Clinical trial NCT04726059: Motor & Autonomic Concomitant Health Improvements With Neuromodulation & Exercise Training: An SCI RCT
Official title: Motor and Autonomic Concomitant Health Improvements With Neuromodulation and Exercise (MACHINE) Training: A Randomized Controlled Trial in Individuals With SCI
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Spinal Cord Injuries
Neurogenic Bladder
Neurogenic Bowel
Keywords: Activity-based Therapy
Spinal Cord Stimulation
Transcutaneous Spinal Cord Stimulation
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Praxis Spinal Cord Institute
First posted: 2021-01-27
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants are assigned to either an ABT+TSCS or ABT+SHAM arm. Participants who are assigned to ABT+SHAM will have the opportunity to complete an ABT+TSCS open-label follow-up.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in attempted voluntary motor activation (supine)
timeFrame: Weeks 2 and 14
measure: Change in attempted voluntary motor activation (walking)
timeFrame: Weeks 2 and 14
measure: Change in lower limb proprioceptive sense
timeFrame: Weeks 2 and 14
measure: Change in blood pressure regulation
timeFrame: Weeks 2 and 14
Secondary outcomes:
measure: Change in corticospinal excitability
timeFrame: Weeks 2 and 14
measure: Change in spinal excitability
timeFrame: Weeks 2 and 14
measure: Change in seated, static balance control
timeFrame: Weeks 2 and 14
measure: Change in seated, dynamic balance control
timeFrame: Weeks 2 and 14
measure: Change in severity of cardiovascular dysfunction by the ADFSCI
timeFrame: Weeks 2 and 14
measure: Change in severity of orthostatic hypotension
timeFrame: Weeks 2 and 14
measure: Change in cardiac structure and function
timeFrame: Weeks 2 and 14
measure: Change in lower urinary tract function measured by the NBSS
timeFrame: Weeks 2 and 14
measure: Change in lower urinary tract function measured by the I-QOL
timeFrame: Weeks 2 and 14
measure: Change in bowel function measured by the NBDS
timeFrame: Weeks 2 and 14
measure: Change in sexual function (for male participants) measured by the IIEF-15
timeFrame: Weeks 2 and 14
measure: Change in sexual function (for female participants) measured by the FSFI
timeFrame: Weeks 2 and 14
measure: Change in subjective experience of sexual functioning measured by a semi-structed interview
timeFrame: Weeks 2 and 14
measure: Change in fatigue measured by the FSS
timeFrame: Weeks 2 and 14
measure: Change in spasticity measured by the SCI-SET
timeFrame: Weeks 2 and 14
measure: Change in pain measured by the International SCI Pain Basic Data Set (version 2)
timeFrame: Weeks 2 and 14
measure: Change in quality of life measured by the SF-36
timeFrame: Weeks 2 and 14
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: Blusson Spinal Cord Centre
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: Andrei Krassioukov, MD,PhD,FRCPC
role: PRINCIPAL_INVESTIGATOR
References: