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 ↗ | |
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| 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 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 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
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 | 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
|
| 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%)
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
|
| 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%)
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:
|
| 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 | ? |
|---|---|
| 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
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