AgingPhase 2NitriteNCT04405180
Nitrites, Skeletal Muscle Mitochondrial Bioenergetics, and Physical Activity in Old Age
A Phase 2 study testing 20mg sodium nitrite tid in people with Aging and Sedentary Lifestyle, run by Gladwin, Mark, MD at 1 site in United States.
Trial summary
This 2-site randomized double blinded controlled trial is to confirm and more definitively clarify the impact of a 12-week course of nitrite versus placebo on mitochondrial bioenergetics in older sedentary adults. Read more about this study
- Who is it for?
- Ages 70 years and older
- Conditions the study is for
- Aging, Sedentary Lifestyle, Frailty
- What is being tested?
- 20mg sodium nitrite tid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 64 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Apr 2021to 14 Jul 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 70 years and older
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Age ≥70 years
- Sedentary (<1 hour/week of volitional exercise activity)
- Clinically stable (euvolemic; baseline HR <100 bpm) and without hospitalization or invasive cardiac procedure for 6 weeks
Who cannot join
- Blood pressure <110 or >160/95 mmHg
- Orthopedic or other chronic condition which limits physical activity or exercise testing assessments
- If valve replacement has been performed, patient may not be enrolled for 12 months after this procedure
- Severe peripheral or pulmonary artery disease
- Anemia: Hgb <11.0 (♂),10.0 (♀) gm/dl
- Participants with diabetes whose HgbA1c >10.0%
Show all 16Show fewer
- Chronic alcohol (>14 drinks ETOH a week) or drug (any cocaine, methamphetamine, and cannabis ≥4 x week) dependency
- Allergy to lidocaine and red dye
- Chronic use of oral corticosteroids or other medications that affect muscle function
- Current use of organic nitrates or phosphodiesterase type 5 (PDE5) inhibitors
- Unable to hold warfarin, direct-acting oral anticoagulants (DOACs), non-steroidal anti-inflammatory medications (NSAIDs) or aspirin for 3 days prior to muscle biopsy, or to hold thienopyridine medications for 5 days prior to muscle biopsy. Participants unable or unwilling to hold will follow the modified ASA hold plan
- Any bleeding disorder that would contraindicate biopsy such as history of clinically significant bleeding diathesis (e.g., Hemophilia A or B, Von Willebrand's Disease or congenital Factor VII deficiency)
- Unstable psychiatric diagnosis that would affect adherence and ability to complete the protocol
- Dementia or inability to give informed consent or follow study protocol
- End-stage disease
- Other chronic unstable disease such as active neoplasm, end stage chronic kidney, liver or other organ disease
Trial locations and contacts
1 site in 1 country.
United States1 site
University Of Pittsburgh
Pittsburgh, Pennsylvania, 15213
About this study
This 2-site randomized double blinded controlled trial is to confirm and more definitively clarify the impact of a 12-week course of nitrite versus placebo on mitochondrial bioenergetics in older sedentary adults. This investigator will take an integrative physiology approach to determine the effect of nitrite therapy on a comprehensive assessment of mitochondrial energetics, skeletal muscle vascular function, and whole body physical function (cardiorespiratory function, exercise endurance, strength, balance, and physical activity) and fatigability.
Read the detailed description
Old age is associated with declining skeletal muscle mitochondrial bioenergetics with related decrements in cardiorespiratory fitness (CRF) and physical function that predispose to frailty, disability, and diminished quality of life. While exercise training may moderate and possibly even reverse declines in mitochondrial bioenergetics, potential for such benefit is typically confounded by exercise intolerance with early fatigability that results from the same age-related mitochondrial declines. Consequently, sedentariness is endemic and insidious among the growing population of older adults. This trial is to study the utility of inorganic nitrite salts as a novel means to modify this detrimental pattern. Classic studies demonstrate that nitrite facilitates hypoxic vasodilation in muscle. This investigator's preliminary data suggests that nitrite treatment also augments skeletal muscle mitochondrial bioenergetics in older adults. This investigator proposes improving mitochondrial function will also be reflected in clinical parameters, including CRF as well as broader functional attributes (endurance, strength, and balance) that enable physical activity (PA) and opportunity to mitigate frailty and disability. As such, this application is in line with the National Institute on Aging's mission to develop targeted interventions to prevent and treat age-associated conditions. This multi-disciplinary team has published seminal work indicating that mitochondrial bioenergetics and CRF are significant determinants of physical function in older adults. In parallel efforts, this investigative team showed efficacy of chronic nitrite therapy to improve mitochondrial bioenergetics in older sedentary adults. Only one month of nitrite therapy significantly improved ex vivo assessments of mitochondrial energetics in skeletal muscle biopsies, concomitant with increased skeletal muscle sirtuin-3 expression, a nicotinamide adenine dinucleotide (NAD) dependent lysine deacetylase and key regulator of mitochondrial metabolism. These key data reinforce the premise that nitrite enhances vital mitochondrial metabolism in older adults. Moreover, improvement in muscle energetics in nitrite-treated older adults was linked with increased exercise efficiency as evidenced by reduced oxygen consumption (VO2) during submaximal steady-state walking. This data supports the hypothesis that nitrite will make physical function easier such that physical activity will increase.
- Conditions
- Aging, Sedentary Lifestyle, Frailty
- Being tested
- Placebos, 20mg sodium nitrite tid
- Keywords
- 70 and Older, Bioenergetics, Frailty
- Medical subject headings
- Sedentary Behavior, Frailty
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlacebosDrug
Also called Placebo
Oral placebo capsule at a dose of 20 mg administered three times per day, during the day.
20mg sodium nitrite tidDrug
Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day.
| Study group | Role | What they receive |
|---|---|---|
| 20 mg Sodium Nitrite TID Arm | Experimental | Subject is to receive active study drug three times per day during treatment (12 weeks +/- 5 days) period and then after the treatment period (up to 16 weeks total). Receives: Drug: 20mg sodium nitrite tid |
| Placebo Control Arm | Placebo comparator | Subject is to receive placebo three times per day during treatment period (12 weeks +/- 5 days) and then after the treatment testing period (up to 16 weeks total). Receives: Drug: Placebos |
What is being measured
The primary outcome is the main question the study is designed to answer.
Skeletal Muscle Mitochondrial Respiration State 3; Baseline to 12-week Change.
High resolution respirometry via Oroboros Oxygraph 2k is used to assess the effects of 12 weeks of inorganic nitrite vs placebo on skeletal muscle mitochondrial respiration from samples obtained via vastus lateralis muscle biopsy.
Measured: 12-week course of study drug supplementation, up to 16 weeks total
Secondary outcomes (1)
Skeletal Muscle Adenosine Triphosphate (ATP) Production, Baseline to 12-week Change
Using phosphorus-magnetic resonance spectroscopy, we will measure ATPmax (recovery rate) and how it will change after 12 weeks (up to 16 weeks) of inorganic nitrite supplementation vs placebo
Measured: 12-week course of study drug supplementation, up to 16 weeks total
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 May 2020
- Study start23 Apr 2021
- Primary completion14 Jul 2023
- Study completion14 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for AgingStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Parallel assignment
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 64 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gladwin, Mark, MD
- Collaborators
- National Institutes of Health (NIH), National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Daniel Forman, MD, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04405180
- Sponsor's protocol ID
- STUDY20110334
- Other IDs
- R01AG058883
- Acronym
- Nitrite
- Status last verified
- Oct 2024
- First submitted
- 15 Apr 2019
- Last updated
- 10 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-Identified data may be shared with other future investigators as research questions arise.
Publications
Forman DE, Perera S, Shiva S, Glynn NW, Stakich TS, Ramos SV, Distefano G, Wolf C, Kendi A, Sterczala AJ, Sipula IJ, Bello FM, Jurczak MJ, Sciurba FC, Gladwin MT, Newman AB, Coen PM. Benefits of oral nitrite supplementation on mitochondrial respiration and physical function in older adults. J Gerontol A Biol Sci Med Sci. 2026 Mar 10;81(4):glag034. doi: 10.1093/gerona/glag034.
PubMed 41691463
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nitrites, Skeletal Muscle Mitochondrial Bioenergetics, and Physical Activity in Old Age
- ClinicalTrials.gov ID
- NCT04405180
- Acronym / sponsor ID
- Nitrite / STUDY20110334
- Conditions
- Aging, Sedentary Lifestyle, Frailty
- Keywords
- 70 and Older, Bioenergetics, Frailty
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 64 participants (actual)
- Lead sponsor
- Gladwin, Mark, MD
- Collaborators
- National Institutes of Health (NIH), National Institute on Aging (NIA)
- Study start
- 23 Apr 2021 (actual)
- Primary completion
- 14 Jul 2023 (actual)
- Study completion
- 14 Jul 2023 (actual)
- First posted
- 28 May 2020 (actual)
- Results
- Posted 10 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This 2-site randomized double blinded controlled trial is to confirm and more definitively clarify the impact of a 12-week course of nitrite versus placebo on mitochondrial bioenergetics in older sedentary adults. This investigator will take an integrative physiology approach to determine the effect of nitrite therapy on a comprehensive assessment of mitochondrial energetics, skeletal muscle vascular function, and whole body physical function (cardiorespiratory function, exercise endurance, strength, balance, and physical activity) and fatigability.
Detailed description
Old age is associated with declining skeletal muscle mitochondrial bioenergetics with related decrements in cardiorespiratory fitness (CRF) and physical function that predispose to frailty, disability, and diminished quality of life. While exercise training may moderate and possibly even reverse declines in mitochondrial bioenergetics, potential for such benefit is typically confounded by exercise intolerance with early fatigability that results from the same age-related mitochondrial declines. Consequently, sedentariness is endemic and insidious among the growing population of older adults. This trial is to study the utility of inorganic nitrite salts as a novel means to modify this detrimental pattern. Classic studies demonstrate that nitrite facilitates hypoxic vasodilation in muscle. This investigator's preliminary data suggests that nitrite treatment also augments skeletal muscle mitochondrial bioenergetics in older adults. This investigator proposes improving mitochondrial function will also be reflected in clinical parameters, including CRF as well as broader functional attributes (endurance, strength, and balance) that enable physical activity (PA) and opportunity to mitigate frailty and disability. As such, this application is in line with the National Institute on Aging's mission to develop targeted interventions to prevent and treat age-associated conditions. This multi-disciplinary team has published seminal work indicating that mitochondrial bioenergetics and CRF are significant determinants of physical function in older adults. In parallel efforts, this investigative team showed efficacy of chronic nitrite therapy to improve mitochondrial bioenergetics in older sedentary adults. Only one month of nitrite therapy significantly improved ex vivo assessments of mitochondrial energetics in skeletal muscle biopsies, concomitant with increased skeletal muscle sirtuin-3 expression, a nicotinamide adenine dinucleotide (NAD) dependent lysine deacetylase and key regulator of mitochondrial metabolism. These key data reinforce the premise that nitrite enhances vital mitochondrial metabolism in older adults. Moreover, improvement in muscle energetics in nitrite-treated older adults was linked with increased exercise efficiency as evidenced by reduced oxygen consumption (VO2) during submaximal steady-state walking. This data supports the hypothesis that nitrite will make physical function easier such that physical activity will increase.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Parallel assignment
| Arm | Type | Receives |
|---|---|---|
| 20 mg Sodium Nitrite TID Arm | Experimental | Drug: 20mg sodium nitrite tidSubject is to receive active study drug three times per day during treatment (12 weeks +/- 5 days) period and then after the treatment period (up to 16 weeks total). |
| Placebo Control Arm | Placebo comparator | Drug: PlacebosSubject is to receive placebo three times per day during treatment period (12 weeks +/- 5 days) and then after the treatment testing period (up to 16 weeks total). |
Who may qualify
- Ages
- 70 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (3 listed)
- Age ≥70 years
- Sedentary (<1 hour/week of volitional exercise activity)
- Clinically stable (euvolemic; baseline HR <100 bpm) and without hospitalization or invasive cardiac procedure for 6 weeks
Key exclusion criteria (16 listed)
- Blood pressure <110 or >160/95 mmHg
- Orthopedic or other chronic condition which limits physical activity or exercise testing assessments
- If valve replacement has been performed, patient may not be enrolled for 12 months after this procedure
- Severe peripheral or pulmonary artery disease
- Anemia: Hgb <11.0 (♂),10.0 (♀) gm/dl
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlacebosAlso: PlaceboOral placebo capsule at a dose of 20 mg administered three times per day, during the day. | Drug | Placebo Control Arm |
| 20mg sodium nitrite tidOral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day. | Drug | 20 mg Sodium Nitrite TID Arm |
Primary outcome
Skeletal Muscle Mitochondrial Respiration State 3; Baseline to 12-week Change.
Time frame: 12-week course of study drug supplementation, up to 16 weeks total
High resolution respirometry via Oroboros Oxygraph 2k is used to assess the effects of 12 weeks of inorganic nitrite vs placebo on skeletal muscle mitochondrial respiration from samples obtained via vastus lateralis muscle biopsy.
1 secondary outcome
Skeletal Muscle Adenosine Triphosphate (ATP) Production, Baseline to 12-week Change
Time frame: 12-week course of study drug supplementation, up to 16 weeks total
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41691463Forman DE, Perera S, Shiva S, Glynn NW, Stakich TS, Ramos SV, Distefano G, Wolf C, Kendi A, Sterczala AJ, Sipula IJ, Bello FM, Jurczak MJ, Sciurba FC, Gladwin MT, Newman AB, Coen PM. Benefits of oral nitrite supplementation on mitochondrial respiration and physical function in older adults. J Gerontol A Biol Sci Med Sci. 2026 Mar 10;81(4):glag034. doi: 10.1093/gerona/glag034.
- Individual participant dataSharing planned: Yes. De-Identified data may be shared with other future investigators as research questions arise.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 20mg sodium nitrite tid in people with Aging and Sedentary Lifestyle, run by Gladwin, Mark, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Skeletal Muscle Mitochondrial Respiration State 3; Baseline to 12-week Change. (time frame: 12-week course of study drug supplementation, up to 16 weeks total). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04405180, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2024.