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

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ClinicalTrials.gov Identifier: NCT04052776
Recruitment Status : Enrolling by invitation
First Posted : August 12, 2019
Last Update Posted : September 21, 2020
Sponsor:
Collaborator:
Ecole Polytechnique Fédérale de Lausanne
Information provided by (Responsible Party):
Jocelyne Bloch, Centre Hospitalier Universitaire Vaudois

Tracking Information
First Submitted Date  ICMJE July 29, 2019
First Posted Date  ICMJE August 12, 2019
Last Update Posted Date September 21, 2020
Actual Study Start Date  ICMJE September 11, 2020
Estimated Primary Completion Date May 4, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 9, 2019)
  • Rate of AEs/SAEs/Side effects [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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 [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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 [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 9, 2019)
  • Spasticity of the Lower Extremities (score according to the Pendulum test) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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) [ Time Frame: Changes from baseline condition over a treatment session of 4 hours ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES
Official Title  ICMJE Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With Spinal Cord Injury Treated With Epidural Electrical Stimulation
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:

  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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes 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.
Primary Purpose: Treatment
Condition  ICMJE
  • Spinal Cord Injuries
  • Drug Effect
Intervention  ICMJE
  • Drug: Buspirone
    40mg
  • Drug: Levodopa-Carbidopa
    400mg/100mg
  • Drug: Buspirone + Levodopa-Carbidopa
    40mg + 400mg/100mg
  • Drug: Placebo oral tablet
    Non-active metabolite
Study Arms  ICMJE
  • Active Comparator: Buspirone
    40mg
    Intervention: Drug: Buspirone
  • Active Comparator: Levodopa-Carbidopa
    400mg/100mg
    Intervention: Drug: Levodopa-Carbidopa
  • Active Comparator: Buspirone + Levodopa-Carbidopa
    40mg + 400mg/100mg
    Intervention: Drug: Buspirone + Levodopa-Carbidopa
  • Placebo Comparator: Placebo
    Mannitol pill
    Intervention: Drug: Placebo oral tablet
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: August 9, 2019)
8
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 4, 2023
Estimated Primary Completion Date May 4, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04052776
Other Study ID Numbers  ICMJE 2019-01057
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The SAP, CSR, AEs, SAEs will be made available to other researchers once the study is completed and data have been analyzed
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Three years after
Responsible Party Jocelyne Bloch, Centre Hospitalier Universitaire Vaudois
Study Sponsor  ICMJE Centre Hospitalier Universitaire Vaudois
Collaborators  ICMJE Ecole Polytechnique Fédérale de Lausanne
Investigators  ICMJE
Principal Investigator: Jocelyne Bloch, Pr MD CHUV
PRS Account Centre Hospitalier Universitaire Vaudois
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP