Strasser et al. (2006): Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled (…)

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Title	Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group
Topic	Cannabinoids
Author	Strasser, F, Luftner, D, Possinger, K, Ernst, G, Ruhstaller, T, Meissner, W, Ko, YD, Schnelle, M, Reif, M, Cerny, T
Year	2006
Journal	Journal of clinical oncology
DOI	https://doi.org/10.1200/JCO.2005.05.1847

Brief summary

The study included 243 patients with various types of advanced cancer. Randomly divided into three arms, one received a cannabis extract (THC and cannabidiol) for six weeks, one only THC and one a placebo. The main focus was on the influence on appetite and quality of life. After six weeks, no differences were found for appetite, quality of life, weight, mood or nausea. Also no differences were found with regard to the side effects associated with the use of cannabis extract/ THC. This elaborate study is characterised by a good study design and detailed statistics. Unfortunately, few tables are given with exact statistical values of the symptoms symptoms recorded.

In der Studie wurden 243 Patienten mit verschiedenen Krebsarten im fortgeschrittenen Stadium eingeschlossen. Zufällig in drei Gruppen eingeteilt bekam eine über sechs Wochen ein Cannabis-Extrakt (THC und Cannabidiol), eine nur THC und eine ein Placebo. Gemessen wurde vor allem der Einfluss auf Appetit und Lebensqualität. Nach sechs Wochen konnten keine Unterschiede gefunden werden für Appetit, Lebensqualität, Gewicht, Stimmung oder Übelkeit. Auch konnten keine Unterschiede bezüglich den Nebenwirkungen im Zusammenhang mit der Einnahme von Cannabisextrakt/ THC gefunden werden. Diese aufwändige Studie zeichnet sich durch ein gutes Studiendesign und detaillierte Statistik aus. Leider werden wenig Tabellen gegeben mit genauen statistischen Werten der erhobenen Symptome.

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	Advanced, incurable cancer; cancer-related anorexia-cachexia syndrome; weight loss (≥ 5% over 6 months), not explained by other diseases or recent surgery; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2: estimated life expectancy of 3 months; Creatinine, bilirubin, and transaminase values no higher than 3x the maximum normal value; Unchanged antineoplastic therapy for 4 weeks and unchanged supportive treatment (analgesics, sedatives, tranquilizers, and anticholinergics) for 1 week before baseline assessments
Exclusion criteria	Enteral or parenteral nutrition; had taken; taken anabolic agents, gestagens, cannabinoids, or corticosteroids within the past month; significant cause of secondary anorexia or psychiatric disorder (substance abuse or schizophrenia)
N randomized	243
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	n for ITT: 243, only for tests between THC/Cannabis extract vs. Placebo n for PP: 80, tests between THC vs. Cannabis extract ITT and PP only for primary endpoint, sucessive testing labeled explorative
Countries of data collection	Germany, Netherlands, Switzerland
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline T1: after 2 weeks T2: after 4 weeks T3: after 6 weeks

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	Gastrointestinal Cancers, Head and Neck 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	Advanced Stage
Specifications on cancer stages	Advanced, incurable cancer
Comorbidities	NI
Current cancer therapies	Chemotherapy, NI
Specifications on cancer therapies	Chemotherapy patients (received chemotherapy in the 4 weeks before baseline and who intended to continue chemotherapy during the study), per arm: THC = 52% Cannabis extract = 47% Placebo = 52%
Previous cancer therapies	Chemotherapy, NI
Gender	Mixed
Gender specifications	Male per arm: THC = 54% Cannabis extract = 56% Placebo = 52%
Age groups	Adults (18+)
Age groups specification	Mean age = 61 years Mean (SD) age per arm: THC = 60 (12) years Cannabis extract = 61 (12) years Placebo = 62 (10) 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	100
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	35
Drop-out reasons	Reason (n): Withdrawn consent (20) Serious adverse event (3) Other exclusion criterion (1) Death (8) Loss to follow-up (3)
Intervention	THC
Dosage and regime	2.5mg THC orally, 2x a day, preferably taken before lunch and dinner/at bedtime
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.	42
Side effects / Interactions	Total adverse events: n=197, of which possibly intervention-associated n=45 and likely intervention-associated n=7 Temporary or permanent dose reduction was necessary for 30 patients Adverse events that occurred more than 10 times were: Nausea/vomiting (n=21), fatigue (n=14), pain (n=17), anemia (n=14), dizziness (n=11), dyspnea (n=7), diarrhea (n=7), obstipation (n=7), vertigo (n not reported); no differences in frequencies between arm Of all side effects n=101 were mild, n=71 moderate, n=24 severe (mainly dizziness, nausea/vomiting, dyspnea) 33 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 6 of which were life-threatening, 27 required hospitalization

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	95
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	29
Drop-out reasons	Reason (n): Withdrawn consent (17) Serious adverse event (4) Other exclusion criterion (1) Death (4) Loss to follow-up (1) Other protocol violation (2)
Intervention	Cannabis extract
Dosage and regime	2,5mg THC + 1mg cannabidiol, 2x a day, preferably taken before lunch and dinner/at bedtime
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.	42
Side effects / Interactions	Total adverse events: n=238, of which possibly intervention-associated n=28 and likely intervention-associated n=9 Temporary or permanent dose reduction was necessary for 34 patients Adverse events that occurred more than 10 times were: Nausea/vomiting (n=23), fatigue (n=16), pain (n=11), anemia (n=9), dizziness (n=9), dyspnea (n=9), diarrhea (n=6), obstipation (n=6), vertigo (n not reported); no differences in frequencies between arms Of all side effects n=104 were mild, n=113 moderate, n=21 severe (mainly dizziness, nausea/vomiting, dyspnea) 32 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 6 of which were life-threatening, 25 required hospitalization

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	48
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	15
Drop-out reasons	Reason (n): Withdrawn consent (8) Serious adverse event (4) Other exclusion criterion (2) Death (1)
Intervention	Placebo
Dosage and regime	2x a day, preferably taken before lunch and dinner/at bedtime
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.	42
Side effects / Interactions	Total adverse events: n=91, of which possibly intervention-associated n=17 and likely intervention-associated n=4 Temporary or permanent dose reduction was necessary for 14 patients Adverse events that occurred more than 10 times were: Nausea/vomiting (n=11), fatigue (n=4), pain (n=5), anemia (n=6), dizziness (n=7), dyspnea (n=2), diarrhea (n=2), obstipation (n=2), vertigo (n not reported); no differences in frequencies between arms Of all side effects n=36 were mild, n=43 moderate, n=12 severe (mainly dizziness, nausea/vomiting, dyspnea) 17 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 1 of which were life-threatening, 16 required hospitalization

Outcomes

Appetite

Outcome type As specificed by the authors	Primary
Outcome specification	Change from baseline to week 6
Type of measurement	VAS (Visual Analogue 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".	After 6 weeks: No significant differences between the intervention arms and placebo arm for mean improvement (ITT Cannabis extract vs. Placebo p=0.46, THC vs. Placebo p=0.95) or increased appetite (p=0.068)
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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	high risk
Bias in measurement of the outcome	high risk
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	Primary
Outcome specification	Change from baseline to week 6, measured with a composite score (mean) of questions 29 (Global Health Status) and 30 (QOL) of the EORTC QLQ-C30, twice a week
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".	After 6 weeks: No significant differences between Cannabis extract arm and Placebo arm (ITT p=0.80) or THC arm and Placebo arm (ITT p=0.43), as well as THC arm and Cannabis extract arm (PP analysis p=0.90)
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	high 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

Mood/Affect

Outcome type As specificed by the authors	Others
Outcome specification	Mood, measured daily
Type of measurement	VAS (Visual Analogue 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".	Overall Improvement but without significant differences between arms (p=0.461)
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	high 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	Others
Outcome specification	Measured daily
Type of measurement	VAS (Visual Analogue 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".	Overall Improvement but without significant differences between arm (p=0.367)
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	high 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

Anorexia/Cachexia

Outcome type As specificed by the authors	Others
Outcome specification	Measured with the anorexia-cachexia module of the EORTC QLQ-C30
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".	After 2 weeks: improvement of all arms by 5% (no statistical values/comparisons) After 6 weeks: further 5% improvement for Placebo arm, after 2 weeks unchanged for THC arm and decline by 2.5% for Cannabis extract arm (no statistical values/comparisons)
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	high 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

Toxicity

Outcome type As specificed by the authors	Others
Outcome specification	Cannabinoid-related toxicity with CannTox module (based on the Drug Reaction Scale of adjectives describing mood, physical feelings, and perceptions of mental or cognitive functions of healthy volunteers under the influence of cannabis); measured twice a week
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".	No significant differences in frequencies between arms for common adverse events, e.g. nausea/vomiting, fatigue, pain, anemia, dizziness, dyspnea, diarrhea, obstipation, vertigo (all p's ≥ .42) No differences for CannTox scales dizziness, feeling good, feeling high, hallucinations, palpitations, panic attacks, feeling active or unsteady walking See Arms/Side effects for detailed description
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)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	high 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

Functionality

Outcome type As specificed by the authors	NI
Outcome specification	Measured with functional scales and individual items of the EORTC QLQ-C30 (physical, role, emotional, cognitive, and social functioning; and dyspnea, diarrhea, and financial problems)
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".	Overall Steady-state or slight deterioration in all treatment arms (no statistical values/comparisons)
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	high 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

Weight

Outcome type As specificed by the authors	NI
Outcome specification	NI
Type of measurement	Scale
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No differences for weight or weight loss after 6 weeks (no statistical values)
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	high 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	Sponsored by the Institute for Clinical Research, Berlin
Conflicts of Interest	Financial interest: Martin Schnelle and Marcus Reif (Institute for Clinical Research, Berlin)

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	No
- Reasons for insufficient sample size based on power analysis	First unblinded interim analysis showed insufficient differences in the primary end point between placebo and intervention arms (final n=243 out of 445)
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	No
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	NA

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	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)	NA
Side effects systematically recorded	Yes
Side effects considered in result interpretation	Yes
Ethics votum	Yes

Additional Notes

PRO:

• Ethics vote
• Indication of the reliability of the measurement instruments
• Power analysis
• Intent-to-treat analysis (but see CONTRA)
• Very detailed description of the statistics
• Control for compliance and high compliance (44-60%), compliance with treatment was similar between arms (Cannabis extract 49%, THC 44%, and Placebo 60%; p > .15)

CONTRA:

• ITT only for tests between both intervention arm vs. placebo, tests between the 2 intervention arms with PP analysis
• Sample too small according to power analysis, recruitment was stopped after interim analysis due to lack of effects
• 84 patients had severe deviations from the protocol and/or took less than 90% of the intervention, had missing data on the primary endpoint, or had THC in serum at baseline
• Patients in PP analysis mostly male, older with better baseline scores for mood, nausea, daily food intake and QoL