Oral Bacterial Extract for the Prevention of Wheezing Lower Respiratory Tract Illness

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate if Broncho-Vaxom® given to high risk infants for 10 days, monthly, for two consecutive years can increase time to occurrence of the first episode of wheezing lower respiratory tract illness (WLRI) during a three year observation period off therapy.

Detailed Description
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This is a five year parallel arm, double-blind, placebo-controlled trial for the prevention of WLRI into the third to seventh year of life (30 to 78 mo inclusive) in young children (6-18 months old) at increased risk for asthma. The trial will be divided into 2 periods. During the initial treatment period (first and second years in the study) participants will receive Broncho- Vaxom® (3.5 mg) or placebo for ten days each month for two consecutive years. This period will allow the observation of key secondary outcomes while participants are receiving therapy. The second period (third through fifth years in the study) will be a three year observation of the time to occurrence of the first WLRI episode (primary outcome) while off study drug along with the secondary outcomes noted above. During both the treatment and observation periods, participants will be managed by study physicians using a rescue algorithm applied in the PEAK trial commensurate with the NAEPP Expert Panel Report (EPR) III guidelines.

Official Title
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Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety and Tolerability of ORal Bacterial EXtract for the Prevention of Wheezing Lower Respiratory Tract Illness (ORBEX)

Conditions
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Asthma, Wheezing

Intervention / Treatment
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* Drug: Broncho-Vaxom (BV)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate completion of informed consent process with written documentation. The participant's legally acceptable representative must have provided the appropriate written informed consent. Assent forms will not be used due to the age of the participant population; however, for procedures later in the study when participants are older, age appropriate assent will be obtained, if required by local Institutional Review Board (IRB). Age: 6-18 months of age inclusive at randomization which means 5 to 17 months of age inclusive on entry into the one month run-in period. At least half of all enrolled children will be between 6 and 12 months of age at randomization. Participants will meet at least one of the following criteria, which have been associated with an increased risk of wheezing respiratory illnesses and asthma: a) Parental history of asthma -or- b) Physician-diagnosed atopic dermatitis in the participant - or- c) Physician-diagnosed asthma in a blood sibling aged 4 years or more. Participants may be either male or female. Participants will have at least one parent/guardian who can communicate with the study staff to allow assessment of study outcomes. All study materials used by parent/guardian will be made available in English and in Spanish. The child's parent/guardian must have a working direct contact telephone. Exclusion Criteria: Participants may not have had more than two prior WLRI episodes. Participants may not have had any SWLRI episodes. Participants may not have a physician's diagnosis of asthma. Participants may not have a systemic illness (other than allergy) including (but not limited to) recurrent seizures, chronic gastroesophageal reflux (GER) requiring medical treatment, major congenital anomalies, physical and intellectual delay, cerebral palsy, chest surgery, tuberculosis or other chronic infections, primary or secondary immunodeficiency, gastrointestinal malformation or disease or cardiac disorder (except a hemodynamically insignificant atrial septal defect (ASD), ventricular septal defect (VSD) or benign heart murmur). Participants may not have been born earlier than 36 weeks of gestation. Participants may not have received oxygen for more than 5 days in the neonatal period, or received mechanical ventilation with the exclusion of ventilation during anesthesia for a minor surgical procedure. Participants may not have significant neurodevelopmental delay. Participants may not be below the 3rd percentile for weight. Participants may not have any other chronic lung disease; e.g. chronic lung disease of prematurity (CLDP) or cystic fibrosis. Participants may not have a history of any life-threatening respiratory illness that required intubation and mechanical ventilation. The participant's family may not be expected to relocate out of study area within 3 years of the initiation of the study. Participants may not have received inhaled or systemic corticosteroids for respiratory related illness ever, or for other conditions in the month prior to randomization. Participants may not have ever received immunotherapy. Participants may not have ever received i.v. gammaglobulins or systemic immunosuppressants. Participants may not have received probiotics (Lactobacilli and Bifidobacteria) in medicinal form; (i.e. not including food), regularly for more than 4 months in the 6 to <12 mo age group or 6 months in the 12 to 18 month group prior to enrollment. Participant has known sensitivity to any of the study products and any of the ingredients to be administered. Participant has previously been randomized in this study. Participants who failed run-in and were not randomized may have study participation terminated and then be re-enrolled for a second run-in period. Participant is currently enrolled in or has completed any other investigational device or drug study <30 days prior to screening, or is receiving other investigational agent(s). Participant has a significant medical condition(s), anticipated need for major surgery during the study, or any other kind of disorder that may be associated with increased risk to the participant, or may interfere with study assessments, outcomes, or the ability to provide written informed consent or comply with study procedures, in the Investigator's opinion. The one month run-in period will be used to evaluate adherence to study drug administration and electronic communication. At randomization the participant must continue to meet enrolment criteria and also have demonstrated 80% adherence to the placebo during treatment period; i.e. 8 out of 10 days and a75% response rate to weekly mobile phone text queries; i.e. 3 out of 4 weekly text queries. Ongoing infection (of any organ system) at the time of randomization. This includes infections that are being adequately treated. Unable or unlikely to complete study assessments or the study intervention poses undue risk to patient in the opinion of the Investigator. Families will speak English and/or Spanish.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 18 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Broncho-Vaxom (BV)<br>One capsule of Broncho-Vaxom for children contains: 3.5 mg of lyophilized bacterial lysates of Haemophilus influenzae, Streptococcus (pneumonia, pyogenes and sanguinis (viridans)), Klebsiella (pneumoniae and ozaenae), Staphylococcus aureus and Moraxella catarrhalis. The content of the capsule will be mixed with a palatable liquid such as fruit juice. | Drug: Broncho-Vaxom (BV)<br>* Active Ingredient: Lyophilised bacterial extract; Chemical Name: OM-85 BV; Strength: 3.5 mg; Excipients: bacterial extract, propyl gallate, sodium glutamate, mannitol, pregelatinised starch, magnesium stearate; Appearance: Blue and white capsule; Dosage Form: 3.5 mg capsule; Manufacturer: OM Pharma, Switzerland (OM stands for Omnia Medicamenta) Storage: Store in the original package<br>* Other names: Broncho-Vaxom concentrate (bacterial lysate);|
| Placebo Comparator: Placebo<br>A placebo capsule will be used that will be indistinguishable from the active study drug. | Other: Placebo<br>* A placebo capsule will be used that 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 |
| --- | --- | --- |
| The time to the occurrence of the first WLRI episode in the observation period while not receiving study drug | The time to the occurrence of the first WLRI episode in the observation period while not receiving study drug | ages 30 to 42 months at the end of treatment; ages 66 to 78 months at completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time to first WLRI during the two treatment years while receiving study drug | The time to first WLRI during the two treatment years while receiving study drug | ages 6 to 18 months at start of therapy; ages 30 to 42 months at completion | 
| The annualized rate of WLRI episodes during the two years while receiving study drug | The annualized rate of WLRI episodes during the two years while receiving study drug | ages 6 to 18 months at start of therapy; ages 30 to 42 months at completion | 
| The annualized rate of WLRI episodes during the observation period while not receiving study drug | The annualized rate of WLRI episodes during the observation period while not receiving study drug | ages 30 to 42 months at the end of treatment; ages 66 to 78 months at completion | 
| The annualized rate of severe wheezing respiratory tract illness (SWLRI) episodes during the two treatment years while receiving study drug. | SWLRI episodes are defined as cough and wheezing > 24 hours AND any one of the following: Use of more than 6 albuterol treatments in ≤48 hours. Unscheduled care visit for acute wheezing in doctor's office, urgent care or emergency department -or- hospitalization for wheezing. Use of systemic corticosteroid prescribed by a licensed medical provider for a wheezing illness with or without a clinical visit. The annualized rate of SWLRI episodes during the two years while receiving study drug. | ages 6 to 18 months at start of therapy; ages 30 to 42 months at completion | 
| The annualized rate of severe wheezing respiratory tract illness (SWLRI) episodes during the observation period while not receiving study drug. | The annualized rate of severe wheezing respiratory tract illness (SWLRI) episodes during the observation period while not receiving study drug. | ages 30 to 42 months at the end of treatment; ages 66 to 78 months at completion | 
| Asthma at the end of the observation period | Asthma at the end of the observation period defined by any of the following three elements: (a) a health care provider diagnosis of asthma with reports of: at least one episode of wheezing or asthma in the previous year or asthma controllers prescribed for at least 6 months during the previous year; or (b) >3 episodes of wheezing during the previous year 38 (frequent wheezers); or (c) any wheezing during the third observation year in children who wheezed during the first three years of life (persistent wheezers). | ages 30 to 42 months at the end of treatment; ages 66 to 78 months at completion | 
| Safety and tolerability of Broncho-Vaxom® while receiving study drug during the two year treatment period. | Safety and tolerability of Broncho-Vaxom® while receiving study drug during the two year treatment period | ages 6 to 18 months at start of therapy; ages 30 to 42 months at completion | 
| Safety and tolerability of Broncho-Vaxom® while receiving study drug during the observation period. | Safety and tolerability of Broncho-Vaxom® while receiving study drug during the observation period, after study drug has been stopped. | ages 30 to 42 months at the end of treatment; ages 66 to 78 months at completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wheezing, Lower respiratory tract illness, Asthma, Atopy