Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04658849 |
| Other study ID # |
30509 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
December 2, 2020 |
| Est. completion date |
March 29, 2023 |
Study information
| Verified date |
May 2023 |
| Source |
St. Louis University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Prostate cancer is the most common cancer in men in the United States. Suppression of male
hormone levels by using GnRH agonist ("hormone blocking therapy") for a few years is
routinely used to treat prostate cancer. While the treatment is very effective, it decreases
muscle mass and increases fat mass. This results in a decrease in insulin action (also called
insulin resistance) and increases the likelihood of diabetes. It may also contribute to risk
of developing heart disease. The investigators propose to conduct a trial that will:-
1. study the mechanisms through which GnRH agonists cause insulin resistance.
2. Evaluate a treatment that can decrease insulin resistance. This is a randomized, placebo
controlled, double-blind trial. Forty-four men with prostate cancer will be recruited in
the trial before starting GnRH agonist therapy. Participants will undergo metabolic
studies to evaluate insulin action (called insulin clamp), abdominal fat tissue biopsy
to study insulin action at the cellular level and blood draws. The study volunteers will
then be given either a placebo tablet or pioglitazone tablet to take once a day for the
next six months. The metabolic tests, blood test and fat tissue biopsy will be obtained
again at the end of the study.
Description:
STUDY PLAN The Study will be conducted at Saint Louis University. The investigators plan to
conduct a prospective, randomized, double-blind, placebo-controlled trial in 44 men with
nonmetastatic prostate cancer who will receive ADT with long acting GnRH agonist. Patients
will be recruited from clinical practice of division of Urology. The patients that are
planning to undergo ADT as part of standard of care treatment for their prostate cancer will
be offered a choice of enrolling in the study prior to initiating ADT.
Study subjects will undergo EHC, subcutaneous fat biopsy and have a blood sample drawn prior
to starting ADT. The subjects will then be randomized to 30 mg pioglitazone or placebo tablet
daily for 6 months. Blood samples will be drawn 2 and 4 months following the initiation of
the study drug. The final study visit will be at 6 months. Subjects will undergo EHC, fat
biopsy and blood sampling and will be discharged from the study. Study visits will be
conducted at clinical research center of division of Endocrinology at Salus Center.
Screening:
All subjects will complete the following procedures prior to participating in the study:-
1. Medical History. Subjects who are on insulin or sulfonylureas for diabetes will be
advised that pioglitazone use may lead to low blood sugars. Subjects with congestive
heart failure will be advised of the possibility that their edema or shortness of breath
may worsen.
2. Physical Exam
3. Informed consent
4. Lab test: CBC and comprehensive metabolic panel (CMP) if not available in medical
records from last 3 months
Subjects who qualify and consent to take part in the study will be assigned a number by a
computerized random number generation program and will be randomized (1:1) to receive either
pioglitazone or placebo. An unblinded pharmacist will prepare the study product. Study
investigators, staff and the study participants will be blinded.
Baseline study visit: This visit will happen prior to starting ADT. The participants will
come fasting and have blood drawn to measure CBC, comprehensive metabolic panel (CMP), total
and free testosterone, SHBG and LH. MNC and serum will be stored for the research laboratory.
Subcutaneous fat biopsy will be performed. Following the biopsy, EHC will be started
(procedures described below). Subjects will be given an 8 week supply of pioglitazone 30 mg
or placebo pills containing cellulose. For patient taking gemfibrozil, the dose will be 15 mg
daily. Subjects will start the study drug one week after initiating the ADT. The subjects
will take the study drug once a day in the morning. Subjects who take insulin or
sulfonylureas will be asked to contact their doctor and report to the study team if
hypoglycemia is experienced. The study physician may change the diabetes therapy if
warranted. A letter will be sent to providers (who manage patient's diabetes) of all patients
notifying them of possible changes in patient's diabetes regimen. All subjects with heart
failure will be advised to report shortness of breath or worsening of edema to their doctors
and to the study team.
Weeks 8 and 16 study visits: The participants will come fasting and have blood drawn for
research laboratory. Participants will be given supply of study drug for another 8 weeks.
Participants will be seen by a study physician for physical exam. Diabetic patients using
insulin or sulfonylureas will discuss their blood sugars with the study physician. The study
physician may choose to decrease the dose or stop insulin or sulfonylureas to avoid
hypoglycemia. If therapy is changed, a letter will be sent to patient's diabetes provider.
Week 24 study visit (end of study): The participants will come fasting and have blood drawn
to measure CBC, CMP, total and free testosterone, SHBG. Blood will be drawn. MNC and serum
will be stored for the research laboratory. Subcutaneous fat biopsy and EHC will be
performed. The subjects will then be discharged from the study and follow with their
physicians. Diabetic patients will be told of the possibility that their blood sugars may
increase.
