Evaluation of Lyophilized Bacterial Lysates for Reducing Respiratory Infections and Wheezing in Moderate-Late Preterm Infants

The primary objective of this study is to evaluate the efficacy of **bacterial lysates** in reducing **lower respiratory tract infections** and wheezing in moderate-late preterm infants during their first years of life. This is clinically relevant as these infants are at an increased risk for respiratory diseases, and early intervention could lead to significant health improvements by enhancing immune maturation and antimicrobial immunity.

Secondary objectives include:

• Comparing the efficacy of 1-year versus 2-year bacterial lysate therapy in preventing lower respiratory episodes in moderate-late preterm infants.
• Analyzing the impact of bacterial lysates on mucosal and systemic immune maturation, as well as microbiome diversity and maturation.
• Identifying biomarkers that predict the development of early respiratory episodes and response to bacterial lysate administration, facilitating personalized treatment.
• Calculating the cost-effectiveness of various bacterial lysate treatment regimens.

The clinical trial focuses on **lower respiratory tract infections** and wheezing in moderate-late premature infants. The study population includes both male and female infants, with a gestational age at delivery between 30+0 and 35+6 weeks. Participants are required to have a postnatal age of at least 6 weeks at randomization and a postmenstrual age of at least 37 weeks. The trial involves a vulnerable population, as it targets preterm-born infants who are at an enhanced risk for respiratory diseases. The sponsor has not provided information regarding the total number of participants. Written informed consent is required from both parents or formal caregivers. The trial aims to assess the impact of bacterial lysate administration on reducing respiratory tract infections and wheezing episodes in the first years of life. The sponsor did not provide information on lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **lyophilized bacterial lysates** in reducing lower respiratory tract infections and wheezing in moderate-late preterm infants. This is a phase III, randomized, double-blind, controlled study. The trial will span approximately six years, with an estimated recruitment start date of July 1, 2021, and an estimated end date of December 1, 2027. Participants will be randomly assigned to receive either the active treatment or a placebo, with both the participants and investigators blinded to the group assignments to ensure unbiased results.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as gestational age at delivery between 30+0 and 35+6 weeks, and postnatal age of at least six weeks at randomization. Following the screening, participants will undergo regular follow-up visits to monitor health outcomes, including the total number of physician-diagnosed lower respiratory tract infections and wheezing episodes in the first year of life. The primary endpoint is the total number of these episodes, while secondary endpoints include the time to the first episode, distribution of viruses, medication use, lung function, quality of life, and cost-effectiveness.

The expected length of participant involvement is up to 24 months, with conditions for early termination including withdrawal of consent or any adverse events that compromise participant safety. The end-of-study visit will assess the long-term effects of the treatment, including serum specific IgE levels and vaccination titers at 12 months. The trial aims to provide significant health benefits by enhancing immune maturation and reducing respiratory symptoms in this vulnerable population.

The clinical trial involves the administration of **BRONCHO-VAXOM Kinderen**, a hard capsule formulation containing **lyophilized bacterial lysates** of several bacterial species, including **Haemophilus influenzae**, **Streptococcus (Diplococcus) pneumoniae**, **Klebsiella pneumoniae and ozaenae**, **Staphylococcus aureus**, **Streptococcus pyogenes and viridans**, and **Moraxella (Branhamella / Neisseria) catarrhalis**. The pharmaceutical form is a hard capsule, and the medication is administered orally. The maximum daily dose is 3.5 mg, with a treatment period extending up to 24 months. The product is re-packaged and re-labelled to ensure blinding of study subjects and investigators. The medication is not a pediatric formulation and is classified under the ATC code R07AX, indicating it as an "Other Respiratory System Products".

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental medication, BRONCHO-VAXOM Kinderen. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to evaluate the efficacy of the bacterial lysate in reducing respiratory tract infections and wheezing in moderate-late preterm infants during their first year of life.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the total number of physician-diagnosed lower **respiratory tract infections** (RTI) and wheezing episodes in the first year of life, as well as the time to the first lower respiratory episode after 12 months of age. Secondary endpoints will evaluate additional parameters such as the time to the first lower RTI or wheezing episode in the first year of life, the total number of RTI and wheezing episodes in the first and second years of life, and the distribution of viruses during lower RTI/wheezing episodes. Other secondary measures include medication use (bronchodilators, corticosteroids, antibiotics), lung function as measured by the expiratory variability index, quality of life, and serum specific IgE levels at 12 months to assess allergen sensitization. Infant vaccination titers at 12 months and cost-effectiveness will also be evaluated.