Arginine Therapy for Sickle Cell Disease
(R34 pK/PD Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Emory University
Must not be taking: Inhaled nitric oxide, sildenafil
Disqualifiers: Pregnancy, Renal dysfunction, Stroke, others
No Placebo Group
Approved in 3 Jurisdictions
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.12345
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.678910
How does the drug arginine differ from other treatments for sickle cell disease?
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.
See 1 more
Exclusion Criteria
Hemoglobin less than 5 gm/dL
You are allergic to arginine.
I expect to need a blood transfusion soon.
See 10 more
Trial 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 (Amino Acid)
Trial OverviewThe 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
6Treatment groups
Experimental Treatment
Group I: Standard doseExperimental Treatment1 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 doseExperimental Treatment1 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 doseExperimental Treatment1 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 doseExperimental Treatment1 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 doseExperimental Treatment2 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 infusionExperimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Healthcare fo Atlanta at Hughes SpaldingAtlanta, GA
Children's Healthcare of Atlanta at EglestonAtlanta, GA
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Who Is Running the Clinical Trial?
Emory University
Lead Sponsor
Trials
1735
Patients Recruited
2,605,000+
National Center for Complementary and Integrative Health (NCCIH)
Collaborator
Trials
886
Patients Recruited
677,000+
Children's Healthcare of Atlanta
Collaborator
Trials
172
Patients Recruited
108,000+
References
Effect of L-arginine supplementation on immune responsiveness in patients with sickle cell disease. [2017]L-arginine (L-Arg) is deficient in sickle cell disease (SSD) during vasoocclusion. We investigated possible causal relationship between L-Arg deficiency and immune dysfunction in SSD in steady-state.
Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. [2018]L-Arginine may be a conditionally essential amino acid in children and adolescents with sickle cell disease, particularly as required substrate in the arginine-nitric oxide pathway for endogenous nitrovasodilation and vasoprotection. Vasoprotection by arginine is mediated partly by nitric oxide-induced inhibition of endothelial damage and inhibition of adhesion and activation of leukocytes. Activated leukocytes may trigger many of the complications, including vasoocclusive events and intimal hyperplasias. High blood leukocyte counts during steady states in the absence of infection are significant laboratory risk factors for adverse complications. L-Citrulline as precursor amino acid was given orally twice daily in daily doses of approximately 0.1 g/kg in a pilot Phase II clinical trial during steady states in four homozygous sickle cell disease subjects and one sickle cell-hemoglobin C disease patient (ages 10-18). There soon resulted dramatic improvements in symptoms of well-being, raised plasma arginine levels, and reductions in high total leukocyte and high segmented neutrophil counts toward or to within normal limits. Continued L-citrulline supplementation in compliant subjects continued to lessen symptomatology, to maintain plasma arginine concentrations greater than control levels, and to maintain nearly normal total leukocyte and neutrophil counts. Side effects or toxicity from citrulline were not experienced. Oral L-citrulline may portend very useful for palliative therapy in sickle cell disease. Placebo-controlled, long-term trials are now indicated.
Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? [2022]Pulmonary hypertension is a life-threatening complication of sickle cell disease. L-Arginine is the nitrogen donor for synthesis of nitric oxide, a potent vasodilator that is deficient during times of sickle cell crisis. This deficiency may play a role in pulmonary hypertension. The enzyme arginase hydrolyzes arginine to ornithine and urea, and thus, it may compete with nitric oxide synthase, leading to decreased nitric oxide production. Nitric oxide therapy by inhalation has improved pulmonary hypertension associated with acute chest syndrome in sickle cell disease, and several studies demonstrate therapeutic benefits of arginine therapy for primary and secondary pulmonary hypertension. We sought to determine the effects of arginine therapy on pulmonary hypertension in patients with sickle cell disease. Arginase activity was also determined. Oral arginine produced a 15.2% mean reduction in estimated pulmonary artery systolic pressure (63.9 +/- 13 to 54.2 +/- 12 mm Hg, p = 0.002) after 5 days of therapy in 10 patients. Arginase activity was elevated almost twofold (p = 0.07) in patients with pulmonary hypertension and may limit arginine bioavailability. With limited treatment options and a high mortality rate for patients with sickle cell disease who develop pulmonary hypertension, arginine is a promising new therapy that warrants further investigation.
Effects of l-arginine supplementation in patients with sickle cell disease: A systematic review and meta-analysis of clinical trials. [2023]Previous studies have shown that supplementation of some amino acids such as l-arginine or its precursors could exert beneficial effects in patients with sickle cell disease (SCD). The objective of this study is to systematically review the literature to assess the effect of arginine administration on the clinical and paraclinical parameters of patients with SCD.
Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease. [2019]To determine the effects of L-arginine (L-Arg) supplementation on nitric oxide metabolite (NOx) production, oral L-Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso-occlusive crisis (VOC). L-Arg (0.1 g/kg) increased NOx formation by 18.8 +/- 68% in normal controls, whereas steady-state SCD patients demonstrated a paradoxical decrease in NOx of -16.7 +/- 4% (P = 0.004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77.7 +/- 103%, a response that was dose dependent. L-Arg appears to be the rate-limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.
