Deep Brain Stimulation in Patients With Incomplete Spinal Cord Injury for Improvement of Gait

Spinal Cord Injury Clinical Trial

— DBS-SCI  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03053791
• Other study ID #: SNCTP000000598
• Status: Recruiting
• Phase: N/A
• Start date: March 15, 2018
• Est. completion date: December 2027

Study information

• Verified date: April 2024
• Source: University of Zurich
• Contact: Lennart H Stieglitz, MD
• Phone: +4144255
• Email: Lennart.Stieglitz[@]usz.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5
• Est. completion date: December 2027
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

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

Related Conditions & MeSH terms

• Spinal Cord Injuries
• Spinal Cord Injury
• Wounds and Injuries

Intervention

Procedure:
• Deep brain stimulation in mesencephalic locomotor region
Implantation of Electrodes in the Mesencephalic Locomotor Region for improvement of Locomotion and Gait

Device:
• Implantation of a Deep brain stimulation system
Implantation of a Medtronic Percept PC Impulse Generator for chronic Stimulation of the selected target.

Locations

Country	Name	City	State
Switzerland	Balgrist University Hospital	Zurich

Sponsors (4)

Lead Sponsor	Collaborator
University of Zurich	Balgrist University Hospital, ETH Zurich, Wings for Life

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in 6 Minute Walk Test at baseline and 6 months post intervention	Standardized test. Patient is asked to walk for 6 minutes. Result is the distance covered	preoperative, 6 months post intervention
Secondary	Change in 10 Meter Walking Test towards baseline	Standardized test. Patient is asked to walk 10 meters as quickly as possible. Result is the speed (m/s)	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Change in Timed Up and Go test (TUG) towards baseline	Standardized test. Patient is asked to stand up from a sitting into Standing Position and walk 3 m and return to seated position. Result ist time.	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Kinematic assessment during overground and treadmill walking	Individuals are secured using the FLOAT.	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Change in Spinal cord Independence measure (SCIM III) towards baseline	Standardized tool measuring the degree of independence of the subject. Result is score.	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Change in Walking index for spinal cord injury (WISCI II) towards baseline	Standardized tool measuring the subject's ability to walk. Result is score.	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Long-term monitoring of physical activity	Wearable and wireless sensors are mounted to the patient and wheelchair for constant monitoring of physical activity	Continuously between discharge and 6 months follow-up
Secondary	Electrophysiology	SSEPs, MEPs, DBS-EPs, LFPs, EMG	Baseline and several time-points throughout the study.
Secondary	Changes in Electroencephalography towards baseline	Evaluation for the occuracne of EEG abnormalities	preoperative, intraoperative, early postop, 6 months follow-up
Secondary	Change in Quality of life towards baseline	Standardized QOL tool (SF-36). Result is score.	preoperative, 1,3,6 months follow-up
Secondary	Change in lower urinary tract function towards baseline	Standardized tools QUALIVEEN, bladder diary, urodynamic assessments, renal and bladder ultrasound.	preoperative, 6 months follow-up
Secondary	Change in sexual functions towards baseline	Use of the standardized tools FSFI (Female Sexual Function Index), result is score respectively IIEF (International Index of Erectile Function), result is score	preoperative, 1,3,6 months follow-up
Secondary	Change in spasticity towards baseline	Use of the standardized tool MAS (Modified Ashword Scale). Result is score.	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Changes in ASIA impairment scale (AIS)	Assment of neurological status of individual with SCI	preoperative, early postop, before discharge, 1,3,6 months follow-up
Secondary	Change in Upper limb Sensation, Strength and Prehension towards baseline	Standardized tool GRASSP	preoperative, 6 months follow-up
Secondary	Change in sleepiness towards baseline	Standardized tool Epworth Sleepiness Scale	preoperative, 1,3,6 months follow-up
Secondary	Change in Fatigue towards baseline	Standardized tool Fatigue Severity Scale	preoperative, 1,3,6 months follow-up
Secondary	Change in pain sensation towards baseline	Standardized tools EPAF and SCIPI	preoperative, 1,3,6 months follow-up
Secondary	Change in 6 Minute Walk Test at other timepoints towards baseline	Standardized test. Patient is asked to walk for 6 minutes. Result is the distance	Screening, early postop, before discharge, 1,3 months follow-up