Kate Hayward, PhD PT
@kate_hayward_
European Stroke Organisation-World Stroke Organization 2020 Virtual Conference
November 7-9, 2020
ESO-WSO 2020 Large Clinical Trials & Awards
Presenter: Professor Jesse Dawson
Presentation title: Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-Rehab): A randomised, blinded, pivotal, Phase III device trial
There is much work occurring to identify adjuvants that may boost post-stroke motor recovery — particularly upper limb recovery, which often remains an unmet need for many stroke survivors long-term. The current work focused on vagus nerve stimulation (VNS) as an adjunct to motor rehabilitation and built upon two prior pilot randomized controlled trials of this intervention.1,2 The pilot trials suggested potential for a functional benefit of VNS when combined with intensive motor rehabilitation. The mechanistic rationale put forward to underpin this intervention was that VNS activates release of neuromodulators, which may facilitate behavioral and physiological changes that support motor recovery.
In this randomised, blinded, Phase III trial,3 eligible participants had to have experienced a unilateral ischemic stroke 9 months to 10 years prior to enrolment and demonstrated a Fugl Meyer Assessment Upper Extremity (FMA-UE) score of 20 to 50 points (out of 66 points). This is consistent with moderate to moderately-severe impairment as all participants would be expected to demonstrate some movement if scoring within this range. All enrolled participants had a VNS device implanted and were randomized to receive an active or sham stimulation protocol. Of note, all participants received 5 active stimulations (varying intensities) at the commencement of each in-clinic session, which was designed to expose everyone to a very small volume of VNS and to maintain blinding. All participants received 6 weeks of in-clinic rehabilitation (3 session per week for 2 hours aiming for >300 repetitions) followed by 90 days of at home-rehabilitation (daily therapist prescribed home exercises). Follow up occurred at 1, 30, and 90 days post completion of in-clinic rehabilitation.
This trial randomized 108 participants: 53 participants to VNS (FMA-UE baseline mean 34.4 SD 8.2) and 55 participants to sham (FMA-UE baseline mean 35.7 SD 7.8). For the primary endpoint, at day 1 post completion of 6 weeks in-clinic therapy, the mean (±SD) FMA-UE score increased by 5.0 points (±4.4) within the VNS group and by 2.4 points (±3.8) within the sham group. This reflects a between group difference of 2.6 (95%CI 1.03-4.2; p=0.001). At 90 days post completion (secondary endpoint), the between group difference was 3 (5.8 vs 2.8 point change from baseline; p=0.008), and a difference of >6-points on the FMA-UE was achieved by 25 (47%) participants receiving VNS compared to 13 (24%) participants receiving sham (p=0.01). Improvements in Box and Block Test, a measure of upper limb function, were also observed. Few serious adverse were reported.
Some reflections on this trial. The dose of VNS was highly controlled within this trial, which is an important strength of this study. However, the motor rehabilitation provided up to the primary analysis timepoint was 36 hours. This is substantially lower than other recent uncontrolled, e.g., 90 hours over 3 weeks,4 and controlled, e.g., 300 hours over 12 weeks5 studies, which have demonstrated clinically meaningful benefits at substantially higher doses. The between group difference was significant, but was less than a minimal clinical important difference (at primary endpoint, between group different of 2.6 points vs clinically important difference of 6 points6). Future work could seek to understand the trade-off between undergoing invasive surgery to have a VNS implanted prior to motor rehabilitation versus undergoing a higher dose of motor rehabilitation in isolation. All participants had some movement to work with, i.e., FMA-UE >19, but their biological status was unknown, e.g., motor evoked potential status. Future work could identify characteristics of participants who stand to benefit most, i.e., targeted population. It may also be interesting to explore adjuvant therapies in people with poorer FMA-UE scores (i.e., <20), as adjuvants may be a pathway to help them get going with their motor recovery.
The presentation indicated further long-term follow up results are to be expected, which will provide additional information about the impact of this intervention for people living with chronic upper limb disability in the community.
References:
1. Dawson J, Pierce D, Dixit A, et al. Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. Stroke. 2016;47:143-150.
2. Kimberley TJ, Pierce D, Prudente CN, et al. Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke. Stroke. 2018;49:2789-2792.
3. Kimberley TJ, Prudente CN, Engineer ND, et al. Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke. Eur Stroke J. 2019;4:363-377.
4. Ward NS, Brander F, Kelly K. Intensive Upper Limb Neurorehabilitation in Chronic Stroke – The Queen Square Programme. Journal of Neurology, Neurosurgery, and Psychiatry. 2019;90:498-506.
5. Daly JJ, McCabe JP, Holcomb J, Monkiewicz M, Gansen J, Pundik S. Long-Dose Intensive Therapy Is Necessary for Strong, Clinically Significant, Upper Limb Functional Gains and Retained Gains in Severe/Moderate Chronic Stroke. Neurorehabil Neural Repair. 2019:1545968319846120.
6. Page SJ, Fulk GD, Boyne P. Clinically important differences for the upper-extremity Fugl-Meyer Scale in people with minimal to moderate impairment due to chronic stroke. Phys Ther. 2012;92:791-798.
