We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE April 21, 2015
First Posted Date  ICMJE April 24, 2015
Last Update Posted Date October 9, 2019
Study Start Date  ICMJE June 2016
Actual Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2015)
Forced Expiratory Volume in one second z score (FEV1) [ Time Frame: 12 months ]
Change in FEV1after 12 months of initiation of therapy with azithromycin
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2015)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 23, 2015)
  • 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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children
Official Title  ICMJE Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children
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.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lung Disease
  • HIV Infection
Intervention  ICMJE
  • Drug: Azithromycin
  • Drug: Placebo
Study Arms  ICMJE
  • 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
    Intervention: 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
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 8, 2019)
347
Original Estimated Enrollment  ICMJE
 (submitted: April 23, 2015)
400
Actual Study Completion Date  ICMJE August 2019
Actual Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years to 19 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Malawi,   Zimbabwe
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02426112
Other Study ID Numbers  ICMJE QA698
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party London School of Hygiene and Tropical Medicine
Original Responsible Party Same as current
Current Study Sponsor  ICMJE London School of Hygiene and Tropical Medicine
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Biomedical Research and Training Institute, Zimbabwe
  • Malawi-Liverpool-Wellcome Trust Clinical Research Programme
  • University of Tromso
  • University of Cape Town
  • University of Oxford
Investigators  ICMJE
Principal Investigator: Rashida Ferrand London School of Hygiene and Tropical Medicine
Principal Investigator: Jon O Odland University of Tromso
PRS Account London School of Hygiene and Tropical Medicine
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP