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

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 study is the first study of Fallon et al. (2017): 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.

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	?
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	?
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	?
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	-999

Study characteristics

Inclusion criteria	?
Exclusion criteria	?
N randomized	-999
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.	?
Specifications on analyses	?
Countries of data collection	?
LoE Level of evidence	?
Outcome timeline Data collection times	?

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.	?
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	?
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	?
Specifications on cancer stages	?
Comorbidities	?
Current cancer therapies	?
Specifications on cancer therapies	?
Previous cancer therapies	?
Gender	?
Gender specifications	?
Age groups
Age groups specification	?

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	?
Conflicts of Interest	?

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

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
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

?