Clinical trial NCT02080520: Nattokinase Atherothrombotic Prevention Study
Official title: Nattokinase Atherothrombotic Prevention Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Prevention of Subclinical Atherosclerosis Progression
Prevention of Cognitive Decline
Keywords: Arterial compliance
Arterial distensibility
Atherosclerosis
Atherothrombosis
Blood pressure
Cardiovascular disease (CVD)
Carotid artery
Carotid artery intima-media thickness (CIMT)
Coagulation
Cognition
Fermented soy
Fibrinolysis
Natto
Nattokinase
Prevention
Randomized controlled trial
Rheology
Soy
Soybeans
Thrombosis
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2014-03-06
Enrollment: 265
Sex: ALL
Minimum age (years): 55
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression of Subclinical Atherosclerosis
timeFrame: Baseline x 2 and then every 6 months, up to 3 years
measure: Progression of Carotid Artery Stiffness (Distensibility)
timeFrame: Baseline x 2 and then every 6 months, up to 3 years
measure: Carotid Artery Stiffness Progression (Compliance)
timeFrame: Baseline x 2 and then every 6 months, up to 3 years
Secondary outcomes:
measure: Change in Neurocognitive Function (Global Cognition)
timeFrame: Baseline and 36 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Atherosclerosis Research Unit, University of Southern California
state: California
Study officials:
affiliation: Atherosclerosis Research Unit, University of Southern California
name: Howard N. Hodis, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hodis HN, Mack WJ, Meiselman HJ, Kalra V, Liebman H, Hwang-Levine J, Dustin L, Kono N, Mert M, Wenby RB, Huesca E, Rochanda L, Li Y, Yan M, St John JA, Whitfield L. Nattokinase atherothrombotic prevention study: A randomized controlled trial. Clin Hemorheol Microcirc. 2021;78(4):339-353. doi: 10.3233/CH-211147.