Evaluation of Amoxicillin Trihydrate Versus Placebo in Preschool Children with Lower Respiratory Tract Infection: A Randomized Controlled Trial

The primary objective of the Norwegian Antibiotics for Pneumonia in Children (NAPIC) Study is to determine the effect of **amoxicillin** versus placebo in preschool children with pneumonia. This objective is clinically relevant as it aims to evaluate the efficacy of amoxicillin, a commonly used antibiotic, in treating lower respiratory tract infections in a vulnerable pediatric population. Understanding the effectiveness of amoxicillin in this context is crucial for optimizing treatment protocols and improving patient outcomes.

Secondary objectives include:

• Assessing the influence of amoxicillin on bacterial flora in the airways, which is important for understanding potential impacts on microbial resistance and overall respiratory health.
• Conducting subgroup analyses based on findings from chest x-rays, the presence of specific bacteria or viruses, and the rates of inflammatory markers. These analyses will provide insights into the differential effects of treatment across various clinical presentations and pathogen profiles.

The clinical trial focuses on evaluating the effect of amoxicillin versus placebo in preschool children diagnosed with **pneumonia**, specifically targeting those with **lower respiratory tract infection**. The study population comprises both male and female participants aged between 12 to 59 months. Participants are required to have a fever with a temperature of at least 38.0°C at inclusion or reported within the last 24 hours, and exhibit tachypnea specific to their age. Additionally, they must present at least one sign of lower airway inflammation, such as cough, chest retractions, grunting respiration, nasal flaring, crepitations by pulmonary auscultation, or hypoxia with SpO2 ≤90%. The weight range for eligible participants is between 6.0 and 28.0 kg. The trial includes a vulnerable population, but the total number of participants is not provided by the sponsor. The selection process for the trial population is not detailed in the available data.

The clinical trial is designed to evaluate the efficacy of **amoxicillin** compared to a placebo in preschool children diagnosed with pneumonia, specifically targeting lower respiratory tract infections. This study employs a **randomized**, **double-blind**, and **controlled** trial design to ensure the reliability and validity of the results. The trial is expected to span from the estimated recruitment start date of January 1, 2018, to the estimated end date of May 31, 2026, allowing for comprehensive data collection and analysis.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (12-59 months), fever, tachypnea, signs of lower airway inflammation, and weight (6.0 to 28.0 kg). Following successful screening, participants will be randomly assigned to receive either the active treatment, **amoxicillin trihydrate** in the form of an oral suspension, or a placebo. The maximum treatment period is set at 7 days, with a daily dose not exceeding 18 ml and a total dose not exceeding 126 ml.

Subsequent follow-up visits will be scheduled to monitor the participants' response to the treatment, assess the duration of fever and symptoms, and evaluate the presence of bacterial resistance. The primary endpoint is defined as therapy failure within 21 days after treatment initiation. Secondary endpoints include therapy failure necessitating intravenous antibiotic therapy, duration of fever and symptoms, bacterial presence in airways, and detection of resistant bacteria and resistance genes.

The expected length of participant involvement is approximately 21 days, with conditions for early termination including adverse reactions, withdrawal of consent, or any medical condition that contraindicates continued participation. The study concludes with an end-of-study visit to gather final data and ensure participant safety. This trial aims to provide valuable insights into the treatment of pneumonia in children, contributing to evidence-based medical practices.

The clinical trial involves the administration of **amoxicillin trihydrate** as the experimental medication. The product, marketed under the name INFECTOMOX® 500 Saft, is formulated as a powder for the preparation of an **oral suspension**. Each 5 ml of the prepared suspension contains 500 mg of amoxicillin trihydrate. The medication is administered orally, with a maximum daily dose of 18 ml, equivalent to 1800 mg of amoxicillin trihydrate. The total maximum dose over the treatment period is 126 ml, which corresponds to 12,600 mg of the active substance. The treatment duration is limited to a maximum of 7 days. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group to serve as a comparator. The placebo is composed of non-active ingredients, including Amylum solani, sugar, titanium dioxide, silica colloidal anhydrous, sodium citrate, citric acid, magnesium stearate, strawberry aroma, raspberry aroma, xanthan gum, and Gentiana lutea. The placebo is designed to mimic the appearance and administration route of the experimental medication, ensuring blinding of participants and investigators. The placebo does not contain any pharmacologically active substances and is used to assess the efficacy of the experimental treatment by comparison.

The efficacy of the clinical trial titled "The Norwegian Antibiotics for Pneumonia in Children (NAPIC) Study" will be assessed by evaluating both primary and secondary endpoints. The primary endpoint is defined as **therapy failure** determined by 21 days after the start of treatment. Secondary endpoints include therapy failure leading to intravenous antibiotic therapy, duration of fever, duration of symptoms as assessed by the parent or guardian, bacterial presence in the airways, presence of resistant bacteria, and resistance genes in bacteria.