EMAGINE–Study protocol of a randomized controlled trial for determining the efficacy of a frequency tuned electromagnetic field treatment in facilitating recovery within the subacute phase following ischemic stroke

When this study is done how will your stroke hospital implement the results? 

Do you prefer your  doctor and hospital incompetence NOT KNOWING? OR NOT DOING?

EMAGINE–Study protocol of a randomized controlled trial for determining the efficacy of a frequency tuned electromagnetic field treatment in facilitating recovery within the subacute phase following ischemic stroke

Jeffrey L. Saver^1*†, Pamela W. Duncan^2†‡, Joel Stein^3†‡, Steven C. Cramer^1,4, Janice J. Eng⁵, Assaf Lifshitz^6‡, Arielle Hochberg⁶ and Natan M. Bornstein⁷ for the EMAGINE Investigators

• ¹Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
• ²School of Medicine, Wake Forest University, Winston-Salem, NC, United States
• ³Weill Cornell Medicine, Cornell University, White Plains, NY, United States
• ⁴California Rehabilitation Institute, Los Angeles, CA, United States
• ⁵Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada
• ⁶BrainQ Technologies Ltd., Jerusalem, Israel
• ⁷Brain Division, Shaare Zedek Medical Center, Jerusalem, Israel

Stroke is a leading cause of disability with limited effective interventions that improve recovery in the subacute phase. This protocol aims to evaluate the safety and efficacy of a non-invasive, extremely low-frequency, low-intensity, frequency-tuned electromagnetic field treatment [Electromagnetic Network Targeting Field (ENTF) therapy] in reducing disability and promoting recovery in people with subacute ischemic stroke (IS) with moderate-severe disability and upper extremity (UE) motor impairment. Following a sample-size adaptive design with a single interim analysis, at least 150 and up to 344 participants will be recruited to detect a 0.5-point (with a minimum of 0.33 points) difference on the modified Rankin Scale (mRS) between groups with 80% power at a 5% significance level. This ElectroMAGnetic field Ischemic stroke–Novel subacutE treatment (EMAGINE) trial is a multicenter, double-blind, randomized, sham-controlled, parallel two-arm study to be conducted at approximately 20 United States sites, and enroll participants with subacute IS and moderate-severe disability with UE motor impairment. Participants will be assigned to active (ENTF) or sham treatment, initiated 4–21 days after stroke onset. The intervention, applied to the central nervous system, is designed for suitability in multiple clinical settings and at home. Primary endpoint is change in mRS score from baseline to 90 days post-stroke. Secondary endpoints: change from baseline to 90 days post-stroke on the Fugl-Meyer Assessment - UE (lead secondary endpoint), Box and Block Test, 10-Meter Walk, and others, to be analyzed in a hierarchical manner. EMAGINE will evaluate whether ENTF therapy is safe and effective at reducing disability following subacute IS.

Trial registration: www.ClinicalTrials.gov, NCT05044507 (14 September 2021).

Introduction

Stroke is a leading cause of long-term disability, especially as mortality rates are declining (1, 2). Given the aging population and increased stroke risk, annual stroke-related costs in the United States (US) are projected to reach $240.67 billion by 2030 (2). Reperfusion interventions are beneficial but invasive, are only available in the most acute stages, require skilled personnel, and are limited to eligible patients; 73% have a disabled or fatal outcome by 90 days (3).

Beyond the acute phase (1–7 days) (4) and into the early subacute phase (< 3 months) (4), stroke rehabilitation focuses on physical, occupational and speech therapies (PT, OT, SLP). However, standard of care (SOC) varies across facilities, and only a fraction of patients completely recover (5, 6). Moreover, the treatment pathway is fragmented, with patients treated in a variety of inpatient and outpatient clinical settings as well as at home (6). Preclinical (7, 8) and clinical trials (9, 10) indicate heightened plasticity in the post-stroke brain that declines in the first few weeks, highlighting the importance of early intervention. There is an urgent need for effective and accessible early subacute therapy that is suitable across multiple settings.

Following injury, neuronal network connectivity is disrupted, with aberrant oscillatory patterns on electroencephalography (EEG) (11). As network dynamics are sensitive to external electromagnetic fields at specific frequencies (12–14), the proposed mechanism of action of the experimental treatment involves exposing impaired neuronal networks to oscillating fields similar to those of a healthy central nervous system to induce neuroprotective cellular mechanisms and promote network reorganization (13, 15–17). Prominent frequencies of these oscillations were identified using EEG recordings of healthy and impaired populations and translated into a non-invasive, extremely low-frequency, low-intensity, frequency-tuned electromagnetic field treatment [Electromagnetic Network Targeting Field (ENTF) therapy].

Preclinical results suggest that ENTF therapy post-stroke impacts cellular mechanisms and network reorganization (18, 19). In a rodent stroke model, oscillating extremely low-frequency, low-intensity electromagnetic fields (ELF-EMF) stimulation (exposure to sham field, 3.93 Hz or 15.72 Hz, every second day, for 4 weeks) was associated in treated animals with decreased edema, increased white matter integrity, evidence of neural regeneration, and improved sensorimotor function on the modified Neurological Severity Score and forelimb placement test (18). Overall, data suggest that such treatment targets functional neural networks, promotes neural plasticity and modulates the secondary injury cascade, thus aiding clinical recovery.

A pilot randomized controlled trial (n = 21) found that ENTF therapy delivered in the early subacute phase (3–15 days post-ischemic stroke; 21 days if unstable) increased upper extremity (UE) motor function across multiple metrics and reduced disability (20). This was observed by a greater improvement with ENTF compared to sham stimulation on the trial primary outcome of the Fugl-Meyer Assessment–Upper Extremity (FMA-UE): from baseline to week 4 (23.2 ± 14.1 vs. 9.6 ± 9.0, p = 0.007); baseline to week 8 (31.5 ±10.7 vs. 23.1 ± 14). Similar favorable effects at week 8 were observed for other UE assessments, including the Action Research Arm Test (Pinch, 13.4 ± 5.6 vs. 5.3 ± 6.5, p = 0.008) and Box and Blocks Test (affected hand, 22.5 ± 12.4 vs. 8.5 ± 8.6, p < 0.0001). Reduction of global disability was assessed by the modified Rankin Scale (mRS) (20), a global outcome measure scored from 0 (no symptoms) to 6 (death). At baseline, participants were moderate-severely disabled (mRS 3-4) and by day 70 post-stroke, the ENTF therapy group improved by a mean 2.5 (±0.66) points relative to 1.3 (±0.46) points for the sham group. As a comparison, in a novel analysis of data from large trials (detailed in Supplementary File 1), moderate-severely disabled patients, with SOC treatment, improved by a mean of ~1 point by day 90 post-stroke.

The ElectroMAGnetic field Ischemic stroke–Novel subacutE treatment (EMAGINE) trial investigates the impact of ENTF therapy, on disability and functional recovery, in conjunction with SOC; ENTF treatment is introduced within 3 weeks post-stroke, a period in which the post-stroke brain has heightened plasticity potential (7–10). ENTF therapy involves non-invasive stimulation that is suitable and easy to use in multiple settings, including at home. To date, there have been no serious adverse events; EMAGINE is being conducted as a non-significant risk device study.

The primary objective of EMAGINE is to determine the efficacy and safety of ENTF therapy in reducing disability in the subacute phase post-stroke. The hypothesis for efficacy is that mean improvement in the primary outcome, mRS score, from baseline to 90 days post-stroke will be significantly greater in participants allocated to active stimulation (ENTF group) than in participants allocated to sham stimulation (sham) group.

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