Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04732247 |
| Other study ID # |
IRB-2020-0000 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2022 |
| Est. completion date |
September 15, 2023 |
Study information
| Verified date |
June 2023 |
| Source |
Florida Institute for Human and Machine Cognition |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Naval Special Warfare (NSW) operators are exposed to a variety of extreme environmental
conditions and intense physical demands. In addition to breathing high pressure gases at
depth, prolonged cold water immersion and inadequate recovery from sustained physical
exertion negatively impact individual and team performance. Biotechnologies that could
mitigate the effects of cold as well as support physical recovery represent a significant
unmet need for the NSW operational community.
Oxytocin (OT) has a wide range of actions both locally in the brain and peripherally in the
body including skeletal muscle. These peripheral effects can be mediated by classic
ligand-receptor activation given the abundant expression of the oxytocin receptor in
peripheral tissues, along with local expression of OT in peripheral tissues where it is
likely to act in an autocrine manner. Exogenous OT via intranasal administration is FDA
Investigational New Drug (IND)-approved and has been demonstrated as an easy and safe method
to increase circulating OT concentrations that may augment actions on peripheral tissues.
Due to the pleiotropic effects of OT on whole body metabolism, thermogenesis, stress
responses, pain, mood, inflammation, appetite, glycemic control, skeletal homeostasis, and
skeletal muscle repair and regeneration, there is increasing interest in the administration
of exogenous OT for benefits to human health, performance and resilience. However, the
biological mechanisms by which OT exerts tissue-specific effects (e.g., skeletal muscle)
remain poorly understood, particularly in humans. This project is designed to significantly
advance this understanding while testing the central hypothesis that intranasally
administered OT attenuates systemic and skeletal muscle oxidative stress and inflammation
induced by the combined stressor of resistance swim exercise and hyperoxia.
Description:
Naval Special Warfare (NSW) operators are exposed to a variety of extreme environmental
conditions and intense physical demands. In addition to breathing high pressure and hyperoxic
gases at depth, prolonged cold water immersion and inadequate recovery from sustained
physical exertion negatively impact individual and team performance. Biotechnologies that
could mitigate the effects of these extreme conditions as well as support physical recovery
represent a significant unmet need for the NSW operational community.
Oxytocin (OT) has a wide range of actions both locally in the brain and peripherally
including skeletal muscle and a number of peripheral targets. OT may attenuate acute
cardiovascular stress responses, while chronic OT exposure may reduce risk of CVD and other
chronic diseases via anti-inflammatory effects and attenuation of mitochondrial oxidative
stress. These effects can be mediated by classic ligand-receptor activation given the
abundant expression of the oxytocin receptor in peripheral tissues, along with local
expression of OT in peripheral tissues where it is likely to act in an autocrine manner.
Exogenous OT via intranasal administration is FDA Investigational New Drug (IND)-approved and
has been demonstrated as an easy and safe method to increase circulating OT concentrations
that may augment actions on peripheral tissues.
Due to the pleiotropic effects of OT on whole body metabolism, thermogenesis, stress
responses, pain, mood, inflammation, appetite, glycemic control, skeletal homeostasis, and
skeletal muscle repair and regeneration, there is increasing interest in the administration
of exogenous OT for benefits to human health, performance and resilience. However, the
biological mechanisms by which OT exerts tissue-specific effects (e.g., skeletal muscle)
remain poorly understood, particularly in humans.
This project is designed to significantly advance this understanding while testing the
central hypothesis that intranasally administered OT attenuates systemic and skeletal muscle
oxidative stress and inflammation induced by the combined stressor of resistance swim
exercise and hyperoxia. If efficacy is demonstrated, the ultimate deliverable would be an
easily administered, adjunctive biological therapy expected to improve performance and
resilience of undersea warfighters. The planned project will extend current IHMC research
focused on developing biotechnologies to enhance human performance and resilience. The
central hypothesis will be tested via two specific aims - using a rigorous, double-blind,
placebo-controlled, randomized trial leveraging a wash-in design, enrolling N=40 18-39 y/o
men.
Specific Aim 1. To investigate the efficacy of intranasal OT on attenuating systemic and
skeletal muscle oxidative stress and inflammation induced by the combined stressor of
intensive, resistance swim exercise and hyperoxia. Participants will be randomly assigned
with a 1:1 distribution to 48 IU intranasal OT vs. placebo (saline). Investigators will test
the effects of 4x per day (QID) intranasal treatment on performance and the acute
inflammatory and oxidative stress responses to resistance swimming under hyperoxia, along
with the timecourse of recovery over 48 h. To assess blood and muscle oxidative stress
investigators will measure antioxidant enzymes, along with markers of oxidative
stress-induced DNA damage, protein carbonylation, and lipid peroxidation. Systemic
inflammation will be assessed via a 7-plex serum cytokine array, and muscle inflammation will
be assessed via the TNF-a and IL-6 signaling pathways.
Specific Aim 2. To leverage proven molecular mapping strategies to identify key molecular
transducers likely driving any effects of intranasal OT on systemic and muscle oxidative
stress and inflammation throughout 48 h of recovery. Given the paucity of data on mechanisms
by which exogenous OT exerts its effects, the investigators will take a discovery approach to
identify novel molecular networks and pathways that are differentially regulated by OT vs.
placebo during recovery from an intensive, resistance swim exercise under hyperoxia. To
accomplish this the investigators will perform multi-level modeling that integrates data from
metabolomics, transcriptomics (both long and small RNA sequencing from blood plasma and
muscle), and miRNA sequencing of circulating extracellular vesicles (EVs).
If intranasal OT demonstrates efficacy, the deliverable would be an adjunctive biological
therapy that mitigates oxidative stress as well as enhances performance during and recovery
from resistance swimming under hyperoxia.
