A Parallel Group Study to Compare Sativex® With Placebo in the Treatment of Detrusor Overactivity in Patients With Multiple Sclerosis

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00678795
• Collaborator: (none)
• Enrollment: 135
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 3.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of Sativex® compared with placebo in reducing the daily number of episodes on incontinence.

Condition or Disease	Intervention/Treatment	Phase
Detrusor Overactivity; Multiple Sclerosis	Drug: Sativex®; Drug: Placebo	Phase 3

Detailed Description

This is a ten week, multicentre, double blind, randomised, placebo controlled parallel group study to evaluate the efficacy of Sativex® on urge incontinence associated with neurogenic unstable bladder. Multiple sclerosis patients with incontinence symptoms are screened to determine eligibility and complete a two-week baseline period. They then return for a further eligibility check, randomisation and initial dosing. Subjects titrate and self-medicate with study medication between study visits at weeks two and five. They will also complete efficacy assessments in their diary-books and at visits.

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Double Blind, Randomised, Placebo Controlled, Parallel Group Study of Cannabis Based Medicine (CBM) Extract, in Patients Suffering Detrusor Overactivity Associated With Multiple Sclerosis.
• Study Start Date: Aug 1, 2002
• Actual Primary Completion Date: Oct 1, 2005
• Actual Study Completion Date: Oct 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sativex Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Drug: Sativex®; Containing ∆9 tetrahydrocannabinol (THC), 27 mg/ml and cannabidiol (CBD), 25 mg/ml as extract of Cannabis sativa L. Subjects received study medication delivered in 100 µl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three-hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours; Other Names: GW-10000-02
Placebo Comparator: Placebo Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.	Drug: Placebo; containing excipients only. Subjects received study medication delivered in 100 µl actuations from a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three-hour period and 48 actuations in 24 hours.; Other Names: GW-4001-01

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Mean Daily Number of Incontinence Episodes at the End of Treatment [0 - 10 weeks]

   To assess the effect of Sativex in neurogenic overactive bladder, the incontinence episode frequency was selected as the primary endpoint. Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.

Secondary Outcome Measures

1. Change From Baseline in the Mean Daily Episodes of Urgency at the End of Treatment [Daily diary entries throughout 10 week study period]

   Subjects documented in the daily subject diary each instance of urgency, and the time that each took place, as for the recording of incontinence episode frequency. Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.

2. Change From Baseline in the Mean Daily Episodes of Nocturia at the End of Treatment [0 - 10 weeks]

   Subjects documented in the daily subject diary each instance of nocturia, and the time that each took place (as for the recording of incontinence episode frequency). Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.

3. Change From Baseline in the Mean Daily Number of Incontinence Pads Used at the End of Treatment [0 - 10 weeks]

   Subjects documented in the daily subject diary, the total number of incontinence pads they had used each day. Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.

4. Change From Baseline in Mean Total Incontinence Quality of Life (I-QOL) Questionnaire Score at the End of Treatment (Completion or Withdrawal) [0 - 10 weeks]

   The I-QOL consists of 22 items from three subscales; avoidance/limiting behaviour (eight items), psychosocial impact (nine items) and social embarrassment (five items). The responses to each of the 22 items were summed and averaged for a total score and then transformed to a 0-100 scale for ease of interpretation. The transformation formula used for the I-QOL total scores is: Transformed score = 100 x (the sum of the items - lowest possible score) / Possible raw score range. An increase in score indicates an improvement in QOL.

5. Change From Baseline in Mean Overall Bladder Condition 0-10 Numerical Rating Scale Score at the End of Treatment [0 - 10 weeks]

   Subjects subjectively assessed the severity of their urinary incontinence and general bladder symptoms by responding to the following question on a Numerical Rating Scale: My bladder condition, taking everything into account, causes me: 0 = "no problems" and 10 = "intolerable problems". Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.

