Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children

Study Overview
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Brief Summary
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Chronic pulmonary disease (CLD) is the most common manifestation of HIV/AIDS among children, accounting for more than 50% of HIV-associated mortality. Recently, a novel form of CLD, affecting more than 30% of African HIV-infected older children was described by Ferrand et al in Zimbabwe, high-resolution CT scanning findings showed predominantly small airways disease consistent with constrictive obliterative bronchiolitis (OB). . Azithromycin has anti-inflammatory activity and treatment of CLD with this agent may lead to suppression of generalized immune activation. This specific aims of this project are to: Primary objective: To investigate whether adjuvant treatment with azithromycin results in improvement in lung function in HIV-infected children with chronic lung disease, who are stable on antiretroviral therapy. Secondary objectives: To investigate the intervention effect on mortality, exacerbations of lung disease, quality of life, morbidity. To investigate adverse events related to azithromycin treatment In total, 400 children aged 6-16 years, living with HIV and diagnosed with CLD will be enrolled at Harare Children´s Hospital in Harare (Zimbabwe) and Queen Elizabeth Central Hospital in Blantyre (Malawi). These will receive weekly treatment with azithromycin or placebo during 12 months. Another 100 children (50 per site) living with HIV but with no CLD will be enrolled as a comparison group for laboratory sub-studies. Lung function will be assess using spirometry and the Forced expiratory volume in the first minute (FEV1) will be the primary outcome. The mean change in FEV1 z-score levels will be compared between trial arms after 12 months of initiation of azithromycin treatment.

Detailed Description
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Clinical Phase: III Trial Design: Multi-site, individually randomised, double-blinded, placebo-controlled trial of weekly azithromycin for 12 months Trial Participants: Children aged 6-16 years living with HIV and with diagnosis of chronic lung disease. Another 200 children living with HIV but with no chronic lung disease in a comparison arm. Planned Sample Size: 400 cases and 100 in the comparison arm Treatment duration: 12 months Follow up duration: 18 months Planned Trial Period: June 2016-September 2019 Objectives: Primary trial outcome: To investigate whether adjuvant treatment with azithromycin results in improvement in lung function in HIV-infected children with chronic lung disease, who are stable on antiretroviral therapy. Secondary trial outcomes: .To investigate the intervention effect on mortality,exacerbations of lung disease, quality of life and morbidity.. .To investigate adverse events related to azithromycin treatment. .-Laboratory sub-studies .To determine the effect of azithromycin therapy on antimicrobial resistance in bacteria colonizing the respiratory tract. .To investigate the diversity and composition of the respiratory microbiome in HIV-infected children with CLD. .To investigate the diversity and composition of the gut microbiome in HIV-infected children with CLD. .To investigate the effect of azithromycin on biomarkers of systemic inflammation in HIV-infected children with CLD. .-Cardiac sub-study: .Describe the cardiac symptoms and echocardiograph findings of HIV-infected children with chronic lung disease. .To investigate whether adjuvant treatment with azithromycin results in improvement in right-sided cardiac function and/or pulmonary hypertension in HIV-infected children with chronic lung disease. Investigational Medicinal Product(s): Azithromycin and placebo. Formulation:Tablets 250 mg Dose: According to weight bands (30 mg/kg/week): 10-20 kg: 250 mg 20-29 kg: 500 mg 30-39 kg: 750 mg 40-49 kg: 1250 mg Route of Administration:Oral

Official Title
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Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children

Conditions
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Chronic Lung Disease, HIV Infection

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic lung disease (defined as FEV1 and/or FVC <80% predicted) Age 6-19 years Perinatally-acquired HIV infection the most likely source of transmission On first or second-line ART for at least one year HIV-1 viral load undetectable (as defined by each trial site) A firm home address accessible for visiting and intending to remain there for 24 months Willing to agree to participate in the study and to give samples of blood and sputum HIV status disclosed to child for those aged older than 12 years Exclusion Criteria: Any condition (except HIV) that may prove fatal during the study period (e.g. malignancy, end-stage HIV disease or other conditions deemed likely fatal by the trial physician) Diagnosis of active pulmonary TB Infection with non-tuberculous mycobacteria (NTM) Pregnant or breast-feeding Condition likely to lead to lack of understanding of study procedures or to uncooperative behaviour e.g. neurocognitive disease, developmental delay or psychiatric illness History of prolonged QTc syndrome or current or planned therapy with drugs likely to cause cardiac dysrhythmias Abnormal ECG findings Acute respiratory tract infection during enrolment (patients will be eligible once their acute infection is treated) Creatinine clearance of <30mls/minute ALT more than 2 times the upper limit of normal No defined guardian/stable caregiver No consent/assent from guardian/child

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithomycin<br>Azithromycin tablets 250 mg, 30mg/kg/week by mouth, once a week for 12 months. 10-20 kg: 250 mg 20-29 kg: 500 mg 30-39 kg: 750 mg 40-49 kg: 1250 mg | Drug: Azithromycin<br> <br> |
| Placebo Comparator: Placebo<br>Placebo tablets 250 mg, 30 mg/kg/week by mouth, once a week for 12 months. 10-20 kg: 250 mg 20-29 kg: 500 mg 30-39 kg: 750 mg 40-49 kg: 1250 mg | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in one second z score (FEV1) | Change in FEV1after 12 months of initiation of therapy with azithromycin | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in one second z score (FEV1) | Mean change in FEV1 24 months after treatment initiation with azithromycin | 24 months | 
| Time to death | Time to death 12 months after treatment initiation with azithromycin | 12 months | 
| Time to first acute exacerbation |  | 12 months | 
| Number of hospitalizations |  | 12 and 24 months | 
| Number of exacerbations |  | 12 and 24 months | 
| Quality of life scores |  | 12 and 24 months | 
| Mean change in weight-for-age z-score |  | 12 and 24 months | 
| Number of mild, moderate and severe adverse events |  | 12 months | 
| Number of Malaria episodes (Malawi only) |  | 12 months | 
| Number of blood stream infections due to Salmonella typhi and non-typhi |  | 12 months | 
| Number of gastroenteritis episodes |  | 12 months |