Sativex® for Relieving Persistent Pain in Participants With Advanced Cancer

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01262651
• Collaborator: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Enrollment: 397
• Locations: 72
• Arms: 2
• Actual Duration (Months): 55.2
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pain; Advanced Cancer	Drug: Nabiximols; Drug: Placebo (GA-0034)	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 397 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Nov 25, 2010
• Actual Primary Completion Date: Jul 2, 2015
• Actual Study Completion Date: Jul 2, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nabiximols 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; Other Names: Sativex®
Placebo Comparator: Placebo (GA-0034) 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)

Outcome Measures

Primary Outcome Measures

1. Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment [Baseline, End of Treatment (Day 36)]

   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.

Secondary Outcome Measures

1. Change From Baseline In Mean NRS Average Pain At End Of Treatment [Baseline, End Of Treatment (Day 36)]

   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.

2. Change From Baseline In Mean NRS Worst Pain At End Of Treatment [Baseline, End of Treatment (Day 36)]

   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.

3. Change From Baseline In Mean Sleep Disruption NRS At End Of Treatment [Baseline, End of Treatment (Day 36)]

   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.

4. Subject Global Impression Of Change At Last Visit (Up To Day 36) [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.

5. Physician Global Impression Of Change At Last Visit (Up To Day 36) [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.

6. Patient Satisfaction Questionnaire At Last Visit (Up To Day 36) [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.

7. Change From Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment [Baseline, End of Treatment (Day 36)]

   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.

8. Change From Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End of Treatment [Baseline, End of Treatment (Day 36)]

   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.

9. Change From Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment [Baseline, End of Treatment (Day 36)]

   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.

10. Change From Baseline In NRS Constipation At Last Visit (Up To Day 36) [Baseline, 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85027
2		Phoenix	Arizona	United States	85028
3		El Cajon	California	United States	92020
4		Gilroy	California	United States	95020
5		Brandon	Florida	United States	33511
6		Daytona Beach	Florida	United States	32117
7		Holiday	Florida	United States	34691
8		Jacksonville	Florida	United States	32257
9		Lynn Haven	Florida	United States	32444
10		Stuart	Florida	United States	34994
11		Winter Park	Florida	United States	32789
12		Newnan	Georgia	United States	30265
13		Stockbridge	Georgia	United States	30281
14		Shreveport	Louisiana	United States	71105
15		Saint Louis Park	Minnesota	United States	55426
16		Kansas City	Missouri	United States	64132
17		Berlin	New Jersey	United States	08009
18		Hendersonville	North Carolina	United States	28739
19		Winston-Salem	North Carolina	United States	27103
20		Philadelphia	Pennsylvania	United States	19146
21		Houston	Texas	United States	77024
22		Houston	Texas	United States	77089
23		Laredo	Texas	United States	78041
24		Salt Lake City	Utah	United States	84112
25		Salt Lake City	Utah	United States	84124
26		Bruxelles		Belgium	1000
27		Gabrovo		Bulgaria	5300
28		Shumen		Bulgaria	9700
29		Varna		Bulgaria	9010
30		Ceske Budejovice		Czechia	370 01
31		Ceske Budejovice		Czechia	370 87
32		Hradec Kralove		Czechia	500 05
33		Most		Czechia	434 64
34		Nová Ves Pod Pleší		Czechia	262 04
35		Ostrava-Poruba		Czechia	708 52
36		Plzen		Czechia	304 60
37		Lunen		Germany	44534
38		Stadtroda		Germany	07646
39		Wetzlar		Germany	35578
40		Deszk		Hungary	H-6772
41		Kecskemét		Hungary	H-6000
42		Komarom		Hungary	H-2900
43		Miskolc		Hungary	H-3501
44		Nyíregyháza		Hungary	H-4412
45		Szekszard		Hungary	H-7100
46		Rezekne		Latvia	LV-4600
47		Riga		Latvia	LV-1079
48		Klaipeda		Lithuania	LT-92288
49		Siauliai		Lithuania	LT-76307
50		Vilnius		Lithuania	LT-08660
51		Bialystok		Poland	15-250
52		Bielsko-Biala		Poland	43-300
53		Gliwice		Poland	44-101
54		Poznan		Poland	61-245
55		Warszawa		Poland	02-781
56		Ponce		Puerto Rico	00717
57		San Juan		Puerto Rico	00927
58		Baia Mare		Romania	430031
59		Braila		Romania	810325
60		Bucuresti		Romania	010976
61		Craiova		Romania	200385
62		Oradea		Romania	410469
63		Satu Mare		Romania	440055
64		Suceava		Romania	720237
65		Bury Saint Edmunds		United Kingdom	IP33 2QZ
66		Bury		United Kingdom	BL9 7TD
67		Edinburgh		United Kingdom	EH4 2XR
68		Glasgow		United Kingdom	G12 0YN
69		Manchester		United Kingdom	M8 5RB
70		Norwich		United Kingdom	NR4 7UY
71		Weston Super Mare		United Kingdom	BS23 4TQ
72		Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Jazz Pharmaceuticals
• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. J Pain Symptom Manage. 2018 Feb;55(2):179-188.e1. doi: 10.1016/j.jpainsymman.2017.09.001. Epub 2017 Sep 18.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01262651
• Other Study ID Numbers: GWCA0958; 2009-016064-36
• First Posted: Dec 17, 2010
• Last Update Posted: Apr 23, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Jazz Pharmaceuticals: Cancer pain; Opioid therapy; Inadequate analgesia; Optimized chronic opioid therapy
• Additional relevant MeSH terms: Neoplasms; Nabiximols

Study Results

Participant Flow

Pre-assignment Detail	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. However, if a participant randomized to placebo ever took a nabiximols dose, the participant was analyzed as nabiximols-treated in the Safety population.

Arm/Group Title	Nabiximols	Placebo (GA-0034)
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 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.	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.
Period Title: Overall Study
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

Baseline Characteristics

Arm/Group Title	Nabiximols	Placebo (GA-0034)	Total
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.	Total of all reporting groups
Overall Participants	199	198	397
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.2 (12.0)	60.7 (11.1)	59.9 (11.6)
Sex: Female, Male (Count of Participants)
Female	88 44.2%	95 48%	183 46.1%
Male	111 55.8%	103 52%	214 53.9%

Outcome Measures

1. Primary Outcome

Title	Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment
Description	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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Median (Inter-Quartile Range) [percent improvement]	10.7	4.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nabiximols, Placebo (GA-0034)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0854
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.41
	Confidence Interval	(2-Sided) 95%; 0.00 to 8.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline In Mean NRS Average Pain At End Of Treatment
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 - 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)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who receive 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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Mean (Standard Deviation) [units on a scale]	-0.8 (1.4)	-0.6 (1.5)

3. Secondary Outcome

Title	Change From Baseline In Mean NRS Worst Pain At End Of Treatment
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 - 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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Mean (Standard Deviation) [units on a scale]	-0.9 (1.4)	-0.8 (1.6)

4. Secondary Outcome

Title	Change From Baseline In Mean Sleep Disruption NRS At End Of Treatment
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 - 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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Mean (Standard Deviation) [units on a scale]	-0.8 (1.7)	-0.5 (1.6)

5. Secondary Outcome

Title	Subject Global Impression Of Change At Last Visit (Up To Day 36)
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 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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	172	179
Very Much Improved	5 2.5%	3 1.5%
Much Improved	34 17.1%	26 13.1%
Slightly Improved	60 30.2%	55 27.8%
No Change	56 28.1%	72 36.4%
Slightly Worse	9 4.5%	13 6.6%
Much Worse	6 3%	6 3%
Very Much Worse	2 1%	4 2%

6. Secondary Outcome

Title	Physician Global Impression Of Change At Last Visit (Up To Day 36)
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.
Time Frame	Last Visit (up to Day 36)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	174	181
Very much Improved	6 3%	3 1.5%
Much Improved	37 18.6%	25 12.6%
Slightly Improved	56 28.1%	50 25.3%
No Change	41 20.6%	75 37.9%
Slightly Worse	25 12.6%	19 9.6%
Much Worse	7 3.5%	5 2.5%
Very Much Worse	2 1%	4 2%

7. Secondary Outcome

Title	Patient Satisfaction Questionnaire At Last Visit (Up To Day 36)
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.
Time Frame	Last Visit (up to Day 36)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	171	179
Extremely Satisfied	7 3.5%	3 1.5%
Very Satisfied	42 21.1%	38 19.2%
Slightly Satisfied	42 21.1%	37 18.7%
Neutral	46 23.1%	63 31.8%
Slightly Dissatisfied	22 11.1%	20 10.1%
Very Dissatisfied	11 5.5%	13 6.6%
Extremely Dissatisfied	1 0.5%	5 2.5%

8. Secondary Outcome

Title	Change From Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment
Description	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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Mean (Standard Deviation) [mg (morphine equivalent)]	0.3 (34.7)	0.6 (44.8)

9. Secondary Outcome

Title	Change From Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End of Treatment
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 - Baseline daily maintenance opioid dose. A negative value indicates a decrease in dose from Baseline.
Time Frame	Baseline, End of Treatment (Day 36)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Mean (Standard Deviation) [mg (morphine equivalent)]	0.2 (20.9)	-1.3 (38.7)

