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The Effects of Low-intensity Blood-flow Restricted Exercise on Upper Limb Function Following Spinal Cord Injury

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ClinicalTrials.gov Identifier: NCT03690700
Recruitment Status : Not yet recruiting
First Posted : October 1, 2018
Last Update Posted : November 8, 2018
Sponsor:
Collaborators:
University of Southern Denmark
Aarhus University Hospital
Information provided by (Responsible Party):
Helge Kasch, Spinal Cord Injury Centre of Western Denmark

Tracking Information
First Submitted Date  ICMJE September 20, 2018
First Posted Date  ICMJE October 1, 2018
Last Update Posted Date November 8, 2018
Estimated Study Start Date  ICMJE January 1, 2019
Estimated Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
SCAR score change [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
Changes in SCAR measured by combining scores of SCIM and upper limb motor assessments of ISNCSCI at baseline and follow-up.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03690700 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 1, 2018)
  • Change in QoL [ Time Frame: 1 week before treatment; 4-,8- and 12-weeks after start of treatment ]
    Self-reported QoL: 36-Item Short Form Survey (SF-36)
  • Change in functional capacity (COPM) [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    Self-reported functional capacity: Canadian Occupational Performance Measure (COPM)
  • Change in GRASSP [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    The Graded Redefined Assessment of Strength, Sensation and Prehension (GRASSP)
  • Change in MVC for elbow flexion and wrist extension [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    Maximum, voluntary, isometric muscle strength measured by a hand-held dynamometer
  • Change in CSA [ Time Frame: 1 week before treatment; 8- and 12-weeks after start of treatment ]
    Cross sectional area at trained sites measured by ULS and Dexascan/metrical
  • Change in Spasticity - Changes in the amplitude and latency of H-reflex [ Time Frame: 1 week before treatment; 8- and 12-weeks after start of treatment ]
    H-reflex estimation
  • Change in Spasticity - Changes in Tardieu [ Time Frame: 1 week before treatment; 8 and 12-weeks after start of treatment ]
    Tardieu
  • Change in Spasticity - Changes in Modified Ashworth Scale [ Time Frame: 1 week before treatment; 8 and 12-weeks after start of treatment ]
    Modified Ashworth Scale (MAS) measures resistance during passiv soft-tissue stretching and is used as a measure of spasticity. MAS is an ordinal scale from 0-4, 0=No increase in muscle tone, 4=Affected part(s) rigid in flexion or extension
  • Change in neuroplasticity - Changes in the amplitude and latency of Transcranial Magnetic Stimulation needed to recruit extensor-carpi-radialis and m. biceps brachii motor units [ Time Frame: 1 week before treatment; 8- and 12-weeks after start of treatment ]
    Transcranial Magnetic Stimulation
  • Change in self-reported, neuropathic pain level [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    Visual-Analogue-Scale (VAS) is a valdidated, subjective measure for acute and chronic neuropathic pain. Scores are recorded by making a mark on a 100 mm straight horizontal line that represents a continuum "no pain" (0mm) and "pain as bad as it could be" (100mm). Neuropathic pain level during the past week will be documented.
  • Change in medication [ Time Frame: 1 week before treatment; 8 weeks after start of treatment ]
    Electronical Medication List: Patient usage of medication (pain, spasticity, sleep, bladder, bowel
Original Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
  • Change in QoL [ Time Frame: 1 week before treatment; 4-,8- and 12-weeks after start of treatment ]
    Self-reported QoL: 36-Item Short Form Survey (SF-36)
  • Change in functional capacity (COPM) [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    Self-reported functional capacity: Canadian Occupational Performance Measure (COPM)
  • Change in GRASSP [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    The Graded Redefined Assessment of Strength, Sensation and Prehension (GRASSP)
  • Change in MVC [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    Maximum, voluntary, isometric muscle strength
  • Change in CSA [ Time Frame: 1 week before treatment; 8- and 12-weeks after start of treatment ]
    Cross sectional area at trained sites measured by ULS and Dexascan/metrical
  • Change in Spasticity - Changes in the amplitude and latency of H-reflex [ Time Frame: 1 week before treatment; 8- and 12-weeks after start of treatment ]
    H-reflex estimation
  • Change in Spasticity - Changes in Tardieu [ Time Frame: 1 week before treatment; 8 and 12-weeks after start of treatment ]
    Tardieu
  • Change in Spasticity - Changes in Modified Ashworth Scale [ Time Frame: 1 week before treatment; 8 and 12-weeks after start of treatment ]
    Modified Ashworth Upper and Lower Extremities
  • Change in neuroplasticity - Changes in the amplitude and latency of Transcranial Magnetic Stimulation needed to recruit extensor-carpi-radialis and m. biceps brachii motor units [ Time Frame: 1 week before treatment; 8- and 12-weeks after start of treatment ]
    Transcranial Magnetic Stimulation
  • Change in self-reported, neuropathic pain level [ Time Frame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment ]
    0-100mm Visual-Analogue-Scale (VAS)
  • Change in medication [ Time Frame: 1 week before treatment; 8 weeks after start of treatment ]
    Electronical Medication List: Patient usage of medication (pain, spasticity, sleep, bladder, bowel
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effects of Low-intensity Blood-flow Restricted Exercise on Upper Limb Function Following Spinal Cord Injury
Official Title  ICMJE The Effects of Low-intensity Blood-flow Restricted Exercise on Upper Extremity Neuromuscular Recovery in Individuals With Spinal Cord Injury: A Double-blinded Randomized Control Trial
Brief Summary Spinal cord injury (SCI): The World Health Organization estimates an incidence of 250,000 to 500,000 per year worldwide. In Denmark 130 new cases of SCI per year. SCI is a devastating condition: paresis/paralysis of the skeletal muscles below the injury site, partial or complete inability to walk, move and/or feel. Other sequelae are: infections, lifestyle diseases (cardiovascular, diabetes, nephrologic disease), mental wellbeing/suicide-risk profoundly raised , quality of life, next-of-kin affection. Individuals with tetraplegia after SCI experience limited upper extremity function, increased dependency on others when performing activities of daily living (ADL). Recovery of motor function is high clinical priority and crucial for improved ADL outcomes. Clinical trials have not convincingly demonstrated substantial treatment effect on gained motor function, but better classification of patients may reduce variability and enhance sensitivity of assessment methods, this could be achieved by introducing the relatively new "Spinal Cord Ability Ruler" (SCAR) which measures reportedly change in volitional performance in most potential SCI trial participants. Strength training regimens have shown improved muscle strength in healthy subjects using near-maximal voluntary effort contractions, and few studies have demonstrated similar effects in a SCI population. Atrophy and fatigability and spasticity may reduce practical implementation for rehabilitation. Therefore, low-intensity blood-flow restricted exercise (BFRE) may prove beneficial as supplement to traditional rehabilitation, increasing muscle strength and inducing hypertrophy in healthy persons. BFRE is performed as low-intensity strength training (20-30 % of max) while simultaneously involving the use of circumferential placement of cuffs during exercise, to maintain arterial inflow to the muscle while preventing venous return. Based on existing scientific evidence, BFRE is acknowledged as a safe regime without serious side effects. Previously, the method has shown increased muscle strength and inducing skeletal muscle hypertrophy in addition to improvement in gait performance in individuals with various diseases causing reduced mobility. Purposes of this PhD project: to promote rehabilitation and scientific research of individuals with T-SCI, developing more meaningful classifications (retrospective and prospective sub studies and training methods (prospective RCT of consecutive SCI in-patients).
Detailed Description

BACKGROUND Spinal cord injury (SCI) represents a major health concern; the World Health Organization estimates an incidence of 250,000 to 500,000 per year worldwide. On average in Denmark we register 130 new cases of SCI per year. SCI is a devastating condition, in which paresis/paralysis of the skeletal muscles below the injury site results in a partial or complete inability to walk, move and/or feel. Concurrent to functional disabilities, infections, lifestyle diseases such as cardiovascular diseases are frequent sequelae due to inactivity and overweight. Affecting primarily younger and previously healthy individuals traumatic SCI also profoundly impacts the mental wellbeing of the patients and also their next-of-kin; quality of life (QoL) suffers and subsequently the risk of suicide for patients with SCI increases by two to five times as compared to the background population.

