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

Clinicaltrials.gov ID: NCT05515978
db-list-check Status RECRUITING
b-loader Phase EARLY_PHASE1
b-people Age ≥ 18 Years
b-bullseye-arrow Enrollments 200

Conditions

Prostate Cancer

Drugs

Metformin

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.

Locations

4 locations Found with status Recruiting

Status

  • RECRUITING

Contact Person

Principal Investigator

  • Thomas Flaig, MD

Status

  • RECRUITING

Contact Person

Principal Investigator

  • Thomas Flaig, MD

Status

  • RECRUITING

Contact Person

Principal Investigator

  • Thomas Flaig, MD

Status

  • RECRUITING

Contact Person

Principal Investigator

  • Thomas Flaig, MD

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

Study Plan

Metformin and Lifestyle Modification Arm

ACTIVE_COMPARATOR

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.

  • DRUG:

    Metformin

    Description:

    Metformin is a medication used to treat type 2 diabetes, gestational diabetes, and prediabetes. In this study, patients on the Metformin arm will be started on 850 mg daily for 2 weeks, then escalated to a final dose of 850 mg twice daily, which is lower than the maximum recommended dose of 2550 mg total daily.
  • BEHAVIORAL:

    Lifestyle Modification

    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.nnHere are some examples of the educational material from the American Diabetes Association website, and topics will be rotated on quarterly basis:nnHealthy eating: https://www.diabetes.org/nutrition/healthy-food-choices-made-easy Prediabetes: https://www.diabetes.org/diabetes-risk/prediabetes Fitness: https://www.diabetes.org/fitness/get-and-stay-fit Weight loss: https://www.diabetes.org/fitness/weight-loss

Lifestyle Modification Only Arm

PLACEBO_COMPARATOR

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.

  • BEHAVIORAL:

    Lifestyle Modification

    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.nnHere are some examples of the educational material from the American Diabetes Association website, and topics will be rotated on quarterly basis:nnHealthy eating: https://www.diabetes.org/nutrition/healthy-food-choices-made-easy Prediabetes: https://www.diabetes.org/diabetes-risk/prediabetes Fitness: https://www.diabetes.org/fitness/get-and-stay-fit Weight loss: https://www.diabetes.org/fitness/weight-loss

Outcome Measures

Primary Outcome Measures

Successful accrual of 200 patients to the pragmatic trial in the first two years

Time Frame: Two years

Secondary Outcome Measures

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Body Mass Index

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Weight

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on HbA1C

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Blood Pressure

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on Glucose Levels

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - BMI

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - Weight

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - HbA1C

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - blood pressure

Time Frame: 2 years

Effectiveness: 1a: To determine the effectiveness of metformin prescribed in a pragmatic trial on key physiologic parameters - blood glucose levels

Time Frame: 2 years

Effectiveness: 1b: To determine the effectiveness of metformin prescribed in a pragmatic trial on the development of diabetes.

Time Frame: 2 years

Determine the number of additional diabetes medications initiated

Time Frame: 2 years

Determine the number of new diagnoses of diabetes

Time Frame: 2 years

Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on rate of major adverse cardiac events (MACE).

Time Frame: 2 years

Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on rate of major adverse limb events (MALE).

Time Frame: 2 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.

Time Frame: 2 years

Effectiveness: Measure the effectiveness of metformin prescribed on a pragmatic trial on PSA response of prostate cancer.

Time Frame: 2 years

Effectiveness: Measure the effectiveness of metformin prescribed in a pragmatic trial on radiographic progression of prostate cancer.

Time Frame: 10 years

Effectiveness: To determine the effectiveness of metformin prescribed on a pragmatic trial ion overall and prostate cancer specific survival.

Time Frame: 10 years

Safety: To determine the safety, assessed by Adverse Events, of providing metformin via this pragmatic approach.

Time Frame: 2 years

Reach: To determine the proportion of patients approached who enroll and the characteristics and representativeness of those enrolled.

Time Frame: 2 years

Implementation: To determine the accuracy of the Epic screening process to identify

Time Frame: 2 years

Implementation: To determine the effectiveness of different approaches to presenting the consent to patients in MHC/Epic.

Time Frame: 2 years

Implementation: To determine the time period required to identify and enroll 200 eligible patients

Time Frame: 2 years

Implementation: To determine the accuracy of TriNetX in predicting the number of eligible patients identified each month.

Time Frame: 2 years

Adherence: To determine the number and proportion of patients who adhere to the assigned treatment plan.

Time Frame: 10 years

Timeline

  • Last Updated
    September 19, 2024
  • Start Date
    August 25, 2022
  • Today
    February 5, 2025
  • Completion Date ( Estimated )
    November 6, 2036

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