Protecting Preterm Infants From Respiratory Tract Infections and Wheeze by Using Bacterial Lysates.

Study Overview
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Brief Summary
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The primary objective of this study is to reduce respiratory tract infections and wheezing in moderate-late preterms in the first year of life by bacterial lysate administration. Next to determine the correlation of biological markers with respiratory symptoms, immune protection and treatment effect.

Detailed Description
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This is a randomised placebo-controlled trial including 500 otherwise healthy moderate-late preterm infants. Participants will receive bacterial lysate (Broncho-Vaxom, 3,5mg) or placebo powder for ten days each month, from 6 weeks after birth until 12 moths of age. Clinical data will be continuously collected by e-Health and 3 (possibly digital) study visits; with optional biological sampling and lung function at baseline, 6 and 12 months. Main study parameters are doctor diagnosed lower RTI and wheezing episodes in the first year of life. Biological sampling will allow investigation of immune maturation, as well as microbiome development in the respiratory tract and gut. Also, biomarkers for risk-group selection and/or treatment success will be examined.

Official Title
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Protecting Late-moderate Preterm Infants From Respiratory Tract Infections and Wheeze in Their First Year of Life by Using Bacterial Lysates.

Conditions
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LRTI, Wheezing, Premature

Intervention / Treatment
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* Drug: Broncho-Vaxom
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age at delivery between 30+0 and 35+6 weeks Postnatal age at least 6 weeks at randomization & postmenstrual age at least 37 weeks Written informed consent by both parents or formal caregivers Exclusion Criteria: Underlying other severe respiratory disease such as broncho-pulmonary dysplasia (unexpected in this group); hemodynamic significant cardiac disease; immunodefi-ciency; severe failure to thrive; birth asphyxia with predicted poor neurological out-come; syndrome or serious congenital disorder. Lower RTI before randomization Dysmaturity and/or weight < 2.5 kg at age of randomization. Maternal TNF-alpha inhibitors or other immunosuppression during pregnancy and/or breastfeeding Parents unable to speak and read Dutch/English language Known allergic hypersensitivity to the active ingredients/substance or to any of the excipients.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 10 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Half of the participants (250) will receive treatment (Broncho-Vaxom) and the other half will receive placebo. Randomization will be stratified for gestational age (moderate (30+0-32+6) vs. late (33+0-35+6) prematurity).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Broncho-Vaxom treatment<br>Infants in this arm will be given 3,5mg bacterial lysate (OM-85) 10 days per month from 6 weeks after birth until 12 months of age. | Drug: Broncho-Vaxom<br>* Broncho-Vaxom is a bacterial extract comprising lyophilised fractions of 21 different inactivated bacterial strains, which are frequently causing RTI.<br>* Other names: Broncho-Vaxom concentrate (Bacterial lysate);|
| Placebo Comparator: Placebo<br>Infants in this arm will be given a placebo powder from a capsule that will be indistinguishable from the active study drug. | Other: Placebo<br>* Placebo powder from a capsule will be given, which will be indistinguishable from the active study drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of physician diagnosed lower RTI and wheezing episodes in the first year of life | Recorded by frequent questionnaires | In the first year of life. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first lower RTI or wheezing episode | Recorded by short weekly questionnaires (which will be filled in during the first year of life) and more extensive questionnaires every six months in the first and second year of life. | In the first and second year of life. | 
| Total number of RTI | Recorded by short weekly questionnaires (which will be filled in during the first year of life) and more extensive questionnaires every six months in the first and second year of life. | In the first and second year of life. | 
| Total number of wheezing episodes | Recorded by short weekly questionnaires (which will be filled in during the first year of life) and more extensive questionnaires every six months in the first and second year of life. | In the first and second year of life. | 
| Distribution of viruses | Viruses present in the nasofarynx during complaints of lower respiratory tract infection or wheezing. Nasofaryngeal swabs will be taken in case of complaints during the first year of life. In the second year of life this will not be done. | In the first year of life. | 
| Medication use (bronchodilators, corticosteroids, antibiotics) | Recorded by short weekly questionnaires (which will be filled in during the first year of life) and more extensive questionnaires every six months in the first and second year of life. | In the first and second year of life. | 
| Lung function as measured by expiratory variability index (Ventica) | Measured at age 6-10 weeks (baseline), 6 months and 12 months in a subset of participants. | In the first year of life. | 
| Quality of life questionnaires | Recorded by extensive questionnaires every six months in the first and second year of life. | In the first and second year of life. | 
| (serious) adverse events | Will be reported by parents immediately. Respiratory episodes are not regarded as an (S)AE since these episodes comprise primary and secondary outcomes. (S)AE's are only expected in the first year of life because the treatment stops at the age of 12 months. | In the first year of life. | 
| Serum specific IgE (allergen sensitization) at 12 months | Total IgE and house dust mite specific IgE | At age 12 months | 
| Infant vaccination titers at 12 months | Vaccination titers of haemohilus influenza type B, pneumococci, tetanus | At age 12 months | 
| Costs- and cost-effectiveness | Estimated from information from standardized questionnaires | In the first and second year of life. |