Pioglitazone for Oral Premalignant Lesions

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00951379
• Collaborator: (none)
• Enrollment: 52
• Locations: 13
• Arms: 2
• Duration (Months): 48.9
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn how Actos (pioglitazone) may affect oral premalignant lesions (OPLs) and/or the risk of mouth cancer. The safety of this drug will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Oral Leukoplakia	Drug: Pioglitazone hydrochloride; Other: placebo; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the clinical and histologic response of oral premalignant lesions to 24 weeks of therapy with pioglitazone, 45 mg once daily (qd), defined as 50% or greater reduction in the sum of all measured products of perpendicular dimensions of target lesions, or improvement in the degree of dysplasia or hyperplasia.

SECONDARY OBJECTIVES:

1. To determine the degree of change of putative biomarkers of pioglitazone efficacy including (but not restricted to) and in order of priority, tissue levels of:

• PPAR gamma,

• cyclin D1 and p21 as indirect measures of pharmacological effect

• TUNEL for apoptosis and Ki-67 for proliferation

• transglutaminase and involucrin as markers of squamous differentiation

• 15-PGDH, loss of heterozygosity (LOH). II. To determine the degree of change of C-reactive protein (CRP) in plasma. III. To assess tobacco and alcohol use among trial participants and to examine the relationship of tobacco and alcohol use to treatment response.

1. To assess the safety of this agent in this population.

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

ARM I: Patients receive pioglitazone hydrochloride orally (PO) once daily (QD) for 24 weeks.

ARM II: Patients receive placebo PO QD for 24 weeks.

After completion of study treatment, patients are followed up for 2 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase IIB Randomized, Placebo Controlled Trial of Pioglitazone for Oral Premalignant Lesions an Inter-consortium Collaborative Study
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (Pioglitazone Hydrochloride) Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Drug: Pioglitazone hydrochloride; Three (3) pioglitazone 15 mg capsules by mouth once daily for 24 weeks (+/- 1 week); Other Names: Actos pioglitazone ; Other: laboratory biomarker analysis; Correlative studies
Placebo Comparator: Arm II (Placebo) Three (3) placebo capsules by mouth once daily for 24 weeks	Other: placebo; Three (3) pioglitazone placebo capsules by mouth once daily for 24 weeks (+/- 1 week); Other Names: PLCB ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Overall Response <Clinical and Histologic Response Defined as 50% or Greater Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia> [Response assessed at Week 24 ±1 Week]

   Overall Dichotomized Clinical and Histologic Response defined as 50% or greater reduction in sum of the measured products of perpendicular dimensions of the target lesion(s) or improvement in the degree of dysplasia or hyperplasia where complete (CR) or partial response (PR) in either clinical or histologic outcome assessed according to criteria given recorded as Response or No Response and analyzed as a dichotomous variable. Clinical Response = CR: Disappearance all evidence target & non-target lesions; PR: >/=50% reduction in sum products of diameters all target lesion(s). Non-target lesions may not increase >/=25% in size & no new lesion. Histologic Response = CR: Complete reversal of dysplasia or hyperplasia to normal epithelium in all biopsied lesions. PR: Improvement of degree of dysplasia or hyperplasia in all biopsied lesion(s) from advanced to early, or from early to normal epithelium in some lesions while other biopsied lesions remain stable.

2. Dichotomized Histologic Response (HR): Participant Complete or Partial Response Defined as =/>50% Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia [Response assessed at Week 24 ±1 Week]

   HR according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. CR: Complete reversal dysplasia/hyperplasia to normal epithelium in all biopsied lesions. PR: Improvement of degree dysplasia/hyperplasia in all biopsied lesion from advanced to early, or from early to normal epithelium in some lesions while other biopsied lesions remain stable. No Change (NC): No change in degree dysplasia/hyperplasia in all biopsied lesions, anything not CR, PR or PD. Progressive Disease (PD): Any increase in severity histology grade any biopsied lesion. Early premalignant lesion: lesion defined high risk, indicated by presence of one: hyperplasia at high-risk sites (dorsal, lateral or ventral tongue, or floor of mouth) ONLY, or mild dysplasia. Advanced premalignant lesion: lesion with presence of one: moderate dysplasia or severe dysplasia (excluding CIS), erythroplakia with hyperplasia or of any severity of dysplasia.

3. Dichotomized Clinical Response: Participant Complete or Partial Response Defined as =/>50% Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia [Response assessed at Week 24 ±1 Week]

   Clinical Response assessed according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. Complete Response (CR): Disappearance of all evidence of target AND non-target lesions. Partial Response (PR): greater than or equal to 50% reduction in the sum of the products of diameters of all target lesion(s). Non-target lesions may not increase greater than or equal 25% in size and no new lesion may appear. No Change (NC): No change in the size of the lesion(s) and no new lesions appearing, i.e. anything that is not CR, PR or PD. Progressive Disease (PD): Any increase greater than or equal to 25% in the product of the diameters of any measurable lesions or in the estimated size of non-measurable lesions or the appearance of an unequivocal new lesion.

