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

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

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