Acetylsalicylic Acid Compared to Placebo in Treating High-Risk Patients With Subsolid Lung Nodules

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02169271
• Collaborator: (none)
• Enrollment: 109
• Locations: 2
• Arms: 2
• Actual Duration (Months): 62.8
• Patients Per Site: 54.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This randomized phase II trial studies acetylsalicylic acid compared to placebo in treating high-risk patients with subsolid lung nodules. A nodule is a growth or lump that may be malignant (cancer) or benign (not cancer). Chemoprevention is the use of drugs to keep cancer from forming or coming back. The use of acetylsalicylic acid may keep cancer from forming in patients with subsolid lung nodules.

Condition or Disease	Intervention/Treatment	Phase
Current Smoker; Former Smoker; Multiple Pulmonary Nodules; Tobacco Use Disorder	Drug: Aspirin; Other: Laboratory Biomarker Analysis; Other: Placebo	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. The evaluation of the effect of aspirin (acetylsalicylic acid) as a chemopreventive agent for lung cancer.

SECONDARY OBJECTIVES:

1. The modulation of biological markers after treatment and the correlation of these findings with modification of lung nodules diameters.

2. The per-lesion analysis including the evaluation of lung nodule density before and after treatment, the number and size of non target lesions including solid nodules and evaluation of response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive acetylsalicylic acid orally (PO) once daily (QD) for 12 months.

ARM II: Patients receive placebo PO QD for 12 months.

After completion of study treatment, patients are followed up for 1 month.

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized Phase II Trial of Low Dose Aspirin Versus Placebo in High-Risk Individuals With CT-Detected Subsolid Lung Nodules
• Actual Study Start Date: Nov 21, 2014
• Actual Primary Completion Date: Jul 13, 2018
• Actual Study Completion Date: Feb 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (acetylsalicylic acid) Patients receive acetylsalicylic acid PO QD for 12 months.	Drug: Aspirin; Given PO; Other Names: Acetylsalicylic Acid ASA Aspergum Ecotrin Empirin Entericin Extren Measurin ; Other: Laboratory Biomarker Analysis; Correlative studies
Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD for 12 months.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Placebo; Given PO; Other Names: placebo therapy PLCB sham therapy

Outcome Measures

Primary Outcome Measures

1. Change in the Sum of Longest Diameters of Baseline Target Nodules (Person-specific Analysis) [Twelve-month treatment]

   Difference (12 month-baseline) in the sum of longest diameters of baseline target nodules.

Secondary Outcome Measures

1. Change in the Sum of Baseline Target Nodules Diameters (Per Nodules Analysis) [Baseline up to 1 year]

   Difference (12 month-baseline) in the sum of baseline target nodules diameters

2. Change in Lesion Volume [Baseline to 1 year]

   Difference (12 month-baseline) in lesion volume

3. Change in Lesion Density [Baseline up to 1 year]

   Difference (12 month-baseline) in lesion density

4. Modulation of Thromboxane B2 [Baseline up to 1 year]

   Difference (12 month-baseline) in biomarker concentration

5. Modulation of Prostaglandin E Metabolites (Normalized to Urinary Creatinine Concentration) [Baseline up to 1 year]

   Difference (12 month-baseline) in biomarker concentration

6. Modulation of Leukotriene E4 (Normalized to Urinary Creatinine Concentration) [Baseline up to 1 year]

   Difference (12 month-baseline) in biomarker concentration

7. Modulation of High Sensitive CRP [Baseline up to 1 year]

   Difference (12 month-baseline) in biomarker concentration

8. Modulation of miRNA Prediction Risk Score [Baseline up to 1 year]

   Difference (12 month-baseline) of the score on a scale (scale from -20 to +30 which measure the risk of lung cancer. Higher values indicate higher risk. A value<0 is considered negative, a value ≥0 positive for lung cancer).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Asymptomatic current or former smokers (having stopped within the last 20 years)

• Smoking history >= 20 pack/years; subjects must be included in an ongoing annual screening with low dose CT scan or must have two consecutive CT outside the context of a screening program confirming subsolid nodules

