Oral Leukoplakia
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. 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: I. 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. IV. 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.
Interventions
Three (3) pioglitazone 15 mg capsules by mouth once daily for 24 weeks (+/- 1 week)
OTHERplacebo
Three (3) pioglitazone placebo capsules by mouth once daily for 24 weeks (+/- 1 week)
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, Italy, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Pioglitazone Hydrochloride) Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks | 27 |
| Arm II (Placebo) Three (3) placebo capsules by mouth once daily for 24 weeks | 25 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Disease Progression | 0 | 1 |
| Overall Study | Noncompliance | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm II (Placebo) | Total | Arm I (Pioglitazone Hydrochloride) |
|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 10.3 | 59.5 years STANDARD_DEVIATION 9.2 | 59.9 years STANDARD_DEVIATION 8.3 |
| Alcohol Use at Baseline Heavy | 3 participants | 5 participants | 2 participants |
| Alcohol Use at Baseline Light | 17 participants | 34 participants | 17 participants |
| Alcohol Use at Baseline Non-Drinker | 5 participants | 13 participants | 8 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 49 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 49 Participants | 25 Participants |
| Region of Enrollment Italy | 3 participants | 7 participants | 4 participants |
| Region of Enrollment United States | 22 participants | 45 participants | 23 participants |
| Sex: Female, Male Female | 12 Participants | 28 Participants | 16 Participants |
| Sex: Female, Male Male | 13 Participants | 24 Participants | 11 Participants |
| Smoking Use at Baseline Current | 6 participants | 12 participants | 6 participants |
| Smoking Use at Baseline Former | 7 participants | 19 participants | 12 participants |
| Smoking Use at Baseline Never | 12 participants | 21 participants | 9 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 27 | 24 / 25 |
| serious Total, serious adverse events | 3 / 27 | 1 / 25 |
Outcome results
Primary
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
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
Population: Analysis includes all participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | 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 | 11 participants |
| Arm I (Pioglitazone Hydrochloride) | 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 | No Response | 15 participants |
| Arm II (Placebo) | 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 | 8 participants |
| Arm II (Placebo) | 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 | No Response | 17 participants |
Primary
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
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
Population: All participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | 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 | 2 participants |
| Arm I (Pioglitazone Hydrochloride) | 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 | No Response | 24 participants |
| Arm II (Placebo) | 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 | 2 participants |
| Arm II (Placebo) | 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 | No Response | 23 participants |
Primary
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>
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
Population: All participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | 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 | 12 participants |
| Arm I (Pioglitazone Hydrochloride) | 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> | No Response | 14 participants |
| Arm II (Placebo) | 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 | 8 participants |
| Arm II (Placebo) | 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> | No Response | 17 participants |
Secondary
Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) | 2.8 percentage of staining cells positive | Standard Deviation 3.2 |
| Arm II (Placebo) | Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) | 2.3 percentage of staining cells positive | Standard Deviation 2.3 |
| Placebo: CRP> 5 Baseline | Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) | 4.2 percentage of staining cells positive | Standard Deviation 5 |
| Placebo: CRP>5 End of Study | Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) | 4.6 percentage of staining cells positive | Standard Deviation 8.3 |
Secondary
Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 | 15.5 percentage of staining cells positive | Standard Deviation 10 |
| Arm II (Placebo) | Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 | 12.7 percentage of staining cells positive | Standard Deviation 6.9 |
| Placebo: CRP> 5 Baseline | Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 | 12.8 percentage of staining cells positive | Standard Deviation 7.9 |
| Placebo: CRP>5 End of Study | Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 | 12.9 percentage of staining cells positive | Standard Deviation 7 |
Secondary
Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 | 9.2 percentage of staining cells positive | Standard Deviation 4.6 |
| Arm II (Placebo) | Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 | 8.9 percentage of staining cells positive | Standard Deviation 4.2 |
| Placebo: CRP> 5 Baseline | Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 | 10.7 percentage of staining cells positive | Standard Deviation 6.5 |
| Placebo: CRP>5 End of Study | Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 | 8.2 percentage of staining cells positive | Standard Deviation 4.6 |
Secondary
Biomarker Measurements at Scheduled Visits: Tissue Levels of p21
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 | 18.7 percentage of staining cells positive | Standard Deviation 10.2 |
| Arm II (Placebo) | Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 | 19.3 percentage of staining cells positive | Standard Deviation 10.6 |
| Placebo: CRP> 5 Baseline | Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 | 17.7 percentage of staining cells positive | Standard Deviation 10.8 |
| Placebo: CRP>5 End of Study | Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 | 15.6 percentage of staining cells positive | Standard Deviation 7.4 |
Secondary
Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Nucleus | 10.8 percentage of staining cells positive | Standard Deviation 15.7 |
| Arm I (Pioglitazone Hydrochloride) | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Cytoplasm | 21.7 percentage of staining cells positive | Standard Deviation 25.8 |
| Arm II (Placebo) | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Cytoplasm | 23.5 percentage of staining cells positive | Standard Deviation 28 |
| Arm II (Placebo) | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Nucleus | 7.3 percentage of staining cells positive | Standard Deviation 7.5 |
| Placebo: CRP> 5 Baseline | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Nucleus | 12.4 percentage of staining cells positive | Standard Deviation 10.4 |
| Placebo: CRP> 5 Baseline | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Cytoplasm | 20.2 percentage of staining cells positive | Standard Deviation 29.9 |
| Placebo: CRP>5 End of Study | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Nucleus | 6.8 percentage of staining cells positive | Standard Deviation 7.2 |
| Placebo: CRP>5 End of Study | Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | PPARG Cytoplasm | 21.5 percentage of staining cells positive | Standard Deviation 31.3 |
Secondary
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)
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
Population: Population includes all enrolled participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | 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) | General Disorders & Administration Site Conditions | 12 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Musculoskeletal and Connective Tissue Disorders | 7 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Eye Disorders | 7 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Neoplasms Benign, Malignant and Unspecified | 1 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Infections and Infestations | 9 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Nervous System Disorders | 14 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Ear & Labyrinth Disorders | 0 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Psychiatric Disorders | 3 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Injury, Poisoning and Procedural Complications | 0 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Reproductive System and Breast Disorders | 1 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Gastrointestinal Disorders | 23 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Respiratory, Thoracic and Mediastinal Disorders | 18 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Investigations | 3 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Skin and Subcutaneous Tissue Disorders | 4 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Cardiac Disorders | 3 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Surgical and Medical Procedures | 2 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Metabolism and Nutrition Disorders | 2 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Vascular Disorders | 5 participants |
| Arm I (Pioglitazone Hydrochloride) | 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) | Blood & Lymphatic System Disorders | 1 participants |
| Arm II (Placebo) | 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) | Vascular Disorders | 12 participants |
| Arm II (Placebo) | 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) | Blood & Lymphatic System Disorders | 0 participants |
| Arm II (Placebo) | 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) | Cardiac Disorders | 2 participants |
| Arm II (Placebo) | 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) | Ear & Labyrinth Disorders | 2 participants |
| Arm II (Placebo) | 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) | Eye Disorders | 2 participants |
| Arm II (Placebo) | 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) | Gastrointestinal Disorders | 22 participants |
| Arm II (Placebo) | 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) | General Disorders & Administration Site Conditions | 10 participants |
| Arm II (Placebo) | 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) | Infections and Infestations | 8 participants |
| Arm II (Placebo) | 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) | Injury, Poisoning and Procedural Complications | 2 participants |
| Arm II (Placebo) | 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) | Investigations | 2 participants |
| Arm II (Placebo) | 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) | Metabolism and Nutrition Disorders | 0 participants |
| Arm II (Placebo) | 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) | Musculoskeletal and Connective Tissue Disorders | 8 participants |
| Arm II (Placebo) | 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) | Neoplasms Benign, Malignant and Unspecified | 0 participants |
| Arm II (Placebo) | 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) | Nervous System Disorders | 7 participants |
| Arm II (Placebo) | 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) | Psychiatric Disorders | 1 participants |
| Arm II (Placebo) | 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) | Reproductive System and Breast Disorders | 0 participants |
| Arm II (Placebo) | 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) | Respiratory, Thoracic and Mediastinal Disorders | 9 participants |
| Arm II (Placebo) | 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) | Skin and Subcutaneous Tissue Disorders | 2 participants |
| Arm II (Placebo) | 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) | Surgical and Medical Procedures | 3 participants |
Secondary
Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | Yes | 6 participants |
| Arm I (Pioglitazone Hydrochloride) | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | No | 18 participants |
| Arm II (Placebo) | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | No | 19 participants |
| Arm II (Placebo) | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | Yes | 1 participants |
| Placebo: CRP> 5 Baseline | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | Yes | 4 participants |
| Placebo: CRP> 5 Baseline | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | No | 21 participants |
| Placebo: CRP>5 End of Study | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | Yes | 4 participants |
| Placebo: CRP>5 End of Study | Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | No | 17 participants |
Secondary
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
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | 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 | Yes | 3 participants |
| Arm I (Pioglitazone Hydrochloride) | 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 | No | 15 participants |
| Arm II (Placebo) | 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 | Yes | 0 participants |
| Arm II (Placebo) | 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 | No | 21 participants |
Secondary
Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use
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
Population: All participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Non-Drinker | 2 participants |
| Arm I (Pioglitazone Hydrochloride) | Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Light Drinker | 8 participants |
| Arm I (Pioglitazone Hydrochloride) | Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Heavy Drinker | 1 participants |
| Arm II (Placebo) | Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Non-Drinker | 2 participants |
| Arm II (Placebo) | Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Light Drinker | 6 participants |
| Arm II (Placebo) | Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Heavy Drinker | 0 participants |
Secondary
Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use
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
Population: Analysis includes all participants who received at least one dose of treatment. One participant in the Pioglitazone arm never received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Pioglitazone Hydrochloride) | Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Never Smoked | 4 participants |
| Arm I (Pioglitazone Hydrochloride) | Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Former Smoker | 5 participants |
| Arm I (Pioglitazone Hydrochloride) | Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Current Smoker | 2 participants |
| Arm II (Placebo) | Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Never Smoked | 5 participants |
| Arm II (Placebo) | Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Former Smoker | 2 participants |
| Arm II (Placebo) | Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Current Smoker | 1 participants |