Mortality Reduction After Oral Azithromycin: Morbidity Study (MORDORMorb)
15 mars 2021 mis à jour par: University of California, San Francisco
Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Morbidity Study
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.
Aperçu de l'étude
Statut
Complété
Les conditions
Intervention / Traitement
Description détaillée
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
Type d'étude
Interventionnel
Inscription (Réel)
72000
Phase
- Phase 4
Contacts et emplacements
Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.
Lieux d'étude
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Blantyre, Malawi
- College of Medicine at the University of Malawi, Blantyre
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Niamey, Niger
- The Carter Center, Niger
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London, Royaume-Uni
- London School of Hygiene & Tropical Medicine
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Kongwa, Tanzanie
- Kongwa Trachoma Project
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California
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San Francisco, California, États-Unis, 94143-0944
- UCSF Proctor Foundation
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Maryland
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Baltimore, Maryland, États-Unis, 21205
- Johns Hopkins University
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Critères de participation
Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.
Critère d'éligibilité
Âges éligibles pour étudier
1 mois et plus (Enfant, Adulte, Adulte plus âgé)
Accepte les volontaires sains
Oui
Sexes éligibles pour l'étude
Tout
La description
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)
Plan d'étude
Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Quadruple
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Comparateur actif: 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. |
Biannual mass oral azithromycin to children
Autres noms:
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Comparateur placebo: 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 |
Biannual mass oral placebo to children
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
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Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
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Prevalence of macrolide resistance in the stool as determined by genetic determinants or phenotypic testing
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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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
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Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months
Délai: 24 months
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MORDOR Malawi and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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24 months
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Height over time in children aged 1-60 months
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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Weight for Height over time in children aged 1-60 months
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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MORDOR Malawi and Niger Please note:Each outcome will be analyzed separately in each of the two study sites.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Density of asexual stages and gametocytes, in children 1-60 months
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 7-12 years of age
Délai: 24 months
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MORDOR Niger
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24 months
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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
Délai: 24 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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24 months
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Rates of acute respiratory illness among children 1-60 months.
Délai: 6-24 months after baseline
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MORDOR Tanzania
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6-24 months after baseline
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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
Délai: 24 months
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MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately for each study site.
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24 months
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Rates of diarrhea among children (1-60 months)
Délai: 6-24 months after baseline
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MORDOR Tanzania
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6-24 months after baseline
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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
Délai: 6-24 months after baseline; Niger will also report outcomes at 48 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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6-24 months after baseline; Niger will also report outcomes at 48 months
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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.
Délai: 6-24 months after baseline
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MORDOR Tanzania
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6-24 months after baseline
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Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months
Délai: 5 x over 24 weeks after baseline
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MORDOR Malawi
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5 x over 24 weeks after baseline
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Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through urine samples for L:M ratios of children 6 months
Délai: 5 x over 24 weeks after baseline
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MORDOR Malawi
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5 x over 24 weeks after baseline
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Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months
Délai: 5 x over 24 weeks after baseline
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MORDOR Malawi
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5 x over 24 weeks after baseline
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Nasopharyngeal pneumococcal evidence of beta lactam and macrolide resistance in in children 1-60 months as measured by RNA-sequencing of the resistome
Délai: Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
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Nasopharyngeal pneumococcal macrolide resistance determinants (eg erythromycin ribosomal methylase B and mefA), serotype, and multilocus sequence type in children 1-60 months
Délai: 24 months
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MORDOR Niger
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24 months
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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.
Délai: 24 months
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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
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Microbial diversity in the intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing
Délai: 24 months
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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
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Serology for exposure to exotic pathogens of children aged 1-60 months as measured by lateral flow assays or Multiplex bead array
Délai: 24 months
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MORDOR Malawi
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24 months
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Head circumference over time in children aged 1-60 months
Délai: 24 months
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MORDOR Malawi
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24 months
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Knee-heel length over time in children aged 1-60 months
Délai: 24 months
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MORDOR Malawi
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24 months
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Resistance (in E.coli phenotypically or genetic determinants) in stool of children aged 1-60 months.
Délai: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
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MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
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Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
|
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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
Délai: Baseline
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MORDOR Malawi
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Baseline
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Prevalence of helicobacter pylori of children aged 1-60 months
Délai: Baseline
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MORDOR Malawi
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Baseline
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Antibody response to enteric pathogens and malaria measured with a multiplex bead assay from dried blood spots collected from children 1 - 59 months
Délai: Niger will report outcomes at 36, 48 and 60 months
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MORDOR Niger
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Niger will report outcomes at 36, 48 and 60 months
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Collaborateurs et enquêteurs
C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.
Parrainer
Collaborateurs
Les enquêteurs
- Directeur d'études: Elodie J Lebas, RN, University of California, San Francisco
Publications et liens utiles
La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.
Publications générales
- Porco TC, Stoller NE, Keenan JD, Bailey RL, Lietman TM. Public key cryptography for quality assurance in randomization for clinical trials. Contemp Clin Trials. 2015 May;42:167-8. doi: 10.1016/j.cct.2015.03.016. Epub 2015 Apr 7. No abstract available.