Secondary Outcome Measures

1. Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma [Baseline to end of study, 24 weeks]

   Degree of change of C-reactive protein (CRP) in plasma serum via blood tests. The longitudinal regression models for analysis of the change in CRP in plasma used, with suitable transformation if necessary to satisfy the model assumptions, with treatment, stage and biomarker value at screening visit as covariates.

2. Number of Participants With Level of C-reactive Protein in Plasma Decrease From >5.0 mg/L to <= 5.0 mg/L From Baseline to End of Study [Baseline to end of study, 24 weeks]

   The longitudinal regression models for analysis of the change in CRP in plasma will be used, with suitable transformation if necessary to satisfy the model assumptions, with treatment, stage and biomarker value at screening visit as covariates.

3. Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use [Up to 26 weeks]

   Tobacco use summarized by treatment stratified by stage and by group. In addition, the effects of tobacco and alcohol use on the primary endpoint of clinical response assessed.

4. Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use [Up to 26 weeks]

   Alcohol use will be summarized by treatment stratified by stage and by group. In addition, the effects of tobacco and alcohol use on the primary endpoint of clinical and pathological response assessed using statistical regression models in an exploratory fashion. Heavy drinkers are participants who drank every day; Light drinkers are participants who drank on some days; Non-drinkers are former drinkers or those who never drank alcohol.

5. Number of Participants Affected by Adverse Events Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4.0) [Up to 26 weeks]

   All adverse events (including serious) and clinical laboratory toxicity summarized affected organ system. Reporting based on the NCI CTCAE v4.0 by treatment, details included in later Adverse Event Module of results.

6. Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 [Baseline to end of study, 24 weeks]

   Tissue levels of Cyclin D1 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.

7. Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 [Baseline to end of study, 24 weeks]

   Tissue levels of Ki-67 for proliferation assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.

8. Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 [Baseline to end of study, 24 weeks]

   Tissue levels of p21 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.

9. Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) [Baseline to end of study, 24 weeks]

   Tissue levels of Bcl2 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported a percentage of cells staining positive, according to nuclear or cytoplasmic compartments.

10. Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm [Baseline to end of study, 24 weeks]

    Tissue levels of Peroxisome proliferator-activated receptor gamma (PPARG) Nucleus and PPARG Cytoplasm as indirect measures of pharmacological effect, PPAR gamma assessed by immunohistochemistry. Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• STAGE I:

• Males or females with a suspected or histologically confirmed oral premalignant lesion(s) (up to three target lesions may be followed for the purpose of the study) that has a length (longest diameter) of 8 mm or greater and width (diameter perpendicular to greatest length) of 3 mm or greater in size

• If a participant has had a biopsy of the target oral premalignant lesions (OPL) lesion(s) within 6 weeks prior to the screening visit and archival tissue is available and the participant agrees to have archival tissue used for histologic confirmation and biomarker analysis, then NO additional biopsies (of the OPL) need to be performed at the screening visit; the pre-screening biopsy must undergo centralized pathology review before the second stage of registration can be performed; if archival tissue is not available, a waiting period of 6 weeks from the time of the last biopsy must be observed before re-biopsy for study purposes

• If a participant has not had a biopsy of the suspected OPL at the time of the screening visit, then a biopsy of the lesion must be performed during the screening visit; the screening biopsy must undergo centralized pathology review before the second stage of registration can be performed

• The participant's life expectancy is > 6 months

• The participant has discontinued any other oral cancer chemopreventive therapy at least 12 weeks prior to the baseline visit and all toxicities have been fully resolved; daily aspirin is permitted

• The participant is willing and able to fully participate for the duration of the study

• Women must not be pregnant or lactating; women of child-bearing potential (women are considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile) must have used adequate contraception (abstinence; barrier methods such as IUD, diaphragm with spermicidal gel, condom, or others; and hormonal methods such as birth control pills or others) since her last menses prior to study entry; women of child-bearing potential and men must agree to use adequate contraception 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

• STAGE II:

• The participant has one or more target lesions histologically confirmed by a biopsy obtained no more than 9 weeks prior to randomization, that is either:

• An EARLY premalignant lesion defined to be at high risk:

• Mild dysplasia of any site

• Hyperplastic leukoplakia of a high-risk site

• Dorsal, lateral or ventral tongue

• Floor of mouth

• An ADVANCED premalignant lesion defined as the presence of at least one of the following:

• Moderate dysplasia

• Severe dysplasia (excluding carcinoma in situ)

• Erythroplakia (due to the high risk for progression associated with erythroplakia, erythroplakia of any histology will be defined as an ADVANCED oral premalignant lesion)

• Hemoglobin levels equal to or above the lower limit of normal

• White blood cells >= 3,000/uL

• Platelets >= 125,000/uL

• Total bilirubin =< 1.5 * upper limit of normal (ULN)

• BUN and serum creatinine =< 1.5 * ULN

• Glucose, serum < 200 mg/dL

• The participant's Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1

• If the participant is female and of childbearing potential and not lactating she has a documented negative serum pregnancy test within 14 days prior to randomization

• The participant has a baseline EKG that does not show signs of acute cardiac ischemia or cardiac dysrhythmia (except for 1st degree AV block or chronic atrial fibrillation); EKG can be an earlier report within 12 weeks prior to registration

• Participants using the drugs listed below may not be randomized unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 3 days prior to starting pioglitazone or placebo on this study; the use of the following drugs or drug classes is prohibited during pioglitazone/placebo treatment: participants taking inhibitors of CYP2C8 (gemfibrozil, ketoconazole, quercetin, trimethoprim), enzyme inducers of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), and CYP3A4 substrate

Exclusion Criteria:

• The participant has active cancer or carcinoma in situ of the head and neck

• The participant has a contraindication to biopsy

• The participant has presence of congestive heart failure (New York Heart Association (NYHA) class II-IV), uncontrolled hypertension (systolic > 150 or diastolic > 100), or unstable angina

• The participant has any history of congestive heart failure or history of myocardial infarction within the past 6 months

• The participant exhibits clinical evidence of active liver disease or history of chronic liver disease

• The participant has > Common Terminology Criteria for Adverse Events (CTCAE) grade 1 edema

• The participant has known diabetes and is on insulin or oral agents; the participant is receiving medical therapy for dysregulated blood sugar

• The participant who currently receives an enzyme inhibitor of CYP2C8 (gemfibrozil, ketoconazole, quercetin, trimethoprim), or enzyme inducer of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), or CYP3A4 substrate will not be eligible for randomization after assessing eligibility in stage two unless he/she will not be eligible for randomization after assessing eligibility in stage two unless he/she is willing to stop these drugs and possibly replace them with alternative therapies

• The participant currently receives pregabalin or thioridazine

• The participant has experienced jaundice with Rezulin (troglitazone)

• The participant has a history of colorectal cancer, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC)

• The participant has a history of bladder cancer or in situ bladder cancer

• The participant has a history of invasive cancer within the past 18 months (excluding non-melanoma skin cancer and in situ cervical cancer); participants (excluding those with a history of colorectal cancer, FAP, HNPCC, bladder cancer or in situ bladder cancer) who received curative treatment and have shown no evidence of recurrence for 18 months will be eligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
3	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
4	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455
5	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
6	Columbia University Medical Center	New York	New York	United States	10032
7	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
8	Weill Medical College of Cornell University	New York	New York	United States	10065
9	Medical University of South Carolina	Charleston	South Carolina	United States	29425
10	MD Anderson Cancer Center	Houston	Texas	United States	77030
11	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
12	BC Cancer Agency (Vancouver Cancer Centre)	Vancouver	British Columbia	Canada	V5Z 4E6
13	European Institute of Oncology	Milano		Italy	20141

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Powel H. Brown, University of Texas MD Anderson Cancer Center, Consortium PI

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Official Website
• National Cancer Institute (NCI) Central Website for Cancer Research

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00951379
• Other Study ID Numbers: NCI-2012-03152; NCI-2012-03152; UWI H-2009-0106; MDA-2009-0339; INC07-10-01; N01CN35159; N01CN35153; P30CA016672
• First Posted: Aug 4, 2009
• Last Update Posted: Apr 6, 2016
• Last Verified: Jun 1, 2014

• Additional relevant MeSH terms: Precancerous Conditions; Leukoplakia; Leukoplakia, Oral; Pioglitazone

