Johnson et al. (2010): Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain

Reference ↗
Title	Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain
Topic	Cannabinoids
Author	Johnson, JR, Burnell-Nugent, M, Lossignol, D, Ganae-Motan, ED, Potts, R, Fallon, MT
Year	2010
Journal	Journal of pain and symptom management
DOI	https://doi.org/10.1016/j.jpainsymman.2009.06.008

Brief summary

In this study, 177 patients with advanced cancer were randomly divided into three arms. One arm received THC and CBD for two weeks, the other arm only THC and the third arm a placebo. The daily dose varied from person to person depending on their needs. All patients also received opioids for pain management. After two weeks, the THC plus CBD arm showed an advantage in general pain perception compared to the placebo arm. Measured with a different instrument, the THC arm showed an advantage over the placebo arm for pain in the last 24 hours. No differences were found between the THC arm and the placebo arm. There were no differences for number of days or dose of opioid use, as well as sleep quality or nausea. There was a deterioration in appetite, memory and concentration in the THC plus CBD and THC arms compared to the placebo arm. For the measurement of quality of life, there was also an advantage for the placebo arm over the other two arms in the categories "cognitive functions" and an advantage for the placebo arm over the THC plus CBD arm for "nausea and vomiting". A large number of symptoms were recorded in this study, but no correction was made in the analysis. This increases the risk of finding an effect even though it is not there. This alone means, that the results should be interpreted with caution. This is also supported by the fact, that the results for the same symptoms such as nausea and pain differ depending on the measurement instrument. In addition, little information is given about the patients.

In dieser Studie wurden 177 Patienten mit fortgeschrittenen Krebserkrankungen zufällig in drei Gruppen eingeteilt. Die eine Gruppe erhielt über zwei Wochen THC und CBD, die andere Gruppe nur THC und die dritte Gruppe ein Placebo. Die tägliche Dosis variierte von Person zu Person je nach Bedürfnissen. Alle Patienten erhielten zusätzlich noch Opioide zur Schmerzbehandlung. Nach zwei Wochen zeigte sich ein Vorteil für das allgemeine Schmerzempfinden für die THC plus CBD Gruppe im Vergleich zur Placebogruppe. Gemessen mit einem anderen Instrument zeigte sich ein Vorteil der THC Gruppe gegenüber der Placebogruppe für Schmerz in den letzten 24 Stunden. Keine Unterschiede wurden gefunden zwischen der THC Gruppe und der Placebogruppe. Es gab keine Unterschiede für Anzahl der Tage oder Dosis von Opioidnutzung, sowie Schlafqualität oder Übelkeit. Bezüglich Appetit, Gedächtnis und Konzentration zeigte sich eine Verschlechterung in der THC plus CBD Gruppe und THC Gruppe im Vergleich zur Placebogruppe. Für die Messung der Lebensqualität zeigte sich in den Kategorien „kognitive Funktionen“ ebenfalls ein Vorteil für die Placebogruppe gegenüber den anderen beiden Gruppen und für „Übelkeit und Erbrechen“ ein Vorteil für die Placebogruppe gegenüber der THC plus CBD Gruppe. In dieser Studie wurden sehr viele Symptome erhoben, jedoch keine Korrektur dessen in der Analyse vorgenommen. Dies erhöht die Gefahr, einen Effekt zu finden, obwohl dieser nicht da ist. Dies allein führt dazu, dass die Ergebnisse mit Vorsicht interpretiert werden sollten. Gestützt wird dieses auch dadurch, dass sich die Ergebnisse für gleiche Symptome wie Übelkeit und Schmerz je nach Messinstrument unterscheiden. Zudem werden wenig Informationen zu den Patienten gegeben.

