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Spinal Cord Stimulation and Autonomic Response in People With SCI.

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ClinicalTrials.gov Identifier: NCT03924388
Recruitment Status : Not yet recruiting
First Posted : April 23, 2019
Last Update Posted : May 10, 2019
Sponsor:
Collaborator:
International Collaboration on Repair Discoveries
Information provided by (Responsible Party):
Aaron Phillips, University of Calgary

Brief Summary:

Despite being studied less than half as frequently, autonomic dysfunction is a greater priority than walking again in spinal cord injury. One autonomic condition after spinal cord injury is orthostatic hypotension, where blood pressure dramatically declines when patients assume the upright posture. Orthostatic hypotension is associated with all-cause mortality and cardiovascular incidents as well as fatigue and cognitive dysfunction, and it almost certainly contributes to an elevated risk of heart disease and stroke in people with spinal cord injury. In addition, autonomic dysfunction leads to bladder, bowel, sexual dysfunctions, which are major contributors to reduced quality and quantity of life. Unfortunately, the available options for treating this condition, are primarily limited to pharmacological options, which are not effective and are associated with various side effects. It has been recently demonstrated that spinal cord stimulation can modulate autonomic circuits and improve autonomic function in people living with spinal cord injury. Neuroanatomically, the thoracolumbar sympathetic pathways are the primary spinal cord segments involved in blood pressure control. Recently, a pilot study has been published demonstrating that transcutaneous spinal cord stimulation of thoracolumbar afferents can improve cardiovascular function. However, some studies have shown that lumbosacral transcutaneous spinal cord stimulation can also elicit positive cardiovascular effects. Therefore, there is no consensus on the optimal strategy in order to deliver transcutaneous spinal cord stimulation to improve the function of the autonomic system, and it may be that lumbosacral (i.e. the stimulation site being used most commonly for restoring leg function is sufficient). Another key knowledge gap in terms of transcutaneous spinal cord stimulation is whether or not the current is directly or indirectly activating these spinal circuits. Last but not least, the effects of epidural spinal cord stimulation on the function of cardiovascular, bladder, bowel and sexual system in spinal cord injury have been investigated in no study yet.

AIMS AND HYPOTHESES:

Aim 1. To examine the effects of short-term (one session) transcutaneous spinal cord stimulation on the frequency and severity of episodes of orthostatic hypotension/autonomic dysfunction, and bladder, bowel, and sexual functions. These effects will be compared at two sites of stimulation.

Hypothesis 1.1: Short-term transcutaneous mid-thoracic cord stimulation will mitigate the severity and frequency of orthostatic hypotension/autonomic dysfunction.

Hypothesis 1.2: Lumbosacral transcutaneous spinal cord stimulation will improve bladder, bowel, and sexual functions.

Aim 2. To examine the effects of long-term (one month) transcutaneous spinal cord stimulation on the severity and frequency of orthostatic hypotension/autonomic dysfunction.

Hypothesis 2.1: Long-term stimulation of the mid-thoracic cord will result in sustained improvements in mitigated severity and frequency of orthostatic hypotension/autonomic dysfunction that is not dependent on active stimulation.

Hypothesis 2.2: Long-term lumbosacral transcutaneous spinal cord stimulation will result in sustained improvements in bowel, bladder, and sexual function that is not dependent on active stimulation.

Aim 3: To examine the effects of short-term (one session) epidural spinal cord stimulation on the severity and frequency of orthostatic hypotension/autonomic dysfunction, and bladder, bowel, and sexual functions.

Hypothesis 3.1: Epidural spinal cord stimulation will mitigate the severity and frequency of orthostatic hypotension/autonomic dysfunction and improve bladder, bowel, and sexual function.

Hypothesis 3.3: There is no significant difference between immediate effects of lumbosacral transcutaneous spinal cord stimulation and epidural spinal cord stimulation on bladder, bowel, and sexual function.

For aim 1, 14 participants with spinal cord injury and no implanted electrodes on the spinal cord will be recruited. Participants will randomly receive one-hour stimulation under each of the two stimulation conditions in a crossover manner: Mid-thoracic and Lumbosacral. For aim 2, 28 individuals with spinal cord injury and no implanted electrode will be pseudo-randomized (1:1) to one of two stimulation sites. Participants will receive one-hour stimulation, five sessions per week for four weeks. Cardiovascular and neurological outcomes will be measured before the first stimulation session and after the last stimulation session. For aim 3, 4 participants with spinal cord injury with implanted electrodes on the spinal cord will be recruited to study the immediate effects of invasive epidural spinal cord stimulation.

All outcomes will be measured in two positions: a) Supine, b) ~ 70° upright tilt-test. Additionally, bowel, bladder, and sexual functions in project 2 will be assessed weekly.


Condition or disease Intervention/treatment Phase
Spinal Cord Injuries Autonomic Dysreflexia Orthostatic Hypotension, Dysautonomic Device: Epidural spinal cord stimulation Device: Trnascutaneous electrical spinal cord stimulation. Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Project 1 and 2: This multi-site open-label exploratory clinical trial (phase IIb) on examination of the effects of non-invasive transcutaneous spinal cord stimulation will take place at University of Calgary and the University of British Clombia, Canada. In a pseudo-randomized controlled 2×2 between-subject factorial design.

Project 3: This is a multi-site open-label case study exploring the effects of invasive epidural spinal cord stimulation on small number of individuals with SCI who underwent epidural implantation in Canada or abroad.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effects of Spinal Cord Stimulation on Autonomic Function in People With Spinal Cord Injury
Estimated Study Start Date : June 1, 2019
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : March 1, 2022


Arm Intervention/treatment
Experimental: Short-term transcutaneous spinal cord stimulation

In Project 1, we will measure the immediate effects of one-hour mid-thoracic and/or lumbosacral transcutaneous stimulation on autonomic function.

In mid-thoracic stimulation, the self-adhesive cathode electrode with a diameter of 30 mm will be placed on the skin between the TVII and TVIII spinous processes (approximately corresponding to the T8 spinal segment) at the midline over the vertebral column. For lumbosacral stimulation, the cathode will be placed on the skin between the LI and LII spinous processes (approximately corresponding to the L2/3 to S4/5) at the midline over the vertebral column. Two self-adhesive anode electrodes with a size of 5 × 9 cm will be symmetrically located on the skin over the iliac crests. Before and immediately after the stimulation, the outcomes will be measured in 2 positions, supine and ~ 70° upright (adjusted by tilt-up table).

Device: Trnascutaneous electrical spinal cord stimulation.
The measurements will be obtained in 2 positions of supine and ~ 70° upright adjusted by the tilt-up table.

Experimental: Long-term transcutaneous spinal cord stimulation

In Project 2, we will measure the effects of one-month stimulation (five one-hour stimulation sessions per week) of mid-thoracic and lumbosacral transcutaneous spinal cord stimulation on autonomic function.

The electrode placement and duration of stimulation will be identical to Project 1. The outcomes at each time point will be measured in two positions, supine and ~ 70° upright (adjusted by tilt-up table). The cardiovascular outcomes will be measured before, after the last stimulation session. Bladder and bowel function will be assessed weekly.

Device: Trnascutaneous electrical spinal cord stimulation.
The measurements will be obtained in 2 positions of supine and ~ 70° upright adjusted by the tilt-up table.

Experimental: Project 3
For Project 3, only individuals who have previously been implanted with an epidural stimulator will be invited to participate. They will have only one stimulation session. We will not offer participants to undergo implantation surgery.
Device: Epidural spinal cord stimulation
The measurements will be obtained in 2 positions of supine and ~ 70° upright adjusted by the tilt-up table.




Primary Outcome Measures :
  1. Episodic Blood Pressure Changes, the unit of measurement is mmHg [ Time Frame: In project 1 and 3: before stimulation and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    We will monitor beat-to-beat changes of blood pressure by a Finometer. This outcome will be measured in two different positions: supine and 70 degrees upright position.

