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

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ClinicalTrials.gov Identifier: NCT00513617
Recruitment Status : Completed
First Posted : August 8, 2007
Results First Posted : August 4, 2009
Last Update Posted : March 29, 2017
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:
UCSF Benioff Children’s Hospital Oakland

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Anemia, Sickle Cell
Interventions Drug: Arginine
Drug: Placebo
Enrollment 128
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.
Arm/Group Title Low Dose High Dose Placebo
Hide Arm/Group Description 0.05 g/kg/day of Arginine in capsule form 0.10 g/kg/day of Arginine in capsule form [Not Specified]
Period Title: Overall Study
Started 36 35 38
Completed 25 25 30
Not Completed 11 10 8
Arm/Group Title Low Dose High Dose Placebo Total
Hide Arm/Group Description 0.05 g/kg/day of Arginine in capsule form 0.10 g/kg/day of Arginine in capsule form [Not Specified] Total of all reporting groups
Overall Number of Baseline Participants 36 35 38 109
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 35 participants 38 participants 109 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
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants 35 participants 38 participants 109 participants
24.5  (12.85) 20.0  (10.01) 21.0  (11.49) 23.2  (11.75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 35 participants 38 participants 109 participants
Female
21
  58.3%
19
  54.3%
20
  52.6%
60
  55.0%
Male
15
  41.7%
16
  45.7%
18
  47.4%
49
  45.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 36 participants 35 participants 38 participants 109 participants
36 35 38 109
Genotype of SCD  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 36 participants 35 participants 38 participants 109 participants
Sickle cell S-Beta Thalassemia (SB0) 2 3 2 7
Sickle cell Anemia (SS) 34 32 36 102
1.Primary Outcome
Title Gardos Channel Activity
Hide Description Gardos channel activity: a calcium (Ca2+)–activated K+ channel
Time Frame 12 weeks after randomization
Hide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
0.05 g/kg/day of Arginine in capsule form
0.10 g/kg/day of Arginine in capsule form
[Not Specified]
Overall Number of Participants Analyzed 12 11 14
Mean (Standard Deviation)
Unit of Measure: mmol/10^13 cells x min
-0.0342  (0.2341) 0.0043  (0.3028) 0.1076  (0.2822)
Show Statistical Analysis 1 Hide 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 [Not Specified]
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
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0705
Estimation Comments Placebo was subtracted from the Low dose
Show Statistical Analysis 2 Hide 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 [Not Specified]
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
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0713
Estimation Comments Placebo was subtracted from High dose
2.Primary Outcome
Title Nitric Oxide
Hide Description Nitric oxide from plasma amino acids
Time Frame 12 weeks after randomization
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects that were randomized and dosed - ITT No imputation used.
Arm/Group Title Low Dose High Dose Placebo
Hide Arm/Group Description:
0.05 g/kg/day of Arginine in capsule form
0.10 g/kg/day of Arginine in capsule form
[Not Specified]
Overall Number of Participants Analyzed 12 11 14
Mean (Standard Deviation)
Unit of Measure: uM
-3.8697  (15.7574) 2.9250  (11.1646) -3.0265  (18.6887)
Show Statistical Analysis 1 Hide 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 [Not Specified]
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
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0713
Estimation Comments Placebo subtracted from Low dose
Show Statistical Analysis 2 Hide 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 [Not Specified]
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
Parameter Dispersion
Type: Standard Error of the Mean
Value: 4.1047
Estimation Comments Placebo subtracted from High dose
3.Primary Outcome
Title Mean Corpuscular Hemoglobin Concentration
Hide Description Mean corpuscular hemoglobin concentration as measured by an Advia machine
Time Frame 12 weeks after randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose High Dose Placebo
Hide Arm/Group Description:
0.05 g/kg/day of Arginine in capsule form
0.10 g/kg/day of Arginine in capsule form
[Not Specified]
Overall Number of Participants Analyzed 12 11 14
Mean (Standard Deviation)
Unit of Measure: g/dL
-1.8485  (6.3092) 0.7692  (2.2165) -0.0705  (1.4422)
Show Statistical Analysis 1 Hide 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 [Not Specified]
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
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.1101
Estimation Comments Placebo subtracted from Low dose
Show Statistical Analysis 2 Hide 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 [Not Specified]
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
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.1553
Estimation Comments Placebo subtracted from High dose
4.Secondary Outcome
Title Soluble Vascular Cell Adhesion Molecule
Hide Description Soluble vascular cell adhesion molecule (sVCAM) a vascular adhesion molecule
Time Frame 12 weeks after randomization
Outcome Measure Data Not Reported
5.Secondary Outcome
Title 8-iso-PGF2a
Hide 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 Not Reported
6.Secondary Outcome
Title Endothelin-1
Hide 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 Not Reported
7.Secondary Outcome
Title Fetal Hemoglobin
Hide Description Fetal hemoglobin (HbF) as measured by the Advia machine
Time Frame 12 weeks after randomization
Outcome Measure Data Not Reported
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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Karen Kesler, PhD
Organization: Rho Federal Systems Division
Phone: 919-408-8000 ext 244
EMail: karen_kesler@rhoworld.com
Layout table for additonal information
Responsible Party: Lori Styles/Principal Investigator, Childrens Hospital of Oakland and Research Institute
ClinicalTrials.gov Identifier: NCT00513617     History of Changes
Other Study ID Numbers: 485
U54HL070587-04 ( U.S. NIH Grant/Contract )
First Submitted: August 6, 2007
First Posted: August 8, 2007
Results First Submitted: February 23, 2009
Results First Posted: August 4, 2009
Last Update Posted: March 29, 2017