Pivotal Study of VNS During Rehab After Stroke (VNS-REHAB) (VNS-REHAB)

• ClinicalTrials.gov Identifier: NCT03131960
• Recruitment Status: Active, not recruiting
• First Posted: April 27, 2017
• Results First Posted: June 14, 2021
• Last Update Posted: March 31, 2022
• Sponsor: MicroTransponder Inc.
• Collaborator: ResearchPoint Global
• Information provided by (Responsible Party): MicroTransponder Inc.

Tracking Information

• First Submitted Date: April 24, 2017
• First Posted Date: April 27, 2017
• Results First Submitted Date: April 27, 2021
• Results First Posted Date: June 14, 2021
• Last Update Posted Date: March 31, 2022
• Actual Study Start Date: July 1, 2017
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 11, 2021)

Fugl-Meyer Assessment, Upper Limb (FMA-UE) Average Change [ Time Frame: V5, One day after 6-weeks of therapy ]

The Fugl-Meyer Assessment, Upper Limb (FMA-UE) was analyzed for difference in average change at 1-day after 6-weeks of therapy compared to baseline (Difference in average change in FM-A from baseline [V4] to one day after therapy [V5]). The upper extremity portion of the Fugl-Meyer Assessment (FMA-UE) was collected at each visit. The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).

Original Primary Outcome Measures (submitted: April 24, 2017)

Fugl-Meyer Assessment, Upper Limb (FM-A) [ Time Frame: V5, One day after 6-weeks of therapy ]

FM-A 1-day

Current Secondary Outcome Measures (submitted: June 11, 2021)

• Fugl-Meyer Assessment, Upper Limb (FMA-UE) Average Change [ Time Frame: V7, 90 days after 6-weeks of therapy ]
  The Fugl-Meyer Assessment, Upper Limb (FMA-UE) was analyzed for change in average score at 90-days after 6-weeks of therapy (change in average FMA-UE from baseline [V4] to 90 days after therapy [V7]). The upper extremity portion of the Fugl-Meyer Assessment (FMA-UE) was collected at each visit. The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).
• Fugl-Meyer Assessment, Upper Limb (FMA-UE) Response [ Time Frame: V7, 90 days after 6-weeks of therapy ]
  The Fugl-Meyer Assessment, Upper Limb (FMA-UE) Response is the percent of patients with a 6 point or greater improvement on the (FMA-UE). The percent of patients with the 6-point change is calculated at 90-days after 6-weeks of therapy compared to baseline (V4). The upper extremity portion of the Fugl-Meyer Assessment (FMA-UE) was collected at each visit. The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).
• Wolf Motor Function Test (WMFT) Average Change [ Time Frame: V7, 90 days after 6-weeks of therapy ]
  The Wolf Motor Function Test (WMFT) is an assessment scale of upper extremity functional level after stroke. The functional assessment range is an average of 15 sub-items with a range from 0 to 5, with 0 (meaning did not attempt) to 5 (meaning normal). WMFT 90-day - is a measure of the functional assessment change from baseline to 90 days after 6-weeks of therapy.

Original Secondary Outcome Measures (submitted: April 24, 2017)

• Fugl-Meyer Assessment, Upper Limb (FM-A) [ Time Frame: V7, 90 days after 6-weeks of therapy ]
  FM-A 90-day
• Fugl-Meyer Assessment, Upper Limb (FM-A) Response [ Time Frame: V7, 90 days after 6-weeks of therapy ]
  FM-A Response
• Wolf Motor Function Test [ Time Frame: V7, 90 days after 6-weeks of therapy ]
  WMFT 90-day

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pivotal Study of VNS During Rehab After Stroke (VNS-REHAB)
• Official Title: A Pivotal Randomized Study Assessing Vagus Nerve Stimulation (VNS) During Rehabilitation for Improved Upper Limb Motor Function After Stroke (VNS-REHAB)
• Brief Summary: This is a pivotal phase study of up to 120 subjects and 15 clinical sites. All subjects are implanted with the Vivistim System® and then randomized to either study treatment or active-control treatment. The randomization will be stratified by age (<30, >30) and baseline FMA UE (20 to <35; >35 to 50). Study treatment is vagus nerve stimulation (VNS) delivered during rehabilitation. Active control treatment is rehabilitation (standard-of-care treatment) with only a minimal amount of VNS at the start of each session intended to support blinding.

Detailed Description

This study has three distinct stages: Stage I, an acute blinded stage, Stage II, an unblinded stage through one year of standard VNS, and Stage III, an unblinded stage for yearly follow-up after one year of VNS. The Control group crosses over to VNS treatment at Stage II.

For Stage I, subjects have:

• consent and evaluation (screening),
• one pre-implant evaluation,
• surgical implant of the device system and randomization into one of the treatment arms,
• one baseline evaluation after device implant surgery but before initiation of treatment,
• 6 weeks of treatment (standard-of-care rehabilitation + standard VNS or standard-of-care rehabilitation + active control VNS), and then
• post-acute therapy evaluations at 1, 30 and 90 days after the 6 weeks of treatment.
• Between Day 1 (V5) and Day 30 (V6) post-acute therapy, both groups will receive in-home, self-directed rehabilitation (30 minutes of daily rehabilitation as assigned by the therapist) with either in-home activated VNS (VNS group) or no VNS (Control group). This means that the control subjects will not have the in-home activated VNS until they complete the second 6-week session of in-clinic rehabilitation with follow-up assessments as described below in Stage II. At this point (Day 30) subjects start scheduling for their continuing long-term follow-up.
• Between Day 30 and Day 90 post-acute therapy, both groups continue in-home, self-directed rehabilitation (30 minutes of daily rehabilitation as assigned by the therapist). The VNS group continues to receive in-home VNS with magnet use; the Control group continues to use the magnet but does not receive any VNS. The Day 90 post-acute therapy visit is V7; it is the first quarterly visit (3 months after study therapy) for the VNS group and is the re-baseline visit (visit just prior to the initiation of standard VNS therapy) for the Control group.

Stage II:

• VNS subjects will continue to have quarterly assessments through the end of the first year (6m, 9m, 12m).
• Subjects in the control group will crossover for a second 6-week in-clinic rehabilitation period where they will now receive rehabilitation with standard VNS.
• Control subjects will then have the three post therapy assessments (1, 30 and 90 days after therapy ends); in-home VNS initiated by a magnet swipe starts at the Post-1 visit (LT1). Thereafter, control subjects will follow the same schedule as VNS subjects for the remainder of the study (6m, 9m, 12m follow-ups, plus yearly visits thereafter).
• Subjects in both groups will receive "booster" in-clinic rehabilitation plus VNS therapy sessions one month prior to their 6- and 12-month assessment visits. These sessions occur on three days over a one-week period (typically Mon, Wed, Fri).

Stage III:

• After one year of standard VNS therapy (~13.5 months after implant for VNS group subjects and ~18 months after implant for Control group subjects), subjects who wish to keep their device for further use will have annual follow-up assessments until commercial approval.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Double blind, randomized, parallel study with partial crossover (control subjects crossover to treatment after randomized portion)

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Participants, therapists (care providers), investigators, and outcomes assessors do not know which group (VNS or control VNS) the patients are randomized. Only one person at the site - the programmer who programs the device settings - knows which group the subject is randomized into.

Primary Purpose: Treatment

Condition

• Cerebrovascular Stroke
• Upper Extremity Paresis

Intervention

• Device: Paired Vagus Nerve Stimulation
  Stimulation of the vagus nerve that is paired with upper limb rehabilitation movements.
• Other: Rehabilitation
  Rehabilitation movements to improve upper limb function after stroke

Study Arms

• Experimental: VNS + Rehabilitation (1)
  Study treatment is vagus nerve stimulation (VNS) delivered during rehabilitation.
  Interventions:

