Trial Outcomes & Findings for Nitrites, Skeletal Muscle Mitochondrial Bioenergetics, and Physical Activity in Old Age (NCT NCT04405180)

NCT ID: NCT04405180

Last Updated: 2024-10-10

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 64 participants
• Primary outcome timeframe: 12-week course of study drug supplementation, up to 16 weeks total
• Results posted on: 2024-10-10

Participant Flow

Participant milestones

Measure	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.	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.
Overall Study STARTED	32	32
Overall Study COMPLETED	32	32
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.	Total n=64 Participants Total of all reporting groups
Age, Continuous	75.3 years STANDARD_DEVIATION 5.4 • n=5 Participants	76.1 years STANDARD_DEVIATION 6.0 • n=7 Participants	75.7 years STANDARD_DEVIATION 5.7 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	19 Participants n=7 Participants	36 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants n=5 Participants	31 Participants n=7 Participants	63 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) White	27 Participants n=5 Participants	30 Participants n=7 Participants	57 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Skeletal Muscle Mitochondrial Respiration State 3; Baseline to 12-week Change.	2.2 pmol O2/s/mg DW Standard Deviation 23.4	-0.8 pmol O2/s/mg DW Standard Deviation 18.4

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=12 Participants 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.	Placebo Control Arm n=13 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.
Skeletal Muscle Adenosine Triphosphate (ATP) Production, Baseline to 12-week Change	0.0222 mM ATP/s Standard Deviation 0.1223	-0.0131 mM ATP/s Standard Deviation 0.1263

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Cardiorespiratory Fitness Measured as Peak Oxygen Uptake (Non-weight Normalized VO2) During a Progressive Resistance Cycle Ergometer Exercise Test; Baseline to 12-week Change	-50 ml/minute Standard Deviation 212	-82 ml/minute Standard Deviation 192

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Oxygen Utilization (Non-weight Normalized VO2) During a Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change	-92 ml/minute Standard Deviation 123	-35 ml/minute Standard Deviation 188

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Endurance During a Submaximal Constant Workload Cycle Ergometer Exercise Test; Baseline to 12-week Change.	0.8 minutes Standard Deviation 3.8	-0.1 minutes Standard Deviation 4.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Time to Complete a Fast-paced 400 m Corridor Walk; Baseline to 12-week Change	0.0 minutes Standard Deviation 0.9	-0.2 minutes Standard Deviation 0.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Borg Rating of Perceived Exertion During a 5-minute Slow (1.5 Mph) Fixed Rate Walking Speed Test; Baseline to 12-week Change	-0.3 score on a scale Standard Deviation 1.4	-0.5 score on a scale Standard Deviation 2.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 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).

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Short Physical Performance Battery; Baseline to 12-week Change	-0.1 score on a scale Standard Deviation 1.9	0.4 score on a scale Standard Deviation 1.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Grip Strength; Baseline to 12-week Change	1.3 kg Standard Deviation 3.8	-0.5 kg Standard Deviation 2.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	20 mg Sodium Nitrite TID Arm n=32 Participants 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.	Placebo Control Arm n=32 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.
Physical Activity (Accelerometry), Measured as Daily Step Count; Baseline to 12-week Change	118 steps Standard Deviation 1244	-180 steps Standard Deviation 954

Adverse Events

20 mg Sodium Nitrite TID Arm

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Placebo Control Arm

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	20 mg Sodium Nitrite TID Arm n=32 participants at risk 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.	Placebo Control Arm n=32 participants at risk 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.
Cardiac disorders Other	0.00% 0/32 • 16 weeks	3.1% 1/32 • Number of events 1 • 16 weeks

Other adverse events

Measure	20 mg Sodium Nitrite TID Arm n=32 participants at risk 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.	Placebo Control Arm n=32 participants at risk 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.
Gastrointestinal disorders Gastroesophogeal Reflux Disease	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Infections and infestations	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Infections and infestations Sinusitis	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Infections and infestations Upper Respiratory Infection	0.00% 0/32 • 16 weeks	6.2% 2/32 • 16 weeks
Infections and infestations Urinary Tract Infection	0.00% 0/32 • 16 weeks	6.2% 2/32 • 16 weeks
Infections and infestations Other	9.4% 3/32 • 16 weeks	18.8% 6/32 • 16 weeks
Injury, poisoning and procedural complications Fall	3.1% 1/32 • 16 weeks	9.4% 3/32 • 16 weeks
Musculoskeletal and connective tissue disorders Back Pain	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Musculoskeletal and connective tissue disorders Joint Range of Motion Decreased	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Musculoskeletal and connective tissue disorders Pain in Extremity	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Nervous system disorders Presyncope	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks
Psychiatric disorders Depression	3.1% 1/32 • 16 weeks	3.1% 1/32 • 16 weeks
Renal and urinary disorders Urinary Tract Pain	0.00% 0/32 • 16 weeks	3.1% 1/32 • 16 weeks
Respiratory, thoracic and mediastinal disorders Allergic Rhinitis	6.2% 2/32 • 16 weeks	0.00% 0/32 • 16 weeks
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/32 • 16 weeks	3.1% 1/32 • 16 weeks
Respiratory, thoracic and mediastinal disorders Dyspnea	6.2% 2/32 • 16 weeks	3.1% 1/32 • 16 weeks
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	0.00% 0/32 • 16 weeks	3.1% 1/32 • 16 weeks
Respiratory, thoracic and mediastinal disorders Other	0.00% 0/32 • 16 weeks	3.1% 1/32 • 16 weeks
Vascular disorders Hypertension	3.1% 1/32 • 16 weeks	0.00% 0/32 • 16 weeks

Additional Information

Dr. Daniel Forman

University of Pittsburgh

Phone: 412-864-2507

Email: formand@pitt.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place