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Of the 795,000 people who experience a stroke every year in the US, only a small percentage will achieve full recovery. While current therapies promote strength and endurance, none directly address the unique potential of the brain to reorganize following injury. The goal of this project is to explore the effects of a novel therapy, acute intermittent hypoxia (AIH). During this therapy, individuals receive brief bouts of reduced oxygen levels by inhalation through a face mask. (This is akin to being on top of a tall mountain). In brief exposures, AIH is known to trigger the release of specific proteins that help the brain adapt to oxygen reductions. Published results in people with incomplete spinal cord injury have shown that AIH enhances muscle strength and coordination rather quickly. The research team aims to study the effects of AIH in stroke survivors.
Stroke is the second leading cause of death and a leading cause of long-term disability worldwide. Despite the spontaneous recovery that occurs following a hemispheric stroke, more than half of stroke patients show substantial residual impairments, imposing a significant human and economic burden. This burden is likely to increase in coming decades, due to a rapidly aging population, and the associated progression of cardiovascular risk factors. Accordingly, new interventions to alleviate impairment in stroke survivors are urgently needed. The development and testing of one such novel intervention, termed Acute Intermittent Hypoxia (AIH), is the primary focus of this AHA Innovative Project Award.
The aim is to answer questions related to safety and preliminary efficacy of AIH in stroke survivors. First, the Investigators will establish whether brief reductions in inhaled oxygen concentration can be safely tolerated in stroke survivors. A clinician will closely monitor subjects for any adverse events.
The second aim is to establish the effects of AIH on elbow flexion/extension strength, and on hand grip and pinch strength. Subjects 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hypoxia | Experimental | During each session, study participants will receive a single sequence of AIH, consisting of 15 x 60-seconds periods of hypoxia alternating with 90-seconds of normoxia (21% O2), for a total of 30 minutes, whilst in a seated upright position. AIH will be applied by directing gas flow to a reservoir bag connected via plastic tubing to a non re-breathing facemask/respiratory valve system while the participants are in a seated position. Defined gas mixtures will be delivered by manual adjustment of one-way valves attached to a hypoxia generator. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acute Intermittent Hypoxia (AIH) | Other | An oxygen monitor will continuously measure and record the fraction of inspired oxygen delivered to the subject. Inspired fraction of oxygen (FiO2) of the gas mixture will be individually adjusted using the valve settings to reach the targeted SpO2. The gas mixtures administered during the four sessions will be 21% O2 (target SpO2 = 95%), 17% O2 (target SpO2 = 92%), 13% O2 (target SpO2 = 87%) and 9% O2 (target SpO2 = 82%). |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events | All adverse events will be reviewed for safety and study continuation by the medical monitor. | 6 days |
| Measure | Description | Time Frame |
|---|---|---|
| National Institute of Health Stroke Scale (NIHSS) | is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score ranging from 0-44. A change from baseline to follow up 1 (day 6) is reported, calculated from: value at day 6 - value at baseline |
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Inclusion criteria:
Age ≥18 years;
A first time, unilateral, ischemic, hemispheric stroke, confirmed by magnetic resonance imaging (MRI);
Chedoke assessment > 3
Ability to open and close affected hand
Able to understand and communicate in English
Be able to consent independently
≥ 6 months post stroke
Must have a hemoglobin level above 10g/dl (to be confirmed using handheld noninvasive lab equipment)
Must have ability to attend research visits with a companion for assistance
WOCBP must be comfortable confirming negative pregnancy prior to hypoxia experimental therapy.
Exclusion criteria:
Brain stem or cerebellar stroke; mean Fazekas score rated on initial fluid-attenuated inversion recovery MRI ≥3
Severe aphasia, preventing subject from understanding the protocol and giving written consent;
History of prior neurological disorder;
Pre-existing hypoxic pulmonary disease,
Severe hypertension (>160/100)
Ischemic cardiac disease.
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| Name | Affiliation | Role |
|---|---|---|
| Zev Rymer, MD/PhD | Principal Investigator | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shirley Ryan AbilityLab | Chicago | Illinois | 60611 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39996325 | Derived | Pearcey GEP, Barry AJ, Sandhu MS, Carroll TJ, Roth EJ, Rymer WZ. Acute Intermittent Hypoxia in People Living With Chronic Stroke: A Case Series. Stroke. 2025 Apr;56(4):1054-1057. doi: 10.1161/STROKEAHA.124.046620. Epub 2025 Feb 25. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Hypoxia | During each session, study participants will receive a single sequence of AIH, consisting of 15 x 60-seconds periods of hypoxia alternating with 90-seconds of normoxia (21% O2), for a total of 30 minutes, whilst in a seated upright position. AIH will be applied by directing gas flow to a reservoir bag connected via plastic tubing to a non re-breathing facemask/respiratory valve system while the participants are in a seated position. Defined gas mixtures will be delivered by manual adjustment of one-way valves attached to a hypoxia generator. Acute Intermittent Hypoxia (AIH): An oxygen monitor will continuously measure and record the fraction of inspired oxygen delivered to the subject. Inspired fraction of oxygen (FiO2) of the gas mixture will be individually adjusted using the valve settings to reach the targeted SpO2. The gas mixtures administered during the four sessions will be 21% O2 (target SpO2 = 95%), 17% O2 (target SpO2 = 92%), 13% O2 (target SpO2 = 87%) and 9% O2 (target SpO2 = 82%). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Screening |
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| Interventions |
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| ID | Title | Description |
|---|---|---|
| BG000 | Hypoxia | During each session, study participants will receive a single sequence of AIH, consisting of 15 x 60-seconds periods of hypoxia alternating with 90-seconds of normoxia (21% O2), for a total of 30 minutes, whilst in a seated upright position. AIH will be applied by directing gas flow to a reservoir bag connected via plastic tubing to a non re-breathing facemask/respiratory valve system while the participants are in a seated position. Defined gas mixtures will be delivered by manual adjustment of one-way valves attached to a hypoxia generator. Acute Intermittent Hypoxia (AIH): An oxygen monitor will continuously measure and record the fraction of inspired oxygen delivered to the subject. Inspired fraction of oxygen (FiO2) of the gas mixture will be individually adjusted using the valve settings to reach the targeted SpO2. The gas mixtures administered during the four sessions will be 21% O2 (target SpO2 = 95%), 17% O2 (target SpO2 = 92%), 13% O2 (target SpO2 = 87%) and 9% O2 (target SpO2 = 82%). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Adverse Events | All adverse events will be reviewed for safety and study continuation by the medical monitor. | Posted | Count of Participants | Participants | 6 days |
|
Adverse events were collected over the duration of intervention as well as at the single follow up which was within 1 week of interventions /8all occurred at 1 week or less**
Adverse events were specifically questioned before intervention, during intervention, and following intervention for up to 2 hours following intervention initation.
