Lichtmann et al. (2018): Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain

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Title	Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain
Topic	Cannabinoids
Author	Lichtman, AH, Lux, EA, McQuade, R, Rossetti, S, Sanchez, R, Sun, W, Wright, S, Kornyeyeva, E, Fallon, MT
Year	2018
Journal	Journal of Pain and Symptom Management
DOI	https://doi.org/10.1016/j.jpainsymman.2017.09.001

Brief summary

The study included 397 patients with various types of advanced cancer. Randomly divided into two arms, one arm received nabiximol (THC and CBD) and one arm a placebo for five weeks. The daily dose varied from person to person, depending on their needs. All patients also received opioids for pain management. Improvement in pain perception was measured, as well as mean pain scores over the study, extent of sleep disturbance and amount of opioids required. When all patients (including those who dropped out during the study) were included, no benefit was found in the improvement in pain perception. In the analysis with the people, who completed the intervention according to the protocol, there was an advantage for the nabiximol arm. However, the analysis with all patients is more meaningful as it is less susceptible to bias. As no effects were found in the main symptom, the further analyses were only carried out roughly. There was only an advantage for insomnia in the nabiximol arm, but this result should only be taken as information. Furthermore, no difference was found for opioid quantities taken. The study is characterized by a large sample size and a well-designed statistical analysis.

In der Studie wurden 397 mit verschiedenen fortgeschrittenen Krebsarten eingeschlossen. Zufällig in zwei Gruppen eingeteilt, bekam eine Gruppe Nabiximol (THC und CBD) und eine Gruppe ein Placebo für fünf Wochen. Die tägliche Dosis variierte von Person zu Person, je nach Bedürfnissen. Alle Patienten erhielten zusätzlich noch Opioide zur Schmerzbehandlung. Gemessen wurde die Verbesserung des Schmerzempfindens, sowie mittlere Schmerzwerte über die Studie, Ausmaß von Schlafstörung und Menge der benötigten Opioide. Wenn alle Patienten (also auch jene die während der Studie ausstiegen) eingeschlossen wurden, wurde kein Vorteil in der Verbesserung des Schmerzempfindens gefunden. Bei der Analyse mit den Personen, die die Intervention laut Protokoll abgeschlossen hatten, zeigte sich ein Vorteil für die Nabiximol Gruppe. Jedoch ist die Analyse mit allen Patienten aussagekräftiger, da sie weniger verzerrungsanfällig ist. Da im Hauptsymptom keine Effekte gefunden wurden, wurden die weiteren Analysen nur noch grob durchgeführt. Es zeigte sich nur ein Vorteil für Schlafstörungen in der Nabiximol Gruppe, jedoch sollte dieses Ergebnis nur als Information gewertet werden. Es konnte des Weiteren kein Unterschied für eingenommene Opioidmengen gefunden werden. Die Studie zeichnet sich durch eine große Stichprobe aus und durch eine durchdachte statistische Analyse.

