Zick et al. (2008): Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting

Reference ↗
Title	Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting
Topic	Ginger
Author	Zick, S, Ruffin, M, Lee, J, Normolle, D, Siden, R, Alrawi, S, Brenner, D
Year	2008
Journal	Support Care Cancer
DOI	https://doi.org/10.1007/s00520-008-0528-8

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	Patients who were scheduled to have a single-day chemotherapy regime and to receive a 5-HT3 receptor antagonist antiemetic and/or the antiemetic aprepitant. Patients with histologically confirmed diagnosis of cancer currently being treated with chemotherapy. Patients must also have received at least one previous chemotherapy treatment with the same chemotherapeutic agent and have experienced nausea or vomiting of any severity as a result of that treatment.
Exclusion criteria	If they were: - Receiving multiple-day chemotherapy; - Receiving concurrent radiotherapy that was classified as high or intermediate risk of causing emesis (i.e., total body irradiation, hemi-body, upper abdomen, abdominal– pelvic mantle, cranium, or craniospinal irradiation); - taking therapeutic doses of coumadin (individuals on low-dose coumadin to maintain peripheral or central venous catheters were allowed), aspirin (individuals taking low- dose 81 mg aspirin were allowed), or heparin; - Had a history of a bleeding disorder(s) and those experiencing clinically significant thrombocytopenia; - Had an allergy to ginger or had taken ginger in the last week; - Nursing mothers, pregnant women, or planning a pregnancy during the study period.
N randomized	162
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.	ITT Analysis
Specifications on analyses	Kruskal–Wallis statistics for continuous variables and Pearson’s chi-square and Fisher exact tests, as appropriate, for categorical variables. Cochran Mantel–Haenszel tests between treatment arms.
Countries of data collection	United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline T1: After 1 hour of completion of chemotherapy T2: 3 days after the end of their chemotherapy treatment

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	Patients must have had at least one previous round of chemotherapy.
Previous cancer therapies	Chemotherapy
Gender	Mixed
Gender specifications	Female in %: Placebo arm: 76.9, 1.0-g ginger dose-arm: 73.6, 2.0-g ginger dose-arm: 75.4
Age groups	Adults (18+)
Age groups specification	(MW±SD): Placebo: 58.3±12.3, 1.0-g ginger dose-arm: 53.3±12.0, 2.0-g ginger dose: 55.5±11.2 years

Arms

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	57
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Placebo, 250mg lactose powder capsules
Dosage and regime	8 capsules daily
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.	3
Side effects / Interactions	No side effects have been reported.

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	53
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Ginger capsules (dry extract)
Dosage and regime	1.0-g ginger dose, - Each capsule contained 250 mg dry extract of ginger root [10:1 (v/v) extraction solvent (ethanol 50%)/root] standard- ized to 15 mg (5%) of total gingerols - four capsules ginger and four capsules placebo daily
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.	3
Side effects / Interactions	No significant difference between the 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	52
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Ginger capsules (dry extract)
Dosage and regime	2.0-g ginger dose - Each capsule contained 250 mg dry extract of ginger root [10:1 (v/v) extraction solvent (ethanol 50%)/root] standardized to 15 mg (5%) of total gingerols - 8 capsuels daily
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.	3
Side effects / Interactions	No significant difference between the arms.

Outcomes

Nausea and Vomiting

Outcome type As specificed by the authors	Primary
Outcome specification	Prevalence and severity of acute and delayed nausea and vomiting, more than 24 hours after 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".	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".	Prevelence, delayed nausea, no significant differences (without, with aprepitant) in %: Placebo: 42.5, 25.0, 1.0g ginger: 60,5, 25.6, 2.0g ginger: 50.0, 17.4 (p=0.16) Prevalence, delayed vomiting, no significant differences (without, with aprepitant) (in %): Placebo: 17.5, 12.5, 1.0g ginger: 32.6, 11.6, 2.0g ginger: 52.6, 2.2 (p=0.35 and 0.07 respectively) Severity of delayed nausea: (without, with aprepitant) (Mean±SD): Placebo: 3.2±1.1, 3.9±0.9, 1.0g ginger: 3.0±1.1, 2.9±1.3, 2.0g ginger: 3.0±1.3, 2.2±0.7 (p=0.69, 0.01), sign. arm difference for with aprepitant (p=0.01); individual tests show that placebo is significantly higher than 1.0g ginger arm and 2.0g ginger arm (mean±SD: 2.0g ginger=2.8±1.2, 1.0g ginger=2.9±1.1, placebo=3.4±1.1; p=0.03) Severity of delayed vomiting, no significant differences: (without, with aprepitant) (mean±SD): A: 3.7±1.0, 3.6±1.3, B: 2.7±0.9, 3.0±1.4, C: 4.0±1.3, 3.0±0.0 (p= 0.88, 0.77)

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

Nausea and Vomiting

Outcome type As specificed by the authors	Secondary
Outcome specification	Prevalence and severity of acute nausea and vomiting (≤24h after 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".	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".	Prevalence of acute nausea, no significant differences: (without, with aprepitant) (in %): placebo: 20, 10, 1.0g ginger: 21, 12, 2.0g ginger: 23, 8 (p=0.76 and 0.68 respectively); Acute vomiting (without, with aprepitant) (in %): placebo: 11, 6, 1.0g ginger: 14, 5, 2.0g ginger: 11, 3 (p=0.35 and 0.47, respectively) Severity of acute nausea, no significant differences: (without, with aprepitant) (Mean±SD): placebo: 3.0±1.1, 2.8±1.5, 1.0g ginger: 3.1±1.2, 2.8±1.1, 2.0g ginger: 2.8±1.3, 3.1±1.5 (p (without, with aprepitant)=0.47, 0.55) Severity of acute vomiting, no significant differences: (without, with aprepitant) (Mean±SD): placebo: 2.9±0.9, 3.7±1.5, 1.0g ginger: 3.1±1.4, 3.4±0.6, 2.0g ginger: 3.6±1.4, 4.0±1.7 (p = 0.61, 0.91)

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

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	?
Type of measurement	?
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".	Laboratory abnormalities were close to being significantly higher in the placebo and 1.0-g dose (8 of placebo vs. 8 of 1.0-g dose vs. 1 of 2.0-g dose; p=0.06) compared to the 2.0-g dose 2.0g ginger: significantly more fatigue (p=0.03) and other side effects (p=0.02) than in placebo arm, 1.0g ginger: no significant difference in terms of overall side effects, non-serious and serious side effects, dyspnea, gastrointestinal events or laboratory abnormalities

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

Unspecified effects

Outcome type As specificed by the authors	Secondary
Outcome specification	Blinding
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".	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".	Examiners could not guess allocation (p=0.27), patients could guess allocation significantly correctly (p=0.01) Reasons given: Taste: placebo: 33%; 1.0g ginger: 25%, 2.0g ginger: 9%; p=0.01 Effect of the capsule: placebo: 33%, 1.0g ginger: 51%, 2.0g ginger: 16%; p=0.12

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

Funding and Conflicts of Interest

Funding	?
Conflicts of Interest	?

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	?

Additional Notes

?