Nitrate Supplement for Long COVID

Overseen By Daniel E Forman, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Organic nitrates, PDE5 inhibitors

Disqualifiers: Orthopedic condition, End-stage disease, Dementia, Anemia, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a nitrate-rich juice, specifically Beet-It Nitrate Beverage, can improve muscle function and physical abilities in people with Long COVID. Participants will divide into two groups: one will drink the Beet-It beverage, and the other a placebo (a drink without active ingredients). Both groups will also participate in physical therapy to enhance strength and fitness. This trial may suit veterans who remain fatigued after COVID-19. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as warfarin, NOACs, or aspirin for 3 days before a muscle biopsy, and thienopyridine medications for 5 days before a muscle biopsy. You also cannot use organic nitrates, PDE5 inhibitors, or certain other medications that affect muscle function or the nitrate pathway.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that most people can drink the Beet-It nitrate beverage without problems. In earlier studies, beetroot juice raised nitrate levels in the body without causing serious side effects. A recent study found that this juice helped lower inflammation in adults with Long COVID. These findings suggest it might be safe to use, but individual reactions can vary. Therefore, consulting a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Long COVID?

Researchers are excited about the Beet-It nitrate beverage for Long COVID because it offers a unique approach compared to standard treatments, which often include rest, symptom management, and rehabilitation exercises. Unlike these traditional methods, Beet-It is packed with dietary nitrates, which may enhance blood flow and improve oxygen delivery throughout the body. This new mechanism could potentially boost energy and reduce fatigue, a common symptom of Long COVID. Additionally, the treatment is straightforward, involving a simple dietary supplement, making it easy for patients to incorporate into their routine.

What evidence suggests that this treatment might be an effective treatment for Long COVID?

Research has shown that nitrate supplements, such as those in Beet-It nitrate drinks, can raise nitrate levels in the body. In this trial, participants will receive either the Beet-It nitrate beverage or a nitrate-depleted placebo for 14 days. A recent study found that drinking beetroot juice for 14 days helped reduce inflammation in adults with long COVID. However, other studies found that beetroot juice did not significantly enhance physical abilities in these patients compared to a placebo. Thus, while there may be benefits for reducing inflammation, the evidence on improving physical abilities remains mixed. ^{1 3 4 5 6}

Who Is on the Research Team?

Daniel Forman, MD

Principal Investigator

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Are You a Good Fit for This Trial?

This trial is for veterans over 18 who've had COVID-19 and are now experiencing long-term fatigue and reduced physical activity. They must not have low blood pressure, be able to pause certain medications before a muscle biopsy, give informed consent, and should not have conditions that limit their movement or other serious health issues.

Inclusion Criteria

I am a veteran with long COVID, feeling very tired and less active than before.

Exclusion Criteria

Your blood pressure is lower than 110/60 mmHg.

I have a chronic condition that limits my physical activity.

I am currently taking medication for heart problems or erectile dysfunction.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily nitrate-rich beetroot juice or nitrate-depleted placebo for 2 weeks, along with physical therapy sessions 2-3 times per week.

2 weeks

2-3 sessions per week (in-person or at home)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including functional and tissue assessments.

2 weeks

Baseline and follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Beet-It Nitrate Beverage

Trial Overview The study tests if drinking Beet-It nitrate juice daily can help improve muscle function in Long COVID patients compared to a placebo drink. All participants will also receive physical therapy aimed at enhancing strength and aerobic capacity over two weeks.

How Is the Trial Designed?

Group I: Beet-It nitrate beverage Active Control 1 Intervention

Participant will receive 140 ml per day of Beet-It nitrate beverage for for 14 days. All participants will be encouraged to undergo physical therapy 2-3 times per week based on tolerance for activity and recovery needed after each session. Physical therapy will be standardized to include strength, balance, inspiratory muscle training, and aerobic training. Participants randomized to this arm will be assessed at baseline and follow-up visits on all outcome measures.

Group II: Nitrate-depleted placebo Placebo Group 1 Intervention

Participants will receive 210 ml of nitrate-depleted placebo for 14 days. All participants will be encouraged to undergo physical therapy 2-3 times per week based on tolerance for activity and recovery needed after each session. Physical therapy will be standardized to include strength, balance, inspiratory muscle training, and aerobic training. Participants randomized to this arm will be assessed at baseline and follow-up visits on all outcome measures.

Beet-It Nitrate Beverage is already approved in European Union, United Kingdom, United States for the following indications:

Approved in European Union as Beet It for:

• General health and wellness
• Blood pressure management

Approved in United Kingdom as Beet It for:

• General health and wellness
• Blood pressure management
• Athletic performance enhancement

Approved in United States as Beet It for:

• General health and wellness
• Blood pressure management

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

Published Research Related to This Trial

In a cross-over trial with healthy middle- to older-aged adults, beetroot juice significantly increased plasma nitrate and nitrite levels after consumption, indicating its effectiveness in enhancing nitric oxide production.

Co-ingesting beetroot juice with vitamin C or whey protein did not result in significant differences in plasma nitrate and nitrite levels compared to beetroot juice alone, suggesting that these supplements do not enhance the acute response of the nitrate-nitrite-nitric oxide pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Vitamin C and Protein Supplementation on Plasma Nitrate and Nitrite Response following Consumption of Beetroot Juice. Miller, GD., Nesbit, BA., Kim-Shapiro, DB., et al.[2023]

In a study involving 17 chronic kidney disease (CKD) patients, supplementation with beetroot juice, which is high in dietary nitrate, significantly reduced blood pressure and renal resistive index (RRI), suggesting potential cardiovascular benefits.

The reduction in blood pressure and RRI after beetroot juice consumption may be attributed to the release of nitric oxide (NO), a vasodilator, indicating that dietary nitrate could be a useful adjunct therapy for managing hypertension in CKD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary nitrate load lowers blood pressure and renal resistive index in patients with chronic kidney disease: A pilot study. Kemmner, S., Lorenz, G., Wobst, J., et al.[2018]

In a study involving 48 participants with type 2 diabetes, dietary nitrate supplementation from beetroot juice significantly increased plasma nitrate and nitrite levels, indicating successful absorption of the supplement.

However, despite these increases, nitrate supplementation did not reduce the oxygen cost of walking or improve performance in the 6-minute walk test, suggesting it does not enhance exercise response in individuals with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dietary nitrate supplementation on the oxygen cost of exercise and walking performance in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled crossover trial. Shepherd, AI., Gilchrist, M., Winyard, PG., et al.[2015]

In a 14-day study involving 8 subjects with mild to moderate COPD, daily consumption of nitrate-rich beetroot juice significantly increased exercise capacity, as shown by a 14.6% improvement in the incremental shuttle walk test distance.

The increase in exercise tolerance was linked to higher levels of plasma nitrate/nitrite, suggesting that dietary nitrate may enhance performance in COPD patients without affecting blood pressure or lung function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary nitrate improved exercise capacity in COPD but not blood pressure or pulmonary function: a 2 week, double-blind randomised, placebo-controlled crossover trial. Kerley, CP., James, PE., McGowan, A., et al.[2019]

In a 13-week pilot study involving 62 overweight and obese older adults, medium and low doses of dietary nitrate from beetroot juice significantly lowered resting systolic blood pressure compared to a placebo.

The same lower doses of dietary nitrate also improved microvascular blood flow, indicating enhanced endothelial function, which is important for vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moderate doses of dietary nitrate elicit greater effects on blood pressure and endothelial function than a high dose: A 13-week pilot study. Babateen, AM., Shannon, OM., O'Brien, GM., et al.[2023]

In a study involving 15 COPD patients, acute ingestion of beetroot juice significantly improved exercise capacity, allowing patients to exercise longer at a submaximal workload compared to a placebo.

