Anemia, Sickle Cell
Conditions
Keywords
Sickle Cell Disease, Anemia, Nitric Oxide, Vaso Occlusive Events, Arginine Supplementation
Brief summary
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.
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.
Interventions
DRUGArginine
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.
DRUGPlacebo
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
UCSF Benioff Children's Hospital Oakland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gardos Channel Activity | 12 weeks after randomization | Gardos channel activity: a calcium (Ca2+)-activated K+ channel |
| Nitric Oxide | 12 weeks after randomization | Nitric oxide from plasma amino acids |
| Mean Corpuscular Hemoglobin Concentration | 12 weeks after randomization | Mean corpuscular hemoglobin concentration as measured by an Advia machine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fetal Hemoglobin | 12 weeks after randomization | Fetal hemoglobin (HbF) as measured by the Advia machine |
| Endothelin-1 | 12 weeks after randomization | Endothelin-1 is a potent vasoconstrictor and pro-inflammatory agent which is elevated in SCD patients |
| Soluble Vascular Cell Adhesion Molecule | 12 weeks after randomization | Soluble vascular cell adhesion molecule (sVCAM) a vascular adhesion molecule |
| 8-iso-PGF2a | 12 weeks after randomization | 8-iso-PGF2a is a measure of lipid peroxidation and oxidative damage in vivo measured by enzyme immunoassay kit from Cayman chemical |
Countries
United States
Participant flow
Recruitment details
Enrolled subjects at participating sites from May 2004 through July 2007. Sites consisted of sickle cell treatment centers from across the United States.
Pre-assignment details
All subjects were to be without hydroxyurea, transfusion, and arginine for 90 days prior to enrollment. Prior to randomization, blood was drawn for baseline efficacy and safety measurements.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose 0.05 g/kg/day of Arginine in capsule form | 36 |
| High Dose 0.10 g/kg/day of Arginine in capsule form | 35 |
| Placebo | 38 |
| Total | 109 |
Baseline characteristics
| Characteristic | Low Dose | High Dose | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 14 Participants | 18 Participants | 18 Participants | 50 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 17 Participants | 20 Participants | 59 Participants |
| Age, Continuous | 24.5 years STANDARD_DEVIATION 12.85 | 20.0 years STANDARD_DEVIATION 10.01 | 21.0 years STANDARD_DEVIATION 11.49 | 23.2 years STANDARD_DEVIATION 11.75 |
| Genotype of SCD Sickle cell Anemia (SS) | 34 participants | 32 participants | 36 participants | 102.0 participants |
| Genotype of SCD Sickle cell S-Beta Thalassemia (SB0) | 2 participants | 3 participants | 2 participants | 7.0 participants |
| Region of Enrollment United States | 36 participants | 35 participants | 38 participants | 109.0 participants |
| Sex: Female, Male Female | 21 Participants | 19 Participants | 20 Participants | 60 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 18 Participants | 49 Participants |
Outcome results
Primary
Gardos Channel Activity
Gardos channel activity: a calcium (Ca2+)-activated K+ channel
Time frame: 12 weeks after randomization
Population: All subjects that were randomized and dosed - Intent to Treat (ITT) No imputation used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Gardos Channel Activity | -0.0342 mmol/10^13 cells x min | Standard Deviation 0.2341 |
| High Dose | Gardos Channel Activity | 0.0043 mmol/10^13 cells x min | Standard Deviation 0.3028 |
| Placebo | Gardos Channel Activity | 0.1076 mmol/10^13 cells x min | Standard Deviation 0.2822 |
Comparison: Null hypothesis is no difference between high vs. placebo and low vs. placebo in change from baseline at Week 12 post-randomization. Separate models were fit for pediatric and adult populations, however the combined population is entered here.p-value: 0.08Mixed Models Analysis
Comparison: Null hypothesis is no difference between high vs. placebo and low vs. placebo in change from baseline at Week 12 post-randomization. Separate models were fit for pediatric and adult populations, however the combined population is entered here.p-value: 0.133Mixed Models Analysis
Primary
Mean Corpuscular Hemoglobin Concentration
Mean corpuscular hemoglobin concentration as measured by an Advia machine
Time frame: 12 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Mean Corpuscular Hemoglobin Concentration | -1.8485 g/dL | Standard Deviation 6.3092 |
| High Dose | Mean Corpuscular Hemoglobin Concentration | 0.7692 g/dL | Standard Deviation 2.2165 |
| Placebo | Mean Corpuscular Hemoglobin Concentration | -0.0705 g/dL | Standard Deviation 1.4422 |
Comparison: Null hypothesis is no difference between high vs. placebo and low vs. placebo in change from baseline at Week 12 post-randomization. Separate models were fit for pediatric and adult populations, however the combined population is entered here.p-value: 0.015Mixed Models Analysis
Comparison: Null hypothesis is no difference between high vs. placebo and low vs. placebo in change from baseline at Week 12 post-randomization. Separate models were fit for pediatric and adult populations, however the combined population is entered here.p-value: 0.557Mixed Models Analysis
Primary
Nitric Oxide
Nitric oxide from plasma amino acids
Time frame: 12 weeks after randomization
Population: All subjects that were randomized and dosed - ITT No imputation used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Nitric Oxide | -3.8697 uM | Standard Deviation 15.7574 |
| High Dose | Nitric Oxide | 2.9250 uM | Standard Deviation 11.1646 |
| Placebo | Nitric Oxide | -3.0265 uM | Standard Deviation 18.6887 |
Comparison: Null hypothesis is no difference between high vs. placebo and low vs. placebo in change from baseline at Week 12 post-randomization. Separate models were fit for pediatric and adult populations, however the combined population is entered here.p-value: 0.915Mixed Models Analysis
Comparison: Null hypothesis is no difference between high vs. placebo and low vs. placebo in change from baseline at Week 12 post-randomization. Separate models were fit for pediatric and adult populations, however the combined population is entered here.p-value: 0.918Mixed Models Analysis
Secondary
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
Time frame: 12 weeks after randomization
Secondary
Endothelin-1
Endothelin-1 is a potent vasoconstrictor and pro-inflammatory agent which is elevated in SCD patients
Time frame: 12 weeks after randomization
Secondary
Fetal Hemoglobin
Fetal hemoglobin (HbF) as measured by the Advia machine
Time frame: 12 weeks after randomization
Secondary
Soluble Vascular Cell Adhesion Molecule
Soluble vascular cell adhesion molecule (sVCAM) a vascular adhesion molecule
Time frame: 12 weeks after randomization