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

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ClinicalTrials.gov Identifier: NCT01424566
Recruitment Status : Completed
First Posted : August 29, 2011
Results First Posted : April 23, 2018
Last Update Posted : April 23, 2018
Sponsor:
Collaborator:
Otsuka Pharmaceutical Development & Commercialization, Inc.
Information provided by (Responsible Party):
GW Pharmaceuticals Ltd.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Conditions Pain
Advanced Cancer
Interventions Drug: Nabiximols
Drug: Placebo (GA-0034)
Enrollment 406

Recruitment Details  
Pre-assignment Details Per the Statistical Analyses Plan, all randomized participants who received at least 1 dose of study drug were analyzed in the Intent to Treat (ITT) population as per randomized treatment group. Participants were included and analyzed according to the treatment group they were randomized to.
Arm/Group Title Single-blind Nabiximols Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description 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 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 flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in Numerical Rating Scale (NRS) pain scores during the single-blind treatment period (Part A). Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Period Title: Single-blind Treatment
Started 406 0 [1] 0 [1]
Received at Least 1 Dose of Study Drug 404 [2] 0 0
Single-blind Safety Population 404 0 0
Met Randomization Criteria 206 0 0
Completed 206 0 0
Not Completed 200 0 0
Reason Not Completed
Adverse Event             71             0             0
Withdrawal by Subject             16             0             0
Withdrawal by Investigator             2             0             0
Did Not Meet Inclusion Criteria             108             0             0
Met Exclusion Criteria             1             0             0
Did Not Administer Any Study Drug             2             0             0
[1]
Participants were not enrolled in this arm in the single-blind period.
[2]
Two participants did not administer any study drug.
Period Title: Double-blind Treatment
Started 0 [1] 103 [2] 103 [2]
Received at Least 1 Dose of Study Drug 0 103 103
Randomized Safety Population 0 103 103
ITT Population 0 103 103
Completed 0 78 88
Not Completed 0 25 15
Reason Not Completed
Adverse Event             0             21             13
Withdrawal by Subject             0             2             0
Withdrawal by Investigator             0             1             1
Lack of Efficacy             0             1             1
[1]
Participants were not enrolled in this arm in the double-blind period.
[2]
Participants were not enrolled in this arm in the single-blind period.
Arm/Group Title Single-blind Nabiximols
Hide Arm/Group Description Nabiximols 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 2 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Baseline Participants 406
Hide Baseline Analysis Population Description
All participants who were randomized and received at least 1 dose of study drug. Two participants who were randomized in the single-blind treatment period did not administer any study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 406 participants
61.2  (11.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 406 participants
Female
177
  43.6%
Male
229
  56.4%
1.Primary Outcome
Title Change From Randomization Baseline In Mean NRS Average Pain At End Of Treatment
Hide Description 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.
Time Frame Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.5  (1.3) 0.5  (1.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind Nabiximols, Double-blind Placebo (GA-0034)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9173
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.42 to 0.38
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percent Improvement From Eligibility Baseline In Mean NRS Average Pain Score At End Of Treatment
Hide Description

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.

Time Frame Eligibility Baseline, End of Treatment (Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Median (Inter-Quartile Range)
Unit of Measure: percent improvement
33.3
(18.2 to 51.8)
35.7
(18.8 to 51.3)
3.Secondary Outcome
Title Change From Randomization Baseline In Mean NRS Worst Pain At End Of Treatment
Hide Description 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.
Time Frame Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.2  (1.4) 0.5  (1.6)
4.Secondary Outcome
Title Change From Randomization Baseline In Mean Sleep Disruption NRS At End Of Treatment
Hide Description 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.
Time Frame Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.2  (1.3) 0.5  (1.4)
5.Secondary Outcome
Title Subject Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period)
Hide Description 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.
Time Frame Last Visit (up to Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 88 97
Measure Type: Count of Participants
Unit of Measure: Participants
Very Much Improved
6
   6.8%
6
   6.2%
Much Improved
28
  31.8%
35
  36.1%
Slightly Improved
35
  39.8%
26
  26.8%
No Change
8
   9.1%
15
  15.5%
Slightly Worse
8
   9.1%
8
   8.2%
Much Worse
3
   3.4%
6
   6.2%
Very Much Worse
0
   0.0%
1
   1.0%
6.Secondary Outcome
Title Physician Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period)
Hide Description 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.
Time Frame Last Visit (up to Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 90 97
Measure Type: Count of Participants
Unit of Measure: Participants
Very Much Improved
7
   7.8%
7
   7.2%
Much Improved
22
  24.4%
30
  30.9%
Slightly Improved
37
  41.1%
25
  25.8%
No Change
11
  12.2%
20
  20.6%
Slightly Worse
4
   4.4%
12
  12.4%
Much Worse
8
   8.9%
3
   3.1%
Very Much Worse
1
   1.1%
0
   0.0%
7.Secondary Outcome
Title Patient Satisfaction Questionnaire At Last Visit (Up To Day 36 Of The Double-blind Period)
Hide Description 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.
Time Frame Last Visit (up to Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 89 97
Measure Type: Count of Participants
Unit of Measure: Participants
Extremely Satisfied
5
   5.6%
5
   5.2%
Very Satisfied
30
  33.7%
38
  39.2%
Slightly Satisfied
35
  39.3%
28
  28.9%
Neutral
14
  15.7%
10
  10.3%
Slightly Dissatisfied
2
   2.2%
11
  11.3%
Very Dissatisfied
0
   0.0%
4
   4.1%
Extremely Dissatisfied
3
   3.4%
1
   1.0%
8.Secondary Outcome
Title Change From Randomization Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment
Hide Description

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.

Time Frame Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Mean (Standard Deviation)
Unit of Measure: mg (morphine equivalent)
9.0  (45.6) 15.5  (75.9)
9.Secondary Outcome
Title Change From Randomization Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End Of Treatment
Hide Description

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.

Time Frame Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Mean (Standard Deviation)
Unit of Measure: mg (morphine equivalent)
0.0  (11.0) 8.5  (54.6)
10.Secondary Outcome
Title Change From Randomization Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment
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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.

Time Frame Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
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Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 103 103
Mean (Standard Deviation)
Unit of Measure: mg (morphine equivalent)
9.0  (50.7) 7.0  (36.1)
11.Secondary Outcome
Title Change From Randomization Baseline In NRS Constipation At Last Visit (Up To Day 36 Of The Double-blind Period)
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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.

Time Frame Randomization Baseline, Last Visit (up to Day 36 of the double-blind period)
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Hide Analysis Population Description
The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to.
Arm/Group Title Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
Overall Number of Participants Analyzed 89 96
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.0  (1.8) -0.2  (2.2)
Time Frame Up to Day 43 of the double-blind period post-randomization
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Single-blind Nabiximols Double-blind Nabiximols Double-blind Placebo (GA-0034)
Hide Arm/Group Description Nabiximols 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 2 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. Two participants did not receive study drug and are not included in the safety set. Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A). Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
All-Cause Mortality
Single-blind Nabiximols Double-blind Nabiximols Double-blind Placebo (GA-0034)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Single-blind Nabiximols Double-blind Nabiximols Double-blind Placebo (GA-0034)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   80/404 (19.80%)   33/103 (32.04%)   16/103 (15.53%) 
Blood and lymphatic system disorders       
Anaemia  1  1/404 (0.25%)  2/103 (1.94%)  1/103 (0.97%) 
Anaemia of Malignant Disease  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
Gastrointestinal disorders       
Ascites  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Diarrhoea  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Gastrointestinal Haemorrhage  1  1/404 (0.25%)  1/103 (0.97%)  0/103 (0.00%) 
Intestinal Obstruction  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Intestinal Perforation  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Nausea  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Vomiting  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Duodenal Ulcer Haemorrhage  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
Haematemesis  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
General disorders       
Breakthrough Pain  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
General Physical Health Deterioration  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Pain  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Pyrexia  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Hepatobiliary disorders       
Acute Hepatic Failure  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Infections and infestations       
Cellulitis  1  1/404 (0.25%)  0/103 (0.00%)  1/103 (0.97%) 
Lower Respiratory Tract Infection  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Meningitis Listeria  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Pneumonia  1  1/404 (0.25%)  1/103 (0.97%)  0/103 (0.00%) 
Pneumonia Bacterial  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Respiratory Tract Infection  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Sepsis  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Urinary Tract Infection  1  3/404 (0.74%)  0/103 (0.00%)  0/103 (0.00%) 
Catheter Site Cellulitis  1  0/404 (0.00%)  1/103 (0.97%)  0/103 (0.00%) 
Urosepsis  1  0/404 (0.00%)  1/103 (0.97%)  0/103 (0.00%) 
Abdominal Sepsis  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
Bronchopneumonia  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
Injury, poisoning and procedural complications       
Foot Fracture  1  0/404 (0.00%)  1/103 (0.97%)  0/103 (0.00%) 
Investigations       
ECG Signs of Myocardial Ischaemia  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Metabolism and nutrition disorders       
Hypokalaemia  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Musculoskeletal and connective tissue disorders       
Musculoskeletal Chest Pain  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Pain in Extremity  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Cancer Pain  1  4/404 (0.99%)  0/103 (0.00%)  0/103 (0.00%) 
Metastases to Central Nervous System  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Neoplasm Progression  1  41/404 (10.15%)  28/103 (27.18%)  11/103 (10.68%) 
Tumour Pain  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Tumour Haemorrhage  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
Nervous system disorders       
Cerebrovascular Accident  1  1/404 (0.25%)  1/103 (0.97%)  0/103 (0.00%) 
Convulsion  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Hypoglycaemic Coma  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Nerve Root Compression  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Sedation  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Spinal Cord Compression  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Renal and urinary disorders       
Renal Failure Acute  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Hydronephrosis  1  0/404 (0.00%)  1/103 (0.97%)  0/103 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Acute Respiratory Failure  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Dyspnoea  1  2/404 (0.50%)  0/103 (0.00%)  0/103 (0.00%) 
Pleuritic Pain  1  1/404 (0.25%)  0/103 (0.00%)  0/103 (0.00%) 
Vascular disorders       
Deep Vein Thrombosis  1  0/404 (0.00%)  1/103 (0.97%)  0/103 (0.00%) 
Peripheral Embolism  1  0/404 (0.00%)  0/103 (0.00%)  1/103 (0.97%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Single-blind Nabiximols Double-blind Nabiximols Double-blind Placebo (GA-0034)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   97/404 (24.01%)   21/103 (20.39%)   17/103 (16.50%) 
Blood and lymphatic system disorders       
Anaemia  1  0/404 (0.00%)  5/103 (4.85%)  6/103 (5.83%) 
Gastrointestinal disorders       
Nausea  1  25/404 (6.19%)  0/103 (0.00%)  0/103 (0.00%) 
Vomiting  1  21/404 (5.20%)  0/103 (0.00%)  0/103 (0.00%) 
General disorders       
Asthenia  1  0/404 (0.00%)  6/103 (5.83%)  6/103 (5.83%) 
Investigations       
Weight Decreased  1  0/404 (0.00%)  7/103 (6.80%)  4/103 (3.88%) 
Metabolism and nutrition disorders       
Decreased Appetite  1  0/404 (0.00%)  6/103 (5.83%)  3/103 (2.91%) 
Nervous system disorders       
Dizziness  1  27/404 (6.68%)  0/103 (0.00%)  0/103 (0.00%) 
Somnolence  1  46/404 (11.39%)  6/103 (5.83%)  1/103 (0.97%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Medical Enquiries
Organization: GW Pharmaceuticals Ltd.
Publications:
Responsible Party: GW Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT01424566     History of Changes
Other Study ID Numbers: GWCA1103
2010-022905-17 ( EudraCT Number )
First Submitted: August 25, 2011
First Posted: August 29, 2011
Results First Submitted: March 23, 2018
Results First Posted: April 23, 2018
Last Update Posted: April 23, 2018