Beetroot juice also led to notable reductions in both resting and exercise-induced blood pressure, indicating potential cardiovascular benefits alongside improved exercise performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary nitrate supplementation improves exercise performance and decreases blood pressure in COPD patients. Berry, MJ., Justus, NW., Hauser, JI., et al.[2018]

A 3-day supplementation of beetroot juice rich in dietary nitrate significantly improved exercise tolerance during high-intensity intermittent exercise, allowing participants to complete more repetitions before exhaustion (26.1 vs. 21.8 with placebo).

The supplementation increased microvascular total hemoglobin concentration in the muscles, indicating enhanced oxygen delivery during intense exercise, even though it did not affect overall oxygen uptake or muscle contractile function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of dietary nitrate supplementation on tolerance to supramaximal intensity intermittent exercise. Aucouturier, J., Boissière, J., Pawlak-Chaouch, M., et al.[2022]

In a study with 18 healthy participants, four days of dietary supplementation with inorganic nitrate from beetroot juice significantly reduced muscular fatigue during exercise with blood flow restriction, showing better force retention compared to a placebo.

The observed benefits in muscle performance are likely due to improved calcium handling or enhanced blood flow during low-oxygen conditions, indicating that nitrate supplementation can help maintain muscle function during intense physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of nitrate supplementation on muscle contraction in healthy adults. Hoon, MW., Fornusek, C., Chapman, PG., et al.[2015]

In a study involving 12 healthy older adults, dietary nitrate supplementation from concentrated beetroot juice significantly reduced resting blood pressure, with systolic pressure decreasing from 120 mmHg to 115 mmHg and diastolic pressure from 73 mmHg to 70 mmHg.

Nitrate supplementation improved the speed of oxygen uptake response during exercise, reducing the time taken to transition from rest to walking, but did not enhance overall walking performance or cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of short-term dietary nitrate supplementation on blood pressure, O2 uptake kinetics, and muscle and cognitive function in older adults. Kelly, J., Fulford, J., Vanhatalo, A., et al.[2022]

In a 12-week study with adults, those consuming beetroot juice containing 380 mg of nitrate showed a significant increase in plasma nitrite levels (273.2% change) compared to a placebo group (4.9% change).

Long-term consumption of beetroot juice effectively enhances the body's ability to convert dietary nitrate into plasma nitrate and nitrite, indicating its potential benefits for cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Variability in Plasma Nitrite Levels during Long-Term Supplementation with Nitrate Containing Beetroot Juice. Miller, GD., Collins, S., Ives, J., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9668238/

a randomised placebo-controlled feasibility trial - PMC Hence, it is unsurprising that nitrate supplementation with beetroot juice significantly increased both salivary nitrate/nitrite and urinary nitrate ...

2. reaganudall.org reaganudall.org/clinical-trial/nitrite-supplementation-long-covid-patients

Nitrite Supplementation in Long COVID Patients Consentingpatients with Long-COVID will be randomized to receive Beet-It nitrate beverage groupversus a nitrate-depleted placebo beverage.

3. mdpi.com mdpi.com/1422-0067/26/3/1224

Mitochondria-Derived Vesicles and Inflammatory Profiles of ... In a recent clinical trial, beetroot juice supplementation for 14 days yielded positive effects on systemic inflammation in adults with long COVID.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39571342/

Beetroot juice intake positively influenced gut microbiota ... Beetroot juice supplementation for two weeks did not to induce significant improvements in functional outcomes in adults with long COVID compared with placebo.

5. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/counter/pdf/10.1186/s13063-023-07616-2.pdf?utm_source=consensus

A double-blind, randomised, placebo-controlled parallel ... In this study, we will investigate whether sex or a dietary inorganic nitrate intervention modulates endothelial function and inflammatory ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05618574

Nitrite Supplementation in Long COVID Patients Consenting patients with Long-COVID will be randomized to receive Beet-It nitrate beverage group versus a nitrate-depleted placebo beverage. Both groups will ...