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	3

Study characteristics

Inclusion criteria	Adult male or female patients, who had been using strong opioids for at least one week to relieve pain associated with incurable malignancy; pain severity score of 4 or above on a 0-10 Numerical Rating Scale (NRS) on both days of the two-day baseline period
Exclusion criteria	Cancers affecting the oral cavity; radiotherapy to the floor of the mouth; major psychiatric or cardiovascular disorders; epilepsy; renal or hepatic impairment; pregnant, lactating, or not using adequate contraception; therapies expected to confound the study outcome (epidural analgesia within 48 hours of screening; palliative radio-, chemo-, or hormonal therapy within two weeks of screening; CBs within seven days of randomization); use of levodopa, sildenafil, or fentanyl; hypersensitivity to CBs
N randomized	177
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	For the two coprimary efficacy variables (NRS pain score and use of break-through medication), the Hochberg method was used to test the global hypothesis for a treatment effect on pain. The daily pain NRS score was the mean of the three daily assessments. The change in mean NRS pain score from baseline (all days in run-in period) to the end of treatment (last three days on treatment) was analyzed using analysis of covariance (ANCOVA), with baseline pain as a covariate and grouped study center and treatment as factors. The proportions of responders (patients with ≥30% improvement from baseline to end of study NRS pain score) were compared between treatments. Use of breakthrough medication (number of days of use during last three days on treatment) was analyzed using logistic regression with a cumulative logit model. In addition, the change from baseline in mean number of doses of escape medication was analyzed using ANCOVA.
Countries of data collection	Europe
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline (2 days) T1: after 7-10 days T2: after 14-20 days

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	Breast Cancer, Lung Cancer, Prostate 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	Mean (SD) duration of cancer: 3.5 (4.4) years
Comorbidities	NI
Current cancer therapies	No therapy
Specifications on cancer therapies	No therapy in the last 2 weeks
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female n (%): 82 (46) Male n (%): 95 (54)
Age groups	Adults (18+)
Age groups specification	Mean (SD) Age: 60.2 (12.3) 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	60
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	12
Drop-out reasons	Adverse event (n=10); consent withdrawal (n=1); other (n=1)
Intervention	THC:CBD
Dosage and regime	THC:CBD via oral spray (self-applied by patient, one dose 2.7mg THC and 2.5mg CBD) Week 1: dose finding Week 2: stable dose, maximum of 8 sprays every 3 hours and 48 sprays in 24 hours: dose was determined by patients themselves
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.	14
Side effects / Interactions	Intervention-associated events in n=106 (60%): drowsiness, dizziness, nausea, confusion, vomiting, hypotension, hypercalcemia, increased gamma GT Most side effects were mild/moderate; no statistical comparisons given; one case of syncope probably related to THC; other events not associated with intervention

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	58
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	13
Drop-out reasons	Adverse event (n=7); consent withdrawal (n=2); sponsor decision (n=1); protocol violation (n=1); other (n=2)
Intervention	THC
Dosage and regime	THC extract via oral spray (2.7 mg), dosage variable; Week 1: dose finding Week 2: stable dose, maximum of 8 sprays every 3 hours and 48 sprays in 24 hours: dose was determined by patients themselves
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.	14
Side effects / Interactions	Intervention-associated events in n=106 (60%): drowsiness, dizziness, nausea, confusion, vomiting, hypotension, hypercalcemia, increased gamma GT; Most side effects were mild/moderate; no statistical comparisons given; one case of syncope probably related to THC; other events not associated with 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	59
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8
Drop-out reasons	Adverse event (n=3); consent withdrawal (n=2); other (n=3)
Intervention	Placebo
Dosage and regime	NI
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.	14
Side effects / Interactions	NI

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Number of responders (≥ 30% pain reduction NRS scale baseline vs. 14-20 days)
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".	Significant advantage for THC:CBD arm compared to placebo arm after 14-20 days (mean improvement = -1.37 vs. -0.69; p=0.014), no significant difference between THC arm and placebo arm after 14-20 days (mean improvement = -1.01 vs. -0.69; p=0.245) Same results for median differences (THC:CBD arm vs. placebo arm = 0.55, p=0.024; THC arm vs. placebo arm = 0.24, p=0.204) Responders: More patients in THC:CBD arm compared to placebo arm showed improvement of more than 30% from baseline to 14-20 days (n=23 (43%) vs. n=12 (21%); Odds Ratio = 2.81; 95% CI=1.22, 6.50; p=0.006). No difference between THC arm and placebo arm (n=12 (23%) vs. n=12 (21%); Odds Ratio 1.10 (95% CI=0.44, 2.73; p=0.28). No data for comparison between THC:CBD arm and THC 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".	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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Breakthrough pain and corresponding opioid intake and daily opioid use with diary Numeric Rating Scale (NRS) over the last 24h
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".	Background medication opioids baseline to 14-21 days (median to baseline 271mg daily morphine equivalents): no significant changes in dosage Breakthrough pain and corresponding opioid use at 14-21 days: No difference between arms for number of days used (THC:CBD arm vs. placebo arm, p=0.697; THC arm vs. placebo arm, p=0.555); non-significant reduction in each arm (THC:CBD arm = -0.19 vs. THC arm = -0.14; placebo arm = -0.15) with no difference between arms (THC:CBD arm vs. placebo arm, p=0.688; THC arm vs. placebo arm; p=0.899); more patients in placebo arm (n=7) with increased dosage compared to THC:CBD arm (p=0.004)
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Sleep

