Metformin in Patients Initiating ADT as Prevention and Intervention of Metabolic Syndrome

Study Overview
=================
Brief Summary
-----------------
This is a multi-centre, double-blind, randomized phase III trial comparing metformin to placebo in patients with advanced prostate cancer starting (or have recently started) androgen deprivation therapy (ADT).

Detailed Description
-----------------
The primary objective of this study will determine if there are differences between arms with respect to the proportion of participants who meet the diagnostic criteria for metabolic syndrome after 18 months of study treatment. We will also compare arms with regards to severity of individual metabolic syndrome components following 18 months of study treatment. Other objectives are outlined below, and will include quality of life assessments, metabolic and anthropomorphic measurements at additional time points and correlative laboratory studies. It is estimated that one in seven Canadian men will be diagnosed with prostate cancer in their lifetime. In 2015, approximately 23,600 Canadian men were estimated to be diagnosed with prostate cancer and 4,000 died of this disease. Androgen deprivation therapy (ADT) is a standard first-line treatment for men with incurable prostate cancer and has long been known to improve overall survival. Although the effectiveness of ADT is well established in participants with advanced prostate cancer, it is associated with important adverse effects as outlined below. The development of metabolic syndrome in particular is clinically important as it is associated with worsened quality of life and increased all-cause morbidity and mortality. As ADT is now employed, alone or in combination with other therapies, in virtually all men with advanced prostate cancer for increasingly long periods of time (median survival of men presenting with newly diagnosed metastatic disease from recent clinical trials is at least 3 years, during which they are typically on continuous hormonal therapy), the burden of ADT toxicity among men with prostate cancer is significant and increasing. The investigators hypothesize that the addition of metformin to a program of ADT will reduce the proportion of participants with metabolic syndrome at 18 months after initiation of ADT and will reduce the severity of individual components of metabolic syndrome in men with advanced prostate cancer. To test this hypothesis, this is a randomized, double-blinded, placebo-controlled phase 3 clinical trial of metformin in patients undergoing ADT treatment.

Official Title
-----------------
A Randomized Phase 3 Trial of Metformin in Patients Initiating Androgen Deprivation Therapy as Prevention and Intervention of Metabolic Syndrome: The Prime Study