  • Device: Paired Vagus Nerve Stimulation
  • Other: Rehabilitation
• Active Comparator: Control VNS
  Active control treatment is rehabilitation (standard-of-care treatment) with only a minimal amount of VNS at the start of each session intended to support blinding.
  Intervention: Other: Rehabilitation

Publications *

• Kimberley TJ, Prudente CN, Engineer ND, Pierce D, Tarver B, Cramer SC, Dickie DA, Dawson J. 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 Dec;4(4):363-377. doi: 10.1177/2396987319855306. Epub 2019 Jun 17.
• Khodaparast N, Hays SA, Sloan AM, Fayyaz T, Hulsey DR, Rennaker RL 2nd, Kilgard MP. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair. 2014 Sep;28(7):698-706. doi: 10.1177/1545968314521006. Epub 2014 Feb 18.
• Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, Hilmi O, McLean J, Forbes K, Kilgard MP, Rennaker RL, Cramer SC, Walters M, Engineer N. Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. Stroke. 2016 Jan;47(1):143-50. doi: 10.1161/STROKEAHA.115.010477. Epub 2015 Dec 8.
• Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A, Alexander J, Ali R, Brown BL, Feng W, DeMark L, Hochberg LR, Kautz SA, Majid A, O'Dell MW, Pierce D, Prudente CN, Redgrave J, Turner DL, Engineer ND, Kimberley TJ. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021 Apr 24;397(10284):1545-1553. doi: 10.1016/S0140-6736(21)00475-X.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 24, 2019): 108
• Original Estimated Enrollment (submitted: April 24, 2017): 120
• Estimated Study Completion Date: June 30, 2022
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. History of unilateral supratentorial ischemic stroke that occurred at least 9 months but not more than ten 10 years prior to enrollment.
2. Age >22 years and <80 years.
3. FMA-UE score of 20 to 50 (inclusive of 20 and 50).
4. Ability to communicate, understand, and give appropriate consent. Subjects should be able to follow two-step commands.
5. Right- or left-sided weakness of upper extremity.
6. Active wrist flexion/extension; active abduction/extension of thumb and at least two additional digits.

Exclusion Criteria:

1. History of hemorrhagic stroke
2. Presence of ongoing dysphagia or aspiration difficulties.
3. Subject receiving medication that may significantly interfere with the actions of VNS on neurotransmitter systems at study entry. A list of excluded medications will be provided to Investigators.
4. Prior injury to vagus nerve, either bilateral or unilateral (e.g., injury during carotid endarterectomy).
5. Severe or worse depression (Beck Depression Scale > 29) (Beck et al., 1961)
6. Unfavorable candidacy for device implant surgery (e.g., history of adverse reactions to anesthetics, poor surgical candidate in surgeon's opinion, etc.)
7. Current use of any other stimulation device, such as a pacemaker or other neurostimulator; current use of any other investigational device or drug.
8. Medical or mental instability (diagnosis of personality disorder, psychosis, or substance abuse) that would prevent subject from meeting protocol timeline.
9. Pregnancy or plans to become pregnant or to breastfeed during the study period.
10. Current requirement, or likely future requirement, of diathermy during the study duration.
11. Active rehabilitation within 4 weeks prior to consent.
12. Botox injections or any other non-study active rehabilitation of the upper extremity within 4 weeks prior to therapy through the post-30 day visit (Visit 6).
13. Severe spasticity of the upper limb (Modified Ashworth ≥3) (Bohannon and Smith, 1987).
14. Significant sensory loss. Sensory loss will be measured using the Upper Extremity sensory section of the Fugl Meyer Assessment of Physical Performance. The assessment addresses light touch (2 items) and proprioception (4 items).The highest points attained is 12; subjects with scores less than 6 will be excluded from the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 22 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom, United States

Administrative Information

• NCT Number: NCT03131960
• Other Study ID Numbers: MT-St-03
• 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: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: MicroTransponder Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: MicroTransponder Inc.
• Original Study Sponsor: Same as current
• Collaborators: ResearchPoint Global
• Investigators: Not Provided
• PRS Account: MicroTransponder Inc.
• Verification Date: April 2021