A Randomized, Pragmatic, Adaptive Trial of Metformin for Glucose Intolerance or Increased Body Mass Index in Prostate Cancer Patients
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 100
- Locations
- 8
- Primary Endpoint
- Successful accrual of 100 patients to the pragmatic trial in the first four years
Study Overview
Brief Summary
Metformin is used widely in the treatment of type 2 diabetes. It has off-label indications for use in the prevention of diabetes and in hyperinsulinar obesity. In medical practices, the implementation of metformin for these off-label indications is variable, often at the level of the provider. Multiple retrospective investigations have also shown a clinical benefit in men with prostate cancer who are incidentally treated with metformin.
This pragmatic study will test the feasibility of enrolling patients who have glucose intolerance (as defined by HbA1c of 5.7-6.4%) and/or who have increased BMI (BMI greater than or equal to 25 kg/m2) to a randomized pragmatic study of metformin plus lifestyle modification information versus lifestyle modification information only. For purposes of the scope of this project and the study's feasibility, this will be implemented in a group of prostate cancer patients, who may have additional benefits from metformin.
Detailed Description
In this study, subjects with prostate cancer will be randomized to metformin plus educational material for lifestyle modification versus educational material for lifestyle modification alone and followed for up to 10 years. Population-based, retrospective studies have reported improved outcomes, including prostate cancer specific mortality, with the incidental use of metformin in prostate cancer patients. One prominent study is this area from Margel, et al was published in 2013.2 Using the administrative database from several Ontario health districts, men aged 66 with incidental diabetes and prostate cancer antigen (PCA) were studied. The study included over 3000 men and found an adjusted hazard ratio of 0.76 (95% CI, 0.64 to 0.89) for PCA-specific mortality for each additional 6 months of metformin use. There was no relationship to survival with any other diabetic medication.
In addition to the use of metformin for the prevention of metabolic complications related to obesity and the prevention of diabetes, there are several studies reporting a potential benefit in those with prostate cancer. In a Veterans Administration-based study, more than 87,000 subjects were identified with PCA in the sample.3 The subjects were analyzed in 3 cohorts: 1) no diabetic medication (DM), 2) DM without metformin use and 3) DM with metformin use. Men with DM who were treated with metformin were found to have improved OS (HR 0.82, 95% CI 0.78 - 0.86, for mortality) compared to men with DM not on metformin. Reduced cancer specific mortality was also observed in the men with DM on metformin (HR 0.70, 95% CI 0.64 -0.77) in comparison to men with DM not taking metformin (HR 0.93, 95% CI 0.85 -1.00) - the reference group were those without DM. Despite considerable interest in these findings, there is little if any prospective data on the use of metformin in this setting.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria. The patients will be screening for eligibility and offered an electronic consent via the Epic medical record and the patient portal (My Health Connection - MHC) or otherwise through Epic:
- •Provision to sign and date the consent form in MHC or otherwise via Epic.
- •Subjects must have an MHC Account to participate in the study
- •Be a male aged ≥18 years of age on day of signing the informed consent.
- •Impaired glucose tolerance and/or overweight, and appropriate to receive metformin, meeting at least one of the following in the last year (timing relative to the consent presentation not start of therapy):
- •HbA1c of 5.7 - 6.4 %
- •BMI≥25 kg/m^2
- •Have a prostate cancer diagnosis
- •Have a clinical relationship with a participating provider at a UCHealth facility.
Exclusion Criteria
- •On therapy for diabetes including any of the following alone or in combination medications (diet controlled or managed diabetes is allowed - e.g.
- •diagnosis of Diabetes, but without an active prescription for anti-glycemic medication):
- •Glimepiride
- •Pioglitazone
- •Rosiglitazone
- •Sitagliptin
- •Saxagliptin
- •Linagliptin
- •Canagliflozin
- •Dapagliflozin
- •Empagliflozin
- •Ertugliflozin
- •Liraglutide
- •Dulaglutide
- •Semaglutide
- •Lixisenatide
- •Nateglinide
- •Repaglinide
- •Tirzepatide
- •Contraindication for metformin use which include any of the following which are exclusionary (in Epic will use most recent lab values):
- •Estimated glomerular filtration rate (eGFR) of < 50 ml/minute (calculated according to the formula utilized within Epic).
- •Known Total Bilirubin ≥3 mg/dL)
- •Diagnosis of fibrosis or cirrhosis of the liver (ICD10: K74)
- •Diagnosis of alcohol related disorders (ICD10: F10)
- •Metformin allergy in Epic (ICD10: T50.995A)
- •Non-English-speaking patient until Spanish language consent form and relevant materials can be made available. Due to the novel aspect of this trial, we plan to get some experience in treating approximately the first 50 patients, make any changes needed in the study operations and then implement a Spanish consent, as feasible.
- •Taking any medication with a known class D or higher drug interaction with metformin, including:
- •Dolutegravir
- •Tafenoquine
- •The use of any carbonic anhydrase inhibitors since they are a risk factor for lactic acidosis, including:
- •Dichlorphenamide
- •Acetazolamide
- •Methazolamide
- •Dorzolamide
- •Brinzolamide
- •Dichlorphenamide
- •Any treating investigator concern, related to tolerance, safety, adherence or for any other reason
Arms & Interventions
Lifestyle Modification Only Arm
Patients randomized to this arm will receive standard lifestyle modification recommendations. This will include the general recommendation to increase exercise level mildly, after discussing with the medical provider. There is a potential low-level risk in increasing one's exercise levels.
Intervention: Lifestyle Modification (Behavioral)
Metformin and Lifestyle Modification Arm
For the metformin arm: metformin will be obtained as a standard of care medication from the patient's general pharmacy. This will be given for a clinical indication (e.g. prediabetes or overweight/obese). It will not be supplied by the study, but billed to Medicare, self pay or 3rd party payer. Lifestyle modification and prediabetes information will be provided via MHC or other electronic means on a quarterly basis.
Intervention: Lifestyle Modification (Behavioral)
Metformin and Lifestyle Modification Arm
For the metformin arm: metformin will be obtained as a standard of care medication from the patient's general pharmacy. This will be given for a clinical indication (e.g. prediabetes or overweight/obese). It will not be supplied by the study, but billed to Medicare, self pay or 3rd party payer. Lifestyle modification and prediabetes information will be provided via MHC or other electronic means on a quarterly basis.
Intervention: Metformin (Drug)
Outcomes
Primary Outcomes
Successful accrual of 100 patients to the pragmatic trial in the first four years
Time Frame: 4 years
Once there are 6 months of follow-up data on the first 100 patients, a formal analysis will be done to determine the completeness of data and the potential for a powered study. Outcome measure was amended January 2025.
Secondary Outcomes
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Body Mass Index(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Weight(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on HbA1C(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Blood Pressure(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Glucose Levels(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - BMI(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - Weight(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - HbA1C(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - blood pressure(2 years)
- Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - blood glucose levels(2 years)
- Effectiveness: 1b: To determine the effectiveness of metformin prescribed in a pragmatic trial on the development of diabetes.(2 years)
- Determine the number of additional diabetes medications initiated(2 years)
- Determine the number of new diagnoses of diabetes(2 years)
- Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on rate of major adverse cardiac events (MACE).(2 years)
- Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on rate of major adverse limb events (MALE).(2 years)
- Adherence: To determine the number and proportion of patients who adhere to the assigned treatment plan.(10 years)
- Effectiveness: Measure the effectiveness of metformin prescribed on a pragmatic trial in progression-free survival defined as doubling of PSA level or all-cause mortality.(2 years)
- Effectiveness: Measure the effectiveness of metformin prescribed on a pragmatic trial on PSA response of prostate cancer.(2 years)
- Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on radiographic progression of prostate cancer.(10 years)
- Effectiveness: To determine the effectiveness of metformin prescribed on a pragmatic trial ion overall and prostate cancer specific survival.(10 years)
- Safety: To determine the safety, assessed by Adverse Events, of providing metformin via this pragmatic approach.(2 years)
- Reach: To determine the proportion of patients approached who enroll and the characteristics and representativeness of those enrolled.(2 years)
- Implementation: To determine the accuracy of the Epic screening process to identify(2 years)
- Implementation: To determine the effectiveness of different approaches to presenting the consent to patients in MHC/Epic.(2 years)
- Implementation: To determine the time period required to identify and enroll 100 eligible patients(2 years)
- Implementation: To determine the accuracy of TriNetX in predicting the number of eligible patients identified each month.(2 years)