Trial Outcomes & Findings for A Study to Evaluate the Efficacy of Sativex in Relieving Symptoms of Spasticity Due to Multiple Sclerosis (NCT NCT01599234)

Last Updated: 2023-05-03

Results Overview

The average spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. A negative value indicates an improvement in pain score from baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

337 participants

Primary outcome timeframe

0-15 weeks

Results posted on

2023-05-03

Participant Flow

Participant milestones

Participant milestones
Measure	Sativex Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Overall Study STARTED	167	170
Overall Study COMPLETED	150	155
Overall Study NOT COMPLETED	17	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Sativex Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Overall Study Adverse Event	9	5
Overall Study Withdrawal by Subject	2	1
Overall Study Lost to Follow-up	1	2
Overall Study Lack of Efficacy	2	4
Overall Study Unable to operate spray	1	0
Overall Study Sponsor request as creatinine levels <50	0	1
Overall Study Death	1	0
Overall Study Patient would not stop driving	1	0
Overall Study Contra-indication discovered	0	1
Overall Study Pregnancy	0	1

Baseline Characteristics

A Study to Evaluate the Efficacy of Sativex in Relieving Symptoms of Spasticity Due to Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sativex n=167 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=170 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.	Total n=337 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	162 Participants n=5 Participants	168 Participants n=7 Participants	330 Participants n=5 Participants
Age, Categorical >=65 years	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Age, Continuous	48.0 years STANDARD_DEVIATION 10.06 • n=5 Participants	47.1 years STANDARD_DEVIATION 9.15 • n=7 Participants	47.5 years STANDARD_DEVIATION 9.61 • n=5 Participants
Sex: Female, Male Female	106 Participants n=5 Participants	101 Participants n=7 Participants	207 Participants n=5 Participants
Sex: Female, Male Male	61 Participants n=5 Participants	69 Participants n=7 Participants	130 Participants n=5 Participants
Region of Enrollment United Kingdom	65 participants n=5 Participants	63 participants n=7 Participants	128 participants n=5 Participants
Region of Enrollment Czech Republic	102 participants n=5 Participants	107 participants n=7 Participants	209 participants n=5 Participants

PRIMARY outcome

Timeframe: 0-15 weeks

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

Outcome measures

Outcome measures
Measure	Sativex n=166 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=169 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Change From Baseline in Mean Spasticity 0-10 Numerical Rating Scale (NRS) Score During the Last 14 Day of Treatment (End of Treatment)	-1.22 units on a scale Standard Deviation 1.76	-0.91 units on a scale Standard Deviation 1.72

SECONDARY outcome

Timeframe: 0-15 weeks

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

The cumulative response to treatment was the percentage change from baseline in the mean NRS spasticity score as defined as the 30% response. The spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. The number of responders at the 30% level is presented.

Outcome measures

Outcome measures
Measure	Sativex n=166 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=169 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Number of Subjects With a 30% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline	51 participants	42 participants

SECONDARY outcome

Timeframe: Day 0 (Randomisation) and Day 99 (End of Treatment)

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

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.

Outcome measures

Outcome measures
Measure	Sativex n=156 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=160 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Change From Baseline in the Mean Modified Ashworth Scale Score at the End of Treatment	-3.3 units on a scale Standard Deviation 9.25	-2.8 units on a scale Standard Deviation 7.81

SECONDARY outcome

Timeframe: 0-15 weeks

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

The sleep disruption NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate how your spasticity disrupted your sleep last night?" where 0 = did not disrupt sleep and 10 = completely disrupted (unable to sleep at all). A negative value indicates an improvement in sleep disruption score from baseline.

Outcome measures

Outcome measures
Measure	Sativex n=124 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=139 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Change From Baseline in Mean Sleep Quality 0-10 NRS During the Last 14 Days of Treatment (End of Treatment)	-0.7 units on a scale Standard Deviation 2.85	-0.6 units on a scale Standard Deviation 2.37

SECONDARY outcome

Timeframe: 0-15 weeks

Population: All subjects who were randomised, received at least one actuation of study medication and had on-treatment efficacy data were included in the analysis, as were a further two subjects who were excluded from the full analysis set (used for the efficacy analysis) as a result of no on-treatment efficacy data

The number of subjects who experienced and adverse event during the course of the study is presented

Outcome measures

Outcome measures
Measure	Sativex n=167 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=170 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Incidence of Adverse Events as a Measure of Subject Safety	156 participants	132 participants

SECONDARY outcome

Timeframe: Day 0 (Randomisation) and Day 99 (End of Treatment)

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

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.

