravenous Treatment Arm

Placebo OTHER

Placebo intravenous (IV) treatment designed to match the appearance and administration schedule of L-citrulline

Placebo

Eligibility Criteria

• Age: 6 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• SCD (all genotypes)
• Children, adolescents and young adults between ages 6 to 21 years
• In a steady disease state and not in the midst of any acute complication other than VOC due to SCD at study entry
• Baseline NRS score \>5 or Faces Pain Scale score ≥6
• For females of childbearing potential, a negative urine pregnancy test and using an adequate method of contraception including abstinence
• Patients or parents or legal guardian of the patient who are willing and able to sign and provide consent and assent (where appropriate for the age of the child)
• Patients willing to begin study treatment within 120 minutes after providing informed consent/assent and soon after the first/initial dose, but before any subsequent doses of IV opioid or ketamine

You may not qualify if:

• Current pain lasting \>3 days
• History of 9 hospital admissions in the prior year
• Participation in a clinical trial of a new therapy for SCD within the last 1 month
• Presence of any other complication related to SCD such as splenic sequestration, hepatic sequestration, stroke, avascular necrosis of the hip/shoulder, acute priapism, acute renal dysfunction, acute chest syndrome and other major medical conditions or organ dysfunction
• Hypotension requiring clinical intervention; hemodynamic instability; septic shock
• Severe anemia (hemoglobin \<6 g/dL)
• Systemic steroid therapy within the last 24 hours
• Use of inhaled NO or medications that are known to cause hypotension (e.g., nitrates, sildenafil, tadalafil, vardenafil, osildenafil, or arginine) within the last 30 days
• Serum creatinine levels:
• Age 6-13 years: \>0.9 mg/dL
• Age 14-17 years: \>1.0 mg/dL
• Age ≥18 years: \>1.5 mg/dL
• Report of fever (\>38°C) within the last 24 hours
• Presence of acute chest syndrome, sepsis, known bacterial infection, or hemodynamic instability
• Acute mental status or neurological changes

Sponsors & Collaborators

• Asklepion Pharmaceuticals, LLC: lead

Study Sites (6)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

Location

University of Miami

Coral Gables, Florida, 33146, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

East Carolina (University of North Carolina)

Greenville, North Carolina, 27858, United States

Location

Related Publications (13)

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• Davis H, Gergen PJ, Moore RM Jr. Geographic differences in mortality of young children with sickle cell disease in the United States. Public Health Rep. 1997 Jan-Feb;112(1):52-8.

  PMID: 9018289 BACKGROUND

• Sundd P, Gladwin MT, Novelli EM. Pathophysiology of Sickle Cell Disease. Annu Rev Pathol. 2019 Jan 24;14:263-292. doi: 10.1146/annurev-pathmechdis-012418-012838. Epub 2018 Oct 17.

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• Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):226-235. doi: 10.1056/NEJMoa1715971.

  PMID: 30021096 BACKGROUND

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  PMID: 38786070 BACKGROUND

• Niihara Y, Zerez CR, Akiyama DS, Tanaka KR. Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol. 1998 Jun;58(2):117-21. doi: 10.1002/(sici)1096-8652(199806)58:23.0.co;2-v.

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• Brandow AM, Panepinto JA. Hydroxyurea use in sickle cell disease: the battle with low prescription rates, poor patient compliance and fears of toxicities. Expert Rev Hematol. 2010 Jun;3(3):255-60. doi: 10.1586/ehm.10.22. No abstract available.

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• Lanzkron S, Carroll CP, Haywood C Jr. The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database. Am J Hematol. 2010 Oct;85(10):797-9. doi: 10.1002/ajh.21807.

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• Sickle cell disease: managing acute painful episodes in hospital: Clinical guideline. London: National Institute for Health and Care Excellence (NICE); 2012 Jun 27. No abstract available. Available from http://www.ncbi.nlm.nih.gov/books/NBK612041/

  PMID: 39946515 BACKGROUND

• Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010 Apr;38(4 Suppl):S512-21. doi: 10.1016/j.amepre.2009.12.022.

  PMID: 20331952 BACKGROUND

• Ansong D, Akoto AO, Ocloo D, Ohene-Frempong K. Sickle cell disease: management options and challenges in developing countries. Mediterr J Hematol Infect Dis. 2013 Nov 4;5(1):e2013062. doi: 10.4084/MJHID.2013.062. eCollection 2013.

  PMID: 24363877 BACKGROUND

• Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore). 2005 Nov;84(6):363-376. doi: 10.1097/01.md.0000189089.45003.52.

  PMID: 16267411 BACKGROUND

• Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573. doi: 10.1056/NEJMra1510865. No abstract available.

  PMID: 28423290 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Vaso-Occlusive Crises

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 Officials

• Suvankar Majumdar, MD

  Center for Cancer and Blood Disorders, Children's National Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gurdyal Kalsi, MD, MFPM (Hon)

CONTACT

+1 410-736-3750; gurdyal.kalsi@asklepionpharm.com

Heather Hill, BS

CONTACT

+1 443-691-2474; heather.hill@asklepionpharm.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The sponsor and study vendors are also blinded in this study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2025
• First Posted: May 25, 2025
• Study Start: July 25, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2029
• Last Updated: May 29, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)