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

Sponsor

Randy Trumbower, PT, PhD (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05217498

Collaborator

(none)

Enrollment

Location

Arms

57.9

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Injuries Myelopathy	Drug: Istradefylline Device: low oxygen therapy	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Dec 30, 2026

Anticipated Study Completion Date :

Jun 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Istradefylline+low oxygen training 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 Consume 20mg tablet of istradefylline for 28 consecutive days. Other Names: KW6002 Nourianz Device: low oxygen therapy 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. Other Names: acute intermittent hypoxia
Active Comparator: Placebo+low oxygen training 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 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. Other Names: acute intermittent hypoxia
Active Comparator: Istradefylline+SHAM 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 Consume 20mg tablet of istradefylline for 28 consecutive days. Other Names: KW6002 Nourianz

Arm

Intervention/Treatment

Experimental: Istradefylline+low oxygen training

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

Consume 20mg tablet of istradefylline for 28 consecutive days.

Other Names:

KW6002

Nourianz

Device: low oxygen therapy

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.

Other Names:

acute intermittent hypoxia

Active Comparator: Placebo+low oxygen training

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

Other Names:

acute intermittent hypoxia

Active Comparator: Istradefylline+SHAM

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

Consume 20mg tablet of istradefylline for 28 consecutive days.

Other Names:

KW6002

Nourianz

Outcome Measures

Primary Outcome Measures

Pre-Treatment Walking Speed [within 5 days of first treatment]
Pre-Treatment Walking Speed; 10MWT (time, seconds)
Walking Speed Post-Treatment 1 [within 1 day after last treatment]
Post-Treatment Walking Speed; 10MWT (time, seconds)
Walking Speed Post-Treatment 2 [between 7-10 days after Post-Treatment 1]
Post-Treatment Walking Speed; 10MWT (time, seconds)
Walking Speed Post-Treatment 3 [between 17-20 days after Post-Treatment 1]
Post-Treatment 10MWT (time, seconds)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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