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

• Sponsor: Canadian Urologic Oncology Group (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03031821
• Collaborator: Prostate Cancer Canada (Other), British Columbia Cancer Agency (Other)
• Enrollment: 300
• Locations: 17
• Arms: 2
• Anticipated Duration (Months): 72.7
• Patients Per Site: 17.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer; Metabolic Syndrome	Drug: Metformin; Drug: Placebo Oral Tablet	Phase 3

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• 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
• Actual Study Start Date: Jul 12, 2018
• Anticipated Primary Completion Date: Aug 1, 2023
• Anticipated Study Completion Date: Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Metformin 850 mg PO OD X 30 days, then 850mg PO BID for a total of 18 months	Drug: Metformin; Metformin Duration: 18 months 850 mg PO OD x 30 days then 850 mg PO BID for duration
Placebo Comparator: Placebo 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; Placebo Oral Tablet Duration 18 months 1 tablet (850 mg) PO OD x 30 days then 1 tablet PO BID for duration; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 18 months of study treatment [18 months]

   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.

Secondary Outcome Measures

1. Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 9 months of study treatment [9 months]

   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.

2. Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 12 months of study treatment [12 months]

   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.

3. Proportion of participants who meet the diagnostic criteria for metabolic syndrome after 24 months of study treatment [24 months]

   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.

4. Proportion of participants who meet the criteria of reduced high-density lipoprotein cholesterol assessed at 18 months of follow-up. [18 months]

   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

5. Proportion of participants who meet the criteria of elevated triglycerides assessed at 18 months of follow-up. [18 months]

   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

6. Proportion of participants who meet the criteria of elevated blood pressure assessed at 18 months of follow-up. [18 months]

   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.

7. Proportion of participants who meet the criteria of elevated fasting blood glucose levels assessed at 18 months of follow-up. [18 months]

   Elevated Fasting Blood Glucose defined as: HbA1c ≥ 6.5%; or Fasting plasma glucose ≥ 7.0 mmol/L; or drug treatment for elevated blood glucose

8. Proportion of participants who meet the criteria of increased waist circumference assessed at 18 months of follow-up. [18 months]

   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.

9. Health-related Quality of Life assessed at 18 months of follow-up. [18 months]

   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.

10. Treatment-related toxicity [18 months]

    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.

Other Outcome Measures

1. Serum insulin levels assessed at 18 months of follow-up. [18 months]

   Fasting insulin level Test for significance: Two sample independent t-test.

2. Insulin resistance assessed at 18 months of follow-up. [18 months]

   The homoeostasis model assessment insulin resistance (HOMA-IR) (67, 68) and the Quantitative Insulin Sensitivity Check Index (QUICKI) (69), indirect measures of insulin resistance, will be the primary means of classifying insulin resistance status for this study. HOMA-IR = Fasting Insulin (μU/ml) * Fasting glucose (mmol/L) 22.5 QUICKI = 1/[log fasting insulin (mU/L) + log fasting glucose (mg/dl)]

3. Time to re-initiation of androgen deprivation therapy (in the subset of patients receiving intermittent therapy) [18 months]

   The median duration of time off-treatment (i.e. ADT) in days will be compared between study arms using the student t-test.

4. Duration of time off-treatment in days [18 months]

   The median duration of time off-treatment (i.e. ADT) in days will be compared between study arms (in the subset of patients on intermittent ADT) using the student t-test.

5. Testosterone levels assessed at 18 months of follow-up. [18 months]

   Testosterone to be measured as per standard of care (usually every 3 months during initiation of ADT and initial off-ADT period).

