Effectiveness of Arginine as a Treatment for Sickle Cell Anemia (Arginine)

Arginine Supplementation in Sickle Cell Anemia: Physiological and Prophylactic Effects

Sickle cell disease (SCD), also known as sickle cell anemia, is an inherited genetic disease that can cause intense pain episodes. This study will evaluate the effectiveness of the nutritional supplement arginine at improving blood cell function and disease symptoms in people with SCD.

Study Overview

• Status: Completed
• Conditions: Anemia, Sickle Cell
• Intervention / Treatment: Drug: Arginine; Drug: Placebo

Detailed Description

SCD is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain that are called "sickle cell crises." SCD is caused by an abnormal type of hemoglobin, which is a protein inside red blood cells that carries oxygen. In people with SCD, the abnormal hemoglobin distorts the shape of the red blood cells. This causes the red blood cells to clump together, decreasing blood flow and oxygen delivery to the body's tissues. The reduced levels of oxygen can lead to sickle cell crises and tissue damage. Hemolysis, the destruction of red blood cells, is also a hallmark of SCD. During hemolysis, hemoglobin is released into the bloodstream, where it removes nitric oxide (NO), a natural chemical in the body that expands blood vessels. Arginase, another protein released during hemolysis, removes arginine from the bloodstream, which can also lead to decreased NO levels. The lack of NO constricts blood vessels, further contributing to painful sickle cell crises. Arginine supplementation may increase healthy hemoglobin and NO production and, in turn, prevent or reduce sickle cell crises. The purpose of this study is to evaluate the effectiveness of arginine at increasing NO levels, improving red blood cell function, and reducing hospitalizations and pain medication use in people with SCD.

This study will enroll children and adults with SCD. Participants will be randomly assigned to receive twice daily doses of either a low dose of arginine, a high dose of arginine, or placebo for 12 weeks. Study visits will occur at baseline, three times during Month 1, and Weeks 8, 12, 14, and 16. Each study visit will include an echocardiogram to measure heart activity, blood collection, and a medical history review to identify adverse events, pain medication usage, headaches, emergency department visits, and hospitalizations.

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital of Oakland and Research Institute
    • San Francisco, California, United States, 94143
      • University of California - San Francisco
  • Colorado
    • Denver, Colorado, United States, 80262
      • University of Colorado at Denver and Health Sciences Center--Sickle Cell Treatment and Research Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39215
      • University of Mississippi Medical Center (Adult)
    • Jackson, Mississippi, United States, 39215
      • University of Mississippi Medical Center (Pediatric)
  • New York
    • Bronx, New York, United States, 10463
      • Montefiore Medical Center
    • Bronx, New York, United States, 10467
      • Children's Hospital of Montefiore
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Children's Hospital of Oklahoma
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Children's Research Hospital
    • Philadelphia, Pennsylvania, United States, 19444
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • Children's Medical Center of Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Established diagnosis of H SS or S-beta thalassemia
• History of at least one vaso-occlusive pain event in the 12 months prior to study entry
• Regular compliance with comprehensive medical care
• In a steady disease state and not in the midst of any acute complication due to SCD at study entry

Exclusion Criteria:

• Inability to take or tolerate oral medications
• Liver dysfunction (i.e., SGPT level greater than or equal to two times the normal limit and albumin level less than or equal to 3.2 g/dL)
• Kidney dysfunction ( i.e., creatinine level greater than or equal to 1.2 mg/dL for children and greater than or equal to 1.4 mg/dL for adults)
• Allergy to arginine
• Pregnant
• Received a blood transfusion within the 90 days prior to study entry
• More than 10 hospital admissions for pain in the 12 months prior to study entry
• Daily use of opioids and experiencing unstable pain that interferes with work or daily routine
• Required more than 3 hospital admissions and more than 10 emergency department/day hospital visits in the 12 months prior to study entry
• Received treatment with hydroxyurea within the 90 days prior to study entry
• Received treatment with any investigational drug in the 90 days prior to study entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Dose; 0.05 g/kg/day Arginine	Drug: Arginine; Depending on the weight of the child or adult, the patients took any where between 4-10 capsules 2 times a day. Patients weighing less than 45 kilograms were on the low dose active (or placebo) so the capsules were smaller. Patients greater than or equal to 45 kgs were on the high dose active or placebo, so these capsules were larger.
Active Comparator: High Dose; 0.10 g/kg/day Arginine	Drug: Arginine; Depending on the weight of the child or adult, the patients took any where between 4-10 capsules 2 times a day. Patients weighing less than 45 kilograms were on the low dose active (or placebo) so the capsules were smaller. Patients greater than or equal to 45 kgs were on the high dose active or placebo, so these capsules were larger.
Placebo Comparator: Placebo; No Arginine	Drug: Placebo; Depending on the weight of the child or adult, the patients took any where between 4-10 capsules 2 times a day. Patients weighing less than 45 kilograms were on the low dose active (or placebo) so the capsules were smaller. Patients greater than or equal to 45 kgs were on the high dose active or placebo, so these capsules were larger.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gardos Channel Activity	Gardos channel activity: a calcium (Ca2+)-activated K+ channel	12 weeks after randomization
Nitric Oxide	Nitric oxide from plasma amino acids	12 weeks after randomization
Mean Corpuscular Hemoglobin Concentration	Mean corpuscular hemoglobin concentration as measured by an Advia machine	12 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Soluble Vascular Cell Adhesion Molecule	Soluble vascular cell adhesion molecule (sVCAM) a vascular adhesion molecule	12 weeks after randomization
8-iso-PGF2a	8-iso-PGF2a is a measure of lipid peroxidation and oxidative damage in vivo measured by enzyme immunoassay kit from Cayman chemical	12 weeks after randomization
Endothelin-1	Endothelin-1 is a potent vasoconstrictor and pro-inflammatory agent which is elevated in SCD patients	12 weeks after randomization
Fetal Hemoglobin	Fetal hemoglobin (HbF) as measured by the Advia machine	12 weeks after randomization

Collaborators and Investigators

• Sponsor: UCSF Benioff Children's Hospital Oakland
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Lillian McMahon, MD, Boston Medical Center; Principal Investigator: Rathi Iyer, MD, University of Mississippi Medical Center (Pediatric); Principal Investigator: Carolyn Bigelow, MD, University of Mississippi Medical Center (Adult); Principal Investigator: Lennette Benjamin, MD, Montefiore Medical Center; Principal Investigator: Mary Fabry, MD, Albert Einstein College of Medicine; Principal Investigator: Thomas Moulton, MD, Children's Hospital of Montefiore; Principal Investigator: Laura DeCastro, MD, Duke University; Principal Investigator: Kenneth Ataga, MD, University of North Carolina, Chapel Hill; Principal Investigator: Samir K. Ballas, MD, Thomas Jefferson University; Principal Investigator: Sal Bertalone, MD, Norton HealthCare; Principal Investigator: Carlton Dampier, MD, St. Christopher's Childrens Hospital; Principal Investigator: William Mentzer, MD, University of California, San Francisco; Principal Investigator: Winfred Wang, MD, St. Jude's Childrens Research Hospital; Principal Investigator: Ulrike Reiss, MD, St. Jude Children's Research Hospital; Principal Investigator: Cynthia Rutherford, MD, Children's Medical Center Dallas; Principal Investigator: Kathryn Hassell, MD, University of Colorado, Denver; Principal Investigator: Joan Parkhurst Cain, MD, Children's Hospital of Oklahoma

Study record dates

Study Major Dates

• Study Start: June 1, 2004
• Primary Completion (Actual): September 1, 2007
• Study Completion (Actual): January 1, 2008

Study Registration Dates

• First Submitted: August 6, 2007
• First Submitted That Met QC Criteria: August 6, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Actual): March 29, 2017
• Last Update Submitted That Met QC Criteria: February 28, 2017
• Last Verified: June 1, 2009

More Information

Terms related to this study

• Keywords: Anemia; Sickle Cell Disease; Nitric Oxide; Vaso Occlusive Events; Arginine Supplementation
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia; Anemia, Sickle Cell
• Other Study ID Numbers: 485; U54HL070587-04 (U.S. NIH Grant/Contract)