Antibiotics, Microbiology and Immunology in Children with Chronic wet Cough - the AMIC study

The primary objective of the AMIC study is to evaluate the **clinical efficacy** of antibiotics, specifically amoxicillin-clavulanate, in children with **chronic wet cough** (CWC). This involves assessing whether the response to a 14-day treatment with amoxicillin-clavulanate is superior to placebo in resolving symptoms and determining if the time to relapse differs between those receiving 14 days versus 28 days of therapy. The clinical relevance of this objective lies in optimizing treatment duration to improve patient outcomes and reduce unnecessary antibiotic exposure.

Secondary objectives include:

• Determining if the response to treatment and the proportion of relapse differ between 14-day and 28-day therapy durations.
• Identifying clinical characteristics associated with treatment response and time to relapse.
• Describing the time to and number of relapses, and results from diagnostic investigations at 12 and 24 months post-treatment.
• Evaluating differences in quality of life between children with CWC and healthy controls, and before and after antibiotic treatment.
• Comparing time to treatment response and trajectories of VCD scores between those receiving amoxicillin-clavulanate and placebo.
• Detecting respiratory pathogens and differences in microbiome composition in children with CWC compared to healthy controls, and across different treatment durations and time points.
• Comparing inflammatory markers and patterns in laryngeal aspirate and peripheral blood, and assessing the prevalence of primary immunodeficiencies using Next-generation sequencing.

The clinical trial focuses on evaluating the efficacy of antibiotics in children diagnosed with **chronic wet cough**. The study population comprises both male and female participants aged between 9 and 36 months, with a body weight ranging from 7 kg to 24 kg. All participants were born at term with a gestational age of over 37 weeks. The trial does not involve a vulnerable population. Participants were selected based on the presence of a chronic wet cough persisting for more than four weeks, with an average cough score of at least four points in the week prior to inclusion, and without signs of another cause. Written informed consent was obtained from both parents. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **clinical efficacy** of antibiotics in children with **chronic wet cough** (CWC). This study employs a **randomized, double-blind, controlled** trial design to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either a 14-day treatment with **amoxicillin-clavulanate** or a placebo. The trial is expected to run from May 2023 to April 2028, with participant involvement lasting up to 28 days, depending on the treatment group.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed. Key inclusion criteria include age between 9 and 36 months, body weight between 7 kg and 24 kg, and a history of chronic wet cough for more than four weeks. Written informed consent from both parents is required. Following the screening, participants will undergo baseline assessments, including cough scoring and microbiome sampling. The primary endpoint is the response to treatment, defined as a reduction in the cough score to ≤2 or cessation of coughing for at least three days during the treatment period.

Follow-up visits will occur at the end of the treatment period and at specified intervals to monitor for relapse, defined as a new period of wet cough lasting more than four weeks or requiring antibiotic treatment. Secondary endpoints include the detection of respiratory pathogens, analysis of airway and gut microbiome diversity, and assessment of inflammatory markers. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes and any adverse events.

Participants may be withdrawn from the study if they experience significant adverse reactions, fail to comply with study procedures, or if the investigator deems it necessary for the participant's safety. The trial aims to provide valuable insights into the treatment of CWC and its impact on the microbiome and immune response in young children.

The clinical trial involves the administration of **Augmentin**, a combination antibiotic consisting of **amoxicillin** and **clavulanic acid**. The pharmaceutical form of Augmentin used in this study is an **oral suspension** with a concentration of 400 mg of amoxicillin and 57 mg of clavulanic acid per 5 ml. The medication is administered orally. The maximum daily dose is 45 mg per kilogram of body weight, with a total maximum dose of 15 mg per kilogram. The treatment duration varies between 14 to 28 days, depending on the study arm. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group, which receives a placebo granulate. The placebo is designed to match the experimental medication in appearance and administration route to maintain blinding. The placebo is administered orally, following the same dosing schedule as the active treatment group. This allows for a direct comparison of the efficacy of Augmentin against a non-active treatment, ensuring the validity of the study results.

The efficacy of the clinical trial titled "Antibiotics, Microbiology and Immunology in Children with Chronic Wet Cough - the AMIC study" will be assessed using both primary and secondary endpoints. The primary endpoints include the **response to treatment** with amoxicillin-clavulanate, defined as a baseline cough score of ≤2 in the validated Verbal Category Descriptive (VCD) cough score at the end of treatment or cessation of coughing (VCD = 0) for a minimum period of 3 days within the treatment period. The VCD score, ranging from 0 to 10 points, will be reported by parents. Additionally, the time to relapse will be measured, defined as the time from the end of treatment to the start of relapse, characterized by a new period of wet cough lasting more than four weeks or an episode of at least two weeks treated with antibiotics.

Secondary endpoints will include the detection of respiratory pathogens using PCR and culture methods, analysis of airway and gut microbiome diversity, and assessment of inflammatory markers in laryngeal aspirate and peripheral blood. Functional markers of primary immunodeficiencies, such as immunoglobulins and lymphocyte populations, will also be evaluated. The proportion of children diagnosed with primary immunodeficiencies based on a Next-generation sequencing panel will be determined. Additionally, the day-by-day response to treatment, quality of life scores, and other relevant clinical parameters will be monitored. These assessments will provide comprehensive insights into the efficacy of the treatment regimen in children with chronic wet cough.