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

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ClinicalTrials.gov Identifier: NCT04405180
Recruitment Status : Recruiting
First Posted : May 28, 2020
Last Update Posted : June 7, 2022
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Daniel Forman, MD, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Aging Sedentary Lifestyle Frailty Drug: Placebos Drug: 20mg sodium nitrite tid Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Quadruple: Participant, Care Provider, Investigator, Outcome Assessor
Primary Purpose: Treatment
Official Title: Nitrites, Skeletal Muscle Mitochondrial Bioenergetics, and Physical Activity in Old Age
Actual Study Start Date : April 23, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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).
Drug: 20mg sodium nitrite tid
Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day.

Placebo Comparator: 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).
Drug: Placebos
Oral placebo capsule at a dose of 20 mg administered three times per day, during the day.
Other Name: Placebo




Primary Outcome Measures :
  1. 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 ]
    We will use high resolution respirometry via Oroboros Oxygraph 2k 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 Outcome Measures :
  1. 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 ]
    Using phosphorus-magnetic resonance spectroscopy, we will measure ATP production and how it will change after 12 weeks (up to 16 weeks) of inorganic nitrite supplementation vs placebo.

  2. Change in cross-sectional area for each fiber type by skeletal muscle microscopy, Baseline to 12-week change [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using microscopy and immmunofluorescence, we will measure the cross-sectional area for each fiber type, relative fiber type number, and relative area composition of each muscle fiber type and mitochondrial content (area/section) after 12 weeks of inorganic nitrite supplementation vs placebo.

  3. Change in relative fiber type number by skeletal muscle microscopy, Baseline to 12-week change [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using microscopy and immmunofluorescence, we will measure the cross-sectional area for each fiber type, relative fiber type number, and relative area composition of each muscle fiber type and mitochondrial content (area/section) after 12 weeks of inorganic nitrite supplementation vs placebo.

  4. Change in relative area composition of each muscle fiber type by skeletal muscle microscopy, Baseline to 12-week change [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using microscopy and immmunofluorescence, we will measure the cross-sectional area for each fiber type, relative fiber type number, and relative area composition of each muscle fiber type and mitochondrial content (area/section) after 12 weeks of inorganic nitrite supplementation vs placebo.

  5. Change in mitochondrial content (area/section) by skeletal muscle microscopy, Baseline to 12-week change [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using microscopy and immmunofluorescence, we will measure the cross-sectional area for each fiber type, relative fiber type number, and relative area composition of each muscle fiber type and mitochondrial content (area/section) after 12 weeks of inorganic nitrite supplementation vs placebo.


Other Outcome Measures:
  1. Baseline to 12-week change in Peak oxygen uptake (VO2) achieved during progressive resistance exercise testing [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]

    We will measure changes in cardiorespiratory fitness including Peak oxygen uptake (VO2) achieved during progressive resistance exercise testing (Increased VO2 notes increased oxygen uptake).

    These will be assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo.


  2. Baseline to 12-week change in VO2 during steady state exercise [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]

    We will measure changes in cardiorespiratory fitness including VO2 during steady state exercise (Increased VO2 notes increased oxygen uptake).

    These will be assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo.


  3. Baseline to 12-week change in duration of constant work rate exercise [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]

    We will measure changes in cardiorespiratory fitness including duration of constant work rate exercise (longer times denote increased exercise capacity).

    These will be assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo.


  4. Baseline to 12-week change in time of 400 m corridor walking [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]

    We will measure changes in cardiorespiratory fitness including time of 400 m corridor walking (decreased time denote increased exercise capacity).

    These will be assessed before and after 12 weeks (16 weeks total) of oral inorganic nitrite supplementation vs placebo.


  5. Baseline to 12-week change in fatiguability during Steady State walking [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using the Borg Rating of Perceived Exertion (units 6-20), we will measure how much fatiguing the steady-state walking test (at 1.5 mph) is to the participant. We will compare this to the RPE of this test again after 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. Lower RPE notes improvement.

  6. Short Physical Performance Battery, Baseline to 12-week change [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Will assess SPPB Score and its change after 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. Higher score shows improvement.

  7. Handgrip Strength, Baseline to 12-week change [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Will assess handgrip strength in the dominant hand, and its change after 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. Higher score shows improvement.

  8. Steps - Physical activity (accelerometry) [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using an Actigraph accelerometry device on the participant's wrist, will assess daily steps and its change with 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. Higher number of steps note improvement.

  9. Vector Magnitude Counts - Physical activity (accelerometry) [ Time Frame: 12-week course of study drug supplementation, up to 16 weeks total ]
    Using an Actigraph accelerometry device on the participant's wrist, will assess daily vector magnitude counts and its change with 12-weeks (up to 16-weeks) of inorganic nitrite supplementation vs placebo. Higher number of counts note improvement.



Information from the National Library of Medicine

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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04405180


Contacts
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Contact: Tara S Stakich, RN 412-864-2082 TSS54@pitt.edu
Contact: Daniel E Forman, MD 412-864-2507 Formand@pitt.edu

Locations
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United States, Pennsylvania
University Of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Tara Stakich    412-864-2082    tss54@pitt.edu   
Contact: Tara Stakich    4128642082    tss54@pitt.edu   
Principal Investigator: Daniel E Forman, MD         
Sponsors and Collaborators
Gladwin, Mark, MD
National Institutes of Health (NIH)
National Institute on Aging (NIA)
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Responsible Party: Daniel Forman, MD, Professor, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04405180    
Other Study ID Numbers: STUDY20110334
R01AG058883 ( U.S. NIH Grant/Contract )
First Posted: May 28, 2020    Key Record Dates
Last Update Posted: June 7, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-Identified data may be shared with other future investigators as research questions arise.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: A limit in time frame of sharing has not been defined.
Access Criteria: Only de-identified data approved for sharing by PI.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Daniel Forman, MD, University of Pittsburgh:
70 and Older
Bioenergetics
Frailty
Additional relevant MeSH terms:
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Frailty
Pathologic Processes