SPRAY III: Sativex® for Relieving Persistent Pain in Patients With Advanced Cancer

Sponsor
Jazz Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01361607
Collaborator
Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
399
68
2
42
5.9
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
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 that was not wholly alleviated by their current optimized opioid treatment.

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

Study Design

Study Type:
Interventional
Actual Enrollment :
399 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 :
May 27, 2011
Actual Primary Completion Date :
Nov 24, 2014
Actual Study Completion Date :
Nov 24, 2014

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 was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day for 5 weeks. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings.

    Drug: Placebo (GA-0034)

    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 equivalence of daily maintenance dose and break-through dose. Change in daily total opioid use was calculated as: End of Treatment daily total opioid use - Baseline daily total opioid use. A negative value indicates a decrease in use from Baseline.

    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 equivalence dose usages for each break-through opioid was calculated for the summary. Change in daily break-through opioid dose was calculated as: End of Treatment daily break-through opioid dose - Baseline daily break-through opioid dose. A negative value indicates a decrease in dose from Baseline.

    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 Glendale California United States 91204
    2 Santa Rosa California United States 95403
    3 Clearwater Florida United States 33756
    4 Holiday Florida United States 34691
    5 Miami Florida United States 33136
    6 Stuart Florida United States 34994
    7 Marietta Georgia United States 30060
    8 Newnan Georgia United States 30265
    9 Stockbridge Georgia United States 30281
    10 Gurnee Illinois United States 60031
    11 Mount Vernon Illinois United States 62864
    12 Ashland Kentucky United States 41101
    13 Bossier City Louisiana United States 71111
    14 Shreveport Louisiana United States 71105
    15 Missoula Montana United States 59802
    16 Berlin New Jersey United States 08009
    17 New York New York United States 10003
    18 New York New York United States 10010-4086
    19 Cleveland Ohio United States 44119
    20 Lacey Washington United States 98503-1010
    21 Vratsa Bulgaria 3000
    22 Benešov Czechia 256 01
    23 Jablonec Nad Nisou Czechia 466 01
    24 Plzen Czechia 304 60
    25 Sokolov Czechia 356 01
    26 Teplice Czechia 415 01
    27 České Budějovice Czechia 370 01
    28 České Budějovice Czechia 370 87
    29 Berlin Germany 10435
    30 Frankfurt Germany 60311
    31 Fulda Germany 36039
    32 Hannover Germany 30625
    33 Jena Germany 07747
    34 Wiesbaden Germany 65189
    35 Komarom Hungary 2900
    36 Nyíregyháza Hungary 4412
    37 Mexico DF Mexico 10700
    38 Chihuahua Mexico 31238
    39 Monterrey Mexico 64710
    40 Bydgoszcz Poland 85-796
    41 Czestochowa Poland 42-200
    42 Czestochowa Poland 42-217
    43 Dzialdowo Poland 13-200
    44 Gdansk Poland 80-208
    45 Klodzko Poland 57-300
    46 Ostrowiec Swietokrzyski Poland 27-400
    47 Poznan Poland 61-245
    48 Warszawa Poland 02-781
    49 Ponce Puerto Rico 00717
    50 Targoviste Dambovita Romania 130095
    51 Baia Mare Romania 430031
    52 Braila Romania 810325
    53 Brasov Romania 500366
    54 Bucuresti Romania 011461
    55 Cluj-Napoca Romania 400015
    56 Constanta Romania 900591
    57 Focșani Romania 620165
    58 Iasi Romania 700503
    59 Sibiu Romania 550245
    60 Suceava Romania 720237
    61 Cheltenham Gloucestershire United Kingdom GL53 0QJ
    62 Withington Manchester United Kingdom M20 4BX
    63 Great Yarmouth Norfolk United Kingdom NR31 6LA
    64 Coventry United Kingdom CV2 2HJ
    65 Glasgow United Kingdom G12 0YN
    66 Manchester United Kingdom M8 5RB
    67 Norwich United Kingdom NR4 7UY
    68 Plymouth United Kingdom PL6 8DH

    Sponsors and Collaborators

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

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Jazz Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01361607
    Other Study ID Numbers:
    • GWCA0962
    • 2009-016065-29
    First Posted:
    May 27, 2011
    Last Update Posted:
    Apr 23, 2018
    Last Verified:
    Mar 1, 2018
    Keywords provided by Jazz Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    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 200 199
    Received at Least 1 Dose of Study Drug 198 199
    Safety Population 199 198
    ITT Population 198 199
    COMPLETED 136 158
    NOT COMPLETED 64 41

    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 200 199 399
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.0
    (11.0)
    59.6
    (11.0)
    59.8
    (11.0)
    Sex: Female, Male (Count of Participants)
    Female
    94
    47%
    102
    51.3%
    196
    49.1%
    Male
    106
    53%
    97
    48.7%
    203
    50.9%

    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 198 199
    Median (Inter-Quartile Range) [percent improvement]
    7.2
    9.5
    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 0.2735
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Method of Estimation Estimation Parameter Median Difference (Final Values)
    Estimated Value -1.84
    Confidence Interval (2-Sided) 95%
    -6.19 to 1.50
    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
    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, up to a maximum of 10 sprays per day in the morning and evening, 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 198 199
    Mean (Standard Deviation) [units on a scale]
    -0.9
    (1.5)
    -1.0
    (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 198 199
    Mean (Standard Deviation) [units on a scale]
    -1.0
    (1.7)
    -1.2
    (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 198 199
    Mean (Standard Deviation) [units on a scale]
    -0.9
    (1.8)
    -1.1
    (1.7)
    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 175 184
    Very Much Improved
    19
    9.5%
    11
    5.5%
    Much Improved
    36
    18%
    35
    17.6%
    Slightly Improved
    64
    32%
    51
    25.6%
    No Change
    38
    19%
    67
    33.7%
    Slightly Worse
    13
    6.5%
    13
    6.5%
    Much Worse
    5
    2.5%
    6
    3%
    Very Much Worse
    0
    0%
    1
    0.5%
    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 176 184
    Very Much Improved
    13
    6.5%
    11
    5.5%
    Much Improved
    37
    18.5%
    32
    16.1%
    Slightly Improved
    62
    31%
    48
    24.1%
    No Change
    41
    20.5%
    78
    39.2%
    Slightly Worse
    18
    9%
    10
    5%
    Much Worse
    5
    2.5%
    4
    2%
    Very Much Worse
    0
    0%
    1
    0.5%
    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 175 184
    Extremely Satisfied
    18
    9%
    8
    4%
    Very Satisfied
    34
    17%
    43
    21.6%
    Slightly Satisfied
    55
    27.5%
    54
    27.1%
    Neutral
    35
    17.5%
    52
    26.1%
    Slightly Dissatisfied
    13
    6.5%
    15
    7.5%
    Very Dissatisfied
    15
    7.5%
    6
    3%
    Extremely Dissatisfied
    5
    2.5%
    6
    3%
    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 equivalence of daily maintenance dose and break-through dose. Change in daily total opioid use was calculated as: End of Treatment daily total opioid use - Baseline daily total opioid use. A negative value indicates a decrease in use from Baseline.
    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 198 199
    Mean (Standard Deviation) [mg (morphine equivalent)]
    -6.5
    (53.9)
    2.3
    (42.5)
    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 197 199
    Mean (Standard Deviation) [mg (morphine equivalent)]
    -1.5
    (38.2)
    1.9
    (34.3)
    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 equivalence dose usages for each break-through opioid was calculated for the summary. Change in daily break-through opioid dose was calculated as: End of Treatment daily break-through opioid dose - Baseline daily break-through opioid dose. A negative value indicates a decrease in dose from Baseline.
    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 198 199
    Mean (Standard Deviation) [mg (morphine equivalent)]
    -4.4
    (27.7)
    0.5
    (20.5)
    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 174 184
    Mean (Standard Deviation) [units on a scale]
    -0.4
    (2.6)
    -0.6
    (2.7)

