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| ID | Type | Description | Link |
|---|---|---|---|
| 5R01HD081274 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Caffeine/AIH | Active Comparator | Subjects with chronic, motor-incomplete SCI receive Caffeine then AIH |
|
| Placebo/AIH | Active Comparator | Subjects with chronic, motor-incomplete SCI receive Placebo then AIH |
|
| Caffeine/SHAM | Active Comparator | Subjects with chronic, motor-incomplete SCI receive Caffeine then SHAM |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Caffeine | Drug | 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. |
| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Randy D Trumbower, PT, PhD | Harvard Medical School (HMS and HSDM) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Spaulding Rehabilitation Hospital | Cambridge | Massachusetts | 02138 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30009669 | Background | Trumbower RD. Stimulating the Injured Spinal Cord: Plenty to Grasp. J Neurotrauma. 2018 Sep 15;35(18):2143-2144. doi: 10.1089/neu.2018.5993. No abstract available. | |
| 29648987 | Background | Sohn WJ, Tan AQ, Hayes HB, Pochiraju S, Deffeyes J, Trumbower RD. Variability of Leg Kinematics during Overground Walking in Persons with Chronic Incomplete Spinal Cord Injury. J Neurotrauma. 2018 Nov 1;35(21):2519-2529. doi: 10.1089/neu.2017.5538. Epub 2018 Jun 5. |
| Label | URL |
|---|---|
| INSPIRE Lab Website | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Caffeine/AIH First, Then Placebo/AIH, Then Caffeine/SHAM | 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). |
| FG001 | Placebo/AIH First, Then Caffeine/AIH, Then Caffeine/SHAM | 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). |
| FG002 | Caffeine/SHAM First, Then Caffeine/AIH, Then Placebo/AIH | 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). |
| FG003 | Caffeine/AIH First, Then Caffeine/SHAM, Then Placebo/AIH | 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). |
| FG004 | Placebo/AIH First, Then Caffeine/SHAM, Then Caffeine/AIH | 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). |
| FG005 | Caffeine/SHAM First, Then Placebo/AIH, Then Caffeine/AIH | 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). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | 10 Meter Walk Time | Speed will be assessed using the time required to walk 10 meters (10MWT) relative to baseline. | Posted | Mean | Standard Error | Seconds | Baseline, after intervention (day 5), and at follow-ups (one week and two weeks) |
|
1 year
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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 | Caffeine/AIH | Subjects with chronic, motor-incomplete SCI receive Caffeine then AIH Caffeine: 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. AIH: 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Randy D Trumbower, PI | Spaulding Rehabilitation Hospital | (617) 952-6953 | randy.trumbower@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 27, 2021 | May 10, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D013119 | Spinal Cord Injuries |
| D000860 | Hypoxia |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020196 | Trauma, Nervous System |
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| ID | Term |
|---|---|
| D002110 | Caffeine |
| D007317 | Insemination, Artificial, Homologous |
| C005703 | salicylhydroxamic acid |
| ID | Term |
|---|---|
| D014970 | Xanthines |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D011688 | Purinones |
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Balanced design
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|
|
| AIH | Other | 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. |
|
|
| Placebo | Other | 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. |
|
| SHAM | Other | 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. |
|
| 28972191 | Background | Trumbower RD, Hayes HB, Mitchell GS, Wolf SL, Stahl VA. Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study. Neurology. 2017 Oct 31;89(18):1904-1907. doi: 10.1212/WNL.0000000000004596. Epub 2017 Sep 29. |
| 28762876 | Background | Peters DM, Thibaudier Y, Deffeyes JE, Baer GT, Hayes HB, Trumbower RD. Constraints on Stance-Phase Force Production during Overground Walking in Persons with Chronic Incomplete Spinal Cord Injury. J Neurotrauma. 2018 Feb 1;35(3):467-477. doi: 10.1089/neu.2017.5146. Epub 2017 Oct 27. |
| 24618214 | Background | Hayes HB, Chvatal SA, French MA, Ting LH, Trumbower RD. Neuromuscular constraints on muscle coordination during overground walking in persons with chronic incomplete spinal cord injury. Clin Neurophysiol. 2014 Oct;125(10):2024-35. doi: 10.1016/j.clinph.2014.02.001. Epub 2014 Feb 14. |
| 24285617 | Background | Hayes HB, Jayaraman A, Herrmann M, Mitchell GS, Rymer WZ, Trumbower RD. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology. 2014 Jan 14;82(2):104-13. doi: 10.1212/01.WNL.0000437416.34298.43. Epub 2013 Nov 27. |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Number of Participants with Level of Spinal Cord Injury (C2-L5) | Number | Participants |
|
| Time Since Injury | Mean | Standard Deviation | years |
|
| CYP1A2*1F SNP | Participant genotype for CYP1A2 polymorphism was assessed. Homozygosity for A/A is considered a fast metabolizer of caffeine and C/A heterozygosity is considered a slow metabolizer of caffeine. | Number | participants |
|
| 10 Meter Walk Test | Speed will be assessed using the time required to walk 10 meters (10MWT). | Mean | Standard Deviation | Seconds |
|
| OG001 | Placebo/AIH | Subjects with chronic, motor-incomplete SCI receive Placebo then AIH AIH: 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. Placebo: 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. |
| OG002 | Caffeine/SHAM | Subjects with chronic, motor-incomplete SCI receive Caffeine then SHAM Caffeine: 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. SHAM: 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. |
|
|
| Secondary | 6 Minute Walk Test | Measure participant's distance walked in 6 minutes (meters). | Posted | Mean | Standard Error | Meters | Baseline, after intervention (day 5), and at follow-ups (one week and two weeks) |
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | Placebo/AIH | Subjects with chronic, motor-incomplete SCI receive Placebo then AIH AIH: 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. Placebo: 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. | 0 | 12 | 0 | 12 | 0 | 12 |
| EG002 | Caffeine/SHAM | Subjects with chronic, motor-incomplete SCI receive Caffeine then SHAM Caffeine: 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. SHAM: 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. | 0 | 12 | 0 | 12 | 0 | 12 |
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| D014947 | Wounds and Injuries |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D007315 | Insemination, Artificial |
| D027724 | Reproductive Techniques, Assisted |
| D012099 | Reproductive Techniques |
| D013812 | Therapeutics |
| D008919 | Investigative Techniques |
| D007314 | Insemination |
| D012098 | Reproduction |
| D055703 | Reproductive Physiological Phenomena |
| D012101 | Reproductive and Urinary Physiological Phenomena |
|
| Day 19 (Relative to Baseline) |
|