6. Body mass assessed at 18 months of follow-up. [18 months]

   Measurement weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

7. Abdominal girth assessed at 18 months of follow-up. [18 months]

   Measurement of abdominal girth will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

8. Mean BMI assessed at 12 months of follow-up. [12 months]

   Measurement of height and weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

9. Mean BMI assessed at 24 months of follow-up. [24 months]

   Measurement of height and weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

10. Mean BMI assessed at 36 months of follow-up. [36 months]

    Measurement of height and weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

11. Exercise behavior and sedentary behavior assessed at 12 months of follow-up. [12 months]

    Exercise/sedentary questionnaire will be administered at 12 months of follow-up. Analyses of covariance (ANCOVA) to explore the effects of the intervention on moderate exercise minutes, vigorous exercise minutes, combined moderate and vigorous exercise minutes, and sedentary behavior hours will be conducted. Chi-square analyses to examine the effects of the intervention on meeting the exercise guidelines will be done.

12. Exercise behavior and sedentary behavior assessed at 24 months of follow-up. [24 months]

    Exercise/sedentary questionnaire will be administered at 24 months of follow-up. Analyses of covariance (ANCOVA) to explore the effects of the intervention on moderate exercise minutes, vigorous exercise minutes, combined moderate and vigorous exercise minutes, and sedentary behavior hours will be conducted. Chi-square analyses to examine the effects of the intervention on meeting the exercise guidelines will be done.

13. Exercise behavior and sedentary behavior assessed at 36 months of follow-up. [36 months]

    Exercise/sedentary questionnaire will be administered at 36 months of follow-up. Analyses of covariance (ANCOVA) to explore the effects of the intervention on moderate exercise minutes, vigorous exercise minutes, combined moderate and vigorous exercise minutes, and sedentary behavior hours will be conducted. Chi-square analyses to examine the effects of the intervention on meeting the exercise guidelines will be done.

14. Cardiovascular mortality [Through study completion, an average of 3 years]

    For cardiovascular morality, the survival period will be defined as the date of randomization to the date of death due to cardiovascular disease or the date of censoring. All deaths that occur amongst study participants will be reviewed by the study's data safety and monitoring committee (who will be blinded to the treatment allocation of the patient in question). Deaths will be classified into 3 categories: 1) Prostate Cancer 2) Cardiovascular Disease 3) Other. Cardiovascular deaths will include cases in which cardiovascular disease, coronary artery disease, or stroke are identified as one of the causes of death, not just the underlying cause of death.

15. Biochemical progression-free survival [36 months]

    For bPFS, the survival period will be defined as the date of randomization to the date of biochemical progression or the date of censoring. For the purposes of this study, biochemical progression will be defined as a rise in serum PSA above their pre-randomization level (or 10ng/mL for patients who had a baseline PSA >10ng/mL) or the initiation of cancer treatment (i.e. second course of hormonal therapy, systemic therapy, etc.).

16. Castration resistant disease-free survival [36 months]

    For RFS-CR, the survival period will be defined as the date of randomization to the date of confirmed biochemical castration resistance or the date of censoring. For the purposes of this study, castration resistance will be defined as a continuous rise in serum PSA despite castrate levels of serum testosterone (achieved via total androgen blockade).

17. Distant metastasis disease-free survival [36 months]

    For RFS-DM, the survival period will be defined as the date of randomization to the date of confirmation of distant metastases or the date of censoring. Any of the following constitute a confirmation of distant metastases: imaging evidence of de novo bone metastases (X-rays, bone scan, CT, MRI, or PET scan), pathological fracture secondary to a bone metastases, imaging evidence of lymph node metastases (CT, MRI or Ultrasound Scans).

18. Prostate cancer specific survival [Through study completion, an average of 3 years]

    For PCSS, the survival period will be defined as the date of randomization to the date of death due to prostate cancer or the date of censoring. All deaths that occur amongst study participants will be reviewed by the study's data safety and monitoring committee (who will be blinded to the study arm allocation of the patient in question). Any death that is determined to be attributable to a participant's prostate cancer will be deemed a death due to prostate cancer.

