Dietary Nitrate Supplements and Ischemic Stroke Recovery

• ClinicalTrials.gov Identifier: NCT02838901
• Recruitment Status: Completed
• First Posted: July 20, 2016
• Results First Posted: April 10, 2018
• Last Update Posted: April 10, 2018
• Sponsor: Wake Forest University Health Sciences
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Stroke; Ischemic Stroke; Cerebrovascular Accident	Drug: Beet it Beetroot juice; Drug: Beet It Placebo Beetroot juice	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Dietary Nitrate Supplements and Ischemic Stroke Recovery: A Pilot Study
• Study Start Date: June 2012
• Actual Primary Completion Date: June 2016
• Actual Study Completion Date: June 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Beet it Beetroot juice; Concentrated organic beetroot (98%) and lemon juice (2%); 70ml bottle; Other Name: beetroot juice
Placebo Comparator: 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.	Drug: Beet It Placebo Beetroot juice; Concentrated organic beetroot (98%) and lemon juice (2%) with nitrate extracted; 70ml bottle. Beet It Placebo Beetroot juice.; Other Name: beetroot juice placebo

Outcome Measures

Primary Outcome Measures :

1. Adherence With Intervention [ Time Frame: 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.
2. Number of Participants With Adverse Treatment-altering Events [ Time Frame: 30 days ]
   Adverse events that lead to treatment discontinuation
3. Change in Plasma Nitrate Levels, Micromoles/Liter [ Time Frame: 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.
4. Change in Plasma Nitrite Levels, Micromoles/Liter [ Time Frame: 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 Outcome Measures :

1. Gait Speed Change From Baseline [ Time Frame: 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.
2. Cerebral Perfusion Imaging [ Time Frame: 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.
3. Upper Extremity Grip Strength [ Time Frame: 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.
4. Upper Extremity Grip Strength [ Time Frame: 90 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. The score ranges from 0-90kg, higher score denotes better outcomes.
5. Montreal Cognitive Assessment (MoCA) Score [ Time Frame: 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.
6. Montreal Cognitive Assessment (MoCA) Score [ Time Frame: 90 days ]
   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.
7. Modified Rankin Score [ Time Frame: 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.
8. Modified Rankin Score [ Time Frame: 90 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, North Carolina

Wake Forest School of Medicine

Winston-Salem, North Carolina, United States, 27157

Sponsors and Collaborators

Wake Forest University Health Sciences

Investigators

• Principal Investigator: Cheryl Bushnell, MD; Wake Forest University Health Sciences

More Information

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT02838901
• Other Study ID Numbers: IRB00020739
• First Posted: July 20, 2016
• Results First Posted: April 10, 2018
• Last Update Posted: April 10, 2018
• Last Verified: March 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Stroke; Ischemic Stroke; Cerebral Infarction; Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Infarction; Necrosis