Grimison et al. (2020): Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial

Reference ↗
Title	Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial
Topic	Cannabinoids
Author	Grimison, P, Mersiades, A, Kirby, A, Lintzeris, N, Morton, R, Haber, P, Olver, I, Walsh, A, McGregor, I, Cheung, Y, Tognela, A, Hahn, C, Briscoe, K, Aghmesheh, M, Fox, P, Abdi, E, Clarke, S, Della-Fiorentina, S, Shannon, J, Gedye, C, Begbie, S, Simes, J, Stockler, M
Year	2020
Journal	Annals of Oncology
DOI	https://doi.org/10.1016/j.annonc.2020.07.020

Brief summary

The study included 81 patients with different types of cancer and a history of nausea and vomiting due to chemotherapy. They were randomly divided into tweo arms, one arm received THC and CBD daily and the other arm a placebo. After one cycle of chemotherapy, the arms were switched. At the end of two cycles (so that everyone was in each arm), there was overall less and less severe nausea and vomiting in the THC/CBD arm and an improvement on some quality of life measurement scales. However, the patients receiving THC/CBD had more side effects, such as dizziness and sedation, which were tolerable, according to the authors. The study has an elaborate study design. The statistics seem well thought out and take many factors into account, but a few methodological decisions remain unexplained. It should be noted in particular that many of the people involved in the article have direct contacts with the pharmaceutical industry.

In der Studie wurden 81 Patienten mit verschiedenen Krebsarten und Vorgeschichte von Übelkeit und Erbrechen durch Chemotherapie eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt, eine Gruppe bekam täglich THC und CBD und die andere Gruppe ein Placebo. Nach einem Zyklus Chemotherapie wurden die Gruppen getauscht. Am Ende von zwei Zyklen (sodass jeder in jeder Gruppe war) zeigte sich insgesamt weniger und weniger schwere Übelkeit und Erbrechen in der Gruppe mit THC/CBD und eine Verbesserung auf einigen Skalen der Messung der Lebensqualität. Jedoch hatten die Patienten die THC/CBD bekamen mehr Nebenwirkungen, wie Schwindel und Sedierung, die laut den Autoren jedoch tolerierbar waren. Die Studie hat ein aufwändiges Studiendesign. Die Statistik wirkt gut durchdacht und bezieht viele Faktoren mit ein, jedoch bleiben ein paar methodische Entscheidungen unerklärt. Besonders anzumerken ist, dass viele beteiligten Personen in dem Artikel direkte Kontakte zu Pharmaindustrien aufweisen.

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	Yes
Number of arms	2

Study characteristics

Inclusion criteria	Aged ≥18 years; any malignancy of any stage; receiving intravenous chemotherapy of moderate or high emetogenic risk; receive at least two more consecutive cycles; refractory CINV (defined as emesis, and/or nausea of moderate severity on a 5-point rating scale, and/or requiring use of rescue medications) in earlier chemotherapy cycles despite guideline-consistent antiemetic prophylaxis consisting of corticosteroids, a 5-HT3 antagonist, and an NK-1 antagonist with or without olanzapine where indicated
Exclusion criteria	Eastern Cooperative Oncology Group (ECOG) performance status of >2; a contraindication to medicinal cannabis such as unstable cardiovascular disease, substance use disorder, or significant mental health disorder; experiencing disease-related nausea and vomiting; receiving concomitant oral chemotherapy; had received/were planned to receive radiotherapy to the brain or gastrointestinal tract during the study period
N randomized	81
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
Specifications on analyses	Only participants who have received both interventions have been included in the efficacy analyses. Data on safety were sourced from the safety population (all participants who received ≥1 dose of study drug). The primary analysis was a comparison of the proportion of participants with complete response between the two treatment arms during two overall phases of treatment (0-120 h) of cycles A and B, using McNemar’s test to account for the within-patient correlation. Continuous outcomes were analysed with a linear model, and accounted for the correlation within a participant. All tests used a two-sided significance level of 10%. Secondary analyses have not been adjusted for multiple comparisons.
Countries of data collection	Australia
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline T1: one day before chemotherapy T2: day 8 of each cycle T3: between 30-42 days after end of intervention

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.	Curative, Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Colorectal Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Pancreatic Cancer, Genitourinary Cancers - Testicular Cancer, Gynecologic Cancers, Hematologic Cancers, Lung Cancer, Other Cancers
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NI
Specifications on cancer stages	Any malignancy of any stage
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Moderate-to-high emetogenic intravenous chemotherapy Chemotherapy regimen, n(%): Doxorubicin + cyclophosphamide = 20 (26) FOLFOX ± biological = 13 (17) Cisplatin based = 12 (15) FOLFIRINOX = 6 (8) Other = 27 (35)
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female : 61 (78%) Male: 17 (22%)
Age groups	Adults (18+)
Age groups specification	Median age (range): 55 (29-80) 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	40
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	Discontinued after THC:CBD (n = 4): Death (n = 1); failure to comply (n = 1); chemotherapy stopped (n = 1); patient preference (n = 1)
Intervention	THC:CBD
Dosage and regime	1-4 capsules (each THC 2.5mg/CBD 2.5mg) 3x daily from one day before chemotherapy to day 5; median (SD) number of capsules: 2 (1-3)
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.	-999
Side effects / Interactions	Moderate or severe cannabinoid-related side effects in intervention arm and placebo arm (31% vs. 7%, p=0.002): Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03) No differences for disorientation (p=0.5) and anxiety (p=1.00) No cannabinoid-related serious adverse events reported 83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001)

