Nitrites, Skeletal Muscle Mitochondrial Bioenergetics, and Physical Activity in Old Age

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04405180

Acronym

Nitrite

Enrollment

Registered

2020-05-28

Start date

2021-04-23

Completion date

2023-07-14

Last updated

2024-10-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Aging, Frailty, Sedentary Lifestyle

Keywords

70 and Older, Bioenergetics, Frailty

Brief 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. 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.

Interventions

DRUGPlacebos

Oral placebo capsule at a dose of 20 mg administered three times per day, during the day.

DRUG20mg sodium nitrite tid

Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Quadruple: Participant, Care Provider, Investigator, Outcome Assessor

Intervention model description

Parallel assignment

Eligibility

Sex/Gender

ALL

Age

70 Years to No maximum

Healthy volunteers

Inclusion criteria

* 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

Exclusion criteria

* 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% * 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

Design outcomes

Primary

Measure	Time frame	Description
Skeletal Muscle Mitochondrial Respiration State 3; Baseline to 12-week Change.	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.

Secondary

Measure	Time frame	Description
Skeletal Muscle Adenosine Triphosphate (ATP) Production, Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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

Other

Measure	Time frame	Description
Endurance During a Submaximal Constant Workload Cycle Ergometer Exercise Test; Baseline to 12-week Change.	12-week course of study drug supplementation, up to 16 weeks total	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.
Time to Complete a Fast-paced 400 m Corridor Walk; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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.
Borg Rating of Perceived Exertion During a 5-minute Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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.
Cardiorespiratory Fitness Measured as Peak Oxygen Uptake (Non-weight Normalized VO2) During a Progressive Resistance Cycle Ergometer Exercise Test; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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.
Grip Strength; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	Maximum grip strength is assessed before and after 12 weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo.
Physical Activity (Accelerometry), Measured as Daily Step Count; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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.
Short Physical Performance Battery; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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).
Oxygen Utilization (Non-weight Normalized VO2) During a Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change	12-week course of study drug supplementation, up to 16 weeks total	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	32
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.	32
Total	64

Baseline characteristics

Characteristic	20 mg Sodium Nitrite TID Arm	Total	Placebo Control Arm
Age, Continuous	75.3 years STANDARD_DEVIATION 5.4	75.7 years STANDARD_DEVIATION 5.7	76.1 years STANDARD_DEVIATION 6
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants	63 Participants	31 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	5 Participants	6 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	27 Participants	57 Participants	30 Participants
Sex: Female, Male Female	15 Participants	28 Participants	13 Participants
Sex: Female, Male Male	17 Participants	36 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 32	0 / 32
other Total, other adverse events	10 / 32	14 / 32
serious Total, serious adverse events	0 / 32	1 / 32

Outcome results

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.