Clinical trial NCT03595774: Dose-response Effect of Dietary Nitrate on Muscle Function in Older Individuals
Official title: Dose-response Effect of Dietary Nitrate on Muscle Function in Older Individuals
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Aging
Sarcopenia
Keywords: nitric oxide
Lead sponsor: Indiana University
Sponsor class: OTHER
First posted: 2018-07-23
Enrollment: 13
Sex: ALL
Minimum age (years): 65
Maximum age (years): 79
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double-blind, placebo-controlled, crossover
Primary purpose: TREATMENT

Brief summary: Nitrate is a naturally-occurring substance found in foods, especially green leafy vegetables and beets. Increasing nitrate intake (by drinking beetroot juice (BRJ) has been shown to improve muscle function young and middle-aged subjects, athletes, and patients with heart failure. The purpose of this study is to determine whether dietary nitrate provides a similar benefit in older individuals, and if so, the optimal dose. We will be comparing the effects of ingesting BRJ containing a smaller or greater amount of nitrate versus the effects of a placebo (BRJ from which the nitrate has been removed).

Detailed description: This study consists of four visits that will take a minimum of 15 days to complete.

Study Visit One (Screening) 1-2 hours The purpose of the screening visit is to explain all aspects of the study. The investigators will also determine if individuals can participate in the study. Eligible subjects will undergo a complete medical history and physical exam. They will have their blood drawn, and will provide a urine sample (to determine if they are pregnant). Subjects will also practice the entire neuromuscular function exercise test. During this test, the strength of the subject's muscles will be determined by having them kick, push and/or pull back as hard as they can while their leg is strapped to an exercise device. Blood pressure and heart rate and rhythm will be monitored.

Subjects will be instructed to consume their normal diet throughout the study. However, they will be asked to avoid eating foods high in nitrate such as beets, spinach, and collard greens the evening before each visit. They will be asked to refrain from the use of antibacterial mouthwash, such as Listerine or Cepacol, during the study. Subjects will also be asked to not chew gum or to consume alcohol or food and drinks that contain caffeine for 24 hour before each visit. This includes coffee, tea, chocolate and soft drinks such as Mountain Dew. Finally, they will be asked to fast for 12 hour prior to each study visit.

Study Visit Two - Approximately 5 hours At the beginning of this visit a catheter (small, flexible, sterile plastic tube) will be placed through a vein in one of the subject's arms. This is for collection of blood samples. Blood will be drawn four times during this visit. Each draw will be 6mL or about 1.2 teaspoons. The first blood draw will check nitrate and nitrogen levels. Subjects will then have a breath test to check nitric oxide. They will then drink about 280 mL (about 1 cup) of BRJ. In one trial, this will be a placebo, that is, BRJ from which the essentially all of the nitrate has been removed. In another trial, they will drink BRJ still containing nitrate. In a third trial, they will drink an equal mixture of the placebo and nitrate-containing BRJ. Blood and breath samples will be obtained every hour. Heart rate and blood pressure will be measured at the same times the blood and breath samples are obtained. About 2 hours after ingestion of BRJ (or placebo) subjects will be asked to perform the neuromuscular function test that was practiced during the screening visit. After completing the exercise test one final blood and breath sample will be obtained.

Study Visits Three and Four

The same procedures completed during Study Visit Two will be performed. The order of treatment (placebo vs. lower dose vs. higher dose of nitrate) will be randomized using a computer program. Neither the subjects nor the investigators will know the treatment they receive during each visit until the entire study is completed.

Eligibility criteria: Inclusion Criteria:

• In good health, as determined by the investigator's review of history (provided by subject at screening visit), physical examination, and routine blood and urine tests (done at screening visit)

Exclusion Criteria:

* Men and women \<65 or \>79 years of age
* Unable to provide informed consent
* Currently pregnant or lactating (given the age range for the study, verbal confirmation by subject is believed to be sufficient)
* Current smokers
* Significant orthopedic limitations or other contraindications to strenuous exercise
* Those taking phosphodiesterase inhibitors (e.g., Viagra)
* Those taking proton pump inhibitors, antacids, xanthine oxidase inhibitors, or on hormone replacement therapy
* Those taking anti-coagulants (e.g., Coumadin) or on anti-platelet therapy
* History of neuromuscular disease (e.g., cervical spondylotic radiculomyelpathy, lumbar spondylosis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, and acquired demyelinating polyneuropathies), cardiovascular disease (e.g., \> stage I hypertension, heart failure, myocardial infarction/ischemia, significant myocardial or pericardial diseases (e.g. amyloidosis, constriction), moderate or severe valvular disease, renal disease, liver disease, or anemia

Primary outcomes:
measure: Maximal Knee Extensor Velocity
timeFrame: 1 day
measure: Maximal Knee Extensor Power
timeFrame: 1 day
Secondary outcomes:
measure: Plasma Nitrite
timeFrame: 0, 1, 2, 3 h after ingestion
measure: Plasma Nitrate
timeFrame: 0, 1, 2, 3 h after ingestion
measure: Breath Nitric Oxide
timeFrame: 0, 1, 2, 3 h after ingestion
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University School of Health and Human Sciences
state: Indiana
Study officials:
affiliation: Indiana University School of Medicine
name: Andrew R Coggan, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Coggan AR. Dietary Nitrate and Muscle Function in Humans: Acute versus Chronic Mechanisms. Med Sci Sports Exerc. 2018 Apr;50(4):874. doi: 10.1249/MSS.0000000000001489. No abstract available.
citation: Coggan AR, Broadstreet SR, Mahmood K, Mikhalkova D, Madigan M, Bole I, Park S, Leibowitz JL, Kadkhodayan A, Thomas DP, Thies D, Peterson LR. Dietary Nitrate Increases VO2peak and Performance but Does Not Alter Ventilation or Efficiency in Patients With Heart Failure With Reduced Ejection Fraction. J Card Fail. 2018 Feb;24(2):65-73. doi: 10.1016/j.cardfail.2017.09.004. Epub 2017 Sep 12.
citation: Coggan AR, Peterson LR. Dietary Nitrate and Skeletal Muscle Contractile Function in Heart Failure. Curr Heart Fail Rep. 2016 Aug;13(4):158-65. doi: 10.1007/s11897-016-0293-9.
citation: Rimer EG, Peterson LR, Coggan AR, Martin JC. Increase in Maximal Cycling Power With Acute Dietary Nitrate Supplementation. Int J Sports Physiol Perform. 2016 Sep;11(6):715-720. doi: 10.1123/ijspp.2015-0533. Epub 2016 Aug 24.
citation: Coggan AR, Leibowitz JL, Spearie CA, Kadkhodayan A, Thomas DP, Ramamurthy S, Mahmood K, Park S, Waller S, Farmer M, Peterson LR. Acute Dietary Nitrate Intake Improves Muscle Contractile Function in Patients With Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Trial. Circ Heart Fail. 2015 Sep;8(5):914-20. doi: 10.1161/CIRCHEARTFAILURE.115.002141. Epub 2015 Jul 15.
citation: Coggan AR, Leibowitz JL, Kadkhodayan A, Thomas DP, Ramamurthy S, Spearie CA, Waller S, Farmer M, Peterson LR. Effect of acute dietary nitrate intake on maximal knee extensor speed and power in healthy men and women. Nitric Oxide. 2015 Aug 1;48:16-21. doi: 10.1016/j.niox.2014.08.014. Epub 2014 Sep 6.