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Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies: Difference between revisions

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{{Study Note
{{Study Note
|Study Note=This study is the first study of [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]]  
|Study Note=This is the first study [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].


Second study: [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
 
Second study: [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
}}
}}
=Brief summary=
=Brief summary=
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one group (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients who then showed an improvement in pain perception of at least 15% were then randomly divided into 2 groups to receive either Sativex® or a placebo.
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.
 
In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.


In the first study 399 and in the second study (after division into groups) 206 patients were included. After 5 weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the 1st study did the Sativex® group show improvement in some of the questionnaires (personal and physician-assessed improvement). In the 2nd study, there were no differences between the groups in the questionnaires.
Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.




In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.


In diesem Artikel wurden 2 Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der 2. Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten wurden anschließend zufällig in 2 Gruppen eingeteilt um entweder weiterhin Sativex® zu bekommen oder ein Placebo.
In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.


In der ersten Studie wurden 399 und in der 2. Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach 5 Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der 1. Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der 2. Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.
Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.
Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.


=Study Design=
=Study Design=
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{{RCT study general properties
{{RCT study general properties
|Inclusion criteria=Advanced incurable stage of cancer; ≥18years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|Inclusion criteria=Advanced incurable stage of cancer; ≥ 18 years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤ 4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤ 8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|Exclusion criteria=Baseline use of morphine at >500mg morphine equivalents/day (inclusive of maintenance and breakthrough opioids); current use of more than one type of breakthrough opioid analgesic; planned clinical interventions that would affect pain; any  
|Exclusion criteria=Baseline use of morphine at > 500 mg morphine equivalents/day (inclusive of maintenance and breakthrough opioids); current use of more than one type of breakthrough opioid analgesic; planned clinical interventions that would affect pain; any history of schizophrenia or substance abuse including recreational use of cannabis product
history of schizophrenia or substance abuse including recreational use of cannabis product
|N randomized=399
|N randomized=399
|Analysis=ITT Analysis
|Analysis=ITT Analysis
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pre-treatment baseline to end of treatment in study 2).  
pre-treatment baseline to end of treatment in study 2).  
Analysis of covariance (ANCOVA) was applied on the primary and the key secondary efficacy endpoints, including percent improvement, average pain/worst pain/sleep disruption scores, with corresponding baseline value as a covariate and treatment group as a factor. The time-course of these four efficacy endpoints from week 1 through week 5 was also analysed using Mixed-Effect Model Repeat Measurement (MMRM) on the ITT analysis set in both studies.
Analysis of covariance (ANCOVA) was applied on the primary and the key secondary efficacy endpoints, including percent improvement, average pain/worst pain/sleep disruption scores, with corresponding baseline value as a covariate and treatment group as a factor. The time-course of these four efficacy endpoints from week 1 through week 5 was also analysed using Mixed-Effect Model Repeat Measurement (MMRM) on the ITT analysis set in both studies.
For both study 1 and study 2, the primary endpoint and the key secondary endpoints were tested with their Type I error controlled by use of a hierarchical gate-keeping procedure.
For both study 1 and study 2, the primary endpoint and the key secondary endpoints were tested with their Type I error controlled by use of a hierarchical gate-keeping procedure.
In each study, p-values from Wilcoxon rank-sum tests on percent improvement and ANCOVA on average pain/worst pain/sleep disruption scores were used for the hierarchical gate-keeping procedure in the sequence of the primary endpoint and the key secondary endpoints. No adjustments for covariates were made for the analyses of the other secondary endpoints in both studies with analysis of variance (ANOVA), including PGIC, SGIC or PSQ, and daily total, maintenance, and breakthrough opioid dose. Subgroup analyses for region (United States and rest of world (ROW)) were performed for the primary and the key secondary endpoints.
In each study, p-values from Wilcoxon rank-sum tests on percent improvement and ANCOVA on average pain/worst pain/sleep disruption scores were used for the hierarchical gate-keeping procedure in the sequence of the primary endpoint and the key secondary endpoints. No adjustments for covariates were made for the analyses of the other secondary endpoints in both studies with analysis of variance (ANOVA), including PGIC, SGIC or PSQ, and daily total, maintenance, and breakthrough opioid dose. Subgroup analyses for region (United States and rest of world (ROW)) were performed for the primary and the key secondary endpoints.
|Countries of data collection=Belgium, Bulgaria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, United Kingdom, United States
|Countries of data collection=Belgium, Bulgaria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, United Kingdom, United States
|LoE=Level 2 Oxford 2011
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline
|Outcome timeline=T0: baseline
T1: after 3 weeks (day 22)
T1: after 3 weeks (day 22)
T2: after 5 weeks (day 36)
T2: after 5 weeks (day 36)
T3: after 7 weeks follow-up (up to day 43)
 
