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The purpose of this study was to assess the efficacy of Sativex in relieving symptoms of spasticity in multiple sclerosis
This was a 15 week (one week baseline and fourteen weeks treatment period), multicentre, double blind, randomised, placebo controlled, parallel group study to evaluate the efficacy of Sativex in subjects with symptoms of spasticity due to multiple sclerosis. Eligible subjects entered a seven day baseline period. Subjects then returned to the centre for randomisation and dose introduction. Visits occurred at the end of treatment weeks two, six, ten and at the end of the study (treatment week 14) or earlier if they withdrew.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sativex | Experimental | Active treatment |
|
| Placebo | Placebo Comparator | Control |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sativex | Drug | Contains delta-9-tetrahydrocannabinol (THC) (27mg/ml): cannabidiol (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 |
|---|---|---|
| Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment) | The average spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. A negative value indicates an improvement in pain score from baseline. | 0-15 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | The cumulative response to treatment was the percentage change from baseline in the mean NRS spasticity score as defined as the 30% response. The spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. The number of responders at the 30% level is presented. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christine Collin | The Royal Berkshire and Battle Hospitals NHS Trust, London Road, Reading, Berkshire, RG1 5AN. | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Royal Berkshire and Battle Hospitals NHS Trust | Reading | RG1 5AN | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20307378 | Result | Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K, Notcutt W, O'Leary C, Ratcliffe S, Novakova I, Zapletalova O, Pikova J, Ambler Z. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010 Jun;32(5):451-9. doi: 10.1179/016164109X12590518685660. Epub 2010 Mar 19. | |
| 25475413 |
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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 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours. |
| FG001 | Placebo | Contains no active drug but colourants and excipients. Maximum permitted dose was 24 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 24 actuations (THC 65 mg: CBD 60 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 | Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment) | The average spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. A negative value indicates an improvement in pain score from baseline. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Mean | Standard Deviation | units on a scale | 0-15 weeks |
|
All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected.
All adverse 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 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Irritability | General disorders | MedDRA 8.1 | Systematic Assessment | Irritability may have been misclassified to the General Disorders and Administration Site Conditions SOC from the Psychiatric Disorders SOC. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | MedDRA 8.1 | 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 |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| C587251 | nabiximols |
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|
|
| Placebo | Drug | Contains peppermint oil flavouring, 0.05%(v/v); quinoline yellow,0.005% (w/v) and sunset yellow, 0.0025% (w/v) colourants, in a and ethanol:propylene glycol (50:50) excipient. |
|
| 0-15 weeks |
| Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment | 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. | Day 0 (Randomisation) and Day 99 (End of Treatment) |
| Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment) | The sleep disruption NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate how your spasticity disrupted your sleep last night?" where 0 = did not disrupt sleep and 10 = completely disrupted (unable to sleep at all). A negative value indicates an improvement in sleep disruption score from baseline. | 0-15 weeks |
| Incidence of Adverse Events as a Measure of Subject Safety | The number of subjects who experienced and adverse event during the course of the study is presented | 0-15 weeks |
| Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment | 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. | Day 0 (Randomisation) and Day 99 (End of Treatment) |
| Carer Global Impression of Change at the End of Treatment | The carer of the subject gave their opinion of any noticeable change in the subject's overall functional ability at the end of the study. A 7-point Likert-type scale was used, with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". The number of carers who reported an improvement at the end of treatment is presented. | Day 99 (end of treatment) |
| Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment | The Barthel Index consists of 10 items that measure a person's daily functioning specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. The person receives a score based on whether they have received help while doing the task. The scores for each of the items are summed to create a total score of 100. An increase in score indicates an improvement. | Day 0 (Randomisation) and Day 99 (End of Treatment) |
| Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | The cumulative response to treatment was the percentage change from baseline in the mean NRS spasticity score as defined as the 50% response. The spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. The number of responders at the 50% level is presented. | 0 - 15 weeks |
| 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. |
| Lost to Follow-up |
|
| Lack of Efficacy |
|
| Unable to operate spray |
|
| Sponsor request as creatinine levels <50 |
|
| Death |
|
| Patient would not stop driving |
|
| Contra-indication discovered |
|
| Pregnancy |
|
Contains no active drug but colourants and excipients. Maximum permitted dose was 24 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 |
|
| OG001 | Placebo | Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours. |
|
|
|
| Secondary | Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | The cumulative response to treatment was the percentage change from baseline in the mean NRS spasticity score as defined as the 30% response. The spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. The number of responders at the 30% level is presented. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Number | participants | 0-15 weeks |
|
|
|
|
| Secondary | Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment | 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 subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Mean | Standard Deviation | units on a scale | Day 0 (Randomisation) and Day 99 (End of Treatment) |
|
|
|
|
| Secondary | Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment) | The sleep disruption NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate how your spasticity disrupted your sleep last night?" where 0 = did not disrupt sleep and 10 = completely disrupted (unable to sleep at all). A negative value indicates an improvement in sleep disruption score from baseline. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Mean | Standard Deviation | units on a scale | 0-15 weeks |
|
|
|
|
| Secondary | Incidence of Adverse Events as a Measure of Subject Safety | The number of subjects who experienced and adverse event during the course of the study is presented | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis, as were a further two subjects who were excluded from the full analysis set (used for the efficacy analysis) as a result of no on-treatment efficacy data | Posted | Number | participants | 0-15 weeks |
|
|
|
| Secondary | Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment | 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. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Mean | Standard Deviation | time (seconds) | Day 0 (Randomisation) and Day 99 (End of Treatment) |
|
|
|
|
| Secondary | Carer Global Impression of Change at the End of Treatment | The carer of the subject gave their opinion of any noticeable change in the subject's overall functional ability at the end of the study. A 7-point Likert-type scale was used, with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". The number of carers who reported an improvement at the end of treatment is presented. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis, as were a further two subjects who were excluded from the full analysis set as a result of no on-treatment efficacy data | Posted | Number | participants | Day 99 (end of treatment) |
|
|
|
|
| Secondary | Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment | The Barthel Index consists of 10 items that measure a person's daily functioning specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. The person receives a score based on whether they have received help while doing the task. The scores for each of the items are summed to create a total score of 100. An increase in score indicates an improvement. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Mean | Standard Deviation | units on a scale | Day 0 (Randomisation) and Day 99 (End of Treatment) |
|
|
|
|
| Secondary | Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | The cumulative response to treatment was the percentage change from baseline in the mean NRS spasticity score as defined as the 50% response. The spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. The number of responders at the 50% level is presented. | All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis | Posted | Number | participants | 0 - 15 weeks |
|
|
|
|
| 15 |
| 167 |
| 156 |
| 167 |
| EG001 | Placebo | Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours. | 7 | 170 | 132 | 170 |
|
| Asthenia | General disorders | MedDRA 8.1 | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA 8.1 | Systematic Assessment |
|
| Orchitis | Infections and infestations | MedDRA 8.1 | Systematic Assessment |
|
| Erysipelas | Infections and infestations | MedDRA 8.1 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA 8.1 | Systematic Assessment |
|
| Burns third degree | Injury, poisoning and procedural complications | MedDRA 8.1 | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 8.1 | Systematic Assessment |
|
| Foot Fracture | Injury, poisoning and procedural complications | MedDRA 8.1 | Systematic Assessment |
|
| Road Traffic Accident | Injury, poisoning and procedural complications | MedDRA 8.1 | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 8.1 | Systematic Assessment |
|
| Tetany | Metabolism and nutrition disorders | MedDRA 8.1 | Systematic Assessment |
|
| Muscle Spasms | Musculoskeletal and connective tissue disorders | MedDRA 8.1 | Systematic Assessment |
|
| Colon Cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 8.1 | Systematic Assessment |
|
| Metastases to Liver | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 8.1 | Systematic Assessment |
|
| Oesophageal Adenocarcinoma Metastatic | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 8.1 | Systematic Assessment |
|
| Multiple Sclerosis Relapse | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Epilepsy | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Muscle Spasticity | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Aggression | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Confusional State | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Drug Dependence | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Paranoia | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Suicidal Ideation | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Delusions | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Depression Worsened | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Urinary Retention | Renal and urinary disorders | MedDRA 8.1 | Systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Decubitus Ulcer | Skin and subcutaneous tissue disorders | MedDRA 8.1 | Systematic Assessment |
|
| Peripheral Ischaemia | Vascular disorders | MedDRA 8.1 | Systematic Assessment |
|
| Phlebothrombosis | Vascular disorders | MedDRA 8.1 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Muscle Spasticity | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Disturbance in Attention | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Dysarthria | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Multiple Sclerosis Relapse | Nervous system disorders | MedDRA 8.1 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 8.1 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA 8.1 | Systematic Assessment |
|
| Feeling Abnormal | General disorders | MedDRA 8.1 | Systematic Assessment |
|
| Malaise | General disorders | MedDRA 8.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Dry Mouth | Gastrointestinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 8.1 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 8.1 | Systematic Assessment |
|
| Urinary Tract Infection Not Otherwise Specified | Infections and infestations | MedDRA 8.1 | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA 8.1 | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA 8.1 | Systematic Assessment |
|
| Muscle Spasms | Musculoskeletal and connective tissue disorders | MedDRA 8.1 | 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.
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |