L-arginine in Severe Asthma Patients Grouped by Exhaled Nitric Oxide Levels

• Sponsor: Nicholas Kenyon (Other)
• Overall Status: Completed
• CT.gov ID: NCT01841281
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 54
• Location: 1
• Arms: 2
• Duration (Months): 76
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The major impact of this study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. The investigators hypothesize that a subset of adult severe asthma patients will respond to supplemental L-arginine and derive clinical benefit from the addition of this therapy to standard-of-care asthma medications. The investigators hypothesize that the patients that benefit most will have low exhaled nitric oxide concentrations (< 20 ppb) at baseline.

Condition or Disease	Intervention/Treatment	Phase
Asthma; Inflammation	Drug: L-Arginine; Drug: Placebo	Phase 2

Detailed Description

We hypothesize that a subset of adult severe asthma patients will respond to supplemental L-arginine and derive clinical benefit from the addition of this therapy to standard-of-care medications. We hypothesize that these patients will have lower exhaled NO concentrations (<20 ppb) and lower nitric oxide synthase 2 (NOS2)/ arginase I (Arg1) mRNA ratios in their airway epithelial cells than "non-responders." The aim is to test the hypothesis that adult severe asthma subjects with exhaled breath NO concentrations < 20 ppb will have fewer American Thoracic Society (ATS)-defined asthma exacerbations over 3 months when treated with L-arginine compared to subjects with exhaled nitric oxide concentration (FeNO) > 25 ppb. The major impact of this study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy to define the underlying mechanisms of arginine benefit in asthma. This follows our initial 20 subject trial of L-arginine in asthma subjects (Kenyon et al., Pharmaceuticals 2011) that was designed to determine how L-arginine was metabolized (by testing serum markers) and whether certain participants had clinical benefit.

To do this, we will recruit a total of 50 ATS-defined severe asthmatic subjects with ongoing asthma exacerbations in past two months and enroll them in a randomized, blinded, placebo-controlled, cross-over designed trial of L-arginine and placebo. We will compare 25 subjects with "low" FeNO < 20 with 25 subjects that have "high" FeNO > 25 ppb.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase II Study of L-arginine in Severe Asthma Patients Grouped by Exhaled Nitric Oxide Level
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Low Exhaled Nitric Oxide (NO) Subjects with a baseline exhaled NO level less than or equal to 20 ppb will be enrolled in the Low Exhaled Nitric Oxide arm. All subjects will receive L-arginine and placebo in this cross-over design study.	Drug: L-Arginine; L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.; Other Names: Arginine 1000 (Jarrow Formulas, Los Angeles, CA) ; Drug: Placebo; Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
Active Comparator: High Exhaled Nitric Oxide (NO) Subjects with a baseline exhaled NO level greater than or equal to 25 ppb will be enrolled in the High Exhaled Nitric Oxide arm. All subjects will receive L-arginine and placebo in this cross-over design study.	Drug: L-Arginine; L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.; Other Names: Arginine 1000 (Jarrow Formulas, Los Angeles, CA) ; Drug: Placebo; Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.

Outcome Measures

Primary Outcome Measures

1. Number of Acute Exacerbation at 3 Months [3 month]

   The primary endpoint of the study is the number of acute moderate exacerbations at 3 months. A moderate asthma exacerbation is defined as any of the following: 1) A drop in morning peak flow rate (PEFR) >30% from baseline on 2 consecutive days (1 event), 2) Need for initiation of oral steroids or am increased dose of inhaled corticosteroids on any two consecutive days (1 event), 3) Doubling of short-acting β-agonist use (e.g. number of puffs of albuterol) per day for 2 consecutive days (1 event).

Secondary Outcome Measures

1. Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) [3 month]

   The secondary endpoint is the change in FEV1/FVC ratio at 3 months. This calcuation is a ratio between the volume of breath exhaled in the first second divided by the total amount of breath exhaled in a vital capacity maneuver. A normal ratio is usually > 70%.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults >18 yrs of age

• Diagnosis of severe asthma based on American Thoracic Society Workshop definition (Am J Respir Crit Care Med 2000; 162:2341)

• Active asthma medications of high dose inhaled corticosteroids plus long-acting beta agonist

• History of recent asthma exacerbations or Asthma control test score < 20/25

Exclusion Criteria:

• <19 yrs of age

• Forced expiratory volume 1sec <30% predicted

• Pregnant or nursing women

• Current smokers or smoking history > 15 pack years

• Actively taking or known intolerance to L-arginine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Davis CTSC Clinical Research Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• Nicholas Kenyon
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Nicholas Kenyon, MD,MS, Univ. of California, Davis

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 15, 2019

More Information

Publications

None provided.

• Responsible Party: Nicholas Kenyon, Professor, University of California, Davis
• ClinicalTrials.gov Identifier: NCT01841281
• Other Study ID Numbers: 271515; R01HL105573; UCD105573
• First Posted: Apr 26, 2013
• Last Update Posted: Apr 21, 2020
• Last Verified: Apr 1, 2020

• Keywords provided by Nicholas Kenyon, Professor, University of California, Davis: Asthma; Severe Asthma
• Additional relevant MeSH terms: Asthma; Inflammation

Study Results

Participant Flow

Recruitment Details	54 subjects consented and enrolled for the trial, but n=50 were randomized as n=4 participants declined to participate.
Pre-assignment Detail	Participants were assigned to low or high exhaled nitric oxide groups based on their levels at time of Visit 1.

Arm/Group Title	Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo	High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo	Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine	High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine
Arm/Group Description	Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive Placebo first, then L-arginine L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
Period Title: First Intervention (12 Weeks)
STARTED	11	12	13	14
COMPLETED	11	12	13	14
NOT COMPLETED	0	0	0	0
Period Title: First Intervention (12 Weeks)
STARTED	11	12	13	14
COMPLETED	9	9	10	13
NOT COMPLETED	2	3	3	1
Period Title: First Intervention (12 Weeks)
STARTED	9	9	10	13
COMPLETED	9	6	10	13
NOT COMPLETED	0	3	0	0

Baseline Characteristics

Arm/Group Title	Low Exhaled Nitric Oxide (NO)	High Exhaled Nitric Oxide (NO)	Total
Arm/Group Description	Subjects with a baseline exhaled NO level less than or equal to 20 ppb will be enrolled in the Low Exhaled Nitric Oxide arm. Baseline characteristics at the enrollment	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb will be enrolled in the High Exhaled Nitric Oxide arm. Baseline characteristics at the enrollment	Total of all reporting groups
Overall Participants	24	26	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.5 (11.9)	52.4 (14.3)	54.3 (13.2)
Sex: Female, Male (Count of Participants)
Female	17 70.8%	21 80.8%	38 76%
Male	7 29.2%	5 19.2%	12 24%
Race/Ethnicity, Customized (Count of Participants)
White	19 79.2%	20 76.9%	39 78%
Non-White	5 20.8%	6 23.1%	11 22%
Spirometry (Litters) [Mean (Standard Deviation) ]
FEV1	1.8 (0.7)	2.2 (0.9)	2 (0.8)
FVC	2.6 (0.9)	2.8 (1.1)	2.7 (1.0)
Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	94.8 (20.5)	85.6 (27.3)	90.0 (24.5)
Asthma Control Test Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	16.0 (4.6)	16.1 (5.5)	16.1 (5.0)

Outcome Measures

1. Primary Outcome

Title	Number of Acute Exacerbation at 3 Months
Description	The primary endpoint of the study is the number of acute moderate exacerbations at 3 months. A moderate asthma exacerbation is defined as any of the following: 1) A drop in morning peak flow rate (PEFR) >30% from baseline on 2 consecutive days (1 event), 2) Need for initiation of oral steroids or am increased dose of inhaled corticosteroids on any two consecutive days (1 event), 3) Doubling of short-acting β-agonist use (e.g. number of puffs of albuterol) per day for 2 consecutive days (1 event).
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Several patients dropped after the first intervention

Arm/Group Title	Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo	High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo	Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine	High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine
Arm/Group Description	Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive Placebo first, then L-arginine L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
Measure Participants	11	12	13	14
First Intervention	2.7 (2.0)	2.2 (2.2)	1.6 (1.8)	2.2 (3.0)
Second Intervention	2.1 (1.4)	2.7 (4.2)	2.2 (2.2)	2.2 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo, High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo, Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine, High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	The p-value is for the interaction term
	Method	testing for interaction term
	Comments

2. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC)
Description	The secondary endpoint is the change in FEV1/FVC ratio at 3 months. This calcuation is a ratio between the volume of breath exhaled in the first second divided by the total amount of breath exhaled in a vital capacity maneuver. A normal ratio is usually > 70%.
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Several patients dropped after the first intervention

Arm/Group Title	Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo	High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo	Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine	High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine
Arm/Group Description	Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive Placebo first, then L-arginine L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.	Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
Measure Participants	11	12	13	14
First Intervention	-0.02 (0.05)	0.01 (0.06)	0.03 (0.13)	-0.03 (0.04)
Second Intervention	0.01 (0.04)	0.13 (0.06)	0.003 (0.06)	-0.04 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo, High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo, Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine, High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine
	Comments	The treatment effect was tested as an interaction term between treatment and FeNO. The null hypothesis is the effect of treatment is stratified by the FeNO status. We used a regression model instead of t-test or Wilcoxon signed-rank test in order to control period and carry-over effect which is common in a cross-over study design
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments	The p-value is for the interaction term
	Method	testing for interaction term
	Comments

Adverse Events

Time Frame	Adverse events were collected for the duration of the trial,8 months
Arm/Group Title	Low Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		Low Exhaled Nitric Oxide (NO) Washout Phase		Low Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm		High Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		High Exhaled Nitric Oxide (NO) Washout Phase		High Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm
Arm/Group Description	ow Exhaled Nitric Oxide (NO) Phase 1, L-Arginine arm		Low Exhaled Nitric Oxide (NO) Phase 1, placebo arm		Low Exhaled Nitric Oxide (NO) Washout Phase		Low Exhaled Nitric Oxide (NO) Phase 2, L-Arginine arm		Low Exhaled Nitric Oxide (NO) Phase 2, placebo arm		High Exhaled Nitric Oxide (NO) Phase 1, L-Arginine arm		High Exhaled Nitric Oxide (NO) Phase 1, placebo arm		High Exhaled Nitric Oxide (NO) Washout Phase		High Exhaled Nitric Oxide (NO) Phase 2, L-Arginine arm		igh Exhaled Nitric Oxide (NO) Phase 2, Placebo arm
All Cause Mortality
	Low Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		Low Exhaled Nitric Oxide (NO) Washout Phase		Low Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm		High Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		High Exhaled Nitric Oxide (NO) Washout Phase		High Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/13 (0%)		0/19 (0%)		0/10 (0%)		0/9 (0%)		0/12 (0%)		0/14 (0%)		0/22 (0%)		0/16 (0%)		0/6 (0%)
Serious Adverse Events
	Low Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		Low Exhaled Nitric Oxide (NO) Washout Phase		Low Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm		High Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		High Exhaled Nitric Oxide (NO) Washout Phase		High Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/13 (0%)		0/19 (0%)		0/10 (0%)		0/9 (0%)		2/12 (16.7%)		1/14 (7.1%)		1/22 (4.5%)		0/16 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Hospitalization	0/11 (0%)	0	0/13 (0%)	0	0/19 (0%)	0	0/10 (0%)	0	0/9 (0%)	0	2/12 (16.7%)	2	1/14 (7.1%)	1	1/22 (4.5%)	1	0/16 (0%)	0	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Low Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		Low Exhaled Nitric Oxide (NO) Washout Phase		Low Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		Low Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm		High Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm		High Exhaled Nitric Oxide (NO) Washout Phase		High Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm		High Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		1/13 (7.7%)		0/19 (0%)		1/10 (10%)		0/9 (0%)		1/12 (8.3%)		0/14 (0%)		0/22 (0%)		0/16 (0%)		0/6 (0%)
Gastrointestinal disorders
Gastroesophageal reflux disease	0/11 (0%)	0	1/13 (7.7%)	1	0/19 (0%)	0	0/10 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/14 (0%)	0	0/22 (0%)	0	0/16 (0%)	0	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Hives	0/11 (0%)	0	0/13 (0%)	0	0/19 (0%)	0	1/10 (10%)	1	0/9 (0%)	0	0/12 (0%)	0	0/14 (0%)	0	0/22 (0%)	0	0/16 (0%)	0	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

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.