Trial Outcomes & Findings for A Study of Sativex® for Pain Relief in Patients With Advanced Malignancy. (NCT NCT00530764)

Last Updated: 2013-06-20

Results Overview

A positive 30% pain response is defined as a reduction of at least 30% in the mean NRS average pain score from baseline to week 5 (last 3 days). The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain in the last 24 hours" where 0 = no pain and 10 = pain as bad as you can imagine. No pain relates to the time prior to the onset of pain due to cancer. The average pain NRS was completed at the same time each day, i.e. bedtime in the evening.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

360 participants

Primary outcome timeframe

5 Weeks: Baseline (first 3 days) - Week 5 (last 3 days)

Results posted on

2013-06-20

Participant Flow

Participant milestones

Participant milestones
Measure	Sativex High Dose Group Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo Range of 1-16 sprays per day of placebo spray
Overall Study STARTED	90	88	91	91
Overall Study COMPLETED	59	67	71	66
Overall Study NOT COMPLETED	31	21	20	25

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study of Sativex® for Pain Relief in Patients With Advanced Malignancy.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sativex High Dose Group n=90 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=88 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=91 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 Participants Range of 1-16 sprays per day of placebo spray	Total n=360 Participants Total of all reporting groups
Age Continuous	58 years STANDARD_DEVIATION 11.2 • n=5 Participants	59 years STANDARD_DEVIATION 31.1 • n=7 Participants	59 years STANDARD_DEVIATION 12.3 • n=5 Participants	56 years STANDARD_DEVIATION 12.2 • n=4 Participants	58 years STANDARD_DEVIATION 12.2 • n=21 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	39 Participants n=7 Participants	46 Participants n=5 Participants	47 Participants n=4 Participants	174 Participants n=21 Participants
Sex: Female, Male Male	48 Participants n=5 Participants	49 Participants n=7 Participants	45 Participants n=5 Participants	44 Participants n=4 Participants	186 Participants n=21 Participants

PRIMARY outcome

Timeframe: 5 Weeks: Baseline (first 3 days) - Week 5 (last 3 days)

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=90 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=91 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 Participants Range of 1-16 sprays per day of placebo spray
Number of Patients With at Least 30% Improvement in Numerical Rating Scale (NRS) Average Pain Score From Baseline	22 Participants Interval 0.46 to 1.76	26 Participants Interval 0.62 to 2.28	30 Participants Interval 0.72 to 2.6	24 Participants

SECONDARY outcome

Timeframe: Baseline to end of treatment (Week 5)

The cumulative response to treatment is the percentage changes from baseline in the mean NRS pain score as defined as the 30% response. The pain NRS was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain in the last 24 hours" where 0 = no pain and 10 = pain as bad as you can imagine. No pain relates to the time prior to the onset of pain due to cancer.

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=89 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=89 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 Participants Range of 1-16 sprays per day of placebo spray
Change in Cumulative Average Pain Response Curves	-13 Percent Change Interval -30.0 to 6.0	-20 Percent Change Interval -40.0 to -6.0	-20 Percent Change Interval -48.0 to -8.0	-10 Percent Change Interval -33.0 to 5.0

SECONDARY outcome

Timeframe: 5 Weeks: Baseline (first 3 days) - End of Treatment (last 3 days of week 5)

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

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=89 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=89 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 Participants Range of 1-16 sprays per day of placebo spray
Change in Mean Daily NRS Pain Score (Average Pain).	-0.9 Points on scale Standard Deviation 1.9 • Interval -6.3 to 2.3	-1.2 Points on scale Standard Deviation 1.7 • Interval -7.3 to 5.7	-1.6 Points on scale Standard Deviation 2.1 • Interval -8.0 to 3.3	-0.8 Points on scale Standard Deviation 1.8 • Interval -6.0 to 3.7

SECONDARY outcome

Timeframe: 5 Weeks: Baseline (first 3 days) - End of Treatment (last 3 days of week 5)

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

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=89 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=89 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 Participants Range of 1-16 sprays per day of placebo spray
Change in Mean Daily NRS Pain Score (Worst Pain).	-1.0 Points on scale Standard Deviation 1.9	-1.2 Points on scale Standard Deviation 1.8	-1.6 Points on scale Standard Deviation 2.2	-0.9 Points on scale Standard Deviation 2.0

SECONDARY outcome

Timeframe: 5 Weeks: Baseline - End of Treatment (Last 3 days of Week 5)

The sleep disruption NRS was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate how your pain 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 High Dose Group n=89 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=89 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 Participants Range of 1-16 sprays per day of placebo spray
Change in Sleep Disruption NRS	-0.7 Points on scale Standard Deviation 2.1 • Interval -1.45 to -0.31	-0.9 Points on scale Standard Deviation 2.1 • Interval -1.45 to -0.31	-1.5 Points on scale Standard Deviation 2.1 • Interval -1.45 to -0.31	-0.8 Points on scale Standard Deviation 2.2

SECONDARY outcome

Timeframe: Baseline (Visit 2) and End of Treatment (End of Week 5 or premature termination)

The BPI-SF is a 14-item questionnaire that asks patients to rate pain over the prior week and the degree to which it interferes with activities on a 0 to 10 scale, where 0=no pain and 10=pain as bad as you can imagine. Severity is measured as worst pain, least pain, average pain, and pain right now. The severity composite score was calculated as the arithmetic mean of the four severity items(range 0-10). the minimum value is zero and maximum is 10. A higher score represents a poor outcome.

