Combination Therapy to Improve SCI Recovery. (BO2ST)

• ClinicalTrials.gov Identifier: NCT05563103
• Recruitment Status: Not yet recruiting
• First Posted: October 3, 2022
• Last Update Posted: October 3, 2022
• Sponsor: Spaulding Rehabilitation Hospital
• Collaborators: United States Department of Defense; Shirley Ryan AbilityLab
• Information provided by (Responsible Party): Randy Trumbower, PT, PhD, Spaulding Rehabilitation Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Spinal Cord Injuries	Other: Daily acute intermittent hypoxia; Other: Room air (SHAM); Other: Walking + tSTIM; Other: Walking + Sham transcutaneous spinal stimulation (tSHAM)	Not Applicable

Detailed Description:

The goal of the study is to determine whether repeatedly breathing mild bouts of low oxygen for brief periods (termed acute intermittent hypoxia (AIH)) combined with transcutaneous spinal cord stimulation (tSTIM) improves recovery of walking and strength after spinal cord injury. This idea stems from animal studies on respiration, in which investigators showed that mild AIH improves breathing in rats with spinal injuries as well as studies involving spinal cord stimulation. These studies showed that AIH induces plasticity, strengthening neural connections by increasing the production of key proteins and improving the sensitivity of spinal cord circuitry. Additional studies have shown that tSTIM may enhance function and strength for people with spinal cord injuries. The ultimate goal of this research is to assess if 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 for servicemen and civilians may improve.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Breathing Low Oxygen to Enhance Spinal Stimulation Training and Functional Recovery in Persons With Chronic SCI: The BO2ST Trial
• Estimated Study Start Date: October 2022
• Estimated Primary Completion Date: October 2026
• Estimated Study Completion Date: December 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: AIH + Walking Training with transcutaneous spinal stimulation (WALKtSTIM); Acute Intermittent Hypoxia will be used as a pretreatment before walking training paired with transcutaneous spinal cord stimulation.	Other: Daily acute intermittent hypoxia; Each participant will be exposed to 8 sessions of daily acute intermittent hypoxia via air generators over the span of two 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).; Other: 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.
Sham Comparator: Sham + WALKtSTIM; Sham acute intermittent hypoxia will be used as a pretreatment before walking training paired with transcutaneous spinal cord stimulation.	Other: Room air (SHAM); Each participant will be exposed to 8 sessions of daily room air via air generators over the span of two weeks. The generator will fill reservoir bags attached to a non-rebreathing facemask. Each session will consist of 15 episodes of 1.5 minute normoxia (FIO2=0.21±0.02).; Other: 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.
Sham Comparator: AIH + Walking Training with sham transcutaneous spinal stimulation (WALKtSHAM); Acute Intermittent Hypoxia will be used as a pretreatment before walking training paired with sham transcutaneous spinal cord stimulation.	Other: Daily acute intermittent hypoxia; Each participant will be exposed to 8 sessions of daily acute intermittent hypoxia via air generators over the span of two 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).; Other: Walking + Sham transcutaneous spinal stimulation (tSHAM); Individuals will participate in 45 minutes of gait training while having SHAM transcutaneous spinal cord stimulation. The stimulation will briefly increase to 80% involuntary motor threshold and then brought down to 0 within 30 seconds.

Outcome Measures

Primary Outcome Measures :

1. Change in walking recovery, assessed by 10 meter walk test (10MWT) [ Time Frame: Through study completion, an average of 12 weeks ]
   Participants walk ten meters without assistance at their fastest, but safest speed with a minimum of 1-minute of rest between two trials. Average speed across the up to three 10MWT trials will be used for analysis. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
2. Rate of change in walking recovery, assessed by 10 meter walk test (10MWT) [ Time Frame: Through study completion, an average of 12 weeks ]
   Participants walk ten meters without assistance at their fastest, but safest speed with a minimum of 1-minute of rest between two trials. Average speed across the up to three 10MWT trials will be used for analysis. Rate of change is the number of treatment sessions required to achieve an increase in 10MWT speed of at least the minimal clinically important difference (0.06 m/s) as compared to pre-treatment baseline.

Secondary Outcome Measures :

