A Study of the Safety and Effectiveness of Sativex®, for... | NCT00681538

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sativex	Experimental	Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L. Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours	Drug: Sativex®
Placebo	Placebo Comparator	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Sativex®	Drug	containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Maximum dose within any 24-hour interval is 12 sprays (THC 32.4 mg: CBD 30 mg)

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

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

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Willing and able to give written informed consent for participation in the study.
Male or female, aged 18 years or above.
Subject is able (in the investigator's opinion) and willing to comply with all study requirements.
Diagnosed with any disease sub-type of MS of at least six months duration.
Spasticity due to MS of at least three months duration, which is not wholly relieved with current anti-spasticity therapy, and which is expected to remain stable for the duration of the study.
Subject fulfils at least one of the two criteria below. Subject must be either: Currently established on a regular dose of anti-spasticity therapy or Previously tried and failed, or could not tolerate suitable anti-spasticity therapy.
Subject is currently receiving a stable regimen (for at least 30 days prior to study entry) of all medications that may have an effect on spasticity; and willing to maintain this for the duration of the study. If the subject is currently taking disease-modifying medication, this must be at a stable dose for at least three months prior to the screening visit; the dose must also remain stable for the duration of the study.
Willing for his or her name to be notified to his or her primary care physician, and consultant and the responsible authorities for participation in this study, as applicable.

Exclusion Criteria:

Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the subject's level of spasticity.
Subject's medical history suggests that relapse/remission is likely to occur during the study (over the next 19 weeks) which, in the opinion of the investigator, is expected to influence the subject's spasticity.
Currently receiving a prohibited medication and unwilling to stop for the stated period prior to the screening visit and for the duration of the study.
Any known or suspected history of: schizophrenia or other psychotic illness;diagnosed dependence disorder;poorly controlled epilepsy or recurrent seizures;hypersensitivity to cannabinoids.
Significant cardiac, renal or hepatic disease.
Female subjects of child bearing potential and male subjects whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for three months thereafter.
Female subject who is pregnant, lactating or planning pregnancy during the course of the study or for three months thereafter.
Subjects who have received an IMP within the 12 weeks before Visit 1.
Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the result of the study, or the subject's ability to participate in the study.
Following a physical examination, the subject has any abnormalities that, in the opinion of the investigator, would prevent them from safely participating in the study.
Unwilling to abstain from donation of blood during the study.
Travel outside the country of residence planned during the study.
Subjects previously randomised into this study.

Name	Affiliation	Role
Paul Davies, MRCP, FRCP	Department of Neurology	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Department of Neurology, Northampton General Hospital		Cliftonville	Northampton	NN1 5BD	United Kingdom

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
21362108	Result	Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, Gasperini C, Pozzilli C, Cefaro L, Comi G, Rossi P, Ambler Z, Stelmasiak Z, Erdmann A, Montalban X, Klimek A, Davies P; Sativex Spasticity Study Group. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R)) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011 Sep;18(9):1122-31. doi: 10.1111/j.1468-1331.2010.03328.x. Epub 2011 Mar 1.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
BG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG000124 BG001117 BG002241

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Of the 572 subjects who entered Phase A, 241 entered Phase B; 124 randomised to Sativex and 117 to placebo. The data below details that for Phase B.

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00049.1± 9.09 BG00148.1± 9.59 BG00248.6± 9.33

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00072 BG00173 BG002

Duration of Multiple Sclerosis Phase B

Of the 572 subjects who entered Phase A, 241 entered Phase B; 124 randomised to Sativex and 117 to placebo.

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00013.3± 8.29 BG00111.8± 7.38

Duration of Spasticity Phase B

Of the 572 subjects who entered Phase A, 241 entered Phase B; 124 randomised to Sativex and 117 to placebo.

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG0008.6± 6.89 BG0016.7± 5.40

Expanded Disability Status Scale (EDSS)- Phase B

241 entered Phase B; 124 randomised to Sativex and 117 to placebo. EDSS is a method of quantifying disability in multiple sclerosis.The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score in each of these. EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory. EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation. Each score is given a definition and thus can identify for the subject their score depending on their condition e.g. score of 1.0: No disability, minimal signs on 1 FS.

Mean

Standard Deviation

Score

Title

Denominators

Categories

Title	Measurements
	BG0006.5± 1.46 BG001

Baseline Spasticity numerical rating scale (NRS) Score Phase B

Of the 572 subjects who entered Phase A, 241 entered Phase B; 124 randomised to Sativex and 117 to placebo.

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

Mean

Standard Deviation

Score

Title

Denominators

Categories

Title	Measurements
	BG0003.87± 1.49 BG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

The Change in Mean Spasticity Numerical Rating Scale (NRS) Score From Baseline to End of Treatment (Phase B).

Posted

Mean

Standard Deviation

Points on scale

Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants	OG000124 OG001117

Title

Denominators

Categories

Title	Measurements
	OG0003.68± 1.83 OG0014.56± 2.31

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANCOVA		0.0002		Treatment Difference	-0.84			2-Sided	95	-1.29	-0.40					Superiority or Other (legacy)

Secondary

Number of Subjects Showing an Improvement of at Least 30% or 50% in Their Mean NRS Spasticity Score (Phase B) From Baseline.

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

Posted

Number

participants

Baseline (Day 1) - End of treatment (last 7 days of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts

Secondary

Change in Spasm Frequency (Number of Spasms Per Day) From Baseline to End of Treatment (Phase B).

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

Posted

Mean

Standard Deviation

Spasms per day

Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants

Secondary

Change in Sleep Disruption (Daily 11-point NRS) From Baseline to End of Treatment (Phase B).

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

Posted

Mean

Standard Deviation

Points on scale

Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants

Secondary

Change in Spasticity as Measured Using the Modified Ashworth Scale From Baseline to End of Treatment (Phase B).

All 20 muscle groups were assessed for spasticity (using a 1-5 scale): 1= no increase in muscle tone to 5= passive movement is difficult and affected part is rigid in flexion or extension. The score for all 20 muscle groups were added to give a total score out of 100; minimum score was 20. A decrease in score indicates an improvement in condition.

Posted

Mean

Standard Deviation

Score on scale

Baseline (End of Week 4) - End of treatment (End of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants

Secondary

Change in Motricity Index Score From Baseline to End of Treatment (Phase B)for Affected Limbs.

Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. Leg - 3 movements were ankle dorsiflexion, knee extension and hip flexion. The total arm and leg score was the addition of the score for the 3 arm movements and 3 leg movements, respectively. One point was then added to each limb score to give a maximum score of 100; minimum was 1 point. Where both arms (or both legs) were assessed, the average of the two limbs scores was used as the assessment score; otherwise the affected limb total score was used. An increase in score indicates an improvement in condition.

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

Posted

Mean

Standard Deviation

Score on scale

Baseline (End of Week 4) - End of treatment (End of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Secondary

Change in Timed 10-metre Walk From Baseline to End of Treatment (Phase B).

Only those subjects for whom it was appropriate (i.e. ambulatory subjects) were timed how long it took to walk 10 metres. Walk time was only assessed for subjects who successfully completed the Timed 10 Metre Walk. A negative difference from baseline indicates an improvement walk time.

Posted

Mean

Standard Deviation

Seconds

Baseline (End of Week 4) - End of treatment (End of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Secondary

Subject Global Impressions of Change at End of Treatment (Phase B).

Posted

Number

participants

End of Treatment (WeeK 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants	OG000

Secondary

Carer Global Impressions of Change at of Treatment (Phase B).

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

Posted

Number

participants

End of treatment (Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants	OG000

Secondary

Carer Ease of Transfer Global Impressions of Change at End of Treatment (Phase B).

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

Posted

Number

participants

End of treatment (week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants	OG000

Secondary

Physician Global Impressions of Change at End of Treatment (Phase B).

Posted

Number

participants

End of treatment (week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants	OG000

Secondary

Change EuroQoL Quality of Life Questionnaire (EQ-5D)From Baseline to End of Treatment (Phase B)

The EQ-5D questionnaire provided two outcomes:

A weighted health state index visual analogue scale (VAS)
A self-rated health status VAS EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.

The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing.

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

Posted

Mean

Standard Deviation

score on scale

[Baseline (End of Week 4) - End of treatment (End of Week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Secondary

Mood Assessment: Change in Beck Depression Inventory - II (BDI-II)From Baseline to End of Treatment (Phase B)

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

Posted

Mean

Standard Deviation

Score on scale

Baseline (End of week 4) - end of treatment (end of week 17)

ID	Title	Description
OG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.
OG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Sativex (Phase B)	contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours.			6	124	66	124
EG001	Placebo (Phase B)	Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.			1	117	40	117

Serious Adverse Events

Term	Organ System	Statistical Information
Bronchopneumonia	Infections and infestations	EG0001 affected124 at risk EG0010 affected117 at risk
Septic shock	Infections and infestations	EG0001 affected124 at risk EG0010 affected117 at risk
Urosepsis	Infections and infestations	EG0001 affected124 at risk EG0010 affected117 at risk
MS Relapse	Nervous system disorders	EG0001 affected124 at risk EG0010 affected117 at risk
Balance disorder	Nervous system disorders	EG0000 affected124 at risk EG0011 affected117 at risk
Pregnancy	Pregnancy, puerperium and perinatal conditions	EG0001 affected124 at risk EG0010 affected117 at risk
Suicidal Ideation	Psychiatric disorders	EG0001 affected124 at risk EG0010 affected117 at risk

Other Adverse Events

Term	Organ System	Statistical Information
Urinary tract infection	Infections and infestations	EG0009 affected124 at risk EG00112 affected117 at risk
Nasopharyngitis	Infections and infestations	EG0004 affected124 at risk EG0013 affected117 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	EG0007 affected124 at risk EG0018 affected117 at risk
Back pain	Musculoskeletal and connective tissue disorders	EG0005 affected124 at risk EG0014 affected117 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	EG0000 affected124 at risk EG0015 affected117 at risk
Headache	Nervous system disorders	EG0002 affected124 at risk EG0015 affected117 at risk
Muscle spasticity	Nervous system disorders	EG0003 affected124 at risk EG0014 affected117 at risk
Somnolence	Nervous system disorders	EG0004 affected124 at risk EG0011 affected117 at risk
Dizziness	Nervous system disorders	EG0004 affected124 at risk EG0010 affected117 at risk
MS relapse	Nervous system disorders	EG0004 affected124 at risk EG0011 affected117 at risk
Diarrhoea	Gastrointestinal disorders	EG0003 affected124 at risk EG0016 affected117 at risk
Dry mouth	Gastrointestinal disorders	EG0004 affected124 at risk EG0011 affected117 at risk
Nausea	Gastrointestinal disorders	EG0005 affected124 at risk EG0012 affected117 at risk
Abdominal pain upper	Gastrointestinal disorders	EG0004 affected124 at risk EG0010 affected117 at risk
Fatigue	General disorders	EG0006 affected124 at risk EG0011 affected117 at risk
Euphoric mood	Psychiatric disorders	EG0004 affected124 at risk EG0011 affected117 at risk
Vertigo	Ear and labyrinth disorders	EG0007 affected124 at risk EG0011 affected117 at risk

ID	Term
D009135	Muscular Diseases
D009140	Musculoskeletal Diseases
D009122	Muscle Hypertonia
D020879	Neuromuscular Manifestations
D009461	Neurologic Manifestations
D009422	Nervous System Diseases
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D020278	Demyelinating Autoimmune Diseases, CNS
D020274	Autoimmune Diseases of the Nervous System
D003711	Demyelinating Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases