Evaluate the Maintenance of Effect After Long-term Treatment With Sativex® in Subjects With Symptoms of Spasticity Due to Multiple Sclerosis

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00702468
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 2
• Duration (Months): 14
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the maintenance of effect after long-term treatment with Sativex® in subjects with symptoms of spasticity due to Multiple Sclerosis (MS) who have been receiving long-term benefit from treatment with Sativex®.

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

Detailed Description

This five week (one week baseline and four weeks randomised treatment period), multi-centre, placebo controlled, parallel group, randomized withdrawal study will evaluate the maintenance of effect after long-term treatment with Sativex® in subjects with symptoms of spasticity due to MS who have been receiving long-term benefit from treatment with Sativex®. Subjects will be selected from the Supply of Unlicensed Sativex® (SUS) or named patient supply programmes and must have been receiving Sativex® for at least 12 weeks prior to study entry. Following informed consent and screening, eligible subjects will enter the study (Visit 1, Day 1) and commence a seven day open label baseline period, before returning for a randomisation visit (Visit 2, Day 7), at which point they are randomised to receive either Sativex® or placebo (randomised withdrawal period). Subjects will return to the centre for an end of study visit at week five (Visit 3, Day 35) or earlier if they withdraw from treatment. Spasticity and sleep disruption review and dosing diaries will be completed each day from the start of the baseline period until completion or withdrawal.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Placebo Controlled, Parallel Group, Randomised Withdrawal Study of Subjects With Symptoms of Spasticity Due to Multiple Sclerosis Who Are Receiving Long-term Sativex®.
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sativex Sativex	Drug: Sativex; containing delta-9-tetrahydrocannabinol (THC)(27 mg/ml):cannabidiol (CBD)(25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Dose: 100 µl oromucosal spray, as required for symptom relief; Other Names: GW-1000-02
Placebo Comparator: Placebo Placebo	Drug: Placebo; Contains no active drug and is delivered in 100 microlitre actuations by a pump action oromucosal spray

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Who Experience Treatment Failure. [Week 1- Week 5]

   The time to treatment failure was calculated as the number of days from the first day of treatment up to the day of treatment failure. The day of treatment failure was the earliest of:the day of premature cessation of study medication;the first day of the longest period, ending on the last day of treatment, where the mean spasticity NRS had increased by at least 20% and at least 1 unit from the treatment baseline; the day of a clinically relevant increase in anti-spasticity or disease modifying medication. The number of subjects who failed treatment were calculated.

Secondary Outcome Measures

1. Change in Mean Daily Spasticity Severity as Measured on a Spasticity Severity 0-10 Numerical Rating Scale (NRS). [Baseline (Week 1) to Week 5]

   Spasticity NRS was completed daily by answering the following question: "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'. The change in mean spasticity severity NRS from baseline to end of study (last seven days)was calculated. A negative change from baseline indicates an improvement in spasticity.

2. Change in Modified Ashworth Scale. [Day 7 to Day 28]

   The Modified Ashworth Scale was completed at baseline and at the end of treatment at approximately the same time of day. All 20 muscle groups were assessed for spasticity (using a 0=no increase in muscle tone to 4 scale=affected part rigid in flexion or extensions), to result in a total score out of 80. The higher the score the worse the spasticity is. The change from baseline to end of study was assessed. The higher the score the better

3. Change in Motricity Index [Week 2 and Week 5]

   The Motricity Index involves assessing three movements in both the arms and the legs. In the arm the three movements are; pinch grip, elbow flexion and shoulder abduction and the three leg movements are, ankle dorsiflexion, knee extension and hip flexion. The total arm/leg score is then the addition of the score for the three arm/leg movements. One point is then added to each limb score so that the maximum score is 100 points. The higher the score the better the limb movement.

4. Timed 10-metre Walk. [Week 2 and Week 5]

   The time taken to travel 10 metres.

5. Daily Sleep Disruption NRS [Week 1- Week 5]

   Subjects will be asked: "On a scale of 0-10 please indicate how your spasticity disrupted your sleep last night" with the anchors 0 = 'did not disrupt sleep', 10 = 'completely disrupted (unable to sleep at all)'.