    Adverse Events

    Time Frame Up to Day 43 post-randomization
    Adverse Event Reporting Description
    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 35/199 (17.6%) 44/198 (22.2%)
    Blood and lymphatic system disorders
    Anaemia 0/199 (0%) 1/198 (0.5%)
    Coagulopathy 0/199 (0%) 1/198 (0.5%)
    Cardiac disorders
    Acute Myocardial Infarction 0/199 (0%) 1/198 (0.5%)
    Cardiac Failure Congestive 0/199 (0%) 1/198 (0.5%)
    Tachycardia 1/199 (0.5%) 1/198 (0.5%)
    Gastrointestinal disorders
    Constipation 2/199 (1%) 0/198 (0%)
    Vomiting 1/199 (0.5%) 1/198 (0.5%)
    General disorders
    Chest Pain 1/199 (0.5%) 1/198 (0.5%)
    Generalised Oedema 1/199 (0.5%) 0/198 (0%)
    Infections and infestations
    Bronchitis 0/199 (0%) 1/198 (0.5%)
    Device Related Infection 1/199 (0.5%) 0/198 (0%)
    Device Related Sepsis 0/199 (0%) 1/198 (0.5%)
    Groin Abscess 0/199 (0%) 1/198 (0.5%)
    Helicobacter Gastritis 0/199 (0%) 1/198 (0.5%)
    Lobar Pneumonia 1/199 (0.5%) 0/198 (0%)
    Pneumonia 1/199 (0.5%) 0/198 (0%)
    Pseudomembranous Colitis 0/199 (0%) 1/198 (0.5%)
    Pyelonephritis 0/199 (0%) 1/198 (0.5%)
    Staphylococcal Sepsis 0/199 (0%) 1/198 (0.5%)
    Urinary Tract Infection 1/199 (0.5%) 0/198 (0%)
    Injury, poisoning and procedural complications
    Fall 1/199 (0.5%) 0/198 (0%)
    Post Procedural Haemorrhage 0/199 (0%) 1/198 (0.5%)
    Wound Haemorrhage 0/199 (0%) 1/198 (0.5%)
    Metabolism and nutrition disorders
    Cachexia 1/199 (0.5%) 0/198 (0%)
    Dehydration 1/199 (0.5%) 1/198 (0.5%)
    Hypoalbuminaemia 1/199 (0.5%) 0/198 (0%)
    Hypoglycaemia 0/199 (0%) 1/198 (0.5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain 0/199 (0%) 1/198 (0.5%)
    Chondrosarcoma Metastatic 1/199 (0.5%) 0/198 (0%)
    Colorectal Cancer 1/199 (0.5%) 0/198 (0%)
    Meningioma Malignant 0/199 (0%) 1/198 (0.5%)
    Neoplasm Progression 23/199 (11.6%) 31/198 (15.7%)
    Nervous system disorders
    Cerebrovascular Accident 1/199 (0.5%) 0/198 (0%)
    Convulsion 0/199 (0%) 1/198 (0.5%)
    Somnolence 1/199 (0.5%) 0/198 (0%)
    Psychiatric disorders
    Anxiety 1/199 (0.5%) 0/198 (0%)
    Disorientation 1/199 (0.5%) 0/198 (0%)
    Renal and urinary disorders
    Hydronephrosis 0/199 (0%) 1/198 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 1/199 (0.5%) 0/198 (0%)
    Pleural Effusion 1/199 (0.5%) 0/198 (0%)
    Vascular disorders
    Hypotension 1/199 (0.5%) 0/198 (0%)
    Other (Not Including Serious) Adverse Events
    Nabiximols Placebo (GA-0034)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 59/199 (29.6%) 45/198 (22.7%)
    Gastrointestinal disorders
    Constipation 8/199 (4%) 13/198 (6.6%)
    Nausea 19/199 (9.5%) 16/198 (8.1%)
    Vomiting 17/199 (8.5%) 13/198 (6.6%)
    Nervous system disorders
    Dizziness 16/199 (8%) 9/198 (4.5%)
    Somnolence 23/199 (11.6%) 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.

    Results Point of Contact

    Name/Title Medical Enquiries
    Organization GW Pharmaceuticals Ltd.
    Phone
    Email medinfo.USA@gwpharm.com
    Responsible Party:
    Jazz Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01361607
    Other Study ID Numbers:
    • GWCA0962
    • 2009-016065-29
    First Posted:
    May 27, 2011
    Last Update Posted:
    Apr 23, 2018
    Last Verified:
    Mar 1, 2018