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 |
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Recruitment Status :
Enrolling by invitation
First Posted : August 12, 2019
Last Update Posted : September 21, 2020
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Spinal Cord Injuries Drug Effect | Drug: Buspirone Drug: Levodopa-Carbidopa Drug: Buspirone + Levodopa-Carbidopa Drug: Placebo oral tablet | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 8 participants |
| 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 |
| Official Title: | Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With Spinal Cord Injury Treated With Epidural Electrical Stimulation |
| Actual Study Start Date : | September 11, 2020 |
| Estimated Primary Completion Date : | May 4, 2023 |
| Estimated Study Completion Date : | May 4, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Buspirone
40mg
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Drug: Buspirone
40mg |
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Active Comparator: Levodopa-Carbidopa
400mg/100mg
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Drug: Levodopa-Carbidopa
400mg/100mg |
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Active Comparator: Buspirone + Levodopa-Carbidopa
40mg + 400mg/100mg
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Drug: Buspirone + Levodopa-Carbidopa
40mg + 400mg/100mg |
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Placebo Comparator: Placebo
Mannitol pill
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Drug: Placebo oral tablet
Non-active metabolite |
- 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.
- 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.
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| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
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.
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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.)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04052776
| Switzerland | |
| CHUV | |
| Lausanne, Vaud, Switzerland, 1011 | |
| Principal Investigator: | Jocelyne Bloch, Pr MD | CHUV |
Publications:
| Responsible Party: | Jocelyne Bloch, Professor Medical Doctor, Centre Hospitalier Universitaire Vaudois |
| ClinicalTrials.gov Identifier: | NCT04052776 |
| Other Study ID Numbers: |
2019-01057 |
| First Posted: | August 12, 2019 Key Record Dates |
| Last Update Posted: | September 21, 2020 |
| Last Verified: | September 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| 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) Clinical Study Report (CSR) |
| Time Frame: | Three years after |
| 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 |
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Pharmacology Neuromodulation Epidural electrical stimulation |
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Spinal Cord Injuries Wounds and Injuries Spinal Cord Diseases Central Nervous System Diseases Nervous System Diseases Trauma, Nervous System Levodopa Carbidopa Carbidopa, levodopa drug combination Buspirone Antiparkinson Agents Anti-Dyskinesia Agents Dopamine Agents Neurotransmitter Agents |
Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Aromatic Amino Acid Decarboxylase Inhibitors Enzyme Inhibitors Anti-Anxiety Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs Serotonin Receptor Agonists Serotonin Agents Adjuvants, Immunologic Immunologic Factors Dopamine Agonists |