Trial Outcomes & Findings for Pioglitazone for Oral Premalignant Lesions (NCT NCT00951379)

Last Updated: 2016-04-06

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

52 participants

Primary outcome timeframe

Response assessed at Week 24 ±1 Week

Results posted on

2016-04-06

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Arm I (Pioglitazone Hydrochloride) Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) Three (3) placebo capsules by mouth once daily for 24 weeks
Overall Study STARTED	27	25
Overall Study COMPLETED	21	23
Overall Study NOT COMPLETED	6	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Pioglitazone Hydrochloride) Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) Three (3) placebo capsules by mouth once daily for 24 weeks
Overall Study Adverse Event	4	1
Overall Study Withdrawal by Subject	1	0
Overall Study Noncompliance	1	0
Overall Study Disease Progression	0	1

Baseline Characteristics

Pioglitazone for Oral Premalignant Lesions

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Pioglitazone Hydrochloride) n=27 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Total n=52 Participants Total of all reporting groups
Age, Continuous	59.9 years STANDARD_DEVIATION 8.3 • n=5 Participants	59.0 years STANDARD_DEVIATION 10.3 • n=7 Participants	59.5 years STANDARD_DEVIATION 9.2 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	12 Participants n=7 Participants	28 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	13 Participants n=7 Participants	24 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	25 Participants n=5 Participants	24 Participants n=7 Participants	49 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	25 Participants n=5 Participants	24 Participants n=7 Participants	49 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	23 participants n=5 Participants	22 participants n=7 Participants	45 participants n=5 Participants
Region of Enrollment Italy	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Alcohol Use at Baseline Heavy	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants
Alcohol Use at Baseline Light	17 participants n=5 Participants	17 participants n=7 Participants	34 participants n=5 Participants
Alcohol Use at Baseline Non-Drinker	8 participants n=5 Participants	5 participants n=7 Participants	13 participants n=5 Participants
Smoking Use at Baseline Current	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Smoking Use at Baseline Former	12 participants n=5 Participants	7 participants n=7 Participants	19 participants n=5 Participants
Smoking Use at Baseline Never	9 participants n=5 Participants	12 participants n=7 Participants	21 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=26 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
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	8 participants	—	—
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	17 participants	—	—

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=26 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
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	2 participants	—	—
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	23 participants	—	—

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=26 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
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	8 participants	—	—
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	17 participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=24 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=20 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline n=25 Participants Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study n=21 Participants Measure at end of Placebo treatment, approximately 24 weeks
Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma Yes	6 participants	1 participants	4 participants	4 participants
Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma No	18 participants	19 participants	21 participants	17 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=18 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=21 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
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	0 participants	—	—
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	21 participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=26 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use Never Smoked	4 participants	5 participants	—	—
Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use Former Smoker	5 participants	2 participants	—	—
Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use Current Smoker	2 participants	1 participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=26 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use Non-Drinker	2 participants	2 participants	—	—
Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use Light Drinker	8 participants	6 participants	—	—
Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use Heavy Drinker	1 participants	0 participants	—	—

SECONDARY outcome

Timeframe: Up to 26 weeks

Population: Population includes all enrolled participants.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=27 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study Measure at end of Placebo treatment, approximately 24 weeks
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	12 participants	—	—
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	0 participants	—	—
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	2 participants	—	—
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	2 participants	—	—
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	2 participants	—	—
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	22 participants	—	—
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	10 participants	—	—
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	8 participants	—	—
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	2 participants	—	—
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	2 participants	—	—
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	0 participants	—	—
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	8 participants	—	—
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	0 participants	—	—
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	7 participants	—	—
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	1 participants	—	—
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	0 participants	—	—
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	9 participants	—	—
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	2 participants	—	—
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	3 participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=25 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=23 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline n=24 Participants Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study n=24 Participants Measure at end of Placebo treatment, approximately 24 weeks
Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1	15.5 percentage of staining cells positive Standard Deviation 10.0	12.7 percentage of staining cells positive Standard Deviation 6.9	12.8 percentage of staining cells positive Standard Deviation 7.9	12.9 percentage of staining cells positive Standard Deviation 7.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=25 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=21 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline n=24 Participants Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study n=24 Participants Measure at end of Placebo treatment, approximately 24 weeks
Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67	9.2 percentage of staining cells positive Standard Deviation 4.6	8.9 percentage of staining cells positive Standard Deviation 4.2	10.7 percentage of staining cells positive Standard Deviation 6.5	8.2 percentage of staining cells positive Standard Deviation 4.6

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=25 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=23 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline n=24 Participants Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study n=24 Participants Measure at end of Placebo treatment, approximately 24 weeks
Biomarker Measurements at Scheduled Visits: Tissue Levels of p21	18.7 percentage of staining cells positive Standard Deviation 10.2	19.3 percentage of staining cells positive Standard Deviation 10.6	17.7 percentage of staining cells positive Standard Deviation 10.8	15.6 percentage of staining cells positive Standard Deviation 7.4

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=25 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=21 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline n=23 Participants Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study n=24 Participants Measure at end of Placebo treatment, approximately 24 weeks
Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2)	2.8 percentage of staining cells positive Standard Deviation 3.2	2.3 percentage of staining cells positive Standard Deviation 2.3	4.2 percentage of staining cells positive Standard Deviation 5.0	4.6 percentage of staining cells positive Standard Deviation 8.3

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Pioglitazone Hydrochloride) n=25 Participants Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=21 Participants Three (3) placebo capsules by mouth once daily for 24 weeks	Placebo: CRP> 5 Baseline n=22 Participants Measure at baseline, followed by Placebo treatment three capsules orally/day for 24 weeks	Placebo: CRP>5 End of Study n=24 Participants Measure at end of Placebo treatment, approximately 24 weeks
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	7.3 percentage of staining cells positive Standard Deviation 7.5	12.4 percentage of staining cells positive Standard Deviation 10.4	6.8 percentage of staining cells positive Standard Deviation 7.2
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	23.5 percentage of staining cells positive Standard Deviation 28.0	20.2 percentage of staining cells positive Standard Deviation 29.9	21.5 percentage of staining cells positive Standard Deviation 31.3

Adverse Events

Arm I (Pioglitazone Hydrochloride)

Serious events: 3 serious events

Other events: 22 other events

Deaths: 0 deaths

Arm II (Placebo)

Serious events: 1 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm I (Pioglitazone Hydrochloride) n=27 participants at risk Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks	Arm II (Placebo) n=25 participants at risk Three (3) placebo capsules by mouth once daily for 24 weeks
Cardiac disorders heart failure	3.7% 1/27 • Number of events 1 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.	0.00% 0/25 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.
Infections and infestations sepsis	3.7% 1/27 • Number of events 1 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.	0.00% 0/25 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) squamous cell carcinoma of the tongue	3.7% 1/27 • Number of events 1 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.	0.00% 0/25 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.
Surgical and medical procedures laparoscopic hysterectomy	3.7% 1/27 • Number of events 1 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.	0.00% 0/25 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.
Surgical and medical procedures Pre-existing abdominal aortic aneurysm	0.00% 0/27 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.	4.0% 1/25 • Number of events 1 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.
Vascular disorders right femoral artery occlusion	0.00% 0/27 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.	4.0% 1/25 • Number of events 1 • 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. Study source vocabulary for the study began as CTCAE version 3.0 and was translated to version 4.0.

Other adverse events

Additional Information

University of Texas MD Anderson Phase I/II Prevention Consortium

University of Texas (UT) MD Anderson Cancer Center

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60