• Subjects must have subsolid (non solid or partially solid) nodules with size between 4 and 10 mm with any volume doubling time (VDT) not candidate to surgical excision and/or subsolid (non solid or partially solid) nodule larger than 10 mm with VDT higher than 400 days and not candidate to surgical excision

• All nodules should be persistent at least after three months follow up with 1 dimension (1d)-CT; a reduction up to 15% of the diameter of the largest target nodule from the previous CT scan is allowed

• All current smokers should accept to receive support for smoking cessation

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/microliter

• Absolute neutrophil count >= 1,500/microliter

• Platelets >= 100,000/microliter

• Total bilirubin =< 2 x institutional upper limit of normal (ULN) and/or history of Gilbert's syndrome

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional ULN

• Serum creatinine =< institutional ULN

• Women of child-bearing potential (from first menstruation to 1 year after last menstruation) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately

• Ability to understand and the willingness to sign a written informed consent document

• Signed informed consent

Exclusion Criteria:

• Subjects with chronic treatment (at least twice/week for more than 3 months) with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs)

• History of allergic reactions attributed to compounds of similar chemical or biological composition to aspirin, NSAIDs, cyclooxygenase-2 (COX2) inhibitors

• Invasive malignancy (with the exclusion of basal cell carcinoma or skin squamous cell carcinoma) diagnosed during the last 2 years before randomization; stage I-II invasive malignancies that were diagnosed more than 2 years prior to randomization and have been treated curatively are allowed as long as all treatment is finished at least 18 months prior to randomization

• History of therapeutic doses of anticoagulants including warfarin and low molecular weight heparin (e.g. for prior deep venous thrombosis and pulmonary embolisms) in the preceding year

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with aspirin

• Individual may not be receiving any other investigational agents, antiplatelet agents (e.g. aspirin, clopidogrel [Plavix or others]), anticoagulants (e.g. heparin or heparinoids, Coumadin, or others), methotrexate, lithium

• Participants with bleeding diathesis, history of gastric/duodenal ulcers in the last 5 years, NSAID-precipitated bronchospasm, patients unwilling or unable to limit alcohol consumption to i.e. =< 3 alcohol drinks a day

• Participants who in the opinion of the principal investigator (PI) will be at higher risk of acetylsalicylic acid (ASA)-related complications

• Participants with known inability to adequately absorb oral medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030
2	European Institute of Oncology	Milano		Italy	20141

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Bernardo Bonanni, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Mar 13, 2017

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02169271
• Other Study ID Numbers: NCI-2014-01311; NCI-2014-01311; IEO-833/13F; HHSN261201200034I; EIO 833/13F; 2013-004862-32; TO-RFP A; N01-CN-2012-00034; IEO 833/13F (IEO37); MDACC: 2013-0732; IEO 37; 2013-0732; MDA2013-01-01; N01CN00034; P30CA016672; NCT02135497
• First Posted: Jun 23, 2014
• Last Update Posted: May 21, 2020
• Last Verified: May 1, 2020

• Additional relevant MeSH terms: Multiple Pulmonary Nodules; Tobacco Use Disorder; Aspirin

Study Results

Participant Flow

Recruitment Details	A total of 619 ld-CT scans, belonging to the lung screening programs, showed potentially eligible nodules. A total of 109 subjects signed a written informed consent and underwent baseline visit while 98 have been randomized.
Pre-assignment Detail	After enrollment, 11 participants were not randomized (baseline screening failures)

