Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children
- Conditions
- HIV InfectionChronic Lung Disease
- Interventions
- Drug: Placebo
- Registration Number
- NCT02426112
- Lead Sponsor
- London School of Hygiene and Tropical Medicine
- Brief Summary
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:
1. 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.
2. Secondary objectives:
1. To investigate the intervention effect on mortality, exacerbations of lung disease, quality of life, morbidity.
2. 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 ChildrenĀ“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
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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 347
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Placebo Placebo 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 Azithomycin Azithromycin 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
- Primary Outcome Measures
Name Time Method Forced Expiratory Volume in one second z score (FEV1) 12 months Change in FEV1after 12 months of initiation of therapy with azithromycin
- Secondary Outcome Measures
Name Time Method Time to first acute exacerbation 12 months Mean change in weight-for-age z-score 12 and 24 months Time to death 12 months Time to death 12 months after treatment initiation with azithromycin
Number of exacerbations 12 and 24 months Quality of life scores 12 and 24 months Forced Expiratory Volume in one second z score (FEV1) 24 months Mean change in FEV1 24 months after treatment initiation with azithromycin
Number of blood stream infections due to Salmonella typhi and non-typhi 12 months Number of hospitalizations 12 and 24 months Number of Malaria episodes (Malawi only) 12 months Number of mild, moderate and severe adverse events 12 months Number of gastroenteritis episodes 12 months
Trial Locations
- Locations (2)
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
š²š¼Blantyre, Malawi
Biomedical Research and Training Institute
šæš¼Harare, Zimbabwe