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This is a double-blind, randomized, placebo-controlled, pilot study. Participants will be randomized to receive either beetroot juice or a beetroot juice placebo, as a dietary supplement, for 30 days. Beetroot juice is high in nitrates, a chemical when ingested is found to increase blood flow to the brain. The purpose of this research study is to determine the safety and feasibility of using this nutritional intervention in (ischemic)stroke survivors, and prove that plasma levels of nitrate and nitrite increase as expected. Secondary outcomes includes measuring a comprehensive set of outcomes related to functional status post-stroke, including mobility, upper extremity strength, cognition, depression, and disability. Patients will also be randomized to MRI perfusion scanning in the region of the stroke to measure cerebral blood flow.
In this proof of concept study, the investigators will for the first time, determine whether dietary nitrate (commercially available beetroot juice) is safe and feasible to administer in ischemic stroke patients, and whether its use is associated with increased plasma nitrate and nitrite levels and trends toward improvement during the standard 30-day rehabilitation period after a stroke. The investigators will test the hypotheses using a double-blinded randomized placebo-controlled trial of Beet It® shots once daily for 30 days for patients enrolled within 5 days of stroke onset. This novel study will provide key safety and feasibility data on dietary nitrate supplementation and preliminary information on the magnitude of its effect on improving mobility and functional status, cognition and cerebral blood flow. These data are needed to accelerate the pace of development of this novel therapeutic strategy: using a non-pharmacological approach for improving stroke outcomes. The specific aims are to: Aim 1) Test the proof of concept that beetroot juice consumption is feasible and safe in ischemic stroke patients when given during the post-acute rehabilitation period. Primary outcomes are adherence to the intervention, measurement of outcomes and follow-up (feasibility), as well as adverse events (safety), reported as proportions in each group and across the entire study cohort. Hypothesis: Beetroot juice is safe and feasible in this population, and leads to increased plasma nitrate and nitrite levels at 30 days. Secondary outcomes of interest include change in gait speed (m/sec), Modified Rankin score (disability scale), NIHSS, EuroQOL-5D (quality of life),Patient Health Questionnaire-9 (depression), Stroke Impact Scale-16 (SIS-16), Barthel Index, Short Physical Performance Battery, grip strength and the Montreal Cognitive Assessment (MoCA). Aim 2) Determine whether beetroot juice consumption increases cerebral blood flow vs. placebo juice. Cerebral blood flow will be determined from MRI collected 2 hours following ingestion of the beetroot juice on day 30. Anatomic and perfusion imaging (PASL) will be performed. A region of interest will be used to measure blood flow in a 20mm sphere placed adjacent to the ischemic stroke and in the contralateral hemisphere. Hypothesis: Ischemic stroke patients randomized to the beetroot juice intervention will show increased cerebral blood flow as measured by MRI perfusion scanning in the region of the stroke compared with the placebo group at 30 days.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Beet It Beetroot Juice | Experimental | 70 cc (3.8 millimoles nitrate) Beet It organic beetroot juice once a day for 30 days. Vitamin C 500 mg (tablets) will be given along with each dose of the juice. |
|
| Beet It Beetroot Juice Placebo | Placebo Comparator | 70 cc Beet It organic beetroot juice (placebo) once a day for 30 days. The placebo beet juice is identical in appearance and taste with nitrate removed. Vitamin C 500 mg (tablets) will be given along with each dose of the juice.Beet It Placebo Beetroot juice. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Beet it Beetroot juice | Drug | Concentrated organic beetroot (98%) and lemon juice (2%); 70ml bottle |
|
| Measure | Description | Time Frame |
|---|---|---|
| Adherence With Intervention | The primary outcome for this trial is feasibility, which will be measured by how well the participants followed instructions on taking Beet It organic beetroot juice or placebo once a day for 30 days. | 30 days |
| Number of Participants With Adverse Treatment-altering Events | Adverse events that lead to treatment discontinuation | 30 days |
| Change in Plasma Nitrate Levels, Micromoles/Liter | This is the proof-of-concept to see if plasma levels change in those randomized to the active beet juice compared to placebo. Comparing baseline values against values at 30 days. | after 30 days of treatment |
| Change in Plasma Nitrite Levels, Micromoles/Liter | This is the proof-of-concept to see if plasma levels change in those randomized to the active beet juice compared to placebo. Comparing baseline values against values at 30 days. | after 30 days of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Gait Speed Change From Baseline | Gait speed is measured by the time it takes to walk 10 meters. Baseline was reported.Change in gait speed from baseline was assessed at 30 and 90 days. Non-ambulatory at baseline is defined as gait speed less than 0.1 m/s. | baseline, 30, and 90 days |
| Cerebral Perfusion Imaging |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cheryl Bushnell, MD | Wake Forest University Health Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wake Forest School of Medicine | Winston-Salem | North Carolina | 27157 | United States |
Participants will be notified as to which arm of the study they were randomized to. The de-identified participant data will be presented as an abstract, if accepted, and published as a manuscript.
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From June 2012 to June 2016, patients who are admitted to the Stroke Unit and who are within 96 hours of symptom onset, were screened for eligibility by reviewing their admitting history and physicals and imaging results.
The study enrolled adults who have suffered an ischemic stroke with minimum impairments defined by NIHSS scores and physical function measurements.
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| ID | Title | Description |
|---|---|---|
| FG000 | Beet It Beetroot Juice | 70 cc (3.8 millimoles nitrate) Beet It organic beetroot juice once a day for 30 days. Vitamin C 500 mg (tablets) will be given along with each dose of the juice. Beet it Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%); 70ml bottle. Nine participants were randomized to the Beet It Beetroot Juice arm. Participants had blood drawn on study day 1 and day 30 for nitrate and nitrite levels before and one hour after drinking 70 cc (3.8 mM nitrate) plus vitamin C 500 mg daily. On day 30, gait speed (using the 4 m walk) was assessed. Eighteen participants were consented, 15 completed treatment (1 terminated treatment because of nausea), 16 followed for 30 days and 13 for 90 days. Participants selected for the MRI portion of the study had a brain MRI performed on study day 30 to measure cerebral blood flow. |
| FG001 | Beet It Beetroot Juice Placebo | 70 cc Beet It organic beetroot juice (placebo) once a day for 30 days. The placebo beet juice is identical in appearance and taste with nitrate removed. Vitamin C 500 mg (tablets) will be given along with each dose of the juice.Beet It Placebo Beetroot juice. Beet It Placebo Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice. Nine participants were randomized to the Beet It Beetroot Juice Placebo arm. Participants had blood drawn on study day 1 and day 30 for nitrate and nitrite levels before and one hour after drinking 70 cc (3.8 mM nitrate) plus vitamin C 500 mg daily. On day 30, gait speed (using the 4 m walk) was assessed. Eighteen participants were consented, 15 completed treatment (1 terminated treatment because of nausea), 16 followed for 30 days and 13 for 90 days. Participants selected for the MRI portion of the study had a brain MRI performed on study day 30 to measure cerebral b |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Baseline characteristics were balanced with regard to admission NIHSS, age, sex, race, risk factors, baseline gait speed, and baseline nitrate/nitrite levels.
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| ID | Title | Description |
|---|---|---|
| BG000 | Beet It Beetroot Juice | 70 cc (3.8 millimoles nitrate) Beet It organic beetroot juice once a day for 30 days. Vitamin C 500 mg (tablets) will be given along with each dose of the juice. Beet it Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%); 70ml bottle |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Adherence With Intervention | The primary outcome for this trial is feasibility, which will be measured by how well the participants followed instructions on taking Beet It organic beetroot juice or placebo once a day for 30 days. | Two participants were lost to follow-up by 30 days, therefore the analysis included 8 participants in each group. | Posted | Mean | Inter-Quartile Range | percentage of participants | 30 days |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Beet It Beetroot Juice | 70 cc (3.8 millimoles nitrate) Beet It organic beetroot juice once a day for 30 days. Vitamin C 500 mg (tablets) will be given along with each dose of the juice. Beet it Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%); 70ml bottle |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoglycemia | Endocrine disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Stroke | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Cheryl Bushnell | Wake Forest School of Medicine | 336-716-4101 | cbushnel@wakehealth.edu |
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| ID | Term |
|---|---|
| D020521 | Stroke |
| D000083242 | Ischemic Stroke |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| Beet It Placebo Beetroot juice | Drug | Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice. |
|
|
Participants from each group who had an MRI at baseline will be randomly selected to have a repeat MRI perfusion scan at 30 days. Cerebral blood flow will be measured by MRI perfusion scanning (arterial spin labeling) in the region of the stroke. |
| 30 days |
| Upper Extremity Grip Strength | The hand grip strength test is designed to replicate the grip strength required to undertake officer survival and firearms training. The test is completed using a dynamometer which measures grip strength in kilograms (kg). The score ranges from 0-90kg, higher score denotes better outcomes. | 30 days |
| Upper Extremity Grip Strength | The hand grip strength test is designed to replicate the grip strength required to undertake officer survival and firearms training. The test is completed using a dynamometer which measures grip strength in kilograms. The score ranges from 0-90kg, higher score denotes better outcomes. | 90 days |
| Montreal Cognitive Assessment (MoCA) Score | Cognition is measured with the Montreal Cognitive Assessment. MoCA is a 30 question test that assesses different types of cognitive abilities, including orientation, short-term memory, executive function, language abilities, attention and visuospatial ability. Scores on the MoCA range from zero to 30, higher scores denotes better outcomes. | 30 days |
| Montreal Cognitive Assessment (MoCA) Score | Cognition is measured with the Montreal Cognitive Assessment. Cognition is measured with the Montreal Cognitive Assessment. MoCA is a 30 question test that assesses different types of cognitive abilities, including orientation, short-term memory, executive function, language abilities, attention and visuospatial ability. Scores on the MoCA range from zero to 30, higher scores denotes better outcomes. | 90 days |
| Modified Rankin Score | Modified Rankin Scale is a measure of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scores range from 0 (no symptoms) to 5 (bedridden in a nursing home). Lower scores denotes better outcomes. | 30 days |
| Modified Rankin Score | Modified Rankin Scale is a measure of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scores range from 0 (no symptoms) to 5 (bedridden in a nursing home). Lower scores denotes better outcomes. | 90 days |
| Beet It Beetroot Juice Placebo |
70 cc Beet It organic beetroot juice (placebo) once a day for 30 days. The placebo beet juice is identical in appearance and taste with nitrate removed. Vitamin C 500 mg (tablets) will be given along with each dose of the juice.Beet It Placebo Beetroot juice. Beet It Placebo Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Age (yrs) |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| nitrate and nitrite levels | Mean | Standard Deviation | micromoles/L |
|
| gait speed | A total of 17 participants had baseline gait speed data available | Mean | Full Range | m/s |
|
70 cc Beet It organic beetroot juice (placebo) once a day for 30 days. The placebo beet juice is identical in appearance and taste with nitrate removed. Vitamin C 500 mg (tablets) will be given along with each dose of the juice.Beet It Placebo Beetroot juice. Beet It Placebo Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice. |
|
|
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| Primary | Number of Participants With Adverse Treatment-altering Events | Adverse events that lead to treatment discontinuation | Posted | Number | participants | 30 days |
|
|
|
|
| Primary | Change in Plasma Nitrate Levels, Micromoles/Liter | This is the proof-of-concept to see if plasma levels change in those randomized to the active beet juice compared to placebo. Comparing baseline values against values at 30 days. | The median treatment-specific changes in nitrate were analyzed using comparison of pre to post-dosing plasma on day 1. Beetroot It Beetroot juice (Active) was associated with an increase in plasma nitrate and a trend towards increased nitrite levels. The analysis included 8 participants per group since 2 did not come back for follow-up at 30 days. | Posted | Median | Inter-Quartile Range | micromoles/L | after 30 days of treatment |
|
|
|
|
| Primary | Change in Plasma Nitrite Levels, Micromoles/Liter | This is the proof-of-concept to see if plasma levels change in those randomized to the active beet juice compared to placebo. Comparing baseline values against values at 30 days. | The median treatment-specific changes in nitrate were analyzed using comparison of pre to post-dosing plasma on day 1. Beetroot It Beetroot juice (Active) was associated with an increase in plasma nitrate and a trend towards increased nitrite levels. The analysis included 8 participants in active and 7 in placebo based on follow-up at 30 d. | Posted | Median | Inter-Quartile Range | micromoles/L | after 30 days of treatment |
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| Secondary | Gait Speed Change From Baseline | Gait speed is measured by the time it takes to walk 10 meters. Baseline was reported.Change in gait speed from baseline was assessed at 30 and 90 days. Non-ambulatory at baseline is defined as gait speed less than 0.1 m/s. | There were 8 participants in the Active and 8 in the placebo because they did not follow-up at 30 days. BL ambulatory refers to only those participants were able to walk at baseline immediately after enrollment. For this analysis, there were only 6 participants in the active and 7 in the placebo at 30 days and 4 and 5 at 90 days, respectively. | Posted | Median | Inter-Quartile Range | m/s | baseline, 30, and 90 days |
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| Secondary | Cerebral Perfusion Imaging | Participants from each group who had an MRI at baseline will be randomly selected to have a repeat MRI perfusion scan at 30 days. Cerebral blood flow will be measured by MRI perfusion scanning (arterial spin labeling) in the region of the stroke. | MRI cerebral perfusion data could not be analyzed because of a change in the measurement of perfusion after the first participant was enrolled. | Posted | 30 days |
|
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| Secondary | Upper Extremity Grip Strength | The hand grip strength test is designed to replicate the grip strength required to undertake officer survival and firearms training. The test is completed using a dynamometer which measures grip strength in kilograms (kg). The score ranges from 0-90kg, higher score denotes better outcomes. | Only 6 participants in each group had grip strength measured at 30 days. Affected refers to the upper extremity that was affected by the stroke, and unaffected refers to the upper extremity not affected by the stroke. | Posted | Mean | Inter-Quartile Range | kg | 30 days |
|
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| Secondary | Upper Extremity Grip Strength | The hand grip strength test is designed to replicate the grip strength required to undertake officer survival and firearms training. The test is completed using a dynamometer which measures grip strength in kilograms. The score ranges from 0-90kg, higher score denotes better outcomes. | Only 6 in the active and 7 in the placebo had grip strength measured at 90 days. Affected refers to the upper extremity that was affected by the stroke, and unaffected refers to the upper extremity not affected by the stroke. | Posted | Mean | Inter-Quartile Range | kg | 90 days |
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| Secondary | Montreal Cognitive Assessment (MoCA) Score | Cognition is measured with the Montreal Cognitive Assessment. MoCA is a 30 question test that assesses different types of cognitive abilities, including orientation, short-term memory, executive function, language abilities, attention and visuospatial ability. Scores on the MoCA range from zero to 30, higher scores denotes better outcomes. | Only 5 participants in the active and 8 in the placebo were able to complete the MoCA at 30 days. | Posted | Mean | Inter-Quartile Range | units on a scale | 30 days |
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| Secondary | Montreal Cognitive Assessment (MoCA) Score | Cognition is measured with the Montreal Cognitive Assessment. Cognition is measured with the Montreal Cognitive Assessment. MoCA is a 30 question test that assesses different types of cognitive abilities, including orientation, short-term memory, executive function, language abilities, attention and visuospatial ability. Scores on the MoCA range from zero to 30, higher scores denotes better outcomes. | Only 5 participants in the active and 8 in the placebo were able to complete the MoCA at 90 days. | Posted | Mean | Inter-Quartile Range | units on a scale | 90 days |
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| Secondary | Modified Rankin Score | Modified Rankin Scale is a measure of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scores range from 0 (no symptoms) to 5 (bedridden in a nursing home). Lower scores denotes better outcomes. | Only 8 participants in the active and 8 in the placebo returned for the 30 day visit in order to measure the modified Rankin score. | Posted | Mean | Inter-Quartile Range | units on a scale | 30 days |
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| Secondary | Modified Rankin Score | Modified Rankin Scale is a measure of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scores range from 0 (no symptoms) to 5 (bedridden in a nursing home). Lower scores denotes better outcomes. | Only 6 participants in the active and 8 in the placebo returned for the 90 day visit and therefore modified Rankin could not be ascertained. | Posted | Mean | Inter-Quartile Range | units on a scale | 90 days |
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| 0 |
| 9 |
| 1 |
| 9 |
| 5 |
| 9 |
| EG001 | Beet It Beetroot Juice Placebo | 70 cc Beet It organic beetroot juice (placebo) once a day for 30 days. The placebo beet juice is identical in appearance and taste with nitrate removed. Vitamin C 500 mg (tablets) will be given along with each dose of the juice.Beet It Placebo Beetroot juice. Beet It Placebo Beetroot juice: Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice. | 0 | 9 | 0 | 9 | 3 | 9 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Gastroesophageal refluix | Gastrointestinal disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Easy bruising | Blood and lymphatic system disorders | Systematic Assessment |
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| Seizure | Nervous system disorders | Systematic Assessment |
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| Mental alteration | Nervous system disorders | Systematic Assessment |
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| Hypothermia | Endocrine disorders | Systematic Assessment |
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| Hypotension | Cardiac disorders |
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| Urinary tract infection | Infections and infestations | Systematic Assessment |
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| Hyperkalemia | Endocrine disorders | Systematic Assessment |
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| Shortness of Breath | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Chest Pain | Reproductive system and breast disorders | Systematic Assessment |
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| Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Emesis | Gastrointestinal disorders | Systematic Assessment |
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| Non-specific SA nodal disease | Cardiac disorders | Systematic Assessment |
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| Dizziness | Nervous system disorders | Non-systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Blood in stool | Gastrointestinal disorders | Systematic Assessment |
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| Dysphagia | General disorders | Systematic Assessment |
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| Eye floater | Eye disorders | Systematic Assessment |
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| Fall | General disorders | Systematic Assessment |
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| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Gait speed change 30 days |
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| Gait speed change 90 days |
|
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| BL Ambulatory: Gait Speed 30 days |
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| BL Ambulatory: Gait Speed 90 days |
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| Wilcoxon (Mann-Whitney) |
| .6678 |
| Other |
| Other |
| Other |