Effectiveness of Arginine as a Treatment for Sickle Cell Anemia

• Sponsor: UCSF Benioff Children's Hospital Oakland (Other)
• Overall Status: Completed
• CT.gov ID: NCT00513617
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 128
• Locations: 17
• Arms: 3
• Duration (Months): 43
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia, Sickle Cell	Drug: Arginine; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Arginine Supplementation in Sickle Cell Anemia: Physiological and Prophylactic Effects
• Study Start Date: Jun 1, 2004
• Actual Primary Completion Date: Sep 1, 2007
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Gardos Channel Activity [12 weeks after randomization]

   Gardos channel activity: a calcium (Ca2+)-activated K+ channel

2. Nitric Oxide [12 weeks after randomization]

   Nitric oxide from plasma amino acids

3. Mean Corpuscular Hemoglobin Concentration [12 weeks after randomization]

   Mean corpuscular hemoglobin concentration as measured by an Advia machine

Secondary Outcome Measures

1. Soluble Vascular Cell Adhesion Molecule [12 weeks after randomization]

   Soluble vascular cell adhesion molecule (sVCAM) a vascular adhesion molecule

2. 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

3. Endothelin-1 [12 weeks after randomization]

   Endothelin-1 is a potent vasoconstrictor and pro-inflammatory agent which is elevated in SCD patients

4. Fetal Hemoglobin [12 weeks after randomization]

   Fetal hemoglobin (HbF) as measured by the Advia machine

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Oakland and Research Institute	Oakland	California	United States	94609
2	University of California - San Francisco	San Francisco	California	United States	94143
3	University of Colorado at Denver and Health Sciences Center--Sickle Cell Treatment and Research Center	Denver	Colorado	United States	80262
4	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
5	Boston Medical Center	Boston	Massachusetts	United States	02118
6	University of Mississippi Medical Center (Adult)	Jackson	Mississippi	United States	39215
7	University of Mississippi Medical Center (Pediatric)	Jackson	Mississippi	United States	39215
8	Montefiore Medical Center	Bronx	New York	United States	10463
9	Children's Hospital of Montefiore	Bronx	New York	United States	10467
10	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Children's Hospital of Oklahoma	Oklahoma City	Oklahoma	United States	73104
13	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
14	St. Christopher's Children's Research Hospital	Philadelphia	Pennsylvania	United States	19134
15	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19444
16	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
17	Children's Medical Center of Dallas	Dallas	Texas	United States	75390

Sponsors and Collaborators

• UCSF Benioff Children's Hospital Oakland
• 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: Kim Smith-Whitley, MD, Children's Hospital of Philadelphia
• 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 Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00513617
• Other Study ID Numbers: 485; U54HL070587-04
• First Posted: Aug 8, 2007
• Last Update Posted: Mar 29, 2017
• Last Verified: Jun 1, 2009

• Keywords provided by , ,: Sickle Cell Disease; Anemia; Nitric Oxide; Vaso Occlusive Events; Arginine Supplementation
• Additional relevant MeSH terms: Anemia; Anemia, Sickle Cell

Study Results

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 Detail	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.

Arm/Group Title	Low Dose	High Dose	Placebo
Arm/Group Description	0.05 g/kg/day of Arginine in capsule form	0.10 g/kg/day of Arginine in capsule form
Period Title: Overall Study
STARTED	36	35	38
COMPLETED	25	25	30
NOT COMPLETED	11	10	8

Baseline Characteristics

Arm/Group Title	Low Dose	High Dose	Placebo	Total
Arm/Group Description	0.05 g/kg/day of Arginine in capsule form	0.10 g/kg/day of Arginine in capsule form	Total of all reporting groups
Overall Participants	36	35	38	109
Age (Count of Participants)
<=18 years	14 38.9%	18 51.4%	18 47.4%	50 45.9%
Between 18 and 65 years	22 61.1%	17 48.6%	20 52.6%	59 54.1%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.5 (12.85)	20.0 (10.01)	21.0 (11.49)	23.2 (11.75)
Sex: Female, Male (Count of Participants)
Female	21 58.3%	19 54.3%	20 52.6%	60 55%
Male	15 41.7%	16 45.7%	18 47.4%	49 45%
Region of Enrollment (participants) [Number]
United States	36 100%	35 100%	38 100%	109.0 100%
Genotype of SCD (participants) [Number]
Sickle cell S-Beta Thalassemia (SB0)	2 5.6%	3 8.6%	2 5.3%	7.0 6.4%
Sickle cell Anemia (SS)	34 94.4%	32 91.4%	36 94.7%	102.0 93.6%

Outcome Measures

1. Primary Outcome

Title	Gardos Channel Activity
Description	Gardos channel activity: a calcium (Ca2+)-activated K+ channel
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

All subjects that were randomized and dosed - Intent to Treat (ITT) No imputation used.

