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A Study of Sativex in the Treatment of Central Neuropathic Pain Due to Multiple Sclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01604265
Recruitment Status : Completed
First Posted : May 23, 2012
Results First Posted : September 19, 2012
Last Update Posted : June 24, 2013
Sponsor:
Information provided by (Responsible Party):
GW Pharmaceuticals Ltd.

Tracking Information
First Submitted Date  ICMJE May 21, 2012
First Posted Date  ICMJE May 23, 2012
Results First Submitted Date  ICMJE July 18, 2012
Results First Posted Date  ICMJE September 19, 2012
Last Update Posted Date June 24, 2013
Study Start Date  ICMJE March 2002
Actual Primary Completion Date August 2002   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2012)
Change From Baseline in the Mean Pain 0-10 Numerical Rating Scale Score at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
The average pain Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain in the last 24 hours" where 0 = no pain and 10 = pain as bad as you can imagine. A negative value indicates an improvement in pain score from baseline.
Original Primary Outcome Measures  ICMJE
 (submitted: May 22, 2012)
Pain 0-10 Numerical Rating Scale score. [ Time Frame: 4 weeks. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2012)
  • Change From Baseline in the Mean 0-10 Numerical Rating Scale Sleep Score at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
    Each day patients were asked to record in their subject diary, whether or not they were "woken due to nerve pain last night", using a 0-10 Numerical Rating Scale sleep score where zero equated with "did not disrupt sleep" and 10 meant "completely disrupts sleep (unable to sleep due to pain)". A decrease in score from baseline indicates an improvement.
  • Subject Global Impression of Change at Week 4 [ Time Frame: 4 weeks ]
    A 7-point Likert-type scale was used, with the question: 'Please assess the improvement in overall condition since the start of the study using the scale below' with the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse". At Visit 2 (Baseline) patients wrote a brief description of their condition which was used at Week 4 to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported.
  • Change From Baseline in the Mean Neuropathic Pain Scale 0-10 Numerical Rating Scale Score at the End of Treatment (Week 4) [ Time Frame: Baseline to end of treatment (0 - 4 weeks). ]
    The Neuropathic Pain Scale score is the 0-100 sum of 10 individual pain scores (0-10 Numerical Rating Scale, 0= no pain to 10 = worst pain imaginable). A negative change from baseline indicates an improvement in pain.
  • Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Selective Reminding' at the End of Treatment (Week 4) [ Time Frame: Baseline to end of study (0 - 4 weeks) ]
    The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance.
  • Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for '10/36 Spatial Recall' at the End of Treatment (Week 4) [ Time Frame: Weeks 0 - 4 ]
    The 10/36 Spatial Recall Test assesses visual spatial learning and delayed recall. Patients are asked to view a 6 x 6 checkerboard with ten checkers for 10 seconds. They are then asked to recreate the pattern viewed on a blank checkerboard. The number of correct responses from three immediate trials and one delayed trial (7 minute delay) are recorded. The Total number of correct responses is the unweighted sum from the four trials. The score for the 10/36 spatial recall test was the unweighted average of four individual study results (min=0 and max=40). A higher score indicates better cognitive performance.
  • Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Symbol Digit Modalities' at the End of Treatment (Week 4) [ Time Frame: 0 - 4 weeks ]
    The Symbol Digit Modalities Test measures complex attention and concentration in a task which also requires speed and accuracy in visual search and scanning. Patients are required to associate symbols with numbers and quickly generate the number when shown the symbol. The summary endpoint is the number of correct responses in 90 seconds. The symbol digit modalities test had a min of 0 and max score of 99. A higher score indicates better cognitive performance.
  • Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for the 'Paced Auditory Serial Addition Task' (PASAT) at the End of Treatment (Week 4) [ Time Frame: 0 - 4 weeks ]
    The Paced Auditory Serial Addition Task assesses sustained attention and concentration. A pre-recorded tape is used to present two series of 60 numbers, one every 3 seconds and one every 2 seconds. Patients are asked to add each number to the one immediately preceding it and give the result. The task summary score is the percentage of correct answers is calculated. The PASAT score range was 0% to 100%. Higher scores indicate a better cognitive performance.
  • Change From Baseline in the Mean Brief Repeatable Battery of Neuropsychological Test Score for 'Word List Generation' at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
    Word list generation measures verbal associative fluency. Patients are given 60 seconds to give as many words beginning with a particular letter. The Total is the unweighted sum of all admissible words over three different trials. Higher scores indicate a better cognitive performance (min=0, max= not defined).
  • Change From Baseline in the Mean Total Guy's Neurological Disability Scale Score at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
    The Guy's Neurological Disability Scale has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and 'others'. Each category consists of a series of questions, which are scored on a 0 to 5 scale, with 0 being indicative of a better outcome and 5 being indicative of a worse outcome. The total Guy's Neurological Disability Scale score is the unweighted sum from the 12 categories with a minimum score of 0 and maximum of 60. A negative value indicates an improvement in score from baseline.
  • Change From Baseline in the Mean 0-100 mm Visual Analogue Scale Score for Intoxication Levels at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
    Intoxication levels were recorded on a Visual Analogue Scale, where zero equated with "no intoxication" and 100 equated with "extreme intoxication". A decrease in baseline score indicates a reduction in intoxication.
  • Change From Baseline in The Hospital Anxiety and Depression Scale Score for Depression at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
    Depression and anxiety was assessed using The Hospital Anxiety and Depression Scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression. A reduction in score indicates an improvement. The change from baseline in the overall depression score at the end of treatment is presented.
  • Change From Baseline in The Hospital Anxiety and Depression Scale Score for Anxiety at the End of Treatment (4 Weeks) [ Time Frame: 0 - 4 weeks ]
    Depression and anxiety was assessed using The Hospital Anxiety and Depression Scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression. A reduction in score indicates an improvement. The change from baseline in the overall anxiety score at the end of treatment is presented.
  • Change From Baseline in the Multiple Sclerosis Functional Composite Score at the End of Treatment (4 Weeks) [ Time Frame: Baseline to end of treatment (0 - 4 weeks). ]
    The Multiple Sclerosis Functional Composite test is a three-part, standardized, quantitative, assessment instrument for use in clinical studies. The three components of the test measure leg function/ambulation, arm/hand function, and cognitive function. An increase in score indicates an improvement (range -3 to +3).
  • Incidence of Adverse Events as a Measure of Patient Safety. [ Time Frame: 0 - 4 weeks ]
    The number of patients who experienced an adverse event during the course of the study is presented.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2012)
  • 0-10 Numerical Rating Scale sleep score. [ Time Frame: 4 weeks. ]
  • Subject Global Impression of Change. [ Time Frame: 4 weeks. ]
    The Subject Global Impression of Change consisted of a single question relating to improvement in overall condition since the start of the study and was recorded on the Case Report Form at Visit 4 (end of study/withdrawal). The results were recorded as "Very Much Improved", "Much Improved", "Minimally Improved", "No Change", "Minimally Worse", "Much Worse" and "Very Much Worse". These results were converted to a seven point scale, where one = "Very Much Improved", through to seven = "Very Much Worse".
  • Brief Repeatable Battery of Neuropsychological Tests. [ Time Frame: Baseline to end of study (0 - 4 weeks). ]
    A total of five tests analysing:
    1. Long term storage score for the Selective Reminding Test.
    2. Total number of correct responses for the 10/36 Spatial Recall Test.
    3. Number of correct responses for the Symbol Digit Modalities Test.
    4. Percentage of correct response for the Paced Auditory Serial Addition Task.
    5. Total for the Word List Generation.
  • The Hospital Anxiety and Depression Scale. [ Time Frame: Baseline to end of study (0 - 4 weeks). ]
    With analysis of:
    1. Anxiety Score
    2. Depression Score
  • Multiple Sclerosis Functional Composite score. [ Time Frame: Baseline to end of treatment (0 - 4 weeks). ]
  • Guy's Neurological Disability Scale score. [ Time Frame: Baseline to end of treatment (0 - 4 weeks). ]
  • Neuropathic Pain Scale 0-10 Numerical Rating Scale. [ Time Frame: Baseline to end of treatment (0 - 4 weeks). ]
    Subjects were asked to complete a series of questions involving 0-10 Numerical Rating Scales with respect to their pain at the predetermined body site at baseline and Week 4. The pain descriptors were intensity, sharpness, hot, dull, cold, sensitive, itchy, unpleasantness and surface compared with deep.
  • 0-10 Numerical Rating Scale for Pain versus the Neuropathic Pain Scale. [ Time Frame: 4 weeks. ]
    The association between the 0-10 Numerical Rating Scale for pain and the Neuropathic Pain Scale was examined from diary card recordings of the assessment of pain. For the Neuropathic Pain Scale, baseline pain was taken as the mean of the totals of the three completed scales taken from three consecutive days during the run-in week. The on-treatment pain was taken as the mean of the totals of the three completed scales taken from three consecutive days during the final week of treatment.
  • Incidence of adverse events as a measure of subject safety. [ Time Frame: 4 weeks. ]
    All AEs were presented by system organ class and preferred term and were coded using the MedDRA v5.0 coding dictionary.
  • Clinical Laboratory Data. [ Time Frame: 4 weeks. ]
    Haematology, biochemistry and urinalysis parameters were measured at Visits 1 and 4.
  • Vital Signs. [ Time Frame: 4 weeks. ]
    Vital sign parameters (systolic blood pressure, diastolic blood pressure and pulse) were measured at all visits.
  • Intoxication Levels. [ Time Frame: 4 weeks. ]
    Intoxication levels were measured at Visits 2, 3 and 4 (end of study/withdrawal) and were recorded on a Visual Analogue Scale, where zero equated with "no intoxication" and 100 equated with "extreme intoxication".
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Sativex in the Treatment of Central Neuropathic Pain Due to Multiple Sclerosis
Official Title  ICMJE A Double Blind, Randomised, Parallel Group, Placebo Controlled Study of Sativex in the Treatment of Central Neuropathic Pain in Multiple Sclerosis.
