Phase IV Study of Benzydamine Hydrochloride Lozenges for Pain Relief in Pediatric Non-Streptococcal Pharyngotonsillitis

Trial ID: 2025-521526-15-00
Protocol: 030(Z)MD24076
Sponsor: Angelini Pharma Italia Aziende Chimiche Riunite Angelini Francesc O A.C.R.A.F. S.p.A.

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Diseases & Conditions

Tonsillitis

Objectives

The primary objective is to evaluate the association and temporal concordance between the change from baseline in the percentage of the pharyngotonsillar surface area exceeding a pre-specified temperature threshold and the change from baseline in the Wong-Baker FACES Pain Rating Scale (WBFPRS) during the initial 60 minutes following the administration of benzydamine hydrochloride lozenges in pediatric patients with non-streptococcal pharyngotonsillitis. This evaluation aims to correlate thermographic changes with subjective analgesic effects. Secondary objectives include:

Determination of the time to the first clinically meaningful analgesia, defined as a reduction of at least 2 points on the WBFPRS.
Assessment of the time to the first meaningful thermographic improvement, defined as a relative reduction of at least 15% in the pharyngotonsillar surface area above the temperature threshold.
Analysis of the association between thermographic changes and pain evolution over a 72-hour period.
Description of the proportion of participants achieving meaningful pain reduction at scheduled intervals.
Evaluation of changes from baseline in both WBFPRS and thermographic parameters at each time-point.
Performance of supportive analyses relative to the time of complete lozenge dissolution.
Evaluation of the short-term safety and tolerability of the investigated product.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female pediatric patients aged 6 to 11 years diagnosed with non-streptococcal pharyngotonsillitis. Female participants must be in pre-menarche status. Eligible subjects must present with a recent onset of sore throat lasting no more than 36 hours and a diagnosis confirmed by a score of at least 5 on the Tonsillo-Pharyngitis Assessment scale. Additional requirements include a Wong-Baker FACES Pain Rating Scale score of at least two points and an oral body temperature of 38.0°C or lower. Inclusion requires the absence of group A β-hemolytic Streptococcus. Participants must not have used benzydamine hydrochloride in any form within the 24 hours prior to enrollment.

Plans and Procedures

This Phase IV, prospective, open-label, single-arm study evaluates the pain-relief effect of benzydamine hydrochloride 3 mg lozenges in pediatric patients aged 6 to 11 years diagnosed with non-streptococcal pharyngotonsillitis. The primary objective is to estimate the association and temporal concordance between the change from baseline in the percentage of the pharyngotonsillar surface area above a pre-specified temperature threshold and the change in the Wong-Baker FACES Pain Rating Scale (WBFPRS) during the first 60 minutes following the first administration. The study design includes a screening period to confirm eligibility based on criteria such as recent onset of sore throat, a Tonsillo-Pharyngitis Assessment (TPA) score of $\ge$5, and negative results for group A β-hemolytic Streptococcus. Following enrollment, clinical assessments are conducted to monitor pain reduction and thermographic improvements at specific intervals, including 5, 10, 15, 20, 25, 30, and 60 minutes, as well as at 24, 48, and 72 hours. Secondary endpoints encompass the time to clinically meaningful pain reduction, the need for rescue medication, and safety outcomes such as adverse events. The total duration of patient involvement is three days. Study termination may occur if a patient’s menarche status changes or if other clinical conditions necessitating discontinuation arise.

Treatment

The experimental medication consists of benzydamine hydrochloride, administered in a 3 mg lozenge pharmaceutical form with a mint flavor. This substance is intended for oromucosal use. The study protocol specifies a dosage of 9 mg per administration.

Efficacy

The efficacy of benzydamine hydrochloride lozenges in patients with non streptococcal pharyngotonsillitis will be evaluated through several parameters. The primary endpoints consist of the repeated-measures association during the first 60 minutes following the first lozenge placement between the change from baseline in the percentage of pharyngotonsillar surface area above a pre-specified temperature threshold and the change from baseline in the Wong-Baker FACES Pain Rating Scale (WBFPRS). The pharyngotonsillar surface area will be assessed centrally using duplicate infrared images. The WBFPRS will be measured at 5, 10, 15, 20, 25, 30, and 60 minutes.

Secondary efficacy assessments include:

Time from first lozenge placement to the first clinically meaningful pain reduction, defined as a decrease of $\ge$2 points in the WBFPRS.
Time from first lozenge placement to the first predefined thermographic improvement, characterized by a relative reduction from baseline of at least 15% in the percentage of pharyngotonsillar surface area above the pre-specified temperature threshold.
Proportion of participants achieving clinically meaningful pain reduction at 5, 10, 15, 20, 25, 30, and 60 minutes, as well as at 24, 48, and 72 hours.
Mean and median change from baseline in the WBFPRS at each scheduled time-point.
Time to complete pain disappearance, defined as a WBFPRS score of 0.
Total number of lozenges administered before complete pain disappearance.
Descriptive association between the change from baseline in the percentage of pharyngotonsillar surface area above the pre-specified temperature threshold and the change from baseline in the WBFPRS over 24, 48, and 72 hours.
Requirement for paracetamol and/or antibiotics during the study period.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed and dated written Informed Consent (ICF). The ICF for participation in the study and consent to data processing will be signed by both parents/legal guardian, while the child will only sign the assent form appropriate for his/her age based on the judgment of the Principal Investigator; Or in cases where one parent is unable to provide consent due to absence, distance, or other impediments, the present parent must provide a self-declaration certifying the absence or impediment of the other parent
Male and female patients (aged 6-11 years, limits included). Female patients must be in pre-menarche status at the time of informed consent/assent (where applicable) signature; in the unlikely circumstance that the menarche status changes during the 3 (three) days of the duration of the study, child’s parents/caregiver/legal guardian should immediately inform the Investigator who will then discuss the specific case with the Sponsor and decide whether or not to retain the subject in the study.
Recent onset (≤36 hours) of sore throat;
Diagnosis of pharyngotonsillitis confirmed by a score ≥5 on the Tonsillo-Pharyngitis Assessment (TPA) scale;
A score of at least two points (equal to 1 face) in the WBFPRS score;
Oral body temperature ≤38.0°C;
No use of benzydamine hydrochloride in any form (e.g. spray, lozenge) in the 24 (twenty-four) hours prior to the enrolment in the study;
Negative group A β-hemolytic Streptococcus (S. pyogenes).

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Exclusion Criteria

Known hypersensitivity to benzydamine hydrochloride or its excipients (refer to Appendix 1);
Diagnosis or suspect of phenylketonuria;
Diagnosis or suspect of fructose intolerance;
Clinically significant abnormalities at physical examination based on Investigator’s judgement;
Intolerance to acetylsalicylic acid or other NSAIDS;
History or diagnosis of asthma;
Any concomitant disease that compromise breathing (i.e. bronchopneumonia);
Severe coughing which causes throat discomfort (as per investigator judgement);
Purulent plaques on the tonsils;
Any inhaled therapy in the previous week before the first Investigational Medicinal Product (IMP) administration;
Any systemic or local (including sprays and mouthwashes) with anti-inflammatories, antipyretics, corticosteroids, local anaesthetics, antiseptics, decongestants, antihistamines, expectorants, antitussives, antibiotics, or natural medications (e.g. herbal infuses, propolis) in the 48 hours prior to enrolment in the study;
Participation to a clinical trial within 3 months prior to the inclusion in the study;
Parents/legal guardian, who are unable to comprehend the full nature and purpose of the study and to comply with the requirements of the study;
Any other diseases that present sore throat as concomitant symptoms (e.g., but not limited to, gastroesophageal reflux, exposure to toxic substances, allergic reactions).