6. Patient's Global Impression of Change [0 - 10 weeks]

   Subjects were asked at completion or withdrawal to give their impression of the overall change in their condition since entry into the study using the following seven-point scale: 1 = 'Very Much Improved', 2 = 'Much Improved', 3 = 'Minimally Improved', 4 = 'No Change', 5 = 'Minimally Worse', 6 = 'Much Worse', 7 = 'Very Much Worse'. The numbers who scored 1, 2, or 3 are presented.

7. Change From Baseline in the Mean Number of Daily Voids at the End of Treatment [0 - 10 weeks]

   Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to give informed consent.

• Male or female, aged 18 years or over.

• Diagnosed with MS and with detrusor overactivity not wholly relieved by current therapy.

• At least three incontinence episodes within five consecutive days during the baseline period

• Stable dose of anticholinergic medication for at least 14 days leading to study entry.

• Agreement, if female and of child bearing potential or if male with a partner of child bearing potential, to ensure that effective contraception is used during the study and for three months thereafter.

• Has not used cannabinoids (including cannabis, Marinol® or nabilone) for at least seven days before Visit 1 and willing to abstain from any use of cannabinoids during the study.

• Agreement for the UK Home Office, their general practitioner, and their consultant if appropriate, to be notified of their participation in the study.

Exclusion Criteria:

• A symptomatic UTI or any cause of detrusor overactivity other than neurogenic causes due to MS.

• Using ISC.

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

• A history of alcohol or substance abuse.

• A severe cardiovascular disorder, such as ischaemic heart disease, arrhythmias (other than well controlled atrial fibrillation), poorly controlled hypertension or severe heart failure.

• A history of epilepsy.

• If female, are pregnant of lactating, or are planning a pregnancy to occur during the course of the study.

• Significant renal or hepatic impairment.

• Elective surgery or other procedures requiring general anesthesia scheduled to occur during the study.

• Terminal illness or any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or influence the result of the study, or the subjects ability to participate in the study.

• Regular levodopa (Sinement®, Sinement Plus®, Levodopa, L-dopa, Madopar®, Benserazide) within the seven days leading up to study entry.

• Receiving and unwilling to stop fentanyl for the duration of the study.

• Known or suspected hypersensitivity to cannabinoids or any of the excipients of the study medications.

• Intention to travel internationally or to donate blood during the study.

• Participation in another research study in the 12 weeks leading up to study entry.

• Previous randomization in to this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Division of Clinical Neurology, Queen's Medical Centre	Nottingham	Notts	United Kingdom	NG7 2UH

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Cris Constantinescu, MD PhD, Division of Clinical Neurology, Queen's Medical Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00678795
• Other Study ID Numbers: GWMS0208
• First Posted: May 16, 2008
• Last Update Posted: Jun 24, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Jazz Pharmaceuticals: Detrusor overactivity; Multiple Sclerosis
• Additional relevant MeSH terms: Multiple Sclerosis; Urinary Bladder, Overactive; Sclerosis; Nabiximols

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Period Title: Overall Study
STARTED	67	68
COMPLETED	56	62
NOT COMPLETED	11	6

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.	Total of all reporting groups
Overall Participants	67	68	135
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	63 94%	66 97.1%	129 95.6%
>=65 years	4 6%	2 2.9%	6 4.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.61 (9.31)	46.79 (11.20)	47.69 (10.31)
Sex: Female, Male (Count of Participants)
Female	52 77.6%	46 67.6%	98 72.6%
Male	15 22.4%	22 32.4%	37 27.4%
Region of Enrollment (participants) [Number]
United Kingdom	35 52.2%	33 48.5%	68 50.4%
Belgium	23 34.3%	26 38.2%	49 36.3%
Romania	9 13.4%	9 13.2%	18 13.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Mean Daily Number of Incontinence Episodes at the End of Treatment
Description	To assess the effect of Sativex in neurogenic overactive bladder, the incontinence episode frequency was selected as the primary endpoint. Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	60	64
Mean (Standard Deviation) [number of daily episodes]	-1.08 (1.42)	-0.99 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The primary endpoint, the change in the number of incontinence episodes per day, was compared between treatment groups using analysis of covariance (ANCOVA). The model included treatment and centre as factors and baseline number of incontinence episodes per day as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.569
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Mean Daily Episodes of Urgency at the End of Treatment
Description	Subjects documented in the daily subject diary each instance of urgency, and the time that each took place, as for the recording of incontinence episode frequency. Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.
Time Frame	Daily diary entries throughout 10 week study period

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	60	64
Mean (Standard Deviation) [number of daily episodes]	-1.91 (2.44)	-1.12 (2.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change in the number of urgency episodes per day was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline number of urgency episodes per day as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -1.58 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Mean Daily Episodes of Nocturia at the End of Treatment
Description	Subjects documented in the daily subject diary each instance of nocturia, and the time that each took place (as for the recording of incontinence episode frequency). Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	60	64
Mean (Standard Deviation) [number of daily episodes]	-0.55 (0.75)	-0.21 (0.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change in the number of nocturia episodes per day was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline number of nocturia episodes per day as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.50 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the Mean Daily Number of Incontinence Pads Used at the End of Treatment
Description	Subjects documented in the daily subject diary, the total number of incontinence pads they had used each day. Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	48	55
Mean (Standard Deviation) [pads used daily]	-0.88 (1.50)	-0.73 (1.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change in the number of incontinence pads used per day was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline number of number of incontinence pads used per day as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Mean Total Incontinence Quality of Life (I-QOL) Questionnaire Score at the End of Treatment (Completion or Withdrawal)
Description	The I-QOL consists of 22 items from three subscales; avoidance/limiting behaviour (eight items), psychosocial impact (nine items) and social embarrassment (five items). The responses to each of the 22 items were summed and averaged for a total score and then transformed to a 0-100 scale for ease of interpretation. The transformation formula used for the I-QOL total scores is: Transformed score = 100 x (the sum of the items - lowest possible score) / Possible raw score range. An increase in score indicates an improvement in QOL.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	59	61
Mean (Standard Deviation) [units on a scale]	14.21 (17.51)	9.58 (12.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in the I-QOL score at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline I-QOL score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.166
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	3.90
	Confidence Interval	(2-Sided) 95%; -1.65 to 9.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Mean Overall Bladder Condition 0-10 Numerical Rating Scale Score at the End of Treatment
Description	Subjects subjectively assessed the severity of their urinary incontinence and general bladder symptoms by responding to the following question on a Numerical Rating Scale: My bladder condition, taking everything into account, causes me: 0 = "no problems" and 10 = "intolerable problems". Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	61	66
Mean (Standard Deviation) [units on a scale]	-2.3 (2.16)	-0.9 (2.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in the overall bladder condition Numerical Rating Scale score at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline overall bladder condition Numerical Rating Scale score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-1.16
	Confidence Interval	(2-Sided) 95%; -1.82 to -0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Patient's Global Impression of Change
Description	Subjects were asked at completion or withdrawal to give their impression of the overall change in their condition since entry into the study using the following seven-point scale: 1 = 'Very Much Improved', 2 = 'Much Improved', 3 = 'Minimally Improved', 4 = 'No Change', 5 = 'Minimally Worse', 6 = 'Much Worse', 7 = 'Very Much Worse'. The numbers who scored 1, 2, or 3 are presented.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	63	67
Number [participants]	51 76.1%	39 57.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	For Patient Global Impression of Change, the proportions of subjects who considered their condition 'Very Much Improved', 'Much Improved' or 'Minimally Improved' were compared between treatment groups using Fisher's Exact Test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	25.40
	Confidence Interval	(2-Sided) 95%; 10.37 to 40.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the Mean Number of Daily Voids at the End of Treatment
Description	Baseline was the average of all available data recorded during the 14 days immediately prior to the randomisation visit. End of Treatment was the last average available from Week 3, Week 5, and Weeks 7-8. A negative value indicates an improvement in score from baseline.
Time Frame	0 - 10 weeks

