Wheezing, LRTI, Premature
Conditions
Brief summary
The primary objective of this study is to reduce respiratory tract infections and wheezing in moderate-late preterms in the first years of life by bacterial lysate administration. Next to determine the correlation of biological markers with respiratory symptoms, immune protection and treatment effect.
Detailed description
This is a randomised placebo-controlled trial including 500 otherwise healthy moderate-late preterm infants. Participants will receive bacterial lysate (OM-85/Broncho-Vaxom, 3,5mg) or placebo powder for ten days each month, from 6-10 weeks after birth until 12 months after birth. At 12 months, parents of participants are asked to join in Protea-2. If they do, participants in the treatment arm of year 1 are randomised again over placebo and OM-85 and treated until the age of 24 months. 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. And in case of participation in Protea-2 also at 24 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.
Interventions
DRUGBroncho-Vaxom
Broncho-Vaxom is a bacterial extract comprising lyophilised fractions of 21 different inactivated bacterial strains, which are frequently causing RTI.
OTHERPlacebo
Placebo powder from a capsule will be given, which will be indistinguishable from the active study drug.
Sponsors
Leiden University Medical Center
Maastricht University Medical Center
Franciscus Gasthuis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study subjects, all study investigators including the principal investigator and treating physicians will be blinded for the allocation during the complete study period. A sealed envelope with the treatment allocation per code is present at the pharmacy to be used only when 1) crucial for a medical emergency, 2) the participant will continue with Protea-2 and the database concerning year 1 is locked for this specific participant, and 3) at trial completion after the last patient last visit.
Intervention 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). In the follow-up study Protea-2, infants from the treatment arm in year 1 will be randomised to receive Broncho-Vaxom or placebo in year 2. Randomisation will stratified for gestational age again, but also for the amount of lower respiratory episodes in year 1 (\<2 vs. \>/=2) Infants from the control arm in year 1 will not receive treatment in year 2.
Eligibility
Sex/Gender
ALL
Age
6 Weeks to 10 Weeks
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total number of physician diagnosed lower RTI and wheezing episodes in the first year of life | In the first year of life. | Recorded by frequent questionnaires |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total number of RTI | In the first and second year of life. | 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. |
| Total number of wheezing episodes | In the first and second year of life. | 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. |
| Distribution of viruses | In the first year of life. | 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. |
| Medication use (bronchodilators, corticosteroids, antibiotics) | In the first and second year of life. | 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. |
| Lung function as measured by expiratory variability index (Ventica) | In the first year of life. | Measured at age 6-10 weeks (baseline), 6 months and 12 months in a subset of participants. |
| Quality of life questionnaires | In the first and second year of life. | Recorded by extensive questionnaires every six months in the first and second year of life. |
| (serious) adverse events | In the first year of life. | 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. |
| Serum specific IgE (allergen sensitization) at 12 months | At age 12 months | Total IgE and house dust mite specific IgE |
| Infant vaccination titers at 12 months | At age 12 months | Vaccination titers of haemohilus influenza type B, pneumococci, tetanus |
| Costs- and cost-effectiveness | In the first and second year of life. | Estimated from information from standardized questionnaires |
| Time to first lower RTI or wheezing episode | In the first and second year of life. | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immune maturation: immune cells in nasal epithelium | In the first year of life | Collected by nasal scraping at age 6-10 weeks, 6 months and 12 months. Analysed using masscytometry. |
| Immune maturation: chemokines and cytokines in nasal lining fluid | In the first year of life | Collected by nasosorption at age 6-10 weeks, 6 months and 12 months. Analysed using Luminex cyto/chemokine assay. |
| Immune maturation: immune cells in bloodsamples | In the first year of life | Collected by blooddraws at age 6-10 weeks, 6 months and 12 months. Analysed using masscytometry. |
| Serum IgE (total and specific to house dust mite) | At age 12 months | Measured in blood samples which will be drawn at age 12 months |
| Immune maturation: Single cell transcriptomics | At age 12 months | Performed on blood drawn at age 12 months |
| Whole blood stimulation essays | At age 12 months | Performed on blood drawn at age 12 months |
| Biomarkers predictive of high morbidity and/or treatment success | In the first year of life. | From combined microbial and immunological data |
| Secretory IgA in saliva | In the first year of life | Saliva will be collected at age 6-10 weeks, 6 months and 12 months. |
| Gut and respiratory microbiome composition | In the first year of life. | Measured from faeces and nasofaryngeal swabs taken at age 6-10 weeks, 6 months and 12 months. |
Countries
Netherlands
Contacts
Primary ContactInger van Duuren
Outcome results
None listed