Campos et al. (2011): Guarana (Paullinia cupana) Improves Fatigue in Breast Cancer Patients Undergoing Systemic Chemotherapy

Reference ↗
Title	Guarana (Paullinia cupana) Improves Fatigue in Breast Cancer Patients Undergoing Systemic Chemotherapy
Topic	Guarana
Author	Campos, M, Riechelmann, R, Martins, L, Hassan, B, Casa, F, Del Giglio, A
Year	2011
Journal	The journal of alternative and complementary medicine
DOI	https://doi.org/10.1089/acm.2010.0571

Brief summary

Fatigue is a common side effect of chemotherapy. In this study, researchers investigated the effect of guarana on chemotherapy-induced fatigue in patients with breast cancer. Researchers studied 75 women with increasing fatigue or who developed fatigue after chemotherapy. For 21 days, half of the women were asked to take guarana twice a day (every 12 hours), while the other half took a placebo. All patients then took nothing for a week and switched treatment for a further 21 days (i.e. those who took guarana then took the placebo and those who took the placebo then took the guarana). Fatigue improved significantly in women who took guarana, while fatigue worsened or did not change in those who took the placebo. Adverse events were present in both arms, ranging from insomnia and tachycardia to dermatologic reactions and nausea.

Müdigkeit ist ein häufiger Nebeneffekt der Chemotherapie. In dieser Studie untersuchten Forscher die Wirkung von Guarana auf eine Chemotherapie bedingte Fatigue bei Patientinnen mit Brustkrebs. Forscher untersuchten 75 Frauen mit zunehmender Fatigue oder die nach einer Chemotherapie eine Fatigue entwickelten. 21 Tage lang wurde die Hälfte der Frauen gebeten, Guarana zweimal täglich (jede 12 Stunden) einzunehmen, während die andere Hälfte ein Placebo einnahm. Alle Patientinnen nahmen dann eine Woche lang nichts und wechselten die Behandlung für weitere 21 Tage (d.h. diejenigen, die Guarana einnahmen, nahmen dann das Placebo ein und diejenigen, die das Placebo einnahmen, nahmen dann den Guarana ein). Bei Frauen, die Guarana einnahmen, verbesserte sich die Fatigue signifikant, während die Fatigue bei denjenigen, die das Placebo einnahmen, schlechter wurde oder sich nicht veränderte. Unerwünschte Ereignisse waren in beiden Gruppen vorhanden, von Insomnien, Tachykardien bis zu dermatologischen Reaktionen und Übelkeit.

Study Design

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

Study characteristics

Inclusion criteria	Adult woman (22-70 years) with Mamma-carcinoma
Exclusion criteria	Hypothyroidism; depression or other severe psychiatric illness; anemia; previous antineoplastic treatment; contraindications to guarana (insomnia, angina or other cardiovascular disease, uncontrolled hypertension, neurological disease); antidepressant, anxiolytic or sleep-inducing medications
N randomized	75
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, NI
Specifications on analyses	3 weeks of receiving placebo/intervention, 1 week washout, 3 weeks of receiving intervention/placebo Consort diagram shows, that drop-out was excluded from final analysis, even though an ITT-analysis was mentioned in the method section
Countries of data collection	Brazil
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0 = Baseline T1 = Day 21 (after phase 1) T2 = Day 49 (after phase 2)

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	Breast 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	Involved patients with a diagnosis of breast cancer at any stage
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Female
Gender specifications	NA
Age groups	Adults (18+)
Age groups specification	Range: 22-70 years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention, Placebo
Number of participants (arm) N randomized	43
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Placebo-guarana arm: n=8 (first Placebo then guarana)
Drop-out reasons	Discontinued placebo: n = 2, - Rash: n = 1, - Palpitations: n = 1 Excluded for forgetting to take more than 1 pill: n = 6 Note: Time of Drop-Outs unclear, since all patients are noted to start guarana but drop-out occured for placebo
Intervention	Paullinia cupana, dried extract
Dosage and regime	2x/day, every 12 hours (50 mg, Charge E16117007)
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.	21
Side effects / Interactions	Insomnia: Guarana: n = 22, placebo: n = 31, Palpitation: Guarana: n = 10, placebo: n = 12, Nausea: Guarana: n = 25, placebo: n = 35, Anxiety: Guarana: n = 17, placebo: n = 25, Dermatologic: Guarana: n = 1, placebo: n = 3

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention, Placebo
Number of participants (arm) N randomized	32
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Guarana-placebo arm: n = 7 (first guarana then placebo)
Drop-out reasons	Discontinued guarana: n = 2 - Palpitations: n = 1 - Patient discontinued medication due to herpes zoster: n = 1 Excluded for forgetting to take more than 1 pill: n = 5 Note: Time of Drop-Outs unclear, since all patients are noted to start placebo but drop-out occured for guarana
Intervention	Paullinia cupana, dried extract
Dosage and regime	2x/day, every 12 hours (50 mg, Charge E16117007)
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.	21
Side effects / Interactions	Insomnia: Guarana: n = 22, placebo: n = 31, Palpitation: Guarana: n = 10, placebo: n = 12, Nausea: Guarana: n = 25, placebo: n = 35, Anxiety: Guarana: n = 17, placebo: n = 25, Dermatologic: Guarana: n = 1, placebo: n = 3 Total Guarana n=30, Placebo n=45, no statistical comparison conducted

Outcomes

Fatigue

Outcome type As specificed by the authors	Primary
Outcome specification	Specific questionnaires were used: FACIT-F that assesses self-reported QOL and fatigue with total score ranging from 0 to 160 FACIT-ES that includes a subspace evaluating menopausal symptoms, among other components that are totaled to provide an overall score ranging from 0 to 180
Type of measurement	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".	FACIT-F: Significantly lower severity of fatigue with guarana compared to placebo, Significantly more patients with improved FACIT-F global scores on guarana at days 21 (52% versus 10%) and at day 49 (66% versus 13%) as compared with patients who received placebo. After day 1: p = 0.09 After day 21: p = < 0.01 After day 49: p = < 0.01 FACIT-ES: Significantly lower expression of endocrine symptoms with guarana compared to placebo In the intragroup analysis, there were significant differences favoring guarana for the placebo–guarana arm but not for the guarana–placebo arm. After day 1: p = 0.18 After day 21: p = 0.01 After day 49: p = < 0.01

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	?

Fatigue

Outcome type As specificed by the authors	Primary
Outcome specification	Global Chalder Fatigue Scale: Measure of fatigue severity for both physical and mental symptoms that scored in a Likert format with response options ranging from better than usual to much worse than usual, with total possible score of 26.
Type of measurement	BFI (Brief Fatigue Inventory)
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".	Global Chalder Fatigue Scale: Significant differences favoring guarana, with a drop of -4.6 points in the global score versus a significant increase of + 2.2 points for the arm receiving placebo on day 21, Difference was not significant for the intergroup analysis on day 49. Guarana significantly improved the Global Chalder Fatigue Scale scores throughout the treatment in the placebo–guarana arm and there was a positive trend in the guarana–placebo arm (p=0.06) After day 1: p = < 0.01 After day 21: p = < 0.01 After day 49: p = 0.27 BFI: Significantly lower severity of fatigue with guarana compared to placebo. After day 1: p = NI After day 21: p = < 0.01 After day 49: p = < 0.01

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	?

Sleep

Outcome type As specificed by the authors	Primary
Outcome specification	Pittsburgh Sleep Quality Index questionnaire that inquires about frequency of sleep disturbances and subjective sleep quality
Type of measurement	PSQI (Pittsburgh Sleep Quality Index)
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 difference between the arms. Significantly better sleep within the guarana arm compared to baseline. Better sleep quality after the use of guarana only in the day 49 comparison and in guarana-placebo arm of the intragroup analysis Intergroup comparison of guarana and placebo: Day 21: p = .19 Day 49: p .05

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	?

Anxiety

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	HADS (Hospital Anxiety and Depression 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".	No difference between the 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 external funding.
Conflicts of Interest	No competing financial interests exist.

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	?