Nitrite Supplementation in Long COVID Patients

NCT05618574 | Completed Phase 2

• 2 other identifiers: F4409-P1I21RX004409
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

Potential benefits of a nitrate-rich juice supplement to improve skeletal muscle function and associated physical capacity will be studied in patients with Long COVID. Consenting patients with Long-COVID will be randomized to receive Beet-It nitrate beverage group versus a nitrate-depleted placebo beverage. Both groups will receive physical therapy at the long COVID Clinic at VAPHS with therapeutic goals to improve strength, balance, inspiratory, and aerobic capabilities. Physical therapy will last for 2 weeks and include 2 or 3 sessions with a physical therapist a week depending on each individual's exercise tolerance. These sessions can take place on-site or at home (or a hybrid combination) All participants will undergo functional assessments and tissue assessments before and after the 14-day study intervention.

Conditions

Long COVID; Cardiorespiratory Fitness

Keywords

Nitrate therapeutics; Long COVID; Skeletal Muscle Mitochondrial Respiration; Fatigability; Cardiorespiratory Fitness

Outcome Measures

Primary Outcomes (2)

• Fatigability

  Rating of Rate of Perceived Exertion (RPE) during the 5th minute of a 5-min of a 1.5 mile per hour steady-state treadmill walking test is used as an assessment of fatigability. RPE scale is from 6 (no physical exertion) - 20 (maximal exertion/very hard).

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

• Walking Efficiency

  Walking efficiency (VO2/kg) is assessed by incorporating VO2 assessments during the 5-min steady-state walking protocol. This is assessed using cardiopulmonary exercise testing (CPET) equipment. A lower VO2 for the same functional workload indicates improved efficiency.

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

Secondary Outcomes (10)

• 400m Corridor Walk Test (400MCW)

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

• Short Performance Physical Battery (SPPB)

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

• Mitochondrial Respiration

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

• Peak oxygen utilization (VO2) non-normalized

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

• VO2 at anaerobic threshold (AT) non-normalized

  Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks

Study Arms (2)

Beet-It nitrate beverage

ACTIVE COMPARATOR

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.

Dietary Supplement: 140 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK)

Nitrate-depleted placebo

PLACEBO COMPARATOR

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.

Dietary Supplement: 210 ml of nitrate-depleted placebo

Interventions

140 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) DIETARY_SUPPLEMENT

The investigators propose to study the benefits nitrite therapeutics, using nitrate-rich beetroot juice to increase serum nitrite. The investigators hypothesize that increased nitrite will improve functional metrics and reduce fatigability in Veterans with long COVID as a result of enhanced skeletal muscle mitochondrial respiration. Participant will receive 140 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days vs the placebo.

Beet-It nitrate beverage

210 ml of nitrate-depleted placebo DIETARY_SUPPLEMENT

Participants randomized to the placebo arm will receive 210 ml of nitrate-depleted beverage (cranberry juice) per day for 14 days.

Nitrate-depleted placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Veterans with prior COVID-19, with residual symptoms of long COVID including increased fatigability.

You may not qualify if:

• Blood pressure \<110/60 mmHg, either systolic or diastolic value which may affect participant safety during assessments will be at the discretion of the study physician
• Unable to hold warfarin, novel oral anticoagulants (NOACs) or aspirin for 3 days prior to muscle biopsy, or to hold thienopyridine medications for 5 days prior to muscle biopsy
• Current use of organic nitrates or phosphodiesterase type 5 (PDE5) inhibitors
• Orthopedic or other chronic condition which limits physical activity or functional testing assessments
• End-stage disease
• Dementia or other reason unable to give informed consent
• Anemia (hemoglobin \<11.0 g/dL in men or hemoglobin \<10.0 g/dL in women)
• Unstable psychiatric diagnosis
• Clinically significant alcohol intake or substance abuse
• Chronic use of oral corticosteroids or medications that affect muscle function
• Use of anti-bacterial mouthwash or antacids that confound the nitrate/nitrite/NO pathway.
• Suicidal ideations
• Unwilling to hold Viagra-like drugs (i.e. Viagra, Cialis, Levitra, other phosphodiesterase inhibitors)
• Involved in another greater than minimal risk study
• Other clinically unstable medical condition as determined by the study physician

Sponsors & Collaborators

• VA Office of Research and Development: lead
• University of Pittsburgh: collaborator

Study Sites (1)

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Pittsburgh, Pennsylvania, 15240, United States

Location

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MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Daniel E Forman, MD

  VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: After a participant agrees to consent, their group placement is randomly determined using high quality pseudo-random deviate generator in SAS. Participants in both groups will receive either 140 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) for 14 days versus a 210 ml of nitrate depleted placebo depending on their group placement.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: In a randomized controlled, blinded design, participants will receive 140 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) for 14 days versus a 210 ml of nitrate-depleted placebo. All participants are encouraged to participate in the standard physical therapy program in the Long COVID clinic 2-3 times per week based on tolerance for activity and recovery needed after each session.

Study Record Dates

• First Submitted: November 14, 2022
• First Posted: November 16, 2022
• Study Start: December 1, 2023
• Primary Completion: February 12, 2025
• Study Completion: February 14, 2025
• Last Updated: March 19, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)