Validation of Early Prognostic Data for Recovery Outcome After Stroke for Future, Higher Yield Trials

Validation of Early Prognostic Data for Recovery Outcome After Stroke for Future, Higher Yield Trials

VERIFY will validate biomarkers of upper extremity (UE) motor outcome in the acute ischemic stroke window for immediate use in clinical trials, and explore these biomarkers in acute intracerebral hemorrhage. VERIFY will create the first multicenter, large-scale, prospective dataset of clinical, transmagnetic stimulation (TMS), and MRI measures in the acute stroke time window.

Currently, 7 million US stroke survivors have significant disability, more than half with residual motor deficits. Motor function, particularly of the upper extremity (UE), is critical for regaining independence after stroke. UE function largely depends on integrity of motor cortex and its descending fibers, collectively termed the corticomotor system (CMS). Validated, clinically relevant biomarkers that identify biologically distinct patient subgroups are critically needed, particularly for the often affected and functionally important CMS. Their absence is a major obstacle to developing and personalizing new recovery therapies, especially in the early days post stroke.

Presence or absence of motor evoked potential (MEP) responses to TMS and extent of MRI-measured acute lesion load involving corticospinal tract (CST) are ready for formal validation. Also, the Predict Recovery Potential (PREP)-2 prediction tool, which sequentially combines acute clinical information and MEP status, is primed for multi-site validation.

The central objective is to validate the most biologically relevant and primed biomarkers of 90-day UE motor outcomes after ischemic stroke in the first large-scale, prospective, acute dataset of clinical, TMS, and MRI measures. The central hypothesis is that patients have different UE outcomes depending on CMS function measured with TMS, and on CST injury measured with MRI.

The specific aims are:

1. to externally validate the relationships that TMS and MRI biomarkers of CMS integrity have with 90-day UE motor impairment outcome and
2. to externally validate the PREP2 prediction tool to predict 90- day UE functional outcome. The study will also explore these biomarkers in acute intracerebral hemorrhage.

The study will comprehensively measure UE outcomes 90 days post-stroke in three domains of motor performance -impairment, function, and use - identified by the World Health Organization International Classification of Functioning, Disability and Health.

By establishing biomarkers for use in the acute stroke period to identify patient subgroups with distinct 90-day outcomes, the study will improve the efficiency of stroke recovery trials and inform rehabilitation decision-making.

Sample Size: up to 657 participants with complete biomarker data enrolled at up to 45 sites.

Trial Status: VERIFY received formal FDA IDE approval in November 2020 and received NIH funding in September 2021. Participating sites from the United States have been identified, and the study is now enrolling eligible participants.

Inclusion Criteria:

1. Age 18 years or older

2. Unilateral symptomatic stroke due to ischemia. (Note: Bilateral acute stroke is permitted if the stroke that is contralateral to the index stroke is asymptomatic).

3. Motor deficits in the acutely affected UE, defined as a Shoulder Abduction and Finger Extension (SAFE) score ≤ 8 out of 10 points20,61 (i.e., excluding full or nearly full motor strength in both shoulder abduction and finger extension) within 48 to 96 hours of stroke onset (or time last known well).

   a. Please note that, if significant imbalance is observed in SAFE score or MEP+ rates, the enrollment threshold for SAFE score may be updated with a formal study memo.

4. Provision of signed and dated informed consent form within 24 to 96 hours of stroke onset, (or time last known well). Note: Participant is considered "enrolled" upon starting TMS (at least one stimulation is delivered) or starting study-specific MRI pulse sequence (at least one MRI beep occurs)

5. Stated willingness to comply with all study procedures and availability for the duration of the study, including Day 90 visit which must occur in-person.

6. Fluent in study approved languages (i.e., English or Spanish)

Exclusion Criteria:

1. UE injury or conditions on paretic side that limited use prior to the stroke

2. Legally blind

3. Dense sensory loss on paretic side indicated by a score of 2 on NIHSS sensory item

4. Unable to abduct the shoulder or extend the fingers of the non-paretic UE on verbal command

5. Isolated cerebellar stroke

6. Symptomatic stroke in any location within 30 days prior to index stroke.

7. Co-enrollment in a trial of an intervention targeting the incident stroke (acute treatment or rehabilitation/recovery intervention) after baseline assessments for VERIFY are initiated

8. Known or expected inability to maintain follow-up with study procedures through 90 days

9. Cognitive or communication impairment precluding informed consent by the participant.

10. Major medical, neurological, or psychiatric condition that would substantially affect functional status

11. Non-cerebrovascular diagnosis associated with unlikely survival at 90 days

12. Pregnancy

13. Contraindication to noncontrast MRI (certain metallic implants, metallic foreign bodies or severe claustrophobia)

14. Contraindication to TMS

    1. Implanted electronic cardiac devices (e.g., Automatic Implantable Cardioverter-Defibrillator [AICD] or pacemaker)
    2. Any electronic devices in the body at or above the level of the seventh cervical vertebra (such as cochlear implant, cortical stimulator, deep brain stimulator, vagus nerve stimulator, cervical spine epidural stimulator, or ventriculoperitoneal shunt)
    3. Ferromagnetic intracranial metallic implant
    4. Skull defect related to current stroke
    5. Seizure after onset of current stroke
    6. Seizure within the last 12 months while taking anti-epileptic medications
    7. Previous serious adverse reaction to TMS

15. Anticipated inability to perform study procedures within 168 hours of symptom onset

    1. Unable to perform behavioral assessments within 48-120 hours of symptom onset (or time last known well).
    2. Unable to receive TMS within 72-168 hours or get MRI within 48-168 hours of symptom onset (or time last known well).