Antibiotics, Microbiology and Immunology in Children With Chronic Wet Couch - the AMIC Study

Study Overview
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Brief Summary
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The AMIC study is a double-blind, placebo-controlled, multicenter, nationwide, randomized controlled academic pharmaceutical trial. OVERALL PRIMARY OBJECTIVES: To study the clinical efficacy of antibiotics in children with chronic wet cough (CWC). To study if duration of treatment with antibiotics in children with CWC has impact on efficacy or time to relapse of symptoms. OVERALL SECONDARY OBJECTIVE: -To study respiratory pathogens and the diversity/composition of airway and gut microbiome in children with CWC compared to healthy controls, and changes in pathogens/microbiome after treatment with antibiotics. OVERALL TERTIARY OBJECTIVE: -To study inflammatory markers in children with CWC and the impact of treatment with antibiotics. Furthermore, identify children with CWC who have primary immunodeficiency (PID) based on functional laboratory markers and genetic markers of PID. The study will include two different interventions: INTERVENTION 1: Participants will be randomly assigned to 14 days antibiotics or placebo INTERVENTION 2: Participants will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup

Detailed Description
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Study populations: INTERVENTION 1: 90 children with chronic wet cough aged 9-36 months INTERVENTION 2: 210 children with chronic wet cough aged 9-26 months Both intervention groups will be followed until 24 months after the start of the RCT. HEALTHY CONTROL GROUP: To study the role of respiratory pathogens, airway and gut microbiome, inflammatory markers and immunodeficiency, 50 healthy controls will be included for comparison to IV 1. The healthy controls will be followed for 6 months after inclusion.

Official Title
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A Phase 4 Double Blinded Study With Two Different Interventions, Each With Two Arms, to Evaluate the Clinical Efficacy of Antibiotics and the Role of Microbiology, Immunology and Genetics in Children Aged 9-36 Months With Chronic Wet Cough.

Conditions
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Protracted Bacterial Bronchitis

Intervention / Treatment
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* Drug: Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 9 and younger than 36 months. Body weight > 7 kg and < 24 kg. Born term with Gestational age > 37 weeks. Chronic wet cough for > 4 weeks at screening and in addition average cough score last 7 days at randomization ≥ 4 points and without signs of another cause. Written informed consent obtained from both parents at inclusion. The study subject must be assessed as eligble for treatment with Augmentin. Exclusion Criteria: Gestational age < 37 weeks. History of acute upper or lower airway infection the last 4 weeks. History of other viral or bacterial infections the last 2 weeks. Episode with temperature above 38 °C during the last 2 weeks. Previous diagnosed with chronic lung disease such as cystic fibrosis, primary ciliary dyskinesia, interstitial lung disease, asthma, immunodeficiency, esophagus atresia. Cardiac disease, except persisting foramen ovale or ductus arteriosus. Severe feeding problems/aspiration. Gastroesophageal reflux suspicion or confirmed by ph measurement. Suspicion of hypertrophic tonsils or adenoids Episodes of bronchopulmonary obstruction suggesting asthma Presence of gross neurodevelopmental delay, or suspicion of neurological disease. History of known or suspected allergic reactions to amoxicillin-clavulanate or any other betalactam. Episodes with haemoptysis and with unknown cause. Radiographic changes other than perihilar changes confirmed by x-ray at screening. At examination: Digital clubbing, hypoxia, chest wall deformity, dyspnoea at rest. Parents unable to speak and/or understand Norwegian language. Received systemic antibiotics within the last 6 months before inclusion. Participation in another trial.

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 36 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a Phase 4, randomized controlled, parallel group, multicenter, double blind study of amoxicillin-clavulanate in children 9-36 months of age with chronic wet cough. A total of 300 children will be included in the study in two different Intervention groups. Intervention 1 will be performed before Intervention 2.There is no randomization between IV 1 and IV 2. To study the role of respiratory pathogens, microbiome and inflammation, 50 healthy controls will be included for comparison to IV 1.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group 1 (IV 1) Arm A<br>In the first Intervention group (IV 1), 90 children will be randomly be assigned 1:1 to receive either amoxicillin-clavulanate syrup or placebo (Arm A and B) for 14 days. IV 1 Arm A will receive 14 days amoxicillin-clavulanate syrup.. | Drug: Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution<br>* Three times daily<br>|
| Placebo Comparator: Intervention group 1 (IV 1) Arm B<br>In the first Intervention group (IV 1), 90 children will be randomly be assigned 1:1 to receive either amoxicillin-clavulanate syrup or placebo (arm A and B) for 14 days. IV 1 Arm B will receive 14 days placebo syrup. | Drug: Placebo<br>* Three times daily<br>|
| Experimental: Intervention group 2 (IV2) Arm C<br>In the second intervention group (IV 2), 210 children will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup (arm C and D). IV 2 Arm C will receive 14 days amoxicillin-clavulanate syrup and 14 days placebo. | Drug: Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution<br>* Three times daily<br>Drug: Placebo<br>* Three times daily<br>|
| Experimental: Intervention group 2 (IV 2) Arm D<br>In the second intervention group (IV 2), 210 children will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup (arm C and D). IV 2 Arm D will receive 28 days amoxicillin-clavulanate syrup. | Drug: Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution<br>* Three times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to treatment | Response to treatment is defined as an improvement in baseline validated Verbal category descriptive (VCD) cough score ≤2 at the end of treatment or cessation of coughing for a minimum period of 3 days within the treatment period. | Response to treatment will be assessed 14 days after end of antibiotic treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse of symptoms | Relapse of symptoms after antibiotic treatment for chronic wet cough is defined as a new period of wet cough - after a period of at least 7 days without symptoms - lasting for more than four weeks, or an episode of wet cough of at least two weeks duration which was treated with antibiotics by the child's general practitioner or treating physician. The start of relapse is the first day of cough of such a period or episode. | Relapse of symptoms will be assesed up to 24 months after end of antibiotic treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic wet cough, Antibiotic, Children, Microbiology, Immunology