A Randomized Study of Sativex on Cognitive Function and Mood: Multiple Sclerosis Patients

Study Overview
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Brief Summary
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A study to compare the change in cognitive performance and psychological status of patients with spasticity due to Multiple Sclerosis when treated with Sativex or placebo, added to existing anti-spasticity therapy over a period of 48 weeks. Secondary objectives were to evaluate the effect of Sativex on mood and spasticity and to assess the safety and tolerability of Sativex.

Detailed Description
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Eligible patients entered this 50 week multicenter, double-blind, randomised, placebo-controlled, parallel group study which evaluated the effect of Sativex on cognitive performance. At each scheduled clinic visit, patients were assessed for cognitive performance, mood, severity of spasticity, use of investigational medicinal products and number of visits to a healthcare professional. Primary efficacy comparisons were made between scores recorded during baseline and scores recorded at the end of treatment.

Official Title
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A Multicentre, Double-blind, Randomised, Parallel Group, Placebo-controlled Study of the Effect of Long-term Treatment With Sativex on Cognitive Function and Mood of Patients With Spasticity Due to Multiple Sclerosis

Conditions
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Multiple Sclerosis, Spasticity

Intervention / Treatment
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* Drug: Sativex
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (ALL to be fulfilled): Patient is willing and able to give informed consent for participation in the study. Patient is aged 18 years or above. Diagnosed with any disease sub-type of multiple sclerosis. Diagnosed with symptomatic spasticity due to multiple sclerosis. Patient has at least moderate spasticity in the opinion of the investigator. Patient fulfils at least one of the two criteria below. Subject must be either: Currently established on a regular dose of anti-spasticity therapy, or Previously tried and failed anti-spasticity therapy. Stable medication regimen for at least four weeks prior to study entry, for all medications which may have an effect on spasticity and/or cognition. If the patient is taking disease modifying medication this must be at a stable dose for three months prior to the initial visit. Willing and able to comply with all study requirements. Willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable. Willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study. Exclusion Criteria (if ANY apply): Any history or immediate family of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition. Any concomitant disease or disorder (such as poorly controlled epilepsy or seizures) that may influence the patient's level of cognition or mood. Currently using or has used cannabis or cannabinoid-based medications within 30 days of study entry and unwilling to abstain for the duration of the study. Any known or suspected history of a diagnosed dependence disorder, current heavy alcohol consumption (more than 60g of pure alcohol per day for men, and more than 40g of pure alcohol per day for women), current use of an illicit drug or current non-prescribed use of any prescription drug. Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the investigational medicinal products. Female patients of child bearing potential and male subjects whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for three months thereafter. Female patient who is pregnant, lactating or planning pregnancy during the course of the study and for three months thereafter. Patients who have received an investigational medicinal product within the 12 weeks prior to the initial visit. Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study may influence the result of the study, or the patient's ability to participate in the study. Following a physical examination, the patient has any abnormalities that, in the opinion of the investigator would prevent the patient from safe participation in the study. Previously randomised to this 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 |
| --- | --- |
| Active Comparator: Sativex<br>Contains delta-9-tetrahydrocannabinol (THC), 27 mg/mL:cannabidiol (CBD), 25 mg/mL, in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Each actuation delivers THC 2.7 mg and CBD 2.5 mg. Dose: 100 µL oromucosal spray to be administered up to a maximum of 12 sprays per day. There was an initial dose-titration period during which patients gradually increased their dose of study drug according to individual response and tolerability. | Drug: Sativex<br>* Patients self-administered their allocated randomized treatment on an outpatient basis, up to a maximum of 12 sprays to the oral mucosa per day (following an initial titration period).<br>* Other names: THC/CBD spray;|
| Placebo Comparator: Placebo<br>Oromucosal spray, containing ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring and colourings FD&C Yellow No.5 (E102 tartrazine) (0.0260%), FD&C Yellow No.6 (E110 sunset yellow) (0.0038%), FD&C Red No. 40 (E129 Allura red AC) (0.00330%) and FD&C Blue No.1 (E133 Brilliant blue FCF) (0.00058%). Dose: 100 µL oromucosal spray to be administered up to a maximum of 12 sprays per day. There was an initial dose-titration period during which patients gradually increased their dose of study drug according to individual response and tolerability. | Drug: Placebo<br>* Patients self-administered their allocated randomized treatment on an outpatient basis, up to a maximum of 12 sprays to the oral mucosa per day (following an initial titration period).<br>* Other names: Placebo control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to the End of Treatment in Paced Auditory Serial Addition Test (PASAT) Total Score. | The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Stimulus presentation rates were adapted for use with multiple sclerosis patients. The PASAT is presented on audio compact disk to control the rate of stimulus presentation. Single digits are presented either every 3 seconds (PASAT 1) or every 2 seconds (PASAT 2), and the patient must add each new digit to the one immediately prior to it. The test score is the sum of the total number of correct sums given (out of 60 possible) in each trial. An increase in score indicates an improvement in condition. | 0-48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to the End of Treatment in Beck Depression Inventory-II (BDI-II) Total Score. | The BDI-II is a multiple choice self-reported inventory that is one of the most widely used instruments for measuring the severity of depression. There are 21 questions or items, each having four possible responses. Each response is assigned a score ranging from zero to three, indicating the severity of the symptom. Items 1 to 13 assess symptoms that are psychological in nature, while items 14 to 21 assess symptoms that are more physical. The sum of all BDI-II item scores indicates the severity of depression. For patients eligible for this study, a score of 21 or over represents depression. The BDI-II can distinguish between different subtypes of depressive disorders, such as major depression and dysthymia. A reduction in score indicates an improvement in condition. | 0-48 weeks | 
| Subject Global Impression of Change (SGIC) in the Severity of Their Spasticity at the End of Treatment. | Patients were asked the following question, to be rated on a seven-point scale: Please assess the change in your spasticity since immediately before receiving the first dose of study treatment (Visit 1) using the scale below. The markers were: 'Very much worse', 'Much worse', 'Minimally worse', 'No change', 'Minimally better', 'Much better' or 'Very much better'. The number of patients for each of the markers is presented at the final study visit. | 0-48 weeks | 
| Caregiver's Global Impression of Change (CGIC) in the Severity of the Patient's Spasticity at the End of Treatment. | Caregivers were asked the following question to be rated on a seven-point scale: How has the subject's spasticity changed since Visit 1? The markers were: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of patients for each of the markers is presented at the final study visit. | 0-48 weeks | 
| Physician's Global Impression of Change (PGIC) in the Severity of the Patient's Spasticity at the End of Treatment. | Physicians were asked the following question to be rated on a seven-point scale: How has the subject's spasticity changed since Visit 1? The markers were: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of patients for each of the markers is presented at the final study visit. | 0-48 weeks | 
| Change From Baseline to End of Treatment in Modified Ashworth Scale Total Score. | All 20 muscle groups were assessed for spasticity (using a 0-5 scale): 0= 'no increase in muscle tone' to 5= 'affected part(s) rigid in flexion or extension'. The score for all 20 muscle groups were added to give a total score out of 100. A decrease in score indicates an improvement in condition. | 0-48 weeks | 
| Change From Baseline to End of Treatment in Number of Visits to a Healthcare Professional. | At baseline, patients were asked how many times they had visited a healthcare professional in the previous 12 weeks. At subsequent visits, patients were asked how many times they had visited a healthcare professional since their last study visit. The change from baseline to the end of treatment is presented. A decrease in number indicates an improvement in condition. | 0-48 weeks | 
| The Number of Patients With a Treatment-emergent Flag Using the Columbia-Suicide Severity Rating Scale (C-SSRS) During the Course of the Study. | Patients were scored at each clinic visit for the following outcomes using the C-SSRS: suicidal ideation, suicidal behaviour, suicidality (including complete suicidality). Possible flags were as follows: Wish to be Dead, Non-specific Active Suicidal Thoughts, Active Suicidal Ideation Without Intent, Active Suicidal Ideation With Intent, No Plan, Active Suicidal Ideation With Intent and Plan. The number of patients with a treatment-emergent flag is presented. | 0-48 weeks | 
| Change From Baseline to End of Treatment in Timed 10-meter Walk Times. | Only those patients for whom it was appropriate (i.e. ambulatory patients) were timed for how long it took to walk 10 metres. If a patient started the 10-meter walk but was unable to complete it, an estimated time for completion was calculated based on the available data. A negative difference from baseline indicates an improvement in condition. | 0-48 weeks | 
| Incidence of Adverse Events as a Measure of Patient Safety. | The number of subjects who experienced an adverse event during the course of the study is presented. | 0-50 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, Mood