Clinical Trials

MainTitle

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

This study is currently recruiting participants. (see Contacts and Locations)

Verified August 2017 by London School of Hygiene and Tropical Medicine

Sponsor
London School of Hygiene and Tropical Medicine

Collaborator
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
ClinicalTrials.gov Identifier
NCT02426112

First received: April 21, 2015
Last updated: August 23, 2017
Last Verified: August 2017
History of Changes
Purpose

Purpose

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.


  3. 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 Intervention Phase
Chronic Lung Disease
HIV Infection

Drug : Azithromycin
Drug : Placebo
Phase 3

Study Type: Interventional
Study Design: 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

Further study details as provided by London School of Hygiene and Tropical Medicine:

Primary Outcome Measures

  • 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:
  • Forced Expiratory Volume in one second z score (FEV1) [ Time Frame: 24 months ]
    Mean change in FEV1 24 months after treatment initiation with azithromycin
  • Time to death [ Time Frame: 12 months ]
    Time to death 12 months after treatment initiation with azithromycin
  • Time to first acute exacerbation [ Time Frame: 12 months ]
  • Number of hospitalizations [ Time Frame: 12 and 24 months ]
  • Number of exacerbations [ Time Frame: 12 and 24 months ]
  • Quality of life scores [ Time Frame: 12 and 24 months ]
  • Mean change in weight-for-age z-score [ Time Frame: 12 and 24 months ]
  • Number of mild, moderate and severe adverse events [ Time Frame: 12 months ]
  • Number of Malaria episodes (Malawi only) [ Time Frame: 12 months ]
  • Number of blood stream infections due to Salmonella typhi and non-typhi [ Time Frame: 12 months ]
  • Number of gastroenteritis episodes [ Time Frame: 12 months ]
Other Outcome Measures:
  • 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
  • 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)
  • 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
  • Inflammation biomarkers [ Time Frame: baseline, 12 and 24 months ]
    Association between inflammation biomarker levels and FEV1
  • Cardiac dysfunction [ Time Frame: Baseline ]
    prevalence of right sided cardiac dilatation and dysfunction
  • 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

Estimated Enrollment: 400
Study Start Date: June 2016
Estimated Study Completion Date: October 2019
Estimated Primary Completion Date: October 2018 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
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

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

    Eligibility

    Eligibility

    Ages Eligible for Study: 6 Years to 16 Years  
    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 6-16 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

    Contacts and Locations

    Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT02426112

    Contacts

    Contact:   Carmen Gonzalez +265991416730 Carmen.Gonzalez@lstmed.ac.uk

    Locations

    Malawi
    Malawi-Liverpool-Wellcome Trust Clinical Research Programme Recruiting
    Blantyre, Malawi, 30096
    Contact: Carmen Gonzalez    +265991416730    Carmen.Gonzalez@lstmed.ac.uk
    Principal Investigator: Carmen Gonzalez
    Zimbabwe
    Biomedical Research and Training Institute Recruiting
    Harare, Zimbabwe
    Contact: Rashida Ferrand    +263 (4) 333091    rashida.ferrand@lshtm.ac.uk
    Contact: Ethel Dauya    +263 7744 52172    edauya@brti.co.zw
    Principal Investigator: Rashida Ferrand

    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

    Principal Investigator: Rashida Ferrand London School of Hygiene and Tropical Medicine
    Principal Investigator: Jon O Odland University of Tromso
    More Information

    More Information


    Responsible Party: London School of Hygiene and Tropical Medicine  
    ClinicalTrials.gov Identifier: NCT02426112   History of Changes  
    Other Study ID Numbers: QA698  
    Study First Received: April 21, 2015  
    Last Updated: August 23, 2017  

    Additional relevant MeSH terms:
    HIV Infections
    Lung Diseases

    ClinicalTrials.gov processed this data on December 14, 2017
    This information is provided by ClinicalTrials.gov.