L-Citrulline for Sickle Cell Disease

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether intravenous L-citrulline can reduce pain for people with sickle cell disease during hospital stays. The researchers aim to determine if L-citrulline can shorten the duration of pain and assess its safety. Participants will receive either a low or high dose of L-citrulline or a placebo for comparison. Those with sickle cell disease experiencing a pain crisis requiring hospitalization and opioid treatment may qualify if they can participate within 12 hours of starting opioid treatment in the emergency room. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using L-citrulline through an IV is generally safe for people with sickle cell disease. One study found it was well tolerated, with no serious side effects, and the most common minor side effect was drowsiness. Another review found that taking L-citrulline orally is safe and might help reduce oxidative stress, which is linked to pain crises in sickle cell disease.

These findings suggest that L-citrulline, whether taken orally or through an IV, is safe for most people. While this trial tests L-citrulline through an IV, previous studies provide strong evidence of its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments for sickle cell disease?

Most treatments for sickle cell disease focus on managing symptoms or preventing complications, such as pain crises and anemia, often using medications like hydroxyurea or blood transfusions. But L-citrulline works differently by potentially enhancing nitric oxide production, which can improve blood flow and reduce the sickling of red blood cells. Researchers are excited about L-citrulline because it's administered intravenously, allowing for precise dosing and potentially faster relief during acute episodes. This approach could offer a new way to address the root causes of sickle cell complications, rather than just the symptoms.

What evidence suggests that intravenous L-citrulline could be an effective treatment for sickle cell pain?

Research has shown that administering L-citrulline through an IV might help reduce pain episodes in people with sickle cell disease. Some studies found that it can shorten these episodes and make them less intense. In this trial, participants will receive either a low dose or high dose of intravenous L-citrulline, or a placebo. L-citrulline raises levels of a substance called arginine, which improves blood flow and eases pain. Early studies also suggested that L-citrulline is safe for people with sickle cell disease. While more research is needed, initial results are promising for its role in managing sudden pain linked to the condition. ^{1 2 6 7 8}

Who Is on the Research Team?

Suvankar Majumdar, MD

Principal Investigator

Children's National Research Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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, 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, 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04852172

L-citrulline Injection in Patients Aged 6-21 Years Old with ... The purpose of this study is to determine if intravenous L-citrulline can abrogate an active vaso-occlusive crisis in sickle cell disease, resulting in ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06989567

A Study of Intravenous L-Citrulline in Patients Aged 6-21 ... This study is testing whether L-citrulline, given through an IV, can help treat a pain crisis (VOC) in people with sickle cell disease (SCD) more quickly and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9868327/

Design of an adaptive randomized clinical trial ... The study will evaluate efficacy and tolerability of incremental doses of intravenous (IV) l-citrulline in patients with SCD while receiving standard of care ...

4. authorea.com authorea.com/doi/pdf/10.22541/au.175404797.70233011

Systematic Review of L-Citrulline Supplementation Effect in ... Background and Aim: Preliminary studies indicated that L-Citrulline supplementation is safe and could be beneficial in patients with SCD [1] ...

5. medrxiv.org medrxiv.org/content/10.1101/2024.08.08.24311691v1.full-text

Evaluating the Therapeutic Effects of Amino Acid Treatment ... Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc . 2001;93(10):363 ...

6. authorea.com authorea.com/doi/full/10.22541/au.175404797.70233011

Systematic Review of L-Citrulline Supplementation Effect in ... Conclusion: Our systematic review showed that oral L-Citrulline supplementation is safe in patients with SCD and could be beneficial in decreasing oxidative ...

7. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/bjh.15124

A phase 1 dose‐finding study of intravenous L‐citrulline ... Overall, intravenous citrulline in SCD was well tolerated and safe. There were no AEs ≥ grade 2 level of toxicity. Drowsiness was ...

8. webmd.com webmd.com/vitamins/ai/ingredientmono-1245/l-citrulline

L-CITRULLINE - Uses, Side Effects, and More People use L-citrulline for athletic performance, sickle cell disease ... L-citrulline is safe to use when pregnant or breast-feeding. Stay on the safe ...