Outcome measures

Outcome measures
Measure	Sativex n=115 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=120 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Change From Baseline in Mean Timed 10 Metre Walk Time at the End of Treatment	-2.1 time (seconds) Standard Deviation 17.37	9.3 time (seconds) Standard Deviation 63.56

SECONDARY outcome

Timeframe: Day 99 (end of treatment)

The carer of the subject gave their opinion of any noticeable change in the subject's overall functional ability at the end of the study. A 7-point Likert-type scale was used, with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". The number of carers who reported an improvement at the end of treatment is presented.

Outcome measures

Outcome measures
Measure	Sativex n=167 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=170 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Carer Global Impression of Change at the End of Treatment	72 participants	56 participants

SECONDARY outcome

Timeframe: Day 0 (Randomisation) and Day 99 (End of Treatment)

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

The Barthel Index consists of 10 items that measure a person's daily functioning specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. The person receives a score based on whether they have received help while doing the task. The scores for each of the items are summed to create a total score of 100. An increase in score indicates an improvement.

Outcome measures

Outcome measures
Measure	Sativex n=162 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=165 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Change From Baseline in the Mean Total Barthel Activities of Daily Living Index Score at the End of Treatment	-0.1 units on a scale Standard Deviation 10.26	0.5 units on a scale Standard Deviation 8.05

SECONDARY outcome

Timeframe: 0 - 15 weeks

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

The cumulative response to treatment was the percentage change from baseline in the mean NRS spasticity score as defined as the 50% response. The spasticity NRS was completed at the same time each day, i.e. bedtime in the evening. The subject was asked "on a scale of '0 to 10', please indicate the number that best describes your spasticity in the last 24 hours" where 0 = no spasticity and 10 = worst possible spasticity. The number of responders at the 50% level is presented.

Outcome measures

Outcome measures
Measure	Sativex n=166 Participants Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=169 Participants Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Number of Subjects With a 50% or Greater Improvement in Mean Spasticity 0-10 NRS Score at the End of Treatment Compared to Baseline	21 participants	18 participants

Adverse Events

Sativex

Serious events: 15 serious events

Other events: 156 other events

Deaths: 0 deaths

Placebo

Serious events: 7 serious events

Other events: 132 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Mr Richard Potts, Clinical Operations Director

GW Pharma Ltd.

Phone: 0044 1223 266800

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Sativex n=167 participants at risk Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours.	Placebo n=170 participants at risk Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Nervous system disorders Dizziness	31.7% 53/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	10.0% 17/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Somnolence	14.4% 24/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	4.1% 7/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Muscle Spasticity	10.2% 17/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	7.6% 13/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Headache	9.0% 15/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	5.9% 10/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Dysgeusia	5.4% 9/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Disturbance in Attention	4.2% 7/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Dysarthria	4.2% 7/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Multiple Sclerosis Relapse	3.0% 5/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	2.9% 5/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
General disorders Fatigue	25.1% 42/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	18.8% 32/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
General disorders Asthenia	15.6% 26/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	6.5% 11/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
General disorders Feeling Abnormal	3.6% 6/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.59% 1/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
General disorders Malaise	3.6% 6/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.59% 1/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Nausea	31.7% 53/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	10.0% 17/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Dry Mouth	14.4% 24/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	4.1% 7/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Diarrhoea	9.0% 15/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	5.9% 10/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Vomiting	5.4% 9/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Dyspepsia	4.2% 7/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Constipation	4.2% 7/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Psychiatric disorders Insomnia	2.4% 4/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	2.9% 5/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Psychiatric disorders Anxiety	0.60% 1/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	2.9% 5/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Infections and infestations Urinary Tract Infection Not Otherwise Specified	11.4% 19/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	12.4% 21/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Ear and labyrinth disorders Vertigo	11.4% 19/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	4.1% 7/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Musculoskeletal and connective tissue disorders Back Pain	4.2% 7/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	0.59% 1/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.
Musculoskeletal and connective tissue disorders Muscle Spasms	4.2% 7/167 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.	2.9% 5/170 • All adverse events occurring from the time of consent to post study follow up were collected (Days 0 - 134). All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected. All adverse occurring during the study were reported on the running logs at the back of the study case report form.