Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES

Study Overview
=================
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: Spasticity Lower Extremity Motor score (LEMS) Voluntary movements 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.

Official Title
-----------------
Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With Spinal Cord Injury Treated With Epidural Electrical Stimulation

Conditions
-----------------
Spinal Cord Injuries, Drug Effect

Intervention / Treatment
-----------------
* Drug: Buspirone
* Drug: Levodopa-Carbidopa
* Drug: Buspirone + Levodopa-Carbidopa
* Drug: Placebo oral tablet


Participation Criteria
=================
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.)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Buspirone<br>40mg | Drug: Buspirone<br>* 40mg<br>|
| Active Comparator: Levodopa-Carbidopa<br>400mg/100mg | Drug: Levodopa-Carbidopa<br>* 400mg/100mg<br>|
| Active Comparator: Buspirone + Levodopa-Carbidopa<br>40mg + 400mg/100mg | Drug: Buspirone + Levodopa-Carbidopa<br>* 40mg + 400mg/100mg<br>|
| Placebo Comparator: Placebo<br>Mannitol pill | Drug: Placebo oral tablet<br>* Non-active metabolite<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of AEs/SAEs/Side effects | Evaluate the safety of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. The frequency and the severity AEs and SAEs will be collected thoughout the treatment session Reported side effects throughout the treatment sessions will also be collected by a tailored quantitative/qualitative questionnaire | Changes from baseline condition over a treatment session of 4 hours | 
| Changes in blood pressure | Evaluate the safety of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo -Vitals signs will be monitored throughout the treatment session to evaluate the fluctuations from baseline condition. | Changes from baseline condition over a treatment session of 4 hours | 
| Changes in heart rate | Evaluate the safety of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo -Vitals signs will be monitored throughout the treatment session to evaluate the fluctuations from baseline condition. | Changes from baseline condition over a treatment session of 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spasticity of the Lower Extremities (score according to the Pendulum test) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Assessment of the lower extremities' spasticity. | Changes from baseline condition over a treatment session of 4 hours | 
| Lower Extremity Motor Strength (M0-M5 score according to the AIS) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Assessment of the lower extremities' motor strength by a clinician. | Changes from baseline condition over a treatment session of 4 hours | 
| Lower Extremity Motor Strength (muscle activity) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Assessment of the lower extremities' motor strength by EMGs. | Changes from baseline condition over a treatment session of 4 hours | 
| Lower Extremity Voluntary Movements (kinematics assessment through VICON) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Participants' voluntary movements will be assessed by kinematics analyses through the VICON) | Changes from baseline condition over a treatment session of 4 hours | 
| Lower Extremity Voluntary Movements (muscle activity) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Participants' muscles during the voluntary movements will be assessed by EMGs. | Changes from baseline condition over a treatment session of 4 hours | 
| Walking speed (10MWT) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Participants' velocity will be assessed with a 10MWT with and without EES | Changes from baseline condition over a treatment session of 4 hours | 
| Gait pattern (kinematics assessment through VICON) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Participants' gait pattern during a 10MWT will be assessed by kinematics analyses through the VICON | Changes from baseline condition over a treatment session of 4 hours | 
| Gait pattern (muscle activity) | Explore preliminary efficacy of oral, single-dose administration of levodopa/carbidopa, buspirone, the combination of buspirone and levodopa/carbidopa, and placebo. -Participants' muscle activity will be assessed during a 10MWT with EMGs. | Changes from baseline condition over a treatment session of 4 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pharmacology, Neuromodulation, Epidural electrical stimulation