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

Phase 4

Recruiting

• Conditions: Protracted Bacterial Bronchitis
• Interventions: Drug: Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution; Drug: Placebo

• Registration Number: NCT06020716
• Lead Sponsor: Helse Stavanger HF

Brief Summary

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 the role of inflammation, immunology, and genetics in children with chronic wet cough and suspicion of PBB to increase the knowledge of pathophysiological mechanisms associated with PBB.

The study will include two different RCTs AMIC 1 and AMIC 2:

AMIC 1:

Participants will be randomly assigned to 14 days amoxicillin-clavulanate syrup or placebo.

AMIC 2:

Participants will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup.

Detailed Description

Study populations:

AMIC 1:

90 children with chronic wet cough aged 9-36 months.

AMIC 2:

210 children with chronic wet cough aged 9-36 months.

All children will be followed until 24 months after the start of the Randomized Controlled Trial (RCT).

HEALTHY CONTROL GROUP:

To study the role of respiratory pathogens, airway and gut microbiome, inflammation and immunology, 50 healthy controls will be included for comparison to AMIC 1. The healthy controls will have a second visit 6 months after inclusion.

Study Timeline

• Study First Submitted: 2023-07-03
• Study Start: 2023-08-16
• Study First Submitted QC: 2023-08-28
• Study First Posted: 2023-09-01
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-20
• Last Update Posted: 2024-12-27
• Primary Completion: 2028-04-30
• Study Completion: 2028-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 350

Inclusion Criteria

1. Age ≥ 9 and < 36 months.
2. Body weight ≥ 7 kg and < 24 kg.
3. Born term with Gestational age ≥ 37 weeks.
4. 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. Registration ≥ 5 days is mandatory.
5. Written informed consent obtained from both parents at inclusion.
6. The study subject must be assessed as eligible for treatment with Augmentin.

Exclusion Criteria

1. Gestational age < 37 weeks.
2. History of acute upper or lower airway infection the last 2 weeks.
3. History of other viral or bacterial infections the last 2 weeks.
4. Episode with temperature above 38 °C during the last 2 weeks.
5. Previous diagnosed with chronic lung disease such as cystic fibrosis, primary ciliary dyskinesia, interstitial lung disease, asthma, immunodeficiency, esophagus atresia.
6. Cardiac disease, except persisting foramen ovale or ductus arteriosus.
7. Severe feeding problems/aspiration.
8. Gastroesophageal reflux suspicion or confirmed by ph measurement.
9. Suspicion of hypertrophic tonsils or adenoids
10. Episodes of bronchopulmonary obstruction suggesting asthma
11. Presence of gross neurodevelopmental delay, or suspicion of neurological disease.
12. History of known or suspected allergic reactions to amoxicillin-clavulanate or any other betalactam.
13. Episodes with haemoptysis and with unknown cause.
14. Radiographic changes other than perihilar changes confirmed by x-ray at screening.
15. At examination: Digital clubbing, hypoxia, chest wall deformity, dyspnoea at rest.
16. Parents unable to speak and/or understand Norwegian language.
17. Received systemic antibiotics within the last 6 months before inclusion.
18. Participation in another clinical intervention trial.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AMIC 1: Arm A	Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution	In AMIC 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. AMIC 1 Arm A will receive 14 days amoxicillin-clavulanate syrup.
AMIC 1: Arm B	Placebo	In AMIC 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. AMIC 1 Arm B will receive 14 days placebo syrup.
AMIC 2: Arm C	Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution	In AMIC 2, 210 children will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup (arm C and D). AMIC 2 Arm C will receive 14 days amoxicillin-clavulanate syrup and 14 days placebo.
AMIC 2: Arm C	Placebo	In AMIC 2, 210 children will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup (arm C and D). AMIC 2 Arm C will receive 14 days amoxicillin-clavulanate syrup and 14 days placebo.
AMIC 2: Arm D	Amoxicillin-Clavulanate 400 Mg-57 Mg/5 mL Oral Powder for Reconstitution	In AMIC 2, 210 children will be randomly assigned 1:1 to receive either 14 or 28 days with amoxicillin-clavulanate syrup (arm C and D). AMIC 2 Arm D will receive 28 days amoxicillin-clavulanate syrup.

Primary Outcome Measures

Name	Time	Method
Response to treatment	Response to treatment will be assessed 14 days after end of antibiotic 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.The VCD score has a minimum and maxiumum score ranging from 0-10 points, and a higher value corresponds to more severe cough.

Secondary Outcome Measures

Name	Time	Method
Relapse of symptoms	Relapse of symptoms will be assessed up to 24 months after end of antibiotic treatment	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.

Trial Locations

Locations (7)

Haukeland University Hospital; 🇳🇴 Bergen, Norway

Akershus University Hospital; 🇳🇴 Lillestrøm, Norway

Oslo University Hospital; 🇳🇴 Oslo, Norway

University Hospital of North-Norway; 🇳🇴 Tromsø, Norway

Trondheim University Hospital; 🇳🇴 Trondheim, Norway

Ålesund Hospital; 🇳🇴 Ålesund, Norway

Stavanger University Hospital; 🇳🇴 Stavanger, Norway