Use of Cannabinoids in Patients With Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
This is a 10-week, randomised, double blind, placebo-controlled, crossover trial to investigate the effect of Cannabis Based Medicine Extract (Sativex) on patterns of brain activation associated with movement in 20 MS patients suffering from lower limb spasticity. Spasticity is a common symptom in Multiple Sclerosis (MS), occurring all over the course of the disease, particularly in the progressive phase.Physiologically, spasticity and hyperreflexia habitually seen in patients with pyramidal syndrome is due to lesions of other descending pathways, such as the cortico reticulospinal pathways, which participate in voluntary movements.It is now known that an endocannabinoid system acts in humans by at least two types of cannabinoids receptors, CB1 and CB2. There is evidence to support the view that the psychoactive ingredient in cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), and cannabinoids in general, can reduce muscle spasticity in people with MS. Aim of the study will be to evaluate the effect of Sativex on: (i) patterns of brain activation associated with movement (fMRI) in MS patients suffering from spasticity; (ii) changes in level of spasticity (H-reflex); (iii) changes in intracortical excitability and on synaptic intracortical network of the motor areas (double shock TMS).

Detailed Description
-----------------
Baseline assessment will be followed by randomisation and dose introduction. Patients will be randomly assigned to two counterbalanced groups starting either with Sativex or with placebo as the first drug. They will be dispensed sufficient study medication for two weeks together with a diary. During the two-week treatment period all the patients will have to be reached the optimal, individualised dosage to subjectively relief spasticity.Patient will return after three weeks and they will undergo the fMRI and neurophysiological evaluations.Then patients will perform a two-week washout period and they will be requested to intake the alternative medicine. After two weeks patients will perform a second fMRI/neurophysiological study. Two weeks later, after a second washout period, a last visit will be performed to conclude the study.

Official Title
-----------------
fMRI and Neurophysiological Study Protocol on Cannabinoids in Multiple Sclerosis

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Sativex


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects between 18 and 60 years of age (inclusive) Have definite Multiple Sclerosis as per Poser Criteria Have either relapsing remitting or secondary progressive course Baseline EDSS score from 3.0 to 6.5 (inclusive) Stable disease for at least 30 days prior to study entry Be right-handed with normal right hand function Female patients of child bearing potential and male patients whose partner is of child bearing potential who are willing to ensure that they or their partner use effective contraception during the study and for three months thereafter If female, be neither pregnant nor breast-feeding. Confirmation that the subjects not pregnant must be established by a negative serum hCG pregnancy test at baseline. No cannabinoids use (cannabis, Marinol, Nabilone) for at least three months prior to entry into the study and willing to abstain from any use of cannabis during the study Significant spasticity in at least two muscle groups defined as a score of 2 or more on the Ashworth scale for each muscle group Antispastic/antiepileptic treatments (dosage, frequency and route of administration) stable for at least one month prior the study entry - Exclusion Criteria: Have a primary progressive MS Patients under disease modifying therapies prescribed in the 6 months prior the study entry Patients who have participated in another research study in the past 6 months Changes in antispastic/antiepileptic treatments (dosage, frequency and route of administration) within one month prior the study entry Have a psychiatric disorders or cognitive impairment that preclude safe participation in the study Known history of alcohol or substance abuse Concurrent clinically important immunologic, pulmonary, renal, liver, active thyroid, and/or other major disease other than MS Severe cardiovascular, disorders, such as ischaemic heart disease, arrhythmias, poorly controlled hypertension or severe heart failure Patients suffering from acute or chronic pain History of epilepsy Female patient who is pregnant, lactating or planning pregnancy during the course of the study Scheduled elective surgery or other procedures requiring general anaesthesia during the study Patient who is terminally ill or is inappropriate for placebo medication Systemic corticosteroid therapy within 4 weeks of randomization or exacerbation of MS within 30 days Regular levodopa therapy within 7 days of the study entry Male patient currently receiving sildenafil (Viagra) and unwilling to stop medication for the duration of the study Patients who are currently taking antiarrhythmic medications Known or suspected adverse reaction to cannabinoids Travel outside the Italy planned during the study Donation of blood during the study Contraindications to MRI scans -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Sativex|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of Sativex on: a)patterns of brain activation associated with movement(fMRI); b) changes in level of spasticity (H-reflex); c)changes in intracortical excitability and on synaptic intracortical network of the motor areas(TMS). |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple sclerosis, Cannabinoids, Spasticity, fMRI, TMS