The Role of SAtivex® in Robotic-Rehabilitation
Condition: Rehabilitation
Study type: Interventional

Summary: 
      Spasticity is frequently experienced by people with Multiple Sclerosis (MS), negatively
      impacting on patient's motor functional outcome, including walking. Currently, none of the
      available MS disease-modifying medications has been shown to stop or reverse gait disability.
      Recently the nabiximols has been tested for the treatment of spasticity and walking
      impairment in MS. Nabiximols (trade name Sativex®) is an oromucosal spray formulation
      containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)
      derived from cloned Cannabis sativa L. plant. The main active substance, THC, acts as a
      partial agonist at human cannabinoid receptors (CB1 and CB2), and may modulate the effects of
      excitatory (glutamate-GLU-) and inhibitory (gamma-aminobutyric acid -GABA-)
      neurotransmitters, leading to muscle relaxation, which in turn is responsible for spasticity
      improvement. Cannabinoid receptors may modulate both excitatory and inhibitory transmission
      at central synapses, and have been heavily implicated, in animal models, in multiple forms of
      synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD).
      Indeed, in a previous study implying transcranial magnetic stimulation (TMS) technique, it
      has been hypothesized that the activation of cannabinoid receptors by Sativex® could modulate
      the balance between LTP and LTD like plasticity by changing the state of cortical
      excitability. In a recently study it has been proposed that Sativex may modulate the cortical
      excitability changing the activity of inhibitory GABAergic cortico-cortical synapses. Aim of
      our study is to clarify the role of Sativex coupled to a robotic neurehabilitation training
      in MS patients in improving the motor outcome, by means of clinical, kinematic, beside some
      neurophysiological and measures.
    

Detailed description: 
      Forthy MS patients affected by gait disturbances and moderate-severe spasticity will be
      enrolled: 20 out of them in treatment with Sativex (Group A) considered as responders and 20
      treated only with the most common antispastic used in MS (Group B). All the 40 subjects,
      divided into two groups (A: Sativex+Lokomat Training and B: other antispastic+Lokomat
      Training), will perform a neurorobotic-assisted gait training (RAGT, each session will last
      at least 45', 3 times per week, for a total amount of 20 treatment's sessions). All patients
      will undergo a complete blind physical and neurological examination, including evaluation of
      disability by means of the Expanded Disability Scale (EDDS) and assessment of spasticity
      using the Modified Ashworth Scale (MAS) and the numerical rating scale (NRS). To clarify the
      role of Sativex® in improving spasticity gait-related symptoms the following scales will be
      also administered: ten meters walking test (10wt), Ambulation Index (AI). Quality of life
      will be evaluated by means of MSQOL 54. The skilled clinician will be blind to the drug
      treatment.Moreover, some electrophysiological parameters to test cortical excitability will
      be also evaluated: motor evoked potentials (MEP) amplitude, short intracortical inhibition
      (SICI) and facilitation (ICF) from the abductor pollicis brevis muscle (APB) of the most
      affected side. The same assessment will be applied in baseline, at the end of the robotic
      training (T1) and 30 days after the end of the nerehabilitation training (T2).
    

Intervention name(s): Lokomat training; Sativex
Intervention type(s): Device; Drug
Intervention description(s): The neurorobotic treatment will be performed by using the Lokomat (Lokomat, Hocoma, Volketswil, Switzerland) device. The work load will be progressively adjusted based on the improvement of motor performances. Training parameters (weight support, etc) will be individually adapted. During the first Lokomat session, support will be set at 50% of the body weight and will be adapted on observation of the gait. The Lokomat motor guidance system will be first set at 100%, corresponding to a passive walk.; Patients in treatment with Sativex will receive cannabis-based medicine extract presented in a pump action sublingual spray. Sativex is composed of whole cannabis plant extract, containing THC (27 mg/mL) and CBD (25 mg/mL), in ethanol/propylene glycol (50:50) excipient.
Each actuation delivers 100 KL of spray, containing THC 2.7 mg and CBD 2.5 mg. The number and frequency of dosing (sprays) with Sativex will vary from individual to individual and it may take a number of weeks to find the correct dose of Sativex for the individual patient.
Other intervention name(s): RAGT; Nabiximols
Intervention MeSH terms: Nabiximols
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment