Arginine Therapy for Sickle Cell Disease

(R34 pK/PD Trial)

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if extra arginine (an amino acid) can reduce pain during episodes requiring medical care in people with sickle cell disease. Researchers seek to discover if arginine can decrease the need for pain medicine and shorten hospital or emergency visits. The trial includes several groups, each receiving different arginine doses to identify the most effective one. Individuals with sickle cell disease experiencing pain that requires medical treatment in a hospital or emergency setting may be suitable candidates. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in sickle cell disease management.

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.

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

Research has shown that arginine therapy is generally safe. One study found no side effects directly caused by the drug when used to treat painful episodes in sickle cell disease.

However, another study noted some side effects when arginine was administered through an IV, including nausea, vomiting, headaches, skin redness, and difficulty breathing. The likelihood of these effects can depend on the dose.

Arginine has been used safely for many years and is approved by the FDA in a specific form to test growth hormone levels, supporting its safety. Overall, arginine is usually well-tolerated, but like any treatment, some people might experience side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about arginine therapy for sickle cell disease because it offers a fresh approach to managing vaso-occlusive painful events (VOE). Unlike traditional treatments such as hydroxyurea and blood transfusions, which focus on managing symptoms and preventing complications, arginine works by increasing nitric oxide levels, potentially improving blood flow and reducing pain during these events. Additionally, the trial explores varied dosing strategies, including loading doses and continuous infusions, which might offer more immediate relief compared to current therapies. This innovative method could provide faster and more effective pain management for individuals with sickle cell disease.

What evidence suggests that this trial's treatments could be effective for sickle cell disease?

Research has shown that arginine may help relieve pain during vaso-occlusive episodes (VOE) in people with sickle cell disease. Studies with children have demonstrated that arginine can safely lower pain levels during these episodes. One trial found that arginine treatment provided significant pain relief for hospitalized patients. In this trial, participants will receive different dosing regimens of arginine to evaluate its effectiveness in managing pain related to sickle cell disease. While more studies are needed to confirm these results, current evidence suggests that arginine could effectively manage pain related to sickle cell disease. ^{1 3 4 6 7}

Who Is on the Research Team?

Claudia Morris, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

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

I expect to need a blood transfusion soon.

You are allergic to arginine.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 (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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3762093/

A randomized, placebo-controlled trial of arginine therapy ... A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes.

2. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07538-z

Sickle Cell Disease Treatment with Arginine Therapy (STArT) Lower doses of arginine are likely to be subtherapeutic in SCD-VOE as reported in other conditions of endothelial dysfunction [24]. Moreover, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04839354

Sickle Cell Disease Treatment With Arginine Therapy ... The trial is designed to test intravenous (IV) arginine therapy in children with sickle cell disease (SCD) and vaso-occlusive painful episodes (VOE) to further ...

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/ajh.27692

Arginine Therapy for Pain in Sickle Cell Disease Growing evidence supports a role for arginine as a safe adjuvant therapy for VOE in SCD; however, more controlled trials are needed to confirm ...

5. pecarn.org pecarn.org/pecarn_news/start-study-arginine-and-sickle-cell-crisis/

STArT Study: Arginine and sickle cell crisis - PECARN Arginine has shown promise in prior investigations to be safe [7] and effective in reducing pain associated with VOEs [2-3]. Take Home Message. For children ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8722015/

Safety of Intravenous Arginine Therapy in Children with ... Adverse events (AEs) reported with IV Arginine use include nausea, vomiting, headaches, flushing, dyspnea, and dose-dependent effects on blood ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119533869

Arginine Therapy for Vaso-Occlusive Pain Episodes in ... Arginine is a safe and inexpensive intervention with narcotic-sparing effects that should be considered as an adjunct to standard therapy for VOE requiring ...