A Randomized Study of Sativex on Cognitive Function and Mood: Multiple Sclerosis Patients

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01964547
• Collaborator: (none)
• Enrollment: 121
• Location: 1
• Arms: 2
• Duration (Months): 16
• Patients Per Site Per Month: 7.6

Study Details

Study Description

Brief Summary

A study to compare the change in cognitive performance and psychological status of patients with spasticity due to Multiple Sclerosis when treated with Sativex or placebo, added to existing anti-spasticity therapy over a period of 48 weeks. Secondary objectives were to evaluate the effect of Sativex on mood and spasticity and to assess the safety and tolerability of Sativex.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis; Spasticity	Drug: Sativex; Drug: Placebo	Phase 4

Detailed Description

Eligible patients entered this 50 week multicenter, double-blind, randomised, placebo-controlled, parallel group study which evaluated the effect of Sativex on cognitive performance. At each scheduled clinic visit, patients were assessed for cognitive performance, mood, severity of spasticity, use of investigational medicinal products and number of visits to a healthcare professional. Primary efficacy comparisons were made between scores recorded during baseline and scores recorded at the end of treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicentre, Double-blind, Randomised, Parallel Group, Placebo-controlled Study of the Effect of Long-term Treatment With Sativex on Cognitive Function and Mood of Patients With Spasticity Due to Multiple Sclerosis
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sativex Contains 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. Each actuation delivers THC 2.7 mg and CBD 2.5 mg. Dose: 100 µL oromucosal spray to be administered up to a maximum of 12 sprays per day. There was an initial dose-titration period during which patients gradually increased their dose of study drug according to individual response and tolerability.	Drug: Sativex; Patients self-administered their allocated randomized treatment on an outpatient basis, up to a maximum of 12 sprays to the oral mucosa per day (following an initial titration period).; Other Names: Nabiximols GWP42001 THC/CBD spray
Placebo Comparator: Placebo Oromucosal spray, containing ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring and colourings 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%). Dose: 100 µL oromucosal spray to be administered up to a maximum of 12 sprays per day. There was an initial dose-titration period during which patients gradually increased their dose of study drug according to individual response and tolerability.	Drug: Placebo; Patients self-administered their allocated randomized treatment on an outpatient basis, up to a maximum of 12 sprays to the oral mucosa per day (following an initial titration period).; Other Names: Placebo control

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to the End of Treatment in Paced Auditory Serial Addition Test (PASAT) Total Score. [0-48 weeks]

   The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Stimulus presentation rates were adapted for use with multiple sclerosis patients. The PASAT is presented on audio compact disk to control the rate of stimulus presentation. Single digits are presented either every 3 seconds (PASAT 1) or every 2 seconds (PASAT 2), and the patient must add each new digit to the one immediately prior to it. The test score is the sum of the total number of correct sums given (out of 60 possible) in each trial. An increase in score indicates an improvement in condition.

Secondary Outcome Measures

1. Change From Baseline to the End of Treatment in Beck Depression Inventory-II (BDI-II) Total Score. [0-48 weeks]

   The BDI-II is a multiple choice self-reported inventory that is one of the most widely used instruments for measuring the severity of depression. There are 21 questions or items, each having four possible responses. Each response is assigned a score ranging from zero to three, indicating the severity of the symptom. Items 1 to 13 assess symptoms that are psychological in nature, while items 14 to 21 assess symptoms that are more physical. The sum of all BDI-II item scores indicates the severity of depression. For patients eligible for this study, a score of 21 or over represents depression. The BDI-II can distinguish between different subtypes of depressive disorders, such as major depression and dysthymia. A reduction in score indicates an improvement in condition.

2. Subject Global Impression of Change (SGIC) in the Severity of Their Spasticity at the End of Treatment. [0-48 weeks]

   Patients were asked the following question, to be rated on a seven-point scale: "Please assess the change in your spasticity since immediately before receiving the first dose of study treatment (Visit 1) using the scale below". The markers were: 'Very much worse', 'Much worse', 'Minimally worse', 'No change', 'Minimally better', 'Much better' or 'Very much better'. The number of patients for each of the markers is presented at the final study visit.

