Multiple Sclerosis
Conditions
Brief summary
The purpose of this study was to assess the efficacy of Sativex in relieving symptoms of spasticity in multiple sclerosis
Detailed description
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.
Interventions
DRUGSativex
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.
DRUGPlacebo
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.
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to give informed consent. * Aged 18 years or above. * Ability (in the investigator's opinion) and willingness to comply with all study requirements. * Diagnosed with any disease subtype of multiple sclerosis of duration greater than six months. * Diagnosed with spasticity due to multiple sclerosis of at least three months duration and was not wholly relieved with their current therapy. * Stable dose of anti-spasticity and non-pharmacological therapies for at least 30 days prior to the screening visit and willingness for these to be maintained for the duration of the study. * Stable dose of disease modifying medications for at least six months duration prior to the screening visit and willingness to maintain this for the duration of the study. * The last six daily diary spasticity numerical rating scale scores before randomisation had been completed and summed to at least 24. * Agreement for the responsible authorities (as applicable in individual countries), their primary care physician, and their consultant, if appropriate, to be notified of their participation in the study.
Exclusion criteria
* Concomitant disease or disorder that had symptoms of spasticity, or that may have influenced the subject's level of spasticity. * Received a Botulinum Toxin injection within four months prior to the screening visit or unwillingness to stop receiving Botulinum Toxin injections for the relief of spasticity for the duration of the study. * Had used cannabis within 30 days of study entry and unwillingness to abstain for the duration for the study. * Had used cannabinoid based medications within 60 days of study entry and unwillingness to abstain for the duration for the study. * History of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition. * Known or suspected history of alcohol or substance abuse. * History of epilepsy or recurrent seizures. * Known or suspected hypersensitivity to cannabinoids or any of the excipients of the study medication. * Experienced myocardial infarction or clinically relevant cardiac dysfunction within the last 12 months or had a cardiac disorder that, in the opinion of the investigator would put the subject at risk of a clinically relevant arrhythmia or myocardial infarction. * QT interval of \> 450 ms (males) or \> 470 ms (females) at Visit 1. * Secondary to tertiary arterial ventricular block or sinus bradycardia (heart rate \< 50 bpm) or sinus tachycardia (heart rate \> 110 bpm) at Visit 1. * Diastolic blood pressure of \< 50 mmHg or \> 105 mmHg in a sitting position at rest for 5 minutes prior to randomisation. * Impaired renal function i.e. serum creatinine clearance is lower than 50 ml/min at Visit 1. * Significantly impaired hepatic function, at Visit 1, in the investigator's opinion and/or had liver function tests of equal to or greater than three times the upper limit of normal. * Female subjects of child bearing potential and male subjects whose partner was of child bearing potential, unless were willing to ensure that they or their partner used effective contraception during the study and for three months thereafter. * If female, were pregnant or lactating, or were planning pregnancy during the course of the study and for three months thereafter. * 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, may influence the result of the study, or the subject's ability to participate in the study. * Following a physical examination, the subject had any abnormalities that, in the opinion of the investigator, would prevent the subject from safely participating in the study. * Scheduled elective surgery or other procedures, which required general anaesthesia during the study. * Intention to donate blood during the study. * Intention to travel internationally during the study. * Previous randomisation into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment) | 0-15 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment | Day 0 (Randomisation) and Day 99 (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. |
| Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment) | 0-15 weeks | 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. |
| Incidence of Adverse Events as a Measure of Subject Safety | 0-15 weeks | The number of subjects who experienced and adverse event during the course of the study is presented |
| Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | 0-15 weeks | 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. |
| Carer Global Impression of Change at the End of Treatment | Day 99 (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. |
| Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment | Day 0 (Randomisation) and Day 99 (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. |
| Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | 0 - 15 weeks | 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. |
| Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment | Day 0 (Randomisation) and Day 99 (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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 167 |
| Placebo Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours. | 170 |
| Total | 337 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 5 |
| Overall Study | Contra-indication discovered | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 4 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Patient would not stop driving | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Sponsor request as creatinine levels <50 | 0 | 1 |
| Overall Study | Unable to operate spray | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Sativex | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 2 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 162 Participants | 168 Participants | 330 Participants |
| Age, Continuous | 48.0 years STANDARD_DEVIATION 10.06 | 47.1 years STANDARD_DEVIATION 9.15 | 47.5 years STANDARD_DEVIATION 9.61 |
| Region of Enrollment Czech Republic | 102 participants | 107 participants | 209 participants |
| Region of Enrollment United Kingdom | 65 participants | 63 participants | 128 participants |
| Sex: Female, Male Female | 106 Participants | 101 Participants | 207 Participants |
| Sex: Female, Male Male | 61 Participants | 69 Participants | 130 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 156 / 167 | 132 / 170 |
| serious Total, serious adverse events | 15 / 167 | 7 / 170 |
Outcome results
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.
