A Study of the Safety and Effectiveness of Sativex®, for the Relief of Symptoms of Spasticity in Subjects, From Phase B, With Multiple Sclerosis (MS)

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00681538
• Collaborator: (none)
• Enrollment: 572
• Location: 1
• Arms: 2
• Duration (Months): 12
• Patients Per Site Per Month: 47.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether Sativex® versus Placebo is effective in the relief of symptoms of spasticity in subjects with multiple sclerosis, who have been identified as having a capacity to respond to Sativex.

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

Detailed Description

This 19 week, multicentre study was conducted in two phases. Phase A was a preliminary, single-blind four week treatment period to identify subjects with a capacity to respond to Sativex; eligible, consenting subjects entered a seven day screening period prior to returning to the study centre to begin a four week single-blind course of Sativex treatment. At the end of this phase, subjects' response to Sativex was assessed; those with the capacity to respond (i.e. at least a 20% reduction in mean 0-10 point numerical rating scale (NRS) spasticity score between screening and the end of the four week Phase A treatment) were eligible for entry into Phase B while those who did not respond took no further part in the study other than a follow up visit 14 days later.

Phase B was a 12 week double-blind, randomised, placebo controlled, parallel group study with visits at 28 day intervals and a final follow up visit 14 days after completion or withdrawal.

The level of spasticity, spasm frequency and sleep disruption were collected each day during the entire study via an interactive voice response system (IVRS). In addition, study medication dosing data were recorded via IVRS throughout Phases A and B. Assessments of other secondary and functional measures of spasticity, safety and tolerability, QOL (quality of life) and mood were also gathered throughout the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 572 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Two-phase, Phase 3 Study of the Safety and Efficacy of Sativex, in the Symptomatic Relief of Spasticity in Subjects With Spasticity Due to Multiple Sclerosis: Phase A - Single-blind Response Assessment; Phase B - Double-blind, Randomised, Placebo Controlled, Parallel Group Study.
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sativex Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L. Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours	Drug: Sativex®; containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Maximum dose within any 24-hour interval is 12 sprays (THC 32.4 mg: CBD 30 mg); Other Names: GW-1000-02
Placebo Comparator: Placebo Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.	Drug: Placebo; containing ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring and colouring FD&C Yellow No.5 (E102 tartrazine) (0.0260%), FD&C Yellow No.6 (E110 sunset yellow) (0.0038%), FD&C Red No. 40 (E129 Allura red AC) (0.00330%) and FD&C Blue No.1 (E133 Brilliant blue FCF) (0.00058%).; Other Names: GA0034

Outcome Measures

Primary Outcome Measures

1. The Change in Mean Spasticity Numerical Rating Scale (NRS) Score From Baseline to End of Treatment (Phase B). [Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)]

   Subjects were asked "On a scale of '0 to 10' please indicate the average level of your spasticity over the last 24 hours" with the anchors: 0 = 'no spasticity' and 10 = 'worst possible spasticity'. They were asked to relate 'no spasticity' to the time prior to the onset of their spasticity.

Secondary Outcome Measures

1. Number of Subjects Showing an Improvement of at Least 30% or 50% in Their Mean NRS Spasticity Score (Phase B) From Baseline. [Baseline (Day 1) - End of treatment (last 7 days of Week 17)]

   A subject was classified as a responder in the evaluable period provided they did not withdraw due to lack of efficacy and achieved at least a 30% or 50% reduction (i.e. improvement) in the mean NRS spasticity score from baseline (Day 1) to the end of treatment(last 7 days of Week 17 Phase B). All other subjects and subjects without evaluable data were considered non-responders.

2. Change in Spasm Frequency (Number of Spasms Per Day) From Baseline to End of Treatment (Phase B). [Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)]

   The subjects' baseline spasm frequency was the mean of the last seven days scores (Week 4) of Phase A treatment. The variable for analysis was the change in mean spasm frequency from baseline to the end of treatment (last 7 days of Week 17 Phase B).

3. Change in Sleep Disruption (Daily 11-point NRS) From Baseline to End of Treatment (Phase B). [Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)]

   The sleep disruption NRS score was recorded by subjects via a daily call to the interactive voice response system at bedtime. Subjects were asked "On a scale of '0 to 10' please indicate how you your spasticity disrupted your sleep last night" with the anchors: 0 = 'did not disrupt sleep' and 10 = 'completely disrupted (unable to sleep at all)'.

4. Change in Spasticity as Measured Using the Modified Ashworth Scale From Baseline to End of Treatment (Phase B). [Baseline (End of Week 4) - End of treatment (End of Week 17)]

   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.