  2. Cerebral Blood Flow Changes, the unite of measurement is mililitter/(100 gram tissue minute) [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    We will monitor beat-to-beat changes in blood flow by a Finometer. This outcome will be measured in two different positions: supine and 70 degrees upright position.

  3. Heart Rate Changes, the unit is beat per minute (bpm) [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    We will monitor beat-to-beat changes in heart rate by electrocardiography. This outcome will be measured in two different positions: supine and 70 degrees upright position.

  4. Continues Blood Pressure Changes, the unit of measurement is mmHg [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    We will monitor 24 hours of blood pressure changes by 24-hour Ambulatory Blood Pressure Monitoring.


Secondary Outcome Measures :
  1. Sympathetic Skin Responses (SSR) Changes, the unit of measurement is mV [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    The Sympathetic Skin Responses will be elicited by stimulation of median and posterior tibial nerve, and recorded bilaterally and simultaneously from both hands and feet to assess the extent of disruption to spinal autonomic pathways. Ten electrical stimuli (duration 0.2 ms; intensity 8-10 mA) will be applied to the left median nerve and left posterior tibial nerve, in random order and with variable and long-time delays to minimize habituation.

  2. Urodynamic Study Changes [ Time Frame: Project 2 only: before the first stimulation session and one week, two weeks, three weeks, and four weeks after the first stimulation session. ]
    Urodynamic study evaluation typically consists of cystometry with water at 37°C and a filling rate of <30 mL per minute through a 6F double lumen catheter with the participant in the supine position. Abdominal pressure will be measured with a 10F intrarectal balloon catheter. Pelvic floor electromyography will be recorded during cystometry with a bipolar wire electrode in the urethral sphincter. Filling will be stopped when the participants have reported a sensation of fullness, at the moment of urine leakage. The bladder outlet obstruction index (BOOI), will be obtained by formulaic calculations: (BOOI = PdetQmax - 2Qmax). Cystometrogram parameters including first sensation, maximum cystometric capacity (MCC), and the presence of detrusor overactivity with or without incontinence will be annotated. Valsalva leak point pressures will be assessed at a minimum volume of 200 mL. Detrusor compliance was calculated using the formula Compliance= Volume at MCC/Pdet at MCC.

  3. Electromyography (EMG) Changes [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    The Electromyography activity of the skeletal muscles will be also recorded from left and right side to confirm that skeletal muscle contractions are not occurring and therefore the pressure responses are not attributed to the skeletal muscle pump of the venous vasculature. Bipolar surface electrodes will be placed bilaterally on large skeletal muscles such as the vastus lateralis (VL), rectus femoris (RF), and medial hamstrings (MH), tibialis anterior (TA), soleus (SOL), and medial gastrocnemius (MG) muscles. EMG has previously been utilized by our team, as approved by the UBC Clinical Research Ethics Board (H12-02945). Measured EMG potentials range between less than 50 μV and up to 30 mV, depending on the muscle under observation. Typical repetition rate of muscle motor unit firing is about 7-20 Hz, depending on the size of the muscle.

  4. American Spinal Injury Association Impairment Scale (AIS) Changes [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. Project 2: before the first stimulation session and after the last stimulation session (one month after the first stimulation session). ]
    Neurological evaluations of participants with spinal cord injury will be performed using the AIS unless available in the participant chart at the discretion of the investigator. Total duration to do the test is ~ 30 minutes at baseline and ~15 minutes for post-intervention measurements. The level and severity of damage to the motor and sensory pathways will be determined using the standard AIS examination.

  5. Orthostatic Tilt Test Changes [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    Upon arrival to the laboratory, participants will be asked to empty their bladder to minimize the influence of reflex sympathetic activation on peripheral vascular tone (total duration: 25 min). In the supine position, participants will be instrumented with a single- lead ECG. Beat-to-beat systolic (SBP), diastolic (DBP), and mean (MAP) blood pressures will be recorded continuously from the right hand (Finometer; Finapres Medical Systems BV, Arnhem, Netherlands), while discrete blood pressures will be taken every minute from the brachial artery (mmHg). Following instrumentation, baseline recordings will be made during a 10-minute supine rest period. Data acquisition will be performed as detailed above. Participants will then be passively moved to approximately 70° upright stand position by the investigators using the tilt table. This position will be maintained for 15 minutes, during which recordings of heart rate and blood pressure will be continued.

  6. Cerebrovascular Structure Changes [ Time Frame: Project 2 only: before the first stimulation session and after the last stimulation session (one month after the first stimulation session). ]
    For each participant, brachial blood pressure will be measured. The followings will be sampled at 1,000 Hz using an analog-to-digital converter interfaced with data acquisition software on a laptop computer: non-invasive beat-by-beat blood pressure measurement via finger photo plethysmography, electrocardiogram, velocity in the left middle cerebral artery (MCAV) and/or right posterior cerebral artery. These arteries will be insonated using a 2 MHz probe mounted on the temporal bone and a fitted head strap. As described in depth elsewhere, the P1 segment of the posterior cerebral artery and middle cerebral artery (MCA) velocities will be insonated. Arteries will be confirmed using ipsilateral common carotid artery compression, ensuring an increase in posterior cerebral artery velocity and decrease in the middle cerebral artery velocity.

  7. Neurocognitive Changes [ Time Frame: Project 2 only: before the first stimulation session and one month after the first stimulation session. ]
    Participants will remain fitted in the same equipment as used for the cerebrovascular assessment. A visual task will be employed to activate the occipital lobe (while measuring posterior cerebral artery blood flow velocity (cm/sec)). Total duration: 15 minutes.

  8. Autonomic Dysreflexia Health-Related Quality of Life (AD-HR QoL) Questionnaire [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    The AD HR-QoL Questionnaire is derived from the original version of the autonomic dysreflexia sub-section of the Autonomic Dysfunction Following Spinal Cord Injury (ADFSCI) questionnaire which was much more comprehensive in order to assess autonomic dysreflexia frequency and severity on a daily basis and specifically when the bladder is full. The ADFSCI questionnaire was created for use in clinical practice and research to assess blood pressure instability and was designed using the Delphi technique by an expert panel experienced in spinal cord injury treatment. The ADFSCI questionnaire is a 24-item self-reported questionnaire. The questionnaire consists of demographics, medications, frequency/severity of symptoms during autonomic dysreflexia and hypotensive events.

  9. Incontinence Quality of Life (I-QoL) Questionnaire [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    The I-QoL Questionnaire is a self-administered, previously validated and reliable disease-specific questionnaire that measures bladder-related QoL in individuals with neurogenic bladder. The questionnaire is formatted as a 22-items divided into 3 sub-scales: 1) avoidance and limiting behaviour (8 items); 2) psycho-social impact (9 items); and 3) social embarrassment (5 items). Scoring is based on a five-point response scale with values ranging from one (extremely) to five (not at all). Scores are then tallied and transformed into a scale score ranging from 0-100 points with higher scores indicating a greater QoL.

  10. Montreal Cognitive Assessment Scale (MoCA) [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    We will use the MoCA, a standardized cognitive evaluation test. We have utilized this evaluation in our previous studies with spinal cord injury individuals and cognitive deficits related to blood pressure fluctuations. MoCA is a well-accepted general screening tool for individuals with mild cognitive dysfunction. The test assesses eight domains of cognitive functioning, including attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations and orientation. Total scores below 26 (out of a maximum 30) are considered abnormal and suggest presence of cognitive dysfunctions.

  11. Bristol Stool Scale and Neurogenic Bowel Dysfunction (NBD) Score changes [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    The Bristol Stool Scale is a tool designed to classify faeces into seven categories. The NBD score is a measure of both constipation and fecal incontinence and was developed for and validated in the spinal cord injury population. The NBD score is a 10-item symptom-based score for NBD in individuals with spinal cord injury. The maximum total NBD score is 47 points. The interpretation of the total NBD score is very minor NBD (0-6), minor NBD (7-9), moderate NBD (10-13), and severe NBD (≥14).

  12. Catecholamine Levels in Serum, the unit of this measurement is pmol/L [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    Standard hematology and chemistry laboratory blood tests will be collected by a local laboratory three times in each session: before, during, and immediately after tilt up test. The normal range for epinephrine is 0 to 140 pg/mL (764.3 pmol/L).

  13. Sexual Behaviour Changes [ Time Frame: In project 1 and 3: before and after one hour spinal cord stimulation. In project 2: 24 hours before the first stimulation session and after the last stimulation session (session 21, 4 weeks after the first session). ]
    Sexual behaviour changes will be measured by two questionnaires: one for women and one for men. The Questionnaires are • Female Sexual Distress Scale (FSDS) and Female Sexual Function Index (FSFI), females only and International Index of Erectile Function (IIEF)-15, males only.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age limit for Project 1 and Project 2 is 18-65 years, and age limit for Project 3 is 22-65 years (Based on FDA approval, participants below 22 are not allowed undergo to implantation surgery).
  • The volunteer should have >1-year injury, at least 6 months from any spinal surgery
  • Underwent electrode implantation surgery before
  • Documented presence of cardiovascular dysfunction including the presence of persistent resting blood pressure and/or symptoms of AD/OH.
  • Greater than or equal to antigravity strength in deltoids and biceps bilaterally.
  • Participants must have documented 3 days of bladder and bowel history prior to their baseline visit.
  • Willing 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 issue (spasticity management).
  • Women of childbearing potential must not be intending to become pregnant, currently pregnant, or lactating.
  • Sexually active males with female partners of childbearing potential must agree to effective contraception during th eperiod of the tril nad for at least 28 days after completion of treatment.
  • Must provide informed consent.

Exclusion Criteria:

  • Presence of severe acute medical issue that in the investigator's judgement would adversely affect the participant's participation in the study.
  • Recent treatment with OnabotulinumtoxinA into the detrusor muscle (within 9 months of the baseline visit).
  • Ventilator dependent
  • Clinically significant depression or ongoing drug abuse
  • Use of any medication or treatment that in the opinion of the investigator indicates that it is not the best interest of participant to participate in this study
  • Indwelling baclofen pump
  • Any implanted metal in the trunk or spinal cord under the sites of application of electrodes (between anode and cathode) for those who are allocated to receive NTSCS.
  • Severe anemia (Hgb<8 g/dl) or hypovolemia.
  • Participant is a member of the investigational team or his /her immediate family.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03924388


Contacts
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Contact: Aaron Phillips, PhD (Medicine) (+1) 403-220-5672 aaron.phillips@ucalgary.ca

Locations
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Canada, Alberta
University of Calgary Not yet recruiting
Calgary, Alberta, Canada, T2N 1N4
Contact: Aaron Phillips, PhD    (+1) 403-220-5672    aaron.phillips@ucalgary.ca   
Canada, British Columbia
University of British Columbia Not yet recruiting
Vancouver, British Columbia, Canada, V6T 1Z4
Contact: Andrei Krassioukov, MD, PhD         
Sponsors and Collaborators
University of Calgary
International Collaboration on Repair Discoveries

Publications:

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Responsible Party: Aaron Phillips, Assistant Professor, Physiology & Pharmacology, Cardiac Sciences and Clinical Neurosciences, University of Calgary
ClinicalTrials.gov Identifier: NCT03924388     History of Changes
Other Study ID Numbers: REB18- 1592
First Posted: April 23, 2019    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Aaron Phillips, University of Calgary:
Transcutaneous Spinal Cord Stimulation
Epidural Spinal Cord Stimulation
Orthostatic Hypotension
Autonomic Dysreflexia
Spinal Cord Stimulation
Additional relevant MeSH terms:
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Spinal Cord Injuries
Spinal Cord Diseases
Hypotension, Orthostatic
Autonomic Dysreflexia
Shy-Drager Syndrome
Multiple System Atrophy
Hypotension
Wounds and Injuries
Central Nervous System Diseases
Nervous System Diseases
Trauma, Nervous System
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Movement Disorders
Neurodegenerative Diseases