Konmun et al. (2017): A phase II randomized double-blind placebo-controlled study of 6-gingerol as an anti-emetic in solid tumor patients receiving moderately to highly emetogenic chemotherapy

Reference ↗
Title	A phase II randomized double-blind placebo-controlled study of 6-gingerol as an anti-emetic in solid tumor patients receiving moderately to highly emetogenic chemotherapy
Topic	Ginger
Author	Konmun, J, Danwilai, K, Ngamphaiboo, N, Sripanidkulchai, B, Sookprasert, A, Subongkot, S
Year	2017
Journal	Med Oncol
DOI	https://doi.org/10.1007/s12032-017-0931-4

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Above 18 year-old and newly diagnosis with histology of solid tumors with Eastern Cooperative Oncology Group (ECOG) performance status B2. All patients must complete surgical resection of primary tumor and planned for at least 3 consecutive cycles of moderately to highly emetogenic adjuvant chemotherapy for curative intent
Exclusion criteria	Patients with history of ginger hypersensitivity, pregnancy or breast-feeding, and previous chemotherapy
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	Repeated ANOVA
Countries of data collection	Thailand
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T1: Day 1 (Day of the chemotherapy) T2: Day 2 T3: Day 3 T4: Day 4 T5: Day 5 T6: Day 22 T7: Day 43 T8: Day 64

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	NI
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	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Moderately to highly emetogenic chemotherapy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	93 % female
Age groups	Adults (18+)
Age groups specification	Mean: 53 years Range: 19-81 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	46
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	N = 6
Drop-out reasons	Before treatment: - consent withdrawn (n=2) - referred for treatment at another hospital (n=1) - inability to swallow a capsule (n=1) After treatment (but excluded from analysis): - protocol violation (n=1) - consent withdrawn (n=2)
Intervention	Gingerol capsules + Antiemetic treatment: ondansetron + dexamethasone + metoclopramide, optionally rescue anti-emetics
Dosage and regime	2x2 6-gingerol capsules daily (5mg each, standardized), from 3 days before chemotherapy for 12 weeks or until the end of chemotherapy
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	No significant adverse event related to 6-gingerol observed, none of the patients withdrewn from the study due to toxicity/side ffects, no dose reduction required in either arm. 1 patient discontinued the study early due to 3rd degree vomiting requiring hospitalization - placebo-arm: n=2 patients due to discontinuation of Chemotherapy after cycle 2 or due to 2nd degree dyspepsia

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	N = 7
Drop-out reasons	Before treatment: - consent withdrawn (n=1) - referred for treatment at another hospital (n=1) After treatment (but excluded from analysis): - consent withdrawn (n=5)
Intervention	Placebo + Antiemetic treatment: ondansetron + dexamethasone + metoclopramide, optionally rescue anti-emetics
Dosage and regime	2x 2 Placebo capsules daily, from 3 days before chemotherapy for 12 weeks or until the end of chemotherapy
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	No significant adverse event related to intervention observed, none of the patients withdrewn from the study due to toxicity/side ffects, no dose reduction required in either arm. 2 patients discontinued the study early due to discontinuation of Chemotherapy after cycle 2 or due to 2nd degree dyspepsia

Outcomes

"Tolerability" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

"Adherence" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Response rate (i.e. no emetic events, no emergency medication) over all 3 cycles for overall, acute (up to 24h after chemotherapy), and delayed (24-120h after chemotherapy) phase
Type of measurement	Diary 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, acute, delayed phase: significantly higher response rate in intervention arm than in placebo arm - Overall: 77% vs. 32% (p<0.001) - Acute phase: 88% vs. 58% (p=0.003) - Delayed phase: 77% vs. 32% (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".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Secondary
Outcome specification	Response rate (i.e. no emetic events, no emergency medication) for first cycle of chemotherapy (day 1-5 of chemotherapy) for overall, acute (up to 24h after chemotherapy), and delayed (24-120h after chemotherapy) phase
Type of measurement	Diary 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 & delayed phase: significantly higher response rate in intervention arm than in placebo arm: - Overall: 85% vs. 49% (p=0.001) - Delayed phase: 85% vs. 54% (p=0.004) No significant difference between arms in acute phase (p=0.057)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Secondary
Outcome specification	Nausea and vomiting (severity, day 1-5 of chemotherapy)
Type of measurement	NRS (Numeric Rating Scale), CTCAE (Common Terminology Criteria of Adverse Events)
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".	Vomiting all grades/ grade 3: intervention arm significantly lower than placebo arm: - all grades: 22% vs. 68% (p<0.001) - grade 3: 0% vs. 19% (p<0.001); no grade 4 vomiting observed in the study Nausea: significantly lower severity in intervention arm than in placebo arm (p<0.001) - mild: 55% vs.17% - moderate: 15% vs. 39% - severe: 5% vs. 34%
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Appetite

Outcome type As specificed by the authors	Secondary
Outcome specification	Change of appetite score
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".	NA
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".	In intervention arm significantly lower change in appetite score than in placebo arm for day 22, 43, 64, adjusted with baseline values from day 1: r -1.65, 95% CI -2.64 to -0.67; p=0.001

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)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	Health-related quality of life (day 1, 22, 23, and 64 of treatment)
Type of measurement	FACT (Functional Assessment of Cancer Therapy)
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 value, physical, emotional well-being significant improvement in intervention arm compared to placebo-arm, also clinical differences with regard to overall score, mean (SD): - FACT-G total score: 86.21 (13.6) vs. 72.36 (18.9), p<0.001 - Physical well-being: 23.89 (4.24) vs. 18.1 (6.14), p<0.001 - Emotional well-being: 20.92 (3.07) vs. 17.56 (5.23), p<0.001 - Functional wellbeing: 19.97 (5.08) vs. 17.08 (5.86), P = 0.023 Significant difference between arms for mean change from baseline for FACT-G total score (p=0.005), physical (p<0.001) and emotional (P = 0.006) wellbeing (no values reported, only graphs); no significant differences for social or family wellbeing (p=0.203) and functional wellbeing subscale (p=0.147)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Side effects (continuous until 30 days after last intervention)
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	NA
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".	Most common adverse events: anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, myalgia, dyspepsia, headache, increased creatinine, ALT, ALP, AST values. No significant difference between arms (p=0.244-1.000) except for fatigue: significantly lower grade 3 fatigue in intervention arm than in placebo arm (2% vs. 20%, p=0.020)

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)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	This study was funded by National Research University and Thailand research fund. (Grant number: FC 3.1.14 PhD.
Conflicts of Interest	No conflicts of interests reported.

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?