Cerebrovascular Accident, Ischemic Stroke, Stroke
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGBeet it Beetroot juice
Concentrated organic beetroot (98%) and lemon juice (2%); 70ml bottle
DRUGBeet It Placebo Beetroot juice
Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice.
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients 18 years old and over * Diagnosed with an ischemic stroke (acute focal neurological deficit resulting from an ischemic cause, verified by CT or MRI) * Symptom onset within 5 days of admission * National Institutes of Health Stroke Scale Score of 2 or more (but less than 20) * A rating of fair or good on static sitting balance scale on a global balance scale * A score of more that 0 on the hip flexion on the short Fugl-Myer * Passed dysphagia screening for unrestricted or thickened liquids
Exclusion criteria
* Patients with severe stroke (National Institutes of Health Stroke Scale Score of 20 or more) * A score of 0 on hip flexion on the Short Fugl-Myer as a result of weakness from the stroke * A rating of poor on static sitting balance scale on a global balance scale * Patients who received intravenous or intra-arterial recombinant tissue plasminogen activator (rtPA) * Patients who are receiving citicoline * Patients who have had a hemorrhagic stroke (including intraparenchymal, subarachnoid or subdural hemorrhage) * A gait speed of more \> 0.8 m/s * Patient with evidence of brain tumor or other psychiatric or neurological condition that would interfere with outcome measures * Patients who will undergo carotid endarterectomy or other surgery during the study period * Patients not living independently prior to stroke * Survival is expected to be less than 6 months * Any patient on organic nitrate-containing medications; some examples of the medications that are exclusions include nitroglycerin, isosorbide mononitrate, sildenafil (Viagra), and tadalafil (Cialis) * Patients with atrophic gastritis * Patients with hypotension (blood pressure less than 100/60 mmHg) * Patients who do not pass the dysphagia screening test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adherence With Intervention | 30 days | 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. |
| Number of Participants With Adverse Treatment-altering Events | 30 days | Adverse events that lead to treatment discontinuation |
| Change in Plasma Nitrate Levels, Micromoles/Liter | after 30 days of treatment | 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. |
| Change in Plasma Nitrite Levels, Micromoles/Liter | after 30 days of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gait Speed Change From Baseline | baseline, 30, and 90 days | 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. |
| Modified Rankin Score | 30 days | 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. |
| Cerebral Perfusion Imaging | 30 days | 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. |
| Upper Extremity Grip Strength | 30 days | 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. |
| Montreal Cognitive Assessment (MoCA) Score | 30 days | 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. |
Countries
United States
Participant flow
Recruitment details
The study enrolled adults who have suffered an ischemic stroke with minimum impairments defined by NIHSS scores and physical function measurements.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 9 |
| 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. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Beet It Beetroot Juice | Beet It Beetroot Juice Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 63.5 Age (yrs) STANDARD_DEVIATION 8.6 | 66.3 Age (yrs) STANDARD_DEVIATION 9.2 | 64.9 Age (yrs) STANDARD_DEVIATION 8.8 |
| gait speed | 0.23 m/s | 0.22 m/s | 0.22 m/s |
| nitrate and nitrite levels Baseline Nitrate | 63.9 micromoles/L STANDARD_DEVIATION 77.2 | 27.0 micromoles/L STANDARD_DEVIATION 16 | 45.5 micromoles/L STANDARD_DEVIATION 57.3 |
| nitrate and nitrite levels Baseline Nitrite | 0.17 micromoles/L STANDARD_DEVIATION 0.14 | 0.13 micromoles/L STANDARD_DEVIATION 0.08 | 0.15 micromoles/L STANDARD_DEVIATION 0.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 12 Participants |
| Region of Enrollment United States | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 5 / 9 | 3 / 9 |
| serious Total, serious adverse events | 1 / 9 | 0 / 9 |
Outcome results
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.
Time frame: 30 days
Population: Two participants were lost to follow-up by 30 days, therefore the analysis included 8 participants in each group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Beet It Beetroot Juice | Adherence With Intervention | 93.5 percentage of participants |
| Beet It Beetroot Juice Placebo | Adherence With Intervention | 100 percentage of participants |
Comparison: The null hypothesis was used, and the assumption was there would be no difference in adherence between the Active Juice and the Placebo Juice, and therefore a two-sided t approximation was reported. Since this was a pilot study, power calculations were not performed. The adherence in the two groups was compared using the Wilcoxon two-sample test.p-value: 0.058Wilcoxon (Mann-Whitney)
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.
Time frame: after 30 days of treatment
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Beet It Beetroot Juice | Change in Plasma Nitrate Levels, Micromoles/Liter | 174.76 micromoles/L |
| Beet It Beetroot Juice Placebo | Change in Plasma Nitrate Levels, Micromoles/Liter | 0.678 micromoles/L |
Comparison: The null hypothesis was assumed, and no power calculation was performed since this was a pilot study.p-value: 0.0003Wilcoxon (Mann-Whitney)
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.
Time frame: after 30 days of treatment
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Beet It Beetroot Juice | Change in Plasma Nitrite Levels, Micromoles/Liter | 0.114 micromoles/L |
| Beet It Beetroot Juice Placebo | Change in Plasma Nitrite Levels, Micromoles/Liter | 0.014 micromoles/L |
p-value: 0.1023Wilcoxon (Mann-Whitney)
Primary
Number of Participants With Adverse Treatment-altering Events
Adverse events that lead to treatment discontinuation
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Beet It Beetroot Juice | Number of Participants With Adverse Treatment-altering Events | 1 participants |
| Beet It Beetroot Juice Placebo | Number of Participants With Adverse Treatment-altering Events | 0 participants |
Comparison: Null hypothesis was assumed, no power calculation was done since this was a pilot study.p-value: 1Fisher Exact
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.
Time frame: 30 days
Population: MRI cerebral perfusion data could not be analyzed because of a change in the measurement of perfusion after the first participant was enrolled.
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.
Time frame: baseline, 30, and 90 days
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Beet It Beetroot Juice | Gait Speed Change From Baseline | Gait speed change 30 days | 0.330 m/s |
| Beet It Beetroot Juice | Gait Speed Change From Baseline | BL Ambulatory: Gait Speed 30 days | 0.591 m/s |
| Beet It Beetroot Juice | Gait Speed Change From Baseline | Gait speed change 90 days | 0.385 m/s |
| Beet It Beetroot Juice | Gait Speed Change From Baseline | BL Ambulatory: Gait Speed 90 days | 0.572 m/s |
| Beet It Beetroot Juice | Gait Speed Change From Baseline | Baseline | .22 m/s |
| Beet It Beetroot Juice Placebo | Gait Speed Change From Baseline | BL Ambulatory: Gait Speed 90 days | 0.406 m/s |
| Beet It Beetroot Juice Placebo | Gait Speed Change From Baseline | Baseline | .23 m/s |
| Beet It Beetroot Juice Placebo | Gait Speed Change From Baseline | Gait speed change 30 days | 0.193 m/s |
| Beet It Beetroot Juice Placebo | Gait Speed Change From Baseline | Gait speed change 90 days | 0.165 m/s |
| Beet It Beetroot Juice Placebo | Gait Speed Change From Baseline | BL Ambulatory: Gait Speed 30 days | 0.575 m/s |
p-value: 0.9581Wilcoxon (Mann-Whitney)
Comparison: The null hypothesis was assumed, and no power calculation was performed since this was a pilot study and the purpose was to collect preliminary data for a larger trial.p-value: 0.6678Wilcoxon (Mann-Whitney)
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.
Time frame: 90 days
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Beet It Beetroot Juice | Modified Rankin Score | 2.5 units on a scale |
| Beet It Beetroot Juice Placebo | Modified Rankin Score | 3 units on a scale |
p-value: 0.185Wilcoxon (Mann-Whitney)
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.
Time frame: 30 days
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Beet It Beetroot Juice | Modified Rankin Score | 3 units on a scale |
| Beet It Beetroot Juice Placebo | Modified Rankin Score | 3 units on a scale |
p-value: 0.135Wilcoxon (Mann-Whitney)
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.
Time frame: 30 days
Population: Only 5 participants in the active and 8 in the placebo were able to complete the MoCA at 30 days.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Beet It Beetroot Juice | Montreal Cognitive Assessment (MoCA) Score | 23.5 units on a scale |
| Beet It Beetroot Juice Placebo | Montreal Cognitive Assessment (MoCA) Score | 23 units on a scale |
p-value: 0.888Wilcoxon (Mann-Whitney)
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.
Time frame: 90 days
Population: Only 5 participants in the active and 8 in the placebo were able to complete the MoCA at 90 days.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Beet It Beetroot Juice | Montreal Cognitive Assessment (MoCA) Score | 27 units on a scale |
| Beet It Beetroot Juice Placebo | Montreal Cognitive Assessment (MoCA) Score | 23.5 units on a scale |
p-value: 0.475Wilcoxon (Mann-Whitney)
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.
Time frame: 30 days
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Beet It Beetroot Juice | Upper Extremity Grip Strength | Affected | 17.4 kg |
| Beet It Beetroot Juice | Upper Extremity Grip Strength | Unaffected | 28.75 kg |
| Beet It Beetroot Juice Placebo | Upper Extremity Grip Strength | Affected | 20 kg |
| Beet It Beetroot Juice Placebo | Upper Extremity Grip Strength | Unaffected | 34.75 kg |
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 0.876Wilcoxon (Mann-Whitney)
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.
Time frame: 90 days
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Beet It Beetroot Juice | Upper Extremity Grip Strength | Unaffected | 26.75 kg |
| Beet It Beetroot Juice | Upper Extremity Grip Strength | Affected | 17.5 kg |
| Beet It Beetroot Juice Placebo | Upper Extremity Grip Strength | Affected | 11 kg |
| Beet It Beetroot Juice Placebo | Upper Extremity Grip Strength | Unaffected | 33 kg |
p-value: 0.889Wilcoxon (Mann-Whitney)
p-value: 0.532Wilcoxon (Mann-Whitney)