5. Change in Motricity Index Score From Baseline to End of Treatment (Phase B)for Affected Limbs. [Baseline (End of Week 4) - End of treatment (End of Week 17)]

   Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. Leg - 3 movements were ankle dorsiflexion, knee extension and hip flexion. The total arm and leg score was the addition of the score for the 3 arm movements and 3 leg movements, respectively. One point was then added to each limb score to give a maximum score of 100; minimum was 1 point. Where both arms (or both legs) 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.

6. Change in Timed 10-metre Walk From Baseline to End of Treatment (Phase B). [Baseline (End of Week 4) - End of treatment (End of Week 17)]

   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.

7. Subject Global Impressions of Change at End of Treatment (Phase B). [End of Treatment (WeeK 17)]

8. Carer Global Impressions of Change at of Treatment (Phase B). [End of treatment (Week 17)]

9. Carer Ease of Transfer Global Impressions of Change at End of Treatment (Phase B). [End of treatment (week 17)]

10. Physician Global Impressions of Change at End of Treatment (Phase B). [End of treatment (week 17)]

11. Change EuroQoL Quality of Life Questionnaire (EQ-5D)From Baseline to End of Treatment (Phase B) [[Baseline (End of Week 4) - End of treatment (End of Week 17)]

    The EQ-5D questionnaire provided two outcomes: A weighted health state index visual analogue scale (VAS) A self-rated health status VAS EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition. The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing.

12. Mood Assessment: Change in Beck Depression Inventory - II (BDI-II)From Baseline to End of Treatment (Phase B) [Baseline (End of week 4) - end of treatment (end of week 17)]

    This was a 21-question multiple choice self-report inventory. Subjects' responses to the 21 questions were assigned a score ranging from zero to three, indicating the severity of the symptom. The sum of all BDI-II question scores indicated the severity of depression; score range 0-63. An decrease in score indicates an improvement in condition.

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 written informed consent for participation in the study.

• Male or female, aged 18 years or above.

• Subject is able (in the investigator's opinion) and willing to comply with all study requirements.

• Diagnosed with any disease sub-type of MS of at least six months duration.

• Spasticity due to MS of at least three months duration, which is not wholly relieved with current anti-spasticity therapy, and which is expected to remain stable for the duration of the study.

• Subject fulfils at least one of the two criteria below. Subject must be either: Currently established on a regular dose of anti-spasticity therapy or Previously tried and failed, or could not tolerate suitable anti-spasticity therapy.

• Subject is currently receiving a stable regimen (for at least 30 days prior to study entry) of all medications that may have an effect on spasticity; and willing to maintain this for the duration of the study. If the subject is currently taking disease-modifying medication, this must be at a stable dose for at least three months prior to the screening visit; the dose must also remain stable for the duration of the study.

• Willing for his or her name to be notified to his or her primary care physician, and consultant and the responsible authorities for participation in this study, as applicable.

Exclusion Criteria:

• Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the subject's level of spasticity.

• Subject's medical history suggests that relapse/remission is likely to occur during the study (over the next 19 weeks) which, in the opinion of the investigator, is expected to influence the subject's spasticity.

• Currently receiving a prohibited medication and unwilling to stop for the stated period prior to the screening visit and for the duration of the study.

• Any known or suspected history of: schizophrenia or other psychotic illness;diagnosed dependence disorder;poorly controlled epilepsy or recurrent seizures;hypersensitivity to cannabinoids.

• Significant cardiac, renal or hepatic disease.

• Female subjects of child bearing potential and male subjects whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for three months thereafter.

• Female subject who is pregnant, lactating or planning pregnancy during the course of the study or for three months thereafter.

• Subjects who have 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, or may influence the result of the study, or the subject's ability to participate in the study.

• Following a physical examination, the subject has any abnormalities that, in the opinion of the investigator, would prevent them from safely participating in the study.

• Unwilling to abstain from donation of blood during the study.

• Travel outside the country of residence planned during the study.

• Subjects previously randomised into this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Neurology, Northampton General Hospital	Cliftonville	Northampton	United Kingdom	NN1 5BD

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Paul Davies, MRCP, FRCP, Department of Neurology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00681538
• Other Study ID Numbers: GWSP0604
• First Posted: May 21, 2008
• Last Update Posted: Mar 27, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Jazz Pharmaceuticals: Spasticity; Multiple Sclerosis
• Additional relevant MeSH terms: Muscle Spasticity; Multiple Sclerosis; Sclerosis; Nabiximols

Study Results

Participant Flow

Pre-assignment Detail	Only those subjects who were deemed responders to Sativex from Phase A (i.e. at least a 20% reduction in mean 0-10 point numerical rating scale (NRS) spasticity score between screening and the end of the four week Phase A treatment) were eligible to enter Phase B of the study.

