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

London School of Hygiene and Tropical Medicine

Status and phase: Completed; Phase 3

Conditions: Chronic Lung Disease; HIV Infection

Treatments: Drug: Placebo; Drug: Azithromycin

Study type: Interventional

Funder types: Other

Identifiers

NCT02426112

QA698

Details and patient eligibility

About

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 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.

Full 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

Enrollment: 347 patients

Sex: All

Ages: 6 to 19 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Diagnosis of chronic lung disease (defined as FEV1 and/or FVC <80% predicted)
2. Age 6-19 years
3. Perinatally-acquired HIV infection the most likely source of transmission
4. On first or second-line ART for at least one year
5. HIV-1 viral load undetectable (as defined by each trial site)
6. A firm home address accessible for visiting and intending to remain there for 24 months
7. Willing to agree to participate in the study and to give samples of blood and sputum
8. HIV status disclosed to child for those aged older than 12 years

Exclusion criteria

1. 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)
2. Diagnosis of active pulmonary TB
3. Infection with non-tuberculous mycobacteria (NTM)
4. Pregnant or breast-feeding
5. Condition likely to lead to lack of understanding of study procedures or to uncooperative behaviour e.g. neurocognitive disease, developmental delay or psychiatric illness
6. History of prolonged QTc syndrome or current or planned therapy with drugs likely to cause cardiac dysrhythmias
7. Abnormal ECG findings
8. Acute respiratory tract infection during enrolment (patients will be eligible once their acute infection is treated)
9. Creatinine clearance of <30mls/minute
10. ALT more than 2 times the upper limit of normal
11. No defined guardian/stable caregiver
12. No consent/assent from guardian/child

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Quadruple Blind

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347 participants in 2 patient groups, including a placebo group

Azithomycin

Active Comparator group

Description:

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

Treatment:

Drug: Azithromycin

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo