Prevention of Subclinical Atherosclerosis ProgressionNAPSNCT02080520
Nattokinase Atherothrombotic Prevention Study
A study testing Nattokinase in people with Prevention of Subclinical Atherosclerosis Progression and Prevention of Cognitive Decline, run by University of Southern California at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 55 to 100 yearsHealthy volunteers can take part
- Conditions the study is for
- Prevention of Subclinical Atherosclerosis Progression, Prevention of Cognitive Decline
- What is being tested?
- Nattokinase
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 265 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2014to 31 Jul 2019
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 to 100 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age >55 years
- Male or postmenopausal female (no uterine bleeding for >6 months)
Who cannot join
- 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)
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Atherosclerosis Research Unit, University of Southern California
Los Angeles, California, 90033
About this study
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.
Read the 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.
- Being tested
- Nattokinase, Placebo
- 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
- Medical subject headings
- Atherosclerosis, Thrombosis, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NattokinaseDietary supplement
PlaceboOther
| Study group | Role | What they receive |
|---|---|---|
| Nattokinase | Active comparator | Oral nattokinase 2,000 fibrinolytic units daily Receives: Dietary Supplement: Nattokinase |
| Placebo | Placebo comparator | Matched placebo daily Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline x 2 and then every 6 months, up to 3 years
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.
Measured: Baseline x 2 and then every 6 months, up to 3 years
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.
Measured: Baseline x 2 and then every 6 months, up to 3 years
Secondary outcomes (1)
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.
Measured: Baseline and 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Mar 2014 (estimated)
- Study startApr 2014
- Primary completion31 Jul 2019
- Study completion31 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Prevention of Subclinical Atherosclerosis ProgressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 265 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Southern California
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Howard N. Hodis, M.D., University of Southern California
- Investigators
- Howard N. Hodis, M.D., Principal investigator, Atherosclerosis Research Unit, University of Southern California
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02080520
- Sponsor's protocol ID
- SDF-01
- Acronym
- NAPS
- Status last verified
- Mar 2024
- First submitted
- 21 Feb 2014
- Last updated
- 19 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 33843667
Study at a glance
From the registry record, last updated by the sponsor on 19 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nattokinase Atherothrombotic Prevention Study
- ClinicalTrials.gov ID
- NCT02080520
- Acronym / sponsor ID
- NAPS / SDF-01
- Keywords
- Arterial compliance, Arterial distensibility, Atherosclerosis, Atherothrombosis, Blood pressure, Cardiovascular disease (CVD), Carotid artery, Carotid artery intima-media thickness (CIMT)
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 265 participants (actual)
- Lead sponsor
- University of Southern CaliforniaUniversity, hospital or other
- Study start
- Apr 2014
- Primary completion
- 31 Jul 2019 (actual)
- Study completion
- 31 Jul 2019 (actual)
- First posted
- 6 Mar 2014 (estimated)
- Results
- Posted 19 Mar 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nattokinase | Active comparator | Dietary Supplement: NattokinaseOral nattokinase 2,000 fibrinolytic units daily |
| Placebo | Placebo comparator | Other: PlaceboMatched placebo daily |
Who may qualify
- Ages
- 55 to 100 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Age >55 years
- Male or postmenopausal female (no uterine bleeding for >6 months)
Key exclusion criteria (14 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nattokinase | Dietary supplement | Nattokinase |
| Placebo | Other | Placebo |
Primary outcome
Progression of Subclinical Atherosclerosis
Time frame: 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)
Time frame: 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)
Time frame: 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.
1 secondary outcome
Change in Neurocognitive Function (Global Cognition)
Time frame: Baseline and 36 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 33843667Hodis 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.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Howard N. Hodis, M.D. principal investigator
Atherosclerosis Research Unit, University of Southern California
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Nattokinase in people with Prevention of Subclinical Atherosclerosis Progression and Prevention of Cognitive Decline, run by University of Southern California at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression of Subclinical Atherosclerosis (time frame: Baseline x 2 and then every 6 months, up to 3 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02080520, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2024.