Conditions
-----------------
Prostate Cancer, Metabolic Syndrome

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Placebo Oral Tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Participants must fulfill all the following criteria to be eligible for admission to the study: Pathologically confirmed adenocarcinoma of the prostate Eligible for initiating androgen deprivation therapy with either: (Neo-)Adjuvant therapy for localized prostate cancer that is planned continuously for at least 9 months; or Metastatic disease: or Biochemical recurrence of prostate cancer as defined as EITHER: A rising PSA after prior curative intent surgical therapy (e.g., prostatectomy with or without adjuvant/ salvage radiotherapy). Since an absolute consensus for this value has not been established, if a rising PSA has been documented by at least two PSA values at least 2 weeks apart, the criteria for biochemical recurrence are deemed to have been met. Or, PSA ≥ 2ng/mL above their nadir if previously treated with definitive radiotherapy Serum testosterone > 5nmol/L (except for participants who have already started androgen deprivation therapy (within no more than 45 days of commencing study treatment)). The choice of androgen deprivation therapy is at the investigators discretion but must include at minimum the use of luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy. The addition of other hormonal agents (e.g., non-steroidal antiandrogens, abiraterone, enzalutamide, apalutamide) is allowed. The androgen deprivation therapy undertaken can be intermittent or continuous, but the treatment intent must be declared prior to randomization. Participant is able (e.g., sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration/randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the participant ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the participant ineligible. Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrolment in the trial to document their willingness to participate. Participant must be accessible for treatment and follow up. Participants registered on this trial must be treated and followed at the participating centre. Investigators must assure themselves that the participants registered on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. Protocol treatment is to begin within 7 working days of participant randomization. Exclusion Criteria Participants who fulfill any of the following criteria are not eligible for admission to the study: Prior androgen deprivation therapy within 12 months of enrolment (except for participants who have started androgen deprivation therapy within 45 days of commencing study treatment) Prior androgen deprivation therapy associated with definitive treatment is permitted, if it has been completed at least 12 months prior to enrolment (e.g., last injection or tablet taken 12 months prior to study enrolment) Participant that meet ≥ 1 of the Canadian Diabetes Association criteria for the diagnosis of diabetes within 28 days of enrolment: Fasting plasma glucose of ≥ 7mmol/L; or HbA1C ≥ 6.5%. Participant currently taking metformin (or other diabetic medications) or who have taken metformin (or other diabetic medications) within 28 days of enrolment. History of lactic acidosis or conditions that predispose to lactic acidosis: Impaired Renal Function (eGFR <45mL/ minute/ 1.73 m^2); or Liver disease, including alcoholic liver disease, as demonstrated by any of the following parameters: AST > 1.8 x the upper limit of normal ALT > 1.8 x the upper limit of normal Alkaline Phosphatase >2x the upper limit of normal Serum total bilirubin > 1.5x the upper limit of normal (except for participant with Gilbert's Disease who are eligible despite elevated serum bilirubin levels). Alcohol abuse (habitual intake of ≥ 3 alcoholic beverages per day) sufficient to cause hepatic toxicity; or Severe infection; or Congestive heart failure (defined as New York Heart Association Class III or IV functional status). Participant with a history of other invasive malignancies, except adequately treated non-melanoma skin cancer or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin 850 mg PO OD X 30 days, then 850mg PO BID for a total of 18 months | Drug: Metformin<br>* Metformin Duration: 18 months 850 mg PO OD x 30 days then 850 mg PO BID for duration<br>|
| Placebo Comparator: Placebo<br>Placebo Oral Tablet 1 tablet (850mg) PO OD X 30 days, then 850mg PO BID for a total of 18 months | Drug: Placebo Oral Tablet<br>* Placebo Oral Tablet Duration 18 months 1 tablet (850 mg) PO OD x 30 days then 1 tablet PO BID for duration<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 18 months of study treatment | A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose. The prevalence of metabolic syndrome at 18 months post randomization will be calculated and compared between treatment arms using the two-sample t-test. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 9 months of study treatment | A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose. The prevalence of metabolic syndrome at 9 months post randomization will be calculated and compared between treatment arms using the two-sample t-test. | 9 months | 
| Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 12 months of study treatment | A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose. The prevalence of metabolic syndrome at 12 months post randomization will be calculated and compared between treatment arms using the two-sample t-test. | 12 months | 
| Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 24 months of study treatment | A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose. The prevalence of metabolic syndrome at 24 months post randomization will be calculated and compared between treatment arms using the two-sample t-test. | 24 months | 
| Proportion of participants who meet the criteria of reduced high-density lipoprotein cholesterol assessed at 18 months of follow-up. | Reduced High-Density Lipoprotein Cholesterol defined as: < 1.0 mmol/L; or drug treatment for reduced HDL cholesterol* *Patient taking fibrates (Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, or Fenofibrate) or nicotinic acid can be presumed to have high TG and reduced HDL-cholesterol levels; Patients taking high dose omega-3 fatty acids can be presumed to have high TG levels | 18 months | 
| Proportion of participants who meet the criteria of elevated triglycerides assessed at 18 months of follow-up. | Elevated Triglycerides defined as: ≥1.7 mmol/L; or drug treatment for elevated triglycerides* *Patient taking fibrates (Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, or Fenofibrate) or nicotinic acid can be presumed to have high TG and reduced HDL-cholesterol levels; Patients taking high dose omega-3 fatty acids can be presumed to have high TG levels | 18 months | 
| Proportion of participants who meet the criteria of elevated blood pressure assessed at 18 months of follow-up. | Elevated Blood Pressure defined as: Systolic Blood Pressure of ≥ 130 mm of Hg; or Diastolic Blood Pressure of ≥ 85 mm of Hg; or drug treatment for elevated blood pressure Blood pressures will be taken with patients sitting for 5 minutes in a quiet environment prior to measurement and two measurements taken (with a minimum of 5 minutes between each blood pressure measurement), with the mean recorded for this study. | 18 months | 
| Proportion of participants who meet the criteria of elevated fasting blood glucose levels assessed at 18 months of follow-up. | Elevated Fasting Blood Glucose defined as: HbA1c ≥ 6.5%; or Fasting plasma glucose ≥ 7.0 mmol/L; or drug treatment for elevated blood glucose | 18 months | 
| Proportion of participants who meet the criteria of increased waist circumference assessed at 18 months of follow-up. | Increased Waist Circumference defined as: Males (population and country specific) A) Canadians ≥102cm B) Chinese ≥ 85cm C) Japanese ≥ 85 cm D) Other Asians ≥ 90 cm E) Middle Eastern & Mediterranean ≥ 94cm F) Sub-Saharan African ≥ 94 cm G) Central & South American ≥ 90cm H) Europid ≥ 94 cm Measurement of waist circumference will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation. | 18 months | 
| Health-related Quality of Life assessed at 18 months of follow-up. | Patients will undergo quality of life measurements by the EORTC QLQ-C30 core questionnaire (63) and prostate-specific module. The instruments are well validated and widely used in the population of interest. The questionnaire items are transformed for 5 functional domains, global QOL, and specific symptom scales/items relevant to the study intervention. The statistical analysis plan will use the standard CCTG QOL approach (Osoba et al., 1998), and will focus on change of mean scores from baseline over time by treatment allocation group. Depending on the amount of missing data, generalized linear equation modeling of mean scores may be required. The analysis will also consider the proportion of patients improved, stable or deteriorated at 18 months compared to baseline using a cut-point minimal clinical difference of 10 points on all scales. A sensitivity analysis will be executed using a cut-point of 7 points. | 18 months | 
| Treatment-related toxicity | Treatment related toxicity (NCI CTCAE 4.0) All men will be evaluated for toxicity from the time of their first oral dose of study medication. Toxicities will be graded using the current CTCAE version 4.0. The incidence of toxicities by arm will be summarized by type of adverse effect. A Fisher's Exact Test will be used to compare toxicities between the two arms. | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prostate Cancer, ADT, Metabolic Syndrome, Androgen Deprivation Therapy, Phase III, Phase 3, Randomized