Participants were able to list any adverse event on top of the established events.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Hypoxia | During each session, study participants will receive a single sequence of AIH, consisting of 15 x 60-seconds periods of hypoxia alternating with 90-seconds of normoxia (21% O2), for a total of 30 minutes, whilst in a seated upright position. AIH will be applied by directing gas flow to a reservoir bag connected via plastic tubing to a non re-breathing facemask/respiratory valve system while the participants are in a seated position. Defined gas mixtures will be delivered by manual adjustment of one-way valves attached to a hypoxia generator. Acute Intermittent Hypoxia (AIH): An oxygen monitor will continuously measure and record the fraction of inspired oxygen delivered to the subject. Inspired fraction of oxygen (FiO2) of the gas mixture will be individually adjusted using the valve settings to reach the targeted SpO2. The gas mixtures administered during the four sessions will be 21% O2 (target SpO2 = 95%), 17% O2 (target SpO2 = 92%), 13% O2 (target SpO2 = 87%) and 9% O2 (target SpO2 = 82%). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Baseline Elevated Blood pressure | Cardiac disorders | Systematic Assessment | A baseline Blood pressure Greater than 160/80 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alexander Barry | Shirley Ryan AbilityLab | 312-238-1435 | abarry@sralab.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Dec 11, 2023 | Apr 8, 2024 | Prot_SAP_ICF_000.pdf |
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| ID | Term |
|---|---|
| D020521 | Stroke |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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|
| Baseline and Day 6 |
| Fugl- Meyer Assessment | Each test element will be graded on a 3-point ordinal scale and summed up to provide a maximum upper limb score of 66. Reliability and validity have been demonstrated. The FMA will be administered while the subject is seated. A score of 0 indicates no upper extremity function or reflexes, a score of 66 indicates complete control of the paretic upper extremity. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Baseline, Day 6 |
| Modified Ashworth Scale | This scale allows for characterization of increases in muscle tone, from low or normal tone to complete limb rigidity. Specifically, we will evaluate the elbow flexors, bilaterally. A score of zero indicates no residual muscle spasticity, a score of 4 is a completely rigid limb with no possible movement. Each participant had their stroke affected elbow joint tested. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Baseline, Day 6 |
| Grip Strength | A dynamometer measures maximum gross grasp (lb.) averaged over three attempts with each hand. The minimum possible value of zero lb. will be assigned when the participant cannot actively flex the fingers or grasp the dynamometer. Completed bilaterally, if possible The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Baseline, Day 6 |
| Pinch Strength | Hydraulic Handheld Dynamometer): A dynamometer measures maximum gross grasp (lb.) averaged over 3 attempts with each hand. The minimum possible value of zero lb. will be assigned when the participant cannot actively flex the fingers or grasp the dynamometer. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Baseline, Day 6 |
| Elbow Strength | monitoring changes in isometric elbow flexion force using a dynamometer. A total of three trials will be taken on each side, with a rest break between trials. The average of the three trials will be recorded. Strength recorded in lbs, with a minimum value of zero. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Baseline, Day 6 |
| D-KEFS Color-Word Interference Test | A neuropsychological measure that seeks to evaluate attention and inhibition. Subjects will be asked to read words or name ink colors as quickly as possible within a given time limit. The test supplies the examiner with three separate scores, including an ability to calculate an interference score. This final score allows for interpretation of cognitive flexibility, creativity and cognitive stress. This measure will be utilized to monitor subjects throughout their participation at specific time-points. Audio recording may be taken to ensure accurate recording of responses. The scale is from 1-18, with 10 being at expected level,. A score below 10 is worse performance than expected, and a score above 10 is greater than expected level. The score reported here is the change in score between Day 6 and baseline The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Baseline, Day 6 |
| 5 Minute Neurological Test | Quick short tests to assess clinical status performed by physician to ensure no change in neurologic status, The values reported are the count of participants who were found to have no change in neurolgical status from baseline to day 6 by the clinician | Baseline, day 6 |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Chedoke McMaster Hand Score | A measure defining the stages of motor recovery of the hand following a stroke Scores range from 1 (complete flaccid paralysis) to 7 ("Normal" variety of rapid, age appropriate complex movement patterns) | Mean | Standard Deviation | units on a scale |
|
| Time since Stroke Onset | Mean | Standard Deviation | years |
|
|
|
