A Study of Sativex in the Treatment of Central Neuropathic Pain Due to Multiple Sclerosis

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01604265
• Collaborator: (none)
• Enrollment: 66
• Location: 1
• Arms: 2
• Duration (Months): 5
• Patients Per Site Per Month: 13.1

Study Details

Study Description

Brief Summary

To investigate the ability of Sativex to relieve central neuropathic pain in multiple sclerosis subjects.

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

Detailed Description

Multiple sclerosis subjects with a clinical diagnosis of central neuropathic pain entered a seven to ten day baseline period, followed by a four week double blind, randomised, parallel group comparison of Sativex, with placebo. The study medication was self-titrated to symptom resolution or maximum tolerated or allowed dose. Visits occurred at the end of weeks one and four (end of the study) or earlier if they withdrew. A follow-up visit occurred 30 - 40 days after completion or withdrawal.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double Blind, Randomised, Parallel Group, Placebo Controlled Study of Sativex in the Treatment of Central Neuropathic Pain in Multiple Sclerosis.
• Study Start Date: Mar 1, 2002
• Actual Primary Completion Date: Aug 1, 2002
• Actual Study Completion Date: Aug 1, 2002

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo control.	Drug: Placebo; Contained peppermint oil, 0.05% (v/v), quinoline yellow, 0.005% (w/v), sunset yellow, 0.0025% (w/v), in ethanol:propylene glycol (50:50) excipient. Each actuation delivered 100 μl. The maximum permitted dose of study medication was eight actuations in any three hour period, and 48 actuations in any 24 hour period.
Experimental: Sativex Active treatment.	Drug: Sativex; Contained delta-9-tetrahydrocannabinol (THC), (25 mg/ml):cannabidiol (CBD), (25 mg/ml) as extract of Cannabis sativa L., with peppermint oil, 0.05% (v/v), in ethanol:propylene glycol (50:50) excipient. Each actuation delivered 100 μl (THC 2.5 mg and CBD 2.5 mg). The maximum permitted dose of study medication was eight actuations in any three hour period, and 48 actuations in any 24 hour period.; Other Names: GW-1000-02

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Mean Pain 0-10 Numerical Rating Scale Score at the End of Treatment (4 Weeks) [0 - 4 weeks]

   The average pain Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain in the last 24 hours" where 0 = no pain and 10 = pain as bad as you can imagine. A negative value indicates an improvement in pain score from baseline.

Secondary Outcome Measures

1. Change From Baseline in the Mean 0-10 Numerical Rating Scale Sleep Score at the End of Treatment (4 Weeks) [0 - 4 weeks]

   Each day patients were asked to record in their subject diary, whether or not they were "woken due to nerve pain last night", using a 0-10 Numerical Rating Scale sleep score where zero equated with "did not disrupt sleep" and 10 meant "completely disrupts sleep (unable to sleep due to pain)". A decrease in score from baseline indicates an improvement.

2. Subject Global Impression of Change at Week 4 [4 weeks]

   A 7-point Likert-type scale was used, with the question: 'Please assess the improvement in overall condition since the start of the study using the scale below' with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". At Visit 2 (Baseline) patients wrote a brief description of their condition which was used at Week 4 to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported.

3. Change From Baseline in the Mean Neuropathic Pain Scale 0-10 Numerical Rating Scale Score at the End of Treatment (Week 4) [Baseline to end of treatment (0 - 4 weeks).]

   The Neuropathic Pain Scale score is the 0-100 sum of 10 individual pain scores (0-10 Numerical Rating Scale, 0= no pain to 10 = worst pain imaginable). A negative change from baseline indicates an improvement in pain.

4. Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Selective Reminding' at the End of Treatment (Week 4) [Baseline to end of study (0 - 4 weeks)]

   The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance.

5. Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for '10/36 Spatial Recall' at the End of Treatment (Week 4) [Weeks 0 - 4]

   The 10/36 Spatial Recall Test assesses visual spatial learning and delayed recall. Patients are asked to view a 6 x 6 checkerboard with ten checkers for 10 seconds. They are then asked to recreate the pattern viewed on a blank checkerboard. The number of correct responses from three immediate trials and one delayed trial (7 minute delay) are recorded. The Total number of correct responses is the unweighted sum from the four trials. The score for the 10/36 spatial recall test was the unweighted average of four individual study results (min=0 and max=40). A higher score indicates better cognitive performance.

6. Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Symbol Digit Modalities' at the End of Treatment (Week 4) [0 - 4 weeks]

   The Symbol Digit Modalities Test measures complex attention and concentration in a task which also requires speed and accuracy in visual search and scanning. Patients are required to associate symbols with numbers and quickly generate the number when shown the symbol. The summary endpoint is the number of correct responses in 90 seconds. The symbol digit modalities test had a min of 0 and max score of 99. A higher score indicates better cognitive performance.

7. Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for the 'Paced Auditory Serial Addition Task' (PASAT) at the End of Treatment (Week 4) [0 - 4 weeks]

   The Paced Auditory Serial Addition Task assesses sustained attention and concentration. A pre-recorded tape is used to present two series of 60 numbers, one every 3 seconds and one every 2 seconds. Patients are asked to add each number to the one immediately preceding it and give the result. The task summary score is the percentage of correct answers is calculated. The PASAT score range was 0% to 100%. Higher scores indicate a better cognitive performance.

8. Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Word List Generation' at the End of Treatment (4 Weeks) [0 - 4 weeks]

   Word list generation measures verbal associative fluency. Patients are given 60 seconds to give as many words beginning with a particular letter. The Total is the unweighted sum of all admissible words over three different trials. Higher scores indicate a better cognitive performance (min=0, max= not defined).

9. Change From Baseline in the Mean Total Guy's Neurological Disability Scale Score at the End of Treatment (4 Weeks) [0 - 4 weeks]

   The Guy's Neurological Disability Scale has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and 'others'. Each category consists of a series of questions, which are scored on a 0 to 5 scale, with 0 being indicative of a better outcome and 5 being indicative of a worse outcome. The total Guy's Neurological Disability Scale score is the unweighted sum from the 12 categories with a minimum score of 0 and maximum of 60. A negative value indicates an improvement in score from baseline.

10. Change From Baseline in the Mean 0-100 mm Visual Analogue Scale Score for Intoxication Levels at the End of Treatment (4 Weeks) [0 - 4 weeks]

    Intoxication levels were recorded on a Visual Analogue Scale, where zero equated with "no intoxication" and 100 equated with "extreme intoxication". A decrease in baseline score indicates a reduction in intoxication.

11. Change From Baseline in The Hospital Anxiety and Depression Scale Score for Depression at the End of Treatment (4 Weeks) [0 - 4 weeks]

    Depression and anxiety was assessed using The Hospital Anxiety and Depression Scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression. A reduction in score indicates an improvement. The change from baseline in the overall depression score at the end of treatment is presented.

12. Change From Baseline in The Hospital Anxiety and Depression Scale Score for Anxiety at the End of Treatment (4 Weeks) [0 - 4 weeks]

    Depression and anxiety was assessed using The Hospital Anxiety and Depression Scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression. A reduction in score indicates an improvement. The change from baseline in the overall anxiety score at the end of treatment is presented.

13. Change From Baseline in the Multiple Sclerosis Functional Composite Score at the End of Treatment (4 Weeks) [Baseline to end of treatment (0 - 4 weeks).]

    The Multiple Sclerosis Functional Composite test is a three-part, standardized, quantitative, assessment instrument for use in clinical studies. The three components of the test measure leg function/ambulation, arm/hand function, and cognitive function. An increase in score indicates an improvement (range -3 to +3).

14. Incidence of Adverse Events as a Measure of Patient Safety. [0 - 4 weeks]

    The number of patients who experienced an adverse event during the course of the study 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 for participation in the study.

• Male or female subjects aged 18 years or above.