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Period Title: Overall Study
STARTED	49	49
COMPLETED	48	47
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Aspirin	Placebo	Total
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year	Total of all reporting groups
Overall Participants	49	49	98
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 51%	24 49%	49 50%
>=65 years	24 49%	25 51%	49 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.6 (4.1)	64.6 (4.7)	64.6 (4.4)
Sex: Female, Male (Count of Participants)
Female	28 57.1%	27 55.1%	55 56.1%
Male	21 42.9%	22 44.9%	43 43.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	49 100%	49 100%	98 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	1 2%	0 0%	1 1%
Italy	48 98%	49 100%	97 99%
Sum of longest diameters of baseline target nodules (millimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeters]	8.5 (4.3)	11 (11.3)	9.8 (8.6)
Sum of diameters of baseline target nodules (millimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeters]	6.8 (2.8)	7.2 (2.7)	7.0 (2.8)
Baseline lesion volume (Millimeter^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Millimeter^3]	138 (139)	151 (151)	145 (145)
Baseline lesion density (Hounsfield Unit) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Hounsfield Unit]	-628 (76)	-663 (98)	-647 (90)
Circulating biomarkers and miRNA risk score (Score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a scale]	10.4 (9.5)	10 (10.6)	10.2 (10)
Circulating Thromboxane (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	60.4 (32.6)	61.1 (37.3)	60.8 (34.8)
Circulating Prostaglandin E metabolite (PGEM) normalized to uCr concentration (pg/mg creatinine) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mg creatinine]	385 (218)	334 (213)	359 (216)
Circulating Leukotriene E4 normalized to uCr concentration (pg/mg creatinine) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mg creatinine]	1701 (1670)	1226 (909)	1463 (1359)
Circulating High sensitive CRP (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	0.47 (1.01)	0.29 (0.52)	0.38 (0.8)

Outcome Measures

1. Primary Outcome

Title	Change in the Sum of Longest Diameters of Baseline Target Nodules (Person-specific Analysis)
Description	Difference (12 month-baseline) in the sum of longest diameters of baseline target nodules.
Time Frame	Twelve-month treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [millimeter (mm)]	0.3 (2.54)	-0.12 (1.55)

2. Secondary Outcome

Title	Change in the Sum of Baseline Target Nodules Diameters (Per Nodules Analysis)
Description	Difference (12 month-baseline) in the sum of baseline target nodules diameters
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [millimeter (mm)]	0.1 (2.4)	-0.1 (1.1)

3. Secondary Outcome

Title	Change in Lesion Volume
Description	Difference (12 month-baseline) in lesion volume
Time Frame	Baseline to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [millimiter^3 (mm3)]	-4.5 (78)	-4.8 (134)

4. Secondary Outcome

Title	Change in Lesion Density
Description	Difference (12 month-baseline) in lesion density
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [Hounsfield unit (HU)]	24 (65)	28 (78)

5. Secondary Outcome

Title	Modulation of Thromboxane B2
Description	Difference (12 month-baseline) in biomarker concentration
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [ng/mL]	-35.8 (53.4)	20.5 (50.7)

6. Secondary Outcome

Title	Modulation of Prostaglandin E Metabolites (Normalized to Urinary Creatinine Concentration)
Description	Difference (12 month-baseline) in biomarker concentration
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [pg/mg creatinine]	-60.7 (210)	29.8 (215)

7. Secondary Outcome

Title	Modulation of Leukotriene E4 (Normalized to Urinary Creatinine Concentration)
Description	Difference (12 month-baseline) in biomarker concentration
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [pg/mg creatinine]	-235 (1240)	-9 (592)

8. Secondary Outcome

Title	Modulation of High Sensitive CRP
Description	Difference (12 month-baseline) in biomarker concentration
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [mg/dL]	-0.12 (0.88)	-0.08 (0.5)

9. Secondary Outcome

Title	Modulation of miRNA Prediction Risk Score
Description	Difference (12 month-baseline) of the score on a scale (scale from -20 to +30 which measure the risk of lung cancer. Higher values indicate higher risk. A value<0 is considered negative, a value ≥0 positive for lung cancer).
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year	1 tablet of placebo a day for one year
Measure Participants	49	49
Mean (Standard Deviation) [Score on a scale]	0.14 (8.94)	0.36 (7.36)

