Prevention of Metabolic Syndrome and Increased Weight Using Metformin Concurrent to Androgen Deprivation Therapy and Radiotherapy for Locally Advanced Adenocarcinoma of the Prostate (PREMIUM)

In current clinical practice, an acceptable standard treatment for locally advanced prostate cancer is radiation therapy in combination with hormone therapy (called Treatment B or Group B in this study). However, despite our best treatments, there is a risk that the prostate cancer may eventually return. As well, the hormonal therapy that is given to treat the prostate cancer is known to cause some harmful effects, with some patients using the hormones gaining weight, developing diabetes, having increased cholesterol levels, having increased blood pressure, and/or heart problems.

This study is looking at whether Metformin, a drug that is commonly used to treat diabetes, can prevent patients from developing some of the harmful effects of the hormonal therapy. In treating diabetes, Metformin is known to decrease patients' sugar levels and also prevents patients from gaining weight, decreases their cholesterol levels, decreases the number of heart problems and allows patients to live longer. As a result, the researchers in this study are hopeful that Metformin will also be beneficial for men with prostate cancer on hormonal therapy by preventing them from developing these problems.

Study Overview

• Status: Terminated
• Conditions: Prostatic Neoplasm
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

This study will examine the role of Metformin as a means to prevent increases in weight as well as the prevalence and severity of metabolic syndrome, with their associated morbidity, amongst men with locally advanced, biopsy confirmed adenocarcinoma of the prostate (PCa) that are planned to receive curative intent therapy with androgen deprivation therapy (ADT) and external beam radiotherapy (EBRT) to the prostate.

Males of any age with biopsy confirmed high tier intermediate risk PCa (Gleason score 7 and PSA 10-20) or high risk PCa (any T3; and/or Gleason Score ≥ 8.0; and/or PSA ≥ 20 ng/mL) ECOG 0 to 1, non-diabetic with no evidence of metastatic PCa will be randomized to either:

Group A: Metformin 500mg PO TID x 30-36 months total, with neoadjuvant and adjuvant ADT x18-36 months and EBRT of 46 Gy/23# to pelvic lymph nodes (optional); plus prostate boost to 78 Gy/39# or brachytherapy boost (110-115 Gy) or hypofractionated equivalent

OR

Group B: Identical placebo TID x 20-36 months total, with neoadjuvant and adjuvant ADT x18-36 months and EBRT of 46 Gy/23# to pelvic lymph nodes (optional); plus prostate boost to 78 Gy/39# or brachytherapy boost (110-115 Gy) or hypofractionated equivalent

A planned sample size of 104 patients will provide 97% power for a 2-tailed α of 0.05 to detect 4 kg difference in weight at 12 months of follow-up.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Manitoba
    • Brandon, Manitoba, Canada, R7A2B3
      • Prairie Mountain Health - Western Manitoba Cancer Centre
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Males ≥ 18 years of age

2. Pathologically confirmed, adenocarcinoma of the prostate with either high-tier intermediate or high risk prostate cancer:

   a. High-tier intermediate risk prostate cancer: i. Gleason score = 7 and PSA 10 - 20 ng/mL b. High risk prostate cancer: i. any T3; or ii. Gleason Score ≥ 8.0; or iii. PSA ≥ 20 ng/mL.

3. Normoglycemic or Impaired Fasting Glucose45 defined as:

   1. Fasting Plasma Glucose of ≤ 6.9; or
   2. HbA1c of <6.5%
4. Deemed fit to undergo curative intent external beam radiation therapy with concurrent androgen deprivation therapy by their attending radiation oncologist.
5. Accessible for follow-up clinical and laboratory assessments.

Exclusion Criteria:

1. Patients with evidence (either by imaging or pathology) of distant metastatic spread of their disease.

   a. Patients with pelvic lymph nodes (i.e. N1 disease) are NOT considered to have distant metastases and can be included in the trial, if meeting the other study criteria.

2. Patients that meet ≥1 of the Canadian Diabetes Association criteria45 for the diagnosis of diabetes:

   1. Fasting Plasma Glucose of ≥ 7.0 mmol/L; or
   2. HbA1C ≥ 6.5%; or
   3. Plasma Glucose level of ≥ 11.1 mmol/L 2 hours following a 75g oral glucose load, if known, within past 28 days; or
   4. Random Plasma Glucose level of ≥ 11.1 mmol/L, if known, within past 28 days
3. Patient who currently take metformin or those who have taken metformin within the past 12 months.

4. History of lactic acidosis or conditions that predispose to lactic acidosis including32:

   a. Impaired Renal Function (eGFR < 30); or b. Liver disease, including alcoholic liver disease, as demonstrated by any of the following parameters: i. AST >1.8 x the upper limit of normal ii. ALT > 1.8 x the upper limit of normal iii. Alkaline Phosphatase > 2x the upper limit of normal iv. Serum total bilirubin ≥ upper limit of normal c. Alcohol abuse (habitual intake of ≥3 alcoholic beverages per day) sufficient to cause hepatic toxicity d. Severe infection

5. Patients with prior bilateral orchiectomy.
6. Patients with prior prostatectomy
7. Patients who are unable to provide informed consent
8. Prior history of malignancy (with exception of adequately treated non-melanomatous skin cancer or other solid tumors treated curatively with no evidence of disease for ≥ 5 years).

9. Patients on hormonal therapy for more than 3 months prior to registration in the trial.

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Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin 500 mg PO TID x 30-36 months	Drug: Metformin; Metformin 500 mg PO TID x 30-36 months; Other Names: Glucophage; Glucophage XR; Glumetza; Fortamet; Riomet
Placebo Comparator: Placebo; Identical placebo TID x 30-36 months	Drug: Placebo; Identical placebo TID x 30-36 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean body weight at 12 months of follow-up	12 months of follow-up

Secondary Outcome Measures

Outcome Measure	Time Frame
Prevalence and incidence of Metabolic Syndrome	At 6, 12, 24 and 36 months follow-up

Collaborators and Investigators

• Sponsor: AHS Cancer Control Alberta
• Investigators: Principal Investigator: Nawaid Usmani, MD, Cross Cancer Institute

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): November 1, 2020
• Study Completion (Actual): November 1, 2020

Study Registration Dates

• First Submitted: November 22, 2013
• First Submitted That Met QC Criteria: November 22, 2013
• First Posted (Estimated): November 27, 2013

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: metformin; metabolic syndrome; weight gain
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Body Weight; Prostatic Diseases; Insulin Resistance; Hyperinsulinism; Body Weight Changes; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Metabolic Syndrome; Adenocarcinoma; Weight Gain; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: CCI-Usmani-01

Plan for Individual participant data (IPD)

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