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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

3 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-09-11

Study Completion Date

2023-10-04

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Spinal Cord Injuries Drug Effect

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

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 Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Double-blinded and undistinguishable pills will be made by a pharmacy laboratory in order to conceal their nature from the clinicians and the participants.

Study Groups

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Buspirone

40mg

Group Type ACTIVE_COMPARATOR

Buspirone

Intervention Type DRUG

40mg

Levodopa-Carbidopa

400mg/100mg

Group Type ACTIVE_COMPARATOR

Levodopa-Carbidopa

Intervention Type DRUG

400mg/100mg

Buspirone + Levodopa-Carbidopa

40mg + 400mg/100mg

Group Type ACTIVE_COMPARATOR

Buspirone + Levodopa-Carbidopa

Intervention Type DRUG

40mg + 400mg/100mg

Placebo

Mannitol pill

Group Type PLACEBO_COMPARATOR

Placebo oral tablet

Intervention Type DRUG

Non-active metabolite

Interventions

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Buspirone

40mg

Intervention Type DRUG

Levodopa-Carbidopa

400mg/100mg

Intervention Type DRUG

Buspirone + Levodopa-Carbidopa

40mg + 400mg/100mg

Intervention Type DRUG

Placebo oral tablet

Non-active metabolite

Intervention Type DRUG

Eligibility Criteria

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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.)

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes