Genetic Basis for Prediction of Non-responders to Dietary Plant Sterol Intervention (GenePredict-PS)

• ClinicalTrials.gov Identifier: NCT02765516
• Recruitment Status: Terminated
• First Posted: May 6, 2016
• Last Update Posted: June 1, 2020
• Sponsor: University of Manitoba
• Collaborators: Mitacs; Unilever R&D; Nutritional Fundamentals for Health
• Information provided by (Responsible Party): Dr. J. House, University of Manitoba

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia; Cardiovascular Disease	Other: Plant sterols; Other: Placebo	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Genetic Basis for Prediction of Non-responders to Dietary Plant Sterol Intervention
• Actual Study Start Date: July 5, 2017
• Actual Primary Completion Date: December 31, 2019
• Actual Study Completion Date: December 31, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Plant sterols	Other: Plant sterols; 2.0g/day of plant sterols incorporated into margarine to be consumed for 28 days
Placebo Comparator: Placebo	Other: Placebo; Identical margarine without additional plant sterols to be consumed for 28 days

Outcome Measures

Primary Outcome Measures :

1. Change in fasting low-density lipoprotein cholesterol (LDL-C) levels between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]

Secondary Outcome Measures :

1. Change in fasting total cholesterol (TC) levels between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
2. Change in fasting high-density lipoprotein cholesterol levels between placebo and treatment endpoints [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
3. Change in fasting triglyceride (TG) levels between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
4. Change in body weight between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
5. Change in body mass index (BMI) between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
6. Change in waist circumference between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
7. Change in blood pressure between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
8. Change in arterial stiffness-Pulse wave velocity between placebo and treatment endpoints (in a crossover design) [ Time Frame: 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).
9. Change in arterial stiffness-augmentation index between placebo and treatment endpoints (in a crossover design) [ Time Frame: 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).
10. Change in fasting glucose levels between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
11. Change in blood sterols and sterol precursors (non-cholesterol sterols) levels between placebo and treatment endpoints (in a crossover design) [ Time Frame: Endpoint (Days 28,29) of each treatment period ]
12. Change in fractional cholesterol synthesis between placebo and treatment endpoints (in a crossover design) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

Canada, Manitoba

Department of Human Nutritional sciences, University of Manitoba

Winnipeg, Manitoba, Canada, R3T2N2

Sponsors and Collaborators

University of Manitoba

Mitacs

Unilever R&D

Nutritional Fundamentals for Health

Investigators

• Principal Investigator: James House, PhD; University of Manitoba
• Principal Investigator: Dylan Mackay, PhD; University of Manitoba

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Dr. J. House, Head/Professor, University of Manitoba
• ClinicalTrials.gov Identifier: NCT02765516
• Other Study ID Numbers: MITACS Converge MC00009
• First Posted: May 6, 2016
• Last Update Posted: June 1, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cardiovascular Diseases; Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases