Clinical trial NCT05217498: Combining Low Oxygen Therapy and an Adenosine A2a Receptor Antagonist to Improve Functional Mobility After Spinal Cord Injury
Official title: A Selective Adenosine 2a Antagonist to Enhance Training-related Gains in Walking Function for Persons With Chronic, Incomplete Spinal Cord Injury
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Spinal Cord Injuries
Myelopathy
Keywords: spinal cord injury
walking
motor control
istradefylline
adenosine
strength
Lead sponsor: Spaulding Rehabilitation Hospital
Sponsor class: OTHER
First posted: 2022-02-01
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Pre-Treatment Walking Speed
timeFrame: within 5 days of first treatment
measure: Walking Speed Post-Treatment 1
timeFrame: within 1 day after last treatment
measure: Walking Speed Post-Treatment 2
timeFrame: between 7-10 days after Post-Treatment 1
measure: Walking Speed Post-Treatment 3
timeFrame: between 17-20 days after Post-Treatment 1
Secondary outcomes:
measure: Pre-Treatment Walking Distance
timeFrame: within 5 days of first treatment
measure: Walking Distance Post-Treatment 1
timeFrame: within 1 day after last treatment
measure: Walking Distance Post-Treatment 2
timeFrame: between 7-10 days after Post-Treatment 1
measure: Walking Distance Post-Treatment 3
timeFrame: between 17-20 days after Post-Treatment 1
measure: Pre-Treatment Timed Up-and-Go Test
timeFrame: within 5 days of first treatment
measure: Timed Up-and-Go Test Post-Treatment 1
timeFrame: within 1 day after last treatment
measure: Timed Up-and-Go Test Post-Treatment 2
timeFrame: between 7-10 days after Post-Treatment 1
measure: Timed Up-and-Go Test Post-Treatment 3
timeFrame: between 17-20 days after Post-Treatment 1
measure: Pre-treatment Ankle Strength
timeFrame: within 5 days of first treatment
measure: Ankle Strength Post-Treatment 1
timeFrame: within 1 day after last treatment
measure: Ankle Strength Post-Treatment 2
timeFrame: between 7-10 days after Post-Treatment 1
measure: Ankle Strength Post-Treatment 3
timeFrame: between 17-20 days after Post-Treatment 1
Other outcomes:
Locations:
city: Cambridge
country: United States
facility: Spaulding Rehabilitation Hospital
state: Massachusetts
Study officials:
affiliation: Spaulding Rehabilitation Hospital
name: Randy D Trumbower, PT, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
citation: 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.
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.
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.
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.