Combination Therapy to Improve SCI Recovery.

Study Overview
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Brief Summary
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The purpose of this study is to determine how combining bouts of low oxygen, transcutaneous spinal cord stimulation, and walking training may improve walking function for people with chronic spinal cord injury.

Detailed Description
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The goal of the study is to determine whether repeatedly breathing mild bouts of low oxygen for brief periods (termed acute intermittent hypoxia (AIH)) combined with transcutaneous spinal cord stimulation (tSTIM) improves recovery of walking and strength after spinal cord injury. This idea stems from animal studies on respiration, in which investigators showed that mild AIH improves breathing in rats with spinal injuries as well as studies involving spinal cord stimulation. These studies showed that AIH induces plasticity, strengthening neural connections by increasing the production of key proteins and improving the sensitivity of spinal cord circuitry. Additional studies have shown that tSTIM may enhance function and strength for people with spinal cord injuries. The ultimate goal of this research is to assess if combining AIH and tSTIM with walking training can enhance individuals walking training greater than just AIH or tSTIM. By using low oxygen as a pre-treatment to tSTIM during walking training, functional independence and quality of life for servicemen and civilians may improve.

Official Title
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Breathing Low Oxygen to Enhance Spinal Stimulation Training and Functional Recovery in Persons With Chronic SCI: The BO2ST Trial

Conditions
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Spinal Cord Injuries

Intervention / Treatment
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* Other: Daily acute intermittent hypoxia
* Other: Room air (SHAM)
* Other: Walking + tSTIM
* Other: Walking + Sham transcutaneous spinal stimulation (tSHAM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 70 years of age medically stable with medical clearance from study physician to participate SCI at or below C2 (phrenic sparing) and at or above L2 with at least some sensory or motor function preserved below the neurologic level non-progressive etiology of spinal injury American Spinal Injury Association (ASIA) scores of C-D at initial screen ambulatory (able to complete the 10-meter walk test without support from another person) chronic injury (define as > 12 months post-injury) to avoid potential for spontaneous neurological plasticity and recovery Exclusion Criteria: severe concurrent illness or pain, including unhealed decubiti, severe neuropathic or chronic pain syndrome, severe infection (e.g., urinary tract), hypertension, cardiovascular disease, pulmonary disease, severe osteoporosis, active heterotopic ossification in the lower extremities, severe systemic inflammation < 24 on Mini-Mental Exam severe recurrent autonomic dysreflexia history of severe cardiovascular/pulmonary complications including hypertension (systolic blood pressure > 150 mmHg) pregnancy because of unknown effects of AIH or tSTIM on a fetus (individuals of childbearing potential will not otherwise be excluded) botulinum toxin injections in lower extremity muscles within the prior three months history of tendon or nerve transfer surgery in the lower extremity untreated severe sleep-disordered breathing characterized by uncontrolled hypoxia and sleep fractionation that may impact the outcome of this study. active implanted devices (e.g., intrathecal baclofen pump) receiving concurrent electrical stimulation motor threshold evoked by transcutaneous spinal stimulation >200 mA