3. Caregiver's Global Impression of Change (CGIC) in the Severity of the Patient's Spasticity at the End of Treatment. [0-48 weeks]

   Caregivers were asked the following question to be rated on a seven-point scale: "How has the subject's spasticity changed since Visit 1?" The markers were: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of patients for each of the markers is presented at the final study visit.

4. Physician's Global Impression of Change (PGIC) in the Severity of the Patient's Spasticity at the End of Treatment. [0-48 weeks]

   Physicians were asked the following question to be rated on a seven-point scale: "How has the subject's spasticity changed since Visit 1?" The markers were: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of patients for each of the markers is presented at the final study visit.

5. Change From Baseline to End of Treatment in Modified Ashworth Scale Total Score. [0-48 weeks]

   All 20 muscle groups were assessed for spasticity (using a 0-5 scale): 0= 'no increase in muscle tone' to 5= 'affected part(s) rigid in flexion or extension'. The score for all 20 muscle groups were added to give a total score out of 100. A decrease in score indicates an improvement in condition.

6. Change From Baseline to End of Treatment in Number of Visits to a Healthcare Professional. [0-48 weeks]

   At baseline, patients were asked how many times they had visited a healthcare professional in the previous 12 weeks. At subsequent visits, patients were asked how many times they had visited a healthcare professional since their last study visit. The change from baseline to the end of treatment is presented. A decrease in number indicates an improvement in condition.

7. The Number of Patients With a Treatment-emergent Flag Using the Columbia-Suicide Severity Rating Scale (C-SSRS) During the Course of the Study. [0-48 weeks]

   Patients were scored at each clinic visit for the following outcomes using the C-SSRS: suicidal ideation, suicidal behaviour, suicidality (including complete suicidality). Possible flags were as follows: "Wish to be Dead", "Non-specific Active Suicidal Thoughts", "Active Suicidal Ideation Without Intent", "Active Suicidal Ideation With Intent, No Plan", "Active Suicidal Ideation With Intent and Plan". The number of patients with a treatment-emergent flag is presented.

8. Change From Baseline to End of Treatment in Timed 10-meter Walk Times. [0-48 weeks]

   Only those patients for whom it was appropriate (i.e. ambulatory patients) were timed for how long it took to walk 10 metres. If a patient started the 10-meter walk but was unable to complete it, an estimated time for completion was calculated based on the available data. A negative difference from baseline indicates an improvement in condition.

9. Incidence of Adverse Events as a Measure of Patient Safety. [0-50 weeks]

   The number of subjects 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 (ALL to be fulfilled):

• Patient is willing and able to give informed consent for participation in the study.

• Patient is aged 18 years or above.

• Diagnosed with any disease sub-type of multiple sclerosis.

• Diagnosed with symptomatic spasticity due to multiple sclerosis.

• Patient has at least moderate spasticity in the opinion of the investigator.

• Patient 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 anti-spasticity therapy.

• Stable medication regimen for at least four weeks prior to study entry, for all medications which may have an effect on spasticity and/or cognition.

• If the patient is taking disease modifying medication this must be at a stable dose for three months prior to the initial visit.

• Willing and able to comply with all study requirements.

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

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

Exclusion Criteria (if ANY apply):

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

• Any concomitant disease or disorder (such as poorly controlled epilepsy or seizures) that may influence the patient's level of cognition or mood.

• Currently using or has used cannabis or cannabinoid-based medications within 30 days of study entry and unwilling to abstain for the duration of the study.

• Any known or suspected history of a diagnosed dependence disorder, current heavy alcohol consumption (more than 60g of pure alcohol per day for men, and more than 40g of pure alcohol per day for women), current use of an illicit drug or current non-prescribed use of any prescription drug.

• Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the investigational medicinal products.

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

• Patients who have received an investigational medicinal product within the 12 weeks prior to the initial visit.

• Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study may influence the result of the study, or the patient's ability to participate in the study.

• Following a physical examination, the patient has any abnormalities that, in the opinion of the investigator would prevent the patient from safe participation in the study.

• Previously randomised to this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MS Centre, Charles University	Prague		Czech Republic	128 08

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Iveta Nováková, MD MBBS, Charles University, Czech Republic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• P1206: Abstract of study data presented at ECTRIMS 2013

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01964547
• Other Study ID Numbers: GWMS1137
• First Posted: Oct 17, 2013
• Last Update Posted: May 2, 2014
• Last Verified: Apr 1, 2014

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

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains delta-9-tetrahydrocannabinol (THC) (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Period Title: Overall Study
STARTED	62	59
COMPLETED	50	48
NOT COMPLETED	12	11

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.	Total of all reporting groups
Overall Participants	62	59	121
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	61 98.4%	58 98.3%	119 98.3%
>=65 years	1 1.6%	1 1.7%	2 1.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.95 (8.954)	48.21 (10.381)	48.59 (9.642)
Sex: Female, Male (Count of Participants)
Female	39 62.9%	37 62.7%	76 62.8%
Male	23 37.1%	22 37.3%	45 37.2%
Region of Enrollment (participants) [Number]
Czech Republic	62 100%	59 100%	121 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to the End of Treatment in Paced Auditory Serial Addition Test (PASAT) Total Score.
Description	The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Stimulus presentation rates were adapted for use with multiple sclerosis patients. The PASAT is presented on audio compact disk to control the rate of stimulus presentation. Single digits are presented either every 3 seconds (PASAT 1) or every 2 seconds (PASAT 2), and the patient must add each new digit to the one immediately prior to it. The test score is the sum of the total number of correct sums given (out of 60 possible) in each trial. An increase in score indicates an improvement in condition.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	55	52
Mean (Standard Deviation) [units on a scale]	6.8 (16.16)	6.8 (13.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change at end of treatment was compared between treatment groups using ANCOVA. The model included treatment group and center grouping as factors and the baseline score as covariate. The planned sample size was 120 participants(60 patients in the Sativex arm and 60 in the placebo arm).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size is adequate to confirm the non-inferiority of Sativex with a clinical relevant reduction delta of 10%, assuming there is no difference between treatments in the actual change in cognition and also assuming a standard deviation for treatment difference of 10, using a one-tailed 2.5% significance level and power of 90%. Sativex is deemed to be non-inferior to placebo if the lower 1-sided 97.5% CI of the estimated mean treatment difference (Sativex-Placebo) is greater than -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-1.47
	Confidence Interval	(1-Sided) 97.5%; -6.41 to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.492
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to the End of Treatment in Beck Depression Inventory-II (BDI-II) Total Score.
Description	The BDI-II is a multiple choice self-reported inventory that is one of the most widely used instruments for measuring the severity of depression. There are 21 questions or items, each having four possible responses. Each response is assigned a score ranging from zero to three, indicating the severity of the symptom. Items 1 to 13 assess symptoms that are psychological in nature, while items 14 to 21 assess symptoms that are more physical. The sum of all BDI-II item scores indicates the severity of depression. For patients eligible for this study, a score of 21 or over represents depression. The BDI-II can distinguish between different subtypes of depressive disorders, such as major depression and dysthymia. A reduction in score indicates an improvement in condition.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	57	56
Mean (Standard Deviation) [units on a scale]	-3.1 (7.76)	-2.4 (6.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change at end of treatment was compared between treatment groups using ANCOVA. The model included treatment group and center grouping as factors and the baseline score as covariate.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sativex is deemed to be non-inferior to placebo if the upper 1-sided 97.5% CI of the estimated mean treatment difference (Sativex-Placebo) is less than +5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.29
	Confidence Interval	(1-Sided) 97.5%; to 2.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.323
	Estimation Comments

