Back to resultsAcute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES (STIMO-PHARMA)
Primary Purpose
Spinal Cord Injuries, Drug Effect
Status
Completed
Phase
Phase 1
Locations
Switzerland
Study Type
Interventional
Intervention
Buspirone
Levodopa-Carbidopa
Buspirone + Levodopa-Carbidopa
Placebo oral tablet
Sponsored by
About this trial
This is an interventional treatment trial for Spinal Cord Injuries focused on measuring Pharmacology, Neuromodulation, Epidural electrical stimulation
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.)
Sites / Locations
- CHUV
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Active Comparator
Active Comparator
Placebo Comparator
Arm Label
Buspirone
Levodopa-Carbidopa
Buspirone + Levodopa-Carbidopa
Placebo
Arm Description
40mg
400mg/100mg
40mg + 400mg/100mg
Mannitol pill
Outcomes
Primary Outcome Measures
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 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 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.
Secondary Outcome Measures
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.
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.
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.
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)
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.
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
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
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.
Full Information
NCT ID
NCT04052776
First Posted
July 29, 2019
Last Updated
October 4, 2023
Sponsor
Centre Hospitalier Universitaire Vaudois
Collaborators
Ecole Polytechnique Fédérale de Lausanne
1. Study Identification
Unique Protocol Identification Number
NCT04052776
Brief Title
Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES
Acronym
STIMO-PHARMA
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
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
September 11, 2020 (Actual)
Primary Completion Date
October 4, 2023 (Actual)
Study Completion Date
October 4, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Centre Hospitalier Universitaire Vaudois
Collaborators
Ecole Polytechnique Fédérale de Lausanne
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Cord Injuries, Drug Effect
Keywords
Pharmacology, Neuromodulation, Epidural electrical stimulation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blinded and undistinguishable pills will be made by a pharmacy laboratory in order to conceal their nature from the clinicians and the participants.
Allocation
Randomized
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Buspirone
Arm Type
Active Comparator
Arm Description
40mg
Arm Title
Levodopa-Carbidopa
Arm Type
Active Comparator
Arm Description
400mg/100mg
Arm Title
Buspirone + Levodopa-Carbidopa
Arm Type
Active Comparator
Arm Description
40mg + 400mg/100mg
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Mannitol pill
Intervention Type
Drug
Intervention Name(s)
Buspirone
Intervention Description
40mg
Intervention Type
Drug
Intervention Name(s)
Levodopa-Carbidopa
Intervention Description
400mg/100mg
Intervention Type
Drug
Intervention Name(s)
Buspirone + Levodopa-Carbidopa
Intervention Description
40mg + 400mg/100mg
Intervention Type
Drug
Intervention Name(s)
Placebo oral tablet
Intervention Description
Non-active metabolite
Primary Outcome Measure Information:
Title
Rate of AEs/SAEs/Side effects
Description
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
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Changes in blood pressure
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Changes in heart rate
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Secondary Outcome Measure Information:
Title
Spasticity of the Lower Extremities (score according to the Pendulum test)
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Lower Extremity Motor Strength (M0-M5 score according to the AIS)
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Lower Extremity Motor Strength (muscle activity)
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Lower Extremity Voluntary Movements (kinematics assessment through VICON)
Description
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)
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Lower Extremity Voluntary Movements (muscle activity)
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Walking speed (10MWT)
Description
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
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Gait pattern (kinematics assessment through VICON)
Description
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
Time Frame
Changes from baseline condition over a treatment session of 4 hours
Title
Gait pattern (muscle activity)
Description
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.
Time Frame
Changes from baseline condition over a treatment session of 4 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jocelyne Bloch, Pr MD
Organizational Affiliation
CHUV
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHUV
City
Lausanne
State/Province
Vaud
ZIP/Postal Code
1011
Country
Switzerland
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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
Citations:
PubMed Identifier
30382197
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.
Results Reference
background
PubMed Identifier
30382196
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.
Results Reference
background
Links:
URL
http://courtine-lab.epfl.ch/
Description
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
URL
https://www.chuv.ch/fr/chuv-home/
Description
The clinical trial is located at the CHUV in Lausanne, Switzerland.
Learn more about this trial
Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES
We'll reach out to this number within 24 hrs