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Mortality Reduction After Oral Azithromycin: Morbidity Study (MORDOR2)

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ClinicalTrials.gov Identifier: NCT02048007
Recruitment Status : Completed
First Posted : January 29, 2014
Last Update Posted : January 17, 2018
Sponsor:
Collaborators:
Bill and Melinda Gates Foundation
Johns Hopkins University
London School of Hygiene and Tropical Medicine
Information provided by (Responsible Party):
University of California, San Francisco

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 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.

Condition or disease Intervention/treatment Phase
Childhood Mortality Drug: Azithromycin Drug: Placebo Phase 4

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


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 72000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Morbidity Study
Study Start Date : November 2014
Primary Completion Date : December 2017
Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: Biannual mass oral azithromycin

Comparison of childhood infectious and nutritional morbidity in communities randomized to azithromycin versus communities randomized to placebo.

Children aged 1 month to 60 months per community will be offered weight or height-based, directly observed, oral azithromycin suspension every 6 months for 2 years

Morbidity monitoring:

Collect swabs (nasopharyngeal, nasal, conjunctival), blood samples, (thick/thin blood smears, hemoglobin, dried blood spots), and stool samples from 40 randomly selected children aged 1 month to 60 months per community; collect swabs (nasopharyngeal) from 40 randomly selected children aged 7-12 years per community.

Anthropometry for all children aged 1 to 60 months per community.

Collect nasopharyngeal swabs from all children aged 1-60 months who are seen at a local health clinic and have a respiratory complaint.

Drug: Azithromycin
Biannual mass oral azithromycin to children
Other Name: Zithromax
Placebo Comparator: Biannual mass oral placebo

Comparison of childhood infectious and nutritional morbidity in communities randomized to azithromycin versus communities randomized to placebo.

Children aged 1 month to 60 months per community will be offered weight or height-based, directly observed, oral placebo every 6 months for 2 years

Collect swabs (nasopharyngeal, nasal, conjunctival), blood samples, (thick/thin blood smears, hemoglobin, dried blood spots), and stool samples from 40 randomly selected children aged 1 month to 60 months per community; collect swabs (nasopharyngeal) from 40 randomly selected children aged 7-12 years per community

Anthropometry for all children aged 1 to 60 months per community

Collect nasopharyngeal swabs from all children aged 1-60 months who are seen at a local health clinic and have a respiratory complaint

Drug: Placebo
Biannual mass oral placebo to children



Primary Outcome Measures :
  1. Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  2. Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  3. Evidence of E. coli macrolide resistance in stool specimen in children 1-60 months as measured by RNA-sequencing of the resistome [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  4. Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months [ Time Frame: 24 months ]

    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the three study sites.

    Please note: Each outcome will be analyzed separately in each of the three study sites.


  5. Height for Age (HAZ) over time in children aged 1-60 months [ Time Frame: 24 months ]
    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.

  6. Weight for Height (WHZ) over time in children aged 1-60 months [ Time Frame: 24 months ]
    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.


Secondary Outcome Measures :
  1. Presence of malaria parasites in children 1-60 months [ Time Frame: 24 months ]

    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.

    Please note: Each outcome will be analyzed separately in each of the two study sites.


  2. Density of asexual stages and gametocytes, in children 1-60 months [ Time Frame: 24 months ]

    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.

    Please note: Each outcome will be analyzed separately in each of the two study sites.


  3. Rates of malaria parasitemia among children 1-60 months. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  4. Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  5. Nasopharyngeal pneumococcal macrolide resistance in individuals 7-12 years as measured by RNA-sequencing of the resistome [ Time Frame: 24 months ]
    MORDOR Niger

  6. Nasopharyngeal pneumococcal macrolide resistance in children aged 1-60 months seen in local health clinics for a respiratory complaint as measured by RNA-sequencing of the resistome [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  7. Rates of acute respiratory illness among children 1-60 months. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  8. Carriage rates of S. pneumoniae isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months. [ Time Frame: 6-24 months after baseline ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  9. Proportions of S. pneumoniae isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months. [ Time Frame: 6-24 months after baseline ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  10. Carriage rates of S. pneumoniae isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months hospitalized for pneumonia and diarrhea. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  11. Proportions of S. pneumoniae isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months hospitalized for pneumonia and diarrhea. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  12. 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 [ Time Frame: 24 months ]
    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the three study sites.