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	41
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Discontinued after placebo (n = 2): chemotherapy stopped (n = 1); patient preference (n = 1)
Intervention	Placebo
Dosage and regime	Median (SD) number of capsules = 3 (2-4)
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.	-999
Side effects / Interactions	Moderate or severe cannabinoid-related side effects in intervention arm and placebo arm (31% vs. 7%, p=0.002): Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03) No differences for disorientation (p=0.5) and anxiety (p=1.00) No cannabinoid-related serious adverse events reported 83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001)

Outcomes

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Complete response, no vomiting or emergency medication 0-120h of chemotherapy
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".	Results after 2 cycles, after switching to the other arm: Significant advantage for intervention arm (25%) compared to placebo arm (14%): RR=1.77; 90% CI=1.12,2.79; p=0.041.
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	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Secondary
Outcome specification	Self-reported "complete response" ("no vomiting", "no clinically significant nausea", defined as nausea <2 on a 10-point scale, and "no use of emergency medication") during the acute (0-24 h), delayed (24-120 h) and general phase (0-120 h) of chemotherapy with diary day -1 to 6 of each cycle)
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".	Results after 2 cycles, after switching to the other arm: Advantage for intervention arm for percentage for CR (p=0.04), for scales "no vomiting" (p=0.05), "no emergency medication" p=0.04), "no significant nausea" (p=0.03), mean and maximum number of vomiting per day (p=0.003, p=0.001), mean/maximum nausea values (p's<0.001). No difference for complete response and "no significant nausea" (p=0.12)
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	high risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	Quality of life (nausea & vomiting scales) at baseline, day -1, end of treatment
Type of measurement	AQoL-8D (Assessment of Quality of Life), FLIE (Functional Living Index for Emesis)
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".	FLIE: significant advantage for intervention arm for nausea scale (mean difference: 20.9 on 100-point scale, p < 0.001) and vomiting scale (mean difference: 11.9, p < 0.001) AQOL-8D: significant advantage for intervention arm in use-related QoL (mean difference: 0.04, 95% CI 0.01,0.07; p=0.019) physical health (mean difference: 0.06, 95% CI 0.03-0.09, p < 0.001) mental health (mean difference: 0.04, 95% CI 0.01, 0.06, p=0.004) pain (mean difference: 0.08, 95% CI 0.03, 0.13, p=0.003)
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	high risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Self-developed measurement instrument: structured checklist of cannabinoid-specific adverse events
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events), Self-developed measurement instrument
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".	Moderate or severe cannabinoid-related side effects in intervention arm (31%) and placebo arm (7%) (p=0.002): Significant differences for sedation (19% vs. 4%, p=0.002), dizziness (10% vs. 1%, p=0.03) No differences for disorientation (3% vs. 0%, p=0.5), anxiety (1% vs. 1%, p=1.00) No cannabinoid-related serious adverse events were reported. 83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001).
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	high risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	This work was supported by the Department of Health, NSW Government, Australia. Tilray supplied and covered the cost of study treatments and were given the opportunity to review the study protocol and manuscript, but had no role in data analysis.
Conflicts of Interest	Conflict of interest can be seen in the article, many contacts to pharmaceutical industries.

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	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	Knowledge of assignment and believe in positive influence in outcomes assessed with self-report-questionnaires

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	NI
Correction for multiple testing	Yes
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	No
Comprehensive and coherent reporting	No
Cross-over	Yes
- 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
• Power analysis
• Daily contact with staff on days of administration
• Structured assessment of side effects using a checklist
• Adherence monitored through diary entries and capsule counts
• McNemar’s test used to control for within-patient correlation
• Control for order effects (p=0.29)
• Comparability at baseline ensured by study design

CONTRA:

• Correction for multiple testing only for primary endpoints
• 90% confidence interval (CI) (p=0.1) used for primary endpoints and 95% CI for secondary endpoints due to pilot study design (primary endpoint was also significant at 95%)
• No differentiation of primary endpoint into acute or delayed responses, despite being listed in the methodology
• Unclear presentation of when and how each endpoint is measured
• Numerous interactions with pharmaceutical companies
• Capsule dosing individualized, with no subgroup analyses for high vs. low doses