PROCEDURES Measurement of whole body glucose uptake by hyperinsulinemic euglycemic clamp:
Subjects will come to the clinical research center in the morning after an overnight 10 hour
fast. Patients with blood sugar >180 mg/dl will be re-scheduled. Diabetes medications will be
held on the morning of EHC. Long acting insulin (if being taken) will be held the night
before the clamp. Insulin clamp will be started with a priming dose of short acting human
insulin given over 10 minutes and then an infusion at the rate of 80mU/m2/min. 20% glucose
infusion will be started at 5 minutes and glucose infusion rate will be titrated to maintain
blood glucose concentration at 90 mg/dl. Twenty mEq of KCL will be added to one liter of 20%
glucose. Insulin will be infused for three hours. Blood sample will be collected to measure
insulin concentrations at 0, 60, 120, 150 and 180 minutes. Insulin sensitivity will be
calculated from the glucose infusion rates during the last 30 min of the clamp (steady state)
divided by the steady-state plasma insulin concentration divided by body weight.
Fat aspiration procedure: Subcutaneous fat tissue aspiration will be performed on abdomen at
a 10 cm distance from umbilicus. The skin will first be prepared and a sterile drape will be
placed around the appropriate area. Under local anesthesia, 500mg-3g of fat tissue will be
obtained. The adipose tissue will be centrifuged to remove blood and fluid contaminants. The
upper adipose tissue will be collected into a separate sterile tube, washed twice with cold
sterile Phosphate Buffered Saline and centrifuged to remove the saline. Total RNA, nuclear
extracts and total cell lysates will be prepared from the adipose tissue.
Clinical laboratory assays: Total and free testosterone concentrations will be measured by
liquid chromatography tandem mass spectrometry and equilibrium dialysis (12). SHBG, LH, CBC,
CMP will be measured by standard assays. All measurements will be carried out by Quest
diagnostics.
Mononuclear cells (MNC) isolation: Blood samples will be collected in Na-EDTA and carefully
layered on Lympholyte medium (Cedarlane Laboratories, Hornby, ON). Samples will be
centrifuged till two bands separate out at the top of the RBC pellet. The MNC band will be
harvested and washed twice with Hank's balanced salt solution. This method provides yields
greater than 95% MNC preparation.
Quantification of mRNA Expression by RT-PCR: Expression of inflammatory mediators involved in
insulin resistance and those that mediate insulin signaling will be tested by RT-PCR in mRNA
isolated from MNC and adipose tissue. Total RNA will be isolated from MNC and adipose tissue
using commercially available RNAqueous®-4PCR Kit and adipose tissue RNA Isolation kit
(Ambion, Austin, TX). Real Time RT-PCR will be performed using Stratagene Mx3000P QPCR System
(La Jolla, CA), Sybergreen master mix(Qiagen, CA) and gene specific primers for IKK-β,
SOCS-3, PTEN, PTP-IB, JNK-1, TLR-4, IL-1β, IR, IRS-1, AKT-2, GLUT-4 (Life Technologies, MD).
All values will be normalized to the expression of a group of housekeeping genes including
actin, ubiquitin C and cyclophilin A. The normalization factor used is calculated by GeneNorm
software and is based on the values of all housekeeping genes used.
Western blotting: MNC and adipose tissue total cell lysates will be prepared. Electrophoresis
and immunoblotting will be carried as described before (13). Polyclonal antibodies against
IR, AKT-2, SOCS-3, IKK-β and actin will be used and all values will be corrected for loading
to actin.
Plasma measurements: ELISA will be used to measure plasma concentrations of insulin,
C-reactive protein, adiponectin, TNF-α and IL-1β. FFA concentrations will be measured by a
colorimetric assay. The research laboratory measurements will be conducted in the Endocrine
laboratory at Doisy Hall.
Data Analysis: The focus of the proposed research is to evaluate the efficacy of pioglitazone
treatment on insulin sensitivity men receiving ADT. Transformations of the data in order to
meet statistical assumptions may be considered. The results will be computed as mean ±
standard deviation. The primary endpoint of the study is to detect a difference in insulin
sensitivity as measured by whole body glucose uptake during EHC after treatment with
pioglitazone as compared to placebo. There are no prior studies analyzing the effect of
pioglitazone in men undergoing ADT. However, studies of pioglitazone in patients with type 2
diabetes have shown an increase in insulin sensitivity of ~30% (14-16). Change in insulin
sensitivity following pioglitazone or placebo for 24 weeks will be compared among the groups
by unpaired t-test. Estimating a difference in insulin sensitivity of 30%, a sample size of
22 patients per treatment group (assuming a drop-out rate of 20%) should provide adequate
power (Beta = 0.8) to detect a significant difference (alpha = 0.05), provided the standard
deviation of the residuals is not greater than the mean difference. Thus 44 men will be
recruited in the study.
Secondary End Points: The secondary endpoints for the study will be comparison of the
relative change from baseline in HOMA-IR, insulin signaling and inflammatory mediators after
pioglitazone or placebo.