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AIH + Walking Training with transcutaneous spinal stimulation (WALKtSTIM)<br>Acute Intermittent Hypoxia will be used as a pretreatment before walking training paired with transcutaneous spinal cord stimulation. | Other: Daily acute intermittent hypoxia<br>* Each participant will be exposed to 8 sessions of daily acute intermittent hypoxia via air generators over the span of two weeks. The generator will fill reservoir bags attached to a non-rebreathing facemask. Each session will consist of 15 episodes which include intervals of 1.5 minute hypoxia (FIO2=0.10±0.02, i.e. 10% O2) and 1 minute normoxia (FIO2=0.21±0.02).<br>Other: Walking + tSTIM<br>* Individuals will participate in 45 minutes of gait training while having transcutaneous spinal cord stimulation. Stimulation intensity will be 80% involuntary motor threshold.<br>|
| Sham Comparator: Sham + WALKtSTIM<br>Sham acute intermittent hypoxia will be used as a pretreatment before walking training paired with transcutaneous spinal cord stimulation. | Other: Room air (SHAM)<br>* Each participant will be exposed to 8 sessions of daily room air via air generators over the span of two weeks. The generator will fill reservoir bags attached to a non-rebreathing facemask. Each session will consist of 15 episodes of 1.5 minute normoxia (FIO2=0.21±0.02).<br>Other: Walking + tSTIM<br>* Individuals will participate in 45 minutes of gait training while having transcutaneous spinal cord stimulation. Stimulation intensity will be 80% involuntary motor threshold.<br>|
| Sham Comparator: AIH + Walking Training with sham transcutaneous spinal stimulation (WALKtSHAM)<br>Acute Intermittent Hypoxia will be used as a pretreatment before walking training paired with sham transcutaneous spinal cord stimulation. | Other: Daily acute intermittent hypoxia<br>* Each participant will be exposed to 8 sessions of daily acute intermittent hypoxia via air generators over the span of two weeks. The generator will fill reservoir bags attached to a non-rebreathing facemask. Each session will consist of 15 episodes which include intervals of 1.5 minute hypoxia (FIO2=0.10±0.02, i.e. 10% O2) and 1 minute normoxia (FIO2=0.21±0.02).<br>Other: Walking + Sham transcutaneous spinal stimulation (tSHAM)<br>* Individuals will participate in 45 minutes of gait training while having SHAM transcutaneous spinal cord stimulation. The stimulation will briefly increase to 80% involuntary motor threshold and then brought down to 0 within 30 seconds.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in walking recovery, assessed by 10 meter walk test (10MWT) | Participants walk ten meters without assistance at their fastest, but safest speed with a minimum of 1-minute of rest between two trials. Average speed across the up to three 10MWT trials will be used for analysis. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline. | Through study completion, an average of 12 weeks | 
| Rate of change in walking recovery, assessed by 10 meter walk test (10MWT) | Participants walk ten meters without assistance at their fastest, but safest speed with a minimum of 1-minute of rest between two trials. Average speed across the up to three 10MWT trials will be used for analysis. Rate of change is the number of treatment sessions required to achieve an increase in 10MWT speed of at least the minimal clinically important difference (0.06 m/s) as compared to pre-treatment baseline. | Through study completion, an average of 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in walking recovery, assessed by 6 minute walk test (6MWT) | Participants perform the 6MWT at their fastest, most comfortable walking speed sustainable for 6 minutes. Distances will be recorded at 2 and 6 minutes. The test will be based upon the participant's ability to finish each assessment without human assistance. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline. | Through study completion, an average of 12 weeks | 
| Change in walking recovery, assessed by timed up-and-go (TUG) test | The TUG test is used to assess the dynamic balance of an individual. It measures the amount of time (recorded in seconds) it takes for the individual to rise from a standard arm chair, walk a distance of 3 meters and return to the initial position resting against the back of the chair. Participants will perform up to three trials of the TUG test. Average speed across TUG trials will be used for analysis. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline. | Through study completion, an average of 12 weeks | 
| Change in pain severity, assessed by the Numeric Pain Rating Scale (NPRS) | Participants will report their pain level using the Numeric Pain Rating Scale. The scale is from 0 to 10; 0 being no pain and 10 being extreme pain. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline. | Through study completion, an average of 12 weeks | 
| Change in cognitive function, assessed by the California Verbal Learning Test (CVLT) | The CVLT is a brief, individually administered battery to measure cognitive decline or improvement and assesses verbal learning and memory for older adolescents and adults. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline. | Through treatment completion, an average of 4 weeks | 
| Systemic hypertension incidence rate | Participants will have their systolic and diastolic blood pressure measured. A systemic hypertensive event is quantified as a systolic pressure exceeding 140 mmHg and/or diastolic pressure exceeding 90 mmHg. A hypertension incident rate is the number of hypertensive events divided by the total person-time. Person-time is in units of person-measures (the sum of the total number of BP measurements) taken for each person. Person-measures accounts for the total number of chances for detecting a hypertensive event and accounts for measurements not made due to drop-out or a disqualifying adverse event. | Through treatment completion, an average of 4 weeks | 
| Autonomic dysreflexia incidence rate | The occurrence of autonomic dysreflexia will be assessed. An autonomic dysreflexia event will constitute a participant having a SBP increase from baseline of 20 mmHg not associated with exercise or systolic blood pressure (SBP) greater than 150 mmHg with complaints of headache, diaphoresis, and/or blurred vision and will be diagnosed by our study team clinicians. We will compute autonomic dysreflexia incident rate as the number of autonomic dysreflexia events divided by the total person-time. We define person-time in units of person-days (the number of days a person remains in the study). Person-days account for the total number of chances for detecting autonomic dysreflexia and accounts for days on which measurements were not made due to drop-out or a disqualifying adverse event. | Through treatment completion, an average of 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Walk, Rehabilitation, Strength, Movement, Spinal cord injury, low oxygen, electrical stimulation, walking training