Outcome type As specificed by the authors	Secondary
Outcome specification	Sleep quality
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 differences between THC:CBD arm/THC arm and 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".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Nausea

Outcome type As specificed by the authors	Secondary
Outcome specification	Nausea
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 differences between THC:CBD arm/THC arm and 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".	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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Cognitive functioning

Outcome type As specificed by the authors	Secondary
Outcome specification	Memory
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".	Placebo arm with no change (0.01), THC:CBD arm and THC arm with deterioration compared to placebo arm (THC:CBD arm = 0.63 vs. placebo arm = 0.01, p=0.045; THC arm = 0.66 vs. placebo arm = 0.01, p=0.053).
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Cognitive functioning

Outcome type As specificed by the authors	Secondary
Outcome specification	Concentration
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".	Placebo arm with improvement, THC:CBD arm and THC arm with deterioration (placebo arm = -0.35 vs. THC:CBD arm = 0.33, p=0.021; placebo arm = -0.35 vs. THC arm = 0.29, p=0.028)
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Appetite

Outcome type As specificed by the authors	Secondary
Outcome specification	Appetite
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".	Improvement in placebo arm, deterioration in THC:CBD arm and THC arm (placebo arm = -0.59 vs. THC:CBD arm = 0.24, p=0.016; placebo group = -0.59 vs. THC group = 0.06, p=0.056).
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	Quality of life at baseline and 14-21 days after
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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".	At days 14-21: Effects for reduction of "cognitive function" in THC:CBD arm and THC arm compared to placebo arm (THC:CBD arm = -5.33 vs. placebo arm = 3.68, p=0.02; THC arm = -6.77 vs. placebo arm = 3.68, p=0.01) Worsening of "nausea and vomiting" in THC:CBD arm compared to placebo arm (THC:CBD arm = 5.13 vs. placebo arm = -3.43, p=0.02; THC arm = -3.41 vs. placebo arm = -3.43; p=1.0). For "pain" no difference between THC:CBD arm/THC arm and placebo arm. For "social function" significant advantage for THC arm over placebo arm (9.66 vs. 1.58; p=0.038).
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	Pain at baseline and 14-21 days after
Type of measurement	BPI-SF (Brief Pain Inventory - Short Form)
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".	Pain in the last 24h: significant advantage for THC arm over placebo arm (-3.20 vs. 0.87; p=0.048), no difference for interference pain.
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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	This study was sponsored by GW Pharma Ltd. All study medication was supplied by GW Pharma Ltd., and it also funded all sites involved in the study by means of per-patient payments based on recruitment. GW Pharma Ltd. has funded J. R. Johnson (primary author) to attend two conferences to present the results of this study.
Conflicts of Interest	NI

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	No information whether centers were comparable in treatment of patients; especially “optimized” opioid treatment may vary from country to country
- Possibility of placebo effects	NA
- Other reasons	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	No
Measurement of compliance	NI
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
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
• Intent-to-treat analysis
• Power analysis
• Arms comparable at baseline

CONTRA:

• No information on whether centers were comparable in patient treatment; especially as “optimal” opioid treatment may vary from country to country.
• Baseline data: cancer type not specified for 104 patients.
• No control for multiple testing.
• Reported results in the text are unclear.
• No information on cancer stage.
• No explanation of how randomization was conducted or how blinding was ensured.
• Most comparisons are between the interventionarms and the placeboarm, but there are few comparisons between the interventionarms
• No elaboration of the intent-to-treat analysis in the methodology