Acute Effects of Pharmacological Neuromodulation on Leg Motor Activity in Patients With SCI Treated With EES
Condition: Spinal Cord Injuries; Drug Effect
MeSH terms: Spinal Cord Injuries
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Buspirone; Levodopa-Carbidopa; Buspirone + Levodopa-Carbidopa; Placebo oral tablet
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 40mg; 400mg/100mg; 40mg + 400mg/100mg; Non-active metabolite
Intervention MeSH terms: Levodopa; Carbidopa; Carbidopa, levodopa drug combination; Buspirone
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)
Primary purpose: Treatment
Keywords: Pharmacology; Neuromodulation; Epidural electrical stimulation