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The purpose of this study is to evaluate the efficacy of Sativex® compared with placebo in reducing the daily number of episodes on incontinence.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sativex | Experimental | 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. |
|
| Placebo | Placebo Comparator | Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sativex® | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Mean Daily Number of Incontinence Episodes at the End of Treatment | 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. | 0 - 10 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Mean Daily Episodes of Urgency at the End of Treatment | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cris Constantinescu, MD PhD | Division of Clinical Neurology, Queen's Medical Centre | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Division of Clinical Neurology, Queen's Medical Centre | Nottingham | Notts | NG7 2UH | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20829244 | Result | Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010 Nov;16(11):1349-59. doi: 10.1177/1352458510378020. Epub 2010 Sep 9. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Placebo | Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in the Mean Daily Number of Incontinence Episodes at the End of Treatment | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | number of daily episodes | 0 - 10 weeks |
|
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.
All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting Not Otherwise Specified | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mr Richard Potts, Clinical Operations Director | GW Pharma Ltd. | 0044 1223 266800 | rp@gwpharm.com |
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| ID | Term |
|---|---|
| D053201 | Urinary Bladder, Overactive |
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D001745 | Urinary Bladder Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| C587251 | nabiximols |
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|
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| Placebo | Drug | 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. |
|
|
| Daily diary entries throughout 10 week study period |
| Change From Baseline in the Mean Daily Episodes of Nocturia at the End of Treatment | 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. | 0 - 10 weeks |
| Change From Baseline in the Mean Daily Number of Incontinence Pads Used at the End of Treatment | 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. | 0 - 10 weeks |
| Change From Baseline in Mean Total Incontinence Quality of Life (I-QOL) Questionnaire Score at the End of Treatment (Completion or Withdrawal) | 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. | 0 - 10 weeks |
| Change From Baseline in Mean Overall Bladder Condition 0-10 Numerical Rating Scale Score at the End of Treatment | 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. | 0 - 10 weeks |
| Patient's Global Impression of Change | 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. | 0 - 10 weeks |
| Change From Baseline in the Mean Number of Daily Voids at the End of Treatment | 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. | 0 - 10 weeks |
| Protocol Violation |
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| Lost to Follow-up |
|
| Lack of Efficacy |
|
Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period. |
|
|
|
| Secondary | Change From Baseline in the Mean Daily Episodes of Urgency at the End of Treatment | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | number of daily episodes | Daily diary entries throughout 10 week study period |
|
|
|
|
| Secondary | Change From Baseline in the Mean Daily Episodes of Nocturia at the End of Treatment | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | number of daily episodes | 0 - 10 weeks |
|
|
|
|
| Secondary | Change From Baseline in the Mean Daily Number of Incontinence Pads Used at the End of Treatment | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | pads used daily | 0 - 10 weeks |
|
|
|
|
| Secondary | Change From Baseline in Mean Total Incontinence Quality of Life (I-QOL) Questionnaire Score at the End of Treatment (Completion or Withdrawal) | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | 0 - 10 weeks |
|
|
|
|
| Secondary | Change From Baseline in Mean Overall Bladder Condition 0-10 Numerical Rating Scale Score at the End of Treatment | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | 0 - 10 weeks |
|
|
|
|
| Secondary | Patient's Global Impression of Change | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Number | participants | 0 - 10 weeks |
|
|
|
|
| Secondary | Change From Baseline in the Mean Number of Daily Voids at the End of Treatment | 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. | All randomised subjects who received at least one dose of study medication and had on-treatment efficacy data were included in the analysis. | Posted | Mean | Standard Deviation | number of daily episodes | 0 - 10 weeks |
|
|
|
|
| 2 |
| 67 |
| 48 |
| 67 |
| EG001 | Placebo | Each 100 ul actuation contains the colorants plus excipients. A maximum of 48 actuations was permitted in any 24 hour period. | 2 | 68 | 43 | 68 |
| Dehydration | Metabolism and nutrition disorders | MedDRA 5.0 | Systematic Assessment |
|
| Transient Ischaemic Attack | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Multiple Sclerosis Relapse | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Cystitis Haemorrhagic | Renal and urinary disorders | MedDRA 5.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Diarrhoea Not Otherwise Specified | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Feeling Drunk | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Weakness | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Application Site Pain | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Urinary tract infection Not Otherwise Specified | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Cystitis Not Otherwise Specified | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Headache Not Otherwise Specified | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Balance Impaired Not Otherwise Specified | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Multiple Sclerosis Relapse | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Disorientation | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Dissociation | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA 5.0 | Systematic Assessment |
|
| Abdominal Pain Upper | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA 5.0 | Systematic Assessment |
|
| Feeling Abnormal | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Chest Pain | General disorders | MedDRA 5.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 5.0 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
|
| Pharyngitis Viral Not Otherwise Specified | Infections and infestations | MedDRA 5.0 | Systematic Assessment |
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| Anorexia | Metabolism and nutrition disorders | MedDRA 5.0 | Systematic Assessment |
|
| Neck Pain | Musculoskeletal and connective tissue disorders | MedDRA 5.0 | Systematic Assessment |
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| Disturbance in Attention | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
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| Memory Impairment | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 5.0 | Systematic Assessment |
|
| Confusion | Psychiatric disorders | MedDRA 5.0 | Systematic Assessment |
|
| Sweating Increased | Skin and subcutaneous tissue disorders | MedDRA 5.0 | Systematic Assessment |
|
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.
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D059411 | Lower Urinary Tract Symptoms |
| D020924 | Urological Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |