Cervical spinal cord injury (SCI) often results in irreversible impairment of arm and hand function. Preclinical and human case studies have shown that electrical spinal cord stimulation can restore impaired neurological function, with improvements lasting even after stimulation ceases. Non-invasive spinal cord stimulation, delivered through surface electrodes, can modulate neuronal subpopulations within targeted spinal segments. The ARCEX device is designed for this purpose. This pivotal Up-LIFT trial assessed the safety and efficacy of ARCEX Therapy in improving arm and hand function after chronic cervical SCI compared with rehabilitation alone. Structured rehabilitation, while beneficial for functional improvements, typically doesn't significantly affect the underlying neurological status. This trial aimed to determine if ARCEX Therapy could enhance neurological recovery beyond that achieved with rehabilitation alone.

The existing literature demonstrates the potential of electrical spinal cord stimulation to restore various neurological functions after SCI, including standing, walking, managing muscle spasms, and improving hemodynamic regulation and lower urinary tract control. Several case studies have also reported improvements in arm and hand functions following spinal cord stimulation. Importantly, preclinical studies and some clinical observations suggest that the beneficial effects of electrical stimulation can persist even after the stimulation is discontinued, suggesting a potential for lasting neurological reorganization. This phenomenon is thought to be due to the growth of residual white matter tracts onto specific neuronal populations engaged by afferent pathways recruited by electrical stimulation and reorganized during rehabilitation.

The Up-LIFT trial was a prospective, single-arm, multicenter, open-label, non-significant risk trial. Sixty participants with chronic cervical SCI (AIS B, C, or D, with sufficient baseline function) were enrolled. Participants underwent a 2-month period of rehabilitation alone, followed by a 2-month period of rehabilitation augmented with ARCEX Therapy. The ARCEX device delivered electrical stimulation (30 Hz, 10 kHz carrier frequency) to the cervical spinal cord during rehabilitation sessions. Primary outcome measures were safety (incidence of serious adverse events related to ARCEX Therapy) and efficacy (percentage of participants achieving minimally important difference in both strength and functional performance domains). Secondary outcome measures included responder rates, changes in individual outcomes, and self-reported quality of life. Statistical analyses included exact binomial tests, McNemar's tests, and paired t-tests or Wilcoxon rank-sum tests.

No serious adverse events related to ARCEX Therapy were reported. The primary efficacy endpoint was met: 72% of participants showed improvements exceeding minimally important difference criteria for both strength and functional domains; 90% met the criteria for at least one strength or functional outcome. Secondary analysis revealed significant improvements in fingertip pinch force (mean difference = 4.8 N, P = 0.002), GRASSP-Prehension Performance score (mean difference = 1.6, P < 0.001), GRASSP-Strength score (mean difference = 2.8, P < 0.001), and ISNCSCI-UEMS (mean difference = 2.2, P < 0.001). Significant improvements were also observed in the ISNCSCI Total Sensory Score (mean difference = 9.6, P < 0.001). Participants reported improved quality of life (EQ-5D-5L, P = 0.028). Exploratory analyses showed significant decreases in muscle spasm frequency and severity, improved sleep quality, reduced shortness of breath and pain. Post-hoc analysis identified minimum enrollment scores predictive of response to ARCEX Therapy.

ARCEX Therapy was shown to be safe and effective in improving arm and hand function in individuals with chronic cervical SCI. The improvements observed with ARCEX Therapy exceeded those seen with rehabilitation alone, indicating that ARCEX Therapy enhanced neurological recovery beyond the effects of rehabilitation. The trial design, while not a randomized controlled trial, was justified given the limitations of blinding in neuromodulation therapies, ethical considerations regarding sham stimulation, and the potential for carry-over effects from ARCEX Therapy. The identified minimum enrollment scores can guide patient selection for this therapy. Future research should explore the mechanisms underlying the interaction between ARCEX Therapy and rehabilitation, and the potential for earlier intervention.

The Up-LIFT trial demonstrates the safety and efficacy of non-invasive ARCEX Therapy for improving arm and hand function in chronic cervical SCI. This therapy offers a new treatment option for improving neurological recovery in this population. Future research should investigate the optimal duration and timing of ARCEX Therapy, as well as its potential application in other neurological disorders.

The open-label design and lack of a concurrent control group are limitations of this study. The study population included individuals with chronic SCI, limiting the generalizability of the findings to the acute SCI population. The relatively short duration of ARCEX Therapy may have prevented the identification of the full potential of the therapy. Future studies with longer treatment durations and randomized controlled designs are warranted.