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| ID | Type | Description | Link |
|---|---|---|---|
| R01AG058883 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute on Aging (NIA) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
|
| 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebos | Drug | Oral placebo capsule at a dose of 20 mg administered three times per day, during the day. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 12-week course of study drug supplementation, up to 16 weeks total |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 12-week course of study drug supplementation, up to 16 weeks total |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiorespiratory Fitness Measured as Peak Oxygen Uptake (Non-weight Normalized VO2) During a Progressive Resistance Cycle Ergometer Exercise Test; Baseline to 12-week Change | Cardiorespiratory fitness is measured as peak oxygen utilization (non-weight normalized VO2) during a progressive resistance cycle ergometer exercise test that is symptom-limited (maximum). This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Of Pittsburgh | Pittsburgh | Pennsylvania | 15213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41691463 | Derived | 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. |
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De-Identified data may be shared with other future investigators as research questions arise.
A limit in time frame of sharing has not been defined.
Only de-identified data approved for sharing by PI.
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| ID | Title | Description |
|---|---|---|
| FG000 | 20 mg Sodium Nitrite TID Arm | 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). 20mg sodium nitrite tid: Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day. |
| FG001 | Placebo Control Arm | 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). Placebos: Oral placebo capsule at a dose of 20 mg administered three times per day, during the day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 20 mg Sodium Nitrite TID Arm | 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). 20mg sodium nitrite tid: Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | pmol O2/s/mg DW | 12-week course of study drug supplementation, up to 16 weeks total |
|
16 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 20 mg Sodium Nitrite TID Arm | 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). 20mg sodium nitrite tid: Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Other | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastroesophogeal Reflux Disease | Gastrointestinal disorders | Systematic Assessment |
Departures from the muscle preservation protocol resulted in widespread ice artifact in the majority of mounted tissue samples. Nearly all muscle samples are non-viable for histological and morphological analyses. Consequently, skeletal muscle histological and morphological outcomes (cross sectional area, fiber type, fiber type area, and mitochondrial content) were omitted due to to technical limitations and predominant doubts regarding the reliability of the data.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Daniel Forman | University of Pittsburgh | 412-864-2507 | formand@pitt.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 28, 2024 | Sep 16, 2024 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 16, 2024 | Sep 17, 2024 | ICF_003.pdf |
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| ID | Term |
|---|---|
| D057185 | Sedentary Behavior |
| D000073496 | Frailty |
| ID | Term |
|---|---|
| D001519 | Behavior |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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Parallel assignment
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Quadruple: Participant, Care Provider, Investigator, Outcome Assessor
| 20mg sodium nitrite tid | Drug | Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day. |
|
| 12-week course of study drug supplementation, up to 16 weeks total |
| Oxygen Utilization (Non-weight Normalized VO2) During a Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change | Oxygen utilization (non-weight normalized VO2) is measured during slow walking during the last minute of a 5-minute slow (1.5 mph) fixed rate walking speed test. This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | 12-week course of study drug supplementation, up to 16 weeks total |
| Endurance During a Submaximal Constant Workload Cycle Ergometer Exercise Test; Baseline to 12-week Change. | Endurance is measured as duration (minutes) of exercise during a constant submaximal workload cycle ergometer exercise (i.e., calibrated at 75-80% of the maximum resistance [watts] achieved in a prior maximum cycle ergometer exercise test). This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | 12-week course of study drug supplementation, up to 16 weeks total |
| Time to Complete a Fast-paced 400 m Corridor Walk; Baseline to 12-week Change | Time to complete a fast-paced 400 m corridor walk is assessed This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | 12-week course of study drug supplementation, up to 16 weeks total |
| Borg Rating of Perceived Exertion During a 5-minute Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change | Fatigability is assessed using the Borg Rating of Perceived Exertion during minute 5 of a 5-minute fixed rate (1.5 mph) slow walking test. Borg Rating of Perceived Exertion is scored on a scale from 6 to 20 with 6 being the least difficult or intense (better) and 20 being the most difficult or intense (worse). This is assessed before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. | 12-week course of study drug supplementation, up to 16 weeks total |
| Short Physical Performance Battery; Baseline to 12-week Change | The Short Physical Performance Battery is assessed before and after 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. The Short Physical Performance Battery score is the aggregate of three sub-scales for balance, gait speed and repeated sit to stand performance. Each of the three sub-scales is scored from 0 to 4 with 0 being the poorest performance and 4 being the best performance. The scores for balance, gait speed, and repeated sit to stand performance are add for a total score ranging from 0 (worst) to 12 (best). | 12-week course of study drug supplementation, up to 16 weeks total |
| Grip Strength; Baseline to 12-week Change | Maximum grip strength is assessed before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. | 12-week course of study drug supplementation, up to 16 weeks total |
| Physical Activity (Accelerometry), Measured as Daily Step Count; Baseline to 12-week Change | Physical activity is measured as daily step count (assessed using an Actigraph accelerometry device on the participant's wrist), before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. | 12-week course of study drug supplementation, up to 16 weeks total |
| Placebo Control Arm |
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). Placebos: Oral placebo capsule at a dose of 20 mg administered three times per day, during the day. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
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). Placebos: Oral placebo capsule at a dose of 20 mg administered three times per day, during the day. |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | mM ATP/s | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Cardiorespiratory Fitness Measured as Peak Oxygen Uptake (Non-weight Normalized VO2) During a Progressive Resistance Cycle Ergometer Exercise Test; Baseline to 12-week Change | Cardiorespiratory fitness is measured as peak oxygen utilization (non-weight normalized VO2) during a progressive resistance cycle ergometer exercise test that is symptom-limited (maximum). This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | ml/minute | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Oxygen Utilization (Non-weight Normalized VO2) During a Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change | Oxygen utilization (non-weight normalized VO2) is measured during slow walking during the last minute of a 5-minute slow (1.5 mph) fixed rate walking speed test. This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | ml/minute | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Endurance During a Submaximal Constant Workload Cycle Ergometer Exercise Test; Baseline to 12-week Change. | Endurance is measured as duration (minutes) of exercise during a constant submaximal workload cycle ergometer exercise (i.e., calibrated at 75-80% of the maximum resistance [watts] achieved in a prior maximum cycle ergometer exercise test). This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | minutes | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Time to Complete a Fast-paced 400 m Corridor Walk; Baseline to 12-week Change | Time to complete a fast-paced 400 m corridor walk is assessed This is assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | minutes | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Borg Rating of Perceived Exertion During a 5-minute Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change | Fatigability is assessed using the Borg Rating of Perceived Exertion during minute 5 of a 5-minute fixed rate (1.5 mph) slow walking test. Borg Rating of Perceived Exertion is scored on a scale from 6 to 20 with 6 being the least difficult or intense (better) and 20 being the most difficult or intense (worse). This is assessed before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | score on a scale | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Short Physical Performance Battery; Baseline to 12-week Change | The Short Physical Performance Battery is assessed before and after 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. The Short Physical Performance Battery score is the aggregate of three sub-scales for balance, gait speed and repeated sit to stand performance. Each of the three sub-scales is scored from 0 to 4 with 0 being the poorest performance and 4 being the best performance. The scores for balance, gait speed, and repeated sit to stand performance are add for a total score ranging from 0 (worst) to 12 (best). | Posted | Mean | Standard Deviation | score on a scale | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Grip Strength; Baseline to 12-week Change | Maximum grip strength is assessed before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | kg | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| Other Pre-specified | Physical Activity (Accelerometry), Measured as Daily Step Count; Baseline to 12-week Change | Physical activity is measured as daily step count (assessed using an Actigraph accelerometry device on the participant's wrist), before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. | Posted | Mean | Standard Deviation | steps | 12-week course of study drug supplementation, up to 16 weeks total |
|
|
|
|
| 0 |
| 32 |
| 0 |
| 32 |
| 10 |
| 32 |
| EG001 | Placebo Control Arm | 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). Placebos: Oral placebo capsule at a dose of 20 mg administered three times per day, during the day. | 0 | 32 | 1 | 32 | 14 | 32 |
| Infections and infestations | Systematic Assessment |
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| Sinusitis | Infections and infestations | Systematic Assessment |
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| Upper Respiratory Infection | Infections and infestations | Systematic Assessment |
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| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
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| Other | Infections and infestations | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
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| Back Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Joint Range of Motion Decreased | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Pain in Extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Presyncope | Nervous system disorders | Systematic Assessment |
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| Depression | Psychiatric disorders | Systematic Assessment |
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| Urinary Tract Pain | Renal and urinary disorders | Systematic Assessment |
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| Allergic Rhinitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Dyspnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Other | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Hypertension | Vascular disorders | Systematic Assessment |
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