L-Citrulline for Sickle Cell Disease

Overseen By Jillian Baker, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Suvankar Majumdar

Must be taking: Parenteral opioids

Must not be taking: L-glutamine

Disqualifiers: Opioid use disorder, Severe anemia, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 16 hours

99 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using L-glutamine.

What evidence supports the effectiveness of the treatment L-citrulline for sickle cell disease?

Research suggests that L-citrulline, which helps increase levels of L-arginine, may improve symptoms in sickle cell disease by boosting nitric oxide production, which can protect blood vessels and reduce complications. A small study showed that L-citrulline improved well-being and reduced high white blood cell counts in patients with sickle cell disease. ^{1 2 3 4 5}

Is L-Citrulline safe for humans?

In a small study with children and adolescents with sickle cell disease, L-Citrulline was given orally and did not cause any side effects or toxicity, suggesting it is generally safe for humans. ^{1 6 7 8 9}

How is the drug L-citrulline different from other treatments for sickle cell disease?

L-citrulline is unique because it is an amino acid that serves as a precursor to L-arginine, which helps produce nitric oxide, a compound that can protect blood vessels and reduce complications in sickle cell disease. Unlike some other treatments, L-citrulline is taken orally and has shown potential to improve symptoms and blood markers without significant side effects. ^{1 3 6 7 10}

What is the purpose of this 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

Research Team

Suvankar Majumdar, MD

Principal Investigator

Children's National Research Institute

Eligibility Criteria

This trial is for hospitalized patients with sickle cell disease experiencing acute pain episodes. Participants must be willing to receive intravenous treatment and return for a follow-up visit after discharge.

Inclusion Criteria

I am between 4 and 21 years old with sickle cell disease.

I have sickle cell disease.

I have been hospitalized for sickle cell pain and needed strong painkillers.

Exclusion Criteria

History of allergic reaction to L-citrulline products

Severe anemia (hemoglobin <6g/dL)

Pregnant (as confirmed by a positive urine pregnancy test) or lactating female

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive intravenous L-citrulline or placebo for 16 hours during hospitalization

16 hours

Inpatient hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a clinic visit about 30 days post-discharge

30 days

1 visit (in-person)

Treatment Details

Interventions

• L-citrulline
• Placebo

Trial Overview The study tests if intravenous L-citrulline can reduce the duration of pain during hospitalization for sickle cell crises compared to a placebo, along with assessing its safety.

Participant Groups

Group I: Low dose intravenous L-citrulline Experimental Treatment 1 Intervention

Group II: High dose intravenous L-citrulline Experimental Treatment 1 Intervention

Group III: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Suvankar Majumdar

Lead Sponsor

Trials

2

Recruited

100+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a pilot Phase II clinical trial involving five patients with sickle cell disease, oral L-citrulline supplementation significantly improved well-being, increased plasma arginine levels, and reduced high leukocyte and neutrophil counts, suggesting a potential therapeutic benefit.

No side effects or toxicity were reported from L-citrulline, indicating it may be a safe option for palliative therapy in sickle cell disease, warranting further placebo-controlled, long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. Waugh, WH., Daeschner, CW., Files, BA., et al.[2018]

In a pilot study involving 29 children with sickle cell disease, supplementation with arginine and citrulline significantly increased whole-body nitric oxide production compared to baseline levels, indicating a potential therapeutic benefit.

The study successfully demonstrated the feasibility of a non-invasive method to measure nitric oxide production, which could be useful for future research in assessing treatments for sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of a non-invasive oral nitrate stable isotopic method suggests that arginine and citrulline supplementation increases whole-body NO production in Tanzanian children with sickle cell disease. Marealle, AI., Siervo, M., Wassel, S., et al.[2022]

A systematic review of 12 studies involving 399 patients with sickle cell disease (SCD) found that l-arginine supplementation significantly increased levels of nitric oxide metabolites and hemoglobin F, which are beneficial for SCD management.

L-arginine also significantly lowered systolic blood pressure and reduced liver enzyme levels, indicating potential blood pressure-lowering and hepatoprotective effects, although more research is needed to confirm these benefits and support widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of l-arginine supplementation in patients with sickle cell disease: A systematic review and meta-analysis of clinical trials. Sadeghi, A., Taherifard, E., Dehdari Ebrahimi, N., et al.[2023]

In a study of 50 pediatric patients with sickle cell disease, proper hydration and nutrition were linked to fewer annual pain crises, suggesting that these factors can help manage disease severity.

L-Glutamine treatment showed promise in reducing pain crises in young patients, with those on L-Glutamine experiencing significantly fewer crises compared to those not on the treatment, indicating its potential as a beneficial therapy for sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric Patients With Sickle Cell Disease at a Public Hospital: Nutrition, Compliance and Early Experience With L-Glutamine Therapy. Gotesman, M., Elgar, G., Santiago, LH., et al.[2022]

In a study involving 48 mice, L-citrulline supplementation was found to significantly improve nitric oxide production and microcirculation in conditions of acute arginase-induced arginine deficiency, unlike L-arginine supplementation.

L-citrulline effectively increased plasma and tissue arginine levels and enhanced microcirculatory flow, suggesting it may be a more beneficial treatment option for conditions related to sickle cell disease-induced organ failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citrulline Supplementation Improves Organ Perfusion and Arginine Availability under Conditions with Enhanced Arginase Activity. Wijnands, KA., Meesters, DM., van Barneveld, KW., et al.[2022]

Oral L-glutamine supplementation significantly increases plasma glutamine levels within 30 minutes and maintains elevated levels for up to 8 hours in patients with sickle cell disease, indicating effective absorption and bioavailability.

The study also found that glutamine supplementation raises plasma arginine concentrations, suggesting a potential mechanism of action where both amino acids may work together to improve metabolic outcomes in sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications for the metabolic fate of oral glutamine supplementation within plasma and erythrocytes of patients with sickle cell disease: A pharmacokinetics study. Morris, CR., Kuypers, FA., Hagar, R., et al.[2022]

L-glutamine, crizanlizumab, and voxelotor are three new treatments for sickle-cell disease that have shown efficacy in reducing pain crises and hospitalizations, with L-glutamine also decreasing the need for red blood cell transfusions.

While these treatments are generally well-tolerated, barriers such as insurance issues and side effects like abdominal pain, headache, and rash can limit patient access and adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in Sickle-Cell Disease Therapies: A Review of Voxelotor, Crizanlizumab, and L-glutamine. Migotsky, M., Beestrum, M., Badawy, SM.[2023]

L-glutamine, approved by the FDA in 2017 for sickle cell disease, has shown potential in reducing the frequency of vaso-occlusive crises (VOC) and associated pain, based on a systematic review of three studies involving both randomized and non-randomized trials.

While l-glutamine was generally well tolerated, the evidence supporting its efficacy is limited, with only one randomized controlled trial providing strong support for its use, suggesting it may be a viable option for patients who cannot take hydroxyurea or as an adjunct therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of l-glutamine for Prevention of Vaso-occlusive Pain Crisis in Patients with Sickle Cell Disease. Cieri-Hutcherson, NE., Hutcherson, TC., Conway-Habes, EE., et al.[2020]

L-glutamine, voxelotor, and crizanlizumab, recently approved for sickle cell disease, were found to be well tolerated and effective in reducing pain crisis episodes and improving hemoglobin levels in patients.

These new treatments can be used alone or alongside hydroxyurea, offering additional options for managing complications related to sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials. Ali, MA., Ahmad, A., Chaudry, H., et al.[2023]

L-Citrulline is a valuable biomarker for monitoring intestinal health, as its plasma levels decrease with impaired intestinal function.

Supplementation with L-citrulline is generally better tolerated than arginine and may help improve muscle strength and protein balance, making it a potential therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. Maric, S., Restin, T., Muff, JL., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

A pilot study of a non-invasive oral nitrate stable isotopic method suggests that arginine and citrulline supplementation increases whole-body NO production in Tanzanian children with sickle cell disease. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Effects of l-arginine supplementation in patients with sickle cell disease: A systematic review and meta-analysis of clinical trials. [2023]

4. Greece pubmed.ncbi.nlm.nih.gov

Pediatric Patients With Sickle Cell Disease at a Public Hospital: Nutrition, Compliance and Early Experience With L-Glutamine Therapy. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Citrulline Supplementation Improves Organ Perfusion and Arginine Availability under Conditions with Enhanced Arginase Activity. [2022]

6. Scotland pubmed.ncbi.nlm.nih.gov

Implications for the metabolic fate of oral glutamine supplementation within plasma and erythrocytes of patients with sickle cell disease: A pharmacokinetics study. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Advances in Sickle-Cell Disease Therapies: A Review of Voxelotor, Crizanlizumab, and L-glutamine. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Systematic Review of l-glutamine for Prevention of Vaso-occlusive Pain Crisis in Patients with Sickle Cell Disease. [2020]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. [2021]