Low Oxygen Therapy to Enhance Walking Recovery After SCI.

Official title

Breathing Low Oxygen to Enhance Spinal Stimulation Training and Functional Recovery for Aging Adults With Chronic SCI: The BO2ST-II Trial

Overview

The purpose of this study is to determine how combining bouts of low oxygen, transcutaneous spinal cord stimulation, and walking training may improve walking function for people with chronic spinal cord injury of different age groups.

Detailed description

The goal of the study is to determine the optimal dosage for different age groups of repeatedly breathing mild bouts of low oxygen for brief periods (termed acute intermittent hypoxia (AIH)) combined with transcutaneous spinal cord stimulation (tSTIM) to improve recovery of walking and strength after spinal cord injury. Preliminary studies have shown that combining AIH and tSTIM with walking training can enhance individuals walking training greater than just AIH or tSTIM. By using low oxygen as a pre-treatment to tSTIM during walking training, functional independence and quality of life may improve. Despite exciting preliminary results supporting the efficacy of AIH and tSTIM to enhance walking recovery after SCI, understanding factors that may enhance or undermine treatment responsiveness is warranted. Factors include establishing the role of age and sex dependency on appropriate dosing (number of sessions) AIH to provide the greatest plasticity-promoting effects on walking recovery for our aging population of persons living with SCI.

Interventions

• Other Daily acute intermittent hypoxia
  Each participant will be exposed to 16 sessions of daily acute intermittent hypoxia via air generators over the span of four weeks. The generator will fill reservoir bags attached to a non-rebreathing facemask. Each session will consist of 15 episodes which include intervals of 1.5 minute hypoxia (FIO2=0.10±0.02, i.e. 10% O2) and 1 minute normoxia (FIO2=0.21±0.02).
• Device Walking + tSTIM
  Individuals will participate in 45 minutes of gait training while having transcutaneous spinal cord stimulation. Stimulation intensity will be 80% involuntary motor threshold.

Primary outcome measures

• Change in walking recovery, assessed by 10 meter walk test (10MWT) [Time frame: Through study completion, an average of 14 weeks]
• Rate of change in walking recovery, assessed by 10 meter walk test (10MWT) [Time frame: Through study completion, an average of 14 weeks]

Secondary outcome measures (12)

• Change in walking recovery, assessed by 6 minute walk test (6MWT) [Time frame: Through study completion, an average of 14 weeks]
• Change in walking recovery, assessed by timed up-and-go (TUG) test [Time frame: Through study completion, an average of 14 weeks]
• Change in pain severity, assessed by the Numeric Pain Rating Scale (NPRS) [Time frame: Through study completion, an average of 14 weeks]
• Change in cognitive function, assessed by the California Verbal Learning Test (CVLT) [Time frame: Through treatment completion, an average of 6 weeks]
• Counts of hypertensive events [Time frame: Through treatment completion, an average of 6 weeks]
• Counts of blood pressure measurements [Time frame: Through treatment completion, an average of 6 weeks]
• Systemic hypertension incidence rate [Time frame: Through treatment completion, an average of 6 weeks]
• Number of autonomic dysreflexia events [Time frame: Through treatment completion, an average of 6 weeks]
• Total person-time for autonomic dysreflexia [Time frame: Through treatment completion, an average of 6 weeks]
• Autonomic dysreflexia incidence rate [Time frame: Through treatment completion, an average of 6 weeks]
• Change in lower extremity strength, assessed by American Spinal Injury Association Impairment Scale (AIS) lower extremity motor scores (LEMS) [Time frame: Through study completion, an average of 14 weeks]
• Change in spasticity, assessed by the Spinal Cord Assessment Tool for Spastic Reflexes (SCATS) [Time frame: Through study completion, an average of 14 weeks]

Eligibility criteria

Inclusion criteria

• 18 to 80 years of age
• medically stable with medical clearance from study physician to participate
• SCI at or below C1 and at or above L2 with at least some sensory or motor function preserved below the neurologic level
• non-progressive etiology of spinal injury
• American Spinal Injury Association (ASIA) scores of C-D at initial screen
• ambulatory (able to complete the 10-meter walk test without support from another person)
• chronic injury (define as > 12 months post-injury) to avoid potential for spontaneous neurological plasticity and recovery

Exclusion criteria

• severe concurrent illness or pain, including unhealed decubiti, severe neuropathic or chronic pain syndrome, severe infection (e.g., urinary tract), hypertension, cardiovascular disease, pulmonary disease, severe osteoporosis, active heterotopic ossification in the lower extremities, severe systemic inflammation
• < 24 on Mini-Mental Exam
• severe recurrent autonomic dysreflexia
• history of severe cardiovascular/pulmonary complications including hypertension (systolic blood pressure > 150 mmHg)
• pregnancy because of unknown effects of AIH or tSTIM on a fetus (individuals of childbearing potential will not otherwise be excluded)
• botulinum toxin injections in lower extremity muscles within the prior three months
• history of tendon or nerve transfer surgery in the lower extremity
• untreated severe sleep-disordered breathing characterized by uncontrolled hypoxia and sleep fractionation that may impact the outcome of this study.
• active implanted devices (e.g., intrathecal baclofen pump)
• receiving concurrent electrical stimulation
• motor threshold evoked by transcutaneous spinal stimulation >200 mA

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 2 centers

• Brooks Rehabilitation Hospital — Jacksonville
• Spaulding Rehabilitation Hospital — Cambridge

Publications

• Cutler MJ, Swift NM, Keller DM, Wasmund WL, Smith ML. Hypoxia-mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea. J Appl Physiol (1985). 2004 Feb;96(2):754-61. doi: 10.1152/japplphysiol.00506.2003. Epub 2003 Oct 10. PMID 14555683
• Dale-Nagle EA, Hoffman MS, MacFarlane PM, Mitchell GS. Multiple pathways to long-lasting phrenic motor facilitation. Adv Exp Med Biol. 2010;669:225-30. doi: 10.1007/978-1-4419-5692-7_45. PMID 20217354
• Estes S, Zarkou A, Hope JM, Suri C, Field-Fote EC. Combined Transcutaneous Spinal Stimulation and Locomotor Training to Improve Walking Function and Reduce Spasticity in Subacute Spinal Cord Injury: A Randomized Study of Clinical Feasibility and Efficacy. J Clin Med. 2021 Mar 11;10(6):1167. doi: 10.3390/jcm10061167. PMID 33799508
• Gad P, Hastings S, Zhong H, Seth G, Kandhari S, Edgerton VR. Transcutaneous Spinal Neuromodulation Reorganizes Neural Networks in Patients with Cerebral Palsy. Neurotherapeutics. 2021 Jul;18(3):1953-1962. doi: 10.1007/s13311-021-01087-6. Epub 2021 Jul 9. PMID 34244928
• 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. PMID 33647273
• 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. PMID 24285617
• 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. PMID 21821826
• Muter WM, Mansson L, Tuthill C, Aalla S, Barth S, Evans E, McKenzie K, Prokup S, Yang C, Sandhu M, Rymer WZ, Edgerton VR, Gad P, Mitchell GS, Wu SS, Shan G, Jayaraman A, Trumbower RD. A Research Protocol to Study the Priming Effects of Breathing Low Oxygen on Enhancing Training-Related Gains in Walking Function for Persons With Spinal Cord Injury: The BO2ST Trial. Neurotrauma Rep. 2023 Nov 6;4(1): PMID 38028272

Identifiers

NCT: NCT06521723 · 2024P001608 · HT94252410708 · CDMRP-SC230232

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