The Combined Portfolio Diet and Exercise Study

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a dietary portfolio of cholesterol-lowering foods (viscous fibres, soy protein, plant sterols and nuts) further enhanced by increased levels of monounsaturated fatty acids (MUFA) and low glycemic index foods; together with a structured exercise program reduce the progression of carotid and coronary atheromatous lesions, Low density lipoprotein-cholesterol (LDL-C), and blood pressure, while reducing the number of individuals requiring statins.

Detailed Description
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Presently in Canada, 29% of deaths are due to cardiovascular disease (CVD), costing $20.9 billion annually. The investigators have, therefore, brought together an unique network of investigators at different stages in their careers with a range of disciplines (nutrition, cardiology, diabetes, exercise physiology, imaging, physics, clinical trials, statistics, laboratory medicine, primary care, genetics, psychology, knowledge translation (KT), epidemiology), and with international recognition, experience and connections, to undertake a Canada-wide, multi-centre study which will test the ability of an effective cholesterol-lowering diet (dietary portfolio) and an exercise program, developed at Laval University, over 3 years to reduce the progression of plaque build-up in the carotid artery as assessed by Magnetic Resonance Imaging (MRI) in individuals with hypercholesterolemia and or type 2 diabetes. The dietary portfolio which has been proven in many of our studies to be an effective cholesterol-lowering diet will be enhanced to include features from other dietary strategies which the investigators have tested or developed; such as high monounsaturated fat (from Mediterranean diet) (CMAJ 2010) and low glycemic index foods (JAMA 2008). The investigators plan to recruit194 (approximately 200) men and postmenopausal women, who have measurable thickening (as assessed by ultrasound) due to plaque build up in the carotid arteries, in a 1.5 year period for this 3 year study. Ultrasound selection will be of individuals with intima-media thickness (IMT) >/=1.2mm as relevant arterial thickening to ensure a relatively low risk for the majority of the group, yet with some measurable arterial thickening. Those selected will be randomly assigned to receive advice in one of four experimental arms: 1) Portfolio Plus diet and intensive increased physical activity program, 2) Portfolio Plus diet and a copy of Health Canada Physical Activity Guidelines with advice to increase physical activity, 3) DASH-like diet and an intensive increased physical activity program and 4) DASH-like diet and a copy of Health Canada Physical Activity Guidelines with advice to increase physical activity. The results of the study will have a major influence on dietary and exercise guidelines for coronary heart disease (CH risk reduction and provide evidence for the larger international trial that will focus on hard endpoints, myocardial infarction (MI) and CHD events). It is hoped that this cohort of participants will continue on and form part of the planned 9 year hard end point (MACE) study if funded. Prior to starting treatments, participants will undergo screening ultrasound examination of both right and left carotids to enable selection of those individuals whose intima-media thickness (IMT) would be 5-30% below the cut point considered by the Mannheim Consensus as relevant arterial thickening to ensure a relatively low risk group, yet with some measurable arterial thickening. It will be emphasized at the outset that both the dietary portfolio and the DASH-like diets have been associated with benefits in terms of cholesterol reduction to provide equal encouragement for all study arms. Portfolio and DASH-like dietary advice will consist of half hour individual sessions with the dietitian at baseline, and at 3-month intervals throughout the trial except for the first month when dietary advice will be reinforced, every 2 weeks, by telephone call to the participant or participant visit to the clinic. Prior to starting each diet, instruction will be given on achieving the dietary goals. At follow-up visits, the participants' completed 7-day diet records will be discussed and the original advice reinforced. For the treatments with intensive increased physical activity the standardized physical activity/exercise component will be supervised by trained kinesiologists (exercise physiologists) for the 4 visits followed by monthly phone calls for the first year for the exercise component, when the major exercise training is provided. 7-day Exercise diaries will be collected at each visit. Using well-established procedures standardized across centers by the Quebec Heart and Lung Institute, the baseline visit will be used to provide a broad qualitative assessment of participants' lifestyle habits and preferences. Standardized physical activity questionnaires will be completed and participants will be asked to wear a pedometer for seven days prior to the intervention to quantify baseline physical activity (daily step count Cardiorespiratory fitness (CRF) is assessed using a submaximal treadmill test adapted from a progressive submaximal power output test performed on a cycle ergometer. The protocol begins with a warm-up workload of 2.5 mph with a 0% slope. The second stage is performed at a speed of 3.5 mph with a 2% slope. The third stage is adjusted in an attempt to reach 75% of the age-estimated maximal heart rate (HR). If necessary, a 4th stage is performed. Estimated VO2max is predicted by extrapolation to age-predicted maximal heart rate at a standardized submaximal treadmill stage (3.5 mph, 2% slope) and estimated maximal oxygen consumption (VO2max) are the variables considered as indicators of CRF in the present study. For treatments with routine advice to increase physical activity, Health Canada Physical Activity Guidelines for adults 18-64 years or for older adults 65 years & older will be provided. They will be seen at the start and the end of each year for their formal exercise testing and will bring with them completed physical activities questionnaires. They will receive no other physical activities instruction. Every effort will be made to obtain study blood samples and carotid imaging data from all subjects at the designated times regardless of adherence to the dietary aspects of the study protocol. All subjects will be included in the intention-to-treat analysis.

