Nitrite Supplementation in Long COVID Patients

Long COVID Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05618574
• Other study ID #: F4409-P
• Status: Recruiting
• Phase: Phase 3
• Start date: December 1, 2023
• Est. completion date: February 28, 2025

Study information

• Verified date: December 2023
• Source: VA Office of Research and Development
• Contact: Daniel E Forman, MD
• Phone: (412) 360-2917
• Email: Daniel.Forman[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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: To conduct a pilot randomized controlled trial to study the benefits of beetroot juice versus placebo in 30 Veterans with prior COVID-19 infection 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), 400 meter walk test (400MWT), and short physical performance battery (SPPB) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: February 28, 2025
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiorespiratory Fitness
• Long COVID

Intervention

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.

Locations

Country	Name	City	State
United States	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
VA Office of Research and Development	University of Pittsburgh

Country where clinical trial is conducted

United States, 

References & Publications (20)

Ansehn S, Winblad B. Surface morphology of Candida albicans after treatment with antimycotic drugs. Mykosen Suppl. 1978;1:322-7. No abstract available. — View Citation

Appelboom T, Famaey JP. [Allopurinol and gouty hyperuricemia : apropos of 30 cases treated by a single daily dose]. Brux Med. 1977 Mar;57(3):133-7. No abstract available. French. — View Citation

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available. Erratum In: Am J Respir Crit Care Med. 2016 May 15;193(10):1185. — View Citation

Baggiolini M. [The release of proteinases from neutrophil leukocytes and macrophages]. Bull Schweiz Akad Med Wiss. 1979 Sep;35(4-6):283-99. German. — View Citation

Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV; American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee of the Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council on Peripheral Vascular Disease; Interdisciplinary Council on Quality of Care and Outcomes Research. Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010 Jul 13;122(2):191-225. doi: 10.1161/CIR.0b013e3181e52e69. Epub 2010 Jun 28. No abstract available. — View Citation

Czyzewski K, Pudelski J, Dzielicki J, Guzy R. [Respiratory disorders as a consequence of thoracic injuries]. Pol Przegl Chir. 1979 Jan;51(1):1-6. No abstract available. Polish. — View Citation

Devine CJ Jr, Franz JP, Horton CE. Evaluation and treatment of patients with failed hypospadias repair. Trans Am Assoc Genitourin Surg. 1977;69:4-7. — View Citation

Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10. — View Citation

Ferguson SK, Woessner MN, Holmes MJ, Belbis MD, Carlstrom M, Weitzberg E, Allen JD, Hirai DM. Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure. J Appl Physiol (1985). 2021 Apr 1;130(4):914-922. doi: 10.1152/japplphysiol.00780.2020. Epub 2021 Jan 21. — View Citation

Forman DE, Arena R, Boxer R, Dolansky MA, Eng JJ, Fleg JL, Haykowsky M, Jahangir A, Kaminsky LA, Kitzman DW, Lewis EF, Myers J, Reeves GR, Shen WK; American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Stroke Council. Prioritizing Functional Capacity as a Principal End Point for Therapies Oriented to Older Adults With Cardiovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2017 Apr 18;135(16):e894-e918. doi: 10.1161/CIR.0000000000000483. Epub 2017 Mar 23. — View Citation

Gullis RJ, Rowe CE. Pharmacological studies on the stimulation of the phospholipase A2-acylation system of synaptic membranes of brain, by neurotransmitters and other agonists. J Neurochem. 1976 Jun;26(6):1217-30. doi: 10.1111/j.1471-4159.1976.tb07010.x. No abstract available. — View Citation

Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, Scherr PA, Wallace RB. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994 Mar;49(2):M85-94. doi: 10.1093/geronj/49.2.m85. — View Citation

Hirai DM, Zelt JT, Jones JH, Castanhas LG, Bentley RF, Earle W, Staples P, Tschakovsky ME, McCans J, O'Donnell DE, Neder JA. Dietary nitrate supplementation and exercise tolerance in patients with heart failure with reduced ejection fraction. Am J Physiol Regul Integr Comp Physiol. 2017 Jan 1;312(1):R13-R22. doi: 10.1152/ajpregu.00263.2016. Epub 2016 Oct 26. — View Citation

Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol (1985). 2011 Jun;110(6):1582-91. doi: 10.1152/japplphysiol.00071.2011. Epub 2011 Mar 31. — View Citation

Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol (Oxf). 2007 Sep;191(1):59-66. doi: 10.1111/j.1748-1716.2007.01713.x. Epub 2007 Jul 17. — View Citation

Leuenberger AE. [Clinical experience with the O'Malley LOG2 photocoagulator (author's transl)]. Klin Monbl Augenheilkd. 1977 Jan;170(1):143-6. German. — View Citation

Pesta D, Gnaiger E. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol. 2012;810:25-58. doi: 10.1007/978-1-61779-382-0_3. — View Citation

Vogiatzis I, Zakynthinos S. The physiological basis of rehabilitation in chronic heart and lung disease. J Appl Physiol (1985). 2013 Jul 1;115(1):16-21. doi: 10.1152/japplphysiol.00195.2013. Epub 2013 Apr 25. — View Citation

Westman WE. Problems in implementing U.S. water quality goals. Am Sci. 1977 Mar-Apr;65(2):197-203. No abstract available. — View Citation

Woessner MN, Neil C, Saner NJ, Goodman CA, McIlvenna LC, Ortiz de Zevallos J, Garnham A, Levinger I, Allen JD. Effect of inorganic nitrate on exercise capacity, mitochondria respiration, and vascular function in heart failure with reduced ejection fraction. J Appl Physiol (1985). 2020 May 1;128(5):1355-1364. doi: 10.1152/japplphysiol.00850.2019. Epub 2020 Apr 2. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fatigability	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).	2 weeks
Primary	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.	2 weeks
Secondary	6-minute walking test (6MWT)	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.	2 weeks
Secondary	Short Performance Physical Battery (SPPB)	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.	2 weeks
Secondary	Mitochondrial Respiration	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.	2 weeks
Secondary	Peak oxygen utilization (VO2)	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.	2 weeks
Secondary	VO2 at anaerobic threshold (AT)	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.	2 weeks