6. Subject Global Impressions of Change. [Day 35]

   At baseline subjects will write a brief description of their spasticity caused by MS and how it affects them emotionally, physically and their ability to function with day to day activities. This will be used to aid their memory before they answer the following question which is rated on a seven-point scale. "Please assess the change in your spasticity due to MS since immediately before receiving the first course of study treatment (Baseline) using the scale below" The markers are: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better.

7. Carer Global Impressions of Change for Functional Ability [Day 35]

   The main carer will be asked to assess the change in the subject's condition at the end of the study (completion or withdrawal). It consists of 2 question which is rated on a seven-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The carer will be asked since visit 2 (baseline): "How has the subject's general functional abilities changed?" "How has the subject's ease of transfer?" Not all subjects had carers; a total of 18 subjects from each treatment, of which 10 from Sativex and 14 from placebo completed it.

8. Carer Global Impressions of Change for Ease of Transfer [Day 35]

   The main carer will be asked to assess the change in the subject's condition at the end of the study (completion or withdrawal). It consists of 2 question which is rated on a seven-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The carer will be asked since visit 2 (baseline): "How has the subject's general functional abilities changed?" "How has the subject's ease of transfer?" Not all subjects had carers; a total of 18 subjects from each treatment, of which 10 from Sativex and 14 from placebo completed it.

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 MS.

• Received Sativex for the relief of spasticity for at least 12 weeks prior to screening and willing to stop dosing with their own supply for the duration of the study.

• Judged to have been receiving benefit from and shown tolerability to Sativex, in the investigators' and subjects' opinion.

• Takes a minimum dose of Sativex of two sprays per day.

• If receiving disease-modifying medications, these must have been at a stable dose for at least three months prior to screening, and willing to maintain this for the duration of the study.

• Has had a stable regimen for at least 30 days prior to study entry, for all medications and non-pharmacological therapies that may have an affect on spasticity; and willing to maintain this for the duration of the study (N.B. This should be three months prior to study entry, in the case of Interferon therapy).

• Willing to allow his or her general practitioner and consultant, if appropriate, to be notified of participation in the study.

• Willing for his or her name to be notified to the responsible authorities for participation in this study

Exclusion Criteria:

• Has any concomitant disease or disorder that has symptoms of spasticity or that may influence the subject's level of spasticity.

• Unable to rate their level of spasticity or distinguish it from other MS symptoms.

• Currently receiving a prohibited medication (Botulinum Toxin, or Acomplia (Rimonabant), and unwilling to stop or comply for the duration of the study or had received said medication/ therapy within three months prior to the screening visit.

• Unwilling to stop their own Sativex treatment for the duration of the study.

• Any known or suspected immediate family history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition.

• Has evidence of cardiomyopathy.

• Has experienced myocardial infarction or clinically relevant cardiac dysfunction within the last 12 months or has a cardiac disorder that, in the opinion of the investigator would put the subject at risk of a clinically relevant arrhythmia or myocardial infarction.

• Has a QT interval of > 450 ms (males) or > 470 ms (females) at Visit 1.

• Has a secondary or tertiary atrioventricular (AV) block or sinus bradycardia (HR <50bpm unless physiological) or sinus tachycardia (HR>110bpm) at Visit 1.

• Has a diastolic blood pressure of <50 mmHg or >105 mmHg (when measured in a sitting position at rest for five minutes) prior to randomisation

• Has impaired renal function e.g. creatinine clearance is lower than 50ml/min at Visit 1 and is indicative of renal impairment.

• Has significantly impaired hepatic function, at Visit 1, in the investigator's opinion.

• 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 and for three months thereafter.

• Subjects who have received any 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 has any abnormalities that, in the opinion of the investigator, would prevent them from safely participating in the study.

• Travel outside the UK planned during the study.

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

• Subjects previously randomised into this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	James Paget University Hospital NHS Foundation Trust	Gorleston on Sea	Norfolk	United Kingdom	NR31 6LA

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: William Notcutt, MB ChB, FRCA, James Paget University Hospital NHS Foundation Trust

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00702468
• Other Study ID Numbers: GWSP0702
• First Posted: Jun 20, 2008
• Last Update Posted: Jun 24, 2013
• Last Verified: Jun 1, 2013

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

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Period Title: Overall Study
STARTED	18	18
COMPLETED	15	2
NOT COMPLETED	3	16

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.	Total of all reporting groups
Overall Participants	18	18	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.7 (8.97)	54.4 (10.42)	57.1 (9.94)
Sex: Female, Male (Count of Participants)
Female	9 50%	12 66.7%	21 58.3%
Male	9 50%	6 33.3%	15 41.7%
Duration of Multiple Sclerosis (MS) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17.84 (8.48)	15.05 (10.07)	16.44 (9.29)
Duration of Spasticity (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.38 (9.90)	11.01 (8.25)	12.69 (9.14)
Expanded Disability Status Scale (EDSS) Score (Score on scale) [Median (Full Range) ]
Median (Full Range) [Score on scale]	7.0 (1.67)	7.0 (2.23)	7.0 (1.96)
Baseline Spasticity Numerical Rating Scale (NRS) Score (Score on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on scale]	3.60 (1.67)	4.13 (2.23)	3.87 (1.96)

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Who Experience Treatment Failure.
Description	The time to treatment failure was calculated as the number of days from the first day of treatment up to the day of treatment failure. The day of treatment failure was the earliest of:the day of premature cessation of study medication;the first day of the longest period, ending on the last day of treatment, where the mean spasticity NRS had increased by at least 20% and at least 1 unit from the treatment baseline; the day of a clinically relevant increase in anti-spasticity or disease modifying medication. The number of subjects who failed treatment were calculated.
Time Frame	Week 1- Week 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	18	18
Number [Participants]	8 44.4%	17 94.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.335
	Confidence Interval	(2-Sided) 90%; 0.162 to 0.691
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Mean Daily Spasticity Severity as Measured on a Spasticity Severity 0-10 Numerical Rating Scale (NRS).
Description	Spasticity NRS was completed daily by answering the following question: "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'. The change in mean spasticity severity NRS from baseline to end of study (last seven days)was calculated. A negative change from baseline indicates an improvement in spasticity.
Time Frame	Baseline (Week 1) to Week 5

Outcome Measure Data

Analysis Population Description

It is important to note that 17 of the placebo subjects withdrew from the study early. All subjects were accounted for in this analysis by use of a last-observation-carried-forward approach.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	18	18
Mean (Standard Deviation) [points on scale]	1.11 (1.92)	1.10 (1.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.720
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 90%; -1.22 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative difference indicates the comparison is in favour of Sativex

3. Secondary Outcome

Title	Change in Modified Ashworth Scale.
Description	The Modified Ashworth Scale was completed at baseline and at the end of treatment at approximately the same time of day. All 20 muscle groups were assessed for spasticity (using a 0=no increase in muscle tone to 4 scale=affected part rigid in flexion or extensions), to result in a total score out of 80. The higher the score the worse the spasticity is. The change from baseline to end of study was assessed. The higher the score the better
Time Frame	Day 7 to Day 28

Outcome Measure Data

Analysis Population Description

ITT. The reason for not including some of the data in this analysis is that a number of the subjects who withdrew early from the study restarted their own Sativex before the assessment was done.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	17	8
Mean (Standard Deviation) [score on scale]	21.5 (12.73)	22.9 (17.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 90%; -4.68 to 5.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Motricity Index
Description	The Motricity Index involves assessing three movements in both the arms and the legs. In the arm the three movements are; pinch grip, elbow flexion and shoulder abduction and the three leg movements are, ankle dorsiflexion, knee extension and hip flexion. The total arm/leg score is then the addition of the score for the three arm/leg movements. One point is then added to each limb score so that the maximum score is 100 points. The higher the score the better the limb movement.
Time Frame	Week 2 and Week 5

Outcome Measure Data

Analysis Population Description

ITT. The reason for not including some of the data in this analysis is that a number of the subjects who withdrew early from the study restarted their own Sativex before the assessment was done.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	16	7
Arm	72.4 (6.26)	92.5 (0)
Leg	43.6 (31.40)	47.0 (21.38)