Brief Summary To investigate the ability of Sativex to relieve central neuropathic pain in multiple sclerosis subjects.
Detailed Description Multiple sclerosis subjects with a clinical diagnosis of central neuropathic pain entered a seven to ten day baseline period, followed by a four week double blind, randomised, parallel group comparison of Sativex, with placebo. The study medication was self-titrated to symptom resolution or maximum tolerated or allowed dose. Visits occurred at the end of weeks one and four (end of the study) or earlier if they withdrew. A follow-up visit occurred 30 - 40 days after completion or withdrawal.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Multiple Sclerosis
  • Neuropathic Pain
Intervention  ICMJE
  • Drug: Placebo
    Contained peppermint oil, 0.05% (v/v), quinoline yellow, 0.005% (w/v), sunset yellow, 0.0025% (w/v), in ethanol:propylene glycol (50:50) excipient. Each actuation delivered 100 μl. The maximum permitted dose of study medication was eight actuations in any three hour period, and 48 actuations in any 24 hour period.
  • Drug: Sativex
    Contained delta-9-tetrahydrocannabinol (THC), (25 mg/ml):cannabidiol (CBD), (25 mg/ml) as extract of Cannabis sativa L., with peppermint oil, 0.05% (v/v), in ethanol:propylene glycol (50:50) excipient. Each actuation delivered 100 μl (THC 2.5 mg and CBD 2.5 mg). The maximum permitted dose of study medication was eight actuations in any three hour period, and 48 actuations in any 24 hour period.
    Other Name: GW-1000-02
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Placebo control.
    Intervention: Drug: Placebo
  • Experimental: Sativex
    Active treatment.
    Intervention: Drug: Sativex
Publications * Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005 Sep 27;65(6):812-9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 22, 2012)
66
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 2002
Actual Primary Completion Date August 2002   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Willing and able to give informed consent for participation in the study.
  • Male or female subjects aged 18 years or above.
  • Diagnosed with any disease sub-type of multiple sclerosis, with relapses/remission not expected to influence neuropathic pain.
  • Duration of multiple sclerosis greater than six months.
  • Central neuropathic pain, due to multiple sclerosis, of at least three months duration, for which a nociceptive, peripheral neuropathic or psychogenic cause appeared unlikely and was expected to remain stable for the duration of the study.
  • Pain score with a severity of four or more on at least four completed Numerical Rating Scale scores in the baseline week.
  • Regular medication regime for neuropathic pain had been stable during the previous two weeks, prior to reduction of tricyclic antidepressants, if applicable.
  • Willing to reduce the dosage of amitriptyline, or equivalent of other tricyclic antidepressants, to a maximum of 75 mg per day, if applicable.
  • No cannabinoid use (cannabis, Marinol or Nabilone) at least seven days before study entry and willing to abstain from any use of cannabis during the study.
  • Female subjects of child bearing potential or male subjects whose partner was of child bearing potential, who were willing to ensure that they or their partner used effective contraception during the study and for three months thereafter.
  • Able (in the investigators opinion) and willing to comply with all study requirements.
  • Willing for his or her name to be notified to the Home Office for participation in this study.
  • Willing for his or her general practitioner and consultant, if appropriate, to be notified of participation in the study.

Exclusion Criteria:

  • History of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition.
  • Concomitant severe non-neuropathic pain or the presence of illness such as diabetes mellitus that could have caused peripheral neuropathic pain.
  • Known or strongly suspected alcohol or substance abuse or considered to be at risk of alcohol or substance abuse by the investigator.
  • Severe cardiovascular disorder, such as ischaemic heart disease, arrhythmias (other than well controlled atrial fibrillation), poorly controlled hypertension or severe heart failure.
  • History of epilepsy or convulsions.
  • Significant renal or hepatic impairment as shown in medical history or indicated by clinical laboratory results from samples taken at baseline.
  • Elective surgery or other procedures requiring general anaesthesia scheduled during the study.
  • Terminal illness.
  • Any other significant disease or disorder which, in the opinion of the Investigator, could either have put the subject at risk because of participation in the study, or influenced the result of the study, or the subject's ability to participate in the study.
  • Female subjects who were pregnant, lactating or planning pregnancy during the course of the study.
  • Regular levodopa (Sinemet, Sinemet Plus, Levodopa, L-dopa, Madopar, Benserazide) therapy within seven days of study entry.
  • Known or suspected hypersensitivity to cannabinoids or any of the excipients of the study medications.
  • Known or suspected adverse reaction to cannabinoids.
  • Travel outside the UK planned during study.
  • Donation of blood during the study.
  • Participated in any other pharmacological clinical research study within 30 days of study entry.
  • Previously enrolled into this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01604265
Other Study ID Numbers  ICMJE GWMS0107
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GW Pharmaceuticals Ltd.
Study Sponsor  ICMJE GW Pharmaceuticals Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carolyn Young, MRCP FRCP Walton Centre for Neurology and Neurosurgery
PRS Account GW Pharmaceuticals Ltd.
Verification Date June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP