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

Spinal Cord Injuries Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05217498
• Other study ID #: 2018A004512
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: September 1, 2024
• Est. completion date: June 30, 2027

Study information

• Verified date: November 2023
• Source: Spaulding Rehabilitation Hospital
• Contact: Randy D. Trumbower, PT, PhD
• Phone: 6179526953
• Email: randy.trumbower[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: June 30, 2027
• Est. primary completion date: December 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Myelopathy
• Spinal Cord Diseases
• Spinal Cord Injuries
• Wounds and Injuries

Intervention

Drug:
• Istradefylline
Consume 20mg tablet of istradefylline for 28 consecutive days.

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.

Locations

Country	Name	City	State
United States	Spaulding Rehabilitation Hospital	Cambridge	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Randy Trumbower, PT, PhD

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View Citation

Tan AQ, Barth S, Trumbower RD. Acute intermittent hypoxia as a potential adjuvant to improve walking following spinal cord injury: evidence, challenges, and future directions. Curr Phys Med Rehabil Rep. 2020 Sep;8(3):188-198. doi: 10.1007/s40141-020-00270-8. Epub 2020 Jun 24. — View Citation

Tan AQ, Papadopoulos JM, Corsten AN, Trumbower RD. An automated pressure-swing absorption system to administer low oxygen therapy for persons with spinal cord injury. Exp Neurol. 2020 Nov;333:113408. doi: 10.1016/j.expneurol.2020.113408. Epub 2020 Jul 17. — View Citation

Tan AQ, Sohn WJ, Naidu A, Trumbower RD. Daily acute intermittent hypoxia combined with walking practice enhances walking performance but not intralimb motor coordination in persons with chronic incomplete spinal cord injury. Exp Neurol. 2021 Jun;340:113669. doi: 10.1016/j.expneurol.2021.113669. Epub 2021 Feb 27. — View Citation

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. — View Citation

Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair. 2012 Feb;26(2):163-72. doi: 10.1177/1545968311412055. Epub 2011 Aug 5. — View Citation

Vivodtzev I, Tan AQ, Hermann M, Jayaraman A, Stahl V, Rymer WZ, Mitchell GS, Hayes HB, Trumbower RD. Mild to Moderate Sleep Apnea Is Linked to Hypoxia-induced Motor Recovery after Spinal Cord Injury. Am J Respir Crit Care Med. 2020 Sep 15;202(6):887-890. doi: 10.1164/rccm.202002-0245LE. No abstract available. — View Citation

Outcome

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

External Links

•   Research Lab Website