Effects of Caffeine and Intermittent Hypoxia on Leg Function in Human Spinal Cord Injury

Study Overview
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Brief Summary
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Accumulating evidence suggests that repeatedly breathing low oxygen levels for brief periods (termed intermittent hypoxia) is a safe and effective treatment strategy to promote meaningful functional recovery in persons with chronic spinal cord injury (SCI). The goal of the study is to understand how caffeine may augment the effects of intermittent hypoxia on motor function and spinal plasticity (ability of the nervous system to strengthen neural pathways based on new experiences) following SCI.

Detailed Description
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The investigators will examine the effects of acute intermittent hypoxia (AIH) as a possible therapeutic intervention to promote functionally useful motor recovery. In this sub-study, the investigators will assess changes in leg motor function in response to repetitive AIH with and without caffeine. Participants will receive caffeine+AIH, placebo+AIH, caffeine+SHAM in a randomized order. Before each intervention round, subjects will be asked to avoid caffeine-containing substances for 48 hrs (> 5* half-life of  7 hrs) prior to arrival to control for baseline plasma levels of caffeine. Subjects will then ingest capsules containing either placebo (dextrose) or caffeine (up to 6mg/kg). Capsules will be prepared by Johnson Compounding & Wellness. Blood samples will be collected before and after the breathing intervention to assess caffeine concentrations within the body. During and after each intervention, both the rate and extent of magnitude changes in voluntary and involuntary muscle response behaviors important for walking will be compared between interventions within participants. Repeated measurements will be collected on all subjects that participate in the multiple interventions.

Official Title
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The Effects of Intermittent Hypoxia on Leg Function in Human Spinal Cord Injury (Caffeine Substudy)

Conditions
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Spinal Cord Injuries

Intervention / Treatment
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* Drug: Caffeine
* Other: AIH
* Other: Placebo
* Other: SHAM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 and 75 years (the latter to reduce likelihood of heart disease) medical clearance to participate lesion at or below C2 and above L5 with non-progressive etiology classified as motor-incomplete with visible volitional leg movement injury greater than 6 months ability to advance one step overground without human assistance Exclusion Criteria: Concurrent severe medical illness (i.e., infection, cardiovascular disease, ossification, recurrent autonomic dysreflexia, unhealed decubiti, and history of pulmonary complications) Pregnant women because of the unknown affects of AIH on pregnant women and fetus History of seizures, brain injury, and/or epilepsy Undergoing concurrent physical therapy Diabetes Cirrhosis Caffeine and/or NSAID allergies or intolerances

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Balanced design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Caffeine/AIH<br>Subjects with chronic, motor-incomplete SCI receive Caffeine then AIH | Drug: Caffeine<br>* Subjects will ingest capsules containing caffeine (up to 6mg/kg). Experiments will begin 30min after consumption to approximately coincide with peak plasma concentrations.Throughout the 30min wait time and experimentation, blood pressure and heart rate will be monitored.<br>* Other names: caffeine anhydrous;Other: AIH<br>* Participants will breathe intermittent low oxygen via air generators. The generators will fill reservoir bags attached to a non-rebreathing face mask. Oxygen concentration will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia). Throughout experimentation, blood pressure and heart rate will be monitored.<br>* Other names: Acute intermittent hypoxia;|
| Active Comparator: Placebo/AIH<br>Subjects with chronic, motor-incomplete SCI receive Placebo then AIH | Other: AIH<br>* Participants will breathe intermittent low oxygen via air generators. The generators will fill reservoir bags attached to a non-rebreathing face mask. Oxygen concentration will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia). Throughout experimentation, blood pressure and heart rate will be monitored.<br>* Other names: Acute intermittent hypoxia;Other: Placebo<br>* This is a placebo counterpart to the caffeine drug. Subjects will ingest capsules containing dextrose. Experiments will begin 30min after consumption to mimic the caffeine drug protocol. Throughout experimentation, blood oxygenation, blood pressure and heart rate will be monitored.<br>|
| Active Comparator: Caffeine/SHAM<br>Subjects with chronic, motor-incomplete SCI receive Caffeine then SHAM | Drug: Caffeine<br>* Subjects will ingest capsules containing caffeine (up to 6mg/kg). Experiments will begin 30min after consumption to approximately coincide with peak plasma concentrations.Throughout the 30min wait time and experimentation, blood pressure and heart rate will be monitored.<br>* Other names: caffeine anhydrous;Other: SHAM<br>* This is a placebo counterpart to breathing intermittent low oxygen. Participants will breathe intermittent room air via air generators. The generators will fill reservoir bags attached to a non-rebreathing face mask. Oxygen concentration will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.21±0.02 (normoxia). Throughout experimentation, blood pressure and heart rate will be monitored.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 10 Meter Walk Time | Speed will be assessed using the time required to walk 10 meters (10MWT) relative to baseline. | Baseline, after intervention (day 5), and at follow-ups (one week and two weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Minute Walk Test | Measure participant's distance walked in 6 minutes (meters). | Baseline, after intervention (day 5), and at follow-ups (one week and two weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypoxia, spinal cord injury, rehabilitation, strength, walk, function, low oxygen