The aim of this randomised controlled trial (RCT) nested in a prospective cohort, is to investigate the superior effect of late-phase robot-assisted versus standard training on motor function, physical function, fatigue, and quality of life in a moderately-to-severely impaired chronic stroke population following subacute rehabilitation.

The main hypothesis of the study is:

Robot-assisted training has a superior effect on motor function (Fugl-Meyer Lower Extremity Assessment; primary outcome), physical function, fatigue, and quality of life in moderately-to-severely impaired chronic stroke-affected individuals in comparison to standard training.

Background:

Stroke is the collective term for acute focal injuries to the central nervous system (CNS) caused by a disturbance in the blood circulation of the brain i.e., cerebral infarction (ischemic stroke) or intracerebral hemorrhage (hemorrhagic stroke). On an annual basis, 113,000 UK citizens and 12,000 Danish citizens are hospitalised following a stroke, and worldwide stroke is one of the leading causes of disability. Stroke-affected individuals may display residual impairments in motor, physical and cognitive functions along with mental fatigue and depression. Body weight unloading (BWU) has been suggested as a method of training for people with neurological disorders suffering from severe limitations in walking ability. BWU is the application of a vertical upwards force on the body centre of mass, thereby alleviating individuals of supporting their own body weight against gravity. However, the efficacy of BWU-based training is unclear. Therefore, the aim of the present study is to investigate the superior effect of late-phase robot-assisted versus standard training on motor function, physical function, fatigue, and quality of life in a moderately-to-severely impaired chronic stroke population following subacute rehabilitation.

Trial design overview:

Randomised, assessor-blinded, two-arm, multicentre trial. Participants will be recruited through Odense University Hospital, Herlev Gentofte Hospital and Rigshospitalet. Stroke-affected patients are recruited to the prospective cohort 3 months post-stroke. Stroke-affected individuals will be recruited to the RCT from the prospective cohort 6 months post-stroke and randomised 1:1 for robot-assisted training (intervention group) or standard training (active control group). Cohort participants not eligible and/or interested in participation in the RCT study will continue their participation in the prospective cohort.

The RCT study compares training with the robot-assisted body weight unloading to standard training without the robot. Training programs will be matched for total hours allocated to training and will consist of 2 sessions per week with a physiotherapist (one-on-one) and last 6 months (48 training sessions in total). Each session will last 60 minutes, 75 minutes and 90 minutes during the first, middle and last two months of the training program, respectively. Thus, INT and CON are matched for training time, but the effective training volume (resistance times repetitions) is not controlled.

Blinding:

The primary investigator will be blinded to allocation and will not participate in the randomisation, training or testing of participants. Statistical analysis will be performed on allocation codes. The test leader responsible for RCT-study testing will be blinded. It will not be possible to blind study participants and the physiotherapists conducting the training.

Randomisation Randomisation is performed internet-based using REDCap Randomise allocated 1:1. The randomisation takes place following pre-intervention testing at 6-months post-stroke. The study uses block randomisation in blocks of 2 and 4. Stratification is applied using the Modified Rankin Scale (3,4,5). The primary investigator is blinded with respect to the permuted blocking strategy. A data manager with no clinical involvement in the trial, prepares the randomisation sequence, and the allocation is concealed in a password-protected computer file.

Compliance

No study restrictions are imposed on potential regular 'outside-the-study' visits to physiotherapist or visits from occupational therapists. Acceptable adherence is defined as a completion of minimum 70% of scheduled sessions. Moreover, number/percent of completed training sessions and achievement of target intensity/volume will be registered in a training log by the physiotherapist.

Time points

Time points are reported as time since onset of stroke. The following time-points are therefore included in the present study: 3-, 6-, 12-, and 18-months post-stroke (corresponding to T3, T6, T12 and T18). Onset of stroke is indicated as T0.

Questionnaires are sent to the prospective cohort participants at T3, T6, T12, T18. RCT-outcomes will be assessed at pre-intervention (T6) and post-intervention (T12). Blood samples will be included at T3, T6, T12.

Sample Size

A priori sample size calculation was performed and resulted in a required sample size of 34 study participants. This was based on detecting a minimally clinically important between-group difference (MCID) of 6 points on the FM-LE scale and a standard deviation of 6 points at an α level of 5% and with a statistical power of 80%. Allowing for dropout the aim is to include 40 participants in total.

Statistical analysis

An assessor-blinded intention-to-treat (ITT) analysis will be performed on primary and secondary outcome measures (Primary Analysis). A full analysis data set will be created with two imputation techniques and sensitivity analysis will be performed to examine robustness of any statistically significant differences. The ITT analysis will employ a two-way analysis of variance (ANOVA) to analyse between-group differences in change-scores from pre- to post-intervention. A per protocol analysis (between-group differences in change-scores using ANOVA) will be included as a secondary analysis on participants demonstrating acceptable adherence (>70%).

Ethics:

The study was submitted to The Regional Committees on Health Research Ethics for Southern Denmark. The project approved the project on the 17th of January 2024.

Inclusion:

1. Ischemic and haemorrhagic stroke

2. Chronic state (6-24 months post-stroke).

3. Subacute rehabilitation terminated (subacute phase defined as until 6 months post-stroke).

4. Moderately-severely impaired:

   1. Modified Rankin Scale Score 3-5.
   2. Scandinavian Stroke Scale Leg Motor Function Score 0-4 and/or SSS gait function 0-9.

5. Approved by referring doctor

Exclusion:

1. Prior SAH
2. Infarct located in the cerebellum or brain stem
3. Severe fatigue making study completion improbable.
4. Cognitive deficits impeding study participation.
5. Inability to walk independently pre-stroke.
6. Recurrence of cardiovascular/cerebrovascular accidents.
7. Pre-existing neurological diseases or ongoing cancer treatment.
8. Refusing group allocation.
9. Concurrent participation in another clinical trial potentially interacting with the present trial.

Data will be analysed by the PhD student blinded towards group allocation. The test leader responsible for RCT outcome assessment will be blinded towards group allocation.