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 cancer; ≥18 years of age; clinical diagnosis of cancer-related pain that was unalleviated by an optimized maintenance dose of Step 3 opioid therapy (opioid therapy considered optimized if: 1) a dose increase was clinically inappropriate due to opioid-related side effects or 2) further efficacy benefit was not expected at higher doses (for the second definition, patients had to be receiving ≥90 mg morphine equivalents/day, inclusive of maintenance, and breakthrough opioids); each of three consecutive days during the screening period: ≥four opioid breakthrough analgesic episodes per day (averaged over the three days); a stable maintenance opioid therapy dose; average pain ≥four and ≤eight on a 0-10 Numerical Rating Scale (NRS); average pain scores on the NRS that did not change by more than two points (i.e., no more than a two-point difference between the highest and lowest scores, with all scores remaining between four and eight)
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
N randomized	397
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.	PP Analysis, ITT Analysis
Specifications on analyses	Number of participants evaluated in PP n=291 For the primary efficacy endpoint, that is, percent improvement in average pain NRS score from baseline to end of treatment, the comparison was analyzed using the Wilcoxon rank-sum test. Estimates of the median difference between nabiximols and placebo, together with approximate 95% CI, were calculated using the Hodges-Lehmann approach, and P-values were used for the hierarchical gate-keeping procedure. Other sensitivity analyses for the primary efficacy endpoint included the Wilcoxon rank-sum test based on the PP analysis set, Van der Waerden test, and analysis of covariance with the corresponding baseline value as a covariate and treatment group as a factor, based on the ITT analysis set. Mixed-effect model repeat measurement was also applied with baseline NRS average pain score as a covariate, treatment group as a fixed factor, and the interaction terms for treatment-by-time and baseline-by-time included. For the key secondary efficacy endpoints (average pain score, worst pain score, and sleep disruption score), analysis of covariance was applied, similar to the primary efficacy endpoint analysis. P-values from these analyses were used for the hierarchical gate-keeping procedure. The time course of the treatment effect on the key secondary endpoints was also evaluated in a similar fashion to the primary efficacy endpoint using model repeat measurement on the ITT analysis set. Analysis of variance was applied on the other secondary endpoints, including PGIC, SGIC, or PSQ, daily total/maintenance/breakthrough opioid dose, except NRS constipation score with ordinal logistic regression. Subgroup analyses for region (U.S. and rest of the world (ROW)) were performed for the primary and key secondary efficacy endpoints using the ITT set at the 0.05 level, without formal adjustment for multiplicity.
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 (21 days) T2: after 5 weeks (35 days) T3: after 7 weeks follow-up (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.	Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Bone and Soft Tissue Cancers, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Uterine Cancer, Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Thyroid Cancer, Hematologic Cancers, Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Lung Cancer, Prostate Cancer, Skin Cancer, Stomach Cancer, Other Cancers, Gastrointestinal Cancers - Gallbladder Cancer, Eye Cancer
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); mostly mixed pain
Current cancer therapies	NI
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Intervention arm: female = 95 (48%) Placebo arm: female = 88 (44.2%)
Age groups	Adults (18+)
Age groups specification	Mean (SD) age per arm: Intervention arm = 59.2 (12) years Placebo arm =60.7 (11.1) 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	199
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	85
Drop-out reasons	Side effects (n=40); consent withdrawn (n=18); death (n=27)
Intervention	Nabiximol
Dosage and regime	Nabiximol via oral spray (self-applied by patient, 27 mg/ml THC and 25mg/ml CBD) Week 1: dose finding; week 2-5: stable dose, maximum 10 sprays Mean number of spray bursts in the 1st week: 3.7 and then stabilized: 6.4
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.	35
Side effects / Interactions	Most frequently nausea (n=17) and dizziness (n=15); 1 case of disorientation and 1 case of visual hallucinations

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	198
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	75
Drop-out reasons	Side effects (n=35); consent withdrawn (n = 13); death (n=27)
Intervention	Placebo
Dosage and regime	Oral spray (self-applied by patient) Week 1: dose finding; week 2-5: stable dose, maximum 10 sprays Mean number of spray bursts in the 1st week: 3.8 and then stabilized: 7.3
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.	35
Side effects / Interactions	Most frequently nausea (n=10) and dizziness (n=5); 1 case of vomiting

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Median improvement in 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 significant difference in median improvement for ITT after 5 weeks: Intervention 10.7% vs. placebo 4.5%; treatment difference = 3.41%, 95% CI: 0.00% - 8.16%; p=0.0854; Significant difference for per protocol analysis after 5 weeks: Intervention 15.5% vs. placebo 6.3%; treatment difference = 5.49%, 95% CI: 0.00% - 11.11%; p=0.0378
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".	NA

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	low risk
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 mean 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 significance calculated as primary endpoint showed no effects (to control for alpha error).
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".	NA

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)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
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	high risk

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 significance calculated as primary endpoint showed no effects (to control for alpha error).
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".	NA

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)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
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	high risk

Sleep

Outcome type As specificed by the authors	Secondary
Outcome specification	Extent of sleep disturbance
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 significance calculated as primary endpoint showed no effects (to control for alpha error). Only unadjusted values: advantage for intervention arm over placebo arm for sleep disturbance
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".	NA

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)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
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	high risk

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	General intake, 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 significant differences between arms after 3 weeks and 5 weeks (p=0.6410; p=0.4217).
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".	No significant arm differences after 7 weeks (p=0.9328).

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)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
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	high risk

Unspecified effects

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".	Higher improvement in intervention arm compared to placebo arm after 3 weeks for SGIC, PSQ and after 5 weeks for SGIC, PGIC, PSQ.
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".	At week 7 no significant difference for SGIC, PGIC and PSQ.

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)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
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	high risk

Funding and Conflicts of Interest

Funding	This work was supported by Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA. The efforts of A.H. Lichtman were supported by the Virginia Commonwealth University School of Pharmacy start-up funds.
Conflicts of Interest	According to authors no conflict of interest

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	Unclear if centres were comparable and what "optimized opioid therapy" looked like in every country
- Possibility of placebo effects	NA
- Other reasons	Unclear if centres were comparable and what "optimized opioid therapy" looked like in every 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

• Correction for multiple testing only for primary endpoint