Clinical trial NCT02765516: Genetic Basis for Prediction of Non-responders to Dietary Plant Sterol Intervention
Official title: Genetic Basis for Prediction of Non-responders to Dietary Plant Sterol Intervention
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Hypercholesterolemia
Cardiovascular Disease
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Mitacs
name: Unilever R&D
name: Nutritional Fundamentals for Health
First posted: 2016-05-06
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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.

Eligibility criteria: 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)

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

Primary outcomes:
measure: Change in fasting low-density lipoprotein cholesterol (LDL-C) levels between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
Secondary outcomes:
measure: Change in fasting total cholesterol (TC) levels between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in fasting high-density lipoprotein cholesterol levels between placebo and treatment endpoints
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in fasting triglyceride (TG) levels between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in body weight between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in body mass index (BMI) between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in waist circumference between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in blood pressure between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in arterial stiffness-Pulse wave velocity between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in arterial stiffness-augmentation index between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in fasting glucose levels between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in blood sterols and sterol precursors (non-cholesterol sterols) levels between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Days 28,29) of each treatment period
measure: Change in fractional cholesterol synthesis between placebo and treatment endpoints (in a crossover design)
timeFrame: Endpoint (Day 28,29) of each treatment period
Other outcomes:
Locations:
city: Winnipeg
country: Canada
facility: Department of Human Nutritional sciences, University of Manitoba
state: Manitoba
Study officials:
affiliation: University of Manitoba
name: James House, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Dylan Mackay, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shamloo M, Granger MJ, Trautwein EA, House JD, MacKay D. Genetic basis for prediction of non-responders to dietary plant sterol intervention (GenePredict-PS): a study protocol for a double-blind, placebo-controlled, randomized two-period crossover study. Trials. 2020 Jun 1;21(1):452. doi: 10.1186/s13063-020-04364-5.