A comparative study of the effect of black mulberry and honey syrup with benzydamine hydrochloride mouthwash on the prevention of oral mucositis caused by radiation therapy in patients with head and neck cancer

General Objective: To compare the effect of black mulberry–honey syrup and benzydamine mouthwash on the prevention of radiotherapy-induced oral mucositis in head and neck cancer patients. Specific Objectives: -To assess and compare oral mucositis severity (weekly). -To assess and compare pain intensity (daily during radiotherapy). -To assess and compare quality of life (baseline, week 3, end of RT, and 2 weeks post-RT). -To assess and compare the time to onset of grade 1–2 oral mucositis.

A randomized, controlled, parallel-group clinical trial (phase 2–3) on 80 patients. Randomization will be performed using Random Allocation Software version 2.

The study will be conducted at Imam Khomeini Hospital, Sari, Iran

Inclusion criteria: -Life expectancy more than 1 year -Karnofsky performance status more than 50 -Willingness to participate -At least two oral mucosal subsites in the radiotherapy field -No allergy to black mulberry or honey Exclusion criteria: -Prior radiotherapy/chemotherapy in oral or oropharyngeal region within 6 months -Active oral infection or ulcer before radiotherapy -Pregnancy

Intervention group: Patients with head and neck cancer eligible for radiotherapy who meet the inclusion criteria and receive the black mulberry–honey syrup. Control group: Patients with head and neck cancer eligible for radiotherapy who meet the inclusion criteria and receive benzydamine hydrochloride mouthwash.

Primary outcome: Oral mucositis severity Secondary outcomes: Oral pain intensity (using the Visual Analogue Scale, VAS) Quality of life (using the EORTC QLQ-H&N35 questionnaire)

Randomization will be performed by a biostatistician. Patients will be assigned into two groups, and the study medications will be distributed by the researcher. Recruitment will be carried out in parallel for both groups with an allocation ratio of 1:1. For randomization, a block randomization method will be used. Accordingly, patients will be numbered consecutively from 1 to 80 upon enrollment. The unit of randomization will be individual patients, and randomization will be performed using blocks of four. The type of group allocation for each patient will be determined using the Random Allocation Software version 2. To generate the random sequence, the software will produce codes “A” and “B,” where code A indicates allocation to the intervention group and code B indicates allocation to the control group. The generated codes will be placed in sealed, opaque envelopes, each labeled with the patient’s serial number. Upon the patient’s entry into the study, the physician will open the corresponding envelope and apply the assigned intervention. Completion of the demographic, clinical symptoms, and medical history forms will be performed by the principal investigator. The contact number of the investigator will be given to participants so that they can report any problems with the medication or their condition. In case a patient does not attend after the treatment period, follow-up will be conducted via telephone by the investigator.

Title of documents/data: De-identified patient data (primary and secondary outcomes) Details: Data on oral mucositis severity, pain (VAS), and quality of life (EORTC QLQ-H&N35) will be available for sharing in a de-identified form after removal of personal identifiers.

De-identified data will be available to researchers starting 6 months after the publication of the results and will remain accessible for 5 years after publication

De-identified data will be available to researchers affiliated with universities or recognized research institutions, upon request and after approval by the ethics committee.

Data will be provided solely for research and scientific purposes in accordance with the objectives stated in the request; commercial use is not permitted. Analyses must align with the research plan submitted in the request; changing the primary objectives is not allowed. Data will be de-identified, and the applicant is required to maintain confidentiality and must not attempt to re-identify participants. Use of the data is subject to approval by the ethics committee and the principal investigator. In any reports or publications, data must be presented anonymously, preserving participant identity. Upon completion of analyses, the applicant is required to provide the final results or research report to the principal investigator upon request

Researchers wishing to access de-identified data must submit a formal request to the principal investigator. The request should include the intended use of the data, a proposed research plan, and a commitment to maintain data confidentiality. After review and approval by the ethics committee and the principal investigator, the data will be provided in secure, de-identified files. The review and data provision process typically takes 2 to 4 weeks.

The applicant submits a formal request to the principal investigator, including the intended use of the data, a description of the proposed research plan, and a commitment to maintain data confidentiality. The principal investigator reviews the request and, if complete, forwards it to the ethics committee for approval. Upon approval by the ethics committee and the principal investigator, the de-identified data will be provided to the applicant in secure files. The entire process, from submission of the request to receiving the data, typically takes 2 to 4 weeks