• Diagnosed with any disease sub-type of multiple sclerosis, with relapses/remission not expected to influence neuropathic pain.

• Duration of multiple sclerosis greater than six months.

• Central neuropathic pain, due to multiple sclerosis, of at least three months duration, for which a nociceptive, peripheral neuropathic or psychogenic cause appeared unlikely and was expected to remain stable for the duration of the study.

• Pain score with a severity of four or more on at least four completed Numerical Rating Scale scores in the baseline week.

• Regular medication regime for neuropathic pain had been stable during the previous two weeks, prior to reduction of tricyclic antidepressants, if applicable.

• Willing to reduce the dosage of amitriptyline, or equivalent of other tricyclic antidepressants, to a maximum of 75 mg per day, if applicable.

• No cannabinoid use (cannabis, Marinol or Nabilone) at least seven days before study entry and willing to abstain from any use of cannabis during the study.

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

• Able (in the investigators opinion) and willing to comply with all study requirements.

• Willing for his or her name to be notified to the Home Office for participation in this study.

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

Exclusion Criteria:

• History of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition.

• Concomitant severe non-neuropathic pain or the presence of illness such as diabetes mellitus that could have caused peripheral neuropathic pain.

• Known or strongly suspected alcohol or substance abuse or considered to be at risk of alcohol or substance abuse by the investigator.

• Severe cardiovascular disorder, such as ischaemic heart disease, arrhythmias (other than well controlled atrial fibrillation), poorly controlled hypertension or severe heart failure.

• History of epilepsy or convulsions.

• Significant renal or hepatic impairment as shown in medical history or indicated by clinical laboratory results from samples taken at baseline.

• Elective surgery or other procedures requiring general anaesthesia scheduled during the study.

• Terminal illness.

• Any other significant disease or disorder which, in the opinion of the Investigator, could either have put the subject at risk because of participation in the study, or influenced the result of the study, or the subject's ability to participate in the study.

• Female subjects who were pregnant, lactating or planning pregnancy during the course of the study.

• Regular levodopa (Sinemet, Sinemet Plus, Levodopa, L-dopa, Madopar, Benserazide) therapy within seven days of study entry.

• Known or suspected hypersensitivity to cannabinoids or any of the excipients of the study medications.

• Known or suspected adverse reaction to cannabinoids.

• Travel outside the UK planned during study.

• Donation of blood during the study.

• Participated in any other pharmacological clinical research study within 30 days of study entry.

• Previously enrolled into this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Walton Centre for Neurology and Neurosurgery	Liverpool		United Kingdom	L9 7LJ

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Carolyn Young, MRCP FRCP, Walton Centre for Neurology and Neurosurgery

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01604265
• Other Study ID Numbers: GWMS0107
• First Posted: May 23, 2012
• Last Update Posted: Jun 24, 2013
• Last Verified: Jun 1, 2013

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

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Period Title: Overall Study
STARTED	34	32
COMPLETED	32	32
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.	Total of all reporting groups
Overall Participants	34	32	66
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	34 100%	31 96.9%	65 98.5%
>=65 years	0 0%	1 3.1%	1 1.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.30 (6.70)	48.08 (9.73)	49.23 (8.32)
Sex: Female, Male (Count of Participants)
Female	28 82.4%	24 75%	52 78.8%
Male	6 17.6%	8 25%	14 21.2%
Region of Enrollment (participants) [Number]
United Kingdom	34 100%	32 100%	66 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Mean Pain 0-10 Numerical Rating Scale Score at the End of Treatment (4 Weeks)
Description	The average pain Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain in the last 24 hours" where 0 = no pain and 10 = pain as bad as you can imagine. A negative value indicates an improvement in pain score from baseline.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	32
Mean (Standard Deviation) [units on a scale]	-2.7 (1.91)	-1.4 (1.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way analysis of covariance (ANCOVA). The significance of the treatment effect, after adjusting for baseline pain score, was assessed using the F-test from the ANCOVA. The model was as follows: Change in 0-10 Numerical Rating Scale Pain Score = Baseline Pain Score + Treatment
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-1.25
	Confidence Interval	(2-Sided) 95%; -2.11 to -0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Mean 0-10 Numerical Rating Scale Sleep Score at the End of Treatment (4 Weeks)
Description	Each day patients were asked to record in their subject diary, whether or not they were "woken due to nerve pain last night", using a 0-10 Numerical Rating Scale sleep score where zero equated with "did not disrupt sleep" and 10 meant "completely disrupts sleep (unable to sleep due to pain)". A decrease in score from baseline indicates an improvement.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	32
Mean (Standard Deviation) [units on a scale]	-2.6 (2.35)	-0.8 (1.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline sleep score, was assessed using the F-test from the ANCOVA. The model was as follows: Change in 0-10 Numerical Rating Scale sleep Score = Baseline Sleep Score + Treatment
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -2.27 to -0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Subject Global Impression of Change at Week 4
Description	A 7-point Likert-type scale was used, with the question: 'Please assess the improvement in overall condition since the start of the study using the scale below' with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". At Visit 2 (Baseline) patients wrote a brief description of their condition which was used at Week 4 to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	34	32
Very much improved	1 2.9%	0 0%
Much improved	8 23.5%	4 12.5%
Slightly improved	15 44.1%	6 18.8%
No change	8 23.5%	19 59.4%
Slightly worse	2 5.9%	3 9.4%
Much worse	0 0%	0 0%
Very much worse	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The proportion of patients who considered their condition "Very Much Improved" or "Much Improved" was compared between treatment groups using a Fisher's Exact Test. Results were presented in terms of difference in percentages, and 95% CI based on the normal approximation to the binomial, and p-value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.896
	Confidence Interval	(2-Sided) 95%; 1.510 to 10.055
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the Mean Neuropathic Pain Scale 0-10 Numerical Rating Scale Score at the End of Treatment (Week 4)
Description	The Neuropathic Pain Scale score is the 0-100 sum of 10 individual pain scores (0-10 Numerical Rating Scale, 0= no pain to 10 = worst pain imaginable). A negative change from baseline indicates an improvement in pain.
Time Frame	Baseline to end of treatment (0 - 4 weeks).

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	32
Mean (Standard Deviation) [units on a scale]	-15.3 (13.23)	-8.1 (14.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	estimated mean treatment difference
	Estimated Value	-6.82
	Confidence Interval	(2-Sided) 95%; -13.28 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Selective Reminding' at the End of Treatment (Week 4)
Description	The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance.
Time Frame	Baseline to end of study (0 - 4 weeks)

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	32
Mean (Standard Deviation) [units on a scale]	-0.9 (10.52)	5.7 (10.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-6.95
	Confidence Interval	(2-Sided) 95%; -12.12 to -1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for '10/36 Spatial Recall' at the End of Treatment (Week 4)
Description	The 10/36 Spatial Recall Test assesses visual spatial learning and delayed recall. Patients are asked to view a 6 x 6 checkerboard with ten checkers for 10 seconds. They are then asked to recreate the pattern viewed on a blank checkerboard. The number of correct responses from three immediate trials and one delayed trial (7 minute delay) are recorded. The Total number of correct responses is the unweighted sum from the four trials. The score for the 10/36 spatial recall test was the unweighted average of four individual study results (min=0 and max=40). A higher score indicates better cognitive performance.
Time Frame	Weeks 0 - 4

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	30
Mean (Standard Deviation) [units on a scale]	4.2 (10.84)	-1.5 (8.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	2.54
	Confidence Interval	(2-Sided) 95%; -1.64 to 6.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Symbol Digit Modalities' at the End of Treatment (Week 4)
Description	The Symbol Digit Modalities Test measures complex attention and concentration in a task which also requires speed and accuracy in visual search and scanning. Patients are required to associate symbols with numbers and quickly generate the number when shown the symbol. The summary endpoint is the number of correct responses in 90 seconds. The symbol digit modalities test had a min of 0 and max score of 99. A higher score indicates better cognitive performance.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	32
Mean (Standard Deviation) [units on a scale]	1.2 (6.28)	3.67 (4.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-2.53
	Confidence Interval	(2-Sided) 95%; -5.22 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for the 'Paced Auditory Serial Addition Task' (PASAT) at the End of Treatment (Week 4)
Description	The Paced Auditory Serial Addition Task assesses sustained attention and concentration. A pre-recorded tape is used to present two series of 60 numbers, one every 3 seconds and one every 2 seconds. Patients are asked to add each number to the one immediately preceding it and give the result. The task summary score is the percentage of correct answers is calculated. The PASAT score range was 0% to 100%. Higher scores indicate a better cognitive performance.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	30	30
Mean (Standard Deviation) [percentage of correct answers]	7.0 (10.49)	6.6 (7.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.905
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -4.60 to 5.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.44
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Word List Generation' at the End of Treatment (4 Weeks)
Description	Word list generation measures verbal associative fluency. Patients are given 60 seconds to give as many words beginning with a particular letter. The Total is the unweighted sum of all admissible words over three different trials. Higher scores indicate a better cognitive performance (min=0, max= not defined).
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	33	32
Mean (Standard Deviation) [number of words]	5.1 (9.49)	2.9 (10.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.257
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	2.68
	Confidence Interval	(2-Sided) 95%; -2.01 to 7.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the Mean Total Guy's Neurological Disability Scale Score at the End of Treatment (4 Weeks)
Description	The Guy's Neurological Disability Scale has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and 'others'. Each category consists of a series of questions, which are scored on a 0 to 5 scale, with 0 being indicative of a better outcome and 5 being indicative of a worse outcome. The total Guy's Neurological Disability Scale score is the unweighted sum from the 12 categories with a minimum score of 0 and maximum of 60. A negative value indicates an improvement in score from baseline.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	34	32
Mean (Standard Deviation) [units on a scale]	-1.5 (4.45)	-0.5 (4.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.164
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-1.50
	Confidence Interval	(2-Sided) 95%; -3.64 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in the Mean 0-100 mm Visual Analogue Scale Score for Intoxication Levels at the End of Treatment (4 Weeks)
Description	Intoxication levels were recorded on a Visual Analogue Scale, where zero equated with "no intoxication" and 100 equated with "extreme intoxication". A decrease in baseline score indicates a reduction in intoxication.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	34	32
Mean (Standard Deviation) [units on a scale]	3.3 (9.25)	0.3 (0.97)

12. Secondary Outcome

Title	Change From Baseline in The Hospital Anxiety and Depression Scale Score for Depression at the End of Treatment (4 Weeks)
Description	Depression and anxiety was assessed using The Hospital Anxiety and Depression Scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression. A reduction in score indicates an improvement. The change from baseline in the overall depression score at the end of treatment is presented.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	34	32
Mean (Standard Deviation) [units on a scale]	-0.1 (2.92)	-0.4 (2.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.880
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -1.06 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in The Hospital Anxiety and Depression Scale Score for Anxiety at the End of Treatment (4 Weeks)
Description	Depression and anxiety was assessed using The Hospital Anxiety and Depression Scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression. A reduction in score indicates an improvement. The change from baseline in the overall anxiety score at the end of treatment is presented.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	34	32
Mean (Standard Deviation) [units on a scale]	-1.0 (2.06)	-0.5 (2.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.249
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -1.75 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in the Multiple Sclerosis Functional Composite Score at the End of Treatment (4 Weeks)
Description	The Multiple Sclerosis Functional Composite test is a three-part, standardized, quantitative, assessment instrument for use in clinical studies. The three components of the test measure leg function/ambulation, arm/hand function, and cognitive function. An increase in score indicates an improvement (range -3 to +3).
Time Frame	Baseline to end of treatment (0 - 4 weeks).

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	22	21
Mean (Standard Deviation) [units on a scale]	0.25 (0.364)	0.19 (0.174)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change was compared between treatment groups using a one way ANCOVA. The significance of the treatment effect, after adjusting for baseline score, was assessed using the F-test from the ANCOVA.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.535
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Incidence of Adverse Events as a Measure of Patient Safety.
Description	The number of patients who experienced an adverse event during the course of the study is presented.
Time Frame	0 - 4 weeks

Outcome Measure Data

Analysis Population Description

All patients who were randomised, received at least one actuation of study medication and had some on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.	Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 24 hours.
Measure Participants	34	32
Number [participants]	30 88.2%	22 68.8%

Adverse Events

Time Frame	All adverse events occurring during the four week treatment period were collected. 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 events 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	Each actuation contains 2.5 mg THC and 2.5 mg CBD, delivered through a pump action oromucosal spray. The maximum daily exposure was set at 48 actuations per 24 hours.		Each actuation of placebo delivered the excipients and colourants only. The maximum daily exposure was set at 48 actuations per 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	0/34 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/34 (88.2%)		22/32 (68.8%)
Eye disorders
Diplopia	0/34 (0%)		1/32 (3.1%)
Gastrointestinal disorders
Dry Mouth	4/34 (11.8%)		0/32 (0%)
Nausea	3/34 (8.8%)		2/32 (6.3%)
Glossodynia	0/34 (0%)		3/32 (9.4%)
Oral Pain	0/34 (0%)		3/32 (9.4%)
Diarrhoea not otherwise specified	2/34 (5.9%)		0/32 (0%)
Dyspepsia	0/34 (0%)		1/32 (3.1%)
General disorders
Fall	3/34 (8.8%)		2/32 (6.3%)
Weakness	2/34 (5.9%)		0/32 (0%)
Fatigue	2/34 (5.9%)		2/32 (6.3%)
Feeling drunk	0/34 (0%)		1/32 (3.1%)
Application site burning	0/34 (0%)		1/32 (3.1%)
Chest discomfort	0/34 (0%)		1/32 (3.1%)
Infections and infestations
Urinary tract infection not otherwise specified	2/34 (5.9%)		1/32 (3.1%)
Nasopharyngitis	0/34 (0%)		2/32 (6.3%)
Otitis media not otherwise specified	0/34 (0%)		1/32 (3.1%)
Sinusitis not otherwise specified	0/34 (0%)		1/32 (3.1%)
Injury, poisoning and procedural complications
Ligament sprain	0/34 (0%)		1/32 (3.1%)
Investigations
Gamma-glutamyltransferase increased	0/34 (0%)		1/32 (3.1%)
White blood cell count increased	2/34 (5.9%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/34 (0%)		1/32 (3.1%)
Nervous system disorders
Dizziness	18/34 (52.9%)		5/32 (15.6%)
Somnolence	3/34 (8.8%)		0/32 (0%)
Disturbance in attention	2/34 (5.9%)		0/32 (0%)
Hypoaesthesia	2/34 (5.9%)		1/32 (3.1%)
Headache not otherwise specified	1/34 (2.9%)		3/32 (9.4%)
Migraine not otherwise specified	0/34 (0%)		1/32 (3.1%)
Paraesthesia	0/34 (0%)		1/32 (3.1%)
Psychiatric disorders
Dissociation	3/34 (8.8%)		0/32 (0%)
Euphoric mood	2/34 (5.9%)		0/32 (0%)
Reproductive system and breast disorders
Breast pain	0/34 (0%)		1/32 (3.1%)
Respiratory, thoracic and mediastinal disorders
Pharyngitis	2/34 (5.9%)		1/32 (3.1%)
Dyspnoea not otherwise specified	0/34 (0%)		1/32 (3.1%)
Skin and subcutaneous tissue disorders
Rash not otherwise specified	0/34 (0%)		1/32 (3.1%)
Skin irritation	0/34 (0%)		1/32 (3.1%)

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.