Mortality Reduction After Oral Azithromycin: Morbidity Study

Childhood Mortality Clinical Trial

— MORDORMorb  

Official title:

Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Morbidity Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02048007
• Other study ID #: OPP1032340-B
• Status: Completed
• Phase: Phase 4
• Start date: November 2014
• Est. completion date: August 27, 2020

Study information

• Verified date: March 2021
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72000
• Est. completion date: August 27, 2020
• Est. primary completion date: August 27, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Month and older

Eligibility

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)

Related Conditions & MeSH terms

• Childhood Mortality

Intervention

Drug:
• Azithromycin
Biannual mass oral azithromycin to children
• Placebo
Biannual mass oral placebo to children

Locations

Country	Name	City	State
Malawi	College of Medicine at the University of Malawi, Blantyre	Blantyre
Niger	The Carter Center, Niger	Niamey
Tanzania	Kongwa Trachoma Project	Kongwa
United Kingdom	London School of Hygiene & Tropical Medicine	London
United States	Johns Hopkins University	Baltimore	Maryland
United States	UCSF Proctor Foundation	San Francisco	California

Sponsors (4)

Lead Sponsor	Collaborator
University of California, San Francisco	Bill and Melinda Gates Foundation, Johns Hopkins University, London School of Hygiene and Tropical Medicine

Countries where clinical trial is conducted

United States,  Malawi,  Niger,  Tanzania,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Primary	Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
Primary	Prevalence of macrolide resistance in the stool as determined by genetic determinants or phenotypic testing	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Primary	Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months	MORDOR Malawi and Niger. Please note: Each outcome will be analyzed separately for each study site.	24 months
Primary	Height over time in children aged 1-60 months	MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Primary	Weight for Height over time in children aged 1-60 months	MORDOR Malawi and Niger Please note:Each outcome will be analyzed separately in each of the two study sites.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Secondary	Density of asexual stages and gametocytes, in children 1-60 months	MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Secondary	Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Secondary	Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 7-12 years of age	MORDOR Niger	24 months
Secondary	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	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	24 months
Secondary	Rates of acute respiratory illness among children 1-60 months.	MORDOR Tanzania	6-24 months after baseline
Secondary	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	MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately for each study site.	24 months
Secondary	Rates of diarrhea among children (1-60 months)	MORDOR Tanzania	6-24 months after baseline
Secondary	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	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	6-24 months after baseline; Niger will also report outcomes at 48 months
Secondary	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.	MORDOR Tanzania	6-24 months after baseline
Secondary	Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months	MORDOR Malawi	5 x over 24 weeks after baseline
Secondary	Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through urine samples for L:M ratios of children 6 months	MORDOR Malawi	5 x over 24 weeks after baseline
Secondary	Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months	MORDOR Malawi	5 x over 24 weeks after baseline
Secondary	Nasopharyngeal pneumococcal evidence of beta lactam and macrolide resistance in in children 1-60 months as measured by RNA-sequencing of the resistome	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
Secondary	Nasopharyngeal pneumococcal macrolide resistance determinants (eg erythromycin ribosomal methylase B and mefA), serotype, and multilocus sequence type in children 1-60 months	MORDOR Niger	24 months
Secondary	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.	Investigators will examine the effects of mass azithromycin (pre-treatment and post-treatment) on the human microbiome of African children by performing metagenomic experiments.; MORDOR Niger	24 months
Secondary	Microbial diversity in the intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing	Investigators will examine the effects of mass azithromycin (pre-treatment and post-treatment) on the human microbiome of African children by performing metagenomic experiments.; MORDOR Malawi	24 months
Secondary	Serology for exposure to exotic pathogens of children aged 1-60 months as measured by lateral flow assays or Multiplex bead array	MORDOR Malawi	24 months
Secondary	Head circumference over time in children aged 1-60 months	MORDOR Malawi	24 months
Secondary	Knee-heel length over time in children aged 1-60 months	MORDOR Malawi	24 months
Secondary	Resistance (in E.coli phenotypically or genetic determinants) in stool of children aged 1-60 months.	MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.	Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Secondary	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	MORDOR Malawi	Baseline
Secondary	Prevalence of helicobacter pylori of children aged 1-60 months	MORDOR Malawi	Baseline
Secondary	Antibody response to enteric pathogens and malaria measured with a multiplex bead assay from dried blood spots collected from children 1 - 59 months	MORDOR Niger	Niger will report outcomes at 36, 48 and 60 months