Motor & Autonomic Concomitant Health Improvements With Neuromodulation & Exercise Training: An SCI RCT

NCT ID: NCT04726059

Last Updated: 2024-04-30

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-22
• Study Completion Date: 2024-12-31

Brief Summary

Spinal cord injury (SCI) disrupts many aspects of life, including the loss of volitional movement and involuntary control of bodily functions; both crucial functional recovery priorities for this population. Mobility impairments and secondary complications limit an individual's ability to exercise, a behavior known to have wide-ranging functional and health benefits. This trial will investigate whether activity-based therapy (ABT), using body-weight-supported treadmill training (BWSTT), can change the strength of signals from the brain that control volitional movement, leading to improvements in seated balance as well as other important involuntary bodily (i.e. cardiovascular, urinary tract, bowel and sexual) functions. The investigators aim to determine whether these improvements can be augmented with the addition of non-invasive transcutaneous spinal cord stimulation (TSCS). This therapy has been shown to re-awaken dormant spinal circuits. In this randomized controlled trial, TSCS with ABT, using BWSTT (three sessions/week for twelve weeks), will be compared to ABT+SHAM in individuals with chronic motor-complete spinal cord injury (SCI). Those in the ABT+SHAM group will be given the option to complete an ABT+TSCS open-label follow-up. Before and after training, the following outcomes will be assessed by validated methods: corticospinal excitability, motor function, and seated balance (Hypothesis 1 - Motor Function); severity and frequency of blood pressure instability, urinary tract, bowel, and sexual dysfunctions (Hypothesis 2 - Autonomic Functions); and general health (Hypothesis 3 - Quality of Life). This collaborative project is between consumers with SCI and clinicians/scientists with expertise in SCI care (kinesiologists, physiotherapists, physiatrists, sexual health clinicians). Compared to ABT alone, the investigators anticipate that ABT+TSCS will result in superior improvements in motor and autonomic functions in individuals with SCI.

Detailed Description

Spinal cord injury (SCI) is a severe disorder resulting in not only in motor deficits (i.e. paralysis) but also a myriad of autonomic dysfunctions (i.e. urinary tract/bowel/sexual impairments and blood pressure instability). The restoration of motor as well as autonomic functions remains among the top priorities for individuals with SCI. Individuals with SCI develop cardiovascular (CV) disease at a younger age and at greater rates than individuals without injury. Both low levels of physical activity and profound blood pressure (BP) instability, commonly experienced by individuals with injuries at or above the sixth thoracic level, likely explains the heightened risk.

Neurogenic lower urinary tract (LUT) dysfunction impacts over 90% of individuals with SCI. This dysfunction leads to vesico-ureteral-renal reflux, urinary tract infections, bladder stone formation, and impaired renal function - ultimately leading to significant disease burden and poorer health-related quality of life. Bowel function is also significantly compromised after SCI, presenting as constipation, impaired colonic motility and loss of volitional control resulting in episodes of fecal incontinence - predisposing an individual to increased risk of long-term complications. Over 60% report that bowel dysfunction adversely impacts quality of life. Lastly, severe impairments in sexual function following SCI include erectile dysfunction, ejaculatory disorders/ anejaculation in men and reduced vaginal lubrication in women, with both sexes experiencing orgasmic difficulties or anorgasmia as well as alterations in sexual drive and sexual satisfaction.

Activity-based therapy (ABT) is a common and an effective means to improve walking function post-injury and can facilitate general health maintenance; this includes an enhancement of neural BP control, as well as bladder, bowel, and sexual functions.

Neuromodulation, potentially activating isolated spinal cord neuronal circuitry, has received significant recognition in recent years as a promising approach to target various neurological dysfunctions. The immense therapeutic potential of epidural spinal cord stimulation demonstrates mitigation of spasticity in individuals with motor-incomplete injuries. Moreover, this stimulation improved ability to generate rhythmic, locomotor-like limb movements, and restored voluntary control of functional movements in individuals with motor-complete injuries. Our past exciting and ground-breaking pilot work highlights the capacity for TSCS to modulate spinal circuits (An Autonomic Neuroprosthesis: Noninvasive Electrical Spinal Cord Stimulation Restores Autonomic Cardiovascular Function in Individuals with Spinal Cord Injury. J Neurotrauma. 2018;35(3):446- 451. doi:10.1089/neu.2017.5082). To administer TSCS, small adhesive electrodes are placed on the skin around the spinal cord and hips. The electrodes are connected to a machine that generates a small electric current. After turning the machine on, the participant may feel a small electric current under the electrodes, though it should not elicit any pain.

Despite literature supporting the benefits of TSCS and ABT, the effects of pairing TSCS with ABT is largely unknown. These therapies are adaptable, non-invasive, and relatively affordable, with the potential to simultaneously benefit both motor and autonomic functions. Randomized controlled trials are needed to better validate these interventions for clinical settings.

Project Rationale:

Motor paralysis and autonomic dysfunctions have been identified as a major priority for recovery by individuals with SCI. Addressing these dysfunctions may ultimately translate to improved health-related quality of life (HRQOL). The use of ABT with non-invasive and adaptable TSCS has the potential to reduce CV disease risk factors and other autonomic dysfunctions in this at-risk population.

Conditions

Spinal Cord Injuries; Neurogenic Bladder; Neurogenic Bowel

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

ABT+SHAM

The SHAM is low-intensity, ineffective stimulation delivered at the same anatomical location as TSCS.

Group Type: SHAM_COMPARATOR

SHAM (low-intensity) Transcutaneous Spinal Cord Stimulation

Intervention Type: DEVICE

Ineffective stimulation will be administered at the same anatomical location as therapeutic TSCS.

Activity-Based Therapy

Intervention Type: DEVICE

Using BWSTT, all participants (both arms) will train 3 times per week for 12 weeks with a target to reach 45 minutes of gait training in each session.

For gait training, the level of body weight support and speed of walking will be adjusted to allow the person to bear as much weight as possible while maintaining proper stance limb kinematics.

ABT+TSCS

Therapeutic TSCS will be delivered during ABT using an isolated bipolar constant current stimulator. Continuous TSCS applied over the T11-T12 spinous processes at 5-40 Hz has been shown to induce stepping movements in participants with their legs in a gravity-independent position.

Group Type: EXPERIMENTAL

Transcutaneous Spinal Cord Stimulation

Intervention Type: DEVICE

Therapeutic TSCS will be delivered during ABT using a non-invasive central nervous system stimulator (TESCoN, SpineX Inc., CA, USA). Stimulation will involve charge balanced monophasic rectangular waveforms with 1.0-ms pulses, administered at 30 Hz, with a carrier frequency of 10 kHz and a current ranging from 10 to 130 mA.

Activity-Based Therapy

Intervention Type: DEVICE

Using BWSTT, all participants (both arms) will train 3 times per week for 12 weeks with a target to reach 45 minutes of gait training in each session.

For gait training, the level of body weight support and speed of walking will be adjusted to allow the person to bear as much weight as possible while maintaining proper stance limb kinematics.

Interventions

Transcutaneous Spinal Cord Stimulation

Therapeutic TSCS will be delivered during ABT using a non-invasive central nervous system stimulator (TESCoN, SpineX Inc., CA, USA). Stimulation will involve charge balanced monophasic rectangular waveforms with 1.0-ms pulses, administered at 30 Hz, with a carrier frequency of 10 kHz and a current ranging from 10 to 130 mA.

Intervention Type: DEVICE

SHAM (low-intensity) Transcutaneous Spinal Cord Stimulation

Ineffective stimulation will be administered at the same anatomical location as therapeutic TSCS.

Intervention Type: DEVICE

Activity-Based Therapy

Using BWSTT, all participants (both arms) will train 3 times per week for 12 weeks with a target to reach 45 minutes of gait training in each session.

For gait training, the level of body weight support and speed of walking will be adjusted to allow the person to bear as much weight as possible while maintaining proper stance limb kinematics.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

A participant must meet all of the following criteria in order to be eligible for inclusion:

• Resident of British Columbia, Canada with active provincial medical services plan
• Male or female, 18-60 years of age
• Chronic traumatic SCI (non-progressive, with complete motor paralysis) at or above the T6 spinal segment
• At least 1-year post injury, at least 6 months from any spinal surgery
• American Spinal Injury Association Impairment Scale (AIS) A, B
• Able to tolerate an upright posture for 30 minutes (with or without breaks)
• Willing and able to comply with all clinic visits and study-related procedures
• Able to understand and complete study-related questionnaires (must be able to understand and speak English or have access to an appropriate interpreter as judged by the investigator)
• No painful musculoskeletal dysfunction, unhealed fracture, pressure sore, or active infection that may interfere with testing activities
• Stable management of spinal cord related clinical issues (i.e., spasticity management)
• Women of childbearing potential must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply:

1. Women of childbearing potential must have a confirmed negative pregnancy test prior to the baseline visit. During the trial, all women of childbearing potential will undergo urine pregnancy tests at their monthly clinic visits as outlined in the schedule of events

2. Women of childbearing potential must agree to use adequate contraception during the period of the trial and for at least 28 days after completion of treatment. Effective contraception includes abstinence

• Sexually active males with female partners of childbearing potential must agree to use effective contraception during the period of the trial and for at least 28 days after completion of treatment
• Medication dosage must be stable for period of 4 weeks prior to participation
• Must provide informed consent

Exclusion Criteria

A participant who meets any of the following criteria will be ineligible to participate:

• Ventilator dependent
• Clinically significant, unmanaged, depression (PHQ-9 above 15) or ongoing drug abuse
• Use of any medication or treatment that in the opinion of the investigator indicates that it is not in the best interest of the participant to participate in this study
• Intrathecal baclofen pump
• Oral baclofen dose or other anti-spasticity medications greater than 30mg per day
• Cardiovascular, respiratory, bladder, or renal disease unrelated to SCI or presence of hydronephrosis or presence of obstructive renal stones
• Presence of severe acute medical issue that in the investigator's judgement would adversely affect the participant's participation in the study. Examples include, but are not limited to acute urinary tract infections, active heterotopic ossification, newly changed antidepressant medications [tricyclics], debilitating muscle pain, pressure sores, or unstable diabetes
• Any implanted metal (other than dental implants) in the skull or presence of pacemakers, stimulators, or medication pumps in the trunk
• History of osteoporosis, low bone mineral density, or fragility fractures in the lower limbs
• History of seizures/epilepsy or recurring headaches
• Participant has swollen, infected, and inflamed areas or open wounds on the area of stimulation
• Severe anemia (Hgb<8 g/dl) or hypovolemia as measured by hematocrit via blood test in the last six months
• Participant is a member of the investigational team or his /her immediate family
• Participant has undergone electrode implantation surgery

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Praxis Spinal Cord Institute

OTHER

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Andrei Krassioukov

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrei Krassioukov, MD,PhD,FRCPC

Role: PRINCIPAL_INVESTIGATOR

University of British Columbia

Locations

Blusson Spinal Cord Centre

Vancouver, British Columbia, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Andrea Maharaj, BSc

Role: CONTACT

amaharaj@icord.org

6046758856

Facility Contacts

Andrea Maharaj, BSc

Role: primary

amaharaj@icord.org

6046758856

References

Shackleton C, Samejima S, Williams AM, Malik RN, Balthazaar SJ, Alrashidi A, Sachdeva R, Elliott SL, Nightingale TE, Berger MJ, Lam T, Krassioukov AV. Motor and autonomic concomitant health improvements with neuromodulation and exercise (MACHINE) training: a randomised controlled trial in individuals with spinal cord injury. BMJ Open. 2023 Jul 14;13(7):e070544. doi: 10.1136/bmjopen-2022-070544.

Reference Type: DERIVED

PMID: 37451734 (View on PubMed)

Other Identifiers

H20-01307

Identifier Type: -

Identifier Source: org_study_id