Multiple Sclerosis, Spasticity
Conditions
Keywords
Spasticity, Multiple Sclerosis
Brief summary
The purpose of this study is to evaluate the efficacy, safety and tolerability of Sativex® in subjects diagnosed with MS and spasticity.
Detailed description
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.
Interventions
DRUGSativex®
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
DRUGPlacebo
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.
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
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. * Male or female, aged 18 years or above. * Stable disease for at least three months prior to study entry, in the opinion of the investigator. * Diagnosed with MS whose spasticity was not wholly relieved with the therapy at the time of study entry. * Significant spasticity in at least two muscle groups defined as a score of two or more on the Ashworth Scale for each muscle group. * Stable dose of current anti-spasticity medication for at least 30 days prior to study entry. * Willing to maintain a stable dose of anti-spasticity medication and level of physiotherapy for the duration of the study. * Clinically acceptable laboratory results at Visit 2. * Willing, if female and of child bearing potential or male subjects with a partner of child bearing potential, to ensure that effective contraception was used during the study and for three months thereafter. * No cannabinoid use (cannabis, Marinol® or Nabilone) for at least seven days before Visit 1 and were willing to abstain from any use of cannabis during the study. * Able (in the investigators opinion) and willing to comply with all study requirements. * Willing for the Home Office to be notified of his or her participation in the study (applicable to the UK centres only). * Willing to allow his or her GP and consultant, if appropriate, to be notified of participation in the study.
Exclusion criteria
* History of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition. * Known history of alcohol or substance abuse. * Severe cardiovascular disorder, such as ischaemic heart disease, arrhythmias, poorly controlled hypertension or severe heart failure. * History of epilepsy. * Female subject who was pregnant, lactating or planning pregnancy during the course of the study. * Significant renal or hepatic impairment. * Scheduled elective surgery or other procedures requiring general anaesthesia during the study. * Subject who was terminally ill or was inappropriate for placebo medication. * Any other significant disease or disorder which, in the opinion of the investigator, either put the subject at risk because of participation in the study, or influenced the result of the study, or the subject's ability to participate in the study. * Regular levodopa (Sinemet®, Sinemet Plus®, Levodopa, L-dopa, Madopar®, Benserazide) therapy within seven days of study entry. * Male subject receiving sildenafil (Viagra®) and unwilling to stop medication for the duration of the study. * Subjects who were taking fentanyl (Durogesic®, Actiq®) * Subjects who were taking antiarrhythmic medications. * Known or suspected hypersensitivity to cannabinoids or any of the excipients of the study medications. * Known or suspected adverse reaction to cannabinoids. * Planned travel outside the UK during the study (applicable to the UK centres only). * Donation of blood during the study. * Subjects who had participated in another research study in the 12 weeks prior to study entry. * Subjects previously randomised into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Change From Baseline in the Mean Spasticity 0-10 Numerical Rating Scale Score. | 0-52 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Spasm Frequency Score at the End of Treatment | Days 0 - 52 | 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. |
| Change From Baseline in Mean Motricity Index Score for the Arms | Day 7 and 52 | 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.. |
| Change From Baseline in Mean Ashworth Scale Score at the End of Treatment | Days 0 - 52 | 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. |
| Incidence of Adverse Events as a Measure of Subject Safety | Day 0-52 | The number of subjects who reported an adverse event during the course of the study is presented. |
| Change From Baseline in Mean Motricity Index Score for the Legs | Day 7 and Day 52 | 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. |
| Patient's Global Impression of Change in Condition at the End of Treatment | Day 52 | 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. |
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 48 actuations (THC 130 mg: CBD 120 mg) in 24 hours. | 124 |
| Placebo Contains no active drug but colourants and excipients. Maximum permitted dose was 48 actuations in 24 hours. | 65 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | administrative decision | 0 | 1 |
| Overall Study | Adverse Event | 6 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | patient non-compliance | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | Sativex | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 0 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 118 Participants | 65 Participants | 183 Participants |
| Age, Continuous | 49.7 years STANDARD_DEVIATION 10.2 | 47.8 years STANDARD_DEVIATION 9.5 | 49.1 years STANDARD_DEVIATION 9.9 |
| Region of Enrollment Romania | 16 participants | 9 participants | 25 participants |
| Region of Enrollment United Kingdom | 108 participants | 56 participants | 164 participants |
| Sex: Female, Male Female | 80 Participants | 34 Participants | 114 Participants |
| Sex: Female, Male Male | 44 Participants | 31 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 102 / 124 | 46 / 65 |
| serious Total, serious adverse events | 4 / 124 | 3 / 65 |
Outcome results
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.
