A Study to Evaluate the Effects of Cannabis Based Medicine in Patients With Pain of Neurological Origin

Study Overview
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Brief Summary
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To investigate the ability of a cannabis based medicine extract to relieve chronic refractory pain of neurological origin.

Detailed Description
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Patients with Multiple Sclerosis or other defect of neurological function with a qualifying symptom of chronic refractory pain, entered a seven day baseline period, followed by a 21 day randomised, double blind, parallel group comparison of GW-1000-02 with placebo, self-titrated to symptom resolution or maximum tolerated dose. The ability of the cannabis based medicine extract to relieve chronic refractory pain was assessed by the change from baseline in pain score using Box Scale-11 (BS-11) scores recorded in the patients' daily diary.

Official Title
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A Multi Centre Randomised, Double Blind, Placebo Controlled, Parallel Group Comparison of the Effects of Cannabis Based Medicine Standardised Extracts Over 4 Weeks, in Patients With Chronic Refractory Pain Due to Multiple Sclerosis or Other Defects of Neurological Function.

Conditions
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Pain, Multiple Sclerosis

Intervention / Treatment
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* Drug: GW-1000-02
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient, or legal representative, willing and able to give informed consent for participation in the study. Male or Female, aged 18 years or above. Diagnosed with chronic refractory pain due to Multiple Sclerosis or other defects of neurological function. Diagnosed with pain, not wholly alleviated with current analgesic therapy at Visit 1 and an average score of over 4 on a Box Scale-11 scale on the four consecutive days leading up to Visit 2, where: zero = no pain and 10 = worst possible pain. Stable dose of pain relieving medication for at least two weeks prior to study entry. Willing to ensure that they or their partner use effective contraception during the study and for three months thereafter (applicable to female patients of child bearing potential and male patients whose partners were of child bearing potential). No cannabinoid use (cannabis, Marinol or Nabilone) for at least seven days before Visit 1 and be willing to abstain from any use of cannabis during the study. Able (in the investigator's 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 to allow 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. Known history of alcohol or substance abuse. 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. Female patients who were pregnant, lactating or planning pregnancy during the course of the study. Significant renal or hepatic impairment. Scheduled elective surgery or other procedures requiring general anaesthesia during the study. Terminally ill or inappropriate for placebo medication. Any other significant disease or disorder which, in the opinion of the investigator, may have put the patient at risk because of participation in the study, or may have influenced the result of the study, or the patient's ability to participate in 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 of having adverse reaction to cannabinoids. Travel outside the UK planned during the study. Donation of blood during the study. Patients who had participated in another research study in the 12 weeks leading up to study entry. Patients who had been previously randomised into this study. Male patients who were receiving Sildenafil (Viagra®) at the time of study entry and were unwilling to stop medication for the duration of the study.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GW-1000-02<br>Each 100 μl actuation contains 2.5 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). The maximum permitted dose was 48 actuations in any 24 hour period (120 mg THC/120 mg CBD). | Drug: GW-1000-02<br>* Each actuation of GW-1000-02 (100 μl) delivered a dose containing 2.5 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD). The maximum permitted dose of study medication was eight actuations in any three hour period (20 mg THC/20 mg CBD) and 48 actuations in any 24 hour period (120 mg THC/120 mg CBD).<br>* Other names: Sativex;|
| Placebo Comparator: Placebo<br>Each 100 μl actuation contains the excipients only. The maximum permitted dose was 48 actuations in any 24 hour period | Drug: Placebo<br>* Each actuation of placebo (100 μl) delivered the excipients only. The maximum permitted dose of study medication was eight actuations in any three hour period and 48 actuations in any 24 hour period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Pain Box Scale-11 Score at 3 Weeks. | Each day, in the morning (on waking), at lunchtime and in the evening (just before going to bed), patients recorded in their patient diary their level of pain using a Box Scale-11 pain score ranging from zero no pain to 10 worst possible pain. Week 3 analysis was defined as the mean of the last seven days in the study. The last day was taken as the last day with complete diary card pain data that occurred on or before the last day the patient took study medication. A negative value from baseline indicates and improvement. | 0 - 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Use of Analgesic Escape Medication. | The percentage of days on treatment on which escape medication was used is presented. | 0 - 3 weeks | 
| Change From Baseline in Mean Sleep Disturbance Score at 3 Weeks. | Each day patients were asked to record in their patient diary, whether or not they were woken due to pain the previous night. Answers were recorded as No, Once, Twice, More than twice and Awake most of the night; these were converted to a five point scale, zero to four, respectively. Sleep disturbance was summarised and analysed in the same manner as the analysis of the primary efficacy parameter of Box Scale-11 pain score. A negative value from baseline indicates and improvement. | 0 - 3 weeks | 
| Change From Baseline in Mean Total Pain Disability Index Score at 3 Weeks. | The index consists of seven assessments of pain (representing different aspects) with each assessment scored on a zero no disability to 10 total disability scale. The total Pain Disability Index was calculated as the un-weighted sum of the seven pain scores; if one or more of the pain scores were missing then the total Pain Disability Index was set to missing. A reduction in score from baseline indicates and improvement. | 0 - 3 weeks | 
| Change From Baseline in Mean Total Brief Pain Inventory (Short Form) Score at 3 Weeks. | The Brief Pain Inventory (Short Form) is a 14-item questionnaire that asks patients to rate pain over the prior week and the degree to which it interferes with activities on a 0 to 10 scale, where 0=no pain and 10=pain as bad as you can imagine. Severity is measured as worst pain, least pain, average pain, and pain right now. The severity composite score was calculated as the arithmetic mean of the four severity items (range 0-10). The minimum value is zero and maximum is 10. A reduction in score from baseline indicates an improvement. | 0 - 3 weeks | 
| Change From Baseline in Mean Spitzer Quality of Life Index Scores at 3 Weeks. | The Spitzer Quality of Life Index questionnaire consists of five sections, relating to activity, daily living, health, support and outlook. Each section has three choices (numbered 1, 2 and 3) and the patient was required to choose the one that best described their quality of life during the last week. Choice 1 is scored two, Choice 2 is scored one and Choice 3 is scored zero. The total Spitzer Quality of Life Index was calculated as the unweighted sum of the five scores. A reduction in score from baseline indicates an improvement. | 0 - 3 weeks | 
| Patient Global Impression of Change at the End of 3 Weeks of Treatment. | The Patient Global Impression of Change consisted of a single question relating to improvement in overall condition since the start of the study. The results were recorded as Very Much Improved, Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse and Very Much Worse and were converted to a seven point scale ranging from one to seven, respectively. The number of patients who reported being Very Much Improved or Much Improved is presented. | 0 - 3 weeks | 
| Change From Baseline in Mean Pain Box Scale-11 Scores (Multiple Sclerosis Subset) at 3 Weeks. | Each day, in the morning (on waking), at lunchtime and in the evening (just before going to bed), patients recorded in their patient diary their level of pain using a Box Scale-11 pain score ranging from zero no pain to 10 worst possible pain. Week 3 analysis was defined as the mean of the last seven days in the study. The last day was taken as the last day with complete diary card pain data that occurred on or before the last day the patient took study medication. A negative value from baseline indicates and improvement. | 0 - 3 weeks | 
| Use of Analgesic Escape Medication - Multiple Sclerosis Subset. | The percentage of days on treatment on which escape medication was used is presented. | 0 - 3 weeks | 
| Change From Baseline in Mean Sleep Disturbance Scores (Multiple Sclerosis Subset) at 3 Weeks. | Each day patients were asked to record in their patient diary, whether or not they were woken due to pain the previous night. Answers were recorded as No, Once, Twice, More than twice and Awake most of the night; these were converted to a five point scale, zero to four, respectively. Sleep disturbance was summarised and analysed in the same manner as the analysis of the primary efficacy parameter of Box Scale-11 pain score. A negative value from baseline indicates and improvement. | 0 - 3 weeks | 
| Change From Baseline in Mean Pain Disability Index Scores at 3 Weeks. | The index consists of seven assessments of pain (representing different aspects) with each assessment scored on a zero no disability to 10 total disability scale. The total Pain Disability Index was calculated as the un-weighted sum of the seven pain scores; if one or more of the pain scores were missing then the total Pain Disability Index was set to missing. A reduction in score from baseline indicates and improvement. | 0 - 3 weeks | 
| Change From Baseline in Mean Brief Pain Inventory (Short Form) Scores (Multiple Sclerosis Subset) at 3 Weeks. | The Brief Pain Inventory (Short Form) is a 14-item questionnaire that asks patients to rate pain over the prior week and the degree to which it interferes with activities on a 0 to 10 scale, where 0=no pain and 10=pain as bad as you can imagine. Severity is measured as worst pain, least pain, average pain, and pain right now. The severity composite score was calculated as the arithmetic mean of the four severity items (range 0-10). The minimum value is zero and maximum is 10. A reduction in score from baseline indicates an improvement. | 0 - 3 weeks | 
| Change From Baseline in Mean Spitzer Quality of Life Index Scores (Multiple Sclerosis Subset) at 3 Weeks. | The Spitzer Quality of Life Index questionnaire consists of five sections, relating to activity, daily living, health, support and outlook. Each section has three choices (numbered 1, 2 and 3) and the patient was required to choose the one that best described their quality of life during the last week. Choice 1 is scored two, Choice 2 is scored one and Choice 3 is scored zero. The total Spitzer Quality of Life Index was calculated as the unweighted sum of the five scores. A reduction in score from baseline indicates an improvement. | 0 - 3 weeks | 
| Patient Global Impression of Change - Multiple Sclerosis Subset. | The Patient Global Impression of Change consisted of a single question relating to improvement in overall condition since the start of the study. The results were recorded as Very Much Improved, Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse and Very Much Worse and were converted to a seven point scale ranging from one to seven, respectively. The number of patients who reported being Very Much Improved or Much Improved is presented. | 0 - 3 weeks | 
| Incidence of Adverse Events as a Measure of Patient Safety. | The number of patients who experienced an adverse event in the study is presented. | 0 - 65 days |