1. Change in walking recovery, assessed by 6 minute walk test (6MWT) [ Time Frame: Through study completion, an average of 12 weeks ]
   Participants perform the 6MWT at their fastest, most comfortable walking speed sustainable for 6 minutes. Distances will be recorded at 2 and 6 minutes. The test will be based upon the participant's ability to finish each assessment without human assistance. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
2. Change in walking recovery, assessed by timed up-and-go (TUG) test [ Time Frame: Through study completion, an average of 12 weeks ]
   The TUG test is used to assess the dynamic balance of an individual. It measures the amount of time (recorded in seconds) it takes for the individual to rise from a standard arm chair, walk a distance of 3 meters and return to the initial position resting against the back of the chair. Participants will perform up to three trials of the TUG test. Average speed across TUG trials will be used for analysis. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
3. Change in pain severity, assessed by the Numeric Pain Rating Scale (NPRS) [ Time Frame: Through study completion, an average of 12 weeks ]
   Participants will report their pain level using the Numeric Pain Rating Scale. The scale is from 0 to 10; 0 being no pain and 10 being extreme pain. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
4. Change in cognitive function, assessed by the California Verbal Learning Test (CVLT) [ Time Frame: Through treatment completion, an average of 4 weeks ]
   The CVLT is a brief, individually administered battery to measure cognitive decline or improvement and assesses verbal learning and memory for older adolescents and adults. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
5. Systemic hypertension incidence rate [ Time Frame: Through treatment completion, an average of 4 weeks ]
   Participants will have their systolic and diastolic blood pressure measured. A systemic hypertensive event is quantified as a systolic pressure exceeding 140 mmHg and/or diastolic pressure exceeding 90 mmHg. A hypertension incident rate is the number of hypertensive events divided by the total person-time. Person-time is in units of person-measures (the sum of the total number of BP measurements) taken for each person. Person-measures accounts for the total number of chances for detecting a hypertensive event and accounts for measurements not made due to drop-out or a disqualifying adverse event.
6. Autonomic dysreflexia incidence rate [ Time Frame: Through treatment completion, an average of 4 weeks ]
   The occurrence of autonomic dysreflexia will be assessed. An autonomic dysreflexia event will constitute a participant having a SBP increase from baseline of 20 mmHg not associated with exercise or systolic blood pressure (SBP) greater than 150 mmHg with complaints of headache, diaphoresis, and/or blurred vision and will be diagnosed by our study team clinicians. We will compute autonomic dysreflexia incident rate as the number of autonomic dysreflexia events divided by the total person-time. We define person-time in units of person-days (the number of days a person remains in the study). Person-days account for the total number of chances for detecting autonomic dysreflexia and accounts for days on which measurements were not made due to drop-out or a disqualifying adverse event.

Other Outcome Measures:

1. 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 12 weeks ]
   The LEMS uses ASIA key muscles in both the lower extremities, with a total possible score of 50 (maximum score of 5 for each muscle group). Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
2. Change in spasticity, assessed by the Spinal Cord Assessment Tool for Spastic Reflexes (SCATS) [ Time Frame: Through study completion, an average of 12 weeks ]
   The study team will quantify the total lower extremity spasticity score using the cumulative sum of 3 SCATS subscales: clonus (0=no spasticity; 3=severe), flexor (0=no spasticity; 3=severe), and extensor (0=no spasticity; 3=severe). Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
3. Change in bowel dysfunction, assessed by the Neurogenic Bowel Dysfunction Score (NBDS) [ Time Frame: Through study completion, an average of 12 weeks ]
   This questionnaire is a symptom-based score for neurogenic bowel dysfunction. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
4. Change in bladder dysfunction, assessed by the Neurogenic Bladder Symptom Score (NBSS) [ Time Frame: Through study completion, an average of 12 weeks ]
   This questionnaire is a symptom-based score for neurogenic bladder dysfunction. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
5. Change in walking ability and assistive device use, assessed by Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI). [ Time Frame: Through study completion, an average of 12 weeks ]
   The SCI-FAI assesses functional walking ability in ambulatory individuals with SCI. Component scores range from 0 to 20 in the gait parameter component, 0 to 14 in the assistive device component, and 0 to 5 in the walking mobility component. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.
6. Change in physical assistance needed, assessed by Walking Index for Spinal Cord Injury (WISCI) II [ Time Frame: Through study completion, an average of 12 weeks ]
   The WISCI is used to assess the amount of physical assistance is needed as well as devices required for walking following paralysis. This assessment is from 0-20 with value corresponding to a physical assistance description. Change is the difference between the post-treatment assessment 2 and pre-treatment baseline.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 18 to 70 years of age
• medically stable with medical clearance from study physician to participate
• SCI at or below C2 (phrenic sparing) 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 six 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

Contacts and Locations

Contacts

Contact: William M. Muter, BS; 617-952-6953; wmuter@partners.org

Contact: Randy Trumbower, PT, PhD; randy.trumbower@mgh.harvard.edu

Locations

United States, Illinois

Shirley Ryan AbilityLab

Chicago, Illinois, United States, 60611

Contact: Sara Prokup, PT, DPT 312-238-1355 sprokup@ricres.org

Principal Investigator: Arun Jayaraman, PT, PhD

United States, Massachusetts

Spaulding Rehabilitation Hospital

Cambridge, Massachusetts, United States, 02138

Contact: William M Muter, BS 617-952-6953 wmuter@partners.org

Principal Investigator: Randy Trumbower, PT, PhD

Sponsors and Collaborators

Spaulding Rehabilitation Hospital

United States Department of Defense

Shirley Ryan AbilityLab

Investigators

• Principal Investigator: Randy Trumbower, PT, PhD; Harvard Medical School (HMS and HSDM)

More Information

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.

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.

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.

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.

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.

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.

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.

• Responsible Party: Randy Trumbower, PT, PhD, Principal Investigator, Spaulding Rehabilitation Hospital
• ClinicalTrials.gov Identifier: NCT05563103
• Other Study ID Numbers: 2022P002036; W81XWH-22-1-0998 ( Other Grant/Funding Number: US Dept. of Defense )
• First Posted: October 3, 2022
• Last Update Posted: October 3, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Deidentified IPD will be available to other researchers upon request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: The study protocol and statistical analysis plan will be disseminated by December 2022. Participant data will be available at the end of the trial.
• Access Criteria: Principal investigators will be able to receive deidentified data.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Randy Trumbower, PT, PhD, Spaulding Rehabilitation Hospital:

Walk; Rehabilitation; Strength; Movement; Spinal cord injury; low oxygen; electrical stimulation; walking training

Additional relevant MeSH terms:

Spinal Cord Injuries; Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries