Clinical trial NCT02481466: The Combined Portfolio Diet and Exercise Study
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cardiovascular Diseases
Hypercholesterolemia
Type 2 Diabetes
Metabolic Syndrome
Keywords: 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
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: University of Toronto
name: Laval University
name: University of Manitoba
name: University of British Columbia
First posted: 2015-06-25
Enrollment: 232
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: This is a 2 x 2 factorial design
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

1. Type 2 diabetes
2. Non-diabetic subjects post MI or post percutaneous coronary intervention (angioplasty) on statin therapy;
3. 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.
4. 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

Primary outcomes:
measure: Change from baseline of the maximum vessel wall volume of the carotid arteries by MRI at year 1 and 3
timeFrame: At months 0, 12 and 36
Secondary outcomes:
measure: Coronary atheroma in the large vessels by MRI at year 1 and 3
timeFrame: At months 0, 12 and 36
measure: Lipid rich necrotic core by MRI at year 1 and 3
timeFrame: At months 0, 12 and 36
measure: intra plaque hemorrhage by MRI at year 1 and 3
timeFrame: At months 0, 12 and 36
measure: Blood pressure and pulse rate
timeFrame: At months 0, 12 and 36
measure: Treatment difference in initiation of statin therapy
timeFrame: At month 12 and 36
measure: Composite endpoint of Myocardial Infarction, Revascularization, Cardio Vascular hospitalization, Cardiovascular mortality and stroke
timeFrame: at month 12 and 36
measure: Atrial Fibrillation and heart failure
timeFrame: at month 12 and 36
Other outcomes:
measure: Completeness of clinic attendance and data collection and provision of fasting blood samples for planned tests.
timeFrame: At months -3, -0.5, and then at months 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Serum lipids: total cholesterol, LDL-chol, HDL-chol, and Triglycerides
timeFrame: At months -3, -0.5, and then at months 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Hemoglobin A1c
timeFrame: At months -3, -0.5, 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: C-reactive protein
timeFrame: At months 0,12, 24 and 36
measure: Urinary analyses
timeFrame: At baseline (months -0.5 & 0) and end (months 33 & 36)
measure: Fasting blood Glucose
timeFrame: At months -3, -0.5, 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Blood Pressure
timeFrame: At months -3, -0.5, and then at months 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Treadmill testing
timeFrame: At month -1, and end of years 1, 2, and 3
measure: Diet history
timeFrame: At months -3, -0.5, and then at months 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Exercise history
timeFrame: At months -3, -0.5, and then at months 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Pedometer records
timeFrame: At months -3, -0.5, and then at months 0, 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Survey on quality of life
timeFrame: At months 0 and 36.
measure: Palatability (taste) of diet
timeFrame: At months 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Satiety
timeFrame: At months 3, 6, 9,12, 15, 18, 21, 24, 27, 30, 33 and 36
measure: Sustainability of diet (preparedness to continue on the diet)
timeFrame: At months 33 and 36
measure: Genetic testing for specific genes
timeFrame: Week 0 or any other time point
measure: Complete blood count (CBC)
timeFrame: Months 0, 12, 24 and 36
measure: Renal function tests
timeFrame: Months 0, 12, 24 and 36
measure: Liver function tests
timeFrame: Months 0, 12, 24 and 36
measure: Prostatic specific antigen (PSA)
timeFrame: Months 0, 12, 24 and 36
measure: Cognitive Assessment
timeFrame: months 0, 12, 24 and 36
Locations:
city: Vancouver
country: Canada
facility: Healthy Heart Lipid Clinic, St. Paul's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: Risk Factor Modification Centre, St. Michael's Hospital
state: Ontario
city: Quebec City
country: Canada
facility: Institute of Nutraceuticals and Functional Foods, Laval University
state: Quebec
Study officials:
affiliation: Risk Factor Modification Centre, St. Michael's Hospital
name: David Jenkins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Laval University
name: Benoit Lamarche, PhD
role: STUDY_DIRECTOR
affiliation: University of Manitoba
name: Peter Jones, PhD
role: STUDY_DIRECTOR
affiliation: University of British Columbia
name: Jiri Frohlich, MD
role: STUDY_DIRECTOR
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