An Study to Investigate the Efficacy of Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) in Multiple Sclerosis

Study Overview
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Brief Summary
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An open-label extension study in which patients with multiple sclerosis received GW-1000-02 [named Sativex® in Canada and also named Sativex® Oromucosal Spray] for four weeks in an open-label manner.

Detailed Description
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Subjects who took part in GWMS0001 Part A were invited to continue to receive GW-1000-02 in this four-week open-label part of the study. Subjects received open-label cannabinoid extract (GW-1000-02) for four weeks, either with or without peppermint flavouring, according to their study centre. Subjects who completed the study could choose to continue receiving GW-1000-02 by entering the long-term safety extension follow-on study.

Official Title
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Double Blind, Randomised, Parallel Group, Placebo Controlled Trial of a Combination of THC and CBD in Patients With Multiple Sclerosis, Followed by an Open Label Assessment and Study Extension

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: GW-1000-02


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged at least 18 years. Multiple Sclerosis of any type. Stable Multiple Sclerosis symptomatology during the four weeks before study entry. Symptoms of the required severity (>50 mm on a 100 mm Visual Analogue Scale severity scale) in least one of the specified impairment categories; spasticity, muscle spasms, disturbed bladder control, neuropathic pain, limb tremor. A stable medication regime during the four weeks before study entry. Willing to abstain from cannabis or cannabinoids for at least seven days before study entry, and during the study. Agreed either to use effective contraception during the study and for three months thereafter, or had been surgically sterilised or, if female, were post-menopausal. Clinically acceptable laboratory results for pre-study screening. Willing and able to undertake and comply with all study requirements. Willing and able to read, consider and understand the subject information and consent form and give written informed consent. Subjects unable to read or to sign the document procedures were treated as detailed in the Declaration of Helsinki. Willing for their general practitioner, and consultant if appropriate, to be informed of study participation. Willing for their name to be notified to Home Office for participation in the study. Exclusion Criteria: Known or strongly suspected to be abusing drugs, including alcohol. Not prepared to abstain from cannabis or cannabinoids during the study. Current or past addiction to cannabis. Known or suspected to have had an adverse reaction to cannabinoids causing psychosis or other severe psychiatric illness. History of any type of schizophrenia, any other psychotic illness, or other significant psychiatric illness or personality disorder other than depression associated with chronic illness. Received any drug containing levodopa (Sinemet®, Sinemet plus®, Levodopa®, L-dopa®, Madopar®, Benserazide®). Serious cardiovascular disorder including angina, uncontrolled hypertension, or an uncontrolled symptomatic cardiac arrhythmia. Significant renal or hepatic impairment as shown in medical history or indicated by laboratory results. History of epilepsy. Terminal illness or other condition in which placebo medication would be inappropriate. Pregnant, lactating or at risk of pregnancy. Participated in any other clinical research study during the 12 weeks before study entry. Planned hospital admission between study entry and Visit 6. Planned travel outside the UK between study entry and Visit 6.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GW-1000-02<br>Active treatment. | Drug: GW-1000-02<br>* Containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. The maximum permitted dose of study medication was eight actuations (22 mg THC and 20 mg CBD) in any three hour period, and 48 actuations (130 mg THC and 120 mg CBD) in any 24 hour period.<br>* Other names: Sativex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Mean Part A Primary Impairment Visual Analogue Scale Score (After 6 Weeks) at the End of Four Weeks of Open-label Treatment (10 Weeks Total) | This was achieved by measuring the change in the Part A study score (mean of all scores during the last two weeks of six weeks of double-blind therapy) in the severity of the primary impairment (mean of all scores during the last two weeks of four weeks of open-label therapy), a composite score from one of five multiple sclerosis symptom categories that subjects nominated as their most severe symptom. The severity scores were recorded using a 100 mm Visual Analogue Scale, where 0 = no problem and 100 = very bad. As such, a decrease in score indicates an improvement and a negative value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Mean Part A Guy's Neurological Disability Scale Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. 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. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Care-Giver Strain Index Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Caregiver Strain Index is a 13-item questionnaire designed to detect strain in those that care for subjects. Carers were asked if they found certain situations difficult (i.e. work adjustments, family adjustment, emotional adjustments, physical effort). Each question was scored zero (answered no) or one (answered yes), and was recorded for each of the 13 questions. The summary parameter was the total score, which was the sum score of the 13 questions, giving a minimum possible score of 0 (no strain) and maximum possible score of 13 (maximum possible strain). As such a negative value from baseline indicates an improvement in caregiver strain. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Reading Visual Acuity Test Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Assessment of reading visual acuity was made using a standard reading chart. Scores could range from 1 (good) to 20 (bad), indicating good and poor eyesight, respectively. As such, a negative value from baseline indicates an improvement in eyesight. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Ashworth Scale Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. All 20 muscle groups were assessed for spasticity (using a 1-5 scale): 1= no increase in muscle tone to 5= passive movement is difficult and affected part is rigid in flexion or extension. The score for all 20 muscle groups were added to give a total score out of 100; minimum score was 20. A decrease in score indicates an improvement in condition. As such, a negative value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Short Orientation Memory Concentration Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Short Orientation-Memory-Concentration test is a questionnaire designed to measure orientation, concentration on simple tasks and learning and recall of simple information. The test consists of six items, such as 'what year is it now?' and 'count backwards from 20 to 1'. Each item was scored between 0 (maximum number of errors) and three-10 (best score; no errors), with a point deducted for each error. The summary parameter was the total score from the sum of scores for each item, with an overall possible maximum score of 28 (no errors). Scores over 20 are considered 'normal'. As such, an increased score indicates an improvement, and a positive value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Barthel Activities for Daily Living Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Barthel Index consists of 10 items that measure a person's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. The ability to undertake the different daily activities was assessed on scales of 0-1 to 3, with 0= poorest outcome and upper scores= best outcome. The total score was the sum of scores for each item; minimum score= 0, maximum score= 20. A change of two or greater in the total score indicating a clinically relevant change. A positive value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Total Adult Memory and Information Processing Battery Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Adult Memory and Information Processing Battery test comprises six sub-sections which assess cognition and mental alertness. These include immediate and delayed story recall, word-list learning, copying a complex figure followed by its immediate reproduction, design learning, and information processing (parts A and B). The sum score for each section gave the total score which ranged from 1 (bad) to 105 (good). As such, a positive value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Beck's Depression Inventory (BDI-II) Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The BDI-II was a 21-question multiple choice self-reported inventory. Subjects' responses to the 21 questions were assigned a score ranging from zero (good) to three (bad), indicating the severity of the symptom. The sum of all BDI-II question scores indicated the severity of depression; score range 0-63. A decrease in score indicates an improvement in condition. As such, a negative value indicates in improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Fatigue Severity Scale Questionnaire Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Fatigue Severity Scale is a nine-item questionnaire developed to assess the level of fatigue due to neurological disease, were each assessed on a 0-6 scale (0= no fatigue and 6= severe fatigue). As such a decreased score indicates improvement, and a negative value indicates and improvement from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Rivermead Mobility Index Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Rivermead Mobility Index is a measure of subject self-mobilisation and was developed to enable rehabilitation professionals to document the effect(s) of interventions. This consisted of 15 questions relating to the dexterity and/or mobility of the patient. Each question had a 'yes' / 'no' answer which was scored as yes=1 no=0. The summary parameter was the total for the 15 questions, with a maximum score of 15. An increased score indicates improvement. As such, a positive value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Total 28-item General Health Questionnaire Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The 28-item General Health Questionnaire is a self-reported questionnaire for the detection of non-psychotic mental disorders (anxiety and depression) in the community and primary care settings. A series of four subscale scores (ranging from 0 [good] to 21 [bad]) were combined to give a total score, which ranged from 0 (good) to 84 (bad). As such, a negative value indicates an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Nine Hole Peg Test Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The Nine-Hole Peg Test is a board with nine holes into which subjects have to insert nine pegs and is designed to test dexterity and coordination. Scores range from 0 (good) to 60 (bad). As such a decrease in score indicates an improvement, and a negative value indicates an improvement from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Total Bladder Control Questionnaire Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The total bladder control test score was the sum score from fifteen questions, which were each scored on a 0-2 scale (one question 0-3), where 0 = good and 2/3 = bad. Ten questions were related to bladder symptoms and control and five were related to the effects on the patient's life. The summary parameters were the total score with a minumum possible score of 0 and a maximum possible score of 31. A decrease in score indicates an improvement, as such a negative value indicates an improvement in condition from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Tremor Activities of Daily Living Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The tremor activities of daily living scale is a patient self-reported questionnaire which consists of 25 questions relating to the effect of tremors on different day-to-day activities, such as eating, drinking, threading a needle and tying a shoe. The ability to perform these tasks was scored on a scale of 0 (unable) to 3 (completely able). The summary parameter was the total score with a minimum of 0 (unable to perform tasks) and a maximum of 75 (completely able to perform tasks). As such, a positive value indicates an improvement in condition from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Mean Part A Sleep Quality 100 mm Visual Analogue Scale Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Sleep quality scores were rated using a 100 mm visual analogue scale where 0 = best and 100 = worst. As such, a negative value is indicative of an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Incidence of Adverse Events as a Measure of Patient Safety | The number of patients who recorded an adverse event during the 4 week open-label period is presented. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Sleep Amount 100 mm Visual Analogue Scale Score at the End of Open-label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Sleep amount was rated using a 100 mm visual analogue scale where 0 = best and 100 = worst. As such, a negative value is indicative of an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Feeling Upon Wakening 100 mm Visual Analogue Scale Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Feeling upon wakening was rated using a 100 mm visual analogue scale where 0 = best and 100 = worst. As such, a negative value is indicative of an improvement in score from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Spasticity Visual Analogue Scale Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Severity scores over the last 24 hours were recorded using a 100 mm Visual Analogue Scale on one nominated day each week. Scores ranged from 0 = no problem to 100 = very bad. A decrease in score indicates an improvement, as such a negative value indicates an imrovement in condition from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Pain Visual Analogue Scale Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Severity scores over the last 24 hours were recorded using a 100 mm Visual Analogue Scale on one nominated day each week. Scores ranged from 0 = no problem to 100 = very bad. A decrease in score indicates an improvement. As such, a negative value indicates an improvement in pain from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Muscle Spasm Visual Analogue Scale Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Severity scores over the last 24 hours were recorded using a 100 mm Visual Analogue Scale on one nominated day each week. Scores ranged from 0 = no problem to 100 = very bad. A decrease in score indicates an improvement. As such, a negative value indicates and improvement in spasms from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Tremor Visual Analogue Scale Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Severity scores over the last 24 hours were recorded using a 100 mm Visual Analogue Scale on one nominated day each week. Scores ranged from 0 = no problem to 100 = very bad. A decrease in score indicates an improvement. As such, a negative value indicates an improvement in tremor from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Bladder Problems Visual Analogue Scale Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. Severity scores over the last 24 hours were recorded using a 100 mm Visual Analogue Scale on one nominated day each week. Scores ranged from 0 = no problem to 100 = very bad. A decrease in score indicates an improvement. As such, a negative value indicates an improvement in bladder problems from baseline. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Change From Part A Mean Ten-metre Mobility Score at the End of Open-Label Treatment | This was achieved by measuring the change in the mean Part A study score (during six weeks of therapy) to the mean score at the end of 4 weeks of open-label treatment with GW-1000-02. The 10 Metre Mobility Score is a four point scale assessing a subject's level of mobility. The time taken to walk ten metres was measured for the subset of subjects who were able to walk. A decrease in time indicates and improvement. | End of Part A (week 6) - end of Part B (week 10 [4 weeks total open-label treatment]) | 
| Subject Global Opinion of Effect on Multiple Sclerosis at the End of Open-label Treatment | A 7-point Likert-type scale was used, with the question: 'Please assess the status of your 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. The number of subjects that considered their condition to be better or much better at the end of open-label treatment is presented. | End of Part B (week 10) |