5. Secondary Outcome

Title	Timed 10-metre Walk.
Description	The time taken to travel 10 metres.
Time Frame	Week 2 and Week 5

Outcome Measure Data

Analysis Population Description

ITT. Only 4 placebo subjects were included in the analysis and 11 of the Sativex subjects. The reason for not including some of the data in this analysis is that a number of the subjects who withdrew early from the study restarted their own Sativex before the assessment was done.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	11	4
Mean (Standard Deviation) [Seconds]	47.3 (50.29)	18.3 (4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	It is important to emphasise that only four placebo subjects were included in the analysis and 11 of the Sativex subjects - this sample size is too small for a meaningful comparison between treatments. The reason for not including some of the data in this analysis is that a number of the subjects who withdrew early from the study restarted their own Sativex before the assessment was done.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.81
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-1.78
	Confidence Interval	(2-Sided) 90%; -14.52 to 10.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative difference indicates the comparison is in favour of Sativex

6. Secondary Outcome

Title	Daily Sleep Disruption NRS
Description	Subjects will be asked: "On a scale of 0-10 please indicate how your spasticity disrupted your sleep last night" with the anchors 0 = 'did not disrupt sleep', 10 = 'completely disrupted (unable to sleep at all)'.
Time Frame	Week 1- Week 5

Outcome Measure Data

Analysis Population Description

It is important to note that 16 of the placebo subjects withdrew from the study early. All subjects were accounted for in this analysis by use of a last-observation-carried-forward approach.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	18	18
Mean (Standard Deviation) [points on scale]	2.90 (2.48)	3.36 (2.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	treatment difference
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 90%; -1.60 to 0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative difference indicates the comparison is in favour of Sativex

