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

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 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

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.

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; ≥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
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 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	Procedure Part A: all received Sativex® for 10 days, then 4 days therapy at adjusted dose; patients who showed an improvement of at least 15% for pain (NRS) entered Part B: randomized in A or B with intervention for 5 weeks, follow-up 2 weeks later Discussed is part B of the study.
Countries of data collection	Australia, Bulgaria, Germany, Hungary, India, Israel, Italy, Lithuania, Poland, Romania, Spain, Taiwan, United Kingdom
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	Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Chest Cancer, Eye Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Prostate Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, 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	NI
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	Part A Female = 176 (43.6%) Part B Sativex = 40 (38.8%) female Placebo = 48 (46.6%) female
Age groups	Adults (18+)
Age groups specification	Part A Mean (SD) age: 61.2 (11.2) years Part B Mean (SD) age per arm: Sativex = 61.4 (10.9) years Placebo = 61.6 (11.8) 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	103
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Discontinued n=25 Died during study n=23 Study completed n=78
Drop-out reasons	Adverse Events n=21 Withdrew consent n=2 Withdrawn by investigator n=1 Lack of efficacy n=1 Died during treatment n=23 Died post-treatment but before follow-up n=8 Died post follow-up n=3
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 Part A: first week average number of sprays: 3.6; second week: 6.4 Part B: average daily number: 6.5
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	Part A Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n=128, 31.7%, somnolence (n=42, 10.4%), nausea (n=21, 5.2%) and dizziness (n=21, 5.2%) Part B Overall 72% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=16, 15.5%; somnolence (n=6, 5.8%) More than twice as many patients in Sativex arm discontinued study due to side effects (n=14, 13.6% vs. n=6, 5.8%); no statistical comparison given) 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	103
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Discontinued n=15 Died during study n=9 Study completed n=88
Drop-out reasons	Adverse Events n=13 Withdrawn by investigator n=1 Lack of efficacy n=1 Died during treatment n=9
Intervention	Placebo
Dosage and regime	Week 1: dose finding; week 2-5: stable dose, max. 10 sprays Part A: first week average number of sprays: 3.6, second week: 6.4 Part B: average daily number: 6.3
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	Part A Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n=128, 31.7%, somnolence (n=42, 10.4%), nausea (n=21, 5.2%) and dizziness (n=21, 5.2%) Part B Overall 62% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=12, 11.7%; somnolence n=0

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Change in NRS value for moderate 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".	Deterioration in both arms after 5 weeks: Sativex arm: from 3.2 to 3.7, Placebo arm: 3.1 to 3.6. (treatment effect -0.02; 95% CI: -0.42, 0.38; p = 0.917) No differences for individual subgroups (no US patients in this study)
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	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 arm differences 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 arm differences 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

Sleep

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 arm differences 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

Additional medication

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 arm differences 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".	No arm differences 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)	?
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	No
- Reasons for insufficient sample size based on power analysis	high drop-out due to side effects or withdrawal of consent in Phase A not fitting the inclusion criteria (failure to demonstrate a 15% improvement in average pain NRS score during titration)
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