Prevention of Cognitive Decline, Prevention of Subclinical Atherosclerosis Progression
Conditions
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
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.
Interventions
DIETARY_SUPPLEMENTNattokinase
OTHERPlacebo
Sponsors
University of Southern California
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 100 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression of Subclinical Atherosclerosis | Baseline x 2 and then every 6 months, up to 3 years | Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms will be a co-primary trial endpoint. |
| Progression of Carotid Artery Stiffness (Distensibility) | Baseline x 2 and then every 6 months, up to 3 years | Rate of change in arterial distensibility of the distal common carotid artery (CCA) determined from lumen diameters at systole and diastole and systolic and diastolic blood pressure. CCA lumen diameters will be determined from computer image processed B-mode ultrasonograms. This is a co-primary trial endpoint. |
| Carotid Artery Stiffness Progression (Compliance) | Baseline x 2 and then every 6 months, up to 3 years | Rate of change in arterial compliance of the distal common carotid artery (CCA) determined from lumen diameters at systole and diastole and systolic and diastolic blood pressure. CCA lumen diameters will be determined from computer image processed B-mode ultrasonograms. This is a co-primary trial endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neurocognitive Function (Global Cognition) | Baseline and 36 months | All neuropsychological test scores at baseline and follow-up assessments were standardized (\[raw score - mean score\]/standard deviation) using the baseline means and standard deviations from the entire NAPS sample. Each of three cognitive composite scores was calculated at baseline (composite score of 0 equals performance at the mean of each test at baseline) and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests. The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive composite scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported and there is no clinically relevant threshold. A composite score and change in composite score greater than 0 represent better cognitive performance. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the general population through media campaigns.
Pre-assignment details
1189 individuals were screened by telephone, 857 did not meet inclusion criteria. 332 individuals were screened in research clinic, 67 were excluded (51 did not meet inclusion criteria; 16 declined to participate). 265 individuals were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Nattokinase Oral nattokinase 2,000 fibrinolytic units daily | 132 |
| Placebo Matching placebo daily | 133 |
| Total | 265 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Atrial fibrillation | 1 | 1 |
| Overall Study | Cancer | 1 | 2 |
| Overall Study | Initiated aspirin | 2 | 0 |
| Overall Study | Not interested in study | 1 | 3 |
| Overall Study | Personal reasons | 0 | 3 |
| Overall Study | Self-reported symptoms | 5 | 6 |
| Overall Study | Too busy | 1 | 1 |
| Overall Study | Unable to contact | 2 | 1 |
| Overall Study | Work-related injury | 1 | 0 |
Baseline characteristics
| Characteristic | Nattokinase | Placebo | Total |
|---|---|---|---|
| Age, Customized | 65.4 years | 65.2 years | 65.3 years |
| Race/Ethnicity, Customized Asian, non-Hispanic | 10 Participants | 15 Participants | 25 Participants |
| Race/Ethnicity, Customized Black, non-Hispanic | 11 Participants | 4 Participants | 15 Participants |
| Race/Ethnicity, Customized Hispanic | 16 Participants | 19 Participants | 35 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White, non-Hispanic | 94 Participants | 93 Participants | 187 Participants |
| Region of Enrollment United States | 132 participants | 133 participants | 265 participants |
| Sex: Female, Male Female | 83 Participants | 81 Participants | 164 Participants |
| Sex: Female, Male Male | 49 Participants | 52 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 132 | 1 / 133 |
| other Total, other adverse events | 58 / 132 | 57 / 133 |
| serious Total, serious adverse events | 13 / 132 | 15 / 133 |
Outcome results
Primary
Carotid Artery Stiffness Progression (Compliance)
Rate of change in arterial compliance of the distal common carotid artery (CCA) determined from lumen diameters at systole and diastole and systolic and diastolic blood pressure. CCA lumen diameters will be determined from computer image processed B-mode ultrasonograms. This is a co-primary trial endpoint.
Time frame: Baseline x 2 and then every 6 months, up to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nattokinase | Carotid Artery Stiffness Progression (Compliance) | -0.019 mm^2/kPa per year |
| Placebo | Carotid Artery Stiffness Progression (Compliance) | -0.010 mm^2/kPa per year |
p-value: 0.32Mixed Models Analysis
Primary
Progression of Carotid Artery Stiffness (Distensibility)
Rate of change in arterial distensibility of the distal common carotid artery (CCA) determined from lumen diameters at systole and diastole and systolic and diastolic blood pressure. CCA lumen diameters will be determined from computer image processed B-mode ultrasonograms. This is a co-primary trial endpoint.
Time frame: Baseline x 2 and then every 6 months, up to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nattokinase | Progression of Carotid Artery Stiffness (Distensibility) | -0.501 x(10^-6)(N^-1)(m^2) per year |
| Placebo | Progression of Carotid Artery Stiffness (Distensibility) | -0.389 x(10^-6)(N^-1)(m^2) per year |
p-value: 0.52Mixed Models Analysis
Primary
Progression of Subclinical Atherosclerosis
Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms will be a co-primary trial endpoint.
Time frame: Baseline x 2 and then every 6 months, up to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nattokinase | Progression of Subclinical Atherosclerosis | 0.013 mm per year |
| Placebo | Progression of Subclinical Atherosclerosis | 0.011 mm per year |
p-value: 0.31Mixed Models Analysis
Secondary
Change in Neurocognitive Function (Global Cognition)
All neuropsychological test scores at baseline and follow-up assessments were standardized (\[raw score - mean score\]/standard deviation) using the baseline means and standard deviations from the entire NAPS sample. Each of three cognitive composite scores was calculated at baseline (composite score of 0 equals performance at the mean of each test at baseline) and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests. The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive composite scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported and there is no clinically relevant threshold. A composite score and change in composite score greater than 0 represent better cognitive performance.
Time frame: Baseline and 36 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nattokinase | Change in Neurocognitive Function (Global Cognition) | 0.43 Z-score |
| Placebo | Change in Neurocognitive Function (Global Cognition) | 0.43 Z-score |