Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01433913
• Collaborator: (none)
• Enrollment: 20
• Locations: 3
• Arms: 2
• Duration (Months): 29
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well metformin hydrochloride works compared to placebo in treating patients with prostate cancer undergoing surgery. Metformin hydrochloride may make some enzymes active. These enzymes may block other enzymes needed for cell growth and stop the growth of tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Prostate; Recurrent Prostate Cancer; Stage I Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer	Drug: metformin hydrochloride; Other: placebo; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the effect of 4-12 weeks of metformin (metformin hydrochloride) intervention on cell proliferation in the prostatectomy tissue.

SECONDARY OBJECTIVES:

1. To determine the effect of metformin intervention on prostate tissue bioavailability of metformin.

2. To determine the effect of metformin intervention on apoptosis and angiogenesis in the prostatectomy tissue.

3. To determine the effect of metformin intervention on potential molecular targets of metformin including activated protein kinase (AMPK) activation, mammalian target of rapamycin (mTOR) regulation, and cell cycle regulation in the prostatectomy tissue.

4. To determine the effect of metformin intervention on changes in systemic hormones and growth factors that have been shown to be modulated by metformin in other patient populations including fasting glucose, fasting insulin, insulin-like growth factor axis, testosterone, and sex hormone binding globulin (SHBG).

5. To determine the effect of metformin intervention on changes in prostate-specific antigen (PSA) levels.

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

ARM I: Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) for 4-12 weeks.

ARM II: Patients receive placebo PO QD for 4-12 weeks.

Patients in both arms undergo surgery one day after completion of treatment.

After completion of study treatment, patients are followed up within 30 days of surgery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Metformin in a Pre-prostatectomy Prostate Cancer Cohort
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (metformin hydrochloride) Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.	Drug: metformin hydrochloride; Given PO; Other Names: Glucophage ; Other: laboratory biomarker analysis; Correlative studies
Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD for 4-12 weeks.	Other: placebo; Given PO; Other Names: PLCB ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC) [12 weeks]

   Data between the two study groups will be compared using a two-group t-test at a two-sided 0.05 level of significance. If the data are not normally distributed, a non-parametric rank-sum test will be utilized.

Secondary Outcome Measures

1. Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry [12 weeks]

2. Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3 [12 weeks]

   Average number of positively stained cells that exhibited nuclear fragmentation from five randomly selected high-power fields (40x) in the tumor region was calculated for each participant

3. Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1 [12 weeks]

4. mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K) [12 weeks]

5. Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34 [12 weeks]

6. AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK [12 weeks]

7. Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb) [12 weeks]

8. Changes in Serum PSA [Baseline and 12 weeks]

9. Changes in Serum Fasting Insulin [Baseline and 12 weeks]

10. Changes in Serum IGF-1/IGFBP-3 [Baseline and 12 weeks]

11. Changes in Serum Testosterone [Baseline and 12 weeks]

12. Changes in Serum SHBG [Baseline and 12 weeks]

13. Changes in Serum Fasting Glucose [Baseline and 12 weeks]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men will be eligible to this study if they are diagnosed with a histologically confirmed organ-confined adenocarcinoma of the prostate (PCa) treatable by prostatectomy and have a current PSA less than 50 ng/ml

• Have not received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 5 years

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/uL

• Absolute neutrophil count >= 1,500/uL

• Platelets >= 100,000/uL

• Total bilirubin =< 1.5 times institutional upper limits of normal (ULN)

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

• Creatinine within normal institutional limits

• Willing to use adequate contraception (barrier method, abstinence, subject has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation

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

Exclusion Criteria:

• Type I or type II diabetic patients on treatment with any drug for diabetes or participants with fasting glucose >= 126 mg/dL

• History of impaired liver or kidney function

• Participants with a current history of high alcohol consumption (> 3 standard drinks/day) or binge drinking (5 or more drinks) in one session of 1-3 hours

• History of lactic acidosis or at increased risk for lactic acidosis such as patients with unstable or acute congestive heart failure who are at risk of hypoperfusion with hypoxemia

• Participants may not be receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical composition to metformin

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

• History of acute or chronic metabolic acidosis

• Concurrent use of cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin)

• Concurrent use of non-study metformin or other biguanides

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center - Tucson	Tucson	Arizona	United States	85724-5024
2	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
3	University of Southern California/Norris Cancer Center	Los Angeles	California	United States	90033

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Krouse, Arizona Cancer Center - Tucson

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01433913
• Other Study ID Numbers: NCI-2012-00243; NCI-2012-00243; CDR0000712087; UARIZ-UAZ10-16-01; 11-0211-04; UAZ10-16-01; N01CN35158; P30CA023074; NCT01528527
• First Posted: Sep 14, 2011
• Last Update Posted: Jan 10, 2018
• Last Verified: Dec 1, 2017

• Additional relevant MeSH terms: Prostatic Neoplasms; Metformin

Study Results

Participant Flow

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Period Title: Overall Study
STARTED	10	10
COMPLETED	9	10
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)	Total
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg metformin tablets until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets until the day before surgery) for 4-12 weeks.	Total of all reporting groups
Overall Participants	10	10	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 40%	6 60%	10 50%
>=65 years	6 60%	4 40%	10 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (10)	61 (6)	63 (8)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	10 100%	10 100%	20 100%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC)
Description	Data between the two study groups will be compared using a two-group t-test at a two-sided 0.05 level of significance. If the data are not normally distributed, a non-parametric rank-sum test will be utilized.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants with tissue sections available from prostatectomy

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg metformin tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	9
Median (Inter-Quartile Range) [% positively stained nuclei]	6.5	3.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

analysis limited to patients with fresh frozen prostatectomy tissue

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	7
Median (Inter-Quartile Range) [ug/g tissue]	5.71	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3
Description	Average number of positively stained cells that exhibited nuclear fragmentation from five randomly selected high-power fields (40x) in the tumor region was calculated for each participant
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants with tissue sections available from prostatectomy

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	9
Median (Inter-Quartile Range) [Number of positive cells]	0.07	0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants with tissue sections available from prostatectomy

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	9
Median (Inter-Quartile Range) [% positive cells]	37.5	13.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants with tissue sections available from prostatectomy

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	9
Median (Inter-Quartile Range) [% positive cells]	66.7	63.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data were not collected due to budgetary constraints

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	0	0

7. Secondary Outcome

Title	AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data were not collected due to budgetary constraints

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	0	0

8. Secondary Outcome

Title	Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data were not collected due to budgetary constraints

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	0	0

9. Secondary Outcome

Title	Changes in Serum PSA
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Analysis limited to participants with fasting serum samples

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	10
Median (Inter-Quartile Range) [% change]	-6.53	5.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Changes in Serum Fasting Insulin
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

analysis limited to participants with fasting serum samples

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	10
Median (Inter-Quartile Range) [% change]	-11.42	5.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Changes in Serum IGF-1/IGFBP-3
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

analysis limited to participants with fasting serum samples

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	10
Median (Inter-Quartile Range) [% change]	7.07	-2.24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Changes in Serum Testosterone
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

analysis limited to participants with fasting serum samples

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	10
Median (Inter-Quartile Range) [% change]	-16.12	2.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

13. Secondary Outcome

Title	Changes in Serum SHBG
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

analysis limited to participants with fasting serum samples

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	8	10
Median (Inter-Quartile Range) [% change]	0.48	-6.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Metformin Hydrochloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	Changes in Serum Fasting Glucose
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Data were not collected because insulin is a more relevant outcome measure than glucose

Arm/Group Title	Arm I (Metformin Hydrochloride)	Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD (one 500 mg metformin tablet daily for the first week, followed by two 500 mg metformin tablets daily for the second week, and then three 500 mg tablets daily until the day before surgery) for 4-12 weeks.	Patients receive placebo PO QD (one placebo tablet daily for the first week, followed by two placebo tablets daily for the second week, and then three placebo tablets daily until the day before surgery) for 4-12 weeks.
Measure Participants	0	0

Adverse Events

Arm/Group Title	Arm I (Metformin Hydrochloride)		Arm II (Placebo)
Arm/Group Description	Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks. metformin hydrochloride: Given PO laboratory biomarker analysis: Correlative studies		Patients receive placebo PO QD for 4-12 weeks. placebo: Given PO laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Arm I (Metformin Hydrochloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Metformin Hydrochloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		0/10 (0%)
Infections and infestations
influenza	1/10 (10%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Metformin Hydrochloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/10 (60%)		5/10 (50%)
Cardiac disorders
Chest pain	0/10 (0%)		1/10 (10%)
Gastrointestinal disorders
Constipation	1/10 (10%)		0/10 (0%)
Diarrhea	2/10 (20%)		0/10 (0%)
Bloating	0/10 (0%)		1/10 (10%)
Nausea	1/10 (10%)		1/10 (10%)
Diverticulosis	1/10 (10%)		0/10 (0%)
General disorders
Pain	1/10 (10%)		0/10 (0%)
Infections and infestations
Upper respiratory infection	1/10 (10%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/10 (10%)		0/10 (0%)
Backpain	0/10 (0%)		1/10 (10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Sessile polyps in colon and rectum	1/10 (10%)		0/10 (0%)
Nervous system disorders
Headache	1/10 (10%)		1/10 (10%)
Paresthesia	0/10 (0%)		1/10 (10%)
Psychiatric disorders
Insomnia	0/10 (0%)		1/10 (10%)
Renal and urinary disorders
Urinary retention	1/10 (10%)		1/10 (10%)
Urinary urgency	1/10 (10%)		0/10 (0%)
Increased urinating frequency	0/10 (0%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Chest congestion	0/10 (0%)		1/10 (10%)
Cough	0/10 (0%)		1/10 (10%)
Nasal congestion	0/10 (0%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/10 (10%)		0/10 (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.