Clinical trial NCT06469983: Robotic Vs. Traditional Verticalization in Patients with Severe Acquired Brain Injury: a Randomized Controlled Trial
Official title: Multicentric Study on Combined Verticalization and Mobilization in Patients with Severe Acquired Brain Injury: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Acquired Brain Injury
Disorder of Consciousness
Keywords: Disorders of Consciousness
rehabilitation
verticalization
robotic
Lead sponsor: Fondazione Don Carlo Gnocchi Onlus
Sponsor class: OTHER
Collaborators: name: Istituti Clinici Scientifici Maugeri SpA
name: Ospedale Policlinico San Martino
First posted: 2024-06-24
Enrollment: 198
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In the rehabilitation project for patients with severe Acquired Brain Injury (sABI), it is essential to include exercises that facilitate the recovery of the upright position (or verticalization). Recently, tilt-table equipped with the robot-assisted lower limbs cyclic mobilization has been proposed as a safe and suitable device for accelerating the adaptation to vertical posture in bedridden patients with brain-injury since the acute phase. The present multicentre study aims at evaluating the effectiveness of robotic assisted verticalization (RV) versus traditional verticalization (TV) in a large cohort of patients with sABI.

Detailed description: Background Italian Consensus on rehabilitation of patients with severe acquired brain injury (sABI) and recent American Academy of Neurology guidelines on patients with sABI and prolonged disorder of consciousness (pDoC) provided recommendations for admission of such complex disabled patients to inpatient specialized rehabilitation units with high expertise on multidisciplinary care.

In such dedicated settings (in Italy named as high specialty rehabilitation for sABI, Cod 75) a comprehensive standard rehabilitation programme includes positioning, prolonged passive range of motion exercises, and splinting protocols to prevent or remediate neuromuscular complications (contractures, spasticity, and heterotopic ossifications). Simultaneously, basic multi-sensory stimulation or targeted cognitive training should be implemented for facilitating cognitive functioning recovery. In the rehabilitation project for patients with sABI, it is essential to include exercises that facilitate the recovery of the upright position (or verticalization), in order to prevent secondary complications from immobility (e.g., stasis pneumonias, deep vein thrombosis), to facilitate the stabilization of the haemodynamic balance (known to be altered in this population after the acute event), to promote the improvement of cognitive performance (especially vigilance and attention), and to improve the muscular-cutaneous trophism. Verticalization with traditional tilt-table training can show several adverse events: no leg movements during tilt-table verticalization lead to limited musculoskeletal and cardiovascular response; 2. pooling of blood in the lower extremities which can lead to a drop of the central blood and hypotension; 3. It requires substantial modification of cardiovascular therapy due to presyncope symptoms.

More recently, tilt-table equipped with the robot-assisted lower limbs cyclic mobilization has been proposed as a safe and suitable device for accelerating the adaptation to vertical posture in bedridden patients with brain-injury since the acute phase. However, contrasting, and inconclusive effects of controlled verticalization on functionality, gait/balance and level of consciousness in patients with sABI have been found, likely because of the limited methodological quality of the available clinical trials. All studies present some concerns such as small cohorts or heterogeneous cohorts of patients with sABI (e.g., chronic patients with sequelae of sABI) or the randomization process is not described.

The present multicentre study aims at overcoming these limitations evaluating the effectiveness of robotic assisted verticalization versus traditional verticalization (TV) in a large cohort of patients with sABI. Standardized and validated clinical tools will be used for evaluating effect on patient's motor, cognitive and functional performances. Additional markers will be used as outcome measures for investigating possible brain plasticity. Neurophysiological findings (e.g., EEG background activity and reactivity and quantitative EEG metrics) and blood biomarkers have been correlated to cognitive performance and assist prognostication in patients with sABI and pDoC34,. Brain-derived neurotrophic factor, BDNF, a neurotrophin involved in neurogenesis and synaptic plasticity can be upregulated by physical exercise. However, a recent study showed that BDNF serum levels do not change after robotic assisted verticalization in patients with pDoC. Neurofilament light chain, NF-L, a marker of primary and secondary neurodegeneration in sABI was linked to long-term axonal degeneration and poor outcome. Glial fibrillary acid protein, GFAP, a filament protein is related to brain function recovery.

Methods 198 patients will be randomized to receive either RV or TV at the same period of the day throughout the experiment. In the week before starting study protocol, the RV and TV groups will undergo a preliminary "tolerance session test" of gradual verticalization (starting from 10 min and then progression toward 30 min).

The study protocol will involve 5 RV or 5 TV sessions per week for 4 weeks (total 20 sessions). Each daily RV or SR session last 30 minutes.

RV protocol and parameters: Erigo® gradual verticalization (from supine position up to maximum 90°, in 3 steps), depending on the patient's vital signs compliance. The Erigo verticalization is coupled with the rhythmic passive movement of the lower limbs ensuring the more normal range of motion (ROM) and the alternation of loading and unloading of the lower limbs, based on patient's osteo-articular condition (e.g., ROM=45°; cadence=min. 24 steps per minute).

TV protocol: consists in gradual verticalization (from supine position up to maximum 90°, in 3 steps), depending on the patient's vital signs compliance, using a traditional standing device (i.e., non-robotic traditional tilt table) Both groups received an additional 60 minute-comprehensive daily (60 minutes) rehabilitation programme in the 3 months of the study. This programme consists of alternate bed positioning, passive limbs mobilization, activities to increase arousal (e.g., multisensory stimulation), language and swallowing therapy based on patient's functional condition.

Primary endpoint Coma Recovery-Scale Revised, CRS-R (pDoC) and Level of Cognitive Functioning, LCF (EpDoC) Secondary endpoints Modified Ashworth scale, MAS; Muscle Research Council, MRC (EpDoC) pDoC reflex movement to nociceptive stimulation (pDoC); Disability Rating Scale, DRS; Adverse Events Report (AER)+Agitation Behavior Scale and Nociception Coma Scale respectively; System Usability Scale (SUS); modified Barthel Index (mBI).

Exploratory endpoints EEG architecture (e.g., microstates, functional connectivity, and complexity measures) Blood biomarkers (i.e., BDNF, NF-L, and GFAP); Fondazione Don Gnocchi-Clinical Complications Scale, FDG-CCS.

Adverse Events Report (weekly from enrolment through termination of RV or TV protocol). During VEM session Heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SaO2), agitation, and pain will be monitored. Additionally, agitation and pain will be measured by the Agitation Behavior Scale and Nociception Coma Scale respectively.

Eligibility criteria: Inclusion Criteria:

* Stable clinical diagnosis of pDoC based on repeated Coma Recovery Scale -revised, CRS-R, or emerged from DoC (Level of Cognitive Functioning, LCF ≥4)
* Time post-injury 28 days- 6 months ;
* non-recovered upright station
* Signed informed consent by the patient or by the patient's primary caregiver.

Exclusion Criteria:

* Severe medical conditions influencing clinical diagnosis and EEG activity (e.g., sub-continuous or abundant EEG epileptiform discharges) or hampering verticalization (e.g., severe hypotension or cardio-vascular instability) or lower limb mobilization (e.g., fractures, heterotopic ossifications).

Primary outcomes:
measure: Coma Recovery Scale-Revised
timeFrame: 5 weeks
measure: Levels of cognitive functioning
timeFrame: 5 weeks
Secondary outcomes:
measure: Coma Recovery Scale-Revised
timeFrame: 1 month after treatment
measure: Levels of cognitive functioning
timeFrame: 1 month after treatment
measure: Modified Ashworth scale
timeFrame: 5 weeks - 1 month after treatment
measure: Medical Research Council Scale
timeFrame: 5 weeks - 1 month after treatment
measure: modified Barthel Index
timeFrame: 5 weeks - 1 month after treatment
measure: Disability Rating Scale
timeFrame: 5 weeks - 1 month after treatment
measure: System Usability Scale
timeFrame: 5 weeks - 1 month after treatment
Other outcomes:
measure: Spectral metrics
timeFrame: 5 weeks - 1 month after treatment
measure: Microstate metrics
timeFrame: 5 weeks - 1 month after treatment
measure: Connectivity metrics
timeFrame: 5 weeks - 1 month after treatment
measure: Brain-derived neurotrophic factor
timeFrame: 5 weeks - 1 month after treatment
measure: Neurofilament-Light
timeFrame: 5 weeks - 1 month after treatment
measure: Glial fibrillary acidic protein
timeFrame: 5 weeks - 1 month after treatment
measure: Fondazione Don Gnocchi-Clinical Complications Scale
timeFrame: 5 weeks - 1 month after treatment
Locations:
city: Sant'Angelo Dei Lombardi
country: Italy
facility: Polo Specialistico Riabilitativo Fondazione Don Carlo Gnocchi ONLUS
state: Avellino
city: Pavia
country: Italy
facility: ICS Maugeri
Study officials:
References: