Arginine Therapy for Sickle Cell Disease

(R34 pK/PD Trial)

Recruiting at 1 trial location

Overseen By Claudia Morris, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Emory University

Must not be taking: Inhaled nitric oxide, sildenafil

Disqualifiers: Pregnancy, Renal dysfunction, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 7 days

21 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine whether giving extra arginine to patients with sickle cell disease seeking treatment for vaso-occlusive painful events (VOE) will decrease pain scores, decrease need for pain medications or decrease length of hospital stay or emergency department visit.

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've used inhaled nitric oxide, sildenafil, or arginine in the last 14 days.

What data supports the effectiveness of this drug for sickle cell disease?

Research suggests that L-arginine supplementation can increase nitric oxide production during vaso-occlusive crises in sickle cell disease, potentially improving symptoms. Additionally, L-arginine has shown promise in reducing pulmonary hypertension, a serious complication of sickle cell disease, by lowering pulmonary artery pressure. ^{1 2 3 4 5}

Is arginine therapy safe for humans?

Arginine supplementation is generally considered safe for humans, with an observed safe level of about 20 grams per day. It has been used safely in vulnerable groups like pregnant women and preterm infants, and animal studies show no adverse effects with high doses. However, more research is needed to fully confirm its safety in humans. ^{6 7 8 9 10}

How does the drug arginine differ from other treatments for sickle cell disease?

Arginine is unique because it helps improve blood flow and reduce complications in sickle cell disease by increasing nitric oxide levels, which protect blood vessels and reduce inflammation. This mechanism is different from other treatments that may not target these specific pathways. ^{1 2 4 8 11}

Research Team

Claudia Morris, MD

Principal Investigator

Emory University

Eligibility Criteria

This trial is for children and young adults aged 7-21 with Sickle Cell Disease (specifically Hemoglobin SS or Sβᴼ-thalassemia), weighing at least 55lbs, who are experiencing pain that requires strong painkillers. They must not be pregnant, have had a recent hospitalization, severe liver or kidney issues, certain other types of sickle cell disease, or an allergy to arginine.

Inclusion Criteria

I have been diagnosed with sickle cell disease, either Hb-SS or Sβᴼ-thalassemia.

I am between 7 and 21 years old.

I have pain from sickle cell that needed strong painkillers in a hospital or clinic.

Exclusion Criteria

Hemoglobin less than 5 gm/dL

You are allergic to arginine.

I expect to need a blood transfusion soon.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive intravenous arginine therapy for vaso-occlusive painful events in sickle cell disease

Up to 7 days

Daily visits for intravenous administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Arginine

Trial Overview The study tests if extra arginine can help reduce pain levels in patients with sickle cell disease during painful episodes. It looks at whether this treatment can lessen the need for pain medication or shorten the time spent in hospitals or emergency departments.

Participant Groups

Group I: Standard dose Experimental Treatment 1 Intervention

Subjects with sickle cell disease (SCD) and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first

Group II: Non-Randomized Loading dose 500 mg/kg + standard dose Experimental Treatment 1 Intervention

Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 500 mg/kg once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.

Group III: Non-Randomized Loading dose 400mg/kg + standard dose Experimental Treatment 1 Intervention

Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 400 mg/kg once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.

Group IV: Non-Randomized Loading dose 300 mg/kg + standard dose Experimental Treatment 1 Intervention

Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 300 mg/kg once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.

Group V: Loading dose + standard dose Experimental Treatment 2 Interventions

Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first

Group VI: Loading dose + continuous infusion Experimental Treatment 2 Interventions

Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive a continuous intravenous (IV) infusion of 300 mg/kg/24hr for 7 days or until discharged from the hospital, whichever occurs first

Arginine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as L-arginine for:

• Dietary supplementation
• Angina
• Erectile dysfunction
• High blood pressure

Approved in European Union as L-arginine for:

• Dietary supplementation
• Angina
• Erectile dysfunction
• High blood pressure

Approved in Canada as L-arginine for:

• Dietary supplementation
• Angina
• Erectile dysfunction
• High blood pressure

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Center for Complementary and Integrative Health (NCCIH)

Collaborator

Trials

886

Recruited

677,000+

Children's Healthcare of Atlanta

Collaborator

Trials

172

Recruited

108,000+

Findings from Research

Patients with sickle cell disease (SSD) had significantly lower levels of L-arginine compared to healthy controls, which may contribute to immune dysfunction.

Supplementing with L-arginine improved lymphocyte blastogenesis in response to phytohemagglutinin (PHA) for both SSD patients and controls, but did not enhance responses to specific antigens like candida, indicating a selective effect on immune activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of L-arginine supplementation on immune responsiveness in patients with sickle cell disease. Scavella, A., Leiva, L., Monjure, H., et al.[2017]

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 study of 10 patients with sickle cell disease, oral arginine therapy led to a significant 15.2% reduction in pulmonary artery systolic pressure after just 5 days, suggesting it may effectively lower pulmonary hypertension associated with the disease.

Elevated arginase activity in these patients may limit the availability of arginine, which is crucial for nitric oxide production, indicating that arginine therapy could help counteract this deficiency and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Morris, CR., Morris, SM., Hagar, W., 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]

L-arginine supplementation significantly increased nitric oxide metabolite (NOx) production in patients with vaso-occlusive crisis (VOC) from sickle cell disease by 77.7%, indicating a potential therapeutic benefit during these episodes.

In contrast, L-arginine supplementation led to a decrease in NOx production in steady-state sickle cell disease patients, highlighting the complex effects of L-arginine depending on the patient's condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease. Morris, CR., Kuypers, FA., Larkin, S., et al.[2019]

L-arginine (Arg) plays a crucial role in synthesizing important substances like nitric oxide and creatine, which can improve cardiovascular health and insulin sensitivity, but its use as a dietary supplement is limited due to safety concerns.

Animal studies show that long-term supplementation of Arg (up to 630 mg/kg body weight per day in pigs and 3.6 g/kg body weight per day in rats) is safe, with no adverse effects observed, suggesting that similar doses may be safe for humans as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Catabolism and safety of supplemental L-arginine in animals. Wu, Z., Hou, Y., Hu, S., et al.[2018]

l-Arginine produced by the strain Corynebacterium glutamicum NITE SD 00285 is deemed safe for use in animal feed, with no genetic modifications or antibiotic resistance concerns, based on a review of its production and safety profile.

Despite minor changes in processing, two out of five batches did not meet the required purity specification, but overall, the additive is considered safe for target species and consumers, although it poses some irritant risks to skin and eyes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the application for renewal of authorisation of l-arginine produced by fermentation using Corynebacterium&#160;glutamicum NITE SD 00285 for all animal species. Bampidis, V., Azimonti, G., de Lourdes Bastos, M., et al.[2020]

L-Arginine (Arg) is a crucial amino acid that plays a significant role in various biological processes, including detoxifying ammonia and regulating metabolism across multiple organs, highlighting its importance for overall health.

Supplementation with L-Arginine has shown benefits in improving functions related to reproduction, cardiovascular health, and wound healing, and may also offer potential therapies for conditions like obesity and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arginine metabolism and nutrition in growth, health and disease. Wu, G., Bazer, FW., Davis, TA., et al.[2023]

Arginine is classified as an essential amino acid for young mammals and conditionally essential for adults under certain health conditions, highlighting its critical role in various biological processes.

Supplementing with arginine can improve several health outcomes, including reversing endothelial dysfunction, enhancing wound healing, and supporting cardiovascular and immune functions, suggesting its potential as a therapeutic treatment for various diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The metabolic basis of arginine nutrition and pharmacotherapy. Flynn, NE., Meininger, CJ., Haynes, TE., et al.[2019]

Oral l-Arginine (Arg) supplementation, up to about 20 g per day, is generally safe and well-tolerated, even in vulnerable populations like pregnant women and preterm infants.

Recent studies indicate that Arg may improve metabolic profiles, particularly in individuals with obesity, insulin resistance, and diabetes, suggesting its potential as a beneficial nutriceutical for enhancing nutrient metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Arginine in Adults. McNeal, CJ., Meininger, CJ., Reddy, D., et al.[2023]

L-arginine is crucial for various biological processes, serving as a precursor for important molecules like nitric oxide and proteins, and is essential for growth in young organisms, requiring dietary intake.

In adults, L-arginine becomes conditionally essential under certain health conditions, and its administration can enhance cardiovascular, pulmonary, immune, and digestive functions, while also offering protective effects against early cancer development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Arginine--metabolism and functions in the human organism]. Scibior, D., Czeczot, H.[2016]

References

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

Effect of L-arginine supplementation on immune responsiveness in patients with sickle cell disease. [2017]

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

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

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

Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? [2022]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease. [2019]

6. Austria pubmed.ncbi.nlm.nih.gov

Catabolism and safety of supplemental L-arginine in animals. [2018]

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

Assessment of the application for renewal of authorisation of l-arginine produced by fermentation using Corynebacterium&#160;glutamicum NITE SD 00285 for all animal species. [2020]

8. Austria pubmed.ncbi.nlm.nih.gov

Arginine metabolism and nutrition in growth, health and disease. [2023]

9. France pubmed.ncbi.nlm.nih.gov

The metabolic basis of arginine nutrition and pharmacotherapy. [2019]

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

Safety and Effectiveness of Arginine in Adults. [2023]

11. Poland pubmed.ncbi.nlm.nih.gov

[Arginine--metabolism and functions in the human organism]. [2016]