Follow-up: after 7 weeks (up to day 43)
}}
}}
=Characteristics of participants=
=Characteristics of participants=
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{{Characteristics of participants
{{Characteristics of participants
|Setting=NI
|Setting=NI
|Types of cancer=Other Cancers
|Types of cancer=Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Prostate Cancer, Lung Cancer, Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Chest Cancer, Eye Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Genitourinary Cancers - Kidney (Renal) Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Stage cancer=Advanced Stage
|Cancer stage specification=Time since cancer diagnosis in years, mean (SD) per arm:
|Cancer stage specification=Mean (SD) time since cancer diagnosis per arm:
Sativex:4.1 (4.2), placebo: 3.5 (5.0)
 
Sativex = 4.1 (4.2) years
 
Placebo = 3.5 (5.0) years
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Current cancer therapy=NI
|Current cancer therapy=NI
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|Gender=Mixed
|Gender=Mixed
|Gender specifications=Male, n(%) per arm:
|Gender specifications=Male, n(%) per arm:
Sativex: 106 (53.0), placebo: 97 (48.7)
 
Sativex = 106 (53.0)
 
Placebo = 97 (48.7)
 


Female, n(%) per arm:
Female, n(%) per arm:
Sativex: 194 (47.0), placebo: 102 (51.3)
 
Sativex = 194 (47.0)
 
Placebo = 102 (51.3)
|Age groups=Adults (18+)
|Age groups=Adults (18+)
|Age groups specification=Age in years mean (SD) per arm:  
|Age groups specification=Mean (SD) age per arm:  
Sativex: 60 (11), placebo: 59.6 (11)
 
Sativex = 60 (11) years
 
Placebo = 59.6 (11) years
}}
}}
=Arms=
=Arms=
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|Drop-out reasons=Side effects (n = 38, 19%); consent withdrawn (n = 19, 9.5%); death (n = 20, 10%)
|Drop-out reasons=Side effects (n = 38, 19%); consent withdrawn (n = 19, 9.5%); death (n = 20, 10%)
|Intervention=Sativex
|Intervention=Sativex
|Dosage and regime=Sativex® (nabiximol, THC 27 mg/mL, CBD, 25 mg/mL) via oral spray (self-applied by patient)  
|Dosage and regime=Sativex® (Nabiximol, THC 27 mg/mL, CBD 25 mg/mL) via oral spray (self-applied by patient)  
Week 1: dose finding; week 2-5: stable dose, max. 10 sprays
* week 1: dose finding; week 2-5: stable dose, max. 10 sprays
1st week mean number of sprays 3.7, stabilized over 4 weeks (6.3 sprays per day)
* first week mean number of sprays: 3.7, stabilized over 4 weeks (6.3 sprays per day)
|One-time application=No
|One-time application=No
|Duration in days=36
|Duration in days=36
|Side Effects / Interactions=Overall 68% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=64 (32.2%), of which somnolence n=18 (9%), dizziness n=15 (7.5%), nausea n=10 (5%)
|Side Effects / Interactions=Overall 68% at least one event; assessed as probably intervention-associated with frequency ≥ 5%:  
Total n=64 (32.2%), of which somnolence n=18 (9%), dizziness n=15 (7.5%), nausea n=10 (5%)
 


2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)
2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)


None of the deaths related to intervention
None of the deaths related to intervention
|Order number=1
|Order number=1
|Arm topic=Cannabinoids
}}
}}
{{Arm
{{Arm
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|Drop-out reasons=Side effects (n = 29, 14.6%), consent withdrawn (n = 8, 4%), death (n = 25, 68%)
|Drop-out reasons=Side effects (n = 29, 14.6%), consent withdrawn (n = 8, 4%), death (n = 25, 68%)
|Intervention=Placebo
|Intervention=Placebo
|Dosage and regime=1st week mean number of sprays 3.7, stabilized over 4 weeks (7.4 sprays per day)
|Dosage and regime=First week mean number of sprays 3.7, stabilized over 4 weeks (7.4 sprays per day)
|One-time application=No
|One-time application=No
|Duration in days=36
|Duration in days=36
|Side Effects / Interactions=Overall 64% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=41 (20.7%), of which somnolence n=6 (3%), dizziness n=6 (3%), nausea n=8 (4%)
|Side Effects / Interactions=Overall 64% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=41 (20.7%), of which somnolence n=6 (3%), dizziness n=6 (3%), nausea n=8 (4%)
 


2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)
2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)


None of the deaths related to intervention
None of the deaths related to intervention
|Order number=2
|Order number=2
|Arm topic=Cannabinoids
}}
}}
{{Arm Overview}}
{{Arm Overview}}
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|Outcome specification=Median improvement in pain with NRS in %
|Outcome specification=Median improvement in pain with NRS in %
|Type of measurement=NRS (Numeric Rating Scale)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=NI
|Results during intervention=No significant difference after 5 weeks
|Results after intervention=No significant difference after 5 weeks, Sativex arm 7.2% vs. placebo arm 9.5% (median difference = −1.84%; CI: −6.19%, 1.50%; p=0.274, not significant)
* Sativex arm = 7.2% vs. placebo arm = 9.5% (median difference = −1.84%; CI: −6.19%, 1.50%; p=0.274, not significant)


Subgroup analysis with US population shows effects for Sativex arm (p=0.03), especially for patients under 65 years of age
Subgroup analysis with US population  
|Bias arising from the randomization process=?
* shows effects for Sativex arm (p=0.03), especially for patients under 65 years of age
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=?
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=?
|Bias in selection of the reported result=low risk
|Other sources of bias=?
|Other sources of bias=some concerns
|Overall RoB judgment=?
|Overall RoB judgment=some concerns
|Order number=1
|Order number=1
|Outcome topic=Cannabinoids
}}
}}
{{Outcome
{{Outcome
|Outcome type=Secondary
|Outcome type=Secondary
|Outcome name=Pain
|Outcome name=Pain
|Outcome specification=Change in NRS value for moderate pain
|Outcome specification=Change in NRS value for average pain
|Type of measurement=NRS (Numeric Rating Scale)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=NI
|Results during intervention=No differences between arms after 5 weeks (no p-value)
|Results after intervention=No group differences after 5 weeks
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=?
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=?
|Bias in selection of the reported result=low risk
|Other sources of bias=?
|Other sources of bias=some concerns
|Overall RoB judgment=?
|Overall RoB judgment=some concerns
|Order number=2
|Order number=2
|Outcome topic=Cannabinoids
}}
}}
{{Outcome
{{Outcome
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|Outcome specification=Change in NRS value for the worst pain
|Outcome specification=Change in NRS value for the worst pain
|Type of measurement=NRS (Numeric Rating Scale)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=NI
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=No group differences after 5 weeks
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=?
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=?
|Bias in selection of the reported result=low risk
|Other sources of bias=?
|Other sources of bias=some concerns
|Overall RoB judgment=?
|Overall RoB judgment=some concerns
|Order number=3
|Order number=3
|Outcome topic=Cannabinoids
}}
}}
{{Outcome
{{Outcome
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|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Type of measurement=NRS (Numeric Rating Scale)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=NI
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=No group differences after 5 weeks
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=?
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=?
|Bias in selection of the reported result=low risk
|Other sources of bias=?
|Other sources of bias=some concerns
|Overall RoB judgment=?
|Overall RoB judgment=some concerns
|Order number=4
|Order number=4
|Outcome topic=Cannabinoids
}}
}}
{{Outcome
{{Outcome
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|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Type of measurement=Observation
|Results during intervention=NI
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=No group differences after 5 weeks
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=?
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=?
|Bias in selection of the reported result=low risk
|Other sources of bias=?
|Other sources of bias=some concerns
|Overall RoB judgment=?
|Overall RoB judgment=some concerns
|Order number=5
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|Outcome specification=Specification NRS: constipation NRS
|Type of measurement=NRS (Numeric Rating Scale), SGIC (Subject Global Impression of Change), PSQ (Patient Satisfaction Questionnaire), PGIC (Physician Global Impression of Change)
|Results during intervention=Results:
* Higher change in SGIC for global impression and better change assessed by physician in 'general functional ability' of Sativex arm compared to placebo arm
* Scores in SGIC better in Sativex arm at week 3 (p = 0.041), 5 (p = 0.022) and last visit (p = 0.022)
* PGIC better at week 5 (p=0.037) compared to placebo arm
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
}}
{{Outcome Overview}}
{{Outcome Overview}}
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{{Funding and Conflicts of Interest
{{Funding and Conflicts of Interest
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|Conflicts of Interest=According to authors no conflict of interest
|Conflicts of Interest=According to authors no conflict of interest.
}}
}}
=Further points for assessing the study=
=Further points for assessing the study=


{{Further points for assessing the study
{{Further points for assessing the study
|Samples sufficiently large=?
|power analysis performed=Yes
|power analysis performed=?
|Sample size corresponds to power analysis=Yes
|reasons given for samples being too small according to power analysis=?
|Reasons given for samples being too small according to power analysis=NA
|Ethnicity mentioned=?
|Samples sufficiently large=NA
|Possibility of attention effects=?
|Ethnicity mentioned=Yes
|Possibility of placebo effects=?
|Other explanations for an effect besides the investigated intervention=Yes
|Other reasons=?
|Possibility of attention effects=NA
|Testing for normal distribution=?
|Possibility of placebo effects=NA
|Correct application of statistical tests=?
|Other reasons=* More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
|Correction for multiple testing=?
* No information whether centers were comparable in treatment of patients; especially “optimized” opioid treatment may vary from country to country
|Measurement of compliance=?
|Correct use of parametric and non-parametric tests=Yes
|Blinding reliable=?
|Correction for multiple testing=Yes
|Check whether blinding was successful=?
|Measurement of compliance=NI
|Consistent reporting in numbers=?
|Consistent reporting in numbers=Yes
|sufficient washout period=?
|Comprehensive and coherent reporting=Yes
|Tested for carry-over effects=?
|Cross-over=No
|Were sequence effects tested=?
|sufficient washout period=NA
|Comprehensive and coherent reporting=?
|Tested for carry-over effects=NA
|Were side effects systematically recorded=?
|Were sequence effects tested=NA
|Effect sizes reported=?
|Effect sizes reported=No
|Side effects taken into account in the interpretation of the results=?
|Were side effects systematically recorded=Yes
|mono- or multicentric=?
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=?
|Ethics / CoI / Funding=Yes
}}
}}
{{Additional Notes
{{Additional Notes
|Additional Notes=?
|Additional Notes=PRO:
* Ethical approval obtained
* Arms comparable at baseline
* Power analysis conducted
* Multiple testing controlled for endpoints pain and sleep disruption
* Intent-to-Treat analysis performed
 
 
CONTRA:
* High dropout rate (due to study discontinuation or death)
* No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
* Multiple testing only controlled for pain and sleep disruption
}}
}}

Latest revision as of 17:14, 26 November 2024


Reference ↗
Title Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies
Topic Cannabinoids
Author Fallon, MT, Lux, EA, McQuade, R, Rossetti, S, Sanchez, R, Sun, W, Wright, S, Lichtman, AH,  Kornyeyeva, E
Year 2017
Journal British Journal of Pain
DOI https://doi.org/10.1177/2049463717710042

Study Note

This is the first study Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.


Second study: Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

Brief summary

Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.

In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.

Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.


In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.

In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.

Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties Double
Is randomized Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control No
Number of arms 2

Study characteristics

Inclusion criteria Advanced incurable stage of cancer; ≥ 18 years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤ 4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤ 8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
Exclusion criteria Baseline use of morphine at > 500 mg morphine equivalents/day (inclusive of maintenance and breakthrough opioids); current use of more than one type of breakthrough opioid analgesic; planned clinical interventions that would affect pain; any history of schizophrenia or substance abuse including recreational use of cannabis product
N randomized 399
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment. ITT Analysis
Specifications on analyses n = 2 no intervention received

Wilcoxon rank-sum test was conducted for percent improvement in average pain NRS score (from baseline to end of treatment in study 1, and from eligibility pre-treatment baseline to end of treatment in study 2). Analysis of covariance (ANCOVA) was applied on the primary and the key secondary efficacy endpoints, including percent improvement, average pain/worst pain/sleep disruption scores, with corresponding baseline value as a covariate and treatment group as a factor. The time-course of these four efficacy endpoints from week 1 through week 5 was also analysed using Mixed-Effect Model Repeat Measurement (MMRM) on the ITT analysis set in both studies.

For both study 1 and study 2, the primary endpoint and the key secondary endpoints were tested with their Type I error controlled by use of a hierarchical gate-keeping procedure.

In each study, p-values from Wilcoxon rank-sum tests on percent improvement and ANCOVA on average pain/worst pain/sleep disruption scores were used for the hierarchical gate-keeping procedure in the sequence of the primary endpoint and the key secondary endpoints. No adjustments for covariates were made for the analyses of the other secondary endpoints in both studies with analysis of variance (ANOVA), including PGIC, SGIC or PSQ, and daily total, maintenance, and breakthrough opioid dose. Subgroup analyses for region (United States and rest of world (ROW)) were performed for the primary and the key secondary endpoints.

Countries of data collection Belgium, Bulgaria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, United Kingdom, United States
LoE Level of evidence Level 2 Oxford 2011
Outcome timeline Data collection times T0: baseline

T1: after 3 weeks (day 22)

T2: after 5 weeks (day 36)

Follow-up: after 7 weeks (up to day 43)

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors. NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Prostate Cancer, Lung Cancer, Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Chest Cancer, Eye Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Genitourinary Cancers - Kidney (Renal) Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis Advanced Stage
Specifications on cancer stages Mean (SD) time since cancer diagnosis per arm:

Sativex = 4.1 (4.2) years

Placebo = 3.5 (5.0) years

Comorbidities Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
Current cancer therapies NI
Specifications on cancer therapies NI
Previous cancer therapies NI
Gender Mixed
Gender specifications Male, n(%) per arm:

Sativex = 106 (53.0)

Placebo = 97 (48.7)


Female, n(%) per arm:

Sativex = 194 (47.0)

Placebo = 102 (51.3)

Age groups Adults (18+)
Age groups specification Mean (SD) age per arm:

Sativex = 60 (11) years

Placebo = 59.6 (11) years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment Intervention
Number of participants (arm) N randomized 200
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date 64
Drop-out reasons Side effects (n = 38, 19%); consent withdrawn (n = 19, 9.5%); death (n = 20, 10%)
Intervention Sativex
Dosage and regime Sativex® (Nabiximol, THC 27 mg/mL, CBD 25 mg/mL) via oral spray (self-applied by patient)
  • week 1: dose finding; week 2-5: stable dose, max. 10 sprays
  • first week mean number of sprays: 3.7, stabilized over 4 weeks (6.3 sprays per day)
One-time application No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information. 36
Side effects / Interactions Overall 68% at least one event; assessed as probably intervention-associated with frequency ≥ 5%:

Total n=64 (32.2%), of which somnolence n=18 (9%), dizziness n=15 (7.5%), nausea n=10 (5%)


2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)


None of the deaths related to intervention

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment Placebo
Number of participants (arm) N randomized 199
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date 41
Drop-out reasons Side effects (n = 29, 14.6%), consent withdrawn (n = 8, 4%), death (n = 25, 68%)
Intervention Placebo
Dosage and regime First week mean number of sprays 3.7, stabilized over 4 weeks (7.4 sprays per day)
One-time application No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information. 36
Side effects / Interactions Overall 64% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=41 (20.7%), of which somnolence n=6 (3%), dizziness n=6 (3%), nausea n=8 (4%)


2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)