Time frame: 0-52 days
Population: All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Assessment of Change From Baseline in the Mean Spasticity 0-10 Numerical Rating Scale Score. | -1.18 units on a scale | Standard Deviation 1.83 |
| Placebo | Assessment of Change From Baseline in the Mean Spasticity 0-10 Numerical Rating Scale Score. | -0.63 units on a scale | Standard Deviation 1.62 |
Comparison: The change in mean 11-point Numerical Rating Scale spasticity score was compared between treatment groups using analysis of covariance (ANCOVA). The model included treatment and centre as factors and baseline 11-point Numerical Rating Scale spasticity score as a covariate.p-value: 0.04895% CI: [-1.029, -0.004]ANCOVA
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.
Time frame: Days 0 - 52
Population: All randomised subjects who received at least one dose 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 Ashworth Scale Score at the End of Treatment | -0.64 units on a scale | Standard Deviation 0.56 |
| Placebo | Change From Baseline in Mean Ashworth Scale Score at the End of Treatment | -0.53 units on a scale | Standard Deviation 0.58 |
Comparison: The change in mean Ashworth Scale score was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline Ashworth Scale score as a covariate.p-value: 0.21895% CI: [-0.29, 0.07]ANCOVA
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..
Time frame: Day 7 and 52
Population: All randomised subjects who received at least one dose 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 Motricity Index Score for the Arms | 3.64 units on a scale | Standard Deviation 14.82 |
| Placebo | Change From Baseline in Mean Motricity Index Score for the Arms | 3.07 units on a scale | Standard Deviation 10.08 |
Comparison: The change in mean Motricity Index score was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline Motricity Index score as a covariate.p-value: 0.76695% CI: [-7.47, 10.07]ANCOVA
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.
Time frame: Day 7 and Day 52
Population: All randomised subjects who received at least one dose 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 Motricity Index Score for the Legs | 6.01 units on a scale | Standard Deviation 12.3 |
| Placebo | Change From Baseline in Mean Motricity Index Score for the Legs | 2.15 units on a scale | Standard Deviation 13.41 |
Comparison: The change in mean Motricity Index score was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline Motricity Index score as a covariate.p-value: 0.05495% CI: [-0.06, 7.78]ANCOVA
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.
Time frame: Days 0 - 52
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in Mean Spasm Frequency Score at the End of Treatment | -0.37 units on a scale | Standard Deviation 0.77 |
| Placebo | Change From Baseline in Mean Spasm Frequency Score at the End of Treatment | -0.26 units on a scale | Standard Deviation 0.74 |
Comparison: The change in mean spasm frequency score was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline spasm frequency score as a covariate.p-value: 0.14195% CI: [-0.39, 0.06]ANCOVA
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.
Time frame: Day 0-52
Population: All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Incidence of Adverse Events as a Measure of Subject Safety | 102 participants |
| Placebo | Incidence of Adverse Events as a Measure of Subject Safety | 46 participants |
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.
Time frame: Day 52
Population: All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Very Much Improved | 2 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Much Improved | 24 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Minimally Improved | 40 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | No Change | 38 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Minimally worse | 10 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Much Worse | 2 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Very Much Worse | 0 participants |
| Sativex | Patient's Global Impression of Change in Condition at the End of Treatment | Missing | 8 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Missing | 1 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Very Much Improved | 0 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Minimally worse | 5 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Much Improved | 11 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Very Much Worse | 0 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Minimally Improved | 20 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | Much Worse | 2 participants |
| Placebo | Patient's Global Impression of Change in Condition at the End of Treatment | No Change | 26 participants |
Comparison: The proportion of subjects who considered their condition 'Very Much Improved', 'Much Improved' or 'Minimally Improved' was compared between treatment groups using Fisher's Exact Test.p-value: 0.34995% CI: [-6.74, 23.66]Fisher Exact