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The purpose of this study is to evaluate the efficacy, safety and tolerability of Sativex® in subjects diagnosed with MS and spasticity.
This was an eight week (two weeks baseline, six weeks treatment), multicentre, double blind, randomised, placebo controlled parallel group study to evaluate the efficacy, safety and tolerability of Sativex® in subjects diagnosed with MS and spasticity. Subjects were screened to determine eligibility and completed a two week baseline period. Subjects then returned to the site for assessment, randomisation and dose introduction. Visits occurred at the end of treatment week two and at the end of the study (treatment week six) or withdrawal.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sativex | Experimental |
| |
| Placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sativex® | Drug | containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Maximum permitted dose was eight actuations in any three hour period and 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Assessment of Change From Baseline in the Mean Spasticity 0-10 Numerical Rating Scale Score. | The spasticity Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your average spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst ever spasticity. For the analysis, end of treatment was defined as the mean of the last seven days in the study or the last three days if the subject withdrew due to worsening spasticity or lack of efficacy. A negative value indicates an improvement in spasticity score from baseline. | 0-52 days |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Mean Ashworth Scale Score at the End of Treatment | The mean Ashworth Scale score across muscle groups was calculated using only those muscle groups with a score of greater than or equal to two at baseline. 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christine Collin, MB BS MRCP FRCP | Royal Berkshire Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Royal Berkshire Hospital | Reading | Oxfordshire | RG1 5AN | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17355549 | Result | Collin C, Davies P, Mutiboko IK, Ratcliffe S; Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007 Mar;14(3):290-6. doi: 10.1111/j.1468-1331.2006.01639.x. | |
| 25475413 | Derived | Di Marzo V, Centonze D. Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes. CNS Neurosci Ther. 2015 Mar;21(3):215-21. doi: 10.1111/cns.12358. Epub 2014 Dec 4. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sativex | Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 48 actuations (THC 130 mg: CBD 120 mg) in 24 hours. |
| FG001 | Placebo | Contains no active drug but colourants and excipients. Maximum permitted dose was 48 actuations in 24 hours. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sativex | Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 48 actuations (THC 130 mg: CBD 120 mg) in 24 hours. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Assessment of Change From Baseline in the Mean Spasticity 0-10 Numerical Rating Scale Score. | The spasticity Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your average spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst ever spasticity. For the analysis, end of treatment was defined as the mean of the last seven days in the study or the last three days if the subject withdrew due to worsening spasticity or lack of efficacy. A negative value indicates an improvement in spasticity score from baseline. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | 0-52 days |
|
All adverse events occurring from the time of consent to post study follow up (9 - 10 weeks) were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected.
All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sativex | Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 48 actuations (THC 130 mg: CBD 120 mg) in 24 hours. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting NOS | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mr Richard Potts, Clinical Operations Director | GW Pharma Ltd. | 0044 1223 266800 | rp@gwpharm.com |
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| ID | Term |
|---|---|
| D009128 | Muscle Spasticity |
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D009122 | Muscle Hypertonia |
| D020879 | Neuromuscular Manifestations |
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| ID | Term |
|---|---|
| C587251 | nabiximols |
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|
| Placebo | Drug | containing peppermint oil, 0.05% (v/v), quinoline yellow, 0.005% (w/v), sunset yellow, 0.0025% (w/v), in ethanol:propylene glycol (50:50) excipient. |
|
|
| Days 0 - 52 |
| Change From Baseline in Mean Spasm Frequency Score at the End of Treatment | Each day subjects recorded in their diary the frequency of their spasms using the following scoring system: 0 = no spasms, 1 = one or fewer spasms per day, 2 = between one and five spasms per day, 3 = six to nine spasms per day, 4 = ten or more spasms per day or continuous contraction. For the analysis, end of treatment was defined as the mean of the last seven days in the study or the last three days if the subject withdrew due to worsening spasticity or lack of efficacy. | Days 0 - 52 |
| Change From Baseline in Mean Motricity Index Score for the Arms | Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. The total arm score was the addition of the score for the 3 arm movements. One point was then added to give a maximum score of 100; minimum was 1 point. Where both arms 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.. | Day 7 and 52 |
| Patient's Global Impression of Change in Condition at the End of Treatment | A 7-point Likert-type scale was used, with the question: 'Please assess the change in your condition since entry into the study using the scale below' with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". At Visit 2 (Baseline) patients wrote a brief description of their condition which was used at end of treatment to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported. | Day 52 |
| Incidence of Adverse Events as a Measure of Subject Safety | The number of subjects who reported an adverse event during the course of the study is presented. | Day 0-52 |
| Change From Baseline in Mean Motricity Index Score for the Legs | Ankle dorsiflexion, knee extension and hip flexion were assessed and scored to give a maximum of 100%. The Motricity Index score (scale 1-100) was recorded for limbs that had an associated Ashworth Scale score, which was greater than or equal to two at baseline. | Day 7 and Day 52 |
| Protocol Violation |
|
| Lost to Follow-up |
|
| administrative decision |
|
| patient non-compliance |
|
Contains no active drug but colourants and excipients. Maximum permitted dose was 48 actuations in 24 hours. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 48 actuations (THC 130 mg: CBD 120 mg) in 24 hours.
| OG001 | Placebo | Contains no active drug but colourants and excipients. Maximum permitted dose was 48 actuations in 24 hours. |
|
|
|
| Secondary | Change From Baseline in Mean Ashworth Scale Score at the End of Treatment | The mean Ashworth Scale score across muscle groups was calculated using only those muscle groups with a score of greater than or equal to two at baseline. 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | Days 0 - 52 |
|
|
|
|
| Secondary | Change From Baseline in Mean Spasm Frequency Score at the End of Treatment | Each day subjects recorded in their diary the frequency of their spasms using the following scoring system: 0 = no spasms, 1 = one or fewer spasms per day, 2 = between one and five spasms per day, 3 = six to nine spasms per day, 4 = ten or more spasms per day or continuous contraction. For the analysis, end of treatment was defined as the mean of the last seven days in the study or the last three days if the subject withdrew due to worsening spasticity or lack of efficacy. | Posted | Mean | Standard Deviation | units on a scale | Days 0 - 52 |
|
|
|
|
| Secondary | Change From Baseline in Mean Motricity Index Score for the Arms | Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. The total arm score was the addition of the score for the 3 arm movements. One point was then added to give a maximum score of 100; minimum was 1 point. Where both arms 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.. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | Day 7 and 52 |
|
|
|
|
| Secondary | Patient's Global Impression of Change in Condition at the End of Treatment | A 7-point Likert-type scale was used, with the question: 'Please assess the change in your condition since entry into the study using the scale below' with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". At Visit 2 (Baseline) patients wrote a brief description of their condition which was used at end of treatment to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Number | participants | Day 52 |
|
|
|
|
| Secondary | Incidence of Adverse Events as a Measure of Subject Safety | The number of subjects who reported an adverse event during the course of the study is presented. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Number | participants | Day 0-52 |
|
|
|
| Secondary | Change From Baseline in Mean Motricity Index Score for the Legs | Ankle dorsiflexion, knee extension and hip flexion were assessed and scored to give a maximum of 100%. The Motricity Index score (scale 1-100) was recorded for limbs that had an associated Ashworth Scale score, which was greater than or equal to two at baseline. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | Day 7 and Day 52 |
|
|
|
|
| 4 |
| 124 |
| 102 |
| 124 |
| EG001 | Placebo | Contains no active drug but colourants and excipients. Maximum permitted dose was 48 actuations in 24 hours. | 3 | 65 | 46 | 65 |
| Appendicitis | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Mobility Decreased | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Bartholin's Abscess | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Urinary Tract Infection NOS | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Lower Respiratory Tract Infection NOS | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Pancreatic Carcinoma NOS | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 5.0 | Systematic Assessment |
|
| Urinary Incontinence Aggravated | Renal and urinary disorders | MedDRA 5.0 | Systematic Assessment |
|
| Pulmonary Embolism | Respiratory, thoracic and mediastinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Urinary Tract Infection NOS | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Dry Mouth | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Balance Impaired NOS | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Headache NOS | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Diarrhoea NOS | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Oral Pain | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Confusion | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Depressed Mood | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Disorientation | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Disturbance in Attention | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Euphoric mood | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Vision Blurred | Eye disorders | MedDRA 5.0 | Systematic Assessment |
|
| Weakness | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Pain in Limb | Musculoskeletal and connective tissue disorders | MedDRA 5.0 | Systematic Assessment |
|
GW will coordinate the dissemination of data from this study and may solicit input and assistance from the principal investigator. All publications, for example manuscripts, abstracts, oral/slide presentations or book chapters based on this study, must be submitted to GW for corporate review before release.
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| Minimally Improved |
|
| No Change |
|
| Minimally worse |
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| Much Worse |
|
| Very Much Worse |
|
| Missing |
|