- Arzika AM, Mindo-Panusis D, Abdou A, Kadri B, Nassirou B, Maliki R, Alsoudi AF, Zhang T, Cotter SY, Lebas E, O'Brien KS, Callahan EK, Bailey RL, West SK, Goodhew EB, Martin DL, Arnold BF, Porco TC, Lietman TM, Keenan JD; Macrolides Oraux pour Reduire les Deces Avec un Oeil sur la Resistance (MORDOR)-Niger Study Group. Effect of Biannual Mass Azithromycin Distributions to Preschool-Aged Children on Trachoma Prevalence in Niger: A Cluster Randomized Clinical Trial. JAMA Netw Open. 2022 Aug 1;5(8):e2228244. doi: 10.1001/jamanetworkopen.2022.28244.
- Arzika AM, Maliki R, Goodhew EB, Rogier E, Priest JW, Lebas E, O'Brien KS, Le V, Oldenburg CE, Doan T, Porco TC, Keenan JD, Lietman TM, Martin DL, Arnold BF; MORDOR-Niger Study Group. Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger. Nat Commun. 2022 Feb 21;13(1):976. doi: 10.1038/s41467-022-28565-5.
- Hart JD, Samikwa L, Meleke H, Burr SE, Cornick J, Kalua K, Bailey RL. Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015-17. Lancet Microbe. 2022 Feb;3(2):e142-e150. doi: 10.1016/S2666-5247(21)00279-2.
- Arzika AM, Maliki R, Ali MM, Alio MK, Abdou A, Cotter SY, Varnado NE, Lebas E, Cook C, Oldenburg CE, O'Brien KS, Callahan EK, Bailey RL, West SK, Porco TC, Lietman TM, Keenan JD; MORDOR-Niger Study Group. Effect of Mass Azithromycin Distributions on Childhood Growth in Niger: A Cluster-Randomized Trial. JAMA Netw Open. 2021 Dec 1;4(12):e2139351. doi: 10.1001/jamanetworkopen.2021.39351.
- Bloch EM, Mrango Z, Weaver J, Munoz B, Lietman TM, West SK. Causes of death after biannual azithromycin treatment: A community-level randomized clinical trial. PLoS One. 2021 Sep 24;16(9):e0250197. doi: 10.1371/journal.pone.0250197. eCollection 2021.
- Arzika AM, Maliki R, Boubacar N, Kane S, Cotter SY, Lebas E, Cook C, Bailey RL, West SK, Rosenthal PJ, Porco TC, Lietman TM, Keenan JD; MORDOR Study Group. Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial. PLoS Med. 2019 Jun 25;16(6):e1002835. doi: 10.1371/journal.pmed.1002835. eCollection 2019 Jun.
- West SK, Bloch E, Weaver J, Munoz B, Mrango Z, Kasubi M, Lietman T, Coles C. Morbidity in a Longitudinal Cohort of Children Residing in Villages Randomized to Biannual Treatment With Azithromycin Versus Placebo. Clin Infect Dis. 2020 Feb 3;70(4):574-580. doi: 10.1093/cid/ciz269.
- Oldenburg CE, Arzika AM, Maliki R, Kane MS, Lebas E, Ray KJ, Cook C, Cotter SY, Zhou Z, West SK, Bailey R, Porco TC, Keenan JD, Lietman TM; MORDOR Study Group. Safety of azithromycin in infants under six months of age in Niger: A community randomized trial. PLoS Negl Trop Dis. 2018 Nov 12;12(11):e0006950. doi: 10.1371/journal.pntd.0006950. eCollection 2018 Nov.
- Doan T, Hinterwirth A, Arzika AM, Cotter SY, Ray KJ, O'Brien KS, Zhong L, Chow ED, Zhou Z, Cummings SL, Fry D, Oldenburg CE, Worden L, Porco TC, Keenan JD, Lietman TM. Mass Azithromycin Distribution and Community Microbiome: A Cluster-Randomized Trial. Open Forum Infect Dis. 2018 Jul 24;5(8):ofy182. doi: 10.1093/ofid/ofy182. eCollection 2018 Aug.
- Doan T, Arzika AM, Ray KJ, Cotter SY, Kim J, Maliki R, Zhong L, Zhou Z, Porco TC, Vanderschelden B, Keenan JD, Lietman TM. Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial. Clin Infect Dis. 2017 May 1;64(9):1147-1153. doi: 10.1093/cid/cix141.
Dates d'enregistrement des études
Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.
Dates principales de l'étude
Début de l'étude (Réel)
1 novembre 2014
Achèvement primaire (Réel)
27 août 2020
Achèvement de l'étude (Réel)
27 août 2020
Dates d'inscription aux études
Première soumission
24 janvier 2014
Première soumission répondant aux critères de contrôle qualité
24 janvier 2014
Première publication (Estimation)
29 janvier 2014
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
17 mars 2021
Dernière mise à jour soumise répondant aux critères de contrôle qualité
15 mars 2021
Dernière vérification
1 mars 2021
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- OPP1032340-B
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
NON
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Oui
Étudie un produit d'appareil réglementé par la FDA américaine
Non
produit fabriqué et exporté des États-Unis.
Non
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