Sativex® for Relieving Persistent Pain in Patients With Advanced Cancer

Study Overview
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Brief Summary
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This 9-week study aimed to determine the efficacy, safety, and tolerability of nabiximols (Sativex®) as an adjunctive treatment, compared with placebo in relieving uncontrolled persistent chronic pain in participants with advanced cancer. Eligible participants were not required to stop any of their current treatments or medications.

Detailed Description
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This 9-week, multi-center, double-blind, randomized, placebo-controlled study aimed to determine the efficacy, safety and tolerability of nabiximols, administered as an adjunctive treatment for 5 weeks, versus placebo. Eligible participants had advanced cancer, with a clinical diagnosis of cancer related pain that was not wholly alleviated by their current optimized opioid treatment. Qualifying participants entered the study at screening and commenced a 5 to 14 day eligibility period. During this period, eligible participants had 3 consecutive days where pain severity remained within defined parameters, break-through opioid usage had not exceeded an average of 4 episodes per day, and maintenance opioid medication and dose had not changed. Eligible participants returned for randomization on Day 1 and were randomized to either the nabiximols or placebo treatment arm using a 1:1 allocation ratio. Participants began an initial titration period that lasted up to 14 days. The titration schedule required dosing to a minimum of 3 sprays per day, after which participants were allowed to individualize their dose (3 to 10 sprays per day) until Day 14 when that dose was then fixed for the remainder of the study. Participants returned at Day 22 and Day 36 (end of the randomized treatment period), or earlier if they terminated prematurely from the study. After the end of the 5-week treatment period, participants were offered the option of entering an open-label extension (OLE) study; a safety follow up visit (up to Day 43) was not required if the participant entered the OLE on Day 36. Participants who entered the OLE, up to 7 days after study completion had their follow-up assessments performed on the same day as their first OLE study visit. Participants that did not enter the OLE study had a safety follow up visit 14 days after treatment completion, which could be via telephone.

Official Title
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A Double Blind, Randomized, Placebo-controlled, Parallel Group Study of Sativex Oromucosal Spray (Sativex®; Nabiximols) as Adjunctive Therapy in Relieving Uncontrolled Persistent Chronic Pain in Patients With Advanced Cancer, Who Experience Inadequate Analgesia During Optimized Chronic Opioid Therapy

Conditions
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Pain, Advanced Cancer

Intervention / Treatment
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* Drug: Nabiximols
* Drug: Placebo (GA-0034)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (abbreviated): The participant had advanced cancer for which there was no known curative therapy The participant had a clinical diagnosis of cancer related pain, which was not wholly alleviated with their current optimized opioid treatment The participant received an optimized maintenance dose of Step 3 opioid therapy, preferably with a sustained release preparation, but also allowing a regular maintenance dose of around-the-clock use of immediate release preparations The participant received a daily maintenance dose Step 3 opioid therapy of less than or equal to a total daily opioid dose of 500 mg/day of morphine equivalence (including maintenance and break-through opioids) The participant was using no more than one type of break-through opioid analgesia Exclusion Criteria (abbreviated): The participant had any planned clinical interventions that would have affected their pain (for example, chemotherapy or radiation therapy where, in the clinical judgment of the investigator, these would be expected to affect pain) The participant was using or had used cannabis or cannabinoid-based medications within 30 days of study entry and is unwilling to abstain for the duration of the study The participant had experienced myocardial infarction or clinically significant cardiac dysfunction within the last 12 months or had a cardiac disorder that, in the opinion of the investigator, would have put the participant at risk of a clinically significant arrhythmia or myocardial infarction The participant had significantly impaired renal function The participant had significantly impaired hepatic function Female participants of child-bearing potential and male participants whose partner was of child-bearing potential, unless willing to ensure that they or their partner used effective contraception, for example, oral contraception, double barrier, intra-uterine device, during the study and for 3 months thereafter (however, a male condom was not to be used in conjunction with a female condom as this may not have proven effective)

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nabiximols<br>Nabiximols was self-administered by participants as a 100 microliter (μL) oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day for 5 weeks. Nabiximols oromucosal spray contained delta-9-tetrahydrocannabinol (THC) (27 milligram [mg]/milliliter [mL]):cannabidiol (CBD) (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. | Drug: Nabiximols<br> <br> * Other names: Sativex®;|
| Placebo Comparator: Placebo (GA-0034)<br>Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day for 5 weeks. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. | Drug: Placebo (GA-0034)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment | Participants indicated level of pain in the last 24 hours on an 11-point Numerical Rating Scale (NRS), where a score of 0 was no pain and 10 was pain as bad as you can imagine. Baseline = mean score from first day of 3-day eligibility period through to the day before first dose of study drug. End of Treatment = mean score over last (up to) 7 days to the final pain score at End of Treatment or up until Day 35, whichever is earlier, or final score available (prematurely terminated). Percentage improvement from baseline (Imp%) was calculated as: Imp% = (Baseline pain NRS mean - End of Treatment pain NRS mean)/Baseline pain NRS mean * 100. For participants who died or withdrew due to disease progression, Imp% values were used. For participants who died or withdrew, unrelated to disease progression, before end of Week 5 (no diary data from Day 33 onwards), Imp% was zero for participants whose Imp% value was positive and it was Imp% for participants whose Imp% value was not positive. | Baseline, End of Treatment (Day 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In Mean NRS Average Pain At End Of Treatment | Participants indicated the level of pain experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Change in mean NRS average pain was calculated as: End of Treatment NRS average pain score - Baseline NRS average pain score. A negative value indicates an improvement in average pain score from Baseline. | Baseline, End of Treatment (Day 36) | 
| Change From Baseline In Mean NRS Worst Pain At End Of Treatment | Participants indicated the level of worst pain experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Change in mean NRS worst pain was calculated as: End of Treatment NRS worst pain score - Baseline NRS worst pain score. A negative value indicates an improvement in worst pain score from Baseline. | Baseline, End of Treatment (Day 36) | 
| Change From Baseline In Mean Sleep Disruption NRS At End Of Treatment | Participants indicated the level of sleep disruption experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated did not disrupt sleep and a score of 10 indicated completely disrupted (unable to sleep at all). Change in mean sleep disruption NRS was calculated as: End of Treatment sleep disruption NRS score - Baseline sleep disruption NRS score. A negative value indicates an improvement in sleep disruption score from Baseline. | Baseline, End of Treatment (Day 36) | 
| Subject Global Impression Of Change At Last Visit (Up To Day 36) | The Subject Global Impression of Change (SGIC) was used to assess the overall status of the participant related to their cancer pain, with the markers very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse. The SGIC was assessed at Day 36 or at which a participant's last evaluation was performed, such as in the case of early termination. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36. | Last visit (up to Day 36) | 
| Physician Global Impression Of Change At Last Visit (Up To Day 36) | The Physician Global Impression of Change (PGIC) was used by the treating physician (investigator/sub-investigator) to assess if there was any change in the general functional abilities of the participant since prior to commencement of study medication, with the markers: very much worse, much worse, slightly worse, no change, slightly improved, much improved, very much improved. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36. | Last Visit (up to Day 36) | 
| Patient Satisfaction Questionnaire At Last Visit (Up To Day 36) | The Patient Satisfaction Questionnaire (PSQ) was used to assess level of satisfaction of the participant with the study drug, with the markers extremely satisfied, very satisfied, slightly satisfied, neutral, slightly dissatisfied, very dissatisfied, extremely dissatisfied. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36. | Last Visit (up to Day 36) | 
| Change From Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment | The total daily opioid use (in morphine equivalence) was the sum of morphine equivalence of daily maintenance dose and break-through dose. Change in daily total opioid use was calculated as: End of Treatment daily total opioid use - Baseline daily total opioid use. A negative value indicates a decrease in use from Baseline. | Baseline, End of Treatment (Day 36) | 
| Change From Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End of Treatment | The prescribed daily quantity of opioid maintenance dose was calculated as the product of dose per use and daily frequency of use. Participants were asked: Have you used your maintenance dose painkiller today as prescribed? If the participant answered No to the question, the daily opioid maintenance dose usage on that day was set to 0. Change in daily maintenance opioid dose was calculated as: End of Treatment daily maintenance opioid dose - Baseline daily maintenance opioid dose. A negative value indicates a decrease in dose from Baseline. | Baseline, End of Treatment (Day 36) | 
| Change From Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment | Daily break-through opioid dose usage was calculated as the product of prescribed dose per use, and the number of uses per day. If participants took more than 1 different break-through opioid for more than 1 day, the sum of morphine equivalence dose usages for each break-through opioid was calculated for the summary. Change in daily break-through opioid dose was calculated as: End of Treatment daily break-through opioid dose - Baseline daily break-through opioid dose. A negative value indicates a decrease in dose from Baseline. | Baseline, End of Treatment (Day 36) | 
| Change From Baseline In NRS Constipation At Last Visit (Up To Day 36) | Participants indicated level of constipation on an 11-point NRS, where a score of 0 was no constipation, and 10 was constipation as bad as you can imagine. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36. Change in NRS constipation score was calculated as: Last Visit NRS constipation score - Baseline NRS constipation score. A negative value indicates improvement in condition from Baseline. | Baseline, Last Visit (up to Day 36) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer pain, Opioid therapy, Inadequate analgesia, Optimized chronic opioid therapy