Genetic Basis for Prediction of Non-responders to Dietary Plant Sterol Intervention

Not Applicable

Terminated

• Conditions: Cardiovascular Disease; Hypercholesterolemia
• Interventions: Other: Placebo; Other: Plant sterols

• Registration Number: NCT02765516
• Lead Sponsor: University of Manitoba

Brief Summary

The objective of this study is to utilize information on associations between genetic predisposition pertaining to multiple single nucleotide polymorphisms (SNPs) and the degree of responsiveness of low-density lipoprotein cholesterol (LDL-C) lowering to plant sterols (PS). The predictive potential of SNPs associated with PS responsiveness will be evaluated using a randomized human intervention trial examining responsiveness of lowering blood LDL-C levels to PS intervention.

Detailed Description

On average plant sterol (PS) consumption of 2-3 grams a day leads to a \~10% decrease in low-density lipoprotein cholesterol (LDL-C). However, inter-individual response to PS consumption varies, with some individuals showing low or no reductions in LDL-C levels, while some even showing an increase in levels. Determining factors that predict the direction of response of LDL-C to PS would be helpful in identifying individuals who should consume PS and individuals who should seek another method of treating hypercholesterolemia. The objective of this research proposal is to test the a priori predictive potential of a combination of three single nucleotide polymorphisms (SNPs), i.e., genosets, previously associated with response to PS in a post-hoc manner. A clinical trial with a priori recruitment of participants based on genoset which will test LDL-C response to PS consumption using a randomized, double blind, placebo controlled crossover design is proposed.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2016-04-22
• Study First Submitted QC: 2016-05-04
• Study First Posted: 2016-05-06
• Study Start: 2017-07-05
• Primary Completion: 2019-12-31
• Study Completion: 2019-12-31
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-28
• Last Update Posted: 2020-06-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 43

Inclusion Criteria

• Fasting LDL-C concentration >3.0 and <4.9 mmol/L
• Fasting glucose concentration <6.1 mmol/L
• Fasting triglyceride concentration <4.52 mmol/L
• Genoset required: ; ApoE ε3/ε3 CYP7A1 rs3808607 T/T (n=20); ApoE ε3/ε3 CYP7A1 rs3808607 G/- (n=22); ApoE ε4/- CYP7A1 rs3808607 -/- (n=22)

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Exclusion Criteria

• Consuming, or have consumed in the last 3 months, medications or nutritional supplements which are known to affect lipid metabolism (such as cholestyramine, colestipol, niacin, clofibrate, gemfibrozil, probucol, HMG-CoA R inhibitors, methotrexate, high dose dietary supplements, fish oil capsules or plant sterol or stanol), or have any dietary restrictions which would prevent them from consuming the trial treatments
• BMI >40
• Must not have self-reported weight gain or loss greater than 3 kg in the past three months
• Phytosterolemic
• History of active cardiovascular disease including stroke, congestive heart failure, myocardial infarction, unstable angina pectoris, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, temporal ischemic attacks, anemia, abnormal electrolytes, proteinuria, and abnormal liver, kidney or thyroid function
• Type 1 or type 2 diabetes, a history of cancer or malignancy in the last 5 years, or any metabolic disease, gastrointestinal disorder or other clinically significant disease/disorder which could interfere with the results of the study or the safety of the participant.
• Uncontrolled hypertension having systolic blood pressure >160mm Hg or diastolic blood pressure >100mm Hg
• Smoker, tobacco/snuff/nicotine users, recreational drug users
• Consume more than 14 alcoholic beverages a week
• Participants who are pregnant or plan to become pregnant during the trial period or lactating mothers
• Participants will be excluded if they have clinically significant biochemistry defined as: LDL-C <3.0mmol/L or >4.9 mmol/L; TC > 6.2 mmol/L; fasting glucose: > 6.1 mmol/ l, fasting TG >4.52 mmol/L; AST >100 U/L; ALT >100 U/L or or any other clinically significant abnormality in hematology and/or biochemistry at the investigator's discretion
• Patients with unstable or serious illness, for example, dementia, terminal illness, recent bereavement, recent significant medical diagnosis will also be excluded

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	-
Plant sterols	Plant sterols	-

Primary Outcome Measures

Name	Time	Method
Change in fasting low-density lipoprotein cholesterol (LDL-C) levels between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period

Secondary Outcome Measures

Name	Time	Method
Change in blood sterols and sterol precursors (non-cholesterol sterols) levels between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in fasting total cholesterol (TC) levels between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in fasting high-density lipoprotein cholesterol levels between placebo and treatment endpoints	Endpoint (Days 28,29) of each treatment period
Change in body weight between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in body mass index (BMI) between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in arterial stiffness-Pulse wave velocity between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period	Pulse wave velocity will be determined using an automated oscillometric measurement device (Mobil-O-Graph, IEM, Stolberg, Germany).
Change in fractional cholesterol synthesis between placebo and treatment endpoints (in a crossover design)	Endpoint (Day 28,29) of each treatment period	A fasted blood sample will be taken on day 28 of each study period prior to deuterium oxide administration, as well as fasting samples on day 29. The change in deuterium enrichment within red blood cell (RBC) free cholesterol we be determined as an index of synthesis over days 28 and 29.
Change in fasting triglyceride (TG) levels between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in waist circumference between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in blood pressure between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in fasting glucose levels between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period
Change in arterial stiffness-augmentation index between placebo and treatment endpoints (in a crossover design)	Endpoint (Days 28,29) of each treatment period	Augmentation index will be determined using an automated oscillometric measurement device (Mobil-O-Graph, IEM, Stolberg, Germany).

Trial Locations

Locations (1)

Department of Human Nutritional sciences, University of Manitoba; 🇨🇦 Winnipeg, Manitoba, Canada