Cardiorespiratory Fitness, Long COVID
Conditions
Keywords
Nitrate therapeutics, Long COVID, Skeletal Muscle Mitochondrial Respiration, Fatigability, Cardiorespiratory Fitness
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.
Detailed description
In a proof of concept pilot, the investigators will study 30 Veterans with long COVID, comparing 15 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: We will conduct a pilot randomized controlled trial to study the benefits of nitrate-rich beetroot juice versus placebo in 30 Veterans with a diagnosis of Long COVID. All participants will receive a daily study juice intervention for 2 weeks. All participants will be encouraged to participate in the standard physical therapy program in the Long COVID clinic. Aim 1: To study the efficacy of nitrate-rich juice supplementation to reduce fatigability as measured by rating of perceived exertion (RPE) during submaximal steady-state 1.5 mile per hour walking after two weeks of treatment in patients with Long COVID. Walking efficiency (VO2 per kg) will also be assessed in association with fatigability. Aim 2: To study the benefits of nitrate-rich juice supplementation to increase cardiorespiratory fitness (peak oxygen utilization \[VO2\], VO2 at anaerobic threshold (VAT), 400-meter corridor walk (400MCW), short physical performance battery (SPPB) in patients with Long COVID after two weeks of treatment. Aim 3: To explore the utility of nitrate-rich juice supplementation to enhance skeletal muscle mitochondrial respiration in patients with Long COVID as measured by ex vivo Oroboros analysis.
Interventions
DIETARY_SUPPLEMENT140 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 140 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days vs the placebo.
DIETARY_SUPPLEMENT210 ml of nitrate-depleted placebo
Participants randomized to the placebo arm will receive 210 ml of nitrate-depleted beverage (cranberry juice) per day for 14 days.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
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 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.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Veterans with prior COVID-19, with residual symptoms of long COVID including increased fatigability. * Inclusion limited to age 18 and over
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fatigability | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | 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). This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| Walking Efficiency | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 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. This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 400m Corridor Walk Test (400MCW) | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | This test measures the amount of time it takes the participant to walk a 400-meter course to assess cardiovascular and pulmonary fitness or to predict adverse outcomes such as mobility disability. his is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| Short Performance Physical Battery (SPPB) | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | The SPPB is a test of balance, gait, strength, and endurance that combines gait speed, chair stand and balance tests. SPPB scaled score ranges from 0 - 12. Scores of 0 indicate that the participant is unable/barely able to perform the tasks, while 12 indicates they completed all tasks optimally. This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| Peak Oxygen Utilization (VO2) Non-normalized | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | Peak VO2 (ml/min) non-normalized to weight will be collected using symptom-limited cardiopulmonary exercise testing (CPET). This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| Peak Oxygen Utilization (VO2) Normalized to Weight | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 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. This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| VO2 at Anaerobic Threshold (AT) Non-normalized | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | VO2 (ml/min) non-normalized 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. This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| VO2 at Anaerobic Threshold (AT) Normalized to Weight | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | VO2 (ml/kg/min) 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. This is assessed before and after approx. 14 days of supplementation with Beet-It nitrate beverage vs. placebo. The mean change from baseline to follow-up is used as the outcome measure. |
| Mitochondrial Respiration | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | To determine the impact of nitrite-rich juice supplementation on skeletal muscle mitochondrial respiration on patients with Long COVID, muscle biopsy of the vastus lateralis will be completed at baseline and following 2 weeks of supplementation. At each time point muscle respiratory capacity will be measured using the Oroboros-2k system. The main outcome will be change in state 3 respiration (maxOXPHOS, pmol/mg/min wet.wt.). Data will be reported as Mean +/- standard deviation. |
