Clinical trial NCT02048007: Mortality Reduction After Oral Azithromycin: Morbidity Study
Official title: Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Morbidity Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Childhood Mortality
Keywords: Childhood mortality
Azithromycin
Mass treatment
Infection
Bacterial infections
Trachoma
Chlamydia infections
Malaria
Diarrhea
Respiratory Infections
Antibiotic resistance
Verbal Autopsy
Microbiome
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: Johns Hopkins University
name: London School of Hygiene and Tropical Medicine
First posted: 2014-01-29
Enrollment: 72000
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 in Malawi, Niger, and Tanzania 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.

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.

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. 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).

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, nares, conjunctiva, and gastrointestinal tract

Eligibility 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

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)

Primary outcomes:
measure: Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
measure: Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
measure: Prevalence of macrolide resistance in the stool as determined by genetic determinants or phenotypic testing
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
measure: Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months
timeFrame: 24 months
measure: Height over time in children aged 1-60 months
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
measure: Weight for Height over time in children aged 1-60 months
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Secondary outcomes:
measure: Density of asexual stages and gametocytes, in children 1-60 months
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
measure: Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
measure: Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 7-12 years of age
timeFrame: 24 months
measure: Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 1-60 month olds seen in local health clinics for a respiratory complaint
timeFrame: 24 months
measure: Rates of acute respiratory illness among children 1-60 months.
timeFrame: 6-24 months after baseline
measure: Presence of the trachoma grades "follicular trachoma" (TF) and "intense inflammatory trachoma" (TI), as defined by the World Health Organization (WHO) simplified grading system, in children 1-60 months
timeFrame: 24 months
measure: Rates of diarrhea among children (1-60 months)
timeFrame: 6-24 months after baseline
measure: Proportion of rectal/stool isolates with evidence of resistance (in for example E.coli) to macrolides and other antibiotics commonly used to treat pediatric infections among children 1-60 months
timeFrame: 6-24 months after baseline; Niger will also report outcomes at 48 months
measure: Proportions of E. coli isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months hospitalized for pneumonia and diarrhea.
timeFrame: 6-24 months after baseline
measure: Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months
timeFrame: 5 x over 24 weeks after baseline
measure: Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through urine samples for L:M ratios of children 6 months
timeFrame: 5 x over 24 weeks after baseline
measure: Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months
timeFrame: 5 x over 24 weeks after baseline
measure: Nasopharyngeal pneumococcal evidence of beta lactam and macrolide resistance in in children 1-60 months as measured by RNA-sequencing of the resistome
timeFrame: Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
measure: Nasopharyngeal pneumococcal macrolide resistance determinants (eg erythromycin ribosomal methylase B and mefA), serotype, and multilocus sequence type in children 1-60 months
timeFrame: 24 months
measure: Microbiome in the stool, nasopharynx, nares, and conjunctiva in children aged 1-59 months, as measured using next generation sequencing. Arms will be compared using Euclidean distance and diversity compared using Simpson's index.
timeFrame: 24 months
measure: Microbial diversity in the intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing
timeFrame: 24 months
measure: Serology for exposure to exotic pathogens of children aged 1-60 months as measured by lateral flow assays or Multiplex bead array
timeFrame: 24 months
measure: Head circumference over time in children aged 1-60 months
timeFrame: 24 months
measure: Knee-heel length over time in children aged 1-60 months
timeFrame: 24 months
measure: Resistance (in E.coli phenotypically or genetic determinants) in stool of children aged 1-60 months.
timeFrame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
measure: 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
timeFrame: Baseline
measure: Prevalence of helicobacter pylori of children aged 1-60 months
timeFrame: Baseline
measure: Antibody response to enteric pathogens and malaria measured with a multiplex bead assay from dried blood spots collected from children 1 - 59 months
timeFrame: Niger will report outcomes at 36, 48 and 60 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Proctor Foundation
state: California
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Blantyre
country: Malawi
facility: College of Medicine at the University of Malawi, Blantyre
city: Niamey
country: Niger
facility: The Carter Center, Niger
city: Kongwa
country: Tanzania
facility: Kongwa Trachoma Project
city: London
country: United Kingdom
facility: London School of Hygiene & Tropical Medicine
Study officials:
affiliation: University of California, San Francisco
name: Tom M Lietman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Elodie J Lebas, RN
role: STUDY_DIRECTOR
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