Arm/Group Title	Low Dose	High Dose	Placebo
Arm/Group Description	0.05 g/kg/day of Arginine in capsule form	0.10 g/kg/day of Arginine in capsule form
Measure Participants	12	11	14
Mean (Standard Deviation) [mmol/10^13 cells x min]	-0.0342 (0.2341)	0.0043 (0.3028)	0.1076 (0.2822)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments	Alpha was set at 0.05
	Method	Mixed Models Analysis
	Comments	Null is tested using the F-test from a random effects longitudinal mixed model, with treatment and baseline measurement as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1254
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0705
	Estimation Comments	Placebo was subtracted from the Low dose

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.133
	Comments	Alpha was set at 0.05
	Method	Mixed Models Analysis
	Comments	Null is tested using the F-test from a random effects longitudinal mixed model, with treatment and baseline measurement as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0980
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0713
	Estimation Comments	Placebo was subtracted from High dose

2. Secondary Outcome

Title	Soluble Vascular Cell Adhesion Molecule
Description	Soluble vascular cell adhesion molecule (sVCAM) a vascular adhesion molecule
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Primary Outcome

Title	Nitric Oxide
Description	Nitric oxide from plasma amino acids
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

All subjects that were randomized and dosed - ITT No imputation used.

Arm/Group Title	Low Dose	High Dose	Placebo
Arm/Group Description	0.05 g/kg/day of Arginine in capsule form	0.10 g/kg/day of Arginine in capsule form
Measure Participants	12	11	14
Mean (Standard Deviation) [uM]	-3.8697 (15.7574)	2.9250 (11.1646)	-3.0265 (18.6887)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.915
	Comments	Alpha was set at 0.5
	Method	Mixed Models Analysis
	Comments	Null is tested using the F-test from a random effects longitudinal mixed model, with treatment and baseline measurement as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1826
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0713
	Estimation Comments	Placebo subtracted from Low dose

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.918
	Comments	Alpha was set at 0.05
	Method	Mixed Models Analysis
	Comments	Null is tested using the F-test from a random effects longitudinal mixed model, with treatment and baseline measurement as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.3582
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.1047
	Estimation Comments	Placebo subtracted from High dose

4. Primary Outcome

Title	Mean Corpuscular Hemoglobin Concentration
Description	Mean corpuscular hemoglobin concentration as measured by an Advia machine
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose	High Dose	Placebo
Arm/Group Description	0.05 g/kg/day of Arginine in capsule form	0.10 g/kg/day of Arginine in capsule form
Measure Participants	12	11	14
Mean (Standard Deviation) [g/dL]	-1.8485 (6.3092)	0.7692 (2.2165)	-0.0705 (1.4422)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	Alpha was set at 0.05
	Method	Mixed Models Analysis
	Comments	Null is tested using the F-test from a random effects longitudinal mixed model, with treatment and baseline measurement as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7867
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1101
	Estimation Comments	Placebo subtracted from Low dose

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.557
	Comments	Alpha was set at 0.05
	Method	Mixed Models Analysis
	Comments	Null is tested using the F-test from a random effects longitudinal mixed model, with treatment and baseline measurement as fixed effects.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5213
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1553
	Estimation Comments	Placebo subtracted from High dose

5. Secondary Outcome

Title	8-iso-PGF2a
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Endothelin-1
Description	Endothelin-1 is a potent vasoconstrictor and pro-inflammatory agent which is elevated in SCD patients
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Fetal Hemoglobin
Description	Fetal hemoglobin (HbF) as measured by the Advia machine
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Limitations/Caveats

Adult enrollment was slower than expected. Adult subjects were more likely than peds to drop-out due to SCD pain crisis. Higher doses of arginine (such as used in animal studies) were limited by number of daily pills required.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.