Clinical trial NCT03690700: The Feasibility and Effects of Low-load Blood-flow Restricted Exercise Following Spinal Cord Injury
Official title: The Feasibility and Effects of Low-load Blood-flow Restricted Exercise Following Spinal Cord Injury
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Spinal Cord Injuries
Keywords: BFR Exercise
Spinal Cord Injury
Neuromuscular Recovery
Randomized controlled study
Physical Function
Lead sponsor: Spinal Cord Injury Centre of Western Denmark
Sponsor class: OTHER
Collaborators: name: University of Southern Denmark
name: Aarhus University Hospital
First posted: 2018-10-01
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized placebo controlled parallel group study
Primary purpose: TREATMENT

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. Recovery of motor function is high clinical priority and crucial for improved ADL outcomes. 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-load 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 investigate the feasibility and effects of BFRE in individuals living with the consequences of SCI.

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. Recovery of motor function is of high clinical priority as it is fundamental for improved ADL outcomes.

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-load blood-flow restricted exercise (BFRE) may prove beneficial as a supplement to traditional rehabilitation. Notable, BFRE is found to increase muscle strength and induces skeletal muscle hypertrophy in healthy individuals. Typically, BFRE is performed as low-load strength training (20-30 % 1 Repetition Maximum (RM)) combined with concurrent partial occlusion of limb blood flow by means of pneumatic cuffs placed proximal at the limb, to restrit arterial inflow to the exercising muscle and preventing venous return. Based on existing scientific evidence and applying pre-exercisescreening for known risk factors such as vascular dysfunction (AD) or prior history of trombosis, BFRE is acknowledged as a safe exercise regime without serious side effects. Previously, the method has shown increased muscle strength and skeletal muscle hypertrophy in addition to improvements in gait and sit-to-stand performance in individuals with various diseases causing reduced mobility.

The aim of this PhD project is to;

1. To conduct a pilot study for investigate the safety and feasibility of low-load BFRE training in adults with SCI
2. To conduct a RCT to investigate the effects of low-load blood-flow restricted exercise (BFRE) on physical function and neuromuscular recovery in individuals with SCI

The hypotheses are as following;

* The BFRE training protocol will be safe and applicable to individuals with a spinal cord injury
* Participants randomized to active BFRE treatment will exhibit greater increases in physical function and lower extremity muscle strength and muscle volume, respectively, than participants receiving sham BFRE. Treatment effects will be documented using functional disability assessment tools combined with measurements of maximum voluntary isometric muscle strength, rapid force capacity (rate of force development: RFD) and cross sectional area of the trained muscles.
* Participants allocated to active BFRE will exhibit less neuropathic pain than participants receiving sham BFRE. This will be documented by standardized questionnaires.

Feasibility Study (Study I)

The feasibility study will be conducted by the applicant, Anette Bach Jønsson (ABJ). Consecutively, prior to the RCT, 3 individuals with a SCI will be recruited between 1/4 2020 - 31/7 2021 using the same recruitment strategy and in- and exclusions criteria as in the RCT. Additionally, 3 in-patients with sub-acute SCI (Time since injury \> 1 month and \> 1 year) will be recruited. The 6 patients will follow the same initial examination and training protocol as in the active BFRE group as described below. However, the training will be performed twice a week for 2 weeks.

Outcome variables:

The following outcome measurements will be performed at pre- and postintervention.

Muscle testing Maximum, voluntary, isometric muscle strength that participants are able to exert on a portable knee dynamometer (S2P, Science to Practice, Ljubljana, Slovenia). Portable dynamometers are considered as valid and reliable instruments for measuring strength. Measurements of muscle torque (Nm) and Rate of Force Development (RFD, Nm/s) will be obtained.

Blood samples Blood samples will be obtained pre (30 minutes) and post (0-60 minutes) the first and last training session (4 blood samples in total). In-house physicians or laboratory technician will be responsible for retrieving the blood samples. Markers of coagulation (fibrinogen and D-dimer), fibrinolysis \[tissue plasminogen activator (tPA)\] and inflammation \[high sensitivity C-reactive protein (hsCRP)\] will be analyzed. The blood samples will be destroyed immediately after analyzing. The results will be obtained through the electronic patient record.

Feasibility Tolerance to the selected occlusion pressure and pain perception throughout training will be obtained by using the Numeric Rating Scale (NRS 0-11 point) and interview. Adherence to the planned training scheme will as well be recorded.

Safety considerations Autonomic dysreflexia (AD) may be a potentially life-threatening condition for people with a high injury level (Th6 and above, Tetraplegia) and may be provoked by cutaneous stimulation such as pain. Therefore, patients at risk of AD will be excluded and the ISCOS Autonomic Standards Assesment Form will be fulfilled before and after completion.

Eligibility for inclusion will be approved by specialist neurologist. Training sessions are coordinated with the physician-on-call. To ensure patient safety blood pressure and heart rate will be measured throughout training and will be closely monitored. In case of serious adverse events the MD on duty will be contacted immediately. During study I and II regular safety meetings in the research group will be scheduled. If serious adverse events occurs in study I, a reconsideration of the design of study II would be necessary (e.g. changes in BFR-dosage) and further pilot testing would be necessary.

Randomized controlled trial (Study II)

Methods:

Initial examination:

After inclusion, medical history, demographic and anthropometric data, and the neurological level of SCI will be obtained. Information about the trauma and neurological level (masured by the International Standards for Neurological Classification of SCI (ISNCSCI)) will be obtained through the electronic patient record. Furthermore, functional disability assessment in addition to para-clinical tests will be conducted

Intervention/Control Prior to the first training session, participants will be randomized to either active BFRE (n=14) or sham BFRE (n=14), while controlling for gender. BFR will be performed in the aBFRE group by use of pneumatic occlusion cuffs placed proximally on the thigh close to the inguinal fold, using an occlusion pressure corresponding to 40 % of seated arterial occlusion pressure (AOP). The individual AOP will be documented at baseline using doppler ultrasound (Siemens ACUSON S2000TM). Previous studies have shown that this pressure level can promote significant muscle adaptations to a similar degree and are associated with significantly less discomfort than higher occlusion pressures. The occlusion pressure of the participants in sham BFRE group will be approx.10mmHg.

Subjects from both groups will participate in 45 minutes of low-intensity BFRE (30-40% 1RM) of the lower extremities twice/week for 8 weeks, consisting of 5 minutes light warm-up of low-intensity cycling followed by 4 sets (30x15x15x15 repetitions, 45 sec pause between sets) of seated leg extension and leg curl with BFR. A 3 minutes pause is allowed between exercises where the cuff will be deflated. Blood pressure will be measured before and after each completed exercise (5 measures in total per session).

Data analysis Within-group changes from baseline to follow-up will be analyzed using paired parametric or nonpar-ametric methods. Between-group differences will be compared as unpaired data using a parametric or nonparametric methods. The 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 MVC between the active and sham BFR groups are possible to detect with 24 participants. A total of 28 participants will be recruited to take a 20 % dropout rate into account. A difference of 20 % on MVC 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 the applicant, Anette Bach Jønsson (ABJ). She is an experienced physiotherapist. Training sessions will be guided and supervised by in-house physiotherapists and ABJ.

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

Eligibility criteria: Inclusion Criteria:

* Duration of SCI \> 1 year,
* 18 years of age or older
* Exhibit a grade 2, 3 or 4 muscle function of the knee flexors and/or extensors
* Classification of grades A, B, C or D on the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) scale
* Cognitive ability to follow instructions

Exclusion Criteria:

* Substance abuse
* Severe mental illness
* Uncontrolled hypertension
* Severe arteriosclerosis, coronary arterial disease
* History of severe autonomic dysreflexia
* Deep venous thrombosis (or severe coagulation dysfunction)
* Collagen diseases such as Ehlers-Danlos Syndrome and Marfan's Syndrome
* Severe neuropathies

Primary outcomes:
measure: Changes in MVC
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
Secondary outcomes:
measure: Change in Rate of force development (RFD)
timeFrame: 1 week before treatment; 4-,8- and 12-weeks after start of treatment
measure: Change in muscle and tendon thickness
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Change in The Spinal Cord Ability Ruler (SCAR)
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Timed Up & Go Test (TUG)
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Timed 10 Meter Walk Test
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: 6 Minute Walk Test
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Walking Index for Spinal Cord Injury (WISCI-II)
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Change in self-reported, neuropathic pain level
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Changes in blood marker - Growth hormone, Insulin-like growth factor 1 (IGF-1), creatine kinase, cortisol, testosterone, myoglobin
timeFrame: Immediately before and three hours after the first training session. Additionally, 4-, 8- and 12-weeks after start of treatment
measure: Changes in quality of life
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Changes in WHODAS 2.0
timeFrame: 1 week before treatment; 4-, 8- and 12-weeks after start of treatment
measure: Changes in accelerometer data
timeFrame: Accelerometer data will be obtained 3 x 1 week prior to and during the intervention period.
Other outcomes:
Locations:
city: Viborg
country: Denmark
facility: The Spinal Cord Injury Centre of Western Denmark
Study officials:
affiliation: Spinal Cord Injury Centre of Western Denmark
name: Jørgen Feldbæk Nielsen, MD,PhD,Prof.
role: PRINCIPAL_INVESTIGATOR
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