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

• ClinicalTrials.gov Identifier: NCT02426112
• Recruitment Status: Completed
• First Posted: April 24, 2015
• Last Update Posted: October 9, 2019
• Sponsor: London School of Hygiene and Tropical Medicine
• 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: April 21, 2015
• First Posted Date: April 24, 2015
• Last Update Posted Date: October 9, 2019
• Study Start Date: June 2016
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: 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: Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-infected Children
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Chronic Lung Disease
• HIV Infection

Intervention

• Drug: Azithromycin
• Drug: Placebo

Study Arms

• 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 *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 8, 2019): 347
• Original Estimated Enrollment (submitted: April 23, 2015): 400
• Actual Study Completion Date: August 2019
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years to 19 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Malawi, Zimbabwe

Administrative Information

• NCT Number: NCT02426112
• Other Study ID Numbers: QA698
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: London School of Hygiene and Tropical Medicine
• Original Responsible Party: Same as current
• Current Study Sponsor: London School of Hygiene and Tropical Medicine
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: London School of Hygiene and Tropical Medicine
• Verification Date: October 2019