A Study to Evaluate the Efficacy of Sativex in Relieving Symptoms of Spasticity Due to Multiple Sclerosis

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01599234
• Collaborator: (none)
• Enrollment: 337
• Location: 1
• Arms: 2
• Duration (Months): 9
• Patients Per Site Per Month: 37.3

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the efficacy of Sativex in relieving symptoms of spasticity in multiple sclerosis

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Sativex; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 337 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double Blind, Randomised, Placebo Controlled, Parallel Group Study of Sativex, in Subjects With Symptoms of Spasticity Due to Multiple Sclerosis.
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Dec 1, 2005
• Actual Study Completion Date: Dec 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sativex Active treatment	Drug: Sativex; 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.; Other Names: GW-1000-02
Placebo Comparator: Placebo Control	Drug: Placebo; 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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

5. 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.

6. 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.

7. 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.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Royal Berkshire and Battle Hospitals NHS Trust	Reading		United Kingdom	RG1 5AN

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Christine Collin, The Royal Berkshire and Battle Hospitals NHS Trust, London Road, Reading, Berkshire, RG1 5AN.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01599234
• Other Study ID Numbers: GWCL0403
• First Posted: May 15, 2012
• Last Update Posted: Jun 24, 2013
• Last Verified: Jun 1, 2013

• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Nabiximols

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Period Title: Overall Study
STARTED	167	170
COMPLETED	150	155
NOT COMPLETED	17	15

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.	Total of all reporting groups
Overall Participants	167	170	337
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	162 97%	168 98.8%	330 97.9%
>=65 years	5 3%	2 1.2%	7 2.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.0 (10.06)	47.1 (9.15)	47.5 (9.61)
Sex: Female, Male (Count of Participants)
Female	106 63.5%	101 59.4%	207 61.4%
Male	61 36.5%	69 40.6%	130 38.6%
Region of Enrollment (participants) [Number]
United Kingdom	65 38.9%	63 37.1%	128 38%
Czech Republic	102 61.1%	107 62.9%	209 62%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	166	169
Mean (Standard Deviation) [units on a scale]	-1.22 (1.76)	-0.91 (1.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.220
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.23
	Confidence Interval	() 95%; -0.59 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	166	169
Number [participants]	51 30.5%	42 24.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.341
	Confidence Interval	(2-Sided) 95%; 0.830 to 2.167
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	156	160
Mean (Standard Deviation) [units on a scale]	-3.3 (9.25)	-2.8 (7.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.857
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -1.94 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	124	139
Mean (Standard Deviation) [units on a scale]	-0.7 (2.85)	-0.6 (2.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The two groups were compared using ANCOVA with baseline severity as a covariate and study centre and treatment group as factors.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.734
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Incidence of Adverse Events as a Measure of Subject Safety
Description	The number of subjects who experienced and adverse event during the course of the study is presented
Time Frame	0-15 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	167	170
Number [participants]	156 93.4%	132 77.6%

