Mortality Reduction After Oral Azithromycin: Morbidity Study

Condition(s) targeted: Childhood Mortality

Intervention: Azithromycin (Drug); Placebo (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: University of California, San Francisco

Official(s) and/or principal investigator(s):
Tom M Lietman, MD, Principal Investigator, Affiliation: University of California, San Francisco
Sun Y Cotter, MPH, Study Director, Affiliation: University of California, San Francisco

Overall contact:
Tom M Lietman, MD, Phone: (415) 502-2662, Email: tom.lietman@ucsf.edu

The long-term goal of this study is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood morbidity and increasing growth, and for the potential selection of antibiotic resistance. The investigators propose a set of 3 cluster-randomized trials comparing communities randomized to oral azithromycin with those randomized to placebo. To assess the generalizability of the intervention, investigators will monitor for antibiotic resistance, which could potentially limit adoption of mass antibiotic treatments. The investigators will also assess several measures of infectious diseases. The investigators hypothesize that mass azithromycin treatments will reduce childhood morbidity and will be accompanied by an acceptable level of antibiotic resistance.

Official title: Evaluating Impact of Azithromycin Mass Drug Administrations on Cause-specific Mortality and Antibiotic Resistance: Morbidity Study

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Presence of malaria parasites on thick blood smear in children 1-60 months

Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months

Fraction of isolates of Staphylococcus aureus exhibiting macrolide resistance by nasal swabs in children 1-60 months

Fraction of isolates of Streptococcus pyogenes exhibiting macrolide resistance by oropharyngeal swabs in children 1-60 months

Evidence of E. coli macrolide resistance in stool specimens in children 1-60 months

Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months

Height over time in children aged 1-60 months

Secondary outcome:

Presence of malaria gametocytes, and density of malaria parasites and gametocytes, in children 1-60 months

Rates of malaria parasitemia among children 1-59.9 months.

Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months

Nasopharyngeal pneumococcal macrolide resistance in individuals 7-12 years

Nasopharyngeal pneumococcal macrolide resistance in children aged 1-60 months seen in local health clinics for a respiratory complaint

Rates of acute respiratory illness among children 1-59.9 months.

Carriage rates and proportions of S. pneumoniae isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-59.9 months.

Carriage rates and proportions of S. pneumoniae isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-59.9 months hospitalized for pneumonia and diarrhea.

Presence of the trachoma grades "follicular trachoma" (TF) and "intense inflammatory trachoma" (TI), as defined by the WHO simplified grading system, in children 1-60 months

Trachoma infection and antibody status in children (1-60 months)

Rates of diarrhea among children 1-59.9 months.

Carriage rates and proportions E. coli isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-59.9 months

Carriage rates and proportions of E. coli isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-59.9 months hospitalized for pneumonia and diarrhea.

Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months

Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through urine samples for L:M ratios of children 6 months

Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months

Nasopharyngeal methicillin-resistant Staphylococcus aureus in children 1-60 months

Carriage rates and proportions of S. aureus isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-59.9 months.

Carriage rates and proportions of S. aureus isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-59.9 months hospitalized for pneumonia and diarrhea.

Nasopharyngeal pneumococcal resistance to penicillin and clindamycin in children 1-60 months

Nasopharyngeal pneumococcal macrolide resistance determinants (ermB and mefA), serotype, and multilocus sequence type in children 1-60 months

Oropharyngeal Streptococcus pyogenes macrolide resistance to penicillin and clindamycin in children 1-60 months

Oropharyngeal Streptococcus pyogenes macrolide resistance determinants (mefA, ermB, ermTR) in children 1-60 months

Microbial diversity in the conjunctival, nasopharyngeal, nasal, oropharyngeal, ear, and intestinal microbiomes of children aged 1-60 months

Serology for exposure to exotic pathogens cross sectional sample of children aged 1-60 months

Knee-heel length and head circumference over time in children aged 1-60 months

Commensal and diarrheagenic E. coli carriage in stool of children aged 1-60 months

Prevalence of carriage of a panel of gastrointestinal parasites (Ancylostoma duodenale, Necator americanus, Ascaris lumbricoides, Trichuris trichiura, Giardia lamblia, Cryptosporidium hominis) of children aged 1-60 months

Prevalence of helicobacter pylori of children aged 1-60 months

Microbiota diversity in the intestinal microbiomes of children aged 1-60 months

Microbiota diversity in the intestinal microbiomes of children aged 1-60 months in azithromycin-treated communities and placebo-treated communities, using phylogenetic, and separately, OTU-based distance measures

Detailed description: The investigators will assess childhood infectious disease morbidity and macrolide resistance over two years, comparing communities where children aged 1-60 months receive biannual oral azithromycin to communities where the children receive biannual oral placebo.