3. Secondary Outcome

Title	Subject Global Impression of Change (SGIC) in the Severity of Their Spasticity at the End of Treatment.
Description	Patients were asked the following question, to be rated on a seven-point scale: "Please assess the change in your spasticity since immediately before receiving the first dose of study treatment (Visit 1) using the scale below". The markers were: 'Very much worse', 'Much worse', 'Minimally worse', 'No change', 'Minimally better', 'Much better' or 'Very much better'. The number of patients for each of the markers is presented at the final study visit.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	58	56
Very Much Better	2 3.2%	0 0%
Much Better	16 25.8%	6 10.2%
Minimally Better	24 38.7%	15 25.4%
No Change	13 21%	27 45.8%
Minimally Worse	1 1.6%	7 11.9%
Much Worse	2 3.2%	1 1.7%
Very Much Worse	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	Data were analysed using ordinal logistic regression using the cumulative proportional odds model, with global impression of change as the dependent variable and treatment group as factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.02
	Confidence Interval	(2-Sided) 95%; 1.96 to 8.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Caregiver's Global Impression of Change (CGIC) in the Severity of the Patient's Spasticity at the End of Treatment.
Description	Caregivers were asked the following question to be rated on a seven-point scale: "How has the subject's spasticity changed since Visit 1?" The markers were: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of patients for each of the markers is presented at the final study visit.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	41	40
Very Much Better	1 1.6%	0 0%
Much Better	12 19.4%	6 10.2%
Minimally Better	14 22.6%	10 16.9%
No Change	11 17.7%	18 30.5%
Minimally Worse	3 4.8%	3 5.1%
Much Worse	0 0%	3 5.1%
Very Much Worse	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	Data were analysed using ordinal logistic regression using the cumulative proportional odds model, with global impression of change as the dependent variable and treatment group as factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0142
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.79
	Confidence Interval	(2-Sided) 95%; 1.23 to 6.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Physician's Global Impression of Change (PGIC) in the Severity of the Patient's Spasticity at the End of Treatment.
Description	Physicians were asked the following question to be rated on a seven-point scale: "How has the subject's spasticity changed since Visit 1?" The markers were: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of patients for each of the markers is presented at the final study visit.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	58	56
Very Much Better	0 0%	1 1.7%
Much Better	15 24.2%	6 10.2%
Minimally Better	26 41.9%	15 25.4%
No Change	14 22.6%	29 49.2%
Minimally Worse	3 4.8%	4 6.8%
Much Worse	0 0%	1 1.7%
Very Much Worse	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	Data were analysed using ordinal logistic regression using the cumulative proportional odds model, with global impression of change as the dependent variable and treatment group as factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.07
	Confidence Interval	(2-Sided) 95%; 1.51 to 6.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to End of Treatment in Modified Ashworth Scale Total Score.
Description	All 20 muscle groups were assessed for spasticity (using a 0-5 scale): 0= 'no increase in muscle tone' to 5= 'affected part(s) rigid in flexion or extension'. The score for all 20 muscle groups were added to give a total score out of 100. A decrease in score indicates an improvement in condition.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	58	56
Mean (Standard Deviation) [units on a scale]	-10.6 (11.26)	-7.7 (10.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change at end of treatment was compared between treatment groups using ANCOVA. The model included treatment group and center grouping as factors and the baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-2.36
	Confidence Interval	(2-Sided) 95%; -6.09 to 1.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.880
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to End of Treatment in Number of Visits to a Healthcare Professional.
Description	At baseline, patients were asked how many times they had visited a healthcare professional in the previous 12 weeks. At subsequent visits, patients were asked how many times they had visited a healthcare professional since their last study visit. The change from baseline to the end of treatment is presented. A decrease in number indicates an improvement in condition.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	58	56
Mean (Standard Deviation) [visits]	-0.6 (0.99)	-0.4 (1.30)

