Clinical trial NCT04052776: Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES
Official title: Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With Spinal Cord Injury Treated With Epidural Electrical Stimulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Spinal Cord Injuries
Drug Effect
Keywords: Pharmacology
Neuromodulation
Epidural electrical stimulation
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
Collaborators: name: Ecole Polytechnique Fédérale de Lausanne
First posted: 2019-08-12
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study will be monocentric, randomized, double-blind, placebo-controlled with a four-sequence crossover design.

All participants will undergo the 4 treatment arms. and each of them will be their own control.
Primary purpose: TREATMENT

Brief summary: In a current first-in-man study, called Stimulation Movement Overground (STIMO) (NCT02936453; CER-VD: 04-2014; Swissmedic: 2016-MD-0002), epidural electrical stimulation (EES) of the spinal cord is applied to enable individuals with severe spinal cord injury (SCI) to complete intensive locomotor neurorehabilitation training. In this clinical feasibility study, it was demonstrated that EES results in an immediate enhancement of locomotor functions and that when applied repeatedly as part of a neurorehabilitation program, EES can progressively improve leg motor control in individuals with severe SCI. Mechanistically, EES acts trans-synaptically upon spinal circuitries through the electrical stimulation of proprioceptive fibers.

It is assumed that this stimulation does not increase the level of availability of monoamine neurotransmitters below the SCI level, which are essential for lower extremity movement generation. Specifically, in a non-injured individual, dopamine and serotonin synthesized in the brain and brainstem are released by fibers diffusely innervating the spinal cord, serving to critically mediate excitability of motor neurons and interneurons in lumbar and sacral spinal level. Spinal cord injury would partially or entirely disrupt these modulation pathways, resulting in a detrimental lack of crucial neurotransmitters below the injury level. This lack of endogenous neurotransmitters could potentially be compensated for by pharmacological agents promoting the neurochemical environment necessary for locomotion.

Detailed description: The aim is to test the effects of orally administered buspirone and levodopa/carbidopa taken individually and in combination. Both buspirone and levodopa can cross the blood-brain barrier, and reach the lumbar spinal cord where 5-HT1A receptors are expressed, and levodopa can presumably be synthesized by specialized dopaminergic into dopamine. Alternatively, levodopa effects might be mediated via noradrenaline, following dopamine metabolization. Therefore, it is hypothesized that the combination of pharmacological neuromodulation with EES would further improve locomotor functions and lower extremity motor score.

The primary and safety objective is to evaluate the safety and the tolerability of a single-dose of immediate-release levodopa/carbidopa, buspirone, the combination levodopa/carbidopa and buspirone, and the placebo in individuals with SCI.

The secondary objectives are to assess the following effects of levodopa/carbidopa, buspirone, the combination levodopa/carbidopa and buspirone, and the placebo on the lower extremities:

1. Spasticity
2. Lower Extremity Motor score (LEMS)
3. Voluntary movements
4. Gait patterns and velocity Participants' safety will be ensured with the usage of Rysen, which a CE-marked bodyweight support system robot, and the aid of locomotor assistive device.

Eligibility criteria: Inclusion Criteria:

* Completed the main phase of the STIMO study
* Enrolled in the STIMO study extension
* Age 18-65 (women or men)
* Sensorimotor or motor complete and incomplete SCI graded as AIS A, B, C \& D
* Stable medical, physical and psychological condition as considered by Investigators
* Able to understand and interact with the study team in French or English
* Adequate caregiver support and access to appropriate medical care in the patient's home community
* Agree to comply with all conditions of the study and to attend all required study training and visit
* Must provide and sign Informed Consent prior to any study-related procedures

Exclusion Criteria:

* Epilepsy
* Women who are pregnant (pregnancy test obligatory for women of childbearing potential) or breastfeeding or not willing to take contraception.
* Known or suspected non-compliance, drug or alcohol abuse.
* Gastrointestinal ulcers in the last five years
* Known or suspected eye disorders or diseases
* Known or suspected allergies or hypersensitivity to buspirone, levodopa or carbidopa.
* Taking selective and non-selective serotonin reuptake inhibitors or any other treatments acting upon serotonergic transmission, such as the following:

  * Selective serotonin reuptake inhibitors (SSRIs)
  * Serotonin-norepinephrine reuptake inhibitors (SNRIs)
  * Serotonin antagonists and reuptake inhibitors (SARIs)
  * Tricyclic antidepressants (TCAs)
  * Tetracyclic antidepressants (TeCAs)
  * Norepinephrine-dopamine reuptake inhibitors (NDRIs)
  * Monoamine oxidase inhibitors (MAOIs)
* Patients who are receiving treatments altering the noradrenergic and dopaminergic transmission (e.g., bupropion and levodopa/carbidopa)
* Patients who are taking narcotic pain killers (e.g., opioids) and neuropathic medication (e.g., gabapentin, pregabalin)
* Patients who are taking antihypertensive drugs and diuretics (e.g., furosemide or hydrochlorothiazide)
* Patients who are taking hypnotic drugs (e.g., Zolpidem).
* Patients receiving D2 antagonists or antipsychotic drugs (e.g., butyrophenone, phenothiazines, risperidone)
* Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc.)

Primary outcomes:
measure: Rate of AEs/SAEs/Side effects
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Changes in blood pressure
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Changes in heart rate
timeFrame: Changes from baseline condition over a treatment session of 4 hours
Secondary outcomes:
measure: Spasticity of the Lower Extremities (score according to the Pendulum test)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Lower Extremity Motor Strength (M0-M5 score according to the AIS)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Lower Extremity Motor Strength (muscle activity)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Lower Extremity Voluntary Movements (kinematics assessment through VICON)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Lower Extremity Voluntary Movements (muscle activity)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Walking speed (10MWT)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Gait pattern (kinematics assessment through VICON)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
measure: Gait pattern (muscle activity)
timeFrame: Changes from baseline condition over a treatment session of 4 hours
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: CHUV
state: Vaud
Study officials:
affiliation: CHUV
name: Jocelyne Bloch, Pr MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wagner FB, Mignardot JB, Le Goff-Mignardot CG, Demesmaeker R, Komi S, Capogrosso M, Rowald A, Seanez I, Caban M, Pirondini E, Vat M, McCracken LA, Heimgartner R, Fodor I, Watrin A, Seguin P, Paoles E, Van Den Keybus K, Eberle G, Schurch B, Pralong E, Becce F, Prior J, Buse N, Buschman R, Neufeld E, Kuster N, Carda S, von Zitzewitz J, Delattre V, Denison T, Lambert H, Minassian K, Bloch J, Courtine G. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature. 2018 Nov;563(7729):65-71. doi: 10.1038/s41586-018-0649-2. Epub 2018 Oct 31.
citation: Formento E, Minassian K, Wagner F, Mignardot JB, Le Goff-Mignardot CG, Rowald A, Bloch J, Micera S, Capogrosso M, Courtine G. Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury. Nat Neurosci. 2018 Dec;21(12):1728-1741. doi: 10.1038/s41593-018-0262-6. Epub 2018 Oct 31.