7. Secondary Outcome

Title	Subject Global Impressions of Change.
Description	At baseline subjects will write a brief description of their spasticity caused by MS and how it affects them emotionally, physically and their ability to function with day to day activities. This will be used to aid their memory before they answer the following question which is rated on a seven-point scale. "Please assess the change in your spasticity due to MS since immediately before receiving the first course of study treatment (Baseline) using the scale below" The markers are: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better.
Time Frame	Day 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	18	18
Very much better	0 0%	0 0%
Much better	0 0%	0 0%
Minimally better	0 0%	0 0%
No change	6 33.3%	1 5.6%
Minimally worse	6 33.3%	5 27.8%
Much worse	5 27.8%	9 50%
Very much worse	1 5.6%	3 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.562
	Confidence Interval	(2-Sided) 90%; 1.585 to 13.997
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Carer Global Impressions of Change for Functional Ability
Description	The main carer will be asked to assess the change in the subject's condition at the end of the study (completion or withdrawal). It consists of 2 question which is rated on a seven-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The carer will be asked since visit 2 (baseline): "How has the subject's general functional abilities changed?" "How has the subject's ease of transfer?" Not all subjects had carers; a total of 18 subjects from each treatment, of which 10 from Sativex and 14 from placebo completed it.
Time Frame	Day 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	10	14
Very Much Better	0	0
Much Better	0	0
Minimally Better	0	0
No Change	3	0
Minimally Worse	5	3
Much Worse	2	9
Very Much Worse	0	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	18.550
	Confidence Interval	(2-Sided) 90%; 3.942 to 118.773
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Carer Global Impressions of Change for Ease of Transfer
Description	The main carer will be asked to assess the change in the subject's condition at the end of the study (completion or withdrawal). It consists of 2 question which is rated on a seven-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The carer will be asked since visit 2 (baseline): "How has the subject's general functional abilities changed?" "How has the subject's ease of transfer?" Not all subjects had carers; a total of 18 subjects from each treatment, of which 10 from Sativex and 14 from placebo completed it.
Time Frame	Day 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.	Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations in 24 hours.
Measure Participants	10	14
Very Much Better	0	0
Much Better	0	0
Minimally Better	0	0
No Change	3	2
Minimally Worse	5	5
Much Worse	2	6
Very Much Worse	0	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1151
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.444
	Confidence Interval	(2-Sided) 90%; 0.948 to 13.718
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All AEs occurring from the time of consent to post study follow up (Visit 3) i.e. 5 weeks were collected. All deaths and SAEs occurring within 28 days of the final dose of sudy medication were also collected.
Adverse Event Reporting Description	All AEs occurring during the study were reported in the running logs at the back of the study case report form.
Arm/Group Title	Sativex		Placebo
Arm/Group Description	Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 actuations (delat9-tetrahydrocannabinol (THC)130 mg: 27 mg/ml: cannabidiol (CBD) 120 mg) in 24 hours.		Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose of eight actuations in any three hour period and 48 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	1/18 (5.6%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/18 (5.6%)		0/18 (0%)
Pain in extremity	1/18 (5.6%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/18 (83.3%)		14/18 (77.8%)
Gastrointestinal disorders
Diarrhoea	2/18 (11.1%)		1/18 (5.6%)
Mouth Ulceration	1/18 (5.6%)		0/18 (0%)
Stomach Discomfort	1/18 (5.6%)		0/18 (0%)
Vomitting	1/18 (5.6%)		0/18 (0%)
Nausea	0/18 (0%)		1/18 (5.6%)
General disorders
Fatigue	2/18 (11.1%)		0/18 (0%)
Pain	2/18 (11.1%)		7/18 (38.9%)
Application site pain	1/18 (5.6%)		0/18 (0%)
Asthenia	0/18 (0%)		1/18 (5.6%)
Gait disturbance	0/18 (0%)		1/18 (5.6%)
Infections and infestations
Urinary tract infection	3/18 (16.7%)		0/18 (0%)
Cystitis	1/18 (5.6%)		0/18 (0%)
Lower respiratory tract infection	1/18 (5.6%)		0/18 (0%)
Nasopharyngitis	1/18 (5.6%)		1/18 (5.6%)
Oral Herpes	1/18 (5.6%)		0/18 (0%)
Injury, poisoning and procedural complications
Contusion	0/18 (0%)		1/18 (5.6%)
Investigations
Gamma-glutamyltransferase increase	1/18 (5.6%)		0/18 (0%)
Metabolism and nutrition disorders
Anorexia	0/18 (0%)		1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Muscle spasms	3/18 (16.7%)		2/18 (11.1%)
Back pain	3/18 (16.7%)		1/18 (5.6%)
Musculoskeletal stiffness	2/18 (11.1%)		1/18 (5.6%)
Joint stiffness	1/18 (5.6%)		0/18 (0%)
Arthralgia	1/18 (5.6%)		0/18 (0%)
Pain in extremity	1/18 (5.6%)		0/18 (0%)
Musculoskeletal Discomfort	0/18 (0%)		1/18 (5.6%)
Neck pain	0/18 (0%)		1/18 (5.6%)
Sensation of heaviness	0/18 (0%)		1/18 (5.6%)
Nervous system disorders
Muscle spasticity	2/18 (11.1%)		3/18 (16.7%)
Dizziness	1/18 (5.6%)		0/18 (0%)
Somnolence	1/18 (5.6%)		0/18 (0%)
Tremor	1/18 (5.6%)		0/18 (0%)
Multiple Sclerosis	1/18 (5.6%)		0/18 (0%)
Hyperaesthesia	0/18 (0%)		1/18 (5.6%)
Paraesthesia	0/18 (0%)		1/18 (5.6%)
Trigeminal neuralgia	0/18 (0%)		2/18 (11.1%)
Psychiatric disorders
Depressed mood	0/18 (0%)		2/18 (11.1%)
Insomnia	0/18 (0%)		1/18 (5.6%)
Sleep disorder	0/18 (0%)		1/18 (5.6%)
Renal and urinary disorders
Haematuria	1/18 (5.6%)		0/18 (0%)
Hypertonic Bladder	0/18 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Cough	1/18 (5.6%)		0/18 (0%)
Epistaxis	1/18 (5.6%)		0/18 (0%)
Pharyngolaryngeal pain	1/18 (5.6%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Rash	1/18 (5.6%)		0/18 (0%)
Skin tightness	0/18 (0%)		1/18 (5.6%)
Vascular disorders
Hot flush	0/18 (0%)		1/18 (5.6%)
Hypertension	0/18 (0%)		1/18 (5.6%)

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.