A Study of the Safety and Effectiveness of Sativex®, for the Relief of Symptoms of Spasticity in Subjects, From Phase B, With Multiple Sclerosis (MS)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether Sativex® versus Placebo is effective in the relief of symptoms of spasticity in subjects with multiple sclerosis, who have been identified as having a capacity to respond to Sativex.

Detailed Description
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This 19 week, multicentre study was conducted in two phases. Phase A was a preliminary, single-blind four week treatment period to identify subjects with a capacity to respond to Sativex; eligible, consenting subjects entered a seven day screening period prior to returning to the study centre to begin a four week single-blind course of Sativex treatment. At the end of this phase, subjects' response to Sativex was assessed; those with the capacity to respond (i.e. at least a 20% reduction in mean 0-10 point numerical rating scale (NRS) spasticity score between screening and the end of the four week Phase A treatment) were eligible for entry into Phase B while those who did not respond took no further part in the study other than a follow up visit 14 days later. Phase B was a 12 week double-blind, randomised, placebo controlled, parallel group study with visits at 28 day intervals and a final follow up visit 14 days after completion or withdrawal. The level of spasticity, spasm frequency and sleep disruption were collected each day during the entire study via an interactive voice response system (IVRS). In addition, study medication dosing data were recorded via IVRS throughout Phases A and B. Assessments of other secondary and functional measures of spasticity, safety and tolerability, QOL (quality of life) and mood were also gathered throughout the study.

Official Title
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A Two-phase, Phase 3 Study of the Safety and Efficacy of Sativex, in the Symptomatic Relief of Spasticity in Subjects With Spasticity Due to Multiple Sclerosis: Phase A - Single-blind Response Assessment; Phase B - Double-blind, Randomised, Placebo Controlled, Parallel Group Study.

Conditions
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Spasticity, 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: Willing and able to give written informed consent for participation in the study. Male or female, aged 18 years or above. Subject is able (in the investigator's opinion) and willing to comply with all study requirements. Diagnosed with any disease sub-type of MS of at least six months duration. Spasticity due to MS of at least three months duration, which is not wholly relieved with current anti-spasticity therapy, and which is expected to remain stable for the duration of the study. Subject fulfils at least one of the two criteria below. Subject must be either: Currently established on a regular dose of anti-spasticity therapy or Previously tried and failed, or could not tolerate suitable anti-spasticity therapy. Subject is currently receiving a stable regimen (for at least 30 days prior to study entry) of all medications that may have an effect on spasticity; and willing to maintain this for the duration of the study. If the subject is currently taking disease-modifying medication, this must be at a stable dose for at least three months prior to the screening visit; the dose must also remain stable for the duration of the study. Willing for his or her name to be notified to his or her primary care physician, and consultant and the responsible authorities for participation in this study, as applicable. Exclusion Criteria: Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the subject's level of spasticity. Subject's medical history suggests that relapse/remission is likely to occur during the study (over the next 19 weeks) which, in the opinion of the investigator, is expected to influence the subject's spasticity. Currently receiving a prohibited medication and unwilling to stop for the stated period prior to the screening visit and for the duration of the study. Any known or suspected history of: schizophrenia or other psychotic illness;diagnosed dependence disorder;poorly controlled epilepsy or recurrent seizures;hypersensitivity to cannabinoids. Significant cardiac, renal or hepatic disease. Female subjects of child bearing potential and male subjects whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for three months thereafter. Female subject who is pregnant, lactating or planning pregnancy during the course of the study or for three months thereafter. Subjects who have received an IMP within the 12 weeks before Visit 1. Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the result of the study, or the subject's ability to participate in the study. Following a physical examination, the subject has any abnormalities that, in the opinion of the investigator, would prevent them from safely participating in the study. Unwilling to abstain from donation of blood during the study. Travel outside the country of residence planned during the study. Subjects previously randomised into this study.

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sativex<br>Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L. Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours | Drug: Sativex®<br>* containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Maximum dose within any 24-hour interval is 12 sprays (THC 32.4 mg: CBD 30 mg)<br>* Other names: GW-1000-02;|
| Placebo Comparator: Placebo<br>Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours. | Drug: Placebo<br>* containing ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring and colouring FD&C Yellow No.5 (E102 tartrazine) (0.0260%), FD&C Yellow No.6 (E110 sunset yellow) (0.0038%), FD&C Red No. 40 (E129 Allura red AC) (0.00330%) and FD&C Blue No.1 (E133 Brilliant blue FCF) (0.00058%).<br>* Other names: GA0034;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in Mean Spasticity Numerical Rating Scale (NRS) Score From Baseline to End of Treatment (Phase B). | Subjects were asked On a scale of '0 to 10' please indicate the average level of your spasticity over the last 24 hours with the anchors: 0 = 'no spasticity' and 10 = 'worst possible spasticity'. They were asked to relate 'no spasticity' to the time prior to the onset of their spasticity. | Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Showing an Improvement of at Least 30% or 50% in Their Mean NRS Spasticity Score (Phase B) From Baseline. | A subject was classified as a responder in the evaluable period provided they did not withdraw due to lack of efficacy and achieved at least a 30% or 50% reduction (i.e. improvement) in the mean NRS spasticity score from baseline (Day 1) to the end of treatment(last 7 days of Week 17 Phase B). All other subjects and subjects without evaluable data were considered non-responders. | Baseline (Day 1) - End of treatment (last 7 days of Week 17) | 
| Change in Spasm Frequency (Number of Spasms Per Day) From Baseline to End of Treatment (Phase B). | The subjects' baseline spasm frequency was the mean of the last seven days scores (Week 4) of Phase A treatment. The variable for analysis was the change in mean spasm frequency from baseline to the end of treatment (last 7 days of Week 17 Phase B). | Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17) | 
| Change in Sleep Disruption (Daily 11-point NRS) From Baseline to End of Treatment (Phase B). | The sleep disruption NRS score was recorded by subjects via a daily call to the interactive voice response system at bedtime. Subjects were asked On a scale of '0 to 10' please indicate how you your spasticity disrupted your sleep last night with the anchors: 0 = 'did not disrupt sleep' and 10 = 'completely disrupted (unable to sleep at all)'. | Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17) | 
| Change in Spasticity as Measured Using the Modified Ashworth Scale From Baseline to End of Treatment (Phase B). | All 20 muscle groups were assessed for spasticity (using a 1-5 scale): 1= no increase in muscle tone to 5= passive movement is difficult and affected part is rigid in flexion or extension. The score for all 20 muscle groups were added to give a total score out of 100; minimum score was 20. A decrease in score indicates an improvement in condition. | Baseline (End of Week 4) - End of treatment (End of Week 17) | 
| Change in Motricity Index Score From Baseline to End of Treatment (Phase B)for Affected Limbs. | Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. Leg - 3 movements were ankle dorsiflexion, knee extension and hip flexion. The total arm and leg score was the addition of the score for the 3 arm movements and 3 leg movements, respectively. One point was then added to each limb score to give a maximum score of 100; minimum was 1 point. Where both arms (or both legs) were assessed, the average of the two limbs scores was used as the assessment score; otherwise the affected limb total score was used. An increase in score indicates an improvement in condition. | Baseline (End of Week 4) - End of treatment (End of Week 17) | 
| Change in Timed 10-metre Walk From Baseline to End of Treatment (Phase B). | Only those subjects for whom it was appropriate (i.e. ambulatory subjects) were timed how long it took to walk 10 metres. Walk time was only assessed for subjects who successfully completed the Timed 10 Metre Walk. A negative difference from baseline indicates an improvement walk time. | Baseline (End of Week 4) - End of treatment (End of Week 17) | 
| Subject Global Impressions of Change at End of Treatment (Phase B). |  | End of Treatment (WeeK 17) | 
| Carer Global Impressions of Change at of Treatment (Phase B). |  | End of treatment (Week 17) | 
| Carer Ease of Transfer Global Impressions of Change at End of Treatment (Phase B). |  | End of treatment (week 17) | 
| Physician Global Impressions of Change at End of Treatment (Phase B). |  | End of treatment (week 17) | 
| Change EuroQoL Quality of Life Questionnaire (EQ-5D)From Baseline to End of Treatment (Phase B) | The EQ-5D questionnaire provided two outcomes: A weighted health state index visual analogue scale (VAS) A self-rated health status VAS EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition. The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing. | [Baseline (End of Week 4) - End of treatment (End of Week 17) | 
| Mood Assessment: Change in Beck Depression Inventory - II (BDI-II)From Baseline to End of Treatment (Phase B) | This was a 21-question multiple choice self-report inventory. Subjects' responses to the 21 questions were assigned a score ranging from zero to three, indicating the severity of the symptom. The sum of all BDI-II question scores indicated the severity of depression; score range 0-63. An decrease in score indicates an improvement in condition. | Baseline (End of week 4) - end of treatment (end of week 17) | 

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