A Phase 3 interventional study of Nabiximols and Placebo (GA-0034) in Pain and Advanced Cancer, sponsored by GW Pharmaceuticals Ltd. Completed at 72 sites in 12 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-04-23.
Sponsored by GW Pharmaceuticals Ltd · Phase 3, Interventional, and Treatment
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.
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 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 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.
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Exclusion Criteria (abbreviated):
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
Placebo Comparator: Placebo (GA-0034) 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)
Drug: Placebo (GA-0034)
Also known as: Sativex®
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.
Time frame: Baseline, End of Treatment (Day 36)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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 equivalents 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.
Time frame: 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.
Time frame: 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 equivalents 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.
Time frame: 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.
Time frame: Baseline, Last Visit (up to Day 36)
| Milestone | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Started | 199 | 198 |
| Received at least 1 dose of study drug | 199 | 198 |
| Safety population | 199 | 198 |
| Itt population | 199 | 198 |
| Completed | 141 | 150 |
| Not completed | 58 | 48 |
| Withdrew: Adverse event | 40 | 35 |
| Withdrew: Withdrawal by subject | 15 | 11 |
| Withdrew: Withdrawal by investigator | 2 | 2 |
| Withdrew: Met withdrawal criteria | 1 | 0 |
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.
| percent improvement | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment | 10.7 (0.0 to 30.0) | 4.5 (-2.9 to 25.7) |
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.
| units on a scale | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In Mean NRS Average Pain At End Of Treatment | -0.8 ± 1.4 | -0.6 ± 1.5 |
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.
| units on a scale | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In Mean NRS Worst Pain At End Of Treatment | -0.9 ± 1.4 | -0.8 ± 1.6 |
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.
| units on a scale | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In Mean Sleep Disruption NRS At End Of Treatment | -0.8 ± 1.7 | -0.5 ± 1.6 |
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.
| Participants | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Very Much Improved | 5 | 3 |
| Much Improved | 34 | 26 |
| Slightly Improved | 60 | 55 |
| No Change | 56 | 72 |
| Slightly Worse | 9 | 13 |
| Much Worse | 6 | 6 |
| Very Much Worse | 2 | 4 |
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.
| Participants | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Very much Improved | 6 | 3 |
| Much Improved | 37 | 25 |
| Slightly Improved | 56 | 50 |
| No Change | 41 | 75 |
| Slightly Worse | 25 | 19 |
| Much Worse | 7 | 5 |
| Very Much Worse | 2 | 4 |
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.
| Participants | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Extremely Satisfied | 7 | 3 |
| Very Satisfied | 42 | 38 |
| Slightly Satisfied | 42 | 37 |
| Neutral | 46 | 63 |
| Slightly Dissatisfied | 22 | 20 |
| Very Dissatisfied | 11 | 13 |
| Extremely Dissatisfied | 1 | 5 |
The total daily opioid use (in morphine equivalence) was the sum of morphine equivalents 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.
| mg (morphine equivalent) | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment | 0.3 ± 34.7 | 0.6 ± 44.8 |
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.
| mg (morphine equivalent) | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End of Treatment | 0.2 ± 20.9 | -1.3 ± 38.7 |
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 equivalents 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.
| mg (morphine equivalent) | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment | 0.1 ± 22.2 | 1.8 ± 23.6 |
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.
| units on a scale | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Change From Baseline In NRS Constipation At Last Visit (Up To Day 36) | -0.6 ± 2.9 | -0.3 ± 2.8 |
Collected over Up to Day 43 post-randomization. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Nabiximols | — | 47/199 (23.6%) | 69/199 (34.7%) |
| Placebo (GA-0034) | — | 43/198 (21.7%) | 53/198 (26.8%) |
| Event | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| Neoplasm ProgressionNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 31/199 | 28/198 |
| Lower Respiratory Tract InfectionInfections and infestations | 3/199 | 0/198 |
| Cancer PainNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 3/199 | 0/198 |
| Intestinal ObstructionGastrointestinal disorders | 0/199 | 2/198 |
| VomitingGastrointestinal disorders | 1/199 | 2/198 |
| PneumoniaInfections and infestations | 1/199 | 2/198 |
| NeutropeniaBlood and lymphatic system disorders | 0/199 | 1/198 |
| ThrombocytopeniaBlood and lymphatic system disorders | 0/199 | 1/198 |
| Gastric perforationGastrointestinal disorders | 0/199 | 1/198 |
| Gastrointestinal HaemorrhageGastrointestinal disorders | 0/199 | 1/198 |
| Event | Nabiximols | Placebo (GA-0034) |
|---|---|---|
| NauseaGastrointestinal disorders | 31/199 | 20/198 |
| DizzinessNervous system disorders | 16/199 | 8/198 |
| VomitingGastrointestinal disorders | 15/199 | 11/198 |
| Decreased AppetiteMetabolism and nutrition disorders | 14/199 | 12/198 |
| ConstipationGastrointestinal disorders | 11/199 | 13/198 |
| FatigueGeneral disorders | 12/199 | 10/198 |
Safety population included all participants who received at least one infusion of study drug.
| Age, Continuous(years) | Nabiximols | Placebo (GA-0034) | Total |
|---|---|---|---|
| Mean | 59.2 ± 12.0 | 60.7 ± 11.1 | 59.9 ± 11.6 |
| Sex: Female, Male(Participants) | Nabiximols | Placebo (GA-0034) | Total |
|---|---|---|---|
| Female | 88 | 95 | 183 |
| Male | 111 | 103 | 214 |
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