While a substantial effort is being put into the rehabilitation of individuals with SCI, large gaps in knowledge still exist on this area, especially in individuals with tetraplegia after SCI (T-SCI). Individuals with T-SCI commonly experience limited upper extremity function and increased dependency on others in accomplishing activities of daily living (ADL). Therefore, recovery of motor function is of high clinical priority as it is fundamental for improved ADL outcomes.

Despite the conduct of clinical trials with different promising candidate treatments for SCI, it has been difficult to convincingly demonstrate a treatment effect. Part of the uncertainty surrounding SCI clinical trial outcomes might be removed by introducing the relatively new "Spinal Cord Ability Ruler" (SCAR), a valid and reliable linear interval-level outcome measure. SCAR measures changes in volitional performance in most potential SCI trial participants, regardless of level or severity of injury. It combines selected items from the upper limb motor assessments of the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) and the Spinal Cord Independence Measure (SCIM). Retrospectively, this produces a unique opportunity to investigate data that have already been collected at Spinal Cord Injury Center of Western Denmark (SCIWDK). In addition, SCAR may contribute to convincingly demonstrate the effect of promising treatments. While various strength training regimens have been shown to increase muscle strength in neurologically intact individuals using near-maximal voluntary effort contractions, few studies have demonstrated similar effects from strength training regimens in persons with SCI. Complications such as atrophy and easily fatigable neuromuscular system with various degrees of spasticity often make these kinds of regimes less practical and rewarding for rehabilitation. Therefore, the addition of low-intensity blood-flow restricted exercise (BFRE) may prove beneficial as a supplement to traditional rehabilitation. BFRE increases muscle strength and induces skeletal muscle hypertrophy in healthy individuals. BFRE is performed as low-intensity strength training (20-30 % 1RM) while simultaneously involving the use of circumferential placement of cuffs during exercise, to maintain arterial inflow to the muscle while preventing venous return. Based on existing scientific evidence, BFRE is acknowledged as a safe regime without serious side effects. Previously, the method has shown increased muscle strength and inducing skeletal muscle hypertrophy in addition to improvement in gait performance in individuals with various diseases causing reduced mobility.

AIM & HYPOTHESES

The aim of this PhD project is to:

  1. Investigate the effects of low-intensity blood-flow restricted exercise (BFRE) on physical function and quality of life in addition to neuromuscular recovery in individuals with tetraplegia after SCI,
  2. Investigate the properties of the minimal clinical important difference (MCID) of SCAR.

The hypotheses are as following;

  1. Participants in active BFRE group exhibit greater increase in physical function and quality of life in addition to upper extremity muscle strength and muscle volume than participants receiving sham BFRE. This will be documented by standardized questionnaires, functional disability assessment tools in addition to maximum, voluntary, isometric muscle strength test and measurement of cross sectional area of relevant muscles.
  2. Participants in the active BFRE group will exhibit greater decrease in spasticity, neuropathic pain and usage of medication than participants receiving sham BFRE. This will be documented by standardized questionnaires and quantitative assessment methods.
  3. Participants in active BFRE group will exhibit larger changes in brain and spinal plasticity than participants receiving sham BFRE causing an increase in the amplitude and a decrease in the latency after transcranial magnetic stimulation.

METHODS:

After inclusion, medical history, demographic and anthropometric data will be obtained in addition to questionnaires concerning self-reported QoL and functional capacity. Furthermore, as described below, functional disability assessment in addition to para-clinical tests will be conducted.

Functional disability assessment tools: SCAR measures the performance of volitional tasks along with assessment of functional muscle contractions by combining the right and left strength scores for motor assessment of C5-C8 from the upper limb motor assessments of the ISNCSCI and 16 volitional performance items from the SCIM. SCAR has shown good measurement properties and is identified as a validated linear interval-level measure with repeatable precision across a broad range of SCI levels and SCI severities. SCIM is a valid and reliable multidimensional ordinal clinician-administered disability scale developed to specifically address the ability of SCI patients to perform basic ADL independently. ISNCSCI is an assessment tool for researchers and clinicians to quantify the neurological impairment resulting from SCI. The Graded Redefined Assessment of Strength, Sensation and Prehension (GRASSP) is a valid and reliable clinical impairment measure for the upper limb for use after tetraplegia. The measure includes three domains; strength, sensation and prehension.

Questionnaires: 36-Item Short Form Survey (SF-36) is a reliable and valid questionnaire that provides a direct quantitative indication of an individual's health status. As it is easy to administer, it has become the most widely-used QoL evaluation tool regarding SCI patients. Canadian Occupational Performance Measure (COPM) is reliable and valid client-centered, individualized measure of function measuring the areas of self-care, productivity and leisure, in the context of their environment.

Muscle testing: Maximum, voluntary, isometric muscle strength that participants are able to exert on a hand-held dynamometer (HHD) for elbow flexion and wrist extension. HHD is a reliable and valid instrument for measuring strength of the upper extremity. Cross sectional area (CSA) of mm. biceps brachii, brachialis, extensor carpi radialis longus and extensor digitorum communis will be measured by ultrasound imaging. Previously, this method has shown a substantial intra-rater reliability and precision in individuals with tetraplegia (Intraclass correlation coefficient = 0.87-0.93).

Spasticity: SCI leads to disruption of neural pathways. As a result, the amplitude and latency of the H-reflexes increases. The H-reflex is a reliable electrodiagnostic and noninvasive technique for assessing nerve conduction through entire length of afferent and efferent pathways. Changes in amplitudes and latencies of the H-reflex in mm. flexor carpi radialis and extensor carpi radialis, while electrically stimulating n. medianus and n. radialis, will be measured. In addition, spasticity assessment of the participants will be performed using the Modified Ashworth Scale (MAS) and Tardieu.

Brain and spinal plasticity:Transcranial magnetic stimulation (TMS) is a non-invasive method for measuring changes in brain plasticity. Electrical activation of distinct areas of the motor cortex causes contraction of the intended muscle. Changes in the amplitude and latency of TMS needed to recruit m. extensor carpi radialis and m. biceps brachii motor units will be measured.

Pain: Self-reported, neuropathic pain level during the past week will be documented, using a 100mm Visual-Analogue-Scale (VAS).

Standard care (SC) is carried out by in-house physiotherapist and occupational therapist at SCIWDK. SC consists of hydrotherapy, physiotherapy, orthotics, functional and circuit training. Patients admitted to SCIWDK are individually assigned to various opportunities of SC. In order to control for possible confounding, SC and any other physical activities will be registered.

Intervention:

Subjects from both groups will participate in 45 minutes of low-intensity BFRE (30-40% 1RM) of the upper extremities twice/week for 8 weeks, consisting of 2 minutes warm up using handcycling followed by 4 sets (30x15x15x15) of biceps curl and wrist extension with BFR (Appendix 3). Individual contraction duration will be set to 4 seconds; 2-second flexion/2-second extension, measured by a metronome. To ensure no signs of autonomic dysreflexia, blood pressure will be measured immediately at the end of every training session.

Data analysis: within-group changes from baseline to follow-up will be analyzed using paired parametric or non-parametric methods. Between-group differences will be compared as unpaired data using parametric or nonparametric methods. Type 1 level of significance is set at 0.05. The results will be analyzed according to the intention-to-treat principle. According to sample-size calculation with an 80 % power and 5 % level of significance a difference of 20 % on SCAR between the active and sham BFR groups are possible to detect with 24 participants. A difference of 20 % on SCAR is expected as a realistic suggestion as a minimal clinical important difference.

Practical framework:

This PhD project has received permission from SCIWDK. The initial examination and tests at baseline and follow-up will be conducted at SCIWDK's laboratory by Cand Scient San; PT Anette Bach Jønsson, and supervised by Assoc Prof, MD PhD Helge Kasch.

Ethical considerations:

The study has been approved by The Danish Scientific Ethics Commission (Ref No. 1-10-72-290-18), and by Data Protection Agency (Datatilsynet, Ref No. 1-16-02-640-18) and has been reported to Clinicaltrials.gov.

Economy: Not described here

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
randomized placebo controlled parallel group study
Masking: Double (Participant, Outcomes Assessor)
Masking Description:

Prior to the first training session, participants will be block-randomized to either active BFRE (n=12) or sham BFRE (n=12), (control for gender).

The outcome assessor will be blinded from the randomization.

Primary Purpose: Treatment
Condition  ICMJE
  • Spinal Cord Injuries
  • Tetraplegia
Intervention  ICMJE Other: BFRE

Blood pressure will be measured prior to each session. Active BFRE group train during inflation of the occlusion cuffs placed around the upper arm to 30 % above resting systolic BP. The occlusion pressure of the participants in sham BFRE group will be of 50mmHg.

Subjects from both groups will participate in 45 minutes of low-intensity BFRE (30-40% 1RM) of the upper extremities twice/week for 8 weeks, consisting of 5 minutes warm up using handcycling followed by 4 sets (30x15x15x15) of biceps curl and wrist extension with BFR. Individual contraction duration will be set to 4 seconds; 2-second flexion/2-second extension, measured by a metronome. To ensure no signs of autonomic dysreflexia, blood pressure will be measured immediately at the end of every training session.

Study Arms  ICMJE
  • Active Comparator: active BFRE
    12 consecutive tetraplegic SCI patients are block-randomized to active arm
    Intervention: Other: BFRE
  • Sham Comparator: sham BFRE
    12 consecutive tetraplegic SCI patients are block-randomized to sham arm
    Intervention: Other: BFRE
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: September 27, 2018)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosed with tetraplegia
  • Duration of SCI > 1 month, between 18 and <65 years of age
  • Exhibit a grade 3 or 4 muscle function of the elbow flexors and wrist extensors
  • Admitted at SCIWDK
  • Classification of grades A, B, C or D on the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) scale
  • Understands Danish in writing and speech.

Exclusion Criteria:

  • Substance abuse
  • Severe mental illness
  • Uncontrolled hypertension
  • Severe arteriosclerosis, coronary arterial disease
  • Uncontrolled autonomic dysreflexia
  • Deep venous thrombosis (or severe coagulation dysfunction)
  • Collagen diseases such as Ehlers-Danlos Syndrome and Marfan's Syndrome
  • Need for day-time respirator support.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anette B Jønsson, Sci San, PT 78446156 ext +45 anjoss@rm.dk
Contact: Helge Kasch, MD, PhD 78446177 ext +45 helgkasc@rm.dk
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03690700
Other Study ID Numbers  ICMJE SpinalCICWD
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Helge Kasch, Spinal Cord Injury Centre of Western Denmark
Study Sponsor  ICMJE Spinal Cord Injury Centre of Western Denmark
Collaborators  ICMJE
  • University of Southern Denmark
  • Aarhus University Hospital
Investigators  ICMJE
Principal Investigator: Helge Kasch, MD, PhD Spinal Cord Injury Centre of Western Denmark
PRS Account Spinal Cord Injury Centre of Western Denmark
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP