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

NCT04405180 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: STUDY20110334R01AG058883
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

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.

Conditions

Aging; Sedentary Lifestyle; Frailty

Keywords

70 and Older; Bioenergetics; Frailty

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (1)

• Skeletal Muscle Adenosine Triphosphate (ATP) Production, Baseline to 12-week Change

  12-week course of study drug supplementation, up to 16 weeks total

Other Outcomes (8)

• 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

• 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

• 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

Study Arms (2)

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).

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).

Drug: Placebos

Interventions

Placebos DRUG

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

Also known as: Placebo

Placebo Control Arm

20mg sodium nitrite tid DRUG

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

20 mg Sodium Nitrite TID Arm

Eligibility Criteria

• Age: 70 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gladwin, Mark, MD: lead
• National Institutes of Health (NIH): collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (1)

University Of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Sedentary Behavior; Frailty

Condition Hierarchy (Ancestors)

Behavior; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

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.

Results Point of Contact

• Title: Dr. Daniel Forman
• Organization: University of Pittsburgh

formand@pitt.edu

412-864-2507

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple: Participant, Care Provider, Investigator, Outcome Assessor
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDIV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Parallel assignment

Study Record Dates

• First Submitted: April 15, 2019
• First Posted: May 28, 2020
• Study Start: April 23, 2021
• Primary Completion: July 14, 2023
• Study Completion: July 14, 2023
• Last Updated: October 10, 2024
• Results First Posted: October 10, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (1)