6. Secondary Outcome

Title	Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	115	120
Mean (Standard Deviation) [time (seconds)]	-2.1 (17.37)	9.3 (63.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.624
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -2.0 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Carer Global Impression of Change at the End of Treatment
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	167	170
Number [participants]	72 43.1%	56 32.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.270
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.248
	Confidence Interval	(2-Sided) 95%; 0.842 to 1.849
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	162	165
Mean (Standard Deviation) [units on a scale]	-0.1 (10.26)	0.5 (8.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.867
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -1.95 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	166	169
Number [participants]	21 12.6%	18 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.569
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.215
	Confidence Interval	(2-Sided) 95%; 0.622 to 2.373
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Arm/Group Title	Sativex		Placebo
Arm/Group Description	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.		Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
All Cause Mortality
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/167 (9%)		7/170 (4.1%)
General disorders
Irritability	1/167 (0.6%)		0/170 (0%)
Asthenia	1/167 (0.6%)		0/170 (0%)
Infections and infestations
Urinary Tract Infection	3/167 (1.8%)		2/170 (1.2%)
Orchitis	1/167 (0.6%)		0/170 (0%)
Erysipelas	0/167 (0%)		2/170 (1.2%)
Sepsis	0/167 (0%)		2/170 (1.2%)
Injury, poisoning and procedural complications
Burns third degree	1/167 (0.6%)		0/170 (0%)
Fall	1/167 (0.6%)		0/170 (0%)
Foot Fracture	1/167 (0.6%)		0/170 (0%)
Road Traffic Accident	0/167 (0%)		1/170 (0.6%)
Metabolism and nutrition disorders
Dehydration	1/167 (0.6%)		0/170 (0%)
Tetany	0/167 (0%)		1/170 (0.6%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	1/167 (0.6%)		0/170 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	1/167 (0.6%)		0/170 (0%)
Metastases to Liver	1/167 (0.6%)		0/170 (0%)
Oesophageal Adenocarcinoma Metastatic	1/167 (0.6%)		0/170 (0%)
Nervous system disorders
Multiple Sclerosis Relapse	2/167 (1.2%)		1/170 (0.6%)
Epilepsy	1/167 (0.6%)		0/170 (0%)
Muscle Spasticity	1/167 (0.6%)		0/170 (0%)
Somnolence	1/167 (0.6%)		0/170 (0%)
Psychiatric disorders
Aggression	1/167 (0.6%)		0/170 (0%)
Agitation	1/167 (0.6%)		0/170 (0%)
Confusional State	1/167 (0.6%)		0/170 (0%)
Depression	1/167 (0.6%)		0/170 (0%)
Drug Dependence	1/167 (0.6%)		0/170 (0%)
Insomnia	1/167 (0.6%)		0/170 (0%)
Paranoia	1/167 (0.6%)		0/170 (0%)
Suicidal Ideation	1/167 (0.6%)		0/170 (0%)
Delusions	1/167 (0.6%)		0/170 (0%)
Depression Worsened	1/167 (0.6%)		0/170 (0%)
Renal and urinary disorders
Urinary Retention	1/167 (0.6%)		1/170 (0.6%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/167 (0.6%)		0/170 (0%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	1/167 (0.6%)		0/170 (0%)
Vascular disorders
Peripheral Ischaemia	1/167 (0.6%)		0/170 (0%)
Phlebothrombosis	0/167 (0%)		1/170 (0.6%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	156/167 (93.4%)		132/170 (77.6%)
Ear and labyrinth disorders
Vertigo	19/167 (11.4%)		7/170 (4.1%)
Gastrointestinal disorders
Nausea	53/167 (31.7%)		17/170 (10%)
Dry Mouth	24/167 (14.4%)		7/170 (4.1%)
Diarrhoea	15/167 (9%)		10/170 (5.9%)
Vomiting	9/167 (5.4%)		0/170 (0%)
Dyspepsia	7/167 (4.2%)		0/170 (0%)
Constipation	7/167 (4.2%)		0/170 (0%)
General disorders
Fatigue	42/167 (25.1%)		32/170 (18.8%)
Asthenia	26/167 (15.6%)		11/170 (6.5%)
Feeling Abnormal	6/167 (3.6%)		1/170 (0.6%)
Malaise	6/167 (3.6%)		1/170 (0.6%)
Infections and infestations
Urinary Tract Infection Not Otherwise Specified	19/167 (11.4%)		21/170 (12.4%)
Musculoskeletal and connective tissue disorders
Back Pain	7/167 (4.2%)		1/170 (0.6%)
Muscle Spasms	7/167 (4.2%)		5/170 (2.9%)
Nervous system disorders
Dizziness	53/167 (31.7%)		17/170 (10%)
Somnolence	24/167 (14.4%)		7/170 (4.1%)
Muscle Spasticity	17/167 (10.2%)		13/170 (7.6%)
Headache	15/167 (9%)		10/170 (5.9%)
Dysgeusia	9/167 (5.4%)		0/170 (0%)
Disturbance in Attention	7/167 (4.2%)		0/170 (0%)
Dysarthria	7/167 (4.2%)		0/170 (0%)
Multiple Sclerosis Relapse	5/167 (3%)		5/170 (2.9%)
Psychiatric disorders
Insomnia	4/167 (2.4%)		5/170 (2.9%)
Anxiety	1/167 (0.6%)		5/170 (2.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.