Metformin for Rising PSA Remote Trial

Men with an isolated PSA recurrence after local therapy are an ideal population for the evaluation of novel therapies given the minimal disease burden, generally indolent natural history, and patients' preference to avoid the adverse effects of androgen deprivation therapy. Metformin has shown anti-prostate cancer activity in preclinical models and cohort studies. Metformin, a biguanide oral antihyperglycemic agent, abrogates hyperinsulinemia in individuals with and without diabetes and has shown promising anti-prostate cancer activity in preclinical models, epidemiologic studies, and retrospective cohorts. Several epidemiologic/retrospective studies have shown that metformin has a positive impact on overall survival among men with prostate cancer.

These nonclinical and clinical studies have led to calls for prospective studies of metformin in patients with prostate cancer. This is a pilot telemedicine study of metformin in patients with a rising PSA ("biochemical recurrence") after definitive local therapy for prostate cancer.

The current study is supported by the following rationale:

* A large proportion of clinical trials close prematurely due to poor accrual.
* Geographic inaccessibility is a barrier to clinical trial participation.
* Metformin is a safe and inexpensive medication that has demonstrated anti-prostate cancer activity in nonclinical and epidemiologic studies. Importantly, metformin has been shown to be safe in non-diabetic patients (e.g., patients with polycystic ovary disease) and does not cause hypoglycemia.
* Use of novel technologies may facilitate clinical trial accrual and minimize the burden of participation for patients. Ultimately, these approaches may also decrease the cost of drug development and increase the pace of progress.

In the absence of prohibitive toxicities or disease progression (defined in 4.4), patients may continue treatment for the 6-month study period. This study will include a baseline visit for study enrollment at Mount Sinai. The remainder of the visits will be telemedicine visits conducted using secure video conferencing.

• Metformin (Drug), also known as Glucophage: 850 mg PO twice daily for the remainder of the study period (the dose of metformin will be increased to the 850 mg PO twice daily dose in the absence of grade > 1 toxicities)

Primary outcomes

• Number of Participants That Completed All Telemedicine Visits [6 months]: Feasibility will be defined as completion of all telemedicine visits by > 2/3 of enrolled patients (unless treatment discontinued early for toxicity or disease progression).

Secondary outcomes

• Percentage of Participants With Stable PSA Levels at 6 Months as Defined by a <20% Change [baseline and 6 month]: Percent of patients with 6-month PSA stable 20% change at 6 months as compared to baseline
• Adherence With Metformin as Measured by Electronic Pill Adherence Monitoring [6 months]: Adherence with metformin as measured by electronic pill adherence monitoring. Patients were provided with an electronic medication dispenser/medication adherence monitoring device. The device provided audible and visual reminders to proceed with drug dosing and was equipped with a cellular modem that registers a signal to a cloud-based database each time a patient accessed his or her study medication. However, the size and shape of the metformin pills caused the device to malfunction frequently, which led patients to access the pills from the device manually; the data, therefore, could not be used for analysis.
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 1 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I would participate in a clinical trial in the future".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 2 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I would participate in a telemedicine clinical trial in the future".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 3 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "The time commitment required for participation in this trial was not overly burdensome".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 4 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "Participation in this trial did not disrupt my work or other activities".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 5 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I found it easy to use the telemonitoring tablet computer".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 6 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "This telemedicine approach eases the travel burden for participation in clinical trials for patients".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 7 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "This telemedicine approach eases the financial burden of participation in clinical trials for patients".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 8 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "My local physician was adequately informed about my participation in this trial (if applicable)".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 9 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I felt I was monitored sufficiently closely while enrolled in this trial".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 10 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I would recommend participation in a telemedicine clinical trial to other patients".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 11 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I would participate in a clinical trial where the entire trial was conducted remotely without requiring any visits to the study center".
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 12 [6 months]: Patient satisfaction with the remote clinical trial experience as measured by a patient satisfaction survey - "I felt that I was able to communicate well with the study team, even though most contact was through the tablet computer video instead of in person".
• Urgency to Have a Bowel Movement Episodes [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. Ist reported outcome - Number of episodes of urgency to have a bowel movement
• Increased Frequency of Bowel Movements [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. Ist reported outcome - Number of episodes of Increased frequency of bowel movements
• Episodes of Watery Bowel Movements [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. 2st reported outcome - Number of episodes of watery bowel movements
• Episodes of Flatulence [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. 3rd reported outcome - Number of episodes of flatulence
• Episodes of Bloating [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. 4th reported outcome - Number of episodes of bloating
• Episodes of Nausea [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. 5th reported outcome - Number of episodes of nausea
• Episodes of Vomiting [6 months]: Quality of LIfe as measured by a modified RAND 36-Item Health Survey. 6th reported outcome - Number of episodes of vomiting

Sex: Male, accepts healthy volunteers

Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate. (*in situations where pathology reports documenting prostate cancer are no longer available such as when the initial biopsy or prostatectomy was performed in the remote past, a documented history of prior prostate cancer and prostate cancer treatment in prior medical records will be sufficient)
* Biochemical disease progression after radical prostatectomy and/or radiation therapy (external-beam radiation therapy and/or brachytherapy), and no radiographic evidence of metastases.

