Spinal Cord Injuries
Conditions
Keywords
hypoxia, spinal cord injury, rehabilitation, strength, walk, function, low oxygen
Brief summary
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
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.
Interventions
DRUGCaffeine
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.
OTHERAIH
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.
OTHERPlacebo
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.
OTHERSHAM
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.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Spaulding Rehabilitation Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Balanced design
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 10 Meter Walk Time | Baseline, after intervention (day 5), and at follow-ups (one week and two weeks) | Speed will be assessed using the time required to walk 10 meters (10MWT) relative to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6 Minute Walk Test | Baseline, after intervention (day 5), and at follow-ups (one week and two weeks) | Measure participant's distance walked in 6 minutes (meters). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Subjects ingest Caffeine/Placebo 30 minutes prior to AIH/SHAM breathing intervention in this cross-over study. All participants are assigned to receive all three intervention combinations of Caffeine/AIH, Placebo/AIH, and Caffeine/SHAM in a randomized order with each intervention lasting 5 days followed by 14 days of washout prior to starting the next intervention. Throughout experimentation, blood oxygenation, blood pressure and heart rate are monitored.
Caffeine: Subjects ingest capsules containing caffeine (up to 6mg/kg). Breathing intervention begins 30min after consumption to approximately coincide with peak plasma concentrations.
Placebo: This is a placebo counterpart to the caffeine drug. Subjects ingest capsules containing dextrose. Breathing intervention begins 30min after consumption to mimic the caffeine drug protocol.
AIH: Participants breathe intermittent low oxygen via air generators. The generators fill reservoir bags attached to a non-rebreathing face mask. Oxygen concentration is continuously monitored to ensure intermittent delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia) at 1-minute intervals.
SHAM: This is a placebo counterpart to breathing intermittent low oxygen. Participants breathe intermittent room air via air generators. The generators fill reservoir bags attached to a non-rebreathing face mask. Oxygen concentration is continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.21±0.02 (normoxia). | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Study Participants | — |
|---|---|---|
| 10 Meter Walk Test | 32.8 Seconds STANDARD_DEVIATION 31 | — |
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 2 Participants | — |
| Age, Categorical Between 18 and 65 years | 10 Participants | — |
| CYP1A2*1F SNP A/A | 3 participants | — |
| CYP1A2*1F SNP C/A | 8 participants | — |
| Number of Participants with Level of Spinal Cord Injury (C2-L5) | 10 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 4 Participants | — |
| Sex: Female, Male Male | 8 Participants | — |
| Time Since Injury | 8 years STANDARD_DEVIATION 12 | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
10 Meter Walk Time
Speed will be assessed using the time required to walk 10 meters (10MWT) relative to baseline.
Time frame: Baseline, after intervention (day 5), and at follow-ups (one week and two weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Caffeine/AIH | 10 Meter Walk Time | Day 12 (Relative to Baseline) | -5.5 Seconds | Standard Error 2.7 |
| Caffeine/AIH | 10 Meter Walk Time | Day 5 (Relative to Baseline) | -5.0 Seconds | Standard Error 2.2 |
| Caffeine/AIH | 10 Meter Walk Time | Day 19 (Relative to Baseline) | -6.5 Seconds | Standard Error 3.3 |
| Placebo/AIH | 10 Meter Walk Time | Day 12 (Relative to Baseline) | -1.7 Seconds | Standard Error 1.3 |
| Placebo/AIH | 10 Meter Walk Time | Day 5 (Relative to Baseline) | -4.9 Seconds | Standard Error 2.2 |
| Placebo/AIH | 10 Meter Walk Time | Day 19 (Relative to Baseline) | 0.4 Seconds | Standard Error 2.6 |
| Caffeine/SHAM | 10 Meter Walk Time | Day 5 (Relative to Baseline) | -4.6 Seconds | Standard Error 2.1 |
| Caffeine/SHAM | 10 Meter Walk Time | Day 19 (Relative to Baseline) | -0.1 Seconds | Standard Error 0.6 |
| Caffeine/SHAM | 10 Meter Walk Time | Day 12 (Relative to Baseline) | 0.9 Seconds | Standard Error 1.5 |
Secondary
6 Minute Walk Test
Measure participant's distance walked in 6 minutes (meters).
Time frame: Baseline, after intervention (day 5), and at follow-ups (one week and two weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Caffeine/AIH | 6 Minute Walk Test | Day 12 (Relative to Baseline) | 23.7 Meters | Standard Error 7.7 |
| Caffeine/AIH | 6 Minute Walk Test | Day 5 (Relative to Baseline) | 24.1 Meters | Standard Error 8.3 |
| Caffeine/AIH | 6 Minute Walk Test | Day 19 (Relative to Baseline) | 22.4 Meters | Standard Error 8 |
| Placebo/AIH | 6 Minute Walk Test | Day 12 (Relative to Baseline) | 15.7 Meters | Standard Error 7.3 |
| Placebo/AIH | 6 Minute Walk Test | Day 5 (Relative to Baseline) | 17.1 Meters | Standard Error 7.3 |
| Placebo/AIH | 6 Minute Walk Test | Day 19 (Relative to Baseline) | 24.2 Meters | Standard Error 7.6 |
| Caffeine/SHAM | 6 Minute Walk Test | Day 5 (Relative to Baseline) | 6.2 Meters | Standard Error 8.7 |
| Caffeine/SHAM | 6 Minute Walk Test | Day 19 (Relative to Baseline) | -2.7 Meters | Standard Error 8.8 |
| Caffeine/SHAM | 6 Minute Walk Test | Day 12 (Relative to Baseline) | 9.2 Meters | Standard Error 9.3 |