Catabolism and safety of supplemental L-arginine in animals. [2018]L-arginine (Arg) is utilized via multiple pathways to synthesize protein and low-molecular-weight bioactive substances (e.g., nitric oxide, creatine, and polyamines) with enormous physiological importance. Furthermore, Arg regulates cell signaling pathways and gene expression to improve cardiovascular function, augment insulin sensitivity, enhance lean tissue mass, and reduce obesity in humans. Despite its versatile roles, the use of Arg as a dietary supplement is limited due to the lack of data to address concerns over its safety in humans. Data from animal studies are reviewed to assess arginine catabolism and the safety of long-term Arg supplementation. The arginase pathway was responsible for catabolism of 76-85 and 81-96 % Arg in extraintestinal tissues of pigs and rats, respectively. Dietary supplementation with Arg-HCl or the Arg base [315- and 630-mg Arg/(kg BW d) for 91 d] had no adverse effects on male or female pigs. Similarly, no safety issues were observed for male or female rats receiving supplementation with 1.8- and 3.6-g Arg/(kg BW d) for at least 91 d. Intravenous administration of Arg-HCl to gestating sheep at 81 and 180 mg Arg/(kg BW d) is safe for at least 82 and 40 d, respectively. Animals fed conventional diets can well tolerate large amounts of supplemental Arg [up to 630-mg Arg/(kg BW d) in pigs or 3.6-g Arg/(kg BW d) in rats] for 91 d, which are equivalent to 573-mg Arg/(kg BW d) for humans. Collectively, these results can help guide studies to determine the safety of long-term oral administration of Arg in humans.
Assessment of the application for renewal of authorisation of l-arginine produced by fermentation using Corynebacterium glutamicum NITE SD 00285 for all animal species. [2020]l-Arginine is an amino acid that is conditionally essential for mammalian neonates, some strict carnivores, birds and fish. The subject of this opinion is a request for renewal of authorisation of l-arginine produced by a strain of Corynebacterium glutamicum. The strain designation has changed to its new deposition number, NITE SD 00285, but the strain is otherwise unchanged from the previous opinion. It is not genetically modified and possesses no antibiotic resistance of safety concern. Minor changes in downstream processing following fermentation have been made. The FEEDAP Panel notes that two out of five batches did not meet the specification of the current authorisation (minimum 98% on a dry matter basis). The FEEDAP Panel concludes that l-arginine produced by fermentation to C. glutamicum NITE SD 00285 remains safe for the target species, consumers of products from animals fed the additive and the environment under the approved conditions of authorisation. The additive is considered as irritant to skin, corrosive to eyes and poses a risk by inhalation.
Arginine metabolism and nutrition in growth, health and disease. [2023]L-Arginine (Arg) is synthesised from glutamine, glutamate, and proline via the intestinal-renal axis in humans and most other mammals (including pigs, sheep and rats). Arg degradation occurs via multiple pathways that are initiated by arginase, nitric-oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine, and agmatine with each having enormous biological importance. Arg is also required for the detoxification of ammonia, which is an extremely toxic substance for the central nervous system. There is compelling evidence that Arg regulates interorgan metabolism of energy substrates and the function of multiple organs. The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Additionally, Arg or L-citrulline may provide novel and effective therapies for obesity, diabetes, and the metabolic syndrome. The effect of Arg in treating many developmental and health problems is unique among AAs, and offers great promise for improved health and wellbeing of humans and animals.
The metabolic basis of arginine nutrition and pharmacotherapy. [2019]As an essential precursor for the synthesis of proteins and other molecules with enormous biological importance (including nitric oxide, urea, ornithine, proline, polyamines, glutamate, creatine, agmatine, and dimethylarginines), arginine displays remarkable metabolic and regulatory versatility. Evidence available to date provides a sound reason to classify arginine as an essential amino acid for young mammals (including parenterally fed human infants) and as a conditionally essential amino acid for adults under such conditions as trauma, burn injury, massive small-bowel resection, and renal failure. Arginine administration reverses endothelial dysfunction, enhances wound healing, prevents the early stages of tumorigenesis, and improves cardiovascular, reproductive, pulmonary, renal, digestive, and immune functions. Arginine or its effective precursor citrulline may hold great promise as a nutritional or pharmacotherapeutic treatment for a wide array of human diseases.
Safety and Effectiveness of Arginine in Adults. [2023]l-Arginine (Arg) appears to have a beneficial effect on the regulation of nutrient metabolism to enhance lean tissue deposition and on insulin resistance in humans. The observed safe level for oral administration of Arg is ∼20 g/d, but higher levels have been tested in short-term studies without serious adverse effects; however, more data are needed in both animal models and humans to fully evaluate safety as well as efficacy. The primary objective of this review is to summarize the current knowledge of the safety, pharmacokinetics, and effectiveness of oral Arg in adults. Arg supplementation has been used safely in vulnerable populations, such as pregnant women, preterm infants, and individuals with cystic fibrosis. Several recent studies have shown beneficial effects of Arg in individuals with obesity, insulin resistance, and diabetes. Collectively, the data suggest that Arg supplementation is a safe and generally well-tolerated nutriceutical that may improve metabolic profiles in humans.
[Arginine--metabolism and functions in the human organism]. [2016]L-arginine plays important roles in the metabolism of an organism. It is the precursor for the synthesis of proteins and other molecules of great biological importance, including nitric oxide, ornithine, polyamines, agmatine, proline, glutamate, creatine, dimethylarginine, and urea. For young organisms arginine is an essential amino acid for optimal growth and development, and must therefore be provided in the diet. For adults, arginine is a conditionally essential amino acid, especially in such conditions as trauma, burn injury, small-bowel resection, and renal failure. L-arginine administration improves cardiovascular, pulmonary, immune, and digestive functions and protect against the early stages of cancerogenesis.