Clinical trial NCT05515978: Pragmatic Trial of Metformin for Glucose Intolerance or Increased BMI in Prostate Cancer Patients
Official title: A Randomized, Pragmatic, Adaptive Trial of Metformin for Glucose Intolerance or Increased Body Mass Index in Prostate Cancer Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Prostate Cancer
Keywords: Pragmatic
Prostate
Cancer
Prostate Cancer
Metformin
Lifestyle
Lifestyle changes
Lifestyle Modifications
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2022-08-25
Enrollment: 100
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In this pragmatic trial, a 2-step electronic consent approach to enroll patients in the metformin + lifestyle modification or lifestyle modification arms will be used. The initial consent will invite patients to join a cohort to study prostate cancer and it will describe the general pragmatic framework under which this protocol will take place with the opportunity for additional trial opportunities. Subsequent consents will be limited to those who consented to the initial project and are found to be eligible for a specific trial (e.g. this metformin/lifestyle intervention trial). Within the framework of this pragmatic trial and electronic self-consent, these subsequent consents will be more focused and limited to the specific involvement in the arm in which they have been randomized. This general approach will follow the trials within cohorts paradigm.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Successful accrual of 100 patients to the pragmatic trial in the first four years
timeFrame: 4 years
Secondary outcomes:
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Body Mass Index
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Weight
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on HbA1C
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Blood Pressure
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Glucose Levels
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - BMI
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - Weight
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - HbA1C
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - blood pressure
timeFrame: 2 years
measure: Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - blood glucose levels
timeFrame: 2 years
measure: Effectiveness: 1b: To determine the effectiveness of metformin prescribed in a pragmatic trial on the development of diabetes.
timeFrame: 2 years
measure: Determine the number of additional diabetes medications initiated
timeFrame: 2 years
measure: Determine the number of new diagnoses of diabetes
timeFrame: 2 years
measure: Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on rate of major adverse cardiac events (MACE).
timeFrame: 2 years
measure: Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on rate of major adverse limb events (MALE).
timeFrame: 2 years
measure: 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.
timeFrame: 2 years
measure: Effectiveness: Measure the effectiveness of metformin prescribed on a pragmatic trial on PSA response of prostate cancer.
timeFrame: 2 years
measure: Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on radiographic progression of prostate cancer.
timeFrame: 10 years
measure: Effectiveness: To determine the effectiveness of metformin prescribed on a pragmatic trial ion overall and prostate cancer specific survival.
timeFrame: 10 years
measure: Safety: To determine the safety, assessed by Adverse Events, of providing metformin via this pragmatic approach.
timeFrame: 2 years
measure: Reach: To determine the proportion of patients approached who enroll and the characteristics and representativeness of those enrolled.
timeFrame: 2 years
measure: Implementation: To determine the accuracy of the Epic screening process to identify
timeFrame: 2 years
measure: Implementation: To determine the effectiveness of different approaches to presenting the consent to patients in MHC/Epic.
timeFrame: 2 years
measure: Implementation: To determine the time period required to identify and enroll 100 eligible patients
timeFrame: 2 years
measure: Implementation: To determine the accuracy of TriNetX in predicting the number of eligible patients identified each month.
timeFrame: 2 years
measure: Adherence: To determine the number and proportion of patients who adhere to the assigned treatment plan.
timeFrame: 10 years
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Colorado Research Center
state: Colorado
city: Colorado Springs
country: United States
facility: UCHealth-Southern Colorado
state: Colorado
city: Denver
country: United States
facility: UCHealth-Metro Denver
state: Colorado
city: Fort Collins
country: United States
facility: UCHealth-Northern Colorado
state: Colorado
Study officials:
affiliation: Colorado Research Center
name: Thomas Flaig, MD
role: PRINCIPAL_INVESTIGATOR
References: