Pragmatic Trial of Metformin for Glucose Intolerance or Increased BMI in Prostate Cancer Patients (PragMet)

University of Colorado Denver (CU Denver)

Status and phase: Enrolling; Early Phase 1

Conditions: Prostate Cancer

Treatments: Drug: Metformin; Behavioral: Lifestyle Modification

Study type: Interventional

Funder types: Other

Identifiers

NCT05515978

19-1536

NCI-2021-05911 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 100 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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:

1. Provision to sign and date the consent form in MHC or otherwise via Epic.

2. Subjects must have an MHC Account to participate in the study

3. Be a male aged ≥18 years of age on day of signing the informed consent.

4. 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

5. Have a prostate cancer diagnosis

6. Have a clinical relationship with a participating provider at a UCHealth facility.

Exclusion criteria

1. 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):

   1. Metformin
   2. Insulin
   3. Glipizide
   4. Glyburide
   5. Glimepiride
   6. Pioglitazone
   7. Rosiglitazone
   8. Sitagliptin
   9. Saxagliptin
   10. Linagliptin
   11. Alogliptin
   12. Canagliflozin
   13. Dapagliflozin
   14. Empagliflozin
   15. Ertugliflozin
   16. Liraglutide
   17. Dulaglutide
   18. Semaglutide
   19. Exenatide
   20. Lixisenatide
   21. Nateglinide
   22. Repaglinide
   23. Tirzepatide

2. Contraindication for metformin use which include any of the following which are exclusionary (in Epic will use most recent lab values):

   1. Estimated glomerular filtration rate (eGFR) of < 50 ml/minute (calculated according to the formula utilized within Epic).
   2. Known Total Bilirubin ≥3 mg/dL)
   3. Diagnosis of fibrosis or cirrhosis of the liver (ICD10: K74)
   4. Diagnosis of alcohol related disorders (ICD10: F10)
   5. Metformin allergy in Epic (ICD10: T50.995A)

3. 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.

4. Taking any medication with a known class D or higher drug interaction with metformin, including:

   1. Cimetidine
   2. Dolutegravir
   3. Patiromer
   4. Ranolazine
   5. Tafenoquine

5. The use of any carbonic anhydrase inhibitors since they are a risk factor for lactic acidosis, including:

   1. Topiramate
   2. Dichlorphenamide
   3. Acetazolamide
   4. Methazolamide
   5. Dorzolamide
   6. Brinzolamide
   7. Dichlorphenamide
   8. Sultiame
   9. Zonisamide
   10. Indisulam

6. Any treating investigator concern, related to tolerance, safety, adherence or for any other reason

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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100 participants in 2 patient groups, including a placebo group

Metformin and Lifestyle Modification Arm

Active Comparator group

Description:

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.

Treatment:

Behavioral: Lifestyle Modification

Drug: Metformin

Lifestyle Modification Only Arm

Placebo Comparator group

Description:

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.

Treatment:

Behavioral: Lifestyle Modification