Trial Outcomes & Findings for Sativex Versus Placebo When Added to Existing Treatment for Central Neuropathic Pain in MS (NCT NCT00391079)

Last Updated: 2013-06-24

Results Overview

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 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 multiple sclerosis. A negative value indicates an improvement in pain score from baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

339 participants

Primary outcome timeframe

14 weeks: Baseline - End of Treatment (last 7 days of treatment)

Results posted on

2013-06-24

Participant Flow

Participant milestones

Participant milestones
Measure	Sativex Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo Range of 8-12 sprays per day of placebo spray.
Overall Study STARTED	167	172
Overall Study COMPLETED	141	156
Overall Study NOT COMPLETED	26	16

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Sativex Versus Placebo When Added to Existing Treatment for Central Neuropathic Pain in MS

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sativex n=167 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 Participants Range of 8-12 sprays per day of placebo spray.	Total n=339 Participants Total of all reporting groups
Age Continuous	48.42 years STANDARD_DEVIATION 10.43 • n=5 Participants	49.51 years STANDARD_DEVIATION 10.50 • n=7 Participants	48.97 years STANDARD_DEVIATION 10.47 • n=5 Participants
Sex: Female, Male Female	113 Participants n=5 Participants	117 Participants n=7 Participants	230 Participants n=5 Participants
Sex: Female, Male Male	54 Participants n=5 Participants	55 Participants n=7 Participants	109 Participants n=5 Participants
Duration of Multiple Sclerosis (MS)	11.42 years STANDARD_DEVIATION 8.00 • n=5 Participants	12.53 years STANDARD_DEVIATION 8.50 • n=7 Participants	11.99 years STANDARD_DEVIATION 8.26 • n=5 Participants
Duration of Central Neuropathic Pain (CNP)	5.59 years STANDARD_DEVIATION 6.12 • n=5 Participants	5.33 years STANDARD_DEVIATION 4.80 • n=7 Participants	5.46 years STANDARD_DEVIATION 5.49 • n=5 Participants
Baseline Pain Numerical Rating Scale (NRS) score	6.55 Points on a scale STANDARD_DEVIATION 1.35 • n=5 Participants	6.61 Points on a scale STANDARD_DEVIATION 1.29 • n=7 Participants	6.58 Points on a scale STANDARD_DEVIATION 1.32 • n=5 Participants

PRIMARY outcome

Timeframe: 14 weeks: Baseline - End of Treatment (last 7 days of treatment)

Population: Change in mean daily NRS score

Outcome measures

Outcome measures
Measure	Sativex n=167 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 Participants Range of 8-12 sprays of placebo per day
Change in Mean Pain Due to MS NRS Score	-2.02 units on a scale Standard Deviation 2.15	-1.89 units on a scale Standard Deviation 2.33

PRIMARY outcome

Timeframe: 14 weeks: Baseline - end of treatment (last 7 days)

A positive 30% pain response is defined as a reduction of at least 30% in the mean NRS pain score from baseline to week 14 (last 7 days). The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your 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 multiple sclerosis. The pain NRS was completed at the same time each day, i.e. bedtime in the evening.

Outcome measures

Outcome measures
Measure	Sativex n=167 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 Participants Range of 8-12 sprays of placebo per day
Number of Patients With at Least 30% Improvement in Numerical Rating Scale (NRS) Pain Score From Baseline	84 participants	77 participants

SECONDARY outcome

Timeframe: 14 weeks: Baseline - End of treatment (Week 14)

The NPS score is 0-100 sum of 10 individual pain scores (0-10 NRS, 0= no pain to 10 = most pain imaginable). A negative change from baseline indicates an improvement in pain.

Outcome measures

Outcome measures
Measure	Sativex n=167 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 Participants Range of 8-12 sprays of placebo per day
Change in Pain From Baseline to End of the Treatment Using the NPS (Neuropathic Pain Scale)	-14.24 Points on a scale Standard Deviation 18.17	-11.44 Points on a scale Standard Deviation 17.86

SECONDARY outcome

Timeframe: 14 weeks: baseline - end of treatment (last 7 days)

Use of break through medication was recorded daily during the 14 weeks of the study as the number of paracetamol tablets taken. The change in mean daily quantities of tablets used was calculated from baseline to the last seven days of treatment.

Outcome measures

Outcome measures
Measure	Sativex n=167 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 Participants Range of 8-12 sprays of placebo per day
Change From Baseline to End of Treatment in Break-through Analgesia Usage	-1.16 tablets Standard Deviation 1.61	-1.02 tablets Standard Deviation 2.07

SECONDARY outcome

Timeframe: 14 weeks: Baseline to end of treatment (last 7 days of treatment)

Population: All subjects who completed the BPI-short form were included in the analysis. Four subjects from the sativex group and three subjects from the placebo group did not complete the form.

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 n=163 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=169 Participants Range of 8-12 sprays of placebo per day
Change From Baseline to End of Treatment in BPI (Brief Pain Inventory) Short Form	-1.5 Points on a scale Standard Deviation 2.04	-1.4 Points on a scale Standard Deviation 2.09

SECONDARY outcome

Timeframe: Week 14

Population: All subjects who completed the question were included in the analysis. Two subjects from the Sativex group and six subjects from the placebo group did not complete the question.

A 7-point Likert-type scale was used, with the question: 'Please assess the status of your pain due to multiple sclerosis 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 baseline subjects wrote a brief description of their pain caused by multiple sclerosis which was used at Week 14 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 n=165 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=166 Participants Range of 8-12 sprays of placebo per day
Change in Subject Global Impression of Change (SGIC) Very Much Improved	13 percentage of subjects	8 percentage of subjects
Change in Subject Global Impression of Change (SGIC) Much Improved	18 percentage of subjects	15 percentage of subjects
Change in Subject Global Impression of Change (SGIC) Slightly Improved	32 percentage of subjects	25 percentage of subjects
Change in Subject Global Impression of Change (SGIC) No Change	29 percentage of subjects	43 percentage of subjects
Change in Subject Global Impression of Change (SGIC) Slightly Worse	5 percentage of subjects	5 percentage of subjects
Change in Subject Global Impression of Change (SGIC) Much Worse	2 percentage of subjects	2 percentage of subjects
Change in Subject Global Impression of Change (SGIC) Very Much Worse	1 percentage of subjects	1 percentage of subjects

SECONDARY outcome

Timeframe: 14 weeks; Baseline to end of treatment (last 7 days)

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 n=167 Participants Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 Participants Range of 8-12 sprays of placebo per day
Change in Sleep Disruption NRS	-1.97 points on a scale Standard Deviation 2.21	-2.02 points on a scale Standard Deviation 2.29

Adverse Events

Sativex

Serious events: 3 serious events

Other events: 99 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 65 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Sativex n=167 participants at risk Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 participants at risk Range of 8-12 sprays of placebo per day
Gastrointestinal disorders Diarrhoea	0.60% 1/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Constipation	0.00% 0/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Nausea	0.00% 0/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Vomiting	0.00% 0/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Investigations Hepatic enzyme increased	0.60% 1/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Motor dysfunction	0.00% 0/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Syncope	0.00% 0/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Psychiatric disorders Suicidal Ideation	0.60% 1/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Vascular disorders Orthostatic hypotension	0.00% 0/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.

Other adverse events

Additional Information

Richard Potts Clinical Operations Director

GW Pharmaceuticals

Phone: +44 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 Range of 8 -12 sprays per day. Each actuation of oromucosal spray delivers 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). Thus maximum daily dose is 32.4 mg THC and 30 mg CBD.	Placebo n=172 participants at risk Range of 8-12 sprays of placebo per day
Nervous system disorders Psychomotor skills impaired	3.0% 5/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.00% 0/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Ear and labyrinth disorders Vertigo	9.0% 15/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	3.5% 6/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Nausea	7.8% 13/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	4.1% 7/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Dry mouth	7.2% 12/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	5.8% 10/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Diarrhoea	4.2% 7/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	2.9% 5/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Gastrointestinal disorders Vomitting	3.0% 5/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	2.9% 5/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
General disorders Fatigue	9.6% 16/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	5.2% 9/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
General disorders Feeling Abnormal	3.0% 5/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	1.2% 2/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Dizziness	20.4% 34/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	4.1% 7/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Somnolence	9.6% 16/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	1.7% 3/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Headache	4.2% 7/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	3.5% 6/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events 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	3.6% 6/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Dysgeusia	3.6% 6/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Memory Impairment	3.6% 6/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	0.58% 1/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Nervous system disorders Balance Disorder	3.0% 5/167 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.	1.2% 2/172 • All adverse events occurring from time of consent to post study follow up i.e. 15 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medications were also collected/ All adverse events occurring during the study were reported on the running logs at the back of the study case report form.