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Mortality Reduction After Oral Azithromycin: Morbidity Study (MORDOR2)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified October 2014 by University of California, San Francisco
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
ClinicalTrials.gov Identifier:
NCT02048007
First received: January 24, 2014
Last updated: October 29, 2014
Last verified: October 2014
  Purpose

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 Intervention Phase
Childhood Mortality
Drug: Azithromycin
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluating Impact of Azithromycin Mass Drug Administrations on Cause-specific Mortality and Antibiotic Resistance: Morbidity Study

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Presence of malaria parasites on thick blood smear in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Fraction of isolates of Staphylococcus aureus exhibiting macrolide resistance by nasal swabs in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Fraction of isolates of Streptococcus pyogenes exhibiting macrolide resistance by oropharyngeal swabs in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Evidence of E. coli macrolide resistance in stool specimens in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Height over time in children aged 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.


Secondary Outcome Measures:
  • Presence of malaria gametocytes, and density of malaria parasites and gametocytes, in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Rates of malaria parasitemia among children 1-59.9 months. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Nasopharyngeal pneumococcal macrolide resistance in individuals 7-12 years [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Nasopharyngeal pneumococcal macrolide resistance in children aged 1-60 months seen in local health clinics for a respiratory complaint [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Rates of acute respiratory illness among children 1-59.9 months. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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 [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Trachoma infection and antibody status in children (1-60 months) [ Time Frame: Baseline and 24 months ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • Rates of diarrhea among children 1-59.9 months. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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 [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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 ] [ Designated as safety issue: No ]
    MORDOR Malawi

  • 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 ] [ Designated as safety issue: No ]
    MORDOR Malawi

  • 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 ] [ Designated as safety issue: No ]
    MORDOR Malawi

  • Nasopharyngeal methicillin-resistant Staphylococcus aureus in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • 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. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • 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. [ Time Frame: 6-24 months after baseline ] [ Designated as safety issue: No ]
    MORDOR Tanzania

  • Nasopharyngeal pneumococcal resistance to penicillin and clindamycin in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Nasopharyngeal pneumococcal macrolide resistance determinants (ermB and mefA), serotype, and multilocus sequence type in children 1-60 months [ Time Frame: Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Oropharyngeal Streptococcus pyogenes macrolide resistance to penicillin and clindamycin in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Oropharyngeal Streptococcus pyogenes macrolide resistance determinants (mefA, ermB, ermTR) in children 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • Microbial diversity in the conjunctival, nasopharyngeal, nasal, oropharyngeal, ear, and intestinal microbiomes of children aged 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]

    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, oropharynx, nares, ear, conjunctiva, and intestine.

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


  • Serology for exposure to exotic pathogens cross sectional sample of children aged 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    MORDOR Malawi

  • Knee-heel length and head circumference over time in children aged 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    MORDOR Malawi

  • Commensal and diarrheagenic E. coli carriage in stool of children aged 1-60 months [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Please note: Each outcome will be analyzed separately in each of the three study sites.

  • 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 ] [ Designated as safety issue: No ]
    MORDOR Malawi

  • Prevalence of helicobacter pylori of children aged 1-60 months [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    MORDOR Malawi


Estimated Enrollment: 72000
Study Start Date: November 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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, oropharyngeal, 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, annual mass oral azithromycin to everyone
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, oropharyngeal, 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
Other Name: Placebo
Active Comparator: Annual mass oral azithromycin to everyone

Everyone 1 month and older will be offered weight or height-based, directly observed, oral azithromycin every 6 months for 2 years

Morbidity monitoring:

Collect swabs (nasopharyngeal, oropharyngeal, nasal) and stool samples from 40 randomly selected children aged 1 to 60 months per community; collect swabs (nasopharyngeal) from 40 randomly selected children aged 7-12 years per community

Drug: Azithromycin
Biannual mass oral azithromycin to children, annual mass oral azithromycin to everyone
Other Name: Zithromax

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

  Eligibility

Ages Eligible for Study:   1 Month and older
Genders Eligible for Study:   Both
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
  • 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)
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02048007

Contacts
Contact: Tom M Lietman, MD (415) 502-2662 tom.lietman@ucsf.edu
Contact: Nicole E Stoller, MPH 415.476.2460 Nicole.Stoller@ucsf.edu

Locations
United States, California
UCSF Proctor Foundation Not yet recruiting
San Francisco, California, United States, 94143-0944
Contact: Tom M Lietman, MD    415-502-2662    tom.lietman@ucsf.edu   
Contact: Nicole E Stoller, MPH    415-476-2460    Nicole.Stoller@ucsf.edu   
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21205
Contact: Sheila West, PhD    410-955-2606    shwest@jhmi.edu   
Malawi
College of Medicine at the University of Malawi, Blantyre Not yet recruiting
Blantyre, Malawi
Contact: Khumbo Kalua    +265 999958176    kkalua@medcol.mw   
Niger
The Carter Center, Niger Not yet recruiting
Niamey, Niger
Contact: Mohamed Salissou Kane    +227 20 73 28 57    mohamedsalissoukane@yahoo.fr   
Tanzania
Kongwa Trachoma Project Not yet recruiting
Kongwa, Tanzania
Contact: Harran Mkocha    +255 26232 31 33    hmkocha@yahoo.com, ktp.2012@yahoo.com   
United Kingdom
London School of Hygiene & Tropical Medicine Not yet recruiting
London, United Kingdom
Contact: Robin Bailey, MRCP, PhD    020 7927 2914    Robin.Bailey@lshtm.ac.uk   
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: Nicole E Stoller, MPH University of California, San Francisco
  More Information

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02048007     History of Changes
Other Study ID Numbers: OPP1032340-B
Study First Received: January 24, 2014
Last Updated: October 29, 2014
Health Authority: United States: Institutional Review Board
Niger: Institutional Review Board
Tanzania: National Institute for Medical Research
Malawi: National Health Sciences Research Committee

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

ClinicalTrials.gov processed this record on November 25, 2014