None of the deaths related to intervention

Outcomes

Pain

Outcome type As specificed by the authors Primary
Outcome specification Median improvement in pain with NRS in %
Type of measurement NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No significant difference after 5 weeks
  • Sativex arm = 7.2% vs. placebo arm = 9.5% (median difference = −1.84%; CI: −6.19%, 1.50%; p=0.274, not significant)

Subgroup analysis with US population

  • shows effects for Sativex arm (p=0.03), especially for patients under 65 years of age
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NI
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) low risk
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data some concerns
Bias in measurement of the outcome some concerns
Bias in selection of the reported result low risk
Other sources of bias some concerns
Overall RoB judgment some concerns

Pain

Outcome type As specificed by the authors Secondary
Outcome specification Change in NRS value for average pain
Type of measurement NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No differences between arms after 5 weeks (no p-value)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NI
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) low risk
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data some concerns
Bias in measurement of the outcome some concerns
Bias in selection of the reported result low risk
Other sources of bias some concerns
Overall RoB judgment some concerns

Pain

Outcome type As specificed by the authors Secondary
Outcome specification Change in NRS value for the worst pain
Type of measurement NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No differences between arms after 5 weeks (no p-value).
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NI
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) low risk
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data some concerns
Bias in measurement of the outcome some concerns
Bias in selection of the reported result low risk
Other sources of bias some concerns
Overall RoB judgment some concerns

Pain

Outcome type As specificed by the authors Secondary
Outcome specification Extent of sleep disturbance (assessed with NRS)
Type of measurement NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No differences between arms after 5 weeks (no p-value).
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NI
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) low risk
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data some concerns
Bias in measurement of the outcome some concerns
Bias in selection of the reported result low risk
Other sources of bias some concerns
Overall RoB judgment some concerns

Pain

Outcome type As specificed by the authors Secondary
Outcome specification General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
Type of measurement Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No differences between arms after 5 weeks (no p-value).
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NI
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) low risk
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data some concerns
Bias in measurement of the outcome some concerns
Bias in selection of the reported result low risk
Other sources of bias some concerns
Overall RoB judgment some concerns

Quality of life

Outcome type As specificed by the authors Others
Outcome specification Specification NRS: constipation NRS
Type of measurement NRS (Numeric Rating Scale), SGIC (Subject Global Impression of Change), PSQ (Patient Satisfaction Questionnaire), PGIC (Physician Global Impression of Change)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Results:
  • Higher change in SGIC for global impression and better change assessed by physician in 'general functional ability' of Sativex arm compared to placebo arm
  • Scores in SGIC better in Sativex arm at week 3 (p = 0.041), 5 (p = 0.022) and last visit (p = 0.022)
  • PGIC better at week 5 (p=0.037) compared to placebo arm
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NI
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) low risk
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data some concerns
Bias in measurement of the outcome some concerns
Bias in selection of the reported result low risk
Other sources of bias some concerns
Overall RoB judgment some concerns

Funding and Conflicts of Interest

Funding Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
Conflicts of Interest According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed Yes
- Sample size corresponds to power analysis Yes
- Reasons for insufficient sample size based on power analysis NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm) NA
Ethnicity mentioned Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention Yes
- Possibility of attention effects NA
- Possibility of placebo effects NA
- Other reasons
  • More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
  • No information whether centers were comparable in treatment of patients; especially “optimized” opioid treatment may vary from country to country

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing Yes
Correction for multiple testing Yes
Measurement of compliance NI
Consistent reporting in numbers (figures, flowchart, abstract, results) Yes
Comprehensive and coherent reporting Yes
Cross-over No
- Sufficient washout period NA
- Tested for carry-over effects NA
- Tested for sequence effects NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance) No
Side effects systematically recorded Yes
Side effects considered in result interpretation Yes
Ethics votum Yes


Additional Notes

PRO:

  • Ethical approval obtained
  • Arms comparable at baseline
  • Power analysis conducted
  • Multiple testing controlled for endpoints pain and sleep disruption
  • Intent-to-Treat analysis performed


CONTRA:

  • High dropout rate (due to study discontinuation or death)
  • No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
  • Multiple testing only controlled for pain and sleep disruption
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