Acute Intermittent Hypoxia in Traumatic Brain Injury

NCT ID: NCT04890639

Last Updated: 2024-04-18

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-15
• Study Completion Date: 2024-11-01

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.

Conditions

Brain Injuries, Traumatic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

AIH group

Hypoxia will be administered via a specialized face mask attached to a gas mixing device (HYP123, Hypoxico Inc.), which controls oxygen content in inhaled air. The hypoxia administering unit will be manually adjusted to supply O2 at the target level for a given session (approximately 21%-normal room air, 17%, 13%, and 9% respectively). Each session will include 15 cycles of hypoxia, each lasting up to 60 seconds, interspersed with up to 90-second normoxic episodes. An oxygen monitor will continuously measure and record the fraction of inspired oxygen delivered (MAX-250E, Maxtec Inc.).

Group Type: EXPERIMENTAL

Acute Intermittent Hypoxia

Intervention Type: PROCEDURE

Four hypoxia sessions, consisting of 15 cycles of hypoxia (21%, 17%, 13% or 9% O2), each of which lasts up to 60 seconds, interspersed with up to 90-second normoxic episodes.

Interventions

Acute Intermittent Hypoxia

Four hypoxia sessions, consisting of 15 cycles of hypoxia (21%, 17%, 13% or 9% O2), each of which lasts up to 60 seconds, interspersed with up to 90-second normoxic episodes.

Intervention Type: PROCEDURE

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Shirley Ryan AbilityLab

OTHER

Sponsor Role: lead

Responsible Party

Jordan Grafman, Ph.D

Principle Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jordan Grafman, PhD

Role: PRINCIPAL_INVESTIGATOR

Shirley Ryan AbilityLab

Locations

Shirley Ryan AbilityLab

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Katya Delikishkina, PhD

Role: CONTACT

kdelikishk@sralab.org

312-238-4579

Facility Contacts

Katya Delikishkina, PhD

Role: primary

kdelikishk@sralab.org

312-238-4579

Other Identifiers

1R21NS114815-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU00213969

Identifier Type: -

Identifier Source: org_study_id