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=68 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=68 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=69 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=74 Participants Range of 1-16 sprays per day of placebo spray
Change in Brief Pain Inventory - Short Form (BPI-SF)	-1.0 Score on scale Standard Deviation 1.9 • Interval 0.09 to 0.34	-1.5 Score on scale Standard Deviation 1.6 • Interval 0.09 to 0.34	-1.3 Score on scale Standard Deviation 2.3 • Interval 0.09 to 0.34	-1.0 Score on scale Standard Deviation 1.9

SECONDARY outcome

Timeframe: Baseline (Visit 2) and End of Treatment (Week 5 or premature termination)

The PAC-QoL questionnaire consists of 28 questions divided into the following areas: 4 questions on physical discomfort, 8 questions on psychosocial discomfort, 11 questions on worries/concerns and 5 questions on satisfaction. The PAC-QoL was completed at baseline and then at the end of treatment. An overall score (range 0-4) was calculated at each visit and the difference determined. A positive difference in score represents an improvement.

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=70 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=68 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=70 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=74 Participants Range of 1-16 sprays per day of placebo spray
Change in Patient Assessment of Constipation Quality of Life (PAC-QoL)	0.0 Score on scale Standard Deviation 0.7 • Interval -0.04 to 0.26	-0.1 Score on scale Standard Deviation 0.5 • Interval -0.04 to 0.26	0.0 Score on scale Standard Deviation 0.6 • Interval -0.04 to 0.26	-0.1 Score on scale Standard Deviation 0.6

SECONDARY outcome

Timeframe: End of Week 5

A 7-point Likert-type scale was used, with the question: 'Please assess the status of your pain due to cancer since entry into the study using the scale below' with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". At Visit 2 (Baseline) patients wrote a brief description of their pain caused by cancer which was used at Week 5 to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported.

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=73 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=71 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=70 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=72 Participants Range of 1-16 sprays per day of placebo spray
Change in Patient Global Impression of Change - PGIC Slightly improved	25 Participants	26 Participants	19 Participants	28 Participants
Change in Patient Global Impression of Change - PGIC No change	13 Participants	13 Participants	13 Participants	17 Participants
Change in Patient Global Impression of Change - PGIC Very much worse	2 Participants	2 Participants	0 Participants	0 Participants
Change in Patient Global Impression of Change - PGIC Very much improved	6 Participants Interval 0.46 to 1.49	6 Participants Interval 0.49 to 1.58	10 Participants Interval 0.77 to 2.53	9 Participants
Change in Patient Global Impression of Change - PGIC Much improved	20 Participants	19 Participants	24 Participants	16 Participants
Change in Patient Global Impression of Change - PGIC Slightly worse	6 Participants	5 Participants	3 Participants	1 Participants
Change in Patient Global Impression of Change - PGIC Much worse	1 Participants	0 Participants	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline and End of Treatment (Week 5 or premature termination)

The MADRS comprises of 10 questions that are completed by the patient to determine their depression level. The MADRS was completed at Visit 2 (Baseline) prior to receiving the study drug and at Visit 4 (Week 5 or premature termination). Each item is scored on a 0-6 scale , where 0=no sadness to 6=extreme and continuous gloom and despondency, and the MADRS score is the sum of the 10 item scores (range 0-60). The higher the score the more severe the depression.

Outcome measures

Outcome measures
Measure	Sativex High Dose Group n=67 Participants Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=66 Participants Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=66 Participants Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=69 Participants Range of 1-16 sprays per day of placebo spray
Change in Montgomery Asberg Depression Rating Scale (MADRS)	-0.4 Score on scale Standard Deviation 8.6 • Interval 0.38 to 3.74	-1.0 Score on scale Standard Deviation 8.5 • Interval 0.38 to 3.74	-1.1 Score on scale Standard Deviation 7.0 • Interval 0.38 to 3.74	-2.9 Score on scale Standard Deviation 9.0

Adverse Events

Sativex High Dose Group

Serious events: 28 serious events

Other events: 82 other events

Deaths: 0 deaths

Sativex Medium Dose Group

Serious events: 18 serious events

Other events: 73 other events

Deaths: 0 deaths

Sativex Low Dose Group

Serious events: 35 serious events

Other events: 68 other events

Deaths: 0 deaths

Placebo

Serious events: 23 serious events

Other events: 69 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Matthew Hersch, Senior Clinical Project Manager

GW Pharma Ltd.

Phone: +44 1353 616600

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Publication Policy: 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

Serious adverse events
Measure	Sativex High Dose Group n=90 participants at risk Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 participants at risk Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=91 participants at risk Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 participants at risk Range of 1-16 sprays per day of placebo spray
Blood and lymphatic system disorders Blood and Lymphatic system disorders	0.00% 0/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.4% 4/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.2% 2/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Cardiac disorders Cardiac disorders	0.00% 0/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Gastrointestinal disorders	4.4% 4/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	3.4% 3/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.2% 2/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
General disorders General Disorders	4.4% 4/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.4% 4/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.2% 2/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Hepatobiliary disorders Hepatobiliary disorders	1.1% 1/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Infections and infestations Infections and Infestations	2.2% 2/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	5.7% 5/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.4% 4/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.2% 2/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Injury, poisoning and procedural complications Injury, Poisoning and procedural complications	0.00% 0/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Investigations Investigations	1.1% 1/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Metabolism and nutrition disorders Metabolism and Nutrition disorders	3.3% 3/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	0.00% 0/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (Incl. Cysts and polyps)	14.4% 13/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	13.8% 12/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	28.6% 26/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	16.5% 15/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Nervous system disorders	3.3% 3/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Psychiatric disorders Psychiatric disorders	2.2% 2/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Renal and urinary disorders Renal and urinary disorders	4.4% 4/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	1.1% 1/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Vascular disorders Vascular disorders	3.3% 3/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.

Other adverse events
Measure	Sativex High Dose Group n=90 participants at risk Range of 11 to 16 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 43.2mg THC and 40mg CBD.	Sativex Medium Dose Group n=87 participants at risk Range of 6 to 10 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 27mg THC and 25mg CBD.	Sativex Low Dose Group n=91 participants at risk Range of 1 to 4 sprays per day. Each actuation of oromucosal spray delivers 2.7mg delta-9-tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD). Thus maximum daily dose is 10.8mg THC and 10mg CBD.	Placebo n=91 participants at risk Range of 1-16 sprays per day of placebo spray
Blood and lymphatic system disorders Blood and lymphatic system disorders	10.0% 9/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	9.2% 8/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	9.9% 9/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	7.7% 7/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Cardiac disorders Cardiac disorders	2.2% 2/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.3% 2/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.6% 6/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.6% 6/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Ear and labyrinth disorders Ear and labyrinth disorders	4.4% 4/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.6% 4/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	3.3% 3/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Eye disorders Eye disorders	1.1% 1/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.6% 4/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Gastrointestinal Disorder	52.2% 47/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	48.3% 42/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	39.6% 36/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	31.9% 29/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
General disorders General Disorders	26.7% 24/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	20.7% 18/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	19.8% 18/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	22.0% 20/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Hepatobiliary disorders Hepatobillary Disorders	2.2% 2/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Infections and infestations Infections and Infestations	8.9% 8/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	17.2% 15/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	13.6% 11/81 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	12.1% 11/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	1.1% 1/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.3% 2/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.4% 4/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Investigations Investigations	5.6% 5/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	10.3% 9/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	12.1% 11/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	3.3% 3/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Metabolism and nutrition disorders Metabolism and nutrition disorders	24.4% 22/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	17.2% 15/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	12.1% 11/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	13.2% 12/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	5.6% 5/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	13.8% 12/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.6% 6/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.6% 6/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps)	17.8% 16/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	13.8% 12/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	28.6% 26/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	15.4% 14/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Nervous system disorders	48.9% 44/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	44.8% 39/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	28.6% 26/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	22.0% 20/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Psychiatric disorders Psychiatric disorders	25.6% 23/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	16.1% 14/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	14.3% 13/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	14.3% 13/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Renal and urinary disorders Renal and urinary disorders	8.9% 8/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.6% 4/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.4% 4/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.6% 6/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	7.8% 7/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.9% 6/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	12.1% 11/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	6.6% 6/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Skin and subcutaneous tissue disorders Skin and subcuraneous tissue disorders	7.8% 7/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	3.4% 3/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	3.3% 3/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	1.1% 1/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Surgical and medical procedures Surgical and medical procedures	0.00% 0/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	2.2% 2/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Vascular disorders Vascular Disorders	4.4% 4/90 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	3.4% 3/87 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	5.5% 5/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.	4.4% 4/91 • All adverse events (AEs) occurring from the time of consent to post study follow up (Visit 5) i.e.9 weeks were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected. All AEs occurring during the study were reported on the running logs at the back of the study case report form.