10. Secondary Outcome

Title	Change From Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment
Description	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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	199	198
Mean (Standard Deviation) [mg (morphine equivalent)]	0.1 (22.2)	1.8 (23.6)

11. Secondary Outcome

Title	Change From Baseline In NRS Constipation At Last Visit (Up To Day 36)
Description	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)

Outcome Measure Data

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	Nabiximols	Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.	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.
Measure Participants	172	178
Mean (Standard Deviation) [units on a scale]	-0.6 (2.9)	-0.3 (2.8)

Adverse Events

Time Frame	Up to Day 43 post-randomization
Arm/Group Title	Nabiximols		Placebo (GA-0034)
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 5 weeks. Nabiximols oromucosal spray contained THC (27 mg/mL):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.		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.
All Cause Mortality
	Nabiximols		Placebo (GA-0034)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nabiximols		Placebo (GA-0034)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/199 (23.6%)		43/198 (21.7%)
Blood and lymphatic system disorders
Neutropenia	0/199 (0%)		1/198 (0.5%)
Pancytopenia	1/199 (0.5%)		0/198 (0%)
Thrombocytopenia	0/199 (0%)		1/198 (0.5%)
Cardiac disorders
Atrial Fibrillation	1/199 (0.5%)		0/198 (0%)
Cardiac Failure Congestive	1/199 (0.5%)		0/198 (0%)
Gastrointestinal disorders
Gastric perforation	0/199 (0%)		1/198 (0.5%)
Gastrointestinal Haemorrhage	0/199 (0%)		1/198 (0.5%)
Ileus	0/199 (0%)		1/198 (0.5%)
Intestinal Obstruction	0/199 (0%)		2/198 (1%)
Mouth Haemorrhage	1/199 (0.5%)		0/198 (0%)
Nausea	0/199 (0%)		1/198 (0.5%)
Vomiting	1/199 (0.5%)		2/198 (1%)
General disorders
Device Occlusion	1/199 (0.5%)		0/198 (0%)
Infections and infestations
Clostridium Difficile Colitis	1/199 (0.5%)		0/198 (0%)
Lower Respiratory Tract Infection	3/199 (1.5%)		0/198 (0%)
Pneumonia	1/199 (0.5%)		2/198 (1%)
Respiratory Tract Infection	1/199 (0.5%)		0/198 (0%)
Sepsis	0/199 (0%)		1/198 (0.5%)
Urinary Tract Infection	1/199 (0.5%)		0/198 (0%)
Injury, poisoning and procedural complications
Fall	0/199 (0%)		1/198 (0.5%)
Metabolism and nutrition disorders
Electrolyte Imbalance	1/199 (0.5%)		0/198 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	1/199 (0.5%)		0/198 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain	3/199 (1.5%)		0/198 (0%)
Metastases To Central Nervous System	1/199 (0.5%)		0/198 (0%)
Neoplasm Progression	31/199 (15.6%)		28/198 (14.1%)
Tumour pain	0/199 (0%)		1/198 (0.5%)
Nervous system disorders
Convulsion	1/199 (0.5%)		0/198 (0%)
Spinal Cord Compression	0/199 (0%)		1/198 (0.5%)
Psychiatric disorders
Completed Suicide	0/199 (0%)		1/198 (0.5%)
Disorientation	1/199 (0.5%)		0/198 (0%)
Hallucination, Visual	1/199 (0.5%)		0/198 (0%)
Mental Status Changes	1/199 (0.5%)		1/198 (0.5%)
Renal and urinary disorders
Renal Failure Acute	1/199 (0.5%)		0/198 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/199 (0.5%)		0/198 (0%)
Pleural Effusion	0/199 (0%)		1/198 (0.5%)
Pulmonary Embolism	1/199 (0.5%)		0/198 (0%)
Pulmonary Toxicity	0/199 (0%)		1/198 (0.5%)
Vascular disorders
Deep Vein Thrombosis	1/199 (0.5%)		1/198 (0.5%)
Other (Not Including Serious) Adverse Events
	Nabiximols		Placebo (GA-0034)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/199 (34.7%)		53/198 (26.8%)
Gastrointestinal disorders
Nausea	31/199 (15.6%)		20/198 (10.1%)
Vomiting	15/199 (7.5%)		11/198 (5.6%)
Constipation	11/199 (5.5%)		13/198 (6.6%)
General disorders
Fatigue	12/199 (6%)		10/198 (5.1%)
Metabolism and nutrition disorders
Decreased Appetite	14/199 (7%)		12/198 (6.1%)
Nervous system disorders
Dizziness	16/199 (8%)		8/198 (4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.