An Open-Label Trial of Losartan Potassium in Participants With Eosinophilic Esophagitis (EoE)

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT03029091
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Office of Rare Diseases (ORD) (NIH), National Center for Advancing Translational Science (NCATS) (NIH)
• Enrollment: 15
• Locations: 3
• Arms: 3
• Actual Duration (Months): 27
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to test the safety and effectiveness of Losartan potassium in subjects with eosinophilic esophagitis (EoE) including those with a connective tissue disorder (CTD) and those without a CTD.

Condition or Disease	Intervention/Treatment	Phase
Eosinophilic Esophagitis	Drug: Losartan Potassium	Phase 2

Detailed Description

The purpose of this research study is to test the safety and effects (good and bad) of Losartan potassium on participants with eosinophilic esophagitis (EoE). If a participant has a connective tissue disorder (CTD) the researchers want to see what effects (good or bad) Losartan has on EoE.

EoE is an inflammatory disease of the esophagus that is typically triggered by exposure to food. Connective tissue disorders (CTDs) are disorders that affect the connective tissues in the body such as tendons and ligaments.

A protein called transforming growth factor (TGF)-beta is associated with both EoE and CTD. Losartan may decrease the amount of TGF-beta and therefore help EoE and CTD.

Losartan is a drug that is approved by the United States Food and Drug Administration (FDA) for use in adults and children over 6 years of age who have high blood pressure. This medication has not been studied in people with EoE.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This study is an open-label study which means that all participants receive the study medicine.This study is an open-label study which means that all participants receive the study medicine.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Preliminary Open-Label Trial of Losartan Potassium in Participants With Eosinophilic Esophagitis (EoE) With or Without a Connective Tissue Disorder
• Actual Study Start Date: May 23, 2017
• Actual Primary Completion Date: Jul 22, 2019
• Actual Study Completion Date: Aug 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EoE +/- CTD Participants with EoE with and without CTD receive Losartan Potassium, 0.7 - 0.9 mg/kg (titration)/1.0 - 1.4 mg/kg (maintenance) daily for 16 weeks	Drug: Losartan Potassium; Losartan potassium; Other Names: Losartan
Experimental: EoE + CTD Participants with EoE with CTD receive Losartan Potassium, 0.7 - 0.9 mg/kg (titration)/1.0 - 1.4 mg/kg (maintenance) daily for 16 weeks	Drug: Losartan Potassium; Losartan potassium; Other Names: Losartan
Experimental: EoE - CTD Participants with EoE without CTD receive Losartan Potassium, 0.7 - 0.9 mg/kg (titration)/1.0 - 1.4 mg/kg (maintenance) daily for 16 weeks	Drug: Losartan Potassium; Losartan potassium; Other Names: Losartan

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Peak Eosinophil Count [Baseline, 16 weeks]

   Peak esophageal eosinophil counts were obtained at baseline and 16 weeks. Change in peak eosinophil count is defined as peak count at 16 weeks minus peak count at baseline. A reduction (negative change) in peak count indicates improvement. Peak count is defined as the highest count between the distal and proximal esophageal eosinophil counts.

2. Number of Serious and Grade 3 or Higher Adverse Events [20 weeks after the start of treatment (16 weeks treatment and 4 weeks follow-up)]

   The occurrence of serious adverse events and Grade 3 and higher adverse events from Week 0 to Week 20

Secondary Outcome Measures

1. Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks [16 weeks]

   Percent of participants in complete and partial histologic remission. Complete remission is defined as esophageal peak eosinophil count ≤ 1 eosinophils per high powered field (eos/hpf). Partial remission is defined as esophageal peak eosinophil count of 2 - 14 eos/hpf.

2. Change From Baseline in Total Histology Scoring System [Baseline, 16 weeks]

   The histology scoring system (HSS) measures the severity (grade) and extent (stage) of eight histologic abnormalities in the esophagus including eosinophilic inflammation, eosinophilic abscess, eosinophilic surface layering, surface epithelial alteration, dilated intercellular spaces, basal zone hyperplasia, dyskeratotic epithelial cells, and lamina propria fibrosis. Total score is the sum of grade and stage scores from the esophageal biopsy (distal, mid, or proximal) with the highest score (worst abnormalities) divided by the maximum possible score for the biopsy. Total scores range from 0 - 2 with higher scores indicating worse abnormalities. Histology scores were obtained at baseline and 16 weeks. Change in total histology scoring system (HSS) is defined as total HSS score at 16 weeks minus total HSS score at baseline. A reduction (negative change) in score indicates improvement.

3. Change From Baseline in Total Endoscopic Reference Score [Baseline, 16 weeks]

   The endoscopic reference score (EREFS) utilizes standardized criteria for the presence and degree of 5 major endoscopic features (edema, fixed rings, exudates, furrows, strictures). Total score is the sum of the five feature scores from the distal and proximal esophagus. Total scores range from 0 - 18 with higher scores indicating worse features. Endoscopic features were assessed at baseline and 16 weeks. Change in total endoscopic reference score is defined as total score at 16 weeks minus total score at baseline. A reduction (negative change) in score indicates improvement.

4. Change From Baseline in PEESS V2.0 [Baseline,16 weeks]

   The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) V2.0 questionnaire captures EoE-specific symptoms (dysphagia, gastroesophageal reflux, nausea/vomiting, and pain) as reported by their parents (for children 2-18 years of age). The range for PEESS v2.0 scores is 0 to 100, with a higher score being indicative of more frequent and/or severe symptoms. Scores were obtained at baseline and 16 weeks. Change in score is defined as total score at 16 weeks minus total score at baseline as completed by parent proxy.

5. Change From Baseline in PedsQL EoE [Baseline, 16 weeks]

   The Pediatric Eosinophilic Esophagitis Quality of Life Inventory (PedsQL EoE) measures symptoms and problems related to treatment, worry, communication, food/eating, and feelings. The range for PedsQL 3.0 EoE scores is 0 to 100, with a higher score indicating better quality of life. Scores were obtained at baseline and 16 weeks. Change in score is defined as the PedsQL EoE total score at 16 weeks minus total score at baseline as reported by parent proxy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent/assent

• Confirmed, active EoE (at Screening or within 12 weeks prior to enrollment)

• Does or does not have diagnosis of a connective tissue disorder (CTD)

• Has been on a high dose of proton pump inhibitor (PPI) for at least 8 weeks prior to a diagnostic endoscopy of EoE without histologic resolution (i.e., ≥ 15 eosinophils/HPF).

• Maintain the same diet, swallowed steroid and PPI therapies throughout the duration of the study

• Female participants must be either:

1. Of non-childbearing potential (pre-menarchal or surgically sterile with documentation). OR

2. Have a negative urine pregnancy test at screening and at each monthly study visit.

Exclusion Criteria:

• Any past or planned cardiac surgery.

• An aortic root Z-score ≥ 3.0 on a previous echocardiogram.

• Intolerance to Losartan

• A mean blood pressure measurement (both systolic and diastolic) at screening that is below the 2nd percentile for his/her age

• Renal dysfunction

• Another disorder that causes esophageal eosinophilia (e.g., hypereosinophilic syndrome, Churg Strauss vasculitis, eosinophilic granuloma, or a parasitic infection).

• A diagnosis of hepatic insufficiency (e.g., liver failure, history of liver transplantation or persistent liver transaminase elevation).

• A history of abnormal gastric or duodenal biopsy or documented gastrointestinal disorders (e.g., Celiac Disease, Crohn's disease or Helicobacter pylori infection), not including chronic gastritis, chronic duodenitis, mucosal eosinophilia or other eosinophilic gastrointestinal disorders (EGIDs).

• Use of anti-immunoglobulin (Ig)E monoclonal antibody (mAb), anti-tumor necrosis factor (TNF) mAb, anti-IL-5 agents, or anti-IL-13 within 6 months prior to study entry

• Use of methotrexate, cyclosporine, interferon α, or other systemic immunosuppressive or immunomodulating agents within 3 months prior to the screening visit.

• A stricture during endoscopy procedure that prevents passage of the endoscope

• Taking or is planning to take an angiotensin receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), beta blocker (BB), or calcium-channel blocker therapy at the screening visit or at any time during the study or has been taking any of these medications for 3 months prior to the screening visit.

• Taking or planning to take hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, rifampin, or fluconazole.

• Taking or planning to take potassium supplements or salt substitutes containing potassium.

• A female participant who is pregnant or nursing or, if of childbearing potential, is not using a medically accepted, effective method of birth control (e.g., condom, oral/injectable/subcutaneous contraceptive, intrauterine device, or sexual abstinence).

• Participated/participating in any investigative drug or device study within 30 days prior to study entry.

• Participated/participating in any investigative biologics study within 3 months prior to study entry.

• Unable to be confirmed, active EoE (at Screening or within 12 weeks prior to enrollment)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	La Jolla	California	United States	92093
2	Northwestern University	Chicago	Illinois	United States	60208
3	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Institute of Allergy and Infectious Diseases (NIAID)
• Office of Rare Diseases (ORD)
• National Center for Advancing Translational Science (NCATS)

Investigators

• Principal Investigator: Marc E Rothenberg, MD, PhD, Children's Hospital Medical Center, Cincinnati

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 11, 2019
• Study Protocol - Jun 25, 2018

More Information

Additional Information:

• Study information on the Consortium for Eosinophilic Gastrointestinal Disorders (CEGIR) website

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT03029091
• Other Study ID Numbers: 2015-9021; U54AI117804
• First Posted: Jan 24, 2017
• Last Update Posted: Sep 9, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Esophagitis; Eosinophilic Esophagitis; Losartan

Study Results

Participant Flow

Recruitment Details	Participants were recruited from eosinophilic esophagitis specialty clinics (3 sites) in the USA between May 2017 and April 2019.
Pre-assignment Detail	17 participants screened, 2 excluded (2 met exclusion criteria), and 15 initiated the intervention

Arm/Group Title	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Period Title: Overall Study
STARTED	8	7
COMPLETED	8	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	EoE + CTD	EoE - CTD	Total
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan	Total of all reporting groups
Overall Participants	8	7	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.4 (3.7)	13.8 (5.0)	12.0 (4.5)
Sex: Female, Male (Count of Participants)
Female	4 50%	1 14.3%	5 33.3%
Male	4 50%	6 85.7%	10 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	8 100%	7 100%	15 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 14.3%	1 6.7%
White	7 87.5%	6 85.7%	13 86.7%
More than one race	1 12.5%	0 0%	1 6.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	8 100%	7 100%	15 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Peak Eosinophil Count
Description	Peak esophageal eosinophil counts were obtained at baseline and 16 weeks. Change in peak eosinophil count is defined as peak count at 16 weeks minus peak count at baseline. A reduction (negative change) in peak count indicates improvement. Peak count is defined as the highest count between the distal and proximal esophageal eosinophil counts.
Time Frame	Baseline, 16 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population (protocol violation excluded from data analysis)

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	14	7	7
Baseline	63.3	67.7	58.9
Change	-11.2	-1.9	-20.6

2. Primary Outcome

Title	Number of Serious and Grade 3 or Higher Adverse Events
Description	The occurrence of serious adverse events and Grade 3 and higher adverse events from Week 0 to Week 20
Time Frame	20 weeks after the start of treatment (16 weeks treatment and 4 weeks follow-up)

Outcome Measure Data

Analysis Population Description

Intent to treat analysis including participants enrolled in the study

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	15	8	7
Serious Adverse Events	0	0	0
Grade 3 or higher adverse events	1	0	1

3. Secondary Outcome

Title	Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks
Description	Percent of participants in complete and partial histologic remission. Complete remission is defined as esophageal peak eosinophil count ≤ 1 eosinophils per high powered field (eos/hpf). Partial remission is defined as esophageal peak eosinophil count of 2 - 14 eos/hpf.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population (protocol violation excluded from data analysis)

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	14	7	7
Complete remission (≤ 1 eos/hpf)	7	14	0
Partial remission (2 - 14 eos/hpf)	21	14	29

4. Secondary Outcome

Title	Change From Baseline in Total Histology Scoring System
Description	The histology scoring system (HSS) measures the severity (grade) and extent (stage) of eight histologic abnormalities in the esophagus including eosinophilic inflammation, eosinophilic abscess, eosinophilic surface layering, surface epithelial alteration, dilated intercellular spaces, basal zone hyperplasia, dyskeratotic epithelial cells, and lamina propria fibrosis. Total score is the sum of grade and stage scores from the esophageal biopsy (distal, mid, or proximal) with the highest score (worst abnormalities) divided by the maximum possible score for the biopsy. Total scores range from 0 - 2 with higher scores indicating worse abnormalities. Histology scores were obtained at baseline and 16 weeks. Change in total histology scoring system (HSS) is defined as total HSS score at 16 weeks minus total HSS score at baseline. A reduction (negative change) in score indicates improvement.
Time Frame	Baseline, 16 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population (protocol violation excluded from data analysis).

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	14	7	7
Baseline - Total HSS	0.79	0.89	0.70
Change - Total HSS	-0.09	-0.15	-0.03

5. Secondary Outcome

Title	Change From Baseline in Total Endoscopic Reference Score
Description	The endoscopic reference score (EREFS) utilizes standardized criteria for the presence and degree of 5 major endoscopic features (edema, fixed rings, exudates, furrows, strictures). Total score is the sum of the five feature scores from the distal and proximal esophagus. Total scores range from 0 - 18 with higher scores indicating worse features. Endoscopic features were assessed at baseline and 16 weeks. Change in total endoscopic reference score is defined as total score at 16 weeks minus total score at baseline. A reduction (negative change) in score indicates improvement.
Time Frame	Baseline, 16 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population (protocol violation excluded from data analysis).

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	14	7	7
Baseline - EREFS Total Score	5.1	5.4	4.9
Change - EREFS Total Score	-1.3	-1.7	-0.9

6. Secondary Outcome

Title	Change From Baseline in PEESS V2.0
Description	The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) V2.0 questionnaire captures EoE-specific symptoms (dysphagia, gastroesophageal reflux, nausea/vomiting, and pain) as reported by their parents (for children 2-18 years of age). The range for PEESS v2.0 scores is 0 to 100, with a higher score being indicative of more frequent and/or severe symptoms. Scores were obtained at baseline and 16 weeks. Change in score is defined as total score at 16 weeks minus total score at baseline as completed by parent proxy.
Time Frame	Baseline,16 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population (protocol violation excluded from data analysis)

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	13	7	6
Baseline - PEESS Total Score	29.9	32.7	26.7
Change - PEESS Total Score	-9.7	-12.5	-6.89

7. Secondary Outcome

Title	Change From Baseline in PedsQL EoE
Description	The Pediatric Eosinophilic Esophagitis Quality of Life Inventory (PedsQL EoE) measures symptoms and problems related to treatment, worry, communication, food/eating, and feelings. The range for PedsQL 3.0 EoE scores is 0 to 100, with a higher score indicating better quality of life. Scores were obtained at baseline and 16 weeks. Change in score is defined as the PedsQL EoE total score at 16 weeks minus total score at baseline as reported by parent proxy.
Time Frame	Baseline, 16 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population (protocol violation excluded from data analysis)

Arm/Group Title	EoE +/- CTD	EoE + CTD	EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan	Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
Measure Participants	13	7	6
Baseline - PedsQL Total Score	74.4	73.3	75.6
Change - PedsQL Total Score	6.7	4.8	9.0

Adverse Events

Time Frame	From informed consent to 30 days after the cessation of treatment, an average of about 24 weeks
Arm/Group Title	EoE +/- CTD		EoE + CTD		EoE - CTD
Arm/Group Description	Participants with eosinophilic esophagitis (EoE) with and without connective tissue disorder (CTD) receive Losartan		Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan		Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan
All Cause Mortality
	EoE +/- CTD		EoE + CTD		EoE - CTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/8 (0%)		0/7 (0%)
Serious Adverse Events
	EoE +/- CTD		EoE + CTD		EoE - CTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/8 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	EoE +/- CTD		EoE + CTD		EoE - CTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/15 (80%)		7/8 (87.5%)		5/7 (71.4%)
Blood and lymphatic system disorders
Neutropenia	1/15 (6.7%)		1/8 (12.5%)		0/7 (0%)
Eye disorders
Conjunctivitis	1/15 (6.7%)		1/8 (12.5%)		0/7 (0%)
Gastrointestinal disorders
Gastritis	1/15 (6.7%)		0/8 (0%)		1/7 (14.3%)
Nausea	1/15 (6.7%)		1/8 (12.5%)		0/7 (0%)
Vomiting	2/15 (13.3%)		2/8 (25%)		0/7 (0%)
General disorders
Common Cold	1/15 (6.7%)		0/8 (0%)		1/7 (14.3%)
Transient Dizziness	1/15 (6.7%)		1/8 (12.5%)		0/7 (0%)
Infections and infestations
Upper Respiratory Infection	2/15 (13.3%)		1/8 (12.5%)		1/7 (14.3%)
Fever	1/15 (6.7%)		0/8 (0%)		1/7 (14.3%)
Rhinitis Infective	1/15 (6.7%)		1/8 (12.5%)		0/7 (0%)
Investigations
Creatinine increased	2/15 (13.3%)		1/8 (12.5%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb	1/15 (6.7%)		1/8 (12.5%)		0/7 (0%)
Nervous system disorders
Vasovagal reaction	1/15 (6.7%)		0/8 (0%)		1/7 (14.3%)
Reproductive system and breast disorders
Testicular pain	1/15 (6.7%)		0/8 (0%)		1/7 (14.3%)
Social circumstances
Lightheaded	1/15 (6.7%)		0/8 (0%)		1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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