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

NCT04052776 | Completed Phase 1 DMC

• 1 other identifier: 2019-01057
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

Spinal Cord Injuries; Drug Effect

Keywords

Pharmacology; Neuromodulation; Epidural electrical stimulation

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (8)

• Spasticity of the Lower Extremities (score according to the Pendulum test)

  Changes from baseline condition over a treatment session of 4 hours

• Lower Extremity Motor Strength (M0-M5 score according to the AIS)

  Changes from baseline condition over a treatment session of 4 hours

• Lower Extremity Motor Strength (muscle activity)

  Changes from baseline condition over a treatment session of 4 hours

• Lower Extremity Voluntary Movements (kinematics assessment through VICON)

  Changes from baseline condition over a treatment session of 4 hours

• Lower Extremity Voluntary Movements (muscle activity)

  Changes from baseline condition over a treatment session of 4 hours

Study Arms (4)

Buspirone

ACTIVE COMPARATOR

40mg

Drug: Buspirone

Levodopa-Carbidopa

ACTIVE COMPARATOR

400mg/100mg

Drug: Levodopa-Carbidopa

Buspirone + Levodopa-Carbidopa

ACTIVE COMPARATOR

40mg + 400mg/100mg

Drug: Buspirone + Levodopa-Carbidopa

Placebo

PLACEBO COMPARATOR

Mannitol pill

Drug: Placebo oral tablet

Interventions

Buspirone DRUG

40mg

Buspirone

Levodopa-Carbidopa DRUG

400mg/100mg

Levodopa-Carbidopa

Buspirone + Levodopa-Carbidopa DRUG

40mg + 400mg/100mg

Buspirone + Levodopa-Carbidopa

Placebo oral tablet DRUG

Non-active metabolite

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• Ecole Polytechnique Fédérale de Lausanne: collaborator

Study Sites (1)

CHUV

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Related Publications (2)

• 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.

  PMID: 30382197 BACKGROUND

• 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.

  PMID: 30382196 BACKGROUND

Related Links

• Courtine-Lab is a part of the Center for Neuroprosthetic and Brain Mind Institute of the Life Science School at the Swiss Federal Institute of Technology Lausanne (EPFL). The laboratory is headed by Professor Courtine
• The clinical trial is located at the CHUV in Lausanne, Switzerland.

MeSH Terms

Conditions

Spinal Cord Injuries

Interventions

Buspirone; carbidopa, levodopa drug combination

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Spiro Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Polycyclic Compounds

Study Officials

• Jocelyne Bloch, Pr MD

  CHUV

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blinded and undistinguishable pills will be made by a pharmacy laboratory in order to conceal their nature from the clinicians and the participants.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Medical Doctor

Model Details: 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.

Study Record Dates

• First Submitted: July 29, 2019
• First Posted: August 12, 2019
• Study Start: September 11, 2020
• Primary Completion: October 4, 2023
• Study Completion: October 4, 2023
• Last Updated: October 5, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, CSR
• Time Frame: Three years after

Locations

CH (1)