This was a phase IV, international, open label, single-group study conducted from December 2021 to September 2022. The objective was to assess the activity and feasibility of benzydamine mouthwash in the prevention and treatment of radiation-induced OM in patients with HNC from first day of RT through the end of RT.

A total of seven centers were involved across two countries: Hungary and Poland. Before study start-up, all relevant regulatory authorities and ethics committees provided review and written approval for all clinical study documentation (protocol 030(Z)WO19247) and adequacy of investigational sites. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice principles, and all applicable regulatory requirements including ICH E6 Good Clinical Practice (R2). All relevant regulatory and ethical committees provided review and written approval for all clinical study documentation and investigational sites.

Before enrolment into the study, patients were fully informed about the purposes of the research, as well as all procedures relating to their involvement. Before entering the study, a written and signed informed consent form and the Declaration of Consent for Processing of Personal Data were obtained from all patients.

Benzydamine hydrochloride 1.5 mg/mL mouthwash was assigned to the patients for the prevention/treatment of radiation-induced OM, according to the investigator’s recommendations and to the relevant local SmPC (Summary of Product Characteristics).

Treatment of 15 mL (1 tablespoon) of concentrated or diluted (with water) solution was taken at home, two or three times a day, but not more than five times a day. Patients were asked to wash the mouth and throat for 20 to 30 seconds, according to the investigator’s indications and the local product’s SmPC.

Treatment compliance was defined as taking ≥ 80% of the total dose of benzydamine treatment assigned by the investigator.

The primary outcome for this study was the number of responders, defined as the number of patients with HNC who had OM pain intensity <5 (numeric rating scale [NRS]), expressed as a percentage, at visits 0 to 7/early treatment termination visit (ETTV).

The key secondary outcomes were the number of compliant patients, change in score on the WHO OM grading scale from Visit 0 through Visit 7/ETTV, number of days’ duration and time to onset of severe mucositis, percentage change in body weight and need for nutritional support, number of days duration of RT/CT administered as well as discontinuation, dose modifications and delays, number of days of hospitalization, number and type of opioid analgesics used for OM pain, and changes from Visit 0 in vital signs, physical examination and adverse events to Visit 7/ETTV.

Data were collected during clinical visits at baseline (V0, start of RT), Visit 1 (Day 7 ± 1), Visit 2 (Day 14 ± 1), Visit 3 (Day 21 ± 1), Visit 4 (Day 28 ± 1), Visit 5 (Day 35 ± 1), Visit 6 (Day 42 ± 1) during RT, and Visit 7 (Day 49 ± 1, Final visit/End of RT).

At baseline, which was defined as the start of RT, all patients were fully informed by the investigator about the purpose of the study, patients received standard study information, and patients provided written informed consent forms. Key study data including demographics, medical history, oncology history, physical examination, vital signs, current oncology status and treatment, Eastern Cooperative Oncology Group (ECOG) status, OM evaluation, benzydamine treatment prescription, and AEs were collected.

Eligible patients were enrolled in the study, and one visit per week during the radiotherapy period was scheduled. During these visits, data were collected and recorded in source documents by the investigator who then reported into the electronic case report form. Patients were asked to self-report data on OM pain assessment (NRS) on paper during each visit. Patients were instructed to consider any pain due to mucositis in oral cavity and asked to select the number (0/not present -10/pain as bad you can imagine) best describing the intensity of pain over the past 7 days. OM severity was evaluated at each visit by physicians having at least a 2-year experience in HNC treatment. Sites were trained on OM severity scoring via online training using the WHO classification scale.

The study population consisted of male and female patients 18 years or older with a histologic or cytologic diagnosis of stage III or IV HNC in subsites—including oral cavity, oropharynx, larynx and hypopharynx, according to the VIII American Joint Committee on Cancer (AJCC) staging system—who were candidates and were about to start RT. Exclusion criteria included reported allergy to benzydamine or related components of the formulation used; prior head and neck RT; having received palliative treatment; any metastatic disease, cognitive impairment, or significant comorbid conditions; OM due to other conditions; use of other oromucosal products, rinses, or anti-inflammatory mouthwash solutions; use of antifungal or antibiotic drugs; or having received other therapies that cause mucositis.

Because of the nature of the single-arm study, all statistical analysis was descriptive. Continuous variables were described by mean, standard deviation (SD), median, interquartile range (IQR), minimum, maximum, and number of available patients. Categorical variables were described by frequency and percentages. Two-sided 95% confidence intervals (CIs) were provided for the primary and secondary outcome variables. When relevant, 95% CIs were provided for demographic variables as well. No comparison test was conducted. SAS version 9.4 was used for analysis.

This Phase IV single-arm study had no hypothesis to test, and sample-size justification was based on precision expected for the primary outcome (e.g., the number of responders). A target sample size of 100 patients (including an assumption of 20% dropouts) was considered appropriate to evaluate the percentage of responders, defined as the number of patients with HNC who had OM pain intensity < 5 (NRS).

The following analysis populations were defined for statistical analysis:

It was planned that a sample of 100 patients (including an assumption of 20% dropouts) would be included in the study; 89 were actually enrolled into the study from seven sites in two European countries: Poland and Hungary. Three analysis sets were used: the SP and m-ITT analysis sets each contained 89 patients; the PP analysis set contained 67 patients, because 22 patients had a major protocol violation and were excluded from the PP analysis population (see Figure 1 ). As the patients in the SP and m-ITT analysis populations were exactly the same, all results are presented as m-ITT. As shown in Figure 1 , there were 89 patients in the m-ITT sett and 67 patients in the PP set.

In the m-ITT set, the majority of the study population was male (80.9%) and their mean age was 61.4 years (range: 41-77 years). All patients were White ( Table 1 ).

Among the m-ITT set at baseline, 88 patients (98.9%) had head and neck cancer stage III or IV; one patient had missing information ( Table 2 ). The disease subsite was the oral cavity for 33.7% of patients, the oropharynx and hypopharynx for 36.0% of patients, and the larynx for 29.2% of patients. A majority of patients had stage T3-T4 (73.0%), nearly a quarter (23.6%) had stage T1-T2. 61.8% had stage N2-N3, and approximately a third (34.9%) had stage N0-N1.

The activity of benzydamine mouthwash in the prevention/treatment of radiation-induced OM in patients with HNC, from the first day of RT through end of RT/ETTV was assessed in all patients in the study. The activity was assessed by the primary study outcome, which was response to the benzydamine mouthwash, operationally defined as the number of patients with HNC who had OM pain intensity < 5 (NRS), expressed as a percentage, at Visits 0 to 7/ETTV. Of the 89 patients in the m-ITT set, approximately a third (n=30, 33.7%) were responders ( Table 3 ). The level of response in the PP was similar (29.9%).

The primary study outcome was also investigated in an explorative way by performing the primary analysis using data from Visit 0 to Visit 4 only. Compared with the corresponding results from Visits 0 to Visit 7/ETTV ( Table 3 ), the exploratory primary analyses revealed a higher number of responders during Visits 0 to Visit 4, 52.8% in the m-ITT set and 52.2% in the PP set ( Table 4 ).

Of the 89 patients in the m-ITT set, the vast majority were found to be treatment compliant (n=77, 86.5%) ( Table 5 ). Within the m-ITT, the mean total extent of exposure was 41.9 days, with a minimum of 14 days to a maximum of 65 days. Within the PP, the mean total extent of exposure was similar: 44.7 days (data not shown).

In total, 135 treatment-emergent adverse events (TEAEs) were reported during the study; of these, only two were adverse drug reactions (ADRs), and they occurred in separate patients. The vast majority of TEAEs (93.3%) were reported as unlikely to be correlated to the investigational medicinal product. In total, four patients were reported to have at least one SAE. One patient was reported to have an “infection and infestation” (neutropenic sepsis), another patient was reported to have a “metabolism and nutrition disorder” (Cachexia) and a “general disorder and administration site condition” (pyrexia), one patient was reported to have a “nervous system disorder” (Syncope), and one patient was reported to have an “infection and infestation” (COVID-19) (data not shown).

Severity of OM was assessed through change in score on the WHO OM grading scale from Visit 0 to Visit 7. According to the WHO classification, severity of OM is graded on the following scale: 0 (none), 1 (mild, oral soreness and erythema), 2 (moderate (erythema, ulcers, solid diet tolerated), 3 (severe, oral ulcers, liquid diet only), or 4 (life-threatening, oral alimentation impossible). Nearly all patients (93.3%) had no mucositis at Visit 0 ( Figure 2 ). By contrast, at Visit 7, very few patients (3.7%) did not have mucositis; approximately a third (34.1%) had mild mucositis, nearly half (45.1%) had moderate mucositis, 15.9% had severe mucositis, and 1.2% had life-threatening mucositis.

Duration and time to onset of severe OM was also assessed during the RT. There were no reports of patients with severe mucositis (WHO OM grade 3 or 4) at baseline (Visit 0) or Visit 1 ( Figure 3 ). In total, 26 patients (29.2% of the m-ITT set) were reported to have developed severe mucositis (WHO OM grade 3 or 4) during the study period, across Visits 2 through 7 inclusive. In this graph it is evident that the number of non-responder patients increases during the study, as expected in parallel with the worsening of OM.

Nutritional support (i.e., need of a feeding tube) and type of enteral support (i.e., partial or total and number of days of need) was assessed at Visits 0 to 7/ETTV. In the m-ITT, at Visit 1, a majority of patients did not need nutritional support for OM (n=70, 78.7%). At Visit 7, a majority of patients still did not require nutritional support (58.4%), lower than at Visit 1 (data not shown).

In addition, healthcare resource use consumption was assessed by the number of days of hospitalization on which the main reason was mucositis or an associated complication from Visit 0 to Visit 7. In the m-ITT set, at the first four visits, only one patient reported hospitalization due to mucositis or associated complications; only two patients had this outcome at Visit 5, three patients at Visit 6, and four patients at Visit 7 (data not shown).

Furthermore, the use of opioid analgesics for OM pain was also assessed and measured by the number and type of opioid analgesics used for OM pain at visits 0 to 7. In the m-ITT, opioid analgesics were used for OM pain among 47 (52.8%) patients.