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

NCT02426112 | Completed Phase 3 DMC

• 1 other identifier: QA698
• Study Type: interventional
• Target: 347
• Locations: 2 countries
• Sites: 2

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. 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. 2.Secondary objectives:
3. 3.To investigate the intervention effect on mortality, exacerbations of lung disease, quality of life, morbidity.
4. 4.To investigate adverse events related to azithromycin treatment

Conditions

Chronic Lung Disease; HIV Infection

Outcome Measures

Primary Outcomes (1)

• Forced Expiratory Volume in one second z score (FEV1)

  Change in FEV1after 12 months of initiation of therapy with azithromycin

  12 months

Secondary Outcomes (11)

• Forced Expiratory Volume in one second z score (FEV1)

  24 months

• Time to death

  12 months

• Time to first acute exacerbation

  12 months

• Number of hospitalizations

  12 and 24 months

• Number of exacerbations

  12 and 24 months

Other Outcomes (6)

• Macrolide resistance

  12 months

• Lung microbiome

  baseline, 12 and 14 months

• Gut microbiome

  baseline, 12 and 24 months

Study Arms (2)

Azithomycin

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Azithromycin DRUG

Azithomycin

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 6 Years - 19 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• London School of Hygiene and Tropical Medicine: lead
• Biomedical Research and Training Institute, Zimbabwe: collaborator
• Malawi-Liverpool-Wellcome Trust Clinical Research Programme: collaborator
• University of Tromso: collaborator
• University of Cape Town: collaborator
• University of Oxford: collaborator

Study Sites (2)

Malawi-Liverpool-Wellcome Trust Clinical Research Programme

Blantyre, 30096, Malawi

Location

Biomedical Research and Training Institute

Harare, Zimbabwe

Location

Related Publications (10)

• Mushunje PK, Sovershaeva E, Olwagen CP, Madhi S, Odland JO, Ferrand RA, Nicol MP, Abotsi RE, Dube FS. Weekly azithromycin for 48 weeks impacts nasopharyngeal microbial prevalence and Streptococcus pneumoniae serotypes in children with HIV-associated chronic lung disease. Sci Rep. 2025 Nov 7;15(1):39175. doi: 10.1038/s41598-025-23693-6.

  PMID: 41203736 DERIVED

• Madanhire T, McHugh G, Simms V, Ngwira L, Gonzalez-Martinez C, Semphere R, Moyo B, Calderwood C, Nicol M, Bandason T, Odland JO, Rehman AM, Ferrand RA. Longitudinal lung function trajectories in response to azithromycin therapy for chronic lung disease in children with HIV infection: a secondary analysis of the BREATHE trial. BMC Pulm Med. 2024 Jul 12;24(1):339. doi: 10.1186/s12890-024-03155-x.

  PMID: 38997676 DERIVED

• Mushunje PK, Dube FS, Olwagen C, Madhi S, Odland JO, Ferrand RA, Nicol MP, Abotsi RE; BREATHE study team. Characterization of bacterial and viral pathogens in the respiratory tract of children with HIV-associated chronic lung disease: a case-control study. BMC Infect Dis. 2024 Jun 26;24(1):637. doi: 10.1186/s12879-024-09540-5.

  PMID: 38926682 DERIVED

• Ngwira LG, Maheswaran H, Verstraete J, Petrou S, Niessen L, Smith SC. Psychometric performance of the Chichewa versions of the EQ-5D-Y-3L and EQ-5D-Y-5L among healthy and sick children and adolescents in Malawi. J Patient Rep Outcomes. 2023 Mar 9;7(1):22. doi: 10.1186/s41687-023-00560-4.

  PMID: 36892714 DERIVED

• Rehman AM, Simms V, McHugh G, Mujuru H, Ngwira LG, Semphere R, Moyo B, Bandason T, Odland JO, Ferrand RA. Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy. PLoS One. 2022 Jun 15;17(6):e0269229. doi: 10.1371/journal.pone.0269229. eCollection 2022.

  PMID: 35704559 DERIVED

• Jackson C, Rehman AM, McHugh G, Gonzalez-Martinez C, Ngwira LG, Bandason T, Mujuru H, Odland JO, Corbett EL, Ferrand RA, Simms V. Risk factors for sustained virological non-suppression among children and adolescents living with HIV in Zimbabwe and Malawi: a secondary data analysis. BMC Pediatr. 2022 Jun 11;22(1):340. doi: 10.1186/s12887-022-03400-4.

  PMID: 35690762 DERIVED

• Ferrand RA, McHugh G, Rehman AM, Mujuru H, Simms V, Majonga ED, Nicol MP, Flaegstad T, Gutteberg TJ, Gonzalez-Martinez C, Corbett EL, Rowland-Jones SL, Kranzer K, Weiss HA, Odland JO; BREATHE Trial Group. Effect of Once-Weekly Azithromycin vs Placebo in Children With HIV-Associated Chronic Lung Disease: The BREATHE Randomized Clinical Trial. JAMA Netw Open. 2020 Dec 1;3(12):e2028484. doi: 10.1001/jamanetworkopen.2020.28484.

  PMID: 33331916 DERIVED

• Rehman AM, Ferrand R, Allen E, Simms V, McHugh G, Weiss HA. Exclusion of enrolled participants in randomised controlled trials: what to do with ineligible participants? BMJ Open. 2020 Dec 2;10(12):e039546. doi: 10.1136/bmjopen-2020-039546.

  PMID: 33268410 DERIVED

• McHugh G, Rehman AM, Simms V, Gonzalez-Martinez C, Bandason T, Dauya E, Moyo B, Mujuru H, Rylance J, Sovershaeva E, Weiss HA, Kranzer K, Odland J, Ferrand RA; BREATHE Clinical Trial Team. Chronic lung disease in children and adolescents with HIV: a case-control study. Trop Med Int Health. 2020 May;25(5):590-599. doi: 10.1111/tmi.13375. Epub 2020 Feb 10.

  PMID: 31989731 DERIVED

• Gonzalez-Martinez C, Kranzer K, McHugh G, Corbett EL, Mujuru H, Nicol MP, Rowland-Jones S, Rehman AM, Gutteberg TJ, Flaegstad T, Odland JO, Ferrand RA; BREATHE study team. Azithromycin versus placebo for the treatment of HIV-associated chronic lung disease in children and adolescents (BREATHE trial): study protocol for a randomised controlled trial. Trials. 2017 Dec 28;18(1):622. doi: 10.1186/s13063-017-2344-2.

  PMID: 29282143 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Rashida Ferrand

  London School of Hygiene and Tropical Medicine

  PRINCIPAL INVESTIGATOR

• Jon O Odland

  University of Tromso

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2015
• First Posted: April 24, 2015
• Study Start: June 1, 2016
• Primary Completion: September 1, 2018
• Study Completion: August 1, 2019
• Last Updated: October 9, 2019

Record last verified: 2019-10

Locations

ZI (1); MA (1)