A Single Dose of Intravenous Penicillin as an Adjunct to Oral Penicillin in the Treatment of Acute Tonsillitis, Peritonsillar Phlegmon, and Peritonsillar Abscess

Acute Tonsillitis, Peritonsillar Abscess, Peritonsillar Cellulitis

RCT, Penicillin, Treatment, Acute tonsillitis, Peritonsillar phlegmon, Peritonsillar abscess

Background Tonsillar infections are highly prevalent and are associated with substantial morbidity, including severe sore throat, dysphagia, and general malaise. The disease spectrum ranges from acute tonsillitis (AT) through peritonsillar phlegmon (PP) to peritonsillar abscess (PTA), and clinical data suggest that these conditions often represent a continuum in which inadequate treatment may lead to disease progression. Traditionally, Group A streptococci have been considered the primary pathogen. However, our previous studies have demonstrated that Fusobacterium necrophorum and Streptococcus dysgalactiae also play important roles in moderate to severe tonsillar infections. The predominant pathogens are susceptible to beta-lactam antibiotics, and in Denmark both oral phenoxymethylpenicillin (PMP) and intravenous benzylpenicillin (BP) are commonly used. However, PMP exhibits considerable interindividual variability in bioavailability, which may result in insufficient antibiotic exposure. The efficacy of beta-lactam antibiotics depends on the duration that drug concentrations remain above the minimum inhibitory concentration (T\>MIC), and experimental data from our research group have shown that intravenous BP provides more stable and adequate tissue exposure than oral PMP. In clinical practice, rapid symptomatic improvement is often observed following intravenous BP administration, but this has not been investigated in randomized studies. We hypothesize that a single initial intravenous dose of BP, administered in addition to standard oral PMP therapy, may result in more rapid symptom relief without the need for hospitalization. Treatment effects will be assessed using disease-specific Patient-Reported Outcome Measures (PROMs), namely the STAT-10 and PTAAT-12 questionnaires, both developed by our research group. The project addresses an important clinical and pharmacological knowledge gap and has the potential to optimize treatment, reduce disease burden, and strengthen outpatient management of tonsillar infections. Objectives * To investigate the effects of a single dose of intravenous penicillin as an adjunct to oral penicillin therapy in patients with AT, PP, and PTA, respectively. * To define the minimal clinically important difference (MCID) for the STAT-10 score and the PTAAT-12 score. Study Design This is an investigator-initiated, randomized, double-blind, placebo-controlled, parallel-group trial in which patients with AT, PP, or PTA are randomized 1:1 to receive either a single dose of intravenous benzylpenicillin (2 MIU) or placebo (isotonic saline) in addition to standard oral phenoxymethylpenicillin therapy. Patients will be enrolled into three groups (AT Group, PP Group, and PTA Group), which will be analyzed separately. Inclusion Criteria Adults (≥18 years of age) with clinically diagnosed acute tonsillitis (AT Group), peritonsillar phlegmon (PP Group), or peritonsillar abscess treated with incision and drainage (PTA Group). Perspectives The study has the potential to improve the clinical management of patients with AT, PP, and PTA by providing evidence on whether an initial intravenous dose of penicillin enhances treatment outcomes. Timeline * Anticipated start of patient recruitment: October 2026. * Anticipated primary completion: December 2028. * Anticipated study completion (last participant's 12-month follow-up): December 2029.