| Secondary | National Institute of Health Stroke Scale (NIHSS) | is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score ranging from 0-44. A change from baseline to follow up 1 (day 6) is reported, calculated from: value at day 6 - value at baseline | Posted | Mean | Standard Deviation | Change in score on scale | Baseline and Day 6 |
|
|
|
| Secondary | Fugl- Meyer Assessment | Each test element will be graded on a 3-point ordinal scale and summed up to provide a maximum upper limb score of 66. Reliability and validity have been demonstrated. The FMA will be administered while the subject is seated. A score of 0 indicates no upper extremity function or reflexes, a score of 66 indicates complete control of the paretic upper extremity. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Posted | Mean | Standard Deviation | Change in score on a scale | Baseline, Day 6 |
|
|
|
| Secondary | Modified Ashworth Scale | This scale allows for characterization of increases in muscle tone, from low or normal tone to complete limb rigidity. Specifically, we will evaluate the elbow flexors, bilaterally. A score of zero indicates no residual muscle spasticity, a score of 4 is a completely rigid limb with no possible movement. Each participant had their stroke affected elbow joint tested. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Posted | Mean | Standard Deviation | Change in score on a scale | Baseline, Day 6 | Elbow Flexors | Elbow Flexors |
|
|
|
| Secondary | Grip Strength | A dynamometer measures maximum gross grasp (lb.) averaged over three attempts with each hand. The minimum possible value of zero lb. will be assigned when the participant cannot actively flex the fingers or grasp the dynamometer. Completed bilaterally, if possible The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Each of a participant's two hands were analyzed separately, Stroke primarily affects one side of the body more than the other, so we are reporting both hands separately. | Posted | Mean | Standard Deviation | Change in Pounds | Baseline, Day 6 | Hands | Hands |
|
|
|
| Secondary | Pinch Strength | Hydraulic Handheld Dynamometer): A dynamometer measures maximum gross grasp (lb.) averaged over 3 attempts with each hand. The minimum possible value of zero lb. will be assigned when the participant cannot actively flex the fingers or grasp the dynamometer. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Each participant performed the assessment with each hand, stroke typically affects one side more than the other, so we are reporting each hand separately | Posted | Mean | Standard Deviation | Change in Pounds | Baseline, Day 6 | Hands | Hands |
|
|
|
| Secondary | Elbow Strength | monitoring changes in isometric elbow flexion force using a dynamometer. A total of three trials will be taken on each side, with a rest break between trials. The average of the three trials will be recorded. Strength recorded in lbs, with a minimum value of zero. The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Each participant performed the assessment with each arm, stroke typically affects one side more than the other, so we are reporting each armseparately | Posted | Mean | Standard Deviation | Change in Pounds | Baseline, Day 6 | Arms | Arms |
|
|
|
| Secondary | D-KEFS Color-Word Interference Test | A neuropsychological measure that seeks to evaluate attention and inhibition. Subjects will be asked to read words or name ink colors as quickly as possible within a given time limit. The test supplies the examiner with three separate scores, including an ability to calculate an interference score. This final score allows for interpretation of cognitive flexibility, creativity and cognitive stress. This measure will be utilized to monitor subjects throughout their participation at specific time-points. Audio recording may be taken to ensure accurate recording of responses. The scale is from 1-18, with 10 being at expected level,. A score below 10 is worse performance than expected, and a score above 10 is greater than expected level. The score reported here is the change in score between Day 6 and baseline The values reported are differences from follow up (Day 6) and baseline calculated as: value at day 6 - value at baseline | Posted | Mean | Standard Deviation | Change in score on a scale | Baseline, Day 6 |
|
|
|
| Secondary | 5 Minute Neurological Test | Quick short tests to assess clinical status performed by physician to ensure no change in neurologic status, The values reported are the count of participants who were found to have no change in neurolgical status from baseline to day 6 by the clinician | Posted | Count of Participants | Participants | Baseline, day 6 |
|
|
|
| 0 |
| 16 |
| 0 |
| 16 |
| 4 |
| 16 |
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| Baseline Bradycardia | Cardiac disorders | Systematic Assessment | Decreased heart rate at baseline, below 50 beats per minute |
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| Claustrophobia | General disorders | Systematic Assessment | Claustrophobia due to Magnetic Resonance Imaging Machine |
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| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Less Affected Hand |
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| Less Affected Hand |
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| Less Affected Arm |
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