  * Men with history of radical prostatectomy are required to have baseline PSA > 0.5 ng/mL (Prior treatment with neoadjuvant, adjuvant, or salvage radiation therapy is allowed, again, with screening PSA greater than or equal to 0.5 ng/mL required for eligibility).
  * Men treated with primary radiation therapy are required to have baseline PSA ≥ 1.0 ng/mL above their post radiation nadir for men who were treated with primary radiation therapy (external beam and/or brachytherapy). Men who had primary radiation therapy followed by salvage prostatectomy are eligible if screening PSA is greater than or equal to 0.5 ng/mL.
  * Men with previous neoadjuvant adjuvant hormone therapy are eligible if testosterone level at screening is non-castrate (≥ 50 ng/dl). Men previously treated with intermittent hormonal therapy are also eligible if level of testosterone at screening is non-castrate (≥ 50 ng/dl).
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
* Subjects must have normal organ as defined below:

  * AST(SGOT)/ALT(SGPT) less than or equal to 1.8 X institutional upper limit of normal
  * Serum bilirubin ≤ ULN (except for subjects with Gilbert's Disease who are eligible despite elevated serum bilirubin level)
  * Creatinine ≤ 1.5 mg/dL and/or creatinine clearance > 60 ml/min
* English speaking

Exclusion Criteria:

* Concurrent use of other investigational agents or other prostate cancer therapies (e.g., androgen deprivation therapy)
* Currently taking metformin, sulfonylureas, thiazolidinedione, insulin, or other antidiabetic drugs for any reason.
* Known hypersensitivity or intolerance to metformin
* Condition associated with increased risk of metformin-associated lactic acidosis:

  * New York Heart Association Class III or IV Heart Failure
  * Intake of 3 or more alcoholic beverages per day
  * Known history of lactic acidosis

Participant flow

Outcome results

• Number of Participants That Completed All Telemedicine Visits (Primary), Count of participants, Participants: Metformin 12
• Percentage of Participants With Stable PSA Levels at 6 Months as Defined by a <20% Change (Secondary), Count of participants, Participants: Metformin 7
• Adherence With Metformin as Measured by Electronic Pill Adherence Monitoring (Secondary)
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 1 (Secondary), Count of participants, Participants: Metformin 10
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 2 (Secondary), Count of participants, Participants: Metformin 9
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 3 (Secondary), Count of participants, Participants: Metformin 11
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 4 (Secondary), Count of participants, Participants: Metformin 11
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 5 (Secondary), Count of participants, Participants: Metformin 5
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 6 (Secondary), Count of participants, Participants: Metformin 10
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 7 (Secondary), Count of participants, Participants: Metformin 11
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 8 (Secondary), Count of participants, Participants: Metformin 11
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 9 (Secondary), Count of participants, Participants: Metformin 11
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 10 (Secondary), Count of participants, Participants: Metformin 11
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 11 (Secondary), Count of participants, Participants: Metformin 8
• Patient Satisfaction as Measured by a Patient Satisfaction Survey Question 12 (Secondary), Count of participants, Participants: Metformin 12
• Urgency to Have a Bowel Movement Episodes (Secondary), Number, episodes: Metformin 4
• Increased Frequency of Bowel Movements (Secondary), Number, episodes: Metformin 6
• Episodes of Watery Bowel Movements (Secondary), Number, episodes: Metformin 4
• Episodes of Flatulence (Secondary), Number, episodes: Metformin 8
• Episodes of Bloating (Secondary), Number, episodes: Metformin 8
• 2 more outcome measures not shown.

Adverse events

Serious adverse events by term

Other adverse events by term

Limitations and caveats: One limitation was the need for a single onsite enrollment visit, which likely still represents a significant geographic barrier to trial accrual.

• Results publication: Galsky MD, Shahin M, Jia R, Shaffer DR, Gimpel-Tetra K, Tsao CK, Baker C, Leiter A, Holland J, Sablinski T, Mehrazin R, Sfakianos JP, Acon P, Oh WK. Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer. JCO Clin Cancer Inform. 2017 Nov;1:1-10. doi: 10.1200/CCI.17.00044. PMID 30657386

• Matthew Galsky, MD, Principal investigator, Icahn School of Medicine at Mount Sinai