Study on feasibility of Targeted epidural spinal stimulation to Improve MObility recovery in patients with sub-acute spinal cord injury

The World Health Organization estimates that up to 400,000 people worldwide
experience a Spinal Cord Injury (SCI) every year. More than 6 million
individuals are currently wheelchair-dependent due to paralysis, which
dramatically affects their quality of life. Up to now, no treatment other than
rehabilitation has shown efficacy to improve functional recovery after a SCI.
Epidural Spinal Stimulation (ESS) applied to the lumbar region enables walking
in rodent and primate models of leg paralysis. As demonstrated by the Courtine
laboratory, targeted ESS (termed TESS), stimulating at the correct place at the
correct time, enables and/or augments the ability of the descending commands to
produce the intended movements. Recently, the STIMO pilot study
(ClinicalTrials.gov Identifier: NCT02936453), using existing neurostimulator
technologies (off-label), provided the first evidence that TESS has the
potential to effectively facilitate voluntary leg movements and locomotion
immediately in humans with chronic (>12 months) SCI, and to improve
long-lasting neurological recovery due to neuroplasticity resulting from
rehabilitative training facilitated by TESS.

The objectives of STIMO-2 are to demonstrate the safety and feasibility and to
obtain preliminary evidence on the effectiveness of mobility rehabilitation
facilitated by TESS to improve neurological recovery when this intervention is
delivered in the sub-acute phase (<6 months) after SCI.
Primary objective: Assess the safety and feasibility of targeted ESS at
supporting mobility rehabilitation in patients with sub-acute spinal cord
injury (less than 6 months after injury)
Secondary objective: Evaluate the preliminary effectiveness of mobility
rehabilitation facilitated by TESS to improve the recovery of leg motor
functions and mobility after 12 months post-injury.

Single arm, non-blinded, international multi-center interventional feasibility
study with up to 12 months follow-up after spinal cord injury

The study intervention consists of 4 phases preceded by pre-screening:
baseline, surgery, intensive rehabilitation facilitated by TESS, out-patient
rehabilitation supported by TESS.
0. Pre-screening
- Patients hospitalized after a spinal cord injury are screened for eligibility
in the study.
- Patients fulfilling eligibility criteria and willing to provide signed
informed consent are enrolled.
Clinical evaluations are performed from enrollment until 12 months after date
of injury, according to EMSCI study timeline.
1. Baseline
- After enrollment in the study, an MRI, a CT scan and, if appropriate, a
pregnancy test will be done to confirm eligibility criteria regarding implant.
- Baseline data are collected (imaging, EMSCI URP cohort at 1 month, pregnancy,
anesthesiologist, psychological interview)
- Patients not passing baseline tests terminate the study
- Clinical evaluations are performed from enrollment until 12 months follow-up,
according to EMSCI study timeline
2. Surgery (implantation of neurostimulator at surgical department or
dedicated surgical site)
- As needed, patient is transferred to hospital where neurosurgery is performed
- Standard pre-surgical procedures are performed
- The investigational device is implanted
- Post-operative CT is performed
- When deemed appropriate, the patient is transferred (back) to rehabilitation
center
3. Intensive rehabilitation facilitated by TESS (rehabilitation site)
- TESS stimulation is configured following surgery, and prior to the beginning
of TESS-supported rehabilitation. This procedure aims at optimizing the spatial
and temporal parameters of TESS in order to facilitate recruitment of specific
muscle groups for strength training and/or motor task. This activity will be
repeated over time for optimization purpose.
- In-patient setting
- Duration: target 100 (+/- 10) sessions of rehabilitation training supported
with TESS, spread over a period of 4 to 6 months
- TESS is embedded into the standard clinical rehabilitation program supervised
by physiotherapists, for example, but not limited to, for lower extremity
strength and locomotion training sessions.
4. Out-patient rehabilitation (rehabilitation site, at home)
- Out-patient setting (at least 2 sessions per week in a rehabilitation centre)
- Duration: from end of Intensive phase until 12 months after injury
- The patient will receive continued supervised training by a physiotherapist
on functional use of TESS during activities of daily life. Unsupervised use is
allowed in parallel to out-patient rehabilitation after patient training by
physiotherapist.
During TESS supported rehabilitation sessions (3. and 4. above), technical
tests as well as stimulation evaluations will be regularly performed.
Stimulation evaluations include optimization of stimulation parameters by a
team of Experts.
5. End of study at 12 months
- After final clinical evaluation at 12 months post injury, the patient may
choose between inactivation of the stimulator or explant of the investigational
system, unless further use is deemed beneficial for the patient.The implanted
device has an expected lifetime of 5 years. The study ends after final study
procedures.

The risk associated with study participation is twofold: 1) Risks associated
to the surgery procedure, and 2) risks associated with TESS combined with
rehabilitation. Based on literature review on use of similar systems in
patients with chronic SCI and on the risk assessment of the vestigational
system, the main risks associated with participating in the study include:
* Risks associated to surgery procedures:
* The risks associated with the implant of the IPG and paddle electrode array
are similar to risks associated with implants for chronic pain with epidural
stimulation (see IFU of devices) and include. swelling at implant sites,
hematoma or bleeding, infection, neuropathic pain, cerebrospinal fluid leak and
wound complications.
* The risks associated with general anaesthesia include pneumonia, stroke,
anoxia and post-operative confusion.
* A new paddle electrode array (Go-2 Lead) will be used in the study. The Lead
was designed to recruit individual posterior roots from the lumbosacral spinal
cord unilaterally * preventing crosstalk between roots associated with the left
leg versus right leg. The lead is slightly wider and longer than existing leads
used for chronic pain, which could bring additional (unknown) risks during
implantation, such as pressure to the spinal cord. The Go-2 Lead is also used
in another clinical study setting (STIMO study). Extensive pre-clinical
validation testing was performed to minimize the risk, i.e. computer
simulations, and surgical implant in cadavers by experienced neurosurgeons.
Moreover, personalized computational models of the spinal cord elaborated from
pre-operative MRI scans mitigate risks and increase confidence in the
feasibility of Lead insertion. Only patient with confirmed eligibility after
baseline evaluations will undergo the implant procedure. Risks associated to
the paddle
electrode arrays include lead migration and electrode damage, which, in worst
case scenario, may necessitate a replacement surgery (*redo*, see associated
risk below).
* During the implant procedure, a few low dose fluoroscopy images are needed in
lateral and antero-posterior positions. Additionally, if needed, a CT scan is
performed at the initial placement of the paddle electrode array to confirm
appropriate position in the spinal canal. The total study dose of radiation
from imaging procedures is 18,3 mSv.
* The paddle electrode array is inserted by partial laminectomy at level T12-L2
of the spinal cord (for details see 6. Procedures). In case the initial Go-2
Lead cannot be permanently implanted and the Specify 5-6-5 lead will be used
instead * as allowed per protocol, the same opening will be used.
o Previous studies including STIMO have shown that insertion of the lead
through a partial laminectomy between the T12 and L2 vertebra is appropriate to
access the L1 posterior roots. However, S1 and S2 posterior roots can be
located more caudally, preventing an optimal access to these roots. In this
scenario, the laminectomy needs to be enlarged, or, in rare situations, a
second opening needs to be performed between the L1 and L2 vertebra. These
adjustments could increase the surgical time by approximately 30 minutes.
Additional risks are very limited. Since the lateral window of the
laminectomies remains limited, the stability of the spine is unlikely to be
further compromised. The enlargement of the laminectomy might slightly increase
the haemorrhagic risk or the risk of cerebrospinal fluid leak. Extra care is
taken in this case by the eurosurgeon. Both risks are transient and without
need for further intervention.
o When permanently implanting the Specify 5-6-5 Lead after the larger Go-2 Lead
was inserted, a concern could be raised related to the positional stability of
the lead. The stability of the paddle electrode array is mainly guaranteed by
the quality of lead anchoring to the spine, rather than by the epidural space
per se. Therefore, no problem is anticipated for the stability of the lead in
this case.
o As stated in 5.4.2 Concomitant treatments, an unforeseen medical need for an
MRI should be handled with special caution and the sponsor should be contacted.
* Risks associated with using TESS during rehabilitation:
During the STIMO study, only one device or procedure related serious adverse
event is recorded to date (a replacement surgery of the Lead). In addition,
some of the following risks may exists:
o The patient may feel tingling
o The patient may feel overstimulation
o During device technical verification and optimization of stimulation
parameters, the patient may feel transient electrical discharges due to
impedance and frequency testing as well as following change of trunk
positioning
o Rehabilitation sessions will follow standard of care, but introduction of
TESS supported sessions may result in a higher training intensity, which can
result in fatigue and, in worst case scenario
* bruise and oedema on the calf and the ankle
* decrease of lower limbs motor strength
* fluctuation of mood and motivation levels
* increase frequency of clinical risks known for people with SCI (e.g. urinary
tract infection)
* joint pain
* neuropathic pain
* pain in the lower limb joints or feet
* pain during movement of the lower limb
* psychological distress
* signs of autonomic dysreflexia
* skin erosion
* spasticity
* stress
* tendinitis
o When training in an upright position, the patient may encounter the risk of
falling. As a preventive measure, patients will train using assistive device(s)
deemed appropriate by the therapist, depending on the abilities of the patient,
for example using body weight support, walker, and/or crutches during
overground walking. However, in the long term, the patient is anticipated to
gain balance, stability and become independent, hence the risk will reduce over
time. Patients with SCI at cervical level may develop a scoliosis due to their
inability to properly contract abdominal muscles.
o In case of device deficiency during the course of rehabilitation, low dose
fluoroscopy images may be needed to evaluate the deficiency. A redo procedure
may take place.The risks of the procedure are similar to the initial
implantation, the complication rate is expected to be slightly higher.
At study end, the patient may opt for removal of the implanted device. The
risks of the explant procedure are similar to the ones of the implant
procedure.
o A patient may be a non-responder to the TESS supported therapy. In that case,
the patient will obtain no benefit (equal or worse outcome) from TESS supported
therapy in comparison to regular clinical rehabilitation program.

Risks related to the patient condition and unrelated to the study
The study is recruiting patients who have recently sustained a SCI and are
therefore in a physical and psychological medical situation that can be
unstable. The study starts when the patient is hospitalized. The local
investigational site is in charge of standard of care, including physiological
and psychological support.