Official Title
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The First Cross-Canada Trial of the Nutrition Trialists' Network--Enhanced Dietary Portfolio and Exercise on Arterial Damage (MRI-Enhanced Dietary Portfolio Plus Exercise on Cardiovascular Risk)

Conditions
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Cardiovascular Diseases, Hypercholesterolemia, Type 2 Diabetes, Metabolic Syndrome

Intervention / Treatment
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* Behavioral: Portfolio diet and structured exercise
* Behavioral: DASH-like diet and structured exercise
* Behavioral: Portfolio diet and routine exercise
* Behavioral: DASH-like diet and routine exercise


Participation Criteria
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Eligibility Criteria
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A) Inclusion Criteria: Eligible participants will be men over 21 years post-menopausal women Having a BMI less than or equal to 40 kg/m2 and who have measurable arterial thickening (>/=1.2mm) at screening as assessed by ultrasound. They will include those who have at least 1 of the following characteristics: Type 2 diabetes Non-diabetic subjects post MI or post percutaneous coronary intervention (angioplasty) on statin therapy; Hyper-cholesterolemic and treated with statins or have been prescribed statins but are not taking it because they are either unable (intolerant) or unwilling to take statin drugs. Raised blood pressure, >140/90 (untreated) B) Exclusion Criteria: Individuals with the following conditions will be excluded: cardiovascular disease that precludes exercise e.g. recent stroke or recent myocardial infarction or cardiac condition that severely compromises normal function: mitral valve disease, atrial fibrillation and individuals with Implantable Cardioverter Defibrillator (ICD) heart failure--grades 2-4 (based on New York Heart Association classification), severe angina sufficient to prevent any form of physical activity other conditions preventing exercise. secondary causes of hypercholesterolemia e.g. hypothyroidism (unless treated and on a stable dose of L-thyroxin), clinically significant renal (that precludes dietary change) or liver disease . LDL-cholesterol <1.4mmol/L uncontrolled blood pressure major disability disorder requiring continuous medical attention (on Coumadin) and treatment, such as: chronic heart failure liver disease renal failure or cancer (except non-melanoma skin cancer--basal cell, squamous cell) chronic infections (bacterial or viral) chronic inflammatory diseases (eg. lupus, ulcerative colitis, crohn's disease, celiac disease or gluten sensitivity) other autoimmune disease major surgery <6 months prior to randomization newly diagnosed with diabetes (<3 months) alcohol consumption >3 drinks/d not suitable for MRI examination because of metal implants or claustrophobia food allergies or sensitivity to study foods or study food components (eg. tree nuts, peanuts, soy, wheat, gluten, oats, eggs, milk) already following a portfolio-like diet (and are not prepared to change) or have a structured exercise program which they cannot increase any further do not have a family doctor

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: This is a 2 x 2 factorial design
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Portfolio diet and structured exercise<br>Participants will receive advice on a therapeutic diet appropriate for hypercholesterolemia (ie <7% of energy from saturated fat, <200mg/d cholesterol) PLUS the combination of viscous fibres, soy protein, plant sterols and nuts, 5% extra monounsaturated fat, and selection of low glycemic index foods and be instructed on a standardized physical activity/exercise component supervised by kinesiologists. | Behavioral: Portfolio diet and structured exercise<br>* Diet: Foods will contribute 9 g/1000 kcal viscous fibre as β-glucan (oats, barley and oat bran breads) and psyllium (cereal), 1 g plant sterol/1000 kcal diet (in sterol margarine), 22.5 g soy protein/1000 kcal (soy burgers and other soy meat analogues, soy milks, yogurts and cheese) and 22.5 g nuts/1000 kcal and increased MUFA (as olive and canola oils, avocados, nuts etc.). The glycemic index will be reduced from 83 to 70 GI units (bread scale). Exercise: A program encouraging 150 minutes of exercise, based on the Quebec Heart and Lung Institute exercise program. A short submaximal treadmill test will be used to assess cardiorespiratory fitness. A kinesiologist will work with participants using behavioral strategies to achieve the target of 150 min/week of physical activity or exercise in 3 or 5 sessions weekly (vigorous, moderate or mild depending on goals and tolerance). The target goal will be at least 10,000 steps daily.<br>* Other names: structured exercise;|
| Active Comparator: DASH-like diet and structured exercise<br>Participants will receive advice to follow a DASH-like diet of whole grains, and low-fat dairy products with fruits and vegetables and a be instructed on the Laval exercise program-a standardized physical activity/exercise component supervised by trained kinesiologists (exercise physiologists). | Behavioral: DASH-like diet and structured exercise<br>* Diet: Participants will be encouraged to follow a diet of whole grain foods (brown rice, whole wheat breads, muffins and breakfast cereals), reduce meat consumption, choose low fat dairy foods and a control margarine. Exercise: A physical activity/exercise program encouraging 150 minutes of exercise, based on the exercise program developed at the Quebec Heart and Lung Institute. A short submaximal treadmill test will be used to assess cardiorespiratory fitness. A kinesiologist will work with participants using behavioral strategies to develop and support a plan that aims to achieve the target of 150 min/week of physical activity or exercise in 3 or 5 sessions weekly (vigorous, moderate or mild depending of goals and tolerance) in keeping with maximum achievable goals of participants. The target goal will be at least 10,000 steps daily recorded on their pedometers.<br>* Other names: Laval exercise program;|
| Experimental: Portfolio diet and routine exercise<br>Participants will receive advice that will conform to the current therapeutic diet appropriate for hypercholesterolemia (ie <7% of energy from saturated fat, <200mg/d cholesterol) PLUS the combination of viscous fibres, soy protein, plant sterols and nuts, 5% extra monounsaturated fat, and selection of low glycemic index foods and will be provided with a copy of Health Canada Physical Activity Guidelines with advice to increase physical activity. | Behavioral: Portfolio diet and routine exercise<br>* Diet: Foods on the dietary portfolio plan will contribute 9 g/1000 kcal viscous fibre as β-glucan (oats, barley and oat bran breads) and psyllium (cereal), 1 g plant sterol/1000 kcal diet (in sterol margarine), 22.5 g soy protein/1000 kcal (soy burgers and other soy meat analogues, soy milks, yogurts and cheese) and 22.5 g peanuts or equivalent of tree nuts/1000 kcal (Table 1A) and increased MUFA (as olive and canola oils, avocados, nuts etc.). The glycemic index will be reduced from 83 to 70 GI units (bread scale). Exercise: Participants in this group will receive standard of care for individuals being seen by a general practitioner. They will be advised to achieve the current recommended targets for daily physical activity and educational material published by Health Canada (Canada's Physical Activity Guide, Health Canada). They will undergo treadmill tests at the start and end of each 1 year period. They will not receive the more frequent, targeted visits with a kinesiologist.<br>* Other names: routine exercise;|
| Active Comparator: DASH-like diet and routine exercise<br>Participants will receive advice to follow a DASH-like diet of whole grains, and low-fat dairy products with fruits and vegetables and will be provided with a copy of Health Canada Physical Activity Guidelines with advice to increase physical activity. | Behavioral: DASH-like diet and routine exercise<br>* Diet: Participants will be encouraged to follow a diet of whole grain foods (brown rice, whole wheat breads, muffins and breakfast cereals), reduce meat consumption, choose low fat dairy foods and a control margarine. Exercise: Participants in this group will receive standard of care for individuals being seen by a general practitioner. They will be advised to achieve the current recommended targets for daily physical activity and educational material published by Health Canada (Canada's Physical Activity Guide, Health Canada). They will undergo treadmill tests at the start and end of each 1 year period. They will not receive the more frequent, targeted visits with a kinesiologist.<br>* Other names: routine exercise;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of the maximum vessel wall volume of the carotid arteries by MRI at year 1 and 3 | MRI imaging assessment of the carotid arteries will be done at baseline, end of year 1 and year 3. | At months 0, 12 and 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary atheroma in the large vessels by MRI at year 1 and 3 | This will be assessed by MRI imaging of the Coronary and carotid arteries | At months 0, 12 and 36 | 
| Lipid rich necrotic core by MRI at year 1 and 3 | This will be assessed by MRI imaging of the Coronary and carotid arteries | At months 0, 12 and 36 | 
| intra plaque hemorrhage by MRI at year 1 and 3 | This will be assessed by MRI imaging of the Coronary and carotid arteries | At months 0, 12 and 36 | 
| Blood pressure and pulse rate | This is a composite measure that would by done using an automatic digital BP monitor which simultaneously measures and displays systolic and diastolic pressure (mmHg) and pulse rate (bpm) readings on an output screen. | At months 0, 12 and 36 | 
| Treatment difference in initiation of statin therapy | Assessment will be based on the current Canadian Cardiovascular Society Guidelines | At month 12 and 36 | 
| Composite endpoint of Myocardial Infarction, Revascularization, Cardio Vascular hospitalization, Cardiovascular mortality and stroke | Information will be obtained from medical records of participants affected | at month 12 and 36 | 
| Atrial Fibrillation and heart failure | Information will be obtained from medical records of the participants | at month 12 and 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arterial plaque, Magnetic resonance imaging (MRI), Portfolio diet, Dietary modification, Dietary trials, hypercholesterolemia, diabetes, exercise, cardiovascular disease risk, glycemic index (GI), Carotid Ultrasound, Dietary Approaches to Stop Hypertension (DASH) diet