| Serum Nitrate | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | 5 ml of blood will be collected from participants and spun down using a centrifuge to separate the plasma from the rest of the blood. Serological sampling is completed at baseline and at final visit. Serum nitrite (µmol/L) and nitrate levels (µmol/L) will be measured at baseline and after the study intervention to evaluate the successful metabolism of nitrate (in beetroot juice) to nitrite. |
| Serum Nitrite | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | 5 ml of blood will be collected from participants and spun down using a centrifuge to separate the plasma from the rest of the blood. Serological sampling is completed at baseline and at final visit. Serum nitrite (µmol/L) and nitrate levels (µmol/L) will be measured at baseline and after the study intervention to evaluate the successful metabolism of nitrate (in beetroot juice) to nitrite. |
| Veterans RAND-12 (VR-12) | Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks | The Veterans RAND-12 (VR-12) is a brief self-administered health survey comprised of 12 items used to measure health related quality of life, estimate disease burden, and evaluate disease-specific benchmarks using two score components: Physical Component Score (PCS) and Mental Component Score (MCS). Summary scores are standardized using a t-score transformation (normalized to US population with mean of 50 and standard deviation of 10). A higher PCS represents better self-reported overall physical function; a higher MCS represents better emotional well-being and fewer mental health limitations. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDaniel E Forman, MD
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Baseline characteristics
| Characteristic | — |
|---|---|
| 400m Corridor Walk Test | 5.7 minutes STANDARD_DEVIATION 1.2 |
| Age, Continuous | 61.2 Years STANDARD_DEVIATION 14.3 |
| COVID-19 Hospitalization No | 5 Participants |
| COVID-19 Hospitalization Not Applicable or Not Reported | 2 Participants |
| COVID-19 Hospitalization Yes | 2 Participants |
| COVID-19 Symptoms 1 month to less than 2 months | 1 Participants |
| COVID-19 Symptoms 2 months to less than 3 months | 1 Participants |
| COVID-19 Symptoms 2 weeks to less than 1 month | 1 Participants |
| COVID-19 Symptoms 3 months to less than 4 months | 0 Participants |
| COVID-19 Symptoms 4 months to less than 6 months | 0 Participants |
| COVID-19 Symptoms Greater than 6 months | 9 Participants |
| COVID-19 Symptoms Less than 2 weeks | 0 Participants |
| COVID-19 Symptoms Not Applicable or Not Reported | 2 Participants |
| COVID-19 Vaccination No | 0 Participants |
| COVID-19 Vaccination Not Applicable or Not Reported | 1 Participants |
| COVID-19 Vaccination Yes | 15 Participants |
| Education College degree | 6 Participants |
| Education Graduate or professional degree (Masters or Doctorate) | 5 Participants |
| Education High school degree or GED | 1 Participants |
| Education Less than high school | 0 Participants |
| Education Other | 0 Participants |
| Education Partial college (at least one year) or specialized training | 2 Participants |
| Education Some high school | 0 Participants |
| Employment Status Active duty military service | 0 Participants |
| Employment Status Full time | 3 Participants |
| Employment Status Irregular part time | 1 Participants |
| Employment Status Other | 1 Participants |
| Employment Status Regular part time | 0 Participants |
| Employment Status Retired | 4 Participants |
| Employment Status Unemployed | 0 Participants |
| Employment Status Veteran disability | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Fatigability | 9.3 Score on a scale STANDARD_DEVIATION 2.3 |
| Marital Status Divorced or separated | 3 Participants |
| Marital Status In a relationship | 1 Participants |
| Marital Status Married or permanent partnership | 5 Participants |
| Marital Status Never married | 2 Participants |
| Marital Status Other | 0 Participants |
| Marital Status Widowed | 0 Participants |
| Mitochondrial Respiration | 78.9 pmol/mg/min STANDARD_DEVIATION 13.6 |
| Peak oxygen utilization (VO2) non-normalized (ml/min) | 2012.5 ml/min STANDARD_DEVIATION 824.1 |
| Peak oxygen utilization (VO2) normalized to weight (mL/kg/min) | 21.3 mL/kg/min STANDARD_DEVIATION 7.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Serum Nitrate | 18.3 µmol/L STANDARD_DEVIATION 6.1 |
| Serum Nitrite | 0.9 µmol/L STANDARD_DEVIATION 0.6 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 15 Participants |
| Short Performance Physical Battery (SPPB) | 10.1 Score on a scale STANDARD_DEVIATION 2.2 |
| Social Support Lives alone | 5 Participants |
| Social Support Lives with others | 6 Participants |
| Veterans RAND-12 Mental Component Score | 54.2 T-score STANDARD_DEVIATION 9.4 |
| Veterans RAND-12 Physical Component Score | 36.5 T-score STANDARD_DEVIATION 14.9 |
| VO2 at anaerobic threshold (AT) non-normalized (ml/min) | 1782.7 ml/min STANDARD_DEVIATION 835.3 |
| VO2 at anaerobic threshold (AT) normalized to weight (ml/kg/min) | 16.7 ml/kg/min STANDARD_DEVIATION 6.5 |
| Walking Efficiency | 9.4 ml/kg/min STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 5 / 8 | 0 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
None listed