Combining Low Oxygen Therapy and an Adenosine A2a Receptor Antagonist to Improve Functional Mobility After Spinal Cord Injury

Study Overview
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Brief Summary
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Breathing brief, moderate bouts of low oxygen trigger (low oxygen therapy, LOT) spinal plasticity (the ability of the nervous system to strengthen neural pathways based on new experiences), and improve walking after spinal cord injury (SCI). The greatest improvements in walking ability occur when LOT is administered prior to skill-based walking practice (WALK). However, the enduring benefits of LOT on walking recovery may be undermined by the accumulation of LOT-induced increase in extracellular adenosine. The goal of the study is to understand the extent to which istradefylline (adenosine 2a receptor antagonist) may limit the competing mechanisms of adenosine on LOT-induced walking recovery following SCI.

Detailed Description
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This randomized, placebo-controlled clinical trial will examine the efficacy of a selective adenosine 2a antagonist (istradefylline) to enhance the beneficial effects of LOT-related gains on overground walking performance after spinal cord injury (SCI). Participants will be randomly assigned to a combinatorial intervention: istradefylline+LOT, placebo+LOT, istradefylline+SHAM. Participants will be asked to avoid caffeine-containing substances for 48 hrs (> 5* half-life of  7 hrs) before the start of the study. They also will refrain from consuming caffeine during the 4-week combinatorial intervention. Participants enrolled in istradefylline+AIH will receive 20mg of istradefylline orally for 28 consecutive days. After 14 days of istradefylline treatment, the participants will receive 2 weeks (4 sessions/week) of LOT prior to 45min of skill-based walking practice (WALK) within the INSPIRE Lab. A single session of LOT will consist of 15 episodes of breathing 90s low levels of oxygen (10% O2) with 60s intervals at room air (21% O2). Participants enrolled in istradefylline+SHAM will receive 20mg of istradefylline orally for 28 consecutive days. After 14 days of istradefylline treatment, the participants will receive 2 weeks (4 sessions/week) of SHAM therapy prior to 45min of skill-based walking practice (WALK) within the INSPIRE Lab. A single session of SHAM therapy will consist of 15 episodes of breathing 90s of normal levels of oxygen (21% O2) with 60s intervals at room air (21% O2). Participants enrolled in placebo+AIH will receive 20mg of placebo (dextrose) treatment orally for 28 consecutive days. After 14 days of placebo treatment, the participants will receive 2 weeks (4 sessions/week) of LOT prior to 45min of skill-based walking practice (WALK) within the INSPIRE Lab. A single session of LOT will consist of 15 episodes of breathing 90s low levels of oxygen (10% O2) with 60s intervals at room air (21% O2). Blood samples will be collected at baseline, and at the end of week 2, week 4 to assess for potential confounding effects of systemic inflammation and caffeine on responsiveness to the combinatorial interventions. The study will assess functional outcomes, vital signs, and symptoms before and after each intervention. For our primary outcome measure, the study will assess walking speed (10-meter walk test, 10MWT) relative to baseline at the end of day 5 (D5), and 8 (F1) and 14 days (F2) post-treatment. This study also will assess leg strength, walking distance, and coordination on D5, F1, and F2 as secondary outcome measures. A linear mixed model will be used to compare differences in 10MWT with treatment and time as main effects and participants as random effects. This study will follow the Consolidated Standards of Reporting Trials.

Official Title
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A Selective Adenosine 2a Antagonist to Enhance Training-related Gains in Walking Function for Persons With Chronic, Incomplete Spinal Cord Injury

Conditions
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Spinal Cord Injuries, Myelopathy

Intervention / Treatment
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* Drug: Istradefylline
* Device: low oxygen therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 and 75 years (the latter to reduce the likelihood of heart disease) medical clearance to participate lesion at or below C2 and above T12 with non-progressive etiology classified as motor-incomplete with visible volitional leg movement injury greater than 12 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 effects 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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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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Istradefylline+low oxygen training<br>Drug: Nourianz Other Names: KW6002, Istradefylline Participants enrolled in this study arm will ingest a 20mg tablet/day containing istradefylline starting 14 days prior to the first low oxygen therapy and continuing for 14 additional days. Participants will consume a total of 28 istradefylline tablets. Other: low oxygen training Other Names: therapeutic intermittent hypoxia, acute intermittent hypoxia Participants will breathe 15 episodes/session of acute low oxygen via an automated air generator system (4 sessions/week x 2 weeks). During the 90-second episodes of low oxygen, air concentrations will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia) with 60-second room-air intervals (FIO2 0.21±0.02). Throughout experimentation, blood pressure, respiratory rate, and heart rate will be monitored. We also will assess for changes in sleep quality and pain level. | Drug: Istradefylline<br>* Consume 20mg tablet of istradefylline for 28 consecutive days.<br>* Other names: Nourianz;Device: low oxygen therapy<br>* Breath intermittent low oxygen 4 days/week over 2 consecutive weeks. Intermittent low oxygen consists of 15, 90-second episodes of breathing low oxygen at 10% oxygen with 60-second intervals at 21% oxygen.<br>* Other names: acute intermittent hypoxia;|
| Active Comparator: Placebo+low oxygen training<br>This is a placebo counterpart to the istradefylline drug. Participants enrolled in this study arm will ingest a 20mg placebo tablet/day containing dextrose starting 14 days prior to the first low oxygen therapy (LOT) and continuing for 14 additional days. Participants will consume a total of 28 placebo tablets. Other: low oxygen training Other Names: therapeutic intermittent hypoxia, acute intermittent hypoxia Participants will breathe 15 episodes/session of acute low oxygen via an automated air generator system (4 sessions/week x 2 weeks). During the 90-second episodes of low oxygen, air concentrations will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia) with 60-second room-air intervals (FIO2 0.21±0.02). Throughout experimentation, blood pressure, respiratory rate, and heart rate will be monitored. We also will assess for changes in sleep quality and pain level. | Device: low oxygen therapy<br>* Breath intermittent low oxygen 4 days/week over 2 consecutive weeks. Intermittent low oxygen consists of 15, 90-second episodes of breathing low oxygen at 10% oxygen with 60-second intervals at 21% oxygen.<br>* Other names: acute intermittent hypoxia;|
| Active Comparator: Istradefylline+SHAM<br>Drug: Nourianz Other Names: KW6002, Istradefylline This is a SHAM counterpart to low oxygen therapy. Participants enrolled in this study arm will ingest a 20mg tablet/day containing istradefylline starting 14 days prior to the first SHAM therapy and continuing for 14 additional days. Participants will consume a total of 28 istradefylline tablets. Participants will breathe 15 episodes/session of SHAM via an automated air generator system (4 sessions/week x 2 weeks). The system will fill reservoir bags attached to a non-rebreathing face mask. During the 90-second episodes of SHAM, air concentrations will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.21±0.02 (normoxia) with 60-second room-air intervals (FIO2 0.21±0.02). Throughout experimentation, blood pressure, respiratory rate, and heart rate will be monitored. We also will assess for changes in sleep quality and pain level. | Drug: Istradefylline<br>* Consume 20mg tablet of istradefylline for 28 consecutive days.<br>* Other names: Nourianz;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-Treatment Walking Speed | Pre-Treatment Walking Speed; 10MWT (time, seconds) | within 5 days of first treatment | 
| Walking Speed Post-Treatment 1 | Post-Treatment Walking Speed; 10MWT (time, seconds) | within 1 day after last treatment | 
| Walking Speed Post-Treatment 2 | Post-Treatment Walking Speed; 10MWT (time, seconds) | between 7-10 days after Post-Treatment 1 | 
| Walking Speed Post-Treatment 3 | Post-Treatment 10MWT (time, seconds) | between 17-20 days after Post-Treatment 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-Treatment Walking Distance | Pre-Treatment 6MWT (distance, meters) | within 5 days of first treatment | 
| Walking Distance Post-Treatment 1 | Post-Treatment 6MWT (distance, meters) | within 1 day after last treatment | 
| Walking Distance Post-Treatment 2 | Post-Treatment 6MWT (distance, meters) | between 7-10 days after Post-Treatment 1 | 
| Walking Distance Post-Treatment 3 | Post-Treatment 6MWT (distance, meters) | between 17-20 days after Post-Treatment 1 | 
| Pre-Treatment Timed Up-and-Go Test | Pre-Treatment TUG (walking balance) | within 5 days of first treatment | 
| Timed Up-and-Go Test Post-Treatment 1 | Post-Treatment TUG (walking balance) | within 1 day after last treatment | 
| Timed Up-and-Go Test Post-Treatment 2 | Post-Treatment TUG (walking balance) | between 7-10 days after Post-Treatment 1 | 
| Timed Up-and-Go Test Post-Treatment 3 | Post-Treatment TUG (walking balance) | between 17-20 days after Post-Treatment 1 | 
| Pre-treatment Ankle Strength | Pre-Treatment Plantarflexion Torque (strength, torque) | within 5 days of first treatment | 
| Ankle Strength Post-Treatment 1 | Post-Treatment Plantarflexion Torque (strength, torque) | within 1 day after last treatment | 
| Ankle Strength Post-Treatment 2 | Post-Treatment Plantarflexion Torque (strength, torque) | between 7-10 days after Post-Treatment 1 | 
| Ankle Strength Post-Treatment 3 | Post-Treatment Plantarflexion Torque (strength, torque) | between 17-20 days after Post-Treatment 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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spinal cord injury, walking, motor control, istradefylline, adenosine, strength