Radiation therapy is a type of treatment that involves using radiation beams targeted at a cancer to destroy the cancer cells or slow their growth. This type of treatment has helped many cancer patients for decades and is intended to kill cancer cells directly. Patients with head and neck cancer are commonly treated with radiation, sometimes after surgery and sometimes the radiation is delivered with chemotherapy at the same time. Radiation treatments have side effects, and the treating oncologist works with each patient to determine the best treatment and manage the side effects.

It has been shown that one of these side effects of radiation is irritation or "sunburn" of the lining of the mouth and throat (radiation mucositis), which can cause difficult or painful swallowing, and pain/discomfort in the mouth/throat. These side effects can lead to dehydration, and weight loss, and sometimes can lead to hospital admissions and treatment delays. This is usually treated by the prescription of pain relievers, dietician support and, if necessary, nutrition via a tube (G-tube).

Because of these symptoms involving the mouth and throat, researchers are looking to study the effect of a common ointment antibiotic used to reduce an infection known as Staphylococcus Aureus. The infection is commonly located in the front of the nose, and during treatment this infection can travel from the nose to the throat and worsen the radiation mucositis and the pain it causes. The study will measure if a course of ointment antibiotic in the nose (twice per day, 5 days on, 5 days off, repeated) can reduce your pain during treatment by reducing severe mucositis related to Staphylococcal infection. This study compares the effects of the study treatment with a "placebo," which looks the same but does not contain any active medicine. Neither you nor your doctor will know which one you are receiving until the study ends. The antibiotic used in the study arm is being used "off-label" for intranasal application (it is normally used to treat skin infections). Possible side effects include local skin irritation or allergic reactions, and in rare cases, a severe allergic response (anaphylaxis).

Radiation induced oral mucositis (RIOM) is a significant toxicity associated with curative head and neck radiotherapy leading to burdensome pain, weight loss, treatment interruptions and high healthcare utilisation. With contemporary treatment grade 3 or higher (CTCAE) oral mucositis rates occur in ~40% of all patients despite standardised oral care and supportive measures. There is growing evidence to implicate Staphylococcus aureus as a contributor to mucosal injury and symptom severity in this setting.

Skin and nasal carriage of S. aureus is common in the general population. In oncology patients auto-inoculation to the pharynx from the nose during treatment is biologically plausible. Intranasal antibiotics such as mupirocin are well-established, targeted decolonisation agents with a favourable safety profile when used intermittently, however their role in preventing severe radiation induced mucositis remains unknown.

Given RIOM typically emerges during weeks 2-3 of treatment and peaks towards the final treatment a cyclical short-course of intranasal or topical antibiotic regimen may sustain decolonisation across the vulnerable window while limiting continuous antibiotic exposure and potential resistance selection. The Centres for Disease Control and Protection recommend intranasal mupirocin when implementing decolonisation or pathogen reduction strategies for high risk patients during high risk periods.

A recent single-centre phase 3 randomised trial of 176 nasopharynx patients demonstrated a 25% reduction in grade 3 or higher oral mucositis rates when treated with cyclical nasal mupirocin decolonisation. This evidence led us to our research question- is this result applicable in a more generalised head and neck cancer population? SNIFF is a pragmatically designed randomised, placebo-controlled trial to test whether cyclical intranasal antibiotic reduces patient reported pain outcomes (NRS scale 0-10 measured weekly) due to reduction in rates of severe mucositis in patients receiving curative-intent head and neck radiotherapy (oral cavity, oropharynx, locally- advanced larynx, hypopharynx). The trial will also evaluate its effects on analgesia adjusted pain scores, physician reported mucositis rates patient reported quality of life (QOL) and rates of feeding tubes or treatment interruptions.

Please note: This trial will be run in a single centre (LHSC, London, Ontario)- the medication used in the experimental arm is topical Mupirocin 2% ointment, as the nasal form is not marketed in Canada. As the medication is being used off-label, we have applied to Health Canada via a Clinical Trial Application, and received a No-objection letter on Jan 14th 2026 (Health Canada control number 304222).

Inclusion Criteria:

• Histologically confirmed mucosal squamous cell carcinoma of the head and neck, planned to receive a dose equivalent to 60 Gy in 30 fractions or higher, with or without concurrent systemic treatment. This can include hypofractionated regimens of 55 Gy in 20 fractions. Primary sites considered: oral cavity, oropharynx, larynx (excluding T1-T2N0 glottic cancers), hypopharynx. The radiotherapy treatment planned can be definitive or adjuvant.
• Age ≥18 years.
• ECOG performance status 0-2
• Informed consent provided.

Exclusion Criteria:

• Mupirocin allergy
• Skin or salivary gland malignancy
• Early stage glottic cancers (T1-2N0)

De-identified individual participant data underlying the primary and secondary outcomes will be shared, including weekly odynophagia 11-point numeric rating scale scores, Radiation Therapy Oncology Group mucositis grades, MD Anderson Symptom Inventory scores, morphine-equivalent analgesia data and the derived analgesia-adjusted pain score, and key clinical outcomes (treatment interruptions, feeding tube insertion, hospital admissions), along with baseline demographic and treatment descriptors needed to interpret the dataset (e.g., age group, sex, primary site group, treatment intent, and concurrent systemic therapy category), and adverse event data; no direct identifiers will be shared.

IPD and supporting documentation will be available beginning 6 months after publication of the primary results (or 12 months after study completion if no publication occurs), and will remain available for 5 years thereafter.

Access will be granted to qualified researchers who submit a written request with a brief protocol and analysis plan, and who sign a data sharing agreement approved by the sponsor-investigator. Approved requestors will receive a de-identified dataset containing the IPD described above and supporting documents (data dictionary, annotated case report forms, and the statistical analysis plan) via a secure institutional file-transfer platform; access is for research purposes only and data will not include direct identifiers.