Metformin in Patients Initiating ADT as Prevention and Intervention of Metabolic Syndrome
- Conditions
- Metabolic SyndromeProstate Cancer
- Interventions
- Drug: Placebo Oral TabletDrug: Metformin
- Registration Number
- NCT03031821
- Lead Sponsor
- Canadian Urologic Oncology Group
- 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.
The investigators 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Male
- Target Recruitment
- 168
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Oral Tablet Placebo Oral Tablet 1 tablet (850mg) PO OD X 30 days, then 850mg PO BID for a total of 18 months Metformin Metformin Metformin 850 mg PO OD X 30 days, then 850mg PO BID for a total of 18 months
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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 levelsProportion 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.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.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.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 levelsProportion 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.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.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 glucoseProportion 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.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.
Trial Locations
- Locations (16)
CHU de Quebec - Universite Laval
🇨🇦Laval, Quebec, Canada
Ciusss-Chus
🇨🇦Sherbrooke, Quebec, Canada
Centre Intégré Universitaire de Santé et de Services Sociaux de la Mauricie-Centre-du-Québec / Centre hospitalier régional
🇨🇦Trois-Rivières, Quebec, Canada
Northeast Cancer Centre
🇨🇦Sudbury, Ontario, Canada
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
BC Cancer Agency - Vancouver Cancer Centre
🇨🇦Vancouver, British Columbia, Canada
Cancer Care Manitoba
🇨🇦Winnepeg, Manitoba, Canada
Horizon Health Network
🇨🇦Saint John, New Brunswick, Canada
Central Newfoundland Regional Health Centre
🇨🇦Grand Falls-Windsor, Newfoundland & Labrador, Canada
Dr. H. Bliss Murphy Cancer Centre
🇨🇦St. John's, Newfoundland & Labrador, Canada
Sunnybrook Research Institue
🇨🇦Toronto, Ontario, Canada
Princess Margaret Cancer Centre (Princess Margaret Hospital)
🇨🇦Toronto, Ontario, Canada
Centre Hospitalier de L'Universite de Montreal (CHUM)
🇨🇦Montreal, Quebec, Canada
McGill University Health Center-Cedar Cancer Center
🇨🇦Montreal, Quebec, Canada
Vancouver Prostate Centre
🇨🇦Vancouver, British Columbia, Canada