Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES (STIMO-PHARMA)

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

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.

Study Overview

• Status: Completed
• Conditions: Drug Effect; Spinal Cord Injuries
• Intervention / Treatment: Drug: Buspirone; Drug: Levodopa-Carbidopa; Drug: Buspirone + Levodopa-Carbidopa; Drug: Placebo oral tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • CHUV

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Vaudois
• Collaborators: Ecole Polytechnique Fédérale de Lausanne
• Investigators: Principal Investigator: Jocelyne Bloch, Pr MD, CHUV

Publications and helpful links

General Publications

• 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.
• 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.

Helpful 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2020
• Primary Completion (Actual): October 4, 2023
• Study Completion (Actual): October 4, 2023

Study Registration Dates

• First Submitted: July 29, 2019
• First Submitted That Met QC Criteria: August 9, 2019
• First Posted (Actual): August 12, 2019

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 4, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Neuromodulation; Pharmacology; Epidural electrical stimulation
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Immunologic Factors; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agonists; Dopamine Agents; Serotonin Receptor Agonists; Anti-Anxiety Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Buspirone; Levodopa; Carbidopa; Carbidopa, levodopa drug combination
• Other Study ID Numbers: 2019-01057

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The SAP, CSR, AEs, SAEs will be made available to other researchers once the study is completed and data have been analyzed
• IPD Sharing Time Frame: Three years after
• IPD Sharing Supporting Information Type: SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No