Outcome Measure Data

Analysis Population Description

All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.	Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
Measure Participants	60	64
Mean (Standard Deviation) [number of daily episodes]	-1.73 (1.95)	-0.87 (1.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change in the number of voids per day was compared between treatment groups using ANCOVA. The model included treatment and centre as factors and baseline number of voids per day as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.85
	Confidence Interval	(2-Sided) 95%; -1.47 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All adverse events occurring from the extension study onset to the last study visit (up to 99 days) were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected.
Adverse Event Reporting Description	All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Arm/Group Title	Sativex		Placebo
Arm/Group Description	Each 100 ul actuation contains 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD). A maximum of 48 actuations (130 mg of THC and 120 mg of CBD) was permitted in any 24 hour period.		Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
All Cause Mortality
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/67 (3%)		2/68 (2.9%)
Gastrointestinal disorders
Vomiting	0/67 (0%)		1/68 (1.5%)
Metabolism and nutrition disorders
Dehydration	1/67 (1.5%)		1/68 (1.5%)
Nervous system disorders
Transient Ischaemic Attack	1/67 (1.5%)		0/68 (0%)
Dizziness	0/67 (0%)		1/68 (1.5%)
Multiple Sclerosis Relapse	0/67 (0%)		1/68 (1.5%)
Renal and urinary disorders
Cystitis Haemorrhagic	1/67 (1.5%)		0/68 (0%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/67 (71.6%)		43/68 (63.2%)
Ear and labyrinth disorders
Vertigo	2/67 (3%)		0/68 (0%)
Gastrointestinal disorders
Vomiting Not Otherwise Specified	4/67 (6%)		2/68 (2.9%)
Constipation	3/67 (4.5%)		0/68 (0%)
Nausea	3/67 (4.5%)		3/68 (4.4%)
Diarrhoea Not Otherwise Specified	2/67 (3%)		4/68 (5.9%)
Abdominal Pain Upper	2/67 (3%)		0/68 (0%)
Toothache	0/67 (0%)		2/68 (2.9%)
General disorders
Feeling Drunk	3/67 (4.5%)		0/68 (0%)
Weakness	3/67 (4.5%)		2/68 (2.9%)
Fatigue	0/67 (0%)		3/68 (4.4%)
Application Site Pain	0/67 (0%)		3/68 (4.4%)
Feeling Abnormal	2/67 (3%)		0/68 (0%)
Chest Pain	0/67 (0%)		2/68 (2.9%)
Pyrexia	0/67 (0%)		2/68 (2.9%)
Infections and infestations
Urinary tract infection Not Otherwise Specified	4/67 (6%)		7/68 (10.3%)
Cystitis Not Otherwise Specified	3/67 (4.5%)		0/68 (0%)
Nasopharyngitis	3/67 (4.5%)		0/68 (0%)
Influenza	0/67 (0%)		2/68 (2.9%)
Pharyngitis Viral Not Otherwise Specified	0/67 (0%)		2/68 (2.9%)
Metabolism and nutrition disorders
Anorexia	0/67 (0%)		2/68 (2.9%)
Musculoskeletal and connective tissue disorders
Neck Pain	0/67 (0%)		2/68 (2.9%)
Nervous system disorders
Dizziness	12/67 (17.9%)		5/68 (7.4%)
Headache Not Otherwise Specified	5/67 (7.5%)		5/68 (7.4%)
Balance Impaired Not Otherwise Specified	3/67 (4.5%)		0/68 (0%)
Paraesthesia	3/67 (4.5%)		0/68 (0%)
Multiple Sclerosis Relapse	0/67 (0%)		3/68 (4.4%)
Disturbance in Attention	2/67 (3%)		0/68 (0%)
Memory Impairment	2/67 (3%)		0/68 (0%)
Somnolence	2/67 (3%)		2/68 (2.9%)
Psychiatric disorders
Disorientation	4/67 (6%)		0/68 (0%)
Dissociation	4/67 (6%)		0/68 (0%)
Confusion	2/67 (3%)		0/68 (0%)
Skin and subcutaneous tissue disorders
Sweating Increased	2/67 (3%)		0/68 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.