Nitrite Supplementation in Long COVID Patients

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Not yet recruiting

CT.gov ID

NCT05618574

Collaborator

University of Pittsburgh (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Potential benefits of a nitrate 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.

Condition or Disease	Intervention/Treatment	Phase
Long COVID Cardiorespiratory Fitness	Dietary Supplement: 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK)	Phase 3

Detailed Description

In a proof of concept pilot, the investigators will study 40 Veterans with long COVID, comparing 20 who consume two weeks of daily nitrate-rich beetroot juice versus matched Veterans who consume a nitrate-depleted placebo. Nitrate is metabolized to increase cellular nitric oxide once it is ingested. Nitric oxide (NO) is a signaling molecule that contributes to numerous physiological functions, including enhanced skeletal muscle mitochondrial respiration, which may thereby lead to decreased fatigability and increased physical function. NO is commonly produced from the conversion of the amino acid L-arginine to L-citrulline in the presence of oxygen. However, inorganic nitrate provided as a dietary supplement can serve as an additional substrate for bioactive nitrite and downstream NO, particularly during the ischemic stress of exercise. In this study, consenting patients with Long-COVID will be randomized to receive Beet-It nitrate beverage group as a source of inorganic nitrites and NO, versus a nitrate-depleted placebo beverage. Both groups will undergo simultaneous physical therapy. Primary endpoints center on meaningful clinical changes, including fatigability (i.e., rating of perceived exertion during steady-state walking), cardiorespiratory fitness (i.e., peak oxygen utilization [VO2] as well as submaximal VO2 at anaerobic threshold [VAT]). In addition, serology and skeletal muscle assessments will include nitrate and nitrite levels and mitochondrial respiration to analyze nitrite-mediated mechanisms underlying functional changes.

Principal investigator Daniel Forman, MD has developed expertise in nitrite therapeutics using nitrite capsule supplements for older sedentary adults in relation to sedentariness and heart failure. This SPiRE proposal focuses nitrite therapeutics to both younger and older adults with long COVID.

Aims: To conduct a pilot randomized controlled trial to study the benefits of beetroot juice versus placebo in 40 Veterans with prior COVID-19 infection (within one year) and who have been left with residual symptoms of long COVID. All participants will receive a daily study juice intervention for 2 weeks in association with physical therapy with a standardized exercise regimen designed to increase strength and aerobic function

Aim 1: To study the efficacy of nitrite supplementation to reduce fatigability over two weeks as measured by rating of perceived exertion (RPE) during submaximal steady-state 1.5 mile per hour walking. Walking efficiency (VO2 per kg) will also be assessed during steady-state walking.
Aim 2: To study the benefits of nitrite supplementation to increase cardiorespiratory fitness (peak oxygen utilization [VO2], VO2 at anaerobic threshold (VAT), 6-minute walk distance (6MWD), short physical performance battery (SPPB), and pulmonary function tests (PFT) after two weeks.
Aim 3: To explore the utility of nitrite supplementation to enhance skeletal muscle mitochondrial respiration in long COVID patients as measured by ex vivo Oroboros analysis.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

In a randomized controlled, blinded design, participants will receive 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) for 16 mmol of nitrate/day for 14 days versus a 210 ml of nitrate-depleted placebo. All participants will undergo physical therapy 2-3 times per week based on tolerance for activity and recovery needed after each session. Physical therapy will be offered on site or at home (or a hybrid combination).In a randomized controlled, blinded design, participants will receive 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) for 16 mmol of nitrate/day for 14 days versus a 210 ml of nitrate-depleted placebo. All participants will undergo physical therapy 2-3 times per week based on tolerance for activity and recovery needed after each session. Physical therapy will be offered on site or at home (or a hybrid combination).

Masking:

Double (Participant, Investigator)

Masking Description:

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 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) for 16 mmol of nitrate/day for 14 days versus a 210 ml of nitrate depleted placebo depending on their group placement.

Primary Purpose:

Treatment

Official Title:

Nitrite Supplementation to Mitigate Fatigability and Increase Function in Long COVID Patients

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2025

Anticipated Study Completion Date :

Mar 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Beet-It nitrate beverage Participant will receive 210 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14. All participants will 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.	Dietary Supplement: 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) 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 210 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days vs the placebo.
Placebo Comparator: Nitrate-depleted placebo. Participants will receive 210 ml of nitrate-depleted placebo for 14 days. All participants will 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.	Dietary Supplement: 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) 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 210 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days vs the placebo.

Arm

Intervention/Treatment

Active Comparator: Beet-It nitrate beverage

Participant will receive 210 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14. All participants will 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.

Dietary Supplement: 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK)

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 210 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days vs the placebo.

Placebo Comparator: Nitrate-depleted placebo.

Participants will receive 210 ml of nitrate-depleted placebo for 14 days. All participants will 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.

Dietary Supplement: 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK)

Outcome Measures

Primary Outcome Measures

Fatigability [2 weeks]
Rating of perceived exertion 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 0 (no physical exertion) - 10 (very hard).
Walking Efficiency [2 weeks]
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.

Secondary Outcome Measures

6-minute walking test (6MWT) [2 weeks]
Subjects walk as quickly as possible, back and forth along a 50 m hallway. American Thoracic Society states that healthy participants can walk between 400 - 700m.
Short Performance Physical Battery (SPPB) [2 weeks]
a test of balance, gait, strength, and endurance that combines gait speed, chair stand and balance tests. SPPB scale ranges from 0 - 12. 0 indicating that the participant is unable/barely able to perform the tasks while 12 indicates they are completed all tasks optimally.
Mitochondrial Respiration [2 weeks]
Mitochondrial respiration is assessed at baseline and 2 weeks using Oroboros equipment. The capacity of nitrate supplementation as Beet-root juice supplement to improve State 3 respiration will be assessed.
Peak oxygen utilization (VO2) [2 weeks]
Peak VO2 will be collected using symptom-limited cardiopulmonary exercise testing (CPET). The average sedentary male will achieve a peak VO2 of approximately 35 to 40 mL/kg/min. The average sedentary female will score a VO2 max of between 27 and 30 mL/kg/min.
VO2 at anaerobic threshold (AT) [2 weeks]
VO2 at AT will be assessed using symptom-limited CPET. The VO2 at AT for the general population occurs at approximately 50-60% of the peak VO2.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Veterans with prior COVID-19, with residual symptoms of long COVID including increased fatigability (i.e., RPE 10 during steady-state walking and reduced physical activity (<8 Mets/day)).
Inclusion limited to age 18 and over

Exclusion Criteria:

Blood pressure <110/60 mmHg, either systolic or diastolic value
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 or <10.0 g/dL)
Unstable psychiatric diagnosis
Clinically significant alcohol intake (CAGE score 2 or >) 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.
Involved in another greater than minimal risk study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania	United States	15240

Sponsors and Collaborators

VA Office of Research and Development
University of Pittsburgh

Investigators

Principal Investigator: Daniel E. Forman, MD, VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

VA Office of Research and Development

ClinicalTrials.gov Identifier:

NCT05618574

Other Study ID Numbers:

F4409-P

First Posted:

Nov 16, 2022

Last Update Posted:

Jan 20, 2023

Last Verified:

Jan 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Keywords provided by VA Office of Research and Development

Nitrate therapeutics

Long COVID

Skeletal Muscle Mitochondrial Respiration

Fatigability

Cardiorespiratory Fitness

Study Results

No Results Posted as of Jan 20, 2023