Study Results

Participant Flow

Recruitment Details	Recruitment Period: first participant accrued July 12, 2010 and the last participant accrued on September 10, 2013. Recruitment done in medical clinic settings across the United States, at the European Institute of Oncology in Milan, Italy, and at the BC Cancer Center, Vancouver, British Columbia, Canada.
Pre-assignment Detail	Of the 99 participants screened during recruitment phase, 47 participants failed screening and were excluded from the trial before assignment to groups. Due to slow accrual, the study was terminated in September 2013.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Period Title: Overall Study
STARTED	27	25
COMPLETED	21	23
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)	Total
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks	Total of all reporting groups
Overall Participants	27	25	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.9 (8.3)	59.0 (10.3)	59.5 (9.2)
Sex: Female, Male (Count of Participants)
Female	16 59.3%	12 48%	28 53.8%
Male	11 40.7%	13 52%	24 46.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 7.4%	1 4%	3 5.8%
Not Hispanic or Latino	25 92.6%	24 96%	49 94.2%
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	2 7.4%	1 4%	3 5.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	25 92.6%	24 96%	49 94.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	23 85.2%	22 88%	45 86.5%
Italy	4 14.8%	3 12%	7 13.5%
Alcohol Use at Baseline (participants) [Number]
Heavy	2 7.4%	3 12%	5 9.6%
Light	17 63%	17 68%	34 65.4%
Non-Drinker	8 29.6%	5 20%	13 25%
Smoking Use at Baseline (participants) [Number]
Current	6 22.2%	6 24%	12 23.1%
Former	12 44.4%	7 28%	19 36.5%
Never	9 33.3%	12 48%	21 40.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response <Clinical and Histologic Response Defined as 50% or Greater Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia>
Description	Overall Dichotomized Clinical and Histologic Response defined as 50% or greater reduction in sum of the measured products of perpendicular dimensions of the target lesion(s) or improvement in the degree of dysplasia or hyperplasia where complete (CR) or partial response (PR) in either clinical or histologic outcome assessed according to criteria given recorded as Response or No Response and analyzed as a dichotomous variable. Clinical Response = CR: Disappearance all evidence target & non-target lesions; PR: >/=50% reduction in sum products of diameters all target lesion(s). Non-target lesions may not increase >/=25% in size & no new lesion. Histologic Response = CR: Complete reversal of dysplasia or hyperplasia to normal epithelium in all biopsied lesions. PR: Improvement of degree of dysplasia or hyperplasia in all biopsied lesion(s) from advanced to early, or from early to normal epithelium in some lesions while other biopsied lesions remain stable.
Time Frame	Response assessed at Week 24 ±1 Week

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	26	25
Response	12 44.4%	8 32%
No Response	14 51.9%	17 68%

2. Secondary Outcome

Title	Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma
Description	Degree of change of C-reactive protein (CRP) in plasma serum via blood tests. The longitudinal regression models for analysis of the change in CRP in plasma used, with suitable transformation if necessary to satisfy the model assumptions, with treatment, stage and biomarker value at screening visit as covariates.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Pioglitazone's 26 had 24 evaluable specimens at baseline & 20 evaluable at end of study with 2 of those not available for CRP>5 baseline measure: Placebo's 25 had 25 evaluable specimens at baseline & 21 at end of study. Analysis based on specimen viability/availability, no exclusions made for other reasons, participant needed 1/+ dose of treatment.

Arm/Group Title	Pioglitazone: CRP>5 at Baseline	Pioglitazone: CRP>5 End of Study	Placebo: CRP> 5 Baseline	Placebo: CRP>5 End of Study
Arm/Group Description	Measure at baseline, followed by Pioglitazone treatment three 15 mg capsules orally/day for 24 weeks	Measure at end of Pioglitazone treatment, approximately 24 weeks	Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Measure at end of Placebo treatment, approximately 24 weeks
Measure Participants	24	20	25	21
Yes	6 22.2%	1 4%	4 7.7%	4 NaN
No	18 66.7%	19 76%	21 40.4%	17 NaN

3. Secondary Outcome

Title	Number of Participants With Level of C-reactive Protein in Plasma Decrease From >5.0 mg/L to <= 5.0 mg/L From Baseline to End of Study
Description	The longitudinal regression models for analysis of the change in CRP in plasma will be used, with suitable transformation if necessary to satisfy the model assumptions, with treatment, stage and biomarker value at screening visit as covariates.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Pioglitazone's 26 had 20 evaluable specimens at baseline & 20 at end of study with 2 of those not available for the CRP>5 baseline measure & Placebo's 25 had 25 evaluable at baseline & 21 evaluable at end of study. Analysis based on specimen viability/availability, no exclusions made for other reasons, participants needed 1/+ dose of treatment.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	18	21
Yes	3 11.1%	0 0%
No	15 55.6%	21 84%

4. Secondary Outcome

Title	Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use
Description	Tobacco use summarized by treatment stratified by stage and by group. In addition, the effects of tobacco and alcohol use on the primary endpoint of clinical response assessed.
Time Frame	Up to 26 weeks

Outcome Measure Data

Analysis Population Description

Analysis includes all participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	26	25
Never Smoked	4 14.8%	5 20%
Former Smoker	5 18.5%	2 8%
Current Smoker	2 7.4%	1 4%

5. Secondary Outcome

Title	Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use
Description	Alcohol use will be summarized by treatment stratified by stage and by group. In addition, the effects of tobacco and alcohol use on the primary endpoint of clinical and pathological response assessed using statistical regression models in an exploratory fashion. Heavy drinkers are participants who drank every day; Light drinkers are participants who drank on some days; Non-drinkers are former drinkers or those who never drank alcohol.
Time Frame	Up to 26 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	26	25
Non-Drinker	2 7.4%	2 8%
Light Drinker	8 29.6%	6 24%
Heavy Drinker	1 3.7%	0 0%

6. Secondary Outcome

Title	Number of Participants Affected by Adverse Events Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4.0)
Description	All adverse events (including serious) and clinical laboratory toxicity summarized affected organ system. Reporting based on the NCI CTCAE v4.0 by treatment, details included in later Adverse Event Module of results.
Time Frame	Up to 26 weeks

Outcome Measure Data

Analysis Population Description

Population includes all enrolled participants.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	27	25
Blood & Lymphatic System Disorders	1 3.7%	0 0%
Cardiac Disorders	3 11.1%	2 8%
Ear & Labyrinth Disorders	0 0%	2 8%
Eye Disorders	7 25.9%	2 8%
Gastrointestinal Disorders	23 85.2%	22 88%
General Disorders & Administration Site Conditions	12 44.4%	10 40%
Infections and Infestations	9 33.3%	8 32%
Injury, Poisoning and Procedural Complications	0 0%	2 8%
Investigations	3 11.1%	2 8%
Metabolism and Nutrition Disorders	2 7.4%	0 0%
Musculoskeletal and Connective Tissue Disorders	7 25.9%	8 32%
Neoplasms Benign, Malignant and Unspecified	1 3.7%	0 0%
Nervous System Disorders	14 51.9%	7 28%
Psychiatric Disorders	3 11.1%	1 4%
Reproductive System and Breast Disorders	1 3.7%	0 0%
Respiratory, Thoracic and Mediastinal Disorders	18 66.7%	9 36%
Skin and Subcutaneous Tissue Disorders	4 14.8%	2 8%
Surgical and Medical Procedures	2 7.4%	3 12%
Vascular Disorders	5 18.5%	12 48%

7. Secondary Outcome

Title	Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1
Description	Tissue levels of Cyclin D1 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Two participants in the Pioglitazone arm were not analyzed for Cyclin D1 end of study score. Analysis is based on specimen viability/availability. No exclusions are made for any other reason.

Arm/Group Title	Pioglitazone: Baseline	Pioglitazone: End of Study	Placebo: Baseline	Placebo: End of Study
Arm/Group Description	Measure at baseline, followed by Pioglitazone treatment three 15 mg capsules orally/day for 24 weeks	Measure at end of Pioglitazone treatment, approximately 24 weeks	Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Measure at end of Placebo treatment, approximately 24 weeks
Measure Participants	25	23	24	24
Mean (Standard Deviation) [percentage of staining cells positive]	15.5 (10.0)	12.7 (6.9)	12.8 (7.9)	12.9 (7.0)

8. Secondary Outcome

Title	Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67
Description	Tissue levels of Ki-67 for proliferation assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Four participants in the Pioglitazone arm were not analyzed for Ki-67 end of study score. Analysis is based on specimen viability/availability. No exclusions are made for any other reason.

Arm/Group Title	Pioglitazone: Baseline	Pioglitazone: End of Study	Placebo: Baseline	Placebo: End of Study
Arm/Group Description	Measure at baseline, followed by Pioglitazone treatment three 15 mg capsules orally/day for 24 weeks	Measure at end of Pioglitazone treatment, approximately 24 weeks	Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Measure at end of Placebo treatment, approximately 24 weeks
Measure Participants	25	21	24	24
Mean (Standard Deviation) [percentage of staining cells positive]	9.2 (4.6)	8.9 (4.2)	10.7 (6.5)	8.2 (4.6)

9. Secondary Outcome

Title	Biomarker Measurements at Scheduled Visits: Tissue Levels of p21
Description	Tissue levels of p21 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Two participants in the Pioglitazone arm were not analyzed for p21 end of study score. Analysis is based on specimen viability/availability. No exclusions are made for any other reason.

Arm/Group Title	Pioglitazone: Baseline	Pioglitazone: End of Study	Placebo: Baseline	Placebo: End of Study
Arm/Group Description	Measure at baseline, followed by Pioglitazone treatment three 15 mg capsules orally/day for 24 weeks	Measure at end of Pioglitazone treatment, approximately 24 weeks	Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Measure at end of Placebo treatment, approximately 24 weeks
Measure Participants	25	23	24	24
Mean (Standard Deviation) [percentage of staining cells positive]	18.7 (10.2)	19.3 (10.6)	17.7 (10.8)	15.6 (7.4)

10. Secondary Outcome

Title	Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2)
Description	Tissue levels of Bcl2 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported a percentage of cells staining positive, according to nuclear or cytoplasmic compartments.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Four participants of 25 overall in the Pioglitazone arm were not analyzed for Bcl2 end of study score and one participant in Placebo was not analyzed for Bcl2 baseline score. Analysis is based on specimen viability/availability. No exclusions are made for any other reason.

Arm/Group Title	Pioglitazone: Baseline	Pioglitazone: End of Study	Placebo: Baseline	Placebo: End of Study
Arm/Group Description	Measure at baseline, followed by Pioglitazone treatment three 15 mg capsules orally/day for 24 weeks	Measure at end of Pioglitazone treatment, approximately 24 weeks	Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Measure at end of Placebo treatment, approximately 24 weeks
Measure Participants	25	21	23	24
Mean (Standard Deviation) [percentage of staining cells positive]	2.8 (3.2)	2.3 (2.3)	4.2 (5.0)	4.6 (8.3)

11. Secondary Outcome

Title	Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm
Description	Tissue levels of Peroxisome proliferator-activated receptor gamma (PPARG) Nucleus and PPARG Cytoplasm as indirect measures of pharmacological effect, PPAR gamma assessed by immunohistochemistry. Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments.
Time Frame	Baseline to end of study, 24 weeks

Outcome Measure Data

Analysis Population Description

Four participants in the Pioglitazone arm were not analyzed at end of study, and two participants in Placebo were not analyzed for PPARG baseline scores. Analysis is based on specimen viability/availability. No exclusions are made for any other reason.

Arm/Group Title	Pioglitazone: Baseline	Pioglitazone: End of Study	Placebo: Baseline	Placebo: End of Study
Arm/Group Description	Measure at baseline, followed by Pioglitazone treatment three 15 mg capsules orally/day for 24 weeks	Measure at end of Pioglitazone treatment, approximately 24 weeks	Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Measure at end of Placebo treatment, approximately 24 weeks
Measure Participants	25	21	22	24
PPARG Nucleus	10.8 (15.7)	7.3 (7.5)	12.4 (10.4)	6.8 (7.2)
PPARG Cytoplasm	21.7 (25.8)	23.5 (28.0)	20.2 (29.9)	21.5 (31.3)

12. Primary Outcome

Title	Dichotomized Histologic Response (HR): Participant Complete or Partial Response Defined as =/>50% Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia
Description	HR according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. CR: Complete reversal dysplasia/hyperplasia to normal epithelium in all biopsied lesions. PR: Improvement of degree dysplasia/hyperplasia in all biopsied lesion from advanced to early, or from early to normal epithelium in some lesions while other biopsied lesions remain stable. No Change (NC): No change in degree dysplasia/hyperplasia in all biopsied lesions, anything not CR, PR or PD. Progressive Disease (PD): Any increase in severity histology grade any biopsied lesion. Early premalignant lesion: lesion defined high risk, indicated by presence of one: hyperplasia at high-risk sites (dorsal, lateral or ventral tongue, or floor of mouth) ONLY, or mild dysplasia. Advanced premalignant lesion: lesion with presence of one: moderate dysplasia or severe dysplasia (excluding CIS), erythroplakia with hyperplasia or of any severity of dysplasia.
Time Frame	Response assessed at Week 24 ±1 Week

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	26	25
Response	2 7.4%	2 8%
No Response	24 88.9%	23 92%

13. Primary Outcome

Title	Dichotomized Clinical Response: Participant Complete or Partial Response Defined as =/>50% Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia
Description	Clinical Response assessed according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. Complete Response (CR): Disappearance of all evidence of target AND non-target lesions. Partial Response (PR): greater than or equal to 50% reduction in the sum of the products of diameters of all target lesion(s). Non-target lesions may not increase greater than or equal 25% in size and no new lesion may appear. No Change (NC): No change in the size of the lesion(s) and no new lesions appearing, i.e. anything that is not CR, PR or PD. Progressive Disease (PD): Any increase greater than or equal to 25% in the product of the diameters of any measurable lesions or in the estimated size of non-measurable lesions or the appearance of an unequivocal new lesion.
Time Frame	Response assessed at Week 24 ±1 Week

Outcome Measure Data

Analysis Population Description

Analysis includes all participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.

Arm/Group Title	Arm I (Pioglitazone Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Three (3) placebo capsules by mouth once daily for 24 weeks
Measure Participants	26	25
Response	11 40.7%	8 32%
No Response	15 55.6%	17 68%

Adverse Events

Time Frame	Adverse signs and symptoms recorded at each clinic visit beginning week 4 through week 24 (± 1 week). All adverse events followed according to established standards of care. Overall study period: May 2010 to March 2014.
Adverse Event Reporting Description	Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.
Arm/Group Title	Arm I (Pioglitazone Hydrochloride)		Arm II (Placebo)
Arm/Group Description	Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks		Three (3) placebo capsules by mouth once daily for 24 weeks
All Cause Mortality
	Arm I (Pioglitazone Hydrochloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Pioglitazone Hydrochloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/27 (11.1%)		1/25 (4%)
Cardiac disorders
heart failure	1/27 (3.7%)	1	0/25 (0%)	0
Infections and infestations
sepsis	1/27 (3.7%)	1	0/25 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
squamous cell carcinoma of the tongue	1/27 (3.7%)	1	0/25 (0%)	0
Surgical and medical procedures
laparoscopic hysterectomy	1/27 (3.7%)	1	0/25 (0%)	0
Pre-existing abdominal aortic aneurysm	0/27 (0%)	0	1/25 (4%)	1
Vascular disorders
right femoral artery occlusion	0/27 (0%)	0	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Arm I (Pioglitazone Hydrochloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/27 (81.5%)		24/25 (96%)
Blood and lymphatic system disorders
anemia	1/27 (3.7%)	2	0/25 (0%)	0
Cardiac disorders
palpitations	2/27 (7.4%)	2	0/25 (0%)	0
Ear and labyrinth disorders
hearing issues	0/27 (0%)	0	1/25 (4%)	1
hearing loss, earwax	0/27 (0%)	0	1/25 (4%)	1
Eye disorders
bilateral burning eye	0/27 (0%)	0	1/25 (4%)	1
blurred vision	1/27 (3.7%)	1	1/25 (4%)	1
conjunctival abrasion	1/27 (3.7%)	1	0/25 (0%)	0
conjunctivitis	1/27 (3.7%)	1	0/25 (0%)	0
myopia	1/27 (3.7%)	1	0/25 (0%)	0
red bloodshot eyes	1/27 (3.7%)	1	0/25 (0%)	0
scotoma of right eye	1/27 (3.7%)	1	0/25 (0%)	0
vitreous detachment of left eye	1/27 (3.7%)	1	0/25 (0%)	0
Gastrointestinal disorders
abdominal pain	0/27 (0%)	0	1/25 (4%)	1
constipation	0/27 (0%)	0	2/25 (8%)	2
diarrhea	1/27 (3.7%)	1	1/25 (4%)	1
dry mouth	3/27 (11.1%)	3	1/25 (4%)	1
dyspepsia	0/27 (0%)	0	1/25 (4%)	1
gastritis	1/27 (3.7%)	1	0/25 (0%)	0
gastrointestinal pain	1/27 (3.7%)	1	0/25 (0%)	0
hemorrhoids	1/27 (3.7%)	1	0/25 (0%)	0
lump under tongue	1/27 (3.7%)	1	0/25 (0%)	0
lip pain	0/27 (0%)	0	1/25 (4%)	1
mucositis oral	0/27 (0%)	0	2/25 (8%)	2
nausea	2/27 (7.4%)	2	3/25 (12%)	4
oral dysesthesia	1/27 (3.7%)	1	0/25 (0%)	0
oral hemorrhage	0/27 (0%)	0	1/25 (4%)	1
oral pain	6/27 (22.2%)	11	4/25 (16%)	4
periodontal disease	0/27 (0%)	0	1/25 (4%)	1
rectal hemorrhage	0/27 (0%)	0	1/25 (4%)	1
striations on tongue	1/27 (3.7%)	1	0/25 (0%)	0
red spots right lower lip	1/27 (3.7%)	1	0/25 (0%)	0
stomach pain	0/27 (0%)	0	1/25 (4%)	1
toothache	1/27 (3.7%)	1	1/25 (4%)	1
vomiting	3/27 (11.1%)	3	1/25 (4%)	1
General disorders
edema limbs	2/27 (7.4%)	2	2/25 (8%)	2
facial pain	1/27 (3.7%)	1	1/25 (4%)	1
fatigue	3/27 (11.1%)	3	4/25 (16%)	5
flu like symptoms	2/27 (7.4%)	2	1/25 (4%)	1
malaise	2/27 (7.4%)	2	1/25 (4%)	1
non-cardiac chest pain	0/27 (0%)	0	1/25 (4%)	1
sluggishness	1/27 (3.7%)	1	0/25 (0%)	0
suddenly famished	1/27 (3.7%)	1	0/25 (0%)	0
Infections and infestations
bladder infection	0/27 (0%)	0	1/25 (4%)	1
bronchial infection	1/27 (3.7%)	1	0/25 (0%)	0
toe infection	0/27 (0%)	0	1/25 (4%)	1
lip infection	0/27 (0%)	0	1/25 (4%)	1
lung infection	1/27 (3.7%)	1	1/25 (4%)	1
sinusitis	1/27 (3.7%)	1	1/25 (4%)	1
skin infection	1/27 (3.7%)	1	0/25 (0%)	0
soft tissue infection	0/27 (0%)	0	1/25 (4%)	1
thrush in throat	1/27 (3.7%)	1	0/25 (0%)	0
tooth infection	0/27 (0%)	0	1/25 (4%)	1
upper respiratory infection	2/27 (7.4%)	2	1/25 (4%)	1
urinary tract infection	1/27 (3.7%)	1	0/25 (0%)	0
Injury, poisoning and procedural complications
fall	0/27 (0%)	0	1/25 (4%)	1
fracture	0/27 (0%)	0	1/25 (4%)	1
Investigations
alanine aminotransferase (ALT) Increased	0/27 (0%)	0	1/25 (4%)	1
creatinine increased	1/27 (3.7%)	1	0/25 (0%)	0
weight gain	1/27 (3.7%)	1	0/25 (0%)	0
weight loss	1/27 (3.7%)	1	1/25 (4%)	1
Metabolism and nutrition disorders
hypoglycemia	1/27 (3.7%)	1	0/25 (0%)	0
increased chloride	1/27 (3.7%)	1	0/25 (0%)	0
Musculoskeletal and connective tissue disorders
arms burning sensaton	0/27 (0%)	0	1/25 (4%)	1
arthralgia	0/27 (0%)	0	2/25 (8%)	2
back pain	2/27 (7.4%)	2	2/25 (8%)	2
mild leg cramps at night	1/27 (3.7%)	1	0/25 (0%)	0
muscle pain right hip	1/27 (3.7%)	1	0/25 (0%)	0
myalgia	0/27 (0%)	0	1/25 (4%)	1
neck pain	1/27 (3.7%)	1	0/25 (0%)	0
pain in extremity	1/27 (3.7%)	1	1/25 (4%)	1
rotator cuff trauma resulting from a fall	0/27 (0%)	0	1/25 (4%)	1
superficial soft tissue fibrosis	1/27 (3.7%)	1	0/25 (0%)	0
Nervous system disorders
dizziness	3/27 (11.1%)	3	2/25 (8%)	2
dysgeusia	1/27 (3.7%)	1	0/25 (0%)	0
headache	5/27 (18.5%)	7	2/25 (8%)	2
hypersomnia	0/27 (0%)	0	1/25 (4%)	1
paresthesia	2/27 (7.4%)	2	0/25 (0%)	0
sinus pain	1/27 (3.7%)	1	1/25 (4%)	1
somnolence	1/27 (3.7%)	1	0/25 (0%)	0
tremor	1/27 (3.7%)	1	1/25 (4%)	2
Psychiatric disorders
anxiety	2/27 (7.4%)	2	0/25 (0%)	0
insomnia	1/27 (3.7%)	1	1/25 (4%)	1
Reproductive system and breast disorders
pelvic pain	1/27 (3.7%)	1	0/25 (0%)	0
Respiratory, thoracic and mediastinal disorders
allergic rhinitis	2/27 (7.4%)	5	0/25 (0%)	0
bronchospasm	1/27 (3.7%)	1	0/25 (0%)	0
cough	3/27 (11.1%)	3	4/25 (16%)	4
dry nasal passages	1/27 (3.7%)	1	0/25 (0%)	0
dyspnea	1/27 (3.7%)	1	1/25 (4%)	1
epistaxis	1/27 (3.7%)	1	0/25 (0%)	0
hoarseness	0/27 (0%)	0	1/25 (4%)	1
nasal congestion	1/27 (3.7%)	1	1/25 (4%)	1
productive cough	1/27 (3.7%)	1	0/25 (0%)	0
sinus disorder	1/27 (3.7%)	1	0/25 (0%)	0
slight metallic smell	1/27 (3.7%)	2	0/25 (0%)	0
sore throat	4/27 (14.8%)	5	1/25 (4%)	1
tonsillitis	0/27 (0%)	0	1/25 (4%)	1
wheezing	1/27 (3.7%)	1	0/25 (0%)	0
Skin and subcutaneous tissue disorders
bee sting	1/27 (3.7%)	1	0/25 (0%)	0
pruritus	1/27 (3.7%)	1	0/25 (0%)	0
rash maculo-papular	1/27 (3.7%)	2	0/25 (0%)	0
skin dyschromia of arms	0/27 (0%)	0	1/25 (4%)	1
small non-painful reddened area lower left arm	0/27 (0%)	0	1/25 (4%)	1
keratotic horns on head	1/27 (3.7%)	1	0/25 (0%)	0
Surgical and medical procedures
molar extracted due to failed root canal	0/27 (0%)	0	1/25 (4%)	1
outpatient surgery, knee meniscus repair	0/27 (0%)	0	1/25 (4%)	1
trans oral surgery	1/27 (3.7%)	1	0/25 (0%)	0
Vascular disorders
hypertension	4/27 (14.8%)	6	11/25 (44%)	14
minor venous insufficiency of the legs	1/27 (3.7%)	1	0/25 (0%)	0

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.