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

Primary Purpose

Wheezing, LRTI, Premature

Status
Recruiting
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Broncho-Vaxom
Placebo
Sponsored by
Franciscus Gasthuis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Wheezing

Eligibility Criteria

6 Weeks - 10 Weeks (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Franciscus Gasthuis & VlietlandRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Broncho-Vaxom treatment

Placebo

Arm Description

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.

Infants in this arm will be given a placebo powder from a capsule that will be indistinguishable from the active study drug.

Outcomes

Primary Outcome Measures

Total number of physician diagnosed lower RTI and wheezing episodes in the first year of life
Recorded by frequent questionnaires

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
Quality of life questionnaires
Recorded by extensive questionnaires every six months 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.
Serum specific IgE (allergen sensitization) at 12 months
Total IgE and house dust mite specific IgE
Infant vaccination titers at 12 months
Vaccination titers of haemohilus influenza type B, pneumococci, tetanus
Costs- and cost-effectiveness
Estimated from information from standardized questionnaires

Full Information

First Posted
August 24, 2021
Last Updated
February 19, 2022
Sponsor
Franciscus Gasthuis
Collaborators
Leiden University Medical Center, Maastricht University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT05063149
Brief Title
Protecting Preterm Infants From Respiratory Tract Infections and Wheeze by Using Bacterial Lysates.
Acronym
PROTEA
Official Title
Protecting Late-moderate Preterm Infants From Respiratory Tract Infections and Wheeze in Their First Year of Life by Using Bacterial Lysates.
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 18, 2022 (Actual)
Primary Completion Date
April 2025 (Anticipated)
Study Completion Date
April 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Franciscus Gasthuis
Collaborators
Leiden University Medical Center, Maastricht University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Wheezing, LRTI, Premature

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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. The trial pharmacy has a deblinding key, which only will be requested in case of safety issues. After every participant has completed the study time and visits necessary for the primary endpoint, and after the database has been completed and locked with respect for the primary endpoint, the deblinding key will be released.
Allocation
Randomized
Enrollment
500 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Broncho-Vaxom treatment
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Infants in this arm will be given a placebo powder from a capsule that will be indistinguishable from the active study drug.
Intervention Type
Drug
Intervention Name(s)
Broncho-Vaxom
Other Intervention Name(s)
OM-85, Broncho-Vaxom concentrate (Bacterial lysate)
Intervention Description
Broncho-Vaxom is a bacterial extract comprising lyophilised fractions of 21 different inactivated bacterial strains, which are frequently causing RTI.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo powder from a capsule will be given, which will be indistinguishable from the active study drug.
Primary Outcome Measure Information:
Title
Total number of physician diagnosed lower RTI and wheezing episodes in the first year of life
Description
Recorded by frequent questionnaires
Time Frame
In the first year of life.
Secondary Outcome Measure Information:
Title
Time to first lower RTI or wheezing episode
Description
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.
Time Frame
In the first and second year of life.
Title
Total number of RTI
Description
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.
Time Frame
In the first and second year of life.
Title
Total number of wheezing episodes
Description
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.
Time Frame
In the first and second year of life.
Title
Distribution of viruses
Description
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.
Time Frame
In the first year of life.
Title
Medication use (bronchodilators, corticosteroids, antibiotics)
Description
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.
Time Frame
In the first and second year of life.
Title
Lung function as measured by expiratory variability index (Ventica)
Description
Measured at age 6-10 weeks (baseline), 6 months and 12 months in a subset of participants.
Time Frame
In the first year of life.
Title
Quality of life questionnaires
Description
Recorded by extensive questionnaires every six months in the first and second year of life.
Time Frame
In the first and second year of life.
Title
(serious) adverse events
Description
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.
Time Frame
In the first year of life.
Title
Serum specific IgE (allergen sensitization) at 12 months
Description
Total IgE and house dust mite specific IgE
Time Frame
At age 12 months
Title
Infant vaccination titers at 12 months
Description
Vaccination titers of haemohilus influenza type B, pneumococci, tetanus
Time Frame
At age 12 months
Title
Costs- and cost-effectiveness
Description
Estimated from information from standardized questionnaires
Time Frame
In the first and second year of life.
Other Pre-specified Outcome Measures:
Title
Gut and respiratory microbiome composition
Description
Measured from faeces and nasofaryngeal swabs taken at age 6-10 weeks, 6 months and 12 months.
Time Frame
In the first year of life.
Title
Secretory IgA in saliva
Description
Saliva will be collected at age 6-10 weeks, 6 months and 12 months.
Time Frame
In the first year of life
Title
Immune maturation: immune cells in nasal epithelium
Description
Collected by nasal scraping at age 6-10 weeks, 6 months and 12 months. Analysed using masscytometry.
Time Frame
In the first year of life
Title
Immune maturation: chemokines and cytokines in nasal lining fluid
Description
Collected by nasosorption at age 6-10 weeks, 6 months and 12 months. Analysed using Luminex cyto/chemokine assay.
Time Frame
In the first year of life
Title
Immune maturation: immune cells in bloodsamples
Description
Collected by blooddraws at age 6-10 weeks, 6 months and 12 months. Analysed using masscytometry.
Time Frame
In the first year of life
Title
Serum IgE (total and specific to house dust mite)
Description
Measured in blood samples which will be drawn at age 12 months
Time Frame
At age 12 months
Title
Immune maturation: Single cell transcriptomics
Description
Performed on blood drawn at age 12 months
Time Frame
At age 12 months
Title
Whole blood stimulation essays
Description
Performed on blood drawn at age 12 months
Time Frame
At age 12 months
Title
Biomarkers predictive of high morbidity and/or treatment success
Description
From combined microbial and immunological data
Time Frame
In the first year of life.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Weeks
Maximum Age & Unit of Time
10 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Inger van Duuren
Phone
0031 10 893 61 69
Email
proteastudie@franciscus.nl
Facility Information:
Facility Name
Franciscus Gasthuis & Vlietland
City
Rotterdam
State/Province
Zuid-Holland
ZIP/Postal Code
3045PM
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inger van Duuren
Phone
+31108936169
Email
proteastudie@franciscus.nl

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Researchdata will be shared in data repositories according to the FAIR principle. Clinical data about respiratory health will be shared in the DANS repository. Inlcuding metadata which will ensure reusability. Sequencing data will be shared online in the ENA repository which will provide an unique global identifier. All used bioinformatics pipelines for data analysis will be made accessible on a GitHub account. Immunological data will be shared in NCBI Gene Expression omnibus and ImmPort. Used analysis pipelines for the transcriptomics data will also be tracked and can be shared using a Github account. All data shared will be pneudonymized.
IPD Sharing Time Frame
Data will come available after publication of the data in articles by initating researchers.
IPD Sharing Access Criteria
Data will be available under restricted access. A request for data sharing will include at least the reason for request (for what will the receiver use the data?) and agreements about authorship.
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Protecting Preterm Infants From Respiratory Tract Infections and Wheeze by Using Bacterial Lysates.

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