Neurophysiological Study of Sativex in Multiple Sclerosis (MS) Spasticity

Study Overview
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Brief Summary
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Aim of this randomized, double-blind, placebo-controlled, cross-over study is to investigate cannabinoid-induced changes in neurophysiological parameters in a group of 40 patients with secondary or primary progressive Multiple Sclerosis (MS).

Official Title
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Neurophysiologic Study on Effects of Sativex® on Spasticity in Progressive Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Sativex®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or above Willing and able to comply with the protocol for the duration of the study Diagnosis of Secondary-Progressive or Primary-Progressive MS from at least 12 months Relapse free from at least 3 months before screening visit Lower limb spasticity EDSS from > 3.0 and < 6.5 Moderate to severe spasticity due to MS from at least 6 months and with stable drug treatment not able to relieve symptoms as a whole, deserving a specific add-on treatment Immunomodulatory or immunosuppressant therapies not modified during the study and 6 months before starting the study Stable doses of anti-spasticity agents from at least 2 months prior to screening visit Have given written informed consent Exclusion Criteria: Any concomitant disease that may cause spasticity or that could interfere with subject's spasticity Botulinum Toxin injection for spasticity in the 4 months prior to screening visit Any known or suspected history of psychotic illness, alcohol or substance abuse, epilepsy, hypersensitivity to cannabinoids Significant cardiac, renal or hepatic disease Female subjects of child bearing potentials and male subjects whose partner is child bearing potential, unless willing to ensure that they or their partner use contraception during the study Female subjects who is pregnant lactating or planning pregnancy during the course of the study and for three months thereafter Sativex® SmPC contraindications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: first sativex, second placebo<br>2 weeks first titration period (as per approved SmPC), a 2-week first treatment period (Sativex), a 2-week washout, a cross-over followed by another 2 weeks titration period (as per SmPC), followed by a second 2-week period treatment (placebo) | Drug: Sativex®<br>* THC:CBD 1:1 ratio oromucosal spray. A titration period is required to reach optimal dose. The number and timing of sprays may vary between patients. Duration: 2 weeks<br>Drug: Placebo<br>* Placebo Same frequency and dosage form as Sativex. Duration: 2 weeks<br>|
| Experimental: first placebo, second sativex<br>2 weeks first titration period (as per approved SmPC), a 2-week first treatment period (placebo), a 2-week washout, a cross-over followed by another 2 weeks titration period (as per SmPC), followed by a second 2-week period treatment (Sativex) | Drug: Sativex®<br>* THC:CBD 1:1 ratio oromucosal spray. A titration period is required to reach optimal dose. The number and timing of sprays may vary between patients. Duration: 2 weeks<br>Drug: Placebo<br>* Placebo Same frequency and dosage form as Sativex. Duration: 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| H/M reflex ratio | To evaluate differences in the H/M ratio scores within subjects affected by progressive MS at baseline and week 4. | week 0, 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurophysiology ·H/M ratio ·Transcranial Magnetic Stimulation a) MEP Motor threshold, upper limb b) MEPs amplitudes c) Intracortical facilitation/inhibition (ICI/ICF), upper limb | Neurophysiology H/M ratio: To evaluate differences in the H/M ratio scores within subjects affected by progressive MS at weeks 6 and 10 Transcranial Magnetic Stimulation Motor threshold to obtain MEPs to the upper limb (time 0-4; 6-10 weeks); MEPs amplitudes at 15% above motor threshold, measured as MEP/M ratio to APB (abductor pollicis brevis) and abductor of hallucis, in which M is the compound muscle potential in response to peripheral stimulation (time 0-4; 6-10 weeks); Intracortical facilitation/inhibition (ICI/ICF) to the upper limb (time 0-4; 6-10 weeks); | week 0, 4, 6 and 10 | 
| Adverse Events recording |  | week 0, 4, 6 and 10 | 
| Spasticity: ·0-10 11-point numerical spasticity rating scale (NRS) ·Mean modified Ashworth scale (MAS) | Mean spasticity score recorded using a 0-10 11-point numerical spasticity rating scale (NRS) at baseline (pre-treatment) and week 4, 6 and 10 · Mean modified Ashworth (MAS) score at baseline (pre-treatment), week 4, 6, 10 | week 0, 4, 6, 10 | 
| Function: ·Timed 25 feet and 10 meters walk ·Hand dexterity measured with 9-HPT | Function: Mean Timed 25 feet and 10 meters walk recorded at baseline (pre-treatment) and week 4, 6, 10 Mean Hand dexterity measured with 9-HPT recorded at baseline (pre-treatment) and week 4, 6, 10 | week 0, 4, 6, 10 | 
| Other MS Symptoms: ·Sleep Quality NRS ·Pain NRS and Spasm frequency ·Fatigue Severity Scale (FSS) | Other MS Symptoms: Mean Sleep Quality NRS recorded at baseline (pre-treatment) and week 4, 6, 10 Pain NRS and Spasm frequency recorded at baseline (pre-treatment) and week 4, 6, 10 Fatigue measured with the Fatigue Severity Scale (FSS) recorded at baseline (pre-treatment) and week 4, 6, 10 | week 0, 4, 6, 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spasticity