Time frame: 0-15 weeks
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment) | -1.22 units on a scale | Standard Deviation 1.76 |
| Placebo | Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment) | -0.91 units on a scale | Standard Deviation 1.72 |
Comparison: The initial model used for the analysis of the end of study value was an analysis of covariance (ANCOVA) with baseline as a covariate and treatment group, centre group, ambulatory status at baseline and previous use of cannabis as main effects. Interactions between the main effects were investigated, and if they had little influence then they were dropped from the model. These tests were performed at the 10% significance level as a possible indicator of an interactive effect.p-value: 0.2295% CI: [-0.59, 0.14]ANCOVA
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.
Time frame: Day 99 (end of treatment)
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Carer Global Impression of Change at the End of Treatment | 72 participants |
| Placebo | Carer Global Impression of Change at the End of Treatment | 56 participants |
Comparison: The two treatment groups were to be compared using ordinal logistic regression and the proportional odds model. The model was to incorporate ambulatory status at baseline and centre group.p-value: 0.2795% CI: [0.842, 1.849]Regression, Logistic
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.
Time frame: 0-15 weeks
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment) | -0.7 units on a scale | Standard Deviation 2.85 |
| Placebo | Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment) | -0.6 units on a scale | Standard Deviation 2.37 |
Comparison: The two groups were compared using ANCOVA with baseline severity as a covariate and study centre and treatment group as factors.p-value: 0.73495% CI: [-0.55, 0.4]ANCOVA
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.
Time frame: Day 0 (Randomisation) and Day 99 (End of Treatment)
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment | -2.1 time (seconds) | Standard Deviation 17.37 |
| Placebo | Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment | 9.3 time (seconds) | Standard Deviation 63.56 |
Comparison: The change at end of treatment was compared between treatment groups using ANCOVA. The model included treatment, centre group and ambulatory status at baseline as factors and baseline score as a covariate.p-value: 0.62495% CI: [-2, 1]ANCOVA
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.
Time frame: Day 0 (Randomisation) and Day 99 (End of Treatment)
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment | -3.3 units on a scale | Standard Deviation 9.25 |
| Placebo | Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment | -2.8 units on a scale | Standard Deviation 7.81 |
Comparison: The change at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment, centre group and ambulatory status at baseline as factors and baseline score as a covariate.p-value: 0.85795% CI: [-1.94, 1.61]ANCOVA
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.
Time frame: Day 0 (Randomisation) and Day 99 (End of Treatment)
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment | -0.1 units on a scale | Standard Deviation 10.26 |
| Placebo | Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment | 0.5 units on a scale | Standard Deviation 8.05 |
Comparison: The change at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment, centre group and ambulatory status at baseline as factors and baseline score as a covariate.p-value: 0.86795% CI: [-1.95, 1.64]ANCOVA
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
Time frame: 0-15 weeks
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Incidence of Adverse Events as a Measure of Subject Safety | 156 participants |
| Placebo | Incidence of Adverse Events as a Measure of Subject Safety | 132 participants |
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.
Time frame: 0-15 weeks
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | 51 participants |
| Placebo | Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | 42 participants |
Comparison: The numbers of responders was analysed using the difference in proportions and the odds ratio comparing the treatment groups with the provision of 95% CIs for the difference and odds ratio. The two groups were compared using ANCOVA with baseline severity as a covariate and study centre and treatment group as factors.p-value: 0.23195% CI: [0.83, 2.167]ANCOVA
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.
Time frame: 0 - 15 weeks
Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | 21 participants |
| Placebo | Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline | 18 participants |
Comparison: The numbers of responders was analysed using the difference in proportions and the odds ratio comparing the treatment groups with the provision of 95% CIs for the difference and odds ratio. The two groups were compared using ANCOVA with baseline severity as a covariate and study centre and treatment group as factors.p-value: 0.56995% CI: [0.622, 2.373]ANCOVA