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

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ClinicalTrials.gov Identifier: NCT02426112
Recruitment Status : Completed
First Posted : April 24, 2015
Last Update Posted : October 9, 2019
Sponsor:
Collaborators:
Biomedical Research and Training Institute, Zimbabwe
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
University of Tromso
University of Cape Town
University of Oxford
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

Study Description
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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 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.


Condition or disease Intervention/treatment Phase
Chronic Lung Disease HIV Infection Drug: Azithromycin Drug: Placebo Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 347 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children
Study Start Date : June 2016
Actual Primary Completion Date : September 2018
Actual Study Completion Date : August 2019

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Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Azithomycin

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 Comparator: 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
 Drug: Placebo


Outcome Measures
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Primary Outcome Measures :
  1. Forced Expiratory Volume in one second z score (FEV1) [ Time Frame: 12 months ]
    Change in FEV1after 12 months of initiation of therapy with azithromycin


Secondary Outcome Measures :
  1. Forced Expiratory Volume in one second z score (FEV1) [ Time Frame: 24 months ]
    Mean change in FEV1 24 months after treatment initiation with azithromycin

  2. Time to death [ Time Frame: 12 months ]
    Time to death 12 months after treatment initiation with azithromycin

  3. Time to first acute exacerbation [ Time Frame: 12 months ]
  4. Number of hospitalizations [ Time Frame: 12 and 24 months ]
  5. Number of exacerbations [ Time Frame: 12 and 24 months ]
  6. Quality of life scores [ Time Frame: 12 and 24 months ]
  7. Mean change in weight-for-age z-score [ Time Frame: 12 and 24 months ]
  8. Number of mild, moderate and severe adverse events [ Time Frame: 12 months ]
  9. Number of Malaria episodes (Malawi only) [ Time Frame: 12 months ]
  10. Number of blood stream infections due to Salmonella typhi and non-typhi [ Time Frame: 12 months ]
  11. Number of gastroenteritis episodes [ Time Frame: 12 months ]

Other Outcome Measures:
  1. Macrolide resistance [ Time Frame: 12 months ]
    Prevalence of colonization with macrolide (and multidrug-resistant) Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae in the two trial arms at 12 months of initiation of treatment with azithromycin

  2. Lung microbiome [ Time Frame: baseline, 12 and 14 months ]
    Composition and diversity of the respiratory bacterial microbiome (determined by culture of clinically relevant organisms and sequencing of 16s rRNA gene amplicons)

  3. Gut microbiome [ Time Frame: baseline, 12 and 24 months ]
    Composition and diversity of the gut bacterial microbiome (determined by culture of clinically relevant organisms and sequencing of 16s rRNA gene amplicons

  4. Inflammation biomarkers [ Time Frame: baseline, 12 and 24 months ]
    Association between inflammation biomarker levels and FEV1

  5. Cardiac dysfunction [ Time Frame: Baseline ]
    prevalence of right sided cardiac dilatation and dysfunction

  6. Cardiac dysfunction after treatment [ Time Frame: 12 and 24 months ]
    Prevalence of right sided cardiac dilatation and dysfunction at 12 and 24 months of initiation of azithromycin therapy by intervention arm


Eligibility Criteria
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Ages Eligible for Study:   6 Years to 19 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02426112


Locations
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Malawi
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Blantyre, Malawi, 30096
Zimbabwe
Biomedical Research and Training Institute
Harare, Zimbabwe
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
Biomedical Research and Training Institute, Zimbabwe
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
University of Tromso
University of Cape Town
University of Oxford
Investigators
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Principal Investigator: Rashida Ferrand London School of Hygiene and Tropical Medicine
Principal Investigator: Jon O Odland University of Tromso
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT02426112    
Other Study ID Numbers: QA698
First Posted: April 24, 2015    Key Record Dates
Last Update Posted: October 9, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Lung Diseases
Respiratory Tract Diseases
Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents