Pioglitazone and Insulin Resistance in ADT

Role of Pioglitazone Therapy in Management of Insulin Resistance Associated With Androgen Deprivation Therapy (ADT) in Patients With Prostate Cancer

This study is being done to establish the mechanisms underlying insulin resistance (reduced insulin action that can lead to high blood sugar and maybe diabetes) in patients undergoing androgen deprivation therapy (ADT) for prostate carcinoma as well as to investigate the role of pioglitazone therapy in reduction/ reversal of that insulin resistance

Study Overview

• Status: Withdrawn
• Conditions: Diabetes Mellitus, Type 2; Insulin Resistance; Prostate Cancer; Androgen Deficiency
• Intervention / Treatment: Drug: Pioglitazone 30 mg; Drug: Placebo

Detailed Description

This is a single-center, cross-sectional then prospective, randomized single-blinded study with 2 groups of subjects. One group will be men with prostate cancer in various stages of ADT and the other group will be men with prostate cancer not on ADT as control group.

Patients interested in participating who meet the inclusion/exclusion criteria and who agree to undergo blood draws and fat biopsy will be identified from the Genito-urinary oncology and urology clinics. These patients will be referred to the Diabetes and Endocrinology Research Center of WNY where they will undergo blood draws in fasting state.

On the screening day, participants will be asked to complete the informed consent, medical history and physical exam, and non-fasting blood draws (for CBC, CMP and HbA1c) prior to participating in the study. 30 ml of blood will be drawn at this visit.

Subjects who qualify and consent to take part in the study will be called in for the baseline study visit where they will undergo blood draws in fasting state. HOMA-IR method will be used to determine insulin resistance. Subcutaneous fat biopsies will be performed in all patients.

Within the ADT group, subjects will be assigned a number by a computerized simple random number generation program (Excel, Microsoft Inc.) and will be randomized (1:1) to receive either pioglitazone or placebo. The patient will be blinded to the treatment, however, the research team will not. Subjects will be given a 12 week supply of pioglitazone 30 mg or placebo pills containing cellulose that will take once a day in morning. Subjects who develop side effects (weight gain, pedal edema) on the 30 mg dose will be asked to reduce the dose to 15 mg.

Subjects will then return to the research center in 12 weeks for visit 2 where the fasting blood draws and subcutaneous fat biopsies will be performed again. The subjects will then be discharged from the study and follow with their physicians. Subject will receive a phone call after 1 and 4 weeks following start of treatment to collect any safety data. Patients will be instructed to call the research center anytime they have a question or side effects.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Husam Ghanim, PhD; Phone Number: 716-881-8924; Email: ghanim@buffalo.edu

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14221
      • Diabetes and Endocrinology Research Center of WNY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male, age ≥18 years of age.
2. Body Mass Index of > 25 kg/m2
3. Biopsy-confirmed prostate adenocarcinoma currently on androgen deprivation therapy (ADT) for minimum of 3 months for the ADT group and biopsy-confirmed prostate adenocarcinoma not on ADT for control group

5. Hemoglobin > 11 g/dL, Creatinine < 1.5x ULN and liver function tests < 2x ULN 6. Participant must be able to read, write, and understand the English language and be able to provide written consent 7. Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

1. Known clinically significant severe COPD, ischemic heart disease, congestive heart failure, and/or significant cardiac arrhythmias
2. Any patient with known diabetes (A1c > 6.4%) or an anti-diabetic drug
3. Any condition contraindicating additional blood collection beyond standard of care
4. Subjects with known allergy to lidocaine (this is used to anesthetize area for fat biopsy)
5. Subjects with known allergy to pioglitazone or other thiazolidinediones
6. Subjects with pioglitazone use in last 6 months
7. Subjects with congestive Heart Failure Class 3 or 4
8. Subjects with osteoporosis, including history of fragility fracture
9. Subjects with history of bladder cancer
10. Subjects on chronic use of androgens, or opiates in the last 6 months or with panhypopituitarism, congenital HH (hypogonadotropic hypogonadism), prolactinoma, head trauma
11. Unwilling or unable to follow protocol requirements
12. Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to undergo study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prostate cancer on ADT receiving pioglitazone; Subjects will receive a 12-week supply of pioglitazone 30 mg dose 1 tab daily	Drug: Pioglitazone 30 mg; pioglitazone 30 mg dose 1 tab daily will be given for 12 weeks; Other Names: Actos
Placebo Comparator: Prostate cancer on ADT receiving placebo; Subjects will receive a 12 week supply of placebo pills containing cellulose	Drug: Placebo; placebo pills containing cellulose 1 pill daily will be given for 12 weeks
No Intervention: Prostate cancer not on ADT; No intervention will be done in this group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HOMA-IR	Change in HOMA-IR (the main index for evaluating insulin resistance) following pioglitazone and placebo treatment.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IRS-1 serine phosphorylation	Determine levels of IRS-1 serine phosphorylation in adipose tissue and MNC as a molecular marker of inflammation induced insulin resistance at baseline and after pioglitazone and placebo treatments	12 weeks
IRβ	Changes in expression of insulin signaling gene (IRβ) in both adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
IRS-1	Changes in expression of insulin signaling gene (IRS-1) in both adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
AKT-2	Changes in expression of insulin signaling gene (AKT-2) in both adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
GLUT-4	Changes in expression of GLUT-4 in adipose tissue between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
TNF-α	Changes in expression of proinflammatory gene (TNF-α) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
IL 1β	Changes in expression of proinflammatory gene (IL 1β) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
IKK-β	Changes in expression of proinflammatory gene (IKK-β) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
SOCS-3	Changes in expression of proinflammatory gene (SOCS-3) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
PTB-1B	Changes in expression of proinflammatory gene (PTB-1B) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
JNK-1	Changes in expression of proinflammatory gene (JNK-1) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks
TLR-4	Changes in expression of proinflammatory gene (TLR-4) that interfere with insulin signaling transduction in adipose tissue and MNC between the ADT and non-ADT groups at baseline and after pioglitazone and placebo treatments in ADT group	12 weeks

Collaborators and Investigators

• Sponsor: State University of New York at Buffalo
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Paresh Dandona, MD, PhD, SUNY at Buffalo

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Actual): March 31, 2023
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: October 18, 2021
• First Submitted That Met QC Criteria: October 18, 2021
• First Posted (Actual): October 28, 2021

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 13, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Endocrine System Diseases; Diabetes Mellitus; Genital Neoplasms, Male; Prostatic Diseases; Hyperinsulinism; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Diabetes Mellitus, Type 2; Prostatic Neoplasms; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: STUDY00005310; UL1TR001412 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No