  13. Trachoma infection and antibody status in children (1-60 months) as measured by Polymerase chain reaction (PCR) for chlamydia [ Time Frame: Baseline and 24 months ]
    MORDOR Tanzania

  14. Rates of diarrhea among children (1-60 months) [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  15. Carriage rates E. coli isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months [ Time Frame: 6-24 months after baseline ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  16. 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. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  17. Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months [ Time Frame: 5 x over 24 weeks after baseline ]
    MORDOR Malawi

  18. Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through urine samples for L:M ratios of children 6 months [ Time Frame: 5 x over 24 weeks after baseline ]
    MORDOR Malawi

  19. Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months [ Time Frame: 5 x over 24 weeks after baseline ]
    MORDOR Malawi

  20. Methicillin-resistant Staphylococcus aureus by nasal swab in children 1-60 months [ Time Frame: 24 months ]
    MORDOR Niger

  21. Carriage rates of S. aureus isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months. [ Time Frame: 6-24 months after baseline ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  22. Proportions of S. aureus isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months. [ Time Frame: 6-24 months after baseline ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  23. Carriage rates of S. aureus isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months hospitalized for pneumonia and diarrhea. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  24. Proportions of S. aureus isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months hospitalized for pneumonia and diarrhea. [ Time Frame: 6-24 months after baseline ]
    MORDOR Tanzania

  25. Nasopharyngeal pneumococcal evidence of beta lactam and macrolide resistance in in children 1-60 months as measured by RNA-sequencing of the resistome [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  26. Nasopharyngeal pneumococcal macrolide resistance determinants (ermB and mefA), serotype, and multilocus sequence type in children 1-60 months [ Time Frame: Time Frame: 24 months ]
    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the three study sites.

  27. Microbial diversity in the conjunctival, nasopharyngeal, nasal, and intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing to look at Simpson's diversity [ Time Frame: 24 months ]

    Investigators will examine the effects of mass azithromycin (pre-treatment and post-treatment) on the human microbiome of African children by performing metagenomic experiments. Specifically, investigators will examine the microbiomes present in the nasopharynx, nares, conjunctiva, and intestine.

    MORDOR Niger


  28. Microbial diversity in the intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing [ Time Frame: 24 months ]

    Investigators will examine the effects of mass azithromycin (pre-treatment and post-treatment) on the human microbiome of African children by performing metagenomic experiments. Specifically, investigators will examine the intestine.

    MORDOR Malawi


  29. Serology for exposure to exotic pathogens of children aged 1-60 months as measured by lateral flow assays or Multiplex bead array [ Time Frame: 24 months ]
    MORDOR Malawi

  30. Head circumference over time in children aged 1-60 months [ Time Frame: 24 months ]
    MORDOR Malawi

  31. Knee-heel length over time in children aged 1-60 months [ Time Frame: 24 months ]
    MORDOR Malawi

  32. Commensal and diarrheagenic E. coli carriage in stool of children aged 1-60 months as measured by RNA-sequencing of the resistome [ Time Frame: 24 months ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  33. 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 [ Time Frame: Baseline ]
    MORDOR Malawi

  34. Prevalence of helicobacter pylori of children aged 1-60 months [ Time Frame: Baseline ]
    MORDOR Malawi

  35. Microbiota diversity in the intestinal microbiomes of children aged 1-60 months [ Time Frame: Baseline ]
    MORDOR Niger

  36. Microbiota diversity in the intestinal microbiomes of children aged 1-60 months in azithromycin-treated communities and placebo-treated communities, using phylogenetic, and separately, Operational Taxonomic Unit (OTU)-based distance measures [ Time Frame: Baseline ]
    MORDOR Niger

  37. Weight over time in children aged 1-60 months [ Time Frame: 24 months ]
    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.

  38. Height over time in children aged 1-60 months [ Time Frame: 24 months ]
    MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   1 Month and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02048007


Locations
United States, California
UCSF Proctor Foundation
San Francisco, California, United States, 94143-0944
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21205
Malawi
College of Medicine at the University of Malawi, Blantyre
Blantyre, Malawi
Niger
The Carter Center, Niger
Niamey, Niger
Tanzania
Kongwa Trachoma Project
Kongwa, Tanzania
United Kingdom
London School of Hygiene & Tropical Medicine
London, United Kingdom
Sponsors and Collaborators
University of California, San Francisco
Bill and Melinda Gates Foundation
Johns Hopkins University
London School of Hygiene and Tropical Medicine
Investigators
Principal Investigator: Tom M Lietman, MD University of California, San Francisco
Study Director: Catherine A Cook, MPH University of California, San Francisco

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02048007     History of Changes
Other Study ID Numbers: OPP1032340-B
First Posted: January 29, 2014    Key Record Dates
Last Update Posted: January 17, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of California, San Francisco:
Trachoma
Childhood mortality
Azithromycin
Mass treatment
Infection
Bacterial infections
Chlamydia infections
Malaria
Diarrhea
Respiratory Infections
Antibiotic resistance
Verbal Autopsy
Microbiome