1. Introduction 1.1. Objective To investigate the effect of a single dose of intravenous (IV) benzylpenicillin (BP) as an adjunct to standard treatment with oral (PO) phenoxymethylpenicillin (PMP) in adult patients with acute tonsillitis (AT), peritonsillar phlegmon (PP), or peritonsillar abscess (PTA) treated by incision. In addition, to investigate the effect of the intervention on pain, symptom burden, analgesic consumption, complications, and long-term outcomes in patients with AT, PP, and PTA. 1.2. Background and Scientific Rationale Tonsillar infections are among the most common infectious diseases in Denmark and internationally. They range from self-limiting mucosal infections of the tonsils (acute tonsillitis, AT), through peritonsillar phlegmon (PP), involving the peritonsillar tissue, to purulent infections with abscess formation (peritonsillar abscess, PTA) or spread to the deep neck spaces, including parapharyngeal abscesses. The precise pathogenesis is not fully understood; however, clinical and microbiological findings suggest that these conditions often represent a pathophysiological continuum ranging from mucosal inflammation to deeper suppurative infection. Timely and effective treatment is essential to prevent progression and complications. These infections are associated with substantial morbidity, including severe throat pain, dysphagia with a risk of dehydration and weight loss, and pronounced malaise. AT is a common reason for consultation in primary care \[1\]. The vast majority of patients are assessed and treated primarily in primary care, whereas a smaller and clinically more severe subgroup is referred for specialist assessment in private specialist practice or hospital care. At the Department of Otorhinolaryngology, Aarhus University Hospital (AUH), approximately 70 adult patients with AT are referred annually \[2\]. In addition, approximately 60 patients with PP are referred annually. In both groups, approximately 75% can be managed on an outpatient basis with oral (PO) antibiotics, whereas approximately 25% require hospital admission. The department also treats approximately 100 adult patients with PTA annually; approximately 80 are treated by incision and drainage, whereas approximately 20 undergo acute tonsillectomy. The majority of patients treated by incision are managed as outpatients with oral phenoxymethylpenicillin (PMP). Group A Streptococcus (GAS) is traditionally considered the most important bacterial cause of AT and PP. In Denmark, it is common practice to test for GAS and administer antibiotic treatment only when GAS is detected by throat swab in patients with AT, whereas all patients with PP are treated with antibiotics. However, Streptococcus dysgalactiae, Fusobacterium necrophorum (FN), and Arcanobacterium haemolyticum have also been described as relevant pathogens in AT and PP \[3-9\]. In a retrospective review of 327 patients admitted with AT or PP at AUH, cultures were obtained from 109 throat swabs; GAS was detected in 23%, Streptococcus dysgalactiae in 11%, and FN in 5% \[9\]. In a recent prospective study involving intensive culture-based assessment of tonsillar surface swabs from patients with AT and PP and from healthy controls, GAS, FN, and S. dysgalactiae were found to be significantly associated with both infection types \[10\]. Additional sequencing analyses of the same samples did not identify any further clinically relevant pathogens but increased the overall detection rate of the three aforementioned bacteria from 48% by conventional culture to 70% \[11\]. Collectively, these findings support the notion that a limited number of beta-lactam-susceptible bacteria constitute the primary pathogens in moderate-to-severe tonsillar infection. All identified major pathogens are susceptible to beta-lactam antibiotics, including benzylpenicillin (BP) and PMP. Patients referred to the Department of Otorhinolaryngology, AUH, constitute a selected population with more severe symptoms or clinical signs of peritonsillar infection, with or without abscess formation. In almost all cases, these patients receive empirical antibiotic treatment without prior microbiological confirmation, as severe clinical presentation is considered indicative of bacterial infection. The exception is patients with biochemically confirmed mononucleosis. Studies conducted by our research group on PTA further indicate that FN is likely to be the predominant pathogen in cases progressing to abscess formation \[12-14\]. BP and PMP are both routinely used for the treatment of AT, PP, and PTA in Denmark. BP is administered intravenously (IV) with 100% bioavailability, whereas PMP is administered orally (PO) with a mean bioavailability of approximately 60% \[15\]. However, there is substantial interindividual variability in the bioavailability of PMP (approximately 25-100%), resulting in up to a four-fold variation in serum concentrations \[16-17\]. The bactericidal activity of beta-lactam antibiotics is time-dependent and correlates with the proportion of the dosing interval during which the antibiotic concentration exceeds the minimum inhibitory concentration (MIC) of the relevant pathogen (T\>MIC). The substantial variability in PMP exposure entails a risk of insufficient T\>MIC and, consequently, suboptimal bacterial eradication. In an experimental porcine model, our research group found that the time during which the antibiotic concentration in the pharyngeal mucosa exceeded the MIC was insufficient following oral administration of PMP, whereas the concentration following IV administration of BP remained above the MIC throughout the entire dosing interval \[18\]. Pharmacologically, these findings suggest that BP may provide more stable and sufficient antibiotic exposure in severe tonsillar infection. Clinically, rapid symptomatic improvement is frequently observed in patients treated with IV BP; however, this observation has not been systematically investigated in controlled clinical studies. One possible explanation is that high initial antibiotic exposure may accelerate bacterial eradication during the early phase of infection, when the bacterial burden is greatest. A single IV dose of BP may therefore function as a pharmacological "loading dose", ensuring sufficient T\>MIC in the tonsillar tissue until stable exposure is achieved with subsequent oral treatment. No randomized clinical studies have directly compared BP and PMP in AT, PP, or PTA with respect to symptom relief, disease duration, or complications. At the same time, there is a continuing focus within healthcare systems on reducing hospital admissions and promoting outpatient treatment in order to optimize costs and resource utilization. Optimal pharmacological treatment could theoretically involve continued IV BP during hospitalization until clinical improvement; however, this is unlikely to be compatible with organizational and economic considerations. Our hypothesis is that the addition of a single IV dose of BP to standard PO PMP treatment may result in more rapid symptom reduction and an improved clinical course compared with PO treatment alone, while maintaining a treatment approach that is practical and organizationally implementable. To enable assessment of the intervention's effect at the patient level, our research group has developed Patient-Reported Outcome Measures (PROMs) specifically for tonsillar infections: STAT-10 for AT/PP and PTAAT for PTA \[19-20\]. These instruments allow quantification of the overall symptom complex from the patient's perspective and are suitable as outcome measures in clinical intervention studies. However, correct interpretation of changes in PROM scores requires knowledge of the instruments' minimal clinically important difference (MCID), which has not yet been established for either STAT-10 or PTAAT. Overall, the planned study addresses an important clinical and pharmacological knowledge gap by investigating whether optimization of initial antibiotic exposure can improve patient-reported outcomes in moderate-to-severe tonsillar infection without the use of broad-spectrum antibiotics, while potentially reducing the need for hospital admission. 1.3. Rationale for the Dosing Regimen BP will be administered as a single IV dose of 2 million international units (MIU) at inclusion as an adjunct to standard treatment with PO PMP 660 mg four times daily for 5 days. The selected dosing regimen is based on current clinical practice at the Department of Otorhinolaryngology-Head and Neck Surgery, Aarhus University Hospital, where IV BP is routinely used in patients with moderate-to-severe tonsillar infection. A dose of 2 MIU is within the approved therapeutic dosing range for adults and has a well-established safety profile. The rationale for a single initial IV administration is to ensure rapid and predictable antibiotic exposure during the early treatment phase, when the bacterial burden is expected to be greatest. IV administration provides 100% bioavailability and is expected to ensure sufficient T\>MIC, in contrast to PO PMP, which is characterized by substantial interindividual variability in bioavailability. Experimental pharmacokinetic data from our research group have demonstrated that IV BP provides more stable tissue exposure than PO PMP. The initial IV dose is therefore expected to function as a pharmacological loading dose that optimizes the early bactericidal effect until stable exposure is achieved through subsequent oral treatment. The subsequent standard treatment with PO PMP for 5 days has been selected in accordance with current clinical practice and national treatment principles for tonsillar infections. The overall dosing regimen is considered to have a favourable benefit-risk profile and is not expected to entail an increased risk compared with established standard treatment. 2. Study Design This is an investigator-initiated, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study will be conducted as a superiority trial comprising three clinically defined patient groups: * AT group (acute tonsillitis) * PP group (peritonsillar phlegmon) * PTA group (peritonsillar abscess treated by incision) Patients will be randomized within each group in a 1:1 ratio to either: * intervention treatment consisting of a single dose of IV BP as an adjunct to standard treatment with PO PMP; or * placebo as an adjunct to standard treatment with PO PMP. The three patient groups will be analysed separately. The randomized design has been selected to minimize selection bias and ensure comparability between treatment groups. A placebo control has been selected to enable a valid assessment of the additive effect of IV BP, as all participants will simultaneously receive established standard treatment with PO PMP. The use of placebo therefore does not entail withholding effective treatment. Double blinding has been selected to reduce the risk of: * observer bias * performance bias * reporting bias in patient-reported outcome measures A parallel-group design has been selected because the intervention is administered as a single initial treatment during the acute phase, making a crossover design inappropriate. The division into three clinically defined patient groups has been selected because the disease entities represent different stages of tonsillar infection and are expected to differ in symptom profile and potentially in treatment response. 3. Study Population The planned total sample size is 154 adult patients. Participants will be allocated to three cohorts: 54 patients with AT, 54 patients with PP, and 46 patients with PTA. Within each cohort, participants will be randomized in a 1:1 ratio to either intervention treatment with IV BP as an adjunct to standard treatment or placebo as an adjunct to standard treatment. This corresponds to: * AT: 27 participants in the intervention group and 27 participants in the placebo group * PP: 27 participants in the intervention group and 27 participants in the placebo group * PTA: 23 participants in the intervention group and 23 participants in the placebo group The sample size is based on separate power calculations for each cohort. For the AT cohort, the sample size is based on previously observed STAT-10 data. For the PTA cohort, the sample size is based on previously observed PTAAT-12 data. For the PP cohort, the same sample size as for AT is used, assuming a comparable symptom burden and expected treatment effect. An anticipated dropout rate of 15% has been incorporated into the sample size calculations for all cohorts. The expected participation duration for each participant is 12 months from inclusion to final follow-up. The study course comprises the following phases: * At inclusion, the participant undergoes screening, verification of inclusion and exclusion criteria, informed consent, baseline assessment, randomization, and administration of the investigational medicinal product. * Following inclusion, daily follow-up is conducted for 7 days, during which the participant records symptoms, analgesic consumption, and treatment compliance using PROMs. * Short-term follow-up is subsequently performed at 14 days, including assessment of the clinical course and any complications. Long-term follow-up is performed at: * 6 months * 12 months At long-term follow-up, TOI-14, any tonsillectomy, and recurrence of AT, PP, or PTA are recorded. The active intervention period is limited to a single IV administration at inclusion, whereas the overall clinical follow-up period has been selected to enable assessment of both early treatment effects and longer-term clinical consequences. Study completion for an individual participant is defined as completion of the 12-month follow-up or earlier permanent withdrawal from the study. The study population consists of adult patients with moderate-to-severe acute tonsillar infection who are referred to the Department of Otorhinolaryngology-Head and Neck Surgery, Aarhus University Hospital, for assessment and treatment. Participants will be included in three clinically defined cohorts: * AT cohort: patients with clinical AT * PP cohort: patients with clinical PP * PTA cohort: patients with clinical PTA treated by incision The study includes patients with active disease only. Healthy volunteers will not be included. The planned study population is considered representative of the patient population expected to benefit from the intervention in clinical practice, as the study includes the relevant adult hospital-referred population with moderate-to-severe tonsillar infection, in whom optimization of initial antibiotic exposure is expected to be of greatest clinical relevance. The study is open to participation regardless of biological sex. No sex-based selection will be performed, and the sex distribution is expected to reflect the natural distribution among adult patients referred with AT, PP, and PTA. No sex will be excluded or expected to be systematically underrepresented. The study includes adults aged 18 years or older. Patients younger than 18 years will be excluded. This age restriction has been selected for the following reasons: * The disease course and treatment practices may differ between children and adults. * The PROM instruments STAT-10, PTAAT-12, and TOI-14 have been developed and used in adult patients. * Study participation requires independent provision of informed consent. * Safety and efficacy assessments are intended to be conducted in a homogeneous adult population. The exclusion of patients younger than 18 years is therefore considered methodologically and ethically justified. The study does not include participants from particularly vulnerable populations, such as minors, pregnant individuals, cognitively impaired persons, or other participants requiring special protective measures. Patients who are not considered capable of providing valid informed consent will not be included. 4. Study Treatment 4.1. Investigational Medicinal Product The investigational medicinal product (IMP) is benzylpenicillin (BP), administered as a single IV dose of 2 MIU at inclusion as an adjunct to standard treatment with oral (PO) phenoxymethylpenicillin (PMP) 660 mg four times daily for 5 days. BP is a marketed beta-lactam antibiotic with an established safety profile and extensive clinical use. The dose and route of administration used in the study are approved and routinely used in clinical practice. The study does not involve experimental doses, unapproved routes of administration, or first-in-human exposure. IV administration provides 100% bioavailability and is intended to ensure rapid and predictable antibiotic exposure during the early phase of treatment. The single IV dose is intended to provide sufficient T\>MIC until stable exposure is achieved with subsequent PO PMP treatment. No dose adjustments or dose escalation are planned. In case of suspected allergic reaction or other clinically relevant adverse reaction, treatment will be discontinued and the participant managed according to applicable clinical guidelines. 4.2. Control Treatment The control treatment consists of a single IV dose of placebo administered at inclusion according to the same administration regimen as BP. All participants, irrespective of treatment allocation, will receive standard treatment with PO PMP 660 mg four times daily for 5 days. Thus, placebo does not involve withholding established effective treatment. No dose adjustments or dose escalation are planned for the control treatment. 4.3. Placebo The placebo consists of isotonic sodium chloride solution administered intravenously in a volume and using an administration procedure identical to the active treatment. Placebo is administered as a single dose at inclusion to maintain double blinding and enable valid comparison between treatment groups. 4.4. Preparation, Packaging, Labelling, and Blinding BP and placebo will be prepared, packaged, and labelled by the Hospital Pharmacy, Aarhus University Hospital, in accordance with applicable Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) requirements. Active treatment and placebo will be prepared in identical administration units to maintain blinding. Labelling will comply with applicable regulatory requirements and ensure appropriate identification, traceability, storage, administration, and emergency unblinding. Preparation and dispensing will follow standardized procedures to ensure correct treatment allocation and maintenance of blinding. Access to randomization codes will be restricted to authorized unblinded personnel. 5. Study Assessments and Procedures 5.1. Screening Procedure No study-specific pre-screening will be performed prior to informed consent. Potential participants will be identified during routine acute clinical assessment at the Department of Otorhinolaryngology-Head and Neck Surgery, Aarhus University Hospital. Patients who, based on the initial clinical assessment, are considered potentially eligible for study participation will receive oral and written information about the study. Up to 2 hours will be offered for consideration before providing consent (see also Section 15.2). Following provision of written informed consent, study-specific screening will be performed to assess eligibility for study participation. Screening will include review of the inclusion and exclusion criteria. Only participants who fulfil all inclusion criteria and none of the exclusion criteria will be randomized. Screening, consent, and randomization will be integrated into the acute clinical patient pathway without clinically relevant delay of standard treatment. 5.2. Randomization, Blinding, and Treatment Allocation Participants will be randomized in a 1:1 ratio using permuted block randomization with randomly varying block sizes of 4 and 6 to either intervention treatment with IV BP or placebo. Randomization will be performed separately within each of the three cohorts (AT, PP, and PTA) to ensure balanced allocation between treatment groups within each clinical population. Randomization will be performed electronically using REDCap based on a predefined randomization list. At randomization, each participant will be assigned a unique randomization number corresponding to a specific treatment unit prepared and labelled by the Hospital Pharmacy, Aarhus University Hospital. The study will be double-blinded. Participants, treating clinicians, investigators, and other blinded study personnel will not have access to treatment allocation information. Active treatment and placebo will be prepared, labelled, and administered identically to maintain blinding. Access to the randomization list will be restricted to authorized unblinded personnel who require knowledge of treatment allocation. Unblinding may only be performed when clinically necessary and when knowledge of treatment allocation is considered essential for participant safety. It is important to emphasize that the investigator may contact authorized unblinded personnel with access to the randomization codes at any time to obtain immediate emergency unblinding if this is considered necessary for participant safety or treatment. Unblinded personnel will always be available for this purpose. Any unblinding will be documented, including the time, reason, and personnel involved. Double blinding is not considered to constitute a significant safety risk because all participants receive established standard treatment with PO PMP irrespective of treatment allocation. The risk associated with lack of knowledge of treatment allocation is further reduced because the intervention consists of a single dose of a well-established antibiotic with a well-documented safety profile, and because rapid emergency unblinding is available when clinically required. The randomization and blinding procedures have been selected to minimize selection bias, performance bias, and observer bias and thereby ensure valid assessment of the clinical effect of the intervention. 5.3. Study Procedures and Assessments Study procedures are integrated into the acute clinical patient pathway in order to minimize participant burden and avoid unnecessary additional visits. All study-related procedures will be performed either in connection with the initial clinical assessment or through electronic/remote follow-up. The active intervention period is limited to a single IV administration at inclusion. Follow-up will consist of daily electronic symptom recording during the first 7 days and follow-up at 14 days, 6 months, and 12 months. Study assessments will include clinical classification, administration of study medication, microbiological sampling, blood sampling, and PROM-based assessment of symptoms and long-term outcomes. Blood sampling will be limited to what is necessary, and the total blood volume is not expected to exceed 3 mL per participant. The procedures have been designed to minimize participant burden through: * integration into the existing clinical workflow * limitation of in-person visits * electronic data collection * use of routine clinical procedures 6. Statistical Analysis Data will be analysed separately for the AT, PP, and PTA cohorts. Descriptive data will be presented using appropriate measures of central tendency and dispersion, depending on the type and distribution of the data. Comparisons between the intervention and control groups will be performed using appropriate statistical methods according to the characteristics and distribution of the individual endpoints. Continuous variables will be analysed using appropriate parametric or non-parametric methods. Categorical variables will be analysed using relevant comparative statistical tests. Time to symptom resolution will be analysed using appropriate time-to-event methods. Analyses will primarily be conducted according to the intention-to-treat principle. Additional analyses may be performed as appropriate. Missing data will be handled according to established statistical principles and described in greater detail in the Statistical Analysis Plan. All statistical analyses will be two-sided, with a significance level of 5%. A detailed Statistical Analysis Plan will be finalized before database lock. No interim analysis is planned. The analyses will be based on the following analysis populations: Intention-to-treat population The intention-to-treat (ITT) population will comprise all randomized participants. Participants will be analysed according to the group to which they were originally randomized, irrespective of protocol deviations or premature discontinuation of study participation. The ITT population will constitute the primary analysis population. Per-protocol-population The per-protocol population will comprise participants who complete the study without major protocol deviations. The per-protocol population may be used for supplementary analyses. Safety-population The safety population will comprise all participants who receive administration of the IMP or placebo. This population will be used for safety analyses. The classification of major protocol deviations will be determined before database lock and specified in greater detail in the Statistical Analysis Plan. AT-group: Based on a previous study of patients with AT, the mean STAT-10 score at inclusion is estimated to be 36.3 (SD 7.7) \[19\]. With a power of 80% and p = 0.05, the estimated mean STAT-10 score on Day 2 is: * Treatment group: 29 (SD 7) * Placebo group: 34 (SD 7) A total of n = 46 participants (23 in each treatment group) is required. Assuming a dropout rate of 15%, a total of 54 patients will be enrolled. PP-group No studies have assessed STAT, pain VAS, or duration of symptoms in patients with PP. Assuming that symptom burden is at least as high in PP as in AT and that the effect of BP is at least as large in PP as in AT, 54 patients with PP will likewise be included. PTA-group Based on a previous study of patients with PTA, the mean PTAAT score at inclusion is estimated to be 49.0 (SD 7.5) \[20\]. With a power of 80% and p = 0.05, the estimated mean PTAAT score on Day 2 is: * Treatment group: 34 (SD 6.5) * Placebo group: 40 (SD 6.5) A total of n = 40 participants (20 in each treatment group) is required. Assuming a dropout rate of 15%, a total of 46 patients will be enrolled. 7. Ethical Considerations The Sponsor will ensure that the study is conducted in accordance with the ethical principles set out in the Declaration of Helsinki and in compliance with applicable legislation and Good Clinical Practice (GCP). Recruitment will take place among adult patients (≥18 years) who present to or are referred to the Department of Otorhinolaryngology-Head and Neck Surgery, Aarhus University Hospital, with clinically suspected moderate-to-severe tonsillar infection. Potentially eligible participants will be identified as part of the routine clinical assessment. Inclusion and informed consent procedures will be conducted by physicians at the department who are trained in the study protocol, GCP-related procedures, and informed consent. Potential participants will receive oral and written information about the study, be given the opportunity to ask questions, and be offered up to 2 hours to consider participation. Standard treatment may be deferred during this period if considered clinically safe. If the treating physician considers that treatment must be initiated without further delay, treatment will be commenced immediately, and the patient will not be enrolled in the study. Written informed consent will be obtained before any study-related procedures are performed. Only individuals with full decision-making capacity who can understand the study information and provide valid informed consent will be included. Minors and individuals lacking capacity to provide informed consent will be excluded. The study will not be conducted as research in an emergency, and deferred consent will not be used. Participation is voluntary and may be withdrawn at any time without consequences for the future physician-patient relationship. Further information concerning participant information, consent documents, and informed consent procedures is provided in Part II. Recruitment will take place at the Department of Otorhinolaryngology-Head and Neck Surgery, Aarhus University Hospital. 8. Study Completion and Discontinuation The study will be completed when the last participant has completed the 12-month follow-up, and all study-related data have been collected and documented. For an individual participant, study completion is defined as completion of the 12-month follow-up or earlier permanent withdrawal from the study. The study may be temporarily suspended or terminated prematurely if: * unexpected safety concerns arise * substantial risks to participants are identified * significant protocol-related or practical problems arise that compromise the conduct of the study * the Sponsor or regulatory authorities determine that the study should be suspended or terminated In the event of early study termination, relevant authorities and participants will be informed in accordance with applicable legislation and Good Clinical Practice (GCP). Participant safety will have the highest priority at all times.

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