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Sativex® for Relieving Persistent Pain in Participants With Advanced Cancer

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ClinicalTrials.gov Identifier: NCT01262651
Recruitment Status : Completed
First Posted : December 17, 2010
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.

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 Type : Interventional  (Clinical Trial)
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 : November 25, 2010
Actual Primary Completion Date : July 2, 2015
Actual Study Completion Date : July 2, 2015

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 Name: 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)



Primary Outcome Measures :
  1. Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.




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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01262651


  Hide Study Locations
Locations
United States, Arizona
Phoenix, Arizona, United States, 85027
Phoenix, Arizona, United States, 85028
United States, California
El Cajon, California, United States, 92020
Gilroy, California, United States, 95020
United States, Florida
Brandon, Florida, United States, 33511
Daytona Beach, Florida, United States, 32117
Holiday, Florida, United States, 34691
Jacksonville, Florida, United States, 32257
Lynn Haven, Florida, United States, 32444
Stuart, Florida, United States, 34994
Winter Park, Florida, United States, 32789
United States, Georgia
Newnan, Georgia, United States, 30265
Stockbridge, Georgia, United States, 30281
United States, Louisiana
Shreveport, Louisiana, United States, 71105
United States, Minnesota
Saint Louis Park, Minnesota, United States, 55426
United States, Missouri
Kansas City, Missouri, United States, 64132
United States, New Jersey
Berlin, New Jersey, United States, 08009
United States, North Carolina
Hendersonville, North Carolina, United States, 28739
Winston-Salem, North Carolina, United States, 27103
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19146
United States, Texas
Houston, Texas, United States, 77024
Houston, Texas, United States, 77089
Laredo, Texas, United States, 78041
United States, Utah
Salt Lake City, Utah, United States, 84112
Salt Lake City, Utah, United States, 84124
Belgium
Bruxelles, Belgium, 1000
Bulgaria
Gabrovo, Bulgaria, 5300
Shumen, Bulgaria, 9700
Varna, Bulgaria, 9010
Czechia
Ceske Budejovice, Czechia, 370 01
Ceske Budejovice, Czechia, 370 87
Hradec Kralove, Czechia, 500 05
Most, Czechia, 434 64
Nová Ves Pod Pleší, Czechia, 262 04
Ostrava-Poruba, Czechia, 708 52
Plzen, Czechia, 304 60
Germany
Lunen, Germany, 44534
Stadtroda, Germany, 07646
Wetzlar, Germany, 35578
Hungary
Deszk, Hungary, H-6772
Kecskemét, Hungary, H-6000
Komarom, Hungary, H-2900
Miskolc, Hungary, H-3501
Nyíregyháza, Hungary, H-4412
Szekszard, Hungary, H-7100
Latvia
Rezekne, Latvia, LV-4600
Riga, Latvia, LV-1079
Lithuania
Klaipeda, Lithuania, LT-92288
Siauliai, Lithuania, LT-76307
Vilnius, Lithuania, LT-08660
Poland
Bialystok, Poland, 15-250
Bielsko-Biala, Poland, 43-300
Gliwice, Poland, 44-101
Poznan, Poland, 61-245
Warszawa, Poland, 02-781
Puerto Rico
Ponce, Puerto Rico, 00717
San Juan, Puerto Rico, 00927
Romania
Baia Mare, Romania, 430031
Braila, Romania, 810325
Bucuresti, Romania, 010976
Craiova, Romania, 200385
Oradea, Romania, 410469
Satu Mare, Romania, 440055
Suceava, Romania, 720237
United Kingdom
Bury Saint Edmunds, United Kingdom, IP33 2QZ
Bury, United Kingdom, BL9 7TD
Edinburgh, United Kingdom, EH4 2XR
Glasgow, United Kingdom, G12 0YN
Manchester, United Kingdom, M8 5RB
Norwich, United Kingdom, NR4 7UY
Weston Super Mare, United Kingdom, BS23 4TQ
Wolverhampton, United Kingdom, WV10 0QP
Sponsors and Collaborators
GW Pharmaceuticals Ltd.
Otsuka Pharmaceutical Development & Commercialization, Inc.

Publications:
Responsible Party: GW Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT01262651     History of Changes
Other Study ID Numbers: GWCA0958
2009-016064-36 ( EudraCT Number )
First Posted: December 17, 2010    Key Record Dates
Results First Posted: April 23, 2018
Last Update Posted: April 23, 2018
Last Verified: March 2018

Keywords provided by GW Pharmaceuticals Ltd.:
Cancer pain
Opioid therapy
Inadequate analgesia
Optimized chronic opioid therapy

Additional relevant MeSH terms:
Neoplasms
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents