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

• ClinicalTrials.gov Identifier: NCT00678795
• Recruitment Status: Completed
• First Posted: May 16, 2008
• Results First Posted: September 21, 2012
• Last Update Posted: June 24, 2013
• Sponsor: Jazz Pharmaceuticals
• Information provided by (Responsible Party): Jazz Pharmaceuticals

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 (Clinical Trial)
• 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: August 2002
• Actual Primary Completion Date: October 2005
• Actual Study Completion Date: October 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 Name: 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 Name: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United Kingdom

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

More Information

Publications of Results:

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.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00678795
• Other Study ID Numbers: GWMS0208
• First Posted: May 16, 2008
• Results First Posted: September 21, 2012
• Last Update Posted: June 24, 2013
• Last Verified: June 2013

Keywords provided by Jazz Pharmaceuticals:

Detrusor overactivity; Multiple Sclerosis

Additional relevant MeSH terms:

Multiple Sclerosis; Urinary Bladder, Overactive; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Urinary Bladder Diseases; Urologic Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Nabiximols; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs