Dos Santos Martins (2016): Placebo-Controlled, Double-Blind, Randomized Study of a Dry Guarana Extract in Patients with Head and Neck Tumors Undergoing Chemoradiotherapy: Effects on Fatigue and Quality of Life

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Title	Placebo-Controlled, Double-Blind, Randomized Study of a Dry Guarana Extract in Patients with Head and Neck Tumors Undergoing Chemoradiotherapy: Effects on Fatigue and Quality of Life
Topic	Guarana
Author	dos Santos Martins, SP, Lemos Ferreira, C, del Giglio, A
Year	2016
Journal	Journal of Dietary Supplements
DOI	https://doi.org/10.1080/19390211.2016.1193081

Brief summary

In this study, the researchers investigated the effect of dried guarana extract on the quality of life of patients with head and neck cancer. All patients underwent chemotherapy. During chemotherapy, half of the patients took the guarana extract, while the other half took a placebo provided in identical capsules. After six weeks of chemotherapy, there were no differences in the quality of life of the patients taking guarana and those taking the placebo. Patients taking guarana lost more weight and were more likely to need pain medication and feeding through a nasogastric tube after the fourth round of chemotherapy. There were also no differences in their chances of survival over 30 months. Thus, the researchers concluded that guarana is not recommended for these patients undergoing chemotherapy for head and neck cancer.

In dieser Studie untersuchten die Forscher die Wirkung von getrocknetem Guarana-Extrakt auf die Lebensqualität bei Patienten mit Kopf- und Halskrebs. Alle Patienten unterzogen sich einer Chemotherapie. Während der Chemotherapie nahm die Hälfte der Patienten den Guarana-Extrakt ein, während die andere Hälfte ein Placebo einnahm, das in identischen Kapseln bereitgestellt wurde. Nach der sechswöchigen Chemotherapie gab es keine Unterschiede in der Lebensqualität der Patienten, die Guarana einnahmen, und derjenigen, die das Placebo einnahmen. Patienten, die Guarana einnahmen, verloren mehr Gewicht und brauchten eher Schmerzmittel und eine Ernährung durch eine nasale Magensonde nach der vierten Chemotherapierunde. Es gab auch keine Unterschiede in ihrer Überlebenschance über 30 Monate. So kamen die Forscher zu dem Schluss, dass Guarana für diese Patienten, die sich einer Chemotherapie wegen Kopf- und Halskrebs unterziehen, nicht zu empfehlen ist.

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	NI
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	Patients with localized or locally advanced head and neck cancer (stage I - IV) with indications for chemoradiotherapy, with or without surgical treatment or prior induction chemotherapy.
Exclusion criteria	Patients with chronic diseases that could induce fatigue, such as chronic renal failure, fibromyalgia, chronic anemia, and untreated hypothyroidism or with problems in the oral mucosa unrelated to the cancer. Patients with untreated depression and anxiety.
N randomized	60
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	T-test, ANOVA/Wilcoxon test
Countries of data collection	Brazil
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: After 3 weeks T2: After 6 weeks T3: After 9 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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	Stage I - IV
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Radiotherapy consisted of 30 daily sessions lasting six weeks (total dose = 5,040 cGys in the supraclavicular fossa and lymphatic drainages and reaching 7,040 cGys in the tumor). Platinum-based chemotherapy consisted of three cycles of cisplatin (100 mg/m2) every 21 days during the chemoradiotherapy.
Previous cancer therapies	NI
Gender	NI
Gender specifications	NI
Age groups	NI
Age groups specification	NI

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	31
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	NI
Intervention	Dry extract of Paullinia cupana (guarana) capsules
Dosage and regime	2 daily doses before meals, 100 mg, , D160314, with 7.4% caffeine content, manufactured by PharmaNostra During 6 weeks 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.	42
Side effects / Interactions	NI

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	29
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	6
Drop-out reasons	NI
Intervention	Placebo capsules
Dosage and regime	2 daily doses before meals, During 6 weeks 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.	42
Side effects / Interactions	NI

Outcomes

Fatigue

Outcome type As specificed by the authors	Primary
Outcome specification	FACT-F with 13 specific items to assess fatigue, which constitute the FACIT-F questionnaire
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".	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".	No significant difference between the 2 arms; no further information given

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	?

Quality of life

Outcome type As specificed by the authors	Primary
Outcome specification	FACT-F, FACIT-HN, EORTCQLQ-30 & QLQ H&N35
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), FACT (Functional Assessment of Cancer Therapy), FACIT (Functional Assessment of Chronic Illness 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".	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".	FACT-HN35: After first round of chemoradiotherapy: significant improvement in guarana group for domains pain (p = 0.0133), social eating (p = 0.0227), swallowing (p = 0.0254), coughing (p = 0.0107), and weight loss (p = 0.012) After the fourth round of chemoradiotherapy: significantly worse in domain weight loss (p = 0.0074) and greater use of a nasogastric tube (p = 0.051), in addition to increased use of analgesics (p = 0.0253) in guarana group FACT Questionnaire: Comparison between intervention and placebo arm: trend toward worsening in the overall domain: p = .0054, significant worsening in the functional: p = .018 and symptoms domain: p = .0042 after the second cycle of chemotherapy; no significant differences, in any QOL domains, either for the guarana or placebo group, when the first measures were compared to the last assessments of each domain for each particular group EORTC-QOL C30: No improvement in symptoms in the three domains (functional, overall, and symptoms) in the guarana group compared to the placebo group No further information or statistical values given, domain specific results of the EORTC questionnaire only displayed in a graphic

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	?

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	Disease progression was observed in 63.8% of the patients, and death occurred in 53.4% of the patients treated during the 30 months of the study
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".	No significant differences in overall survival between the placebo and guarana arm (p=0.498, only graphically displayed).

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	?

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	Disease progression was observed in 63.8% of the patients, and death occurred in 53.4% of the patients treated during the 30 months of the study
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".	No significant differences in disease-free survival between the placebo and guarana arm (p=0.363, only graphically displayed).

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	NA
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".	No significant differences were observed between the placebo and guarana arms.

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	No information.
Conflicts of Interest	The authors report no 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	?