A Two-Part Study of Sativex® Oromucosal Spray for Relieving Uncontrolled Persistent Pain in Patients With Advanced Cancer

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the efficacy of nabiximols (Sativex®), compared with placebo, when used as an adjunctive measure in relieving uncontrolled persistent chronic pain (not breakthrough pain) in participants with advanced cancer, who had inadequate analgesia even with optimized chronic opioid therapy. This multi-center study was conducted in two parts. All participants enrolled into the trial received nabiximols during one of two parts of the study, but they did not know which part. Eligible participants were not required to stop any of their current treatments or medications.

Detailed Description
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This 11-week, multi-center, placebo-controlled study aimed to determine the efficacy, safety and tolerability of nabiximols administered as an adjunctive treatment for 5 weeks, versus placebo, assessed by a 2-part, randomized withdrawal design. The first part of the study (Part A) was single-blind (participants) and the second part of the study (Part B) was randomized, double-blind. Eligible participants had advanced cancer, with a clinical diagnosis of cancer related pain which 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 underwent nabiximols titration during a single-blind treatment period lasting 10 days, followed by 4 days of therapy at the titrated dose. Participants who demonstrated an improvement of 15% or more on the score of the pain numerical rating scale were advanced to Part B, where they were randomized 1:1 to nabiximols or placebo in a double-blind fashion. Participants then received study treatments at their self-titrated doses for 5 weeks. After the end of the 5-week treatment period, participants were offered the option of entering an open-label extension (OLE) study; 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 Two-part, Placebo-controlled, Study of the Safety and Efficacy of Sativex® Oromucosal Spray (Sativex®; Nabiximols) as Adjunctive Therapy in Relieving Uncontrolled Persistent Chronic Pain in Patients With Advanced Cancer, Who Have Inadequate Analgesia Even With 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 is no known curative therapy The participant had a clinical diagnosis of cancer related pain, which was not 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): 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 currently using or had used cannabis or cannabinoid-based medications within 30 days of study entry and was unwilling to abstain for the duration of the study 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 Had significantly impaired renal function 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 three 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 2 or 7 weeks. Nabiximols oromucosal spray contained delta-9-tetrahydrocannabinol (THC) (27 milligrams [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 |
| --- | --- | --- |
| Change From Randomization 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 - Randomization (Part B) Baseline NRS average pain score. The participant's Randomization (Part B) baseline pain 0-10 NRS value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates an improvement in average pain score from Randomization (Part B) Baseline. | Randomization Baseline, End of Treatment (Day 36 of the double-blind period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Improvement From Eligibility Baseline In Mean NRS Average Pain Score At End Of Treatment | Participants indicated level of pain in the last 24 hours on an 11-point NRS, where a score of 0 was no pain and 10 was pain as bad as you can imagine. Eligibility Baseline = mean score from the 3-day eligibility period. End of Treatment = mean score over last (up to) 4 days to the final pain score at End of Treatment or up until Day 36 of the double-blind period, whichever is earlier, or final score available (prematurely terminated). Percentage improvement from baseline (Imp%) was calculated as: Imp% = (Eligibility Baseline pain NRS mean - End of Treatment pain NRS mean)/Eligibility 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, Imp% was zero for participants whose Imp% value was positive and it was Imp% for participants whose Imp% value was not positive. | Eligibility Baseline, End of Treatment (Day 36 of the double-blind period) | 
| Change From Randomization 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 - Randomization (Part B) Baseline NRS worst pain score. The participant's Randomization (Part B) baseline worst pain 0-10 NRS value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates an improvement in worst pain score from Randomization (Part B) Baseline. | Randomization Baseline, End of Treatment (Day 36 of the double-blind period) | 
| Change From Randomization 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 - Randomization (Part B) Baseline sleep disruption NRS score. The participant's Randomization (Part B) baseline sleep disruption 0-10 NRS value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates an improvement in sleep disruption score from Randomization (Part B) Baseline. | Randomization Baseline, End of Treatment (Day 36 of the double-blind period) | 
| Subject Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period) | 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 of the double-blind period or the day 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 of the double-blind period. | Last Visit (up to Day 36 of the double-blind period) | 
| Physician Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period) | 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 of the double-blind period. | Last Visit (up to Day 36 of the double-blind period) | 
| Patient Satisfaction Questionnaire At Last Visit (Up To Day 36 Of The Double-blind Period) | 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 of the double-blind period. | Last Visit (up to Day 36 of the double-blind period) | 
| Change From Randomization 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 - Randomization (Part B) Baseline daily total opioid use. The participant's Randomization (Part B) baseline daily total opioid use value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates a decrease in use from Randomization (Part B) Baseline. | Randomization Baseline, End of Treatment (Day 36 of the double-blind period) | 
| Change From Randomization 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 - Randomization (Part B) Baseline daily maintenance opioid dose. The participant's Randomization (Part B) baseline daily maintenance opioid dose value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates a decrease in dose from Randomization (Part B) Baseline. | Randomization Baseline, End of Treatment (Day 36 of the double-blind period) | 
| Change From Randomization 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 - Randomization (Part B) Baseline daily maintenance opioid dose. The participant's Randomization (Part B) baseline daily break-through opioid dose value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates a decrease in dose from Randomization (Part B) Baseline. | Randomization Baseline, End of Treatment (Day 36 of the double-blind period) | 
| Change From Randomization Baseline In NRS Constipation At Last Visit (Up To Day 36 Of The Double-blind Period) | 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. Change in NRS constipation score was calculated as: Last Visit NRS constipation score - Randomization (Part B) Baseline NRS constipation score. The participant's Randomization (Part B) baseline constipation NRS value was the last evaluation (including unscheduled visits) in the single-blind treatment period (Part A) prior to the first dose of study drug in the double-blind treatment period (Part B). A negative value indicates improvement in condition from Randomization (Part B) Baseline. | Randomization Baseline, Last Visit (up to Day 36 of the double-blind period) | 

 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