Clinical trial NCT03053791: Deep Brain Stimulation in Patients With Incomplete Spinal Cord Injury for Improvement of Gait
Official title: A Phase I/II Open-label Multicenter Trial to Evaluate Safety and Preliminary Efficacy of Unilateral Deep Brain Stimulation of the Mesencephalic Locomotor Region in Patients With Incomplete Spinal Cord Injury
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Spinal Cord Injury
Keywords: Deep brain stimulation
DBS
Spinal cord injury
SCI
Paraplegia
Mesencephalic locomotor region
MLR
Pedunculopontine nucleus
PPN
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Balgrist University Hospital
name: ETH Zurich
name: Wings for Life
First posted: 2017-02-15
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single group of patients with spinal cord injury and spared fibers.
Primary purpose: TREATMENT

Brief summary: Spinal cord injuries are anatomically mostly incomplete, showing tissue bridges of the spinal cord at the injury site. Of the 60% functionally incomplete patients, about half face a life in the wheelchair. Besides conventional rehabilitation, no prominsing further treatment options exist. One of the most plastic systems involved in locomotion is the pontomedullary reticulospinal tract, which is the oldest locomotor command system existing in most vertebrates, including primates. Muscle activation patterns for limb movements are programmed in the spinal cord and have to be activated and coordinated through commands from the so called mesencephalic locomotor region (MLR). The MLR consists of nerve cells in the lower mesencephalic tegmentum sending uni- and bilateral signals through the medullary reticulospinal tracts. Classical physiological studies showed that electrical stimulation of the MLR induce locomotion. For the first time this approach was transferred and recently published in a model of induced incomplete spinal cord injury by the Schwab group. Rats severly impaired in motor hindlimb control with only 10-20% spared white matter, recovered with fully functional weight bearing locomotion under MLR deep brain stimulation (DBS). Even rats with only 2-10% spared white matter regained weight supporting stepping. DBS is a clinical standard treatment option in patients with movement disorders but does not relieve all symptoms. Therefore, small studies of MLR stimulations have been safely used in Parkinsonian patients showing freezing of gait and frequent falls with variable results. In a translational approach, we aim at performing a multidisciplinary phase one clinical trial with 5 patients and incomplete spinal cord injury. With the means of our established universitary setup for DBS treatments the operations will be performed unilaterally under local anaesthesia in the Division of Neurosurgery, USZ, with perioperative electrophysiological recordings, clinical assessments and gait analysis under test stimulation in the Spinal Cord Injury Center Balgrist.

Detailed description: After approval by the local ethics committee we will perform a phase I open-label trial to evaluate safety and preliminary efficacy of unilateral deep brain stimulation of the mesencephalic locomotor region in patients with incomplete spinal cord injury. Male or female subjects (18-75 year-old) with completed in-patient rehabilitation will be enrolled for screening evaluations at minimum 3 months post-injury. DBS operation will be performed at minimum 3 months post-injury. Primary endpoint will be improvement of locomotion as determined by the 6-Minute walking test.

Secondary endpoints will be electrophysiological/clinical and image based characterization of the mesencephalic locomotor region, questionnaire based/ professional assessments of quality of life, pain, micturition, sleep behavior, cognitive function and psychiatric evaluations (mood, anxiety, impulse control, delusional and affective disorders). The study population will consist of 5 subjects and the study period for each patient is 6 months postoperatively. Briefly, candidate subjects, able to stand with a walker or 2 crutches and with stable neurological condition will have to meet all of the inclusion and none of the exclusion criteria. Subjects will have preoperative examinations (e.g. MRI scans of the head and spine, neuropsychological, psychiatric and sleep status etc.) according to our standard protocols of DBS for movement disorders, especially Parkinson's disease, based on certification criteria of Highly-Specialized-Medicine DBS centers in Switzerland. Neurological assessments for spinal cord injury impairment as defined by study protocol will be performed at the University Hospital Balgrist.

The operation will be performed in the Division of Neurosurgeon by the neurosurgical PI of this study: awake subjects will have their heads fixed in a stereotactic ring with local anesthesia and high resolution head scans will be performed to define the stereotactic space for targeting through anatomical landmarks defined on individual MRI as described in the literature. In contrast to bilateral implantations in Parkinsonian patients, here, a single burr hole will be opened under local anesthesia on the contralateral side of the worse lower extremity of the subject. Microelectrode recordings of single-cells as well as local field potentials will be mapped starting 1 cm prior the MLR target. Four states will be analyzed: resting state, imagination of walking, passive and active lower limb movement. These recordings will help to further determine the places of stimulation as the next step of surgery. Here, slow increases of the stimulation amplitude with a constant frequency of e.g. 50Hz will be applied to determine activation of lower limb muscle activity with electroneuromyographic recordings and detection of possible amelioration of intended active movements. Since the subject is awake, possible side effects will be professionally monitored at each site of stimulation and amplitude. Next, the electrode for recording and stimulation will be exchanged with the standard 8-contact directional DBS electrode for Parkinson's disease patients (1.28 mm in diameter, 1.5mm length of each contact and 0.5 mm spacing in between). All subjects will receive an intraoperative head scan to verify correct placement and accuracy. If refinement is not necessary, the first operative procedure will be regarded as finished and the subject will be transferred to the intermediate care unit overnight to recover from surgery. The surgeon will decide, if the impulse generator will be implanted in the same surgery or delayed. Subjects will undergo regular assessments until discharge and further on in an outpatient setup around day 30 post-surgery, as well as 3 and 6 months afterwards. Rehabilitative postoperative treatment will be assisted by using the recently CE certificated and award winning FLOAT system ("Free Levitation for Overground Active Training") which allows robotic multidirectional relief of body weight and exact gait/posture analysis.

Eligibility criteria: Inclusion Criteria:

1. Informed Consent
2. Participation in two assessment sessions before enrollment (Screening and baseline)
3. Willingness and ability to comply with the protocol and to attend required study training and visits
4. Male or female subjects
5. Age 18-75
6. Motor incomplete SCI
7. Level of lesion: T10 and above, based on AIS level, preservation of sacral function
8. Focal spinal cord disorder caused by either trauma or non-traumatic and non-progressive condition (like hemorrhage, benign tumor)
9. Minimum 3 months of recovery after SCI, maximum 2 years after trauma
10. Completed in-patient rehabilitation program
11. WISCI II, level \>2 (0-20 items): assistance of one or more persons. Ability to walk at least 10 meters
12. Stable medical and physical condition.
13. Adequate care-giver support and access to appropriate medical care in patient's home community

Exclusion Criteria:

1. Enrollment of the investigator, his/her family members, employees and other dependent persons
2. Limitation of standing and walking function based on accompanying (CNS) disorders
3. Cardiovascular disorders restricting physical training or peripheral nerve disorders
4. Implanted technical devices (pacemaker, defibrillator)
5. History of significant autonomic dysreflexia
6. Cognitive disorders/brain damage
7. Drug refractory epilepsy
8. Severe joint contractures disabling or restricting lower limb movements
9. Haematological disorders with increased risk of bleeding during surgical interventions
10. Participation in another study with investigational drug within the 30 days preceding and during the present study
11. Congenital or acquired lower limb abnormalities (affection of joints and bone)
12. Women who are pregnant or breast feeding or planning a pregnancy during the course of the study
13. Lack of safe contraception
14. Inability of the participant to follow the procedures of the study, e.g. due to language problems, psychological problems, dementia etc.
15. Known or suspected non-compliance, drug or alcohol abuse
16. Current or prior malignancy

Primary outcomes:
measure: Change in 6 Minute Walk Test at baseline and 6 months post intervention
timeFrame: preoperative, 6 months post intervention
Secondary outcomes:
measure: Change in 10 Meter Walking Test towards baseline
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Change in Timed Up and Go test (TUG) towards baseline
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Kinematic assessment during overground and treadmill walking
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Change in Spinal cord Independence measure (SCIM III) towards baseline
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Change in Walking index for spinal cord injury (WISCI II) towards baseline
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Long-term monitoring of physical activity
timeFrame: Continuously between discharge and 6 months follow-up
measure: Electrophysiology
timeFrame: Baseline and several time-points throughout the study.
measure: Changes in Electroencephalography towards baseline
timeFrame: preoperative, intraoperative, early postop, 6 months follow-up
measure: Change in Quality of life towards baseline
timeFrame: preoperative, 1,3,6 months follow-up
measure: Change in lower urinary tract function towards baseline
timeFrame: preoperative, 6 months follow-up
measure: Change in sexual functions towards baseline
timeFrame: preoperative, 1,3,6 months follow-up
measure: Change in spasticity towards baseline
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Changes in ASIA impairment scale (AIS)
timeFrame: preoperative, early postop, before discharge, 1,3,6 months follow-up
measure: Change in Upper limb Sensation, Strength and Prehension towards baseline
timeFrame: preoperative, 6 months follow-up
measure: Change in sleepiness towards baseline
timeFrame: preoperative, 1,3,6 months follow-up
measure: Change in Fatigue towards baseline
timeFrame: preoperative, 1,3,6 months follow-up
measure: Change in pain sensation towards baseline
timeFrame: preoperative, 1,3,6 months follow-up
measure: Change in 6 Minute Walk Test at other timepoints towards baseline
timeFrame: Screening, early postop, before discharge, 1,3 months follow-up
Other outcomes:
Locations:
city: Zurich
country: Switzerland
facility: Balgrist University Hospital
Study officials:
affiliation: University Hospital Zurich, Neurosurgery
name: Lennart H Stieglitz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stieglitz LH, Hofer AS, Bolliger M, Oertel MF, Filli L, Willi R, Cathomen A, Meyer C, Schubert M, Hubli M, Kessler TM, Baumann CR, Imbach L, Krusi I, Prusse A, Schwab ME, Regli L, Curt A. Deep brain stimulation for locomotion in incomplete human spinal cord injury (DBS-SCI): protocol of a prospective one-armed multi-centre study. BMJ Open. 2021 Sep 30;11(9):e047670. doi: 10.1136/bmjopen-2020-047670.