Adverse Events

Time Frame	Baseline up to 13 months
Arm/Group Title	Aspirin		Placebo
Arm/Group Description	1 tablet of aspirin 100 mg a day for one year		1 tablet of placebo a day for one year
All Cause Mortality
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/49 (0%)
Serious Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/49 (16.3%)		4/49 (8.2%)
Gastrointestinal disorders
Hemorrhoids	1/49 (2%)	1	0/49 (0%)	0
Infections and infestations
Balanitis	1/49 (2%)	1	0/49 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer	2/49 (4.1%)	2	2/49 (4.1%)	2
Increased volume of target lesion	0/49 (0%)	0	1/49 (2%)	1
Bladder cancer	2/49 (4.1%)	3	0/49 (0%)	0
Liposarcoma	1/49 (2%)	1	0/49 (0%)	0
Surgical and medical procedures
Anal fissures	1/49 (2%)	1	0/49 (0%)	0
Penile implant	0/49 (0%)	0	1/49 (2%)	1
Other (Not Including Serious) Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/49 (87.8%)		41/49 (83.7%)
Blood and lymphatic system disorders
Leukocytosis	1/49 (2%)	1	0/49 (0%)	0
Cardiac disorders
Sinus tachycardia	0/49 (0%)	0	2/49 (4.1%)	2
Ear and labyrinth disorders
Ear pain	1/49 (2%)	1	0/49 (0%)	0
Vertigo	2/49 (4.1%)	2	0/49 (0%)	0
Other	1/49 (2%)	1	0/49 (0%)	0
Eye disorders
Blurred vision	0/49 (0%)	0	1/49 (2%)	1
Conjunctivitis	1/49 (2%)	1	1/49 (2%)	1
Vitreous hemorrage	0/49 (0%)	0	1/49 (2%)	1
Other	2/49 (4.1%)	4	1/49 (2%)	1
Gastrointestinal disorders
Dyspepsia	4/49 (8.2%)	5	1/49 (2%)	1
Gastroesophageal reflux disease	1/49 (2%)	1	2/49 (4.1%)	2
Abdominal pain	1/49 (2%)	1	0/49 (0%)	0
Oral hemorrage	1/49 (2%)	1	0/49 (0%)	0
Periodontal disease	2/49 (4.1%)	2	0/49 (0%)	0
Diarrhea	7/49 (14.3%)	7	2/49 (4.1%)	2
Lower gastrointestinal hemorrage	1/49 (2%)	1	0/49 (0%)	0
Stomach pain	4/49 (8.2%)	5	3/49 (6.1%)	6
Hemorroidal hemorrage	2/49 (4.1%)	2	2/49 (4.1%)	6
Colitis	1/49 (2%)	1	0/49 (0%)	0
Gastrointestinal pain	1/49 (2%)	2	2/49 (4.1%)	3
Toothache	0/49 (0%)	0	5/49 (10.2%)	5
Gastritis	0/49 (0%)	0	1/49 (2%)	1
Vomiting	0/49 (0%)	0	1/49 (2%)	1
Hemorroids	0/49 (0%)	0	1/49 (2%)	1
Gastrointestinal disorder, other	1/49 (2%)	1	2/49 (4.1%)	2
General disorders
Flu-like symptoms	5/49 (10.2%)	5	7/49 (14.3%)	8
Localized edema	1/49 (2%)	1	0/49 (0%)	0
Non-cardia chest pain	0/49 (0%)	0	1/49 (2%)	1
Fever	0/49 (0%)	0	1/49 (2%)	1
Malaise	0/49 (0%)	0	1/49 (2%)	2
Infections and infestations
Upper respiratory infection	3/49 (6.1%)	6	4/49 (8.2%)	4
Otitis externa	1/49 (2%)	1	0/49 (0%)	0
Bronchial infection	10/49 (20.4%)	18	5/49 (10.2%)	10
Urinary tract infection	4/49 (8.2%)	8	0/49 (0%)	0
Tooth infection	2/49 (4.1%)	2	2/49 (4.1%)	2
Penile Infection	1/49 (2%)	1	0/49 (0%)	0
Laryingitis	1/49 (2%)	1	0/49 (0%)	0