In Niger, a third arm - annual treatment of all persons 1 month and older - will also be

included. Randomization of Treatment Allocation. In each site, 30 communities within a contiguous area of 300,000 to 600,000 individuals will be randomized into the azithromycin or placebo arm. At the Niger site, an additional 15 communities will be randomized to the third arm (azithromycin for everyone). The investigators will use a simple random sample separately for each study site, but without stratification or block randomization within the site. These communities are being randomized from the same pool of communities eligible for a

sister trial (Mortality Reduction After Oral Azithromycin (MORDOR) - Morbidity Study;

clinicaltrials. gov OPP1032340-A). Specific Aims Specific Aim 1: To assess whether macrolide resistance is greater in a population-based community sample of pre-school children, or in a clinic-based sample of ill pre-school children Specific Aim 2: To assess whether biannual mass azithromycin treatments of pre-school children can eliminate ocular chlamydia in a hypoendemic area Specific Aim 3: To assess the diversity of the microbiome of the nasopharynx, oropharynx, nares, conjunctiva, and gastrointestinal tract

Minimum age: 1 Month. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: Communities:

- The community location in target district.

- The community leader consents to participation in the trial

- The community's estimated population is between 200-2,000 people.

- The community is not in an urban area.

Individuals (Intervention):

- Children-treated arms (all 3 sites): All children aged 1-60 months (up to but not

including the 5th birthday), as assessed at the most recent biannual census

- Everyone-treated arm (Niger only): All individuals aged 1 month and up, as assessed

at the most recent biannual census Individuals (Examination & Sample Collection):

- All swabs, blood tests, and stool samples: A random sample of children aged 1-60

months (up to but not including the 5th birthday) based on the previous census

- Anthropometric measurements: All children aged 1-60 months (up to but not including

the 5th birthday) will have anthropometric measurements assessed.

- Nasopharyngeal swabs in untreated children: A random sample of individuals aged 7 -

12 years (7th birthday up to but not including the 12th birthday), as assessed from the previous census

- Clinic-based nasopharyngeal swabs: All children aged 1-60 months (up to but not

including the 5th birthday) who present to a local health clinic in the study area and report symptoms of a respiratory infection Exclusion Criteria: Individuals:

- Pregnant women

- All those who are allergic to macrolides or azalides

- Refusal of village chief (for village inclusion), or refusal of parent or guardian

(for individual inclusion)

Tom M Lietman, MD, Phone: (415) 502-2662, Email: tom.lietman@ucsf.edu

College of Medicine at the University of Malawi, Blantyre, Blantyre, Malawi; Not yet recruiting
Khumbo Kalua, Phone: +265 999958176, Email: kkalua@medcol.mw

The Carter Center, Niger, Niamey, Niger; Recruiting
Mohamed Salissou Kane, Phone: +227 20 73 28 57, Email: mohamedsalissoukane@yahoo.fr

Kongwa Trachoma Project, Kongwa, Tanzania; Recruiting
Harran Mkocha, Phone: +255 26232 31 33, Email: hmkocha@yahoo.com, ktp.2012@yahoo.com

London School of Hygiene & Tropical Medicine, London, United Kingdom; Not yet recruiting
Robin Bailey, MRCP, PhD, Phone: 020 7927 2914, Email: Robin.Bailey@lshtm.ac.uk

UCSF Proctor Foundation, San Francisco, California 94143-0944, United States; Recruiting
Tom M Lietman, MD, Phone: 415-502-2662, Email: tom.lietman@ucsf.edu
Sun Y Cotter, MPH, Phone: 415-476-4243, Email: sun.cotter@ucsf.edu

Johns Hopkins University, Baltimore, Maryland 21205, United States; Recruiting
Sheila West, PhD, Phone: 410-955-2606, Email: shwest@jhmi.edu

Starting date: November 2014
Last updated: July 13, 2015