19. Overall survival [Through study completion, an average of 3 years]

    For OS, the survival period will be defined as the date of randomization to the date of death due to any cause or the date of censoring. All deaths that occur amongst study participants will be reviewed by the study's data safety and monitoring committee (who will be blinded to the treatment allocation of the patient in question). Deaths will be classified into 3 categories: 1) Prostate Cancer 2) Cardiovascular Disease 3) Other.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria

Participants must fulfill all the following criteria to be eligible for admission to the study:

1. Pathologically confirmed adenocarcinoma of the prostate

2. Eligible for initiating androgen deprivation therapy with either:

3. (Neo-)Adjuvant therapy for localized prostate cancer that is planned continuously for at least 9 months; or

4. Metastatic disease: or

5. 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

1. Serum testosterone > 5nmol/L (except for participants who have already started androgen deprivation therapy (within no more than 45 days of commencing study treatment)).

2. 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.

3. The androgen deprivation therapy undertaken can be intermittent or continuous, but the treatment intent must be declared prior to randomization.

4. 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.

5. 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.

6. 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.

7. 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:

1. 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)

1. 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%.

1. Participant currently taking metformin (or other diabetic medications) or who have taken metformin (or other diabetic medications) within 28 days of enrolment.

2. 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:

1. AST > 1.8 x the upper limit of normal

2. ALT > 1.8 x the upper limit of normal

3. Alkaline Phosphatase >2x the upper limit of normal

4. 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).

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2S 3C3
2	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
3	Vancouver Prostate Centre	Vancouver	British Columbia	Canada	V5Z 1M9
4	BC Cancer Agency - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
5	Cancer Care Manitoba	Winnepeg	Manitoba	Canada	R3E 0V9
6	Horizon Health Network	Saint John	New Brunswick	Canada	E3B 4R3
7	Central Newfoundland Regional Health Centre	Grand Falls-Windsor	Newfoundland & Labrador	Canada	A2A 2E1
8	Dr. H. Bliss Murphy Cancer Centre	St. John's	Newfoundland & Labrador	Canada	A1B 8V6
9	Northeast Cancer Centre	Sudbury	Ontario	Canada	P3E 5J1
10	Sunnybrook Research Institue	Toronto	Ontario	Canada	M4N 3M5
11	Princess Margaret Cancer Centre (Princess Margaret Hospital)	Toronto	Ontario	Canada	M5G 2M9
12	CHU de Quebec - Universite Laval	Laval	Quebec	Canada
13	Centre Hospitalier de L'Universite de Montreal (CHUM)	Montreal	Quebec	Canada	H2X 0A9
14	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
15	McGill University Health Center-Cedar Cancer Center	Montreal	Quebec	Canada	H4A 3J1
16	Ciusss-Chus	Sherbrooke	Quebec	Canada	J1H 5N4
17	Centre Intégré Universitaire de Santé et de Services Sociaux de la Mauricie-Centre-du-Québec / Centre hospitalier régional	Trois-Rivières	Quebec	Canada	G8Z 3R9

Sponsors and Collaborators

• Canadian Urologic Oncology Group
• Prostate Cancer Canada
• British Columbia Cancer Agency

Investigators

• Study Chair: Bernie Eigl, MD, British Columbia Cancer Agency
• Study Chair: Nawaid Usmani, MD, University of Alberta

Study Documents (Full-Text)

None provided.

More Information

Publications

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• Responsible Party: Canadian Urologic Oncology Group
• ClinicalTrials.gov Identifier: NCT03031821
• Other Study ID Numbers: PRIME
• First Posted: Jan 26, 2017
• Last Update Posted: Jul 12, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Canadian Urologic Oncology Group: Prostate Cancer; ADT; Metabolic Syndrome; Androgen Deprivation Therapy; Phase III; Phase 3; Randomized
• Additional relevant MeSH terms: Prostatic Neoplasms; Metabolic Syndrome; Syndrome; Metformin

Study Results

No Results Posted as of Jul 12, 2022