8. Secondary Outcome

Title	The Number of Patients With a Treatment-emergent Flag Using the Columbia-Suicide Severity Rating Scale (C-SSRS) During the Course of the Study.
Description	Patients were scored at each clinic visit for the following outcomes using the C-SSRS: suicidal ideation, suicidal behaviour, suicidality (including complete suicidality). Possible flags were as follows: "Wish to be Dead", "Non-specific Active Suicidal Thoughts", "Active Suicidal Ideation Without Intent", "Active Suicidal Ideation With Intent, No Plan", "Active Suicidal Ideation With Intent and Plan". The number of patients with a treatment-emergent flag is presented.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	62	59
Wish to be Dead	0 0%	2 3.4%
Non-specific Active Suicidal Thoughts	0 0%	1 1.7%
Active Suicidal Ideation Without Intent	0 0%	1 1.7%
Active Suicidal Ideation With Intent, No Plan	0 0%	0 0%
Active Suicidal Ideation With Intent and Plan	0 0%	0 0%

9. Secondary Outcome

Title	Change From Baseline to End of Treatment in Timed 10-meter Walk Times.
Description	Only those patients for whom it was appropriate (i.e. ambulatory patients) were timed for how long it took to walk 10 metres. If a patient started the 10-meter walk but was unable to complete it, an estimated time for completion was calculated based on the available data. A negative difference from baseline indicates an improvement in condition.
Time Frame	0-48 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	47	50
Mean (Standard Deviation) [seconds]	6.2 (55.34)	3.0 (24.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change at end of treatment was compared between treatment groups using ANCOVA. The model included treatment group and centre grouping as factors and baseline score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.556
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	4.88
	Confidence Interval	(2-Sided) 95%; -11.51 to 21.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.250
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change at end of treatment was compared between treatment groups using non-parametric methods as the distribution of data was non-normal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hodges-Lehmann median difference
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -3 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Incidence of Adverse Events as a Measure of Patient Safety.
Description	The number of subjects who experienced an adverse event during the course of the study is presented.
Time Frame	0-50 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study medication and yielded on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.	Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
Measure Participants	62	59
Number [participants]	39 62.9%	19 32.2%

Adverse Events

Time Frame	All adverse events occurring during the study (0-50 weeks) 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 100 μl actuation contains THC (27 mg/mL) and CBD (25 mg/mL). The maximum permitted dose was 12 actuations (32.4 mg THC + 30 mg CBD) in any 24 hour period.		Each 100 μl actuation contains no active drug but colorants and excipients. The maximum permitted dose was 12 actuations in any 24 hour period.
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	5/62 (8.1%)		0/59 (0%)
Cardiac disorders
Acute Myocardial Infarction	1/62 (1.6%)		0/59 (0%)
Gastrointestinal disorders
Inguinal Hernia	1/62 (1.6%)		0/59 (0%)
General disorders
Drug Withdrawal Syndrome	1/62 (1.6%)		0/59 (0%)
Infections and infestations
Bronchitis	1/62 (1.6%)		0/59 (0%)
Pneumonia	1/62 (1.6%)		0/59 (0%)
Injury, poisoning and procedural complications
Overdose	1/62 (1.6%)		0/59 (0%)
Metabolism and nutrition disorders
Tetany	1/62 (1.6%)		0/59 (0%)
Nervous system disorders
Dysarthria	1/62 (1.6%)		0/59 (0%)
Psychiatric disorders
Disorientation	1/62 (1.6%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/62 (54.8%)		19/59 (32.2%)
Ear and labyrinth disorders
Vertigo	6/62 (9.7%)		0/59 (0%)
Eye disorders
Visual Impairment	0/62 (0%)		1/59 (1.7%)
Gastrointestinal disorders
Diarrhoea	1/62 (1.6%)		0/59 (0%)
Dry Mouth	2/62 (3.2%)		0/59 (0%)
Gingivitis	0/62 (0%)		2/59 (3.4%)
Nausea	1/62 (1.6%)		1/59 (1.7%)
Oral Mucosal Erythema	0/62 (0%)		1/59 (1.7%)
Vomiting	1/62 (1.6%)		0/59 (0%)
General disorders
Asthenia	2/62 (3.2%)		0/59 (0%)
Fatigue	5/62 (8.1%)		1/59 (1.7%)
Pyrexia	0/62 (0%)		1/59 (1.7%)
Application Site Discomfort	1/62 (1.6%)		0/59 (0%)
Immune system disorders
Drug Hypersensitivity	0/62 (0%)		1/59 (1.7%)
Infections and infestations
Bacterial Infection	1/62 (1.6%)		0/59 (0%)
Herpes Zoster	1/62 (1.6%)		0/59 (0%)
Subcutaneous Abscess	0/62 (0%)		1/59 (1.7%)
Tonsillitis	2/62 (3.2%)		0/59 (0%)
Upper Respiratory Tract Infection	0/62 (0%)		3/59 (5.1%)
Upper Respiratory Tract Infection Bacterial	0/62 (0%)		1/59 (1.7%)
Urinary Tract Infection	5/62 (8.1%)		1/59 (1.7%)
Viral Infection	0/62 (0%)		2/59 (3.4%)
Injury, poisoning and procedural complications
Contusion	1/62 (1.6%)		1/59 (1.7%)
Face Injury	1/62 (1.6%)		0/59 (0%)
Foot Fracture	0/62 (0%)		1/59 (1.7%)
Forearm Fracture	0/62 (0%)		1/59 (1.7%)
Joint Dislocation	1/62 (1.6%)		1/59 (1.7%)
Ligament Sprain	0/62 (0%)		1/59 (1.7%)
Lower Limb Fracture	1/62 (1.6%)		0/59 (0%)
Procedural Vomiting	1/62 (1.6%)		0/59 (0%)
Thermal Burn	1/62 (1.6%)		0/59 (0%)
Upper Limb Fracture	1/62 (1.6%)		0/59 (0%)
Investigations
Blood Alkaline Phosphatase Increased	0/62 (0%)		1/59 (1.7%)
Vitamin D Decreased	0/62 (0%)		1/59 (1.7%)
Weight Decreased	3/62 (4.8%)		0/59 (0%)
Metabolism and nutrition disorders
Decreased Appetite	1/62 (1.6%)		0/59 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	1/62 (1.6%)		0/59 (0%)
Muscle Spasms	1/62 (1.6%)		0/59 (0%)
Pain In Extremity	1/62 (1.6%)		0/59 (0%)
Nervous system disorders
Cerebellar Ataxia	2/62 (3.2%)		0/59 (0%)
Cognitive Disorder	0/62 (0%)		1/59 (1.7%)
Dizziness	5/62 (8.1%)		0/59 (0%)
Headache	1/62 (1.6%)		2/59 (3.4%)
Memory Impairment	1/62 (1.6%)		0/59 (0%)
Multiple Sclerosis	1/62 (1.6%)		0/59 (0%)
Multiple Sclerosis Relapse	3/62 (4.8%)		4/59 (6.8%)
Muscle Spasticity	5/62 (8.1%)		2/59 (3.4%)
Neuralgia	2/62 (3.2%)		0/59 (0%)
Paraesthesia	1/62 (1.6%)		1/59 (1.7%)
Paraparesis	0/62 (0%)		1/59 (1.7%)
Radiculopathy	1/62 (1.6%)		0/59 (0%)
Somnolence	1/62 (1.6%)		1/59 (1.7%)
Stupor	1/62 (1.6%)		0/59 (0%)
Tremor	1/62 (1.6%)		0/59 (0%)
Trigeminal Neuralgia	1/62 (1.6%)		0/59 (0%)
Psychiatric disorders
Anxiety Disorder Due To A General Medical Condition	2/62 (3.2%)		0/59 (0%)
Euphoric Mood	2/62 (3.2%)		0/59 (0%)
Suicidal Ideation	0/62 (0%)		1/59 (1.7%)
Reproductive system and breast disorders
Erectile Dysfunction	0/62 (0%)		1/59 (1.7%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Blistering	0/62 (0%)		1/59 (1.7%)
Skin and subcutaneous tissue disorders
Dermatitis Allergic	1/62 (1.6%)		0/59 (0%)
Surgical and medical procedures
Lipoma Excision	0/62 (0%)		1/59 (1.7%)
Tooth Extraction	1/62 (1.6%)		0/59 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GW Pharma Ltd (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.