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Period Title: Phase A- 4 Weeks Single Blind
STARTED	572	0
COMPLETED	538	0
NOT COMPLETED	34	0
Period Title: Phase A- 4 Weeks Single Blind
STARTED	124	117
COMPLETED	109	115
NOT COMPLETED	15	2

Baseline Characteristics

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)	Total
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.	Total of all reporting groups
Overall Participants	124	117	241
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	49.1 (9.09)	48.1 (9.59)	48.6 (9.33)
Sex: Female, Male (Count of Participants)
Female	72 58.1%	73 62.4%	145 60.2%
Male	52 41.9%	44 37.6%	96 39.8%
Duration of Multiple Sclerosis Phase B (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.3 (8.29)	11.8 (7.38)	12.6 (7.88)
Duration of Spasticity Phase B (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.6 (6.89)	6.7 (5.40)	7.7 (6.27)
Expanded Disability Status Scale (EDSS)- Phase B (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	6.5 (1.46)	6.0 (1.44)	6.0 (1.45)
Baseline Spasticity numerical rating scale (NRS) Score Phase B (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	3.87 (1.49)	3.92 (1.55)	3.90 (1.51)

Outcome Measures

1. Primary Outcome

Title	The Change in Mean Spasticity Numerical Rating Scale (NRS) Score From Baseline to End of Treatment (Phase B).
Description	Subjects were asked "On a scale of '0 to 10' please indicate the average level of your spasticity over the last 24 hours" with the anchors: 0 = 'no spasticity' and 10 = 'worst possible spasticity'. They were asked to relate 'no spasticity' to the time prior to the onset of their spasticity.
Time Frame	Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	124	117
Mean (Standard Deviation) [Points on scale]	3.68 (1.83)	4.56 (2.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.84
	Confidence Interval	(2-Sided) 95%; -1.29 to -0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Subjects Showing an Improvement of at Least 30% or 50% in Their Mean NRS Spasticity Score (Phase B) From Baseline.
Description	A subject was classified as a responder in the evaluable period provided they did not withdraw due to lack of efficacy and achieved at least a 30% or 50% reduction (i.e. improvement) in the mean NRS spasticity score from baseline (Day 1) to the end of treatment(last 7 days of Week 17 Phase B). All other subjects and subjects without evaluable data were considered non-responders.
Time Frame	Baseline (Day 1) - End of treatment (last 7 days of Week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	124	117
30% improvement in spasticity	92 74.2%	60 51.3%
50% improvement in spasticity	56 45.2%	39 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments	30% responders
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.731
	Confidence Interval	(2-Sided) 95%; 1.589 to 4.694
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio>1 indicates an improvement in favour of Sativex

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments	50% Responders
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0612
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.647
	Confidence Interval	(2-Sided) 95%; 0.977 to 2.777
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio>1 indicates an improvement in favour of Sativex

3. Secondary Outcome

Title	Change in Spasm Frequency (Number of Spasms Per Day) From Baseline to End of Treatment (Phase B).
Description	The subjects' baseline spasm frequency was the mean of the last seven days scores (Week 4) of Phase A treatment. The variable for analysis was the change in mean spasm frequency from baseline to the end of treatment (last 7 days of Week 17 Phase B).
Time Frame	Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	124	117
Mean (Standard Deviation) [Spasms per day]	5.56 (10.33)	7.70 (12.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0046
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-2.53
	Confidence Interval	(2-Sided) 95%; -4.27 to -0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative difference indicates an improvement in spasm frequency in favour of Sativex.

4. Secondary Outcome

Title	Change in Sleep Disruption (Daily 11-point NRS) From Baseline to End of Treatment (Phase B).
Description	The sleep disruption NRS score was recorded by subjects via a daily call to the interactive voice response system at bedtime. Subjects were asked "On a scale of '0 to 10' please indicate how you your spasticity disrupted your sleep last night" with the anchors: 0 = 'did not disrupt sleep' and 10 = 'completely disrupted (unable to sleep at all)'.
Time Frame	Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	124	117
Mean (Standard Deviation) [Points on scale]	1.71 (1.65)	2.65 (2.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	-0.88
	Confidence Interval	(2-Sided) 95%; -1.25 to -0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative difference indicates an improvement in sleep disruption in favour of Sativex.

5. Secondary Outcome

Title	Change in Spasticity as Measured Using the Modified Ashworth Scale From Baseline to End of Treatment (Phase B).
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	Baseline (End of Week 4) - End of treatment (End of Week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	121	116
Mean (Standard Deviation) [Score on scale]	-0.1 (8.25)	1.8 (7.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0939
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95%; -3.80 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative difference indicates an improvement in spasticity in favour of Sativex.

6. Secondary Outcome

Title	Change in Motricity Index Score From Baseline to End of Treatment (Phase B)for Affected Limbs.
Description	Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. Leg - 3 movements were ankle dorsiflexion, knee extension and hip flexion. The total arm and leg score was the addition of the score for the 3 arm movements and 3 leg movements, respectively. One point was then added to each limb score to give a maximum score of 100; minimum was 1 point. Where both arms (or both legs) 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	Baseline (End of Week 4) - End of treatment (End of Week 17)

Outcome Measure Data

Analysis Population Description

For Arm subject numbers were 23 for Sativex and 22 for placebo. For Leg subject numbers were 91 for Sativex and 92 for placebo.

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	124	117
Arm	0.5 (15.62)	0.8 (10.60)
Leg	-1.3 (7.64)	-1.0 (9.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments	For Arm
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.56
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	-2.85
	Confidence Interval	(2-Sided) 95%; -12.75 to 7.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	A positive treatment difference indicates an improvement in favour of Sativex.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments	For leg
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -2.56 to 2.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	A positive treatment difference indicates an improvement in favour of Sativex.

7. Secondary Outcome

Title	Change in Timed 10-metre Walk From Baseline to End of Treatment (Phase B).
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	Baseline (End of Week 4) - End of treatment (End of Week 17)

Outcome Measure Data

Analysis Population 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.

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	84	83
Mean (Standard Deviation) [Seconds]	-2.3 (8.38)	2.0 (15.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0687
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-3.34
	Confidence Interval	(2-Sided) 95%; -6.95 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative treatment difference indicates an improvement in favour of Sativex.

8. Secondary Outcome

Title	Subject Global Impressions of Change at End of Treatment (Phase B).
Time Frame	End of Treatment (WeeK 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	121	117
Very much better	14 11.3%	10 8.5%
Much better	40 32.3%	28 23.9%
Minimally better	39 31.5%	33 28.2%
No change	17 13.7%	35 29.9%
Minimally worse	4 3.2%	7 6%
Much worse	6 4.8%	1 0.9%
Very much worse	1 0.8%	3 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0234
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.703
	Confidence Interval	(2-Sided) 95%; 1.075 to 2.698
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio > 1 indicates an improvement in favour of Sativex.

9. Secondary Outcome

Title	Carer Global Impressions of Change at of Treatment (Phase B).
Time Frame	End of treatment (Week 17)

Outcome Measure Data

Analysis Population Description

Sample sizes were reduced as not all subjects had a Carer to make this assessment.

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	71	69
Very much better	2 1.6%	0 0%
Much better	15 12.1%	11 9.4%
Minimally better	31 25%	19 16.2%
No change	16 12.9%	24 20.5%
Minimally worse	4 3.2%	8 6.8%
Much worse	2 1.6%	5 4.3%
Very much worse	1 0.8%	2 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.400
	Confidence Interval	(2-Sided) 95%; 1.297 to 4.443
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio > 1 indicates an improvement in favour of Sativex.

10. Secondary Outcome

Title	Carer Ease of Transfer Global Impressions of Change at End of Treatment (Phase B).
Time Frame	End of treatment (week 17)

Outcome Measure Data

Analysis Population Description

Sample sizes were reduced as not all subjects had a Carer to make this assessment.

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	71	69
Very much better	1 0.8%	1 0.9%
Much better	9 7.3%	8 6.8%
Minimally better	27 21.8%	14 12%
No change	24 19.4%	30 25.6%
Minimally worse	6 4.8%	11 9.4%
Much worse	4 3.2%	3 2.6%
Very much worse	0 0%	2 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0613
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.792
	Confidence Interval	(2-Sided) 95%; 0.973 to 3.301
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio > 1 indicates an improvement in favour of Sativex.

11. Secondary Outcome

Title	Physician Global Impressions of Change at End of Treatment (Phase B).
Time Frame	End of treatment (week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	122	117
Very much better	6 4.8%	8 6.8%
Much better	44 35.5%	29 24.8%
Minimally better	45 36.3%	26 22.2%
No change	17 13.7%	37 31.6%
Minimally worse	4 3.2%	13 11.1%
Much worse	6 4.8%	4 3.4%
Very much worse	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.958
	Confidence Interval	(2-Sided) 95%; 1.232 to 3.112
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio > 1 indicates an improvement in favour of Sativex.

12. Secondary Outcome

Title	Change EuroQoL Quality of Life Questionnaire (EQ-5D)From Baseline to End of Treatment (Phase B)
Description	The EQ-5D questionnaire provided two outcomes: A weighted health state index visual analogue scale (VAS) A self-rated health status VAS EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition. The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing.
Time Frame	[Baseline (End of Week 4) - End of treatment (End of Week 17)

Outcome Measure Data

Analysis Population Description

EQ-5D Health State Index Sativex n=117 and placebo n=111. EQ-5D Health Status VAS Sativex n=121 and placebo n=117.

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	124	117
EQ-5D Health State Index	0.003 (0.155)	-0.013 (0.176)
EQ-5D Health Status VAS	-0.7 (15.3)	-2.8 (19.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments	For Health State Index
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2836
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	A positive difference indicates an improvement in favour of Sativex.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments	Health Status VAS
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5644
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; -3.01 to 5.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	A positive difference indicates an improvement in favour of Sativex.

13. Secondary Outcome

Title	Mood Assessment: Change in Beck Depression Inventory - II (BDI-II)From Baseline to End of Treatment (Phase B)
Description	This was a 21-question multiple choice self-report inventory. Subjects' responses to the 21 questions were assigned a score ranging from zero to three, indicating the severity of the symptom. The sum of all BDI-II question scores indicated the severity of depression; score range 0-63. An decrease in score indicates an improvement in condition.
Time Frame	Baseline (End of week 4) - end of treatment (end of week 17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex (Phase B)	Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Measure Participants	114	113
Mean (Standard Deviation) [Score on scale]	0.5 (5.01)	0.4 (6.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex (Phase B), Placebo (Phase B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9369
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -1.62 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative difference indicates an improvement in depression in favour of Sativex.

Adverse Events

Time Frame	All AEs occurring from Baseline(week 4) to end of treatment (Week 17) (Phase B) i.e. 13 weeks were collected. All deaths and SAEs occurring within 28 days of the final dose of study medication were also collected.
Adverse Event Reporting Description	All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Arm/Group Title	Sativex (Phase B)		Placebo (Phase B)
Arm/Group Description	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.		Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
All Cause Mortality
	Sativex (Phase B)		Placebo (Phase B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sativex (Phase B)		Placebo (Phase B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/124 (4.8%)		1/117 (0.9%)
Infections and infestations
Bronchopneumonia	1/124 (0.8%)		0/117 (0%)
Septic shock	1/124 (0.8%)		0/117 (0%)
Urosepsis	1/124 (0.8%)		0/117 (0%)
Nervous system disorders
MS Relapse	1/124 (0.8%)		0/117 (0%)
Balance disorder	0/124 (0%)		1/117 (0.9%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/124 (0.8%)		0/117 (0%)
Psychiatric disorders
Suicidal Ideation	1/124 (0.8%)		0/117 (0%)
Other (Not Including Serious) Adverse Events
	Sativex (Phase B)		Placebo (Phase B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/124 (53.2%)		40/117 (34.2%)
Ear and labyrinth disorders
Vertigo	7/124 (5.6%)		1/117 (0.9%)
Gastrointestinal disorders
Diarrhoea	3/124 (2.4%)		6/117 (5.1%)
Dry mouth	4/124 (3.2%)		1/117 (0.9%)
Nausea	5/124 (4%)		2/117 (1.7%)
Abdominal pain upper	4/124 (3.2%)		0/117 (0%)
General disorders
Fatigue	6/124 (4.8%)		1/117 (0.9%)
Infections and infestations
Urinary tract infection	9/124 (7.3%)		12/117 (10.3%)
Nasopharyngitis	4/124 (3.2%)		3/117 (2.6%)
Musculoskeletal and connective tissue disorders
Muscle spasms	7/124 (5.6%)		8/117 (6.8%)
Back pain	5/124 (4%)		4/117 (3.4%)
Pain in extremity	0/124 (0%)		5/117 (4.3%)
Nervous system disorders
Headache	2/124 (1.6%)		5/117 (4.3%)
Muscle spasticity	3/124 (2.4%)		4/117 (3.4%)
Somnolence	4/124 (3.2%)		1/117 (0.9%)
Dizziness	4/124 (3.2%)		0/117 (0%)
MS relapse	4/124 (3.2%)		1/117 (0.9%)
Psychiatric disorders
Euphoric mood	4/124 (3.2%)		1/117 (0.9%)

Limitations/Caveats

[Not Specified]

More Information

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.