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

November 27, 2023 updated by: Randy Trumbower, PT, PhD

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Massachusetts
      • Cambridge, Massachusetts, United States, 02138
        • Spaulding Rehabilitation Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. age 18 and 75 years (the latter to reduce the likelihood of heart disease) medical clearance to participate
  2. lesion at or below C2 and above T12 with non-progressive etiology
  3. classified as motor-incomplete with visible volitional leg movement
  4. injury greater than 12 months
  5. ability to advance one step overground without human assistance

Exclusion Criteria:

  1. Concurrent severe medical illness (i.e., infection, cardiovascular disease, ossification, recurrent autonomic dysreflexia, unhealed decubiti, and history of pulmonary complications)
  2. Pregnant women because of the unknown effects of AIH on pregnant women and fetus
  3. History of seizures, brain injury, and/or epilepsy
  4. Undergoing concurrent physical therapy
  5. Diabetes
  6. Cirrhosis Caffeine and/or NSAID allergies or intolerances

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / 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:
  • Nourianz
  • KW6002
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:
  • Nourianz
  • KW6002

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Randy Trumbower, PT, PhD

Investigators

  • Principal Investigator: Randy D Trumbower, PT, PhD, Spaulding Rehabilitation Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2024

Primary Completion (Estimated)

December 30, 2026

Study Completion (Estimated)

June 30, 2027

Study Registration Dates

First Submitted

January 11, 2022

First Submitted That Met QC Criteria

January 26, 2022

First Posted (Actual)

February 1, 2022

Study Record Updates

Last Update Posted (Actual)

November 29, 2023

Last Update Submitted That Met QC Criteria

November 27, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018A004512

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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