Sahebjamee et al. (2015): Comparative Efficacy of Aloe vera and Benzydamine Mouthwashes on Radiation-induced Oral Mucositis: A Triple-blind, Randomised, Controlled Clinical Trial

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Title	Comparative Efficacy of Aloe vera and Benzydamine Mouthwashes on Radiation-induced Oral Mucositis: A Triple-blind, Randomised, Controlled Clinical Trial
Topic	Aloe vera
Author	Sahebjamee, M, Mansourian, A, Haji Mirza Mohammad, M, Taghi Zadeh, M, Bekhradi, R, Kazemian, A, Manifar, S, Ashnagar, S, Doroud, K
Year	2015
Journal	Oral Health and Preventive Dentistry
DOI	https://doi.org/0.3290/j.ohpd.a33091

Brief summary

In this study, researchers investigated the effectiveness of an aloe mouthwash in preventing or alleviating oral mucosal inflammation. Patients with head or neck cancer were divided into two arms: one arm with an aloe mouthwash and one arm with a mouthwash containing benzydamine. The researchers found no differences between these groups in the time to onset of oral mucositis or the maximum degree of mucositis. In this small sample of patients, an aloe-containing mouthrinse was not superior to a benzydamine mouthrinse.

In dieser Studie haben Forscher die Wirksamkeit einer Aloe-Mundspülung zur Vorbeugung bzw. Linderung von einer Mundschleimhautentzündung untersucht. Patienten mit Kopf- oder Halskrebs wurden in zwei Arme eingeteilt: ein Arm mit Aloe-Mundspülung und ein Arm mit Benzydamin enthaltender Mundspülung. Die Forscher fanden keine Unterschiede zwischen diesen Gruppen in der Zeit bis zum Auftreten einer Mundschleimhautentzündung sowie des maximalen Mukositisgrades. In dieser kleinen Stichprobe an Patienten war eine Aloe-haltige Mundspülung einer Benzydamin-Mundspülung nicht überlegen.

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	Monocentric
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	Triple
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	Diagnosis of head or neck cancer; age ≥18 years; Karnofsky performance > 70 (i.e. able to carry out normal activity and work)
Exclusion criteria	Radiotherapy in the past year; food allergy; hypersensitivity to benzydamine, NSAIDs, or aloe; existing lesions in the oral cavity
N randomized	26
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	?
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline visit prior to radiation T2-T7: weekly visits during 6 weeks of radiation Follow-up: one week after the end of radiaton

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
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	Tumor stage per arm: Aloe arm: 1 = 0; 2 = 0; 3 = 9 (69.2%); 4 = 4 (30.8%) Placebo arm: 1 = 0; 2 = 0; 3 = 7 (53.8%); 4 = 6 (46.2%)
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Mean value (range) Radiation dose Aloe arm: 65.54 (50-70) Gy Placebo arm : 66.15 (54 - 70) Gy Previous chemotherapy per arm: Aloe arm: yes = 9 (69.2%); no = 4 (30.8%) Placebo arm: yes = 12 (92.3%); no = 1 (7.7%) Histology: SCC: Aloe arm = 11 (84.6%); Placebo arm = 12 (92.3%) Mucoepidermoid carcinoma: Aloe arm = 1 (7.7%); Placebo arm = 0 Osteosarcoma: Aloe arm = 1 (7.7%); Placebo arm = 1 (7.7%)
Previous cancer therapies	Chemotherapy
Gender	Mixed
Gender specifications	Gender per arm: Aloe arm: male = 8 (61.5%); female = 5 (38.5%) Placebo arm: male = 12 (92.3%); female = 1 (7.7%)
Age groups	Adults (18+)
Age groups specification	Mean age (SD) per arm: Aloe arm: 55.38 (17.99) years Placebo arm: 59.31 (15.03) 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	13
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	Aloe vera
Dosage and regime	Aloe vera mouthwash (containing pure Aloe vera gel; 0.0009% Brilliant Blue dye; 0.0006% tartrazine yellow dye) 5mL mouthwash 3x/day from the start to the end of radiotherapy (six weeks). Patients were asked not to eat or drink for 30 minutes after mouth rinsing. + all patients: radiation therapy
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	Two patients (15.4%) in the aloe arm experienced nausea.

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	13
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
Dosage and regime	0.15% Benzydamine mouthwash 5mL mouthwash 3x/day from the start to the end of radiotherapy (six weeks). Patients were asked not to eat or drink for 30 minutes after mouth rinsing. + all patients: radiation therapy
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	NA

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Burning sensation of the mouth and dysphagia of solid food or liquids were recorded based on the patient reports and erythema and ulcers were observed clinically during weekly visits. WHO Scale: 0 = None 1 = Soreness ± erythema 2 = Erythema, ulcers, patient can swallow solid food 3 = Ulcers with extensive erythema, patient can not swallow solid food 4 = Mucositis to the extent that alimentation is not possible
Type of measurement	WHO-Scale (World Health Organisation)
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 grade 4 was identified in both arms. The mean time between the start of radiation and onset of early signs of mucositis was 15.6 days in the Aloe arm and 15.8 days in the placebo arm, but the difference was not statistically significant (p = 0.97). The mean duration between beginning of radiation and maximum mucositis grade occurrence was 23.3 days in the Aloe arm and 23.5 days in the placebo arm, but the difference was not statistically significant (p = 0.98). There was no significant difference between the arms in terms of mucositis grade changes over time (p = 0.09).
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 statistically significant differences in mucositis grade were found between the two mouthwashes (p = 0.35).

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	The research was supported by the Tehran University of Medical Sciences and Health Services
Conflicts of Interest	NI

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

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