Nattokinase Atherothrombotic Prevention Study

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

265 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-04-30

Study Completion Date

2019-07-31

Brief Summary

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The potential for nattokinase to "thin" blood and to reduce blood clotting by positive antithrombotic and fibrinolytic effects presents a unique opportunity to safely study such effects on cardiovascular disease and cognition. Unfortunately, such studies of antithrombotic and fibrinolytic pathways of prevention have been limited due to lack of safe compounds and the adverse reactions associated with current agents such as Coumadin. Nattokinase, an over-the-counter supplement used for cardiovascular health, is the most active functional constituent of natto, a fermented soy product. Natto has been consumed primarily by the Japanese for over 1000 years, a population with one of the lowest risks for cardiovascular disease and dementia. Cardiovascular disease and dementia remain the most challenging age-related health risks of the 21st century for Americans necessitating development of further effective preemptive strategies. Whether reducing the propensity for thrombus formation and/or increasing fibrinolytic activity can prevent the progression of atherosclerosis and cognitive decline has not yet been determined.

Using nattokinase under primary prevention conditions, the investigators propose to conduct a randomized, double-blinded, placebo-controlled trial to determine whether decreasing atherothrombotic risk can reduce the progression of subclinical atherosclerosis and cognitive decline. The investigators propose to randomize 240 healthy non-demented women and men to nattokinase supplementation or to placebo for three years. The primary trial endpoints will be measurement of carotid arterial wall thickness and arterial stiffness, early changes of atherosclerosis that can be measured safely by non-invasive imaging techniques. The secondary trial endpoint will be ascertained through change in cognition measured by a neuropsychological battery. In addition, biochemical blood measurements and in vitro studies will be conducted to compare the effects of nattokinase relative to placebo on blood coagulation and thrombus break-down capabilities, blood flow properties, inflammation and inflammatory activation of endothelial cells that line blood vessels.

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Detailed Description

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Objectives and Hypotheses: The goal of the proposed study is to determine under randomized controlled trial (RCT) conditions whether nattokinase supplementation reduces subclinical atherosclerosis progression and cognitive decline in healthy women and men. The investigators' hypotheses are: 1) Compared to placebo, nattokinase supplementation will show less subclinical atherosclerosis progression and cognitive decline in healthy women and men; 2) The reduction in subclinical atherosclerosis progression and cognitive decline with nattokinase supplementation will be correlated; and, 3) The reduction in progression of subclinical atherosclerosis and cognitive decline with nattokinase supplementation will be mediated through hemostatic, fibrinolytic, and hemorheological factors as well as attenuation of inflammation, monocyte activation, vascular endothelium injury, and activation of vascular endothelium by circulating monocytes.

Specific Aims: To conduct a RCT to determine the effect of nattokinase supplementation on the progression of subclinical atherosclerosis (primary trial end point) and cognitive decline (secondary trial end point). Healthy non-demented women and men \>55 years old without pre-existing symptomatic CVD and diabetes mellitus will be randomized over a 2-year period to oral nattokinase (2,000 fibrinolysis units) daily versus placebo in this double-blind, placebo-controlled trial; randomized treatment will be 3-years. The following 5 major specific aims will be completed:

To determine the effect of nattokinase supplementation on progression of subclinical carotid artery atherosclerosis determined as the rate of change of the common carotid artery intima-media thickness (CIMT) and arterial stiffness in computer image processed B-mode ultrasonograms.

To determine the effect of nattokinase supplementation on cognitive decline determined with a neuropsychological battery designed to evaluate 7 cognitive domains including: attention, concentration, working memory, executive function; visuospatial/visuoconstructive skills; naming/semantic memory; and verbal and nonverbal episodic memory.

To determine the effect of nattokinase supplementation on cognitive decline according to apolipoprotein (Apo) E4 genotype.

To determine the association of subclinical atherosclerosis progression with cognitive decline.

To determine whether the effects of nattokinase supplementation on subclinical atherosclerosis and cognitive decline are mediated through hemostatic (fibrinogen, factor VIII, platelet activity), fibrinolytic (tPA, PAI-1, D-dimer), hemorheological (plasma and blood viscosity, red blood cell aggregation), and inflammatory (MCP-1, IL-8, TNFα, IL-1β, IL-10, monocyte cell surface markers CD11b/CD11c and VLA-4, and cellular adhesion molecules VCAM-1 and ICAM-1) factors as well as blood pressure.

Conditions

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Prevention of Subclinical Atherosclerosis Progression Prevention of Cognitive Decline

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Nattokinase

Oral nattokinase 2,000 fibrinolytic units daily

Group Type ACTIVE_COMPARATOR

Nattokinase

Intervention Type DIETARY_SUPPLEMENT

Placebo

Matched placebo daily

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type OTHER

Interventions

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Nattokinase

Intervention Type DIETARY_SUPPLEMENT

Placebo

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

* Age \>55 years
* Male or postmenopausal female (no uterine bleeding for \>6 months)

Exclusion Criteria

* Clinical signs, symptoms, or personal history of cardiovascular disease
* Diabetes mellitus or fasting serum glucose \>140 mg/dL
* Plasma triglyceride levels \>500 mg/dL
* Uncontrolled hypertension (systolic blood pressure \>160 mmHg or diastolic blood pressure \>110 mmHg)
* Uncontrolled tachycardia or irregular heart rates (i.e., atrial fibrillation)
* Thyroid disease (untreated)
* Renal insufficiency (defined as serum creatinine \>2.0 mg/dL)
* Life threatening illness with prognosis \<5 years
* Current use of lipid-lowering medication
* Current use of food supplements containing soy, soy protein, isoflavones or other phytoestrogens
* Known sensitivity or allergy to soy or nuts
* Regular aspirin or other antiplatelet medication use
* Use of anticoagulants
* Bleeding diatheses or tendencies

Minimum Eligible Age

55 Years

Maximum Eligible Age

100 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Responsible Party

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Howard N. Hodis, M.D.

Harry J Bauer and Dorothy Bauer Rawlins Professor of Cardiology, Professor of Medicine, Population and Public Health Sciences, and Molecular Pharmacology and Toxicology, Director, Atherosclerosis Research Unit

Responsibility Role PRINCIPAL_INVESTIGATOR