Clinical trial NCT04890639: Acute Intermittent Hypoxia in Traumatic Brain Injury
Official title: Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Brain Injuries, Traumatic
Keywords: Hypoxia
Lead sponsor: Shirley Ryan AbilityLab
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2021-05-18
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: This study is designed to answer questions related to safety and preliminary efficacy of Acute Intermittent Hypoxia (AIH) in Traumatic Brain Injury (TBI) survivors. First, we aim to establish whether brief reductions in inhaled oxygen concentration can be safely tolerated in TBI survivors. Second, we aim to establish whether there are any effects of AIH on memory, cognition, and motor control. Participants will be monitored closely for any adverse events during these experiments. Data will be analyzed to determine if there is an improvement in key outcomes at any dose level.

Detailed description: The purpose of this study is to determine whether Acute Intermittent Hypoxia (AIH) is safe to administer to medically stable chronic traumatic brain injury (TBI) patients. There is evidence indicating that AIH promotes central nervous system (CNS) neuroplasticity. AIH stimulates oxygen-sensitive serotonergic neurons in the brainstem's raphe nucleus leading to serotonin release into different regions of the CNS. This release leads to activation of serotonin receptors on or near cortical neurons and increased synthesis of multiple trophic factors including brain-derived neurotrophic factor, vascular endothelial growth factor, and erythropoietin. These actions also influence the functioning of neurotransmitters such as GABA. Greater expression of growth factors in the brain facilitates neuroplasticity by increasing synaptic strength, cortical neuron and interneuron excitability, and intra- and inter-brain region connectivity. Of note is that hypoxia-induced neuroplasticity only occurs with acute intermittent exposure, but is not evoked by continuous hypoxia of the same duration. Is AIH safe to administer to TBI patients? The preponderance of prior animal and human evidence suggests that daily episodes of mild AIH do not negatively impact important safety parameters such as resting blood pressure, arterial pressure, heart rate, heart rate variability, cardiac output, or cognitive function. To date, AIH protocols that induce beneficial neuroplasticity without triggering pathological sequelae have been restricted to brief episodes of modest hypoxia with a low cycle number, such as 15 x 90-second episodes of 10% inspired oxygen. Recent studies in humans with chronic spinal cord injury and stroke demonstrated that these modest AIH episodes repeated for five consecutive days can be safely tolerated without pathological consequences. Another recent study showed that even a 4-week protocol of moderate daily AIH (cycling 9%/21% oxygen every 1.5 minutes, 15 cycles per day, for 4 weeks) does not elicit adverse medical consequences or cognitive impairment. Thus, the cumulative evidence suggests that repetitive AIH may be safely used to study whether it can enhance neurobehavioral functioning in TBI patients without deleterious effects. In this study, we will administer mild AIH to 16 patients on four different days spread over the course of two to four weeks, starting with normal oxygen concentration (target SpO2 of 98%) and then progressively reducing the oxygen concentrations over the next three sessions (to 93%, 87%, and 82%). Our primary objective is to determine whether it is safe to administer mild AIH to chronic TBI patients with persistent functional impairments, but who are clinically stable. As a secondary objective in this study, we will assess whether mild AIH administration has any post-session or cumulative effects post-study on memory and cognition, cortical activation as assessed by single-pulse Transcranial Magnetic Stimulation, or whether pre-study brain architecture or functional connectivity as detected by structural and resting-state functional magnetic resonance imaging predicts response to AIH. If no adverse effects to mild AIH are observed in this study, clinical trials using mild AIH alone or in conjunction with neurobehavioral therapies could evaluate whether AIH facilitates the improvement of functional performance after TBI.

Eligibility criteria: Inclusion Criteria:

* Aged 18-65 years
* A first time, mild to moderate traumatic brain injury (TBI) confirmed by medical records
* When available, a Glasgow Coma Scale score between 9-15
* Able to use a keyboard
* Able to understand and communicate in English
* Able to consent independently
* Able to leave a research visit with a companion/group transportation
* Women of child-bearing age must be comfortable confirming a negative pregnancy prior to participating in the study
* Not involved in any other research intervention study testing neurobehavioral functioning

Exclusion Criteria:

* Other neurological diagnoses or a diagnosis of severe psychiatric disorder (e.g., psychosis) or a reported childhood learning disability
* Severe aphasia, preventing a participant from understanding the protocol and consent form
* Pre-existing hypoxic pulmonary disease
* Severe hypertension (\>160/100)
* Medically documented history of obstructive lung diseases \[e.g., Chronic obstructive pulmonary disease (COPD) or significant asthma\]
* Ischemic cardiac disease
* Ineligible to undergo MRI or TMS

Primary outcomes:
measure: Change in Vitals
timeFrame: Assessed and reported in real time throughout each 30-minute hypoxia session
measure: Change in Verbal Response to a 9-Item Subjective Symptom Checklist
timeFrame: Assessed and reported at the 2-minute, 6-minute, 14-minute, 24-minute, and 30-minute timepoints throughout each hypoxia session
Secondary outcomes:
measure: Change in MRI- Resting State
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Finger Tapping Test score
timeFrame: Assessed and reported at baseline and between 10-24 days later, as well as approximately 1 hour after each hypoxia session
measure: Change in Grooved Pegboard Test score
timeFrame: Assessed and reported at baseline and between 10-24 days later, as well as approximately 1 hour after each hypoxia session
measure: Change in California Verbal Learning Test (CVLT-II) scores
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Serial Reaction Time Task (SRTT) score
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Word Fluency scores
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Trail Making Test (TMT) scores
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Effort Expenditure for Rewards Task (EEfRT) score
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Rey Auditory Verbal Learning Test (RAVLT) scores
timeFrame: Assessed and reported approximately 1 hour after each hypoxia session
measure: Change in Beck Depression Inventory (BDI-II) score
timeFrame: Assessed and reported at baseline and between 10-24 days later
measure: Change in Visual Analogue Mood Scale (VAM-S) score
timeFrame: Assessed and reported approximately 1 hour after each hypoxia session
measure: Change in Motor Evoked Potentials (MEPs)
timeFrame: Assessed and reported approximately 45 min after the first and the fourth hypoxia session
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Shirley Ryan AbilityLab
state: Illinois
Study officials:
affiliation: Shirley Ryan AbilityLab
name: Jordan Grafman, PhD
role: PRINCIPAL_INVESTIGATOR
References: