ARC Therapy to restore hemodynamic stability and trunk control in people with spinal cord injury

The consequences of a Spinal Cord Injury (SCI) are dramatic. Not only do
affected individuals lose the ability to move, but they also face repeated
hypotensive episodes that can be life-threatening and reduce the potential for
neurological recovery. In the chronic phase, daily hypotensive and hypertensive
(i.e., autonomic dysreflexia) episodes increase the risk of stroke, heart
disease and reduce engagement in social and professional activities.
Individuals with spinal cord damage above the 6th thoracic vertebra often
suffer from severe hemodynamic instability. Pharmacological management of
hemodynamic instability is currently limited to long-acting pressor agents
(e.g., midodrine) and anti-hypertensives (e.g., prazosin, nifedipine). These
drugs require approximately one hour to become active and exert prolonged
cardiovascular effects. Conversely, the hemodynamic instability experienced by
people with SCI occurs most commonly over just a few minutes and tends to cease
rapidly. Using long-acting agents to manage short-acting conditions is, thus,
not the ideal approach. Indeed, this temporal discrepancy can predispose
individuals to more extreme hemodynamic instability or adverse events. In the
absence of alternative treatment options, clinicians have resorted to therapies
that are arduous and are not supported by rigorous evidence (e.g., abdominal
binding, compression stockings, high-sodium diet). Importantly, the quality of
life of people with SCI strongly depends on recovering both autonomic and motor
functions. In particular, the recovery of hemodynamic stability and trunk
stability are associated with greater independence and are consistently ranked
by people with cervical SCI as top health priorities.

Researchers recently dissected the anatomical topology and physiological
dynamics of the sympathetic circuitry and developed the mechanisms behind how
Epidural Electrical Stimulation (EES) can target these physiological processes
and modulate blood pressure. They identified a clear anatomical and functional
enrichment at the three most caudal thoracic spinal segments which they termed
the hemodynamic hotspots. The EES protocol immediately stabilized hemodynamic
in rodent and non-human primate models of SCI. They also validated the features
of hemodynamic EES in ten patients. Moreover, 7 weeks of daily hemodynamic EES
in rodents abrogated autonomic dysreflexia. Consequently, EES has the potential
to become the first-line treatment for hemodynamic instability in people with
chronic or sub-acute SCI. However, its clinical deployment relies on
medical-grade implantable spinal-cord stimulation technologies that are
optimized for hemodynamic management. In addition, spinal segments associated
with trunk stability and spasticity overlap with the hemodynamic hotspots.

In this study, we aim to stimulate specific circuits in the spinal cord thanks
to a new EES therapy named ARC Therapy to manage the regulation of blood
pressure in people with sub-acute and chronic spinal cord injury located
between C3 and T6 and who suffer from orthostatic hypotension.
This therapy also aims to have a positive impact on other clinical functions
such as trunk stability, spasticity (through muscle tone normalization),
respiratory function, cognitive functions, overall quality of life and daily
life activities.

Primary objective:
• Assess the safety of ARC Therapy at supporting the management of hemodynamic
instability in participants with sub-acute or chronic Spinal Cord
Injury suffering from orthostatic hypotension

Secondary objectives with clinical impact:
• Evaluation of the preliminary efficacy of ARC Therapy at supporting
management of hemodynamic instability in participants with sub-acute or
chronic Spinal Cord Injury suffering from orthostatic hypotension
• Evaluation of effect of ARC Therapy on trunk control in participants with
sub-acute or chronic Spinal Cord Injury
• Evaluation of effect of ARC Therapy on spasticity in participants with
sub-acute or chronic Spinal Cord Injury
• Evaluation of effect of ARC Therapy on daily life performance in participants
with sub-acute or chronic Spinal Cord Injury

Secondary objectives with technical impact:
• Evaluation of the independent use of ARC-IM Thoracic System by study
participants
• Evaluation of the robustness of ARC-IM Thoracic System including
effectiveness of risk mitigation
• Evaluation of the usability of ARC-IM Thoracic System for clinicians and
study participants

Other objectives:
• Evaluation of the effect of ARC Therapy on:
o Respiratory function
o Cognitive function
o Vascular anatomy
o Autonomic dysreflexia
o Pressure sores prevention
o Participants Reported Outcomes Measures (PROMs) (quality of life, sleep,
mental,...)

This study is single site, single arm, non-blinded, non-randomized,
interventional.

Consent and eligibility
• Patients fulfilling eligibility criteria and willing to provide signed
informed consent are enrolled.

Baseline assessments (up to 8 weeks)
• A comprehensive assessment of demographics, history of injury, health
history, family history, and history of hospitalizations, surgeries and
interventions will be assessed.
• Medication history for the previous two years will be documented and a
questionnaire about substance use, including alcohol and substances, will be
administered via the CAGE-AID Questionnaire.
• For women of childbearing potential who are participants in the study, a
pregnancy test will be performed.
• A thorough history of rehabilitation will be documented. Rehabilitation
history will apply to all events occurring after the initial spinal cord injury
and will include questions about the type and duration of rehabilitation
interventions received (I.e., tilt-test training).
• After enrolment in the study, baseline data are collected (a pre-operative
MRI, X-ray, and CT scan).
• Further assessments: ASIA impairment scale classification, orthostatic
challenge, seated BP test, steady BP measurement, autonomic dysreflexia
following spinal cord injury (ADFSCI) questionnaire, quality of life
questionnaires, measures of respiratory function, cognitive functions, trunk
stability, daily life performance, spasticity, and vascular anatomy.

Surgical procedure
• Standard pre-surgical procedures are performed (i.e., visit with
anesthesiologist).
• Pre-operative MRI combined with CT-scan acquisitions are used to guide the
precise placement of the paddle array and define the entry point prior to
surgery.
• The ARC-IM Thoracic System will be implanted and guided with intra-operative
electrophysiology and surgical imaging.
• A post-operative CT-scan will be performed.

Configuration phase (phase 1 - 1 month)
• Configuration will include testing a variety of stimulation configurations
and parameters to understand the optimal use of the ARC-IM Thoracic System for
hemodynamic control, trunk stability, improvement of respiratory function and
spasticity.
• Different technical assessments will be performed during this phase.
• Participant will perform standard rehabilitation sessions and optimization
sessions to configure the neuromodulation system.

Supported use phase (phase 2 - 1 month)
• Participants will use the ARC-IM Thoracic System by themselves through the
support of the study team via supported use sessions (telemonitoring).
• Optimization sessions will also be planned to manage the configuration of
ARC-IM Thoracic System.

Independent use phases (phases 3 and 4 - 10 months)
• Participants will use ARC-IM Thoracic System by themselves, during daily life
activities.
• Optimization sessions and telemonitoring sessions will be scheduled upon
request of the study team or of the participants.

Assessments
• Different assessments will be planned throughout the course of the study,
after phases 1, 3 and at the end of the study, with and/or without stimulation:
o Clinical assessments, hemodynamic assessments, trunk assessments,
spasticity assessments, daily life functional assessments, respiratory
assessments, cognitive assessments, and vascular assessments
• Participants Reported Outcomes Measures will be collected:
o Monthly via PROMs questionnaires
o Every 6 months via semi structured interviews
o Weekly via other questionnaires

End of the study
• After final clinical evaluation, the participant may choose between
inactivation of the stimulator or explant of the investigational system, unless
further use is deemed beneficial for the participant as assessed by the
investigators. Cost of explant will be covered by the sponsor. The study ends
after the final study procedures

Participation burden:
Participants will be enrolled for approximately 15.5 months in this study. A
daily presence on-site will be asked during the first 2 months and then, during
2 weeks every 6 months.

Study risks:
1. Risks and side effects associated to the surgery procedure (risks associated
with general anaesthesia, risks associated with implants surgery such as
cerebrospinal fluid leak, infection or inflammation, wound complications,
pain,...)
2. Risks associated to ARC Therapy such as pain, discomfort, overstimulation
feeling, muscle contraction, fluctuation of mood or stress
3. Risks associated with the implanted devices such as failure or malfunction
of the devices, components migration, allergic or immune system response

Study benefits:
The ARC Therapy aims to manage the regulation of blood pressure in people with
sub-acute and chronic spinal cord injury located between C3 and T6 and who
suffer from orthostatic hypotension.
This therapy also aims to have a positive impact on other clinical functions
such as trunk stability, spasticity (through muscle tone normalization),
respiratory function, cognitive functions, overall quality of life and daily
life activities.