Nail infection	1/49 (2%)	1	0/49 (0%)	0
Otitis media	0/49 (0%)	0	2/49 (4.1%)	2
Conjunctivitis infective	0/49 (0%)	0	1/49 (2%)	1
Other	3/49 (6.1%)	3	2/49 (4.1%)	2
Injury, poisoning and procedural complications
Fall	1/49 (2%)	1	0/49 (0%)	0
Fracture	0/49 (0%)	0	1/49 (2%)	1
Other	1/49 (2%)	2	1/49 (2%)	1
Investigations
Cholesterol high	1/49 (2%)	1	0/49 (0%)	0
ALT increased	1/49 (2%)	1	0/49 (0%)	0
AST increased	1/49 (2%)	1	0/49 (0%)	0
Bilirubin increased	2/49 (4.1%)	2	2/49 (4.1%)	2
Other	1/49 (2%)	1	1/49 (2%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/49 (2%)	1	0/49 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	2/49 (4.1%)	2	1/49 (2%)	2
Arthralgia	3/49 (6.1%)	7	7/49 (14.3%)	13
Back pain	4/49 (8.2%)	4	6/49 (12.2%)	13
Neck pain	2/49 (4.1%)	3	1/49 (2%)	2
Myalgia	1/49 (2%)	2	1/49 (2%)	1
Other	0/49 (0%)	0	1/49 (2%)	1
Chest wall pain	0/49 (0%)	0	4/49 (8.2%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other	2/49 (4.1%)	2	2/49 (4.1%)	2
Nervous system disorders
Headache	7/49 (14.3%)	10	4/49 (8.2%)	12
Paresthesia	2/49 (4.1%)	5	1/49 (2%)	1
Dizziness	0/49 (0%)	0	1/49 (2%)	2
Other	0/49 (0%)	0	1/49 (2%)	1
Psychiatric disorders
Insomnia	0/49 (0%)	0	2/49 (4.1%)	2
Other	1/49 (2%)	2	0/49 (0%)	0
Renal and urinary disorders
Hematuria	2/49 (4.1%)	2	0/49 (0%)	0
Cystitis noninfective	1/49 (2%)	2	4/49 (8.2%)	6
Hemoglobinuria	1/49 (2%)	1	0/49 (0%)	0
Proteinuria	1/49 (2%)	1	0/49 (0%)	0
Renal colic	2/49 (4.1%)	3	0/49 (0%)	0
Urinary frequency	0/49 (0%)	0	1/49 (2%)	1
Reproductive system and breast disorders
Vaginal hemorrage	1/49 (2%)	1	0/49 (0%)	0
Prostatic pain	1/49 (2%)	1	0/49 (0%)	0
Vagynal dryness	0/49 (0%)	0	1/49 (2%)	2
Breast pain	0/49 (0%)	0	1/49 (2%)	1
Other	2/49 (4.1%)	2	2/49 (4.1%)	2
Respiratory, thoracic and mediastinal disorders
Nasal congestion	5/49 (10.2%)	7	6/49 (12.2%)	9
Epistaxix	2/49 (4.1%)	5	0/49 (0%)	0
Pharyngolaryngeal pain	1/49 (2%)	1	0/49 (0%)	0
Cough	6/49 (12.2%)	10	7/49 (14.3%)	8
Laryngeal inflammation	1/49 (2%)	1	0/49 (0%)	0
Bronchial obstruction	1/49 (2%)	1	0/49 (0%)	0
Dyspnea	1/49 (2%)	1	0/49 (0%)	0
Bronchospasm	0/49 (0%)	0	2/49 (4.1%)	2
Sore theroat	0/49 (0%)	0	1/49 (2%)	1
Hoarseness	0/49 (0%)	0	1/49 (2%)	1
Skin and subcutaneous tissue disorders
Erythroderma	1/49 (2%)	1	0/49 (0%)	0
Pruritus	0/49 (0%)	0	1/49 (2%)	1
Other	2/49 (4.1%)	2	2/49 (4.1%)	3
Surgical and medical procedures
Other	4/49 (8.2%)	5	4/49 (8.2%)	4
Vascular disorders
Hematoma	2/49 (4.1%)	3	0/49 (0%)	0
Phlebitis	1/49 (2%)	1	0/49 (0%)	0
Hypertension	4/49 (8.2%)	4	3/49 (6.1%)	18
Other	0/49 (0%)	0	1/49 (2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.