Mortality Reduction After Oral Azithromycin: Morbidity Study (MORDORMorb)
15. mars 2021 oppdatert av: 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.
Studieoversikt
Status
Fullført
Forhold
Intervensjon / Behandling
Detaljert beskrivelse
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
Studietype
Intervensjonell
Registrering (Faktiske)
72000
Fase
- Fase 4
Kontakter og plasseringer
Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.
Studiesteder
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California
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San Francisco, California, Forente stater, 94143-0944
- UCSF Proctor Foundation
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Maryland
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Baltimore, Maryland, Forente stater, 21205
- Johns Hopkins University
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-
-
-
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Blantyre, Malawi
- College of Medicine at the University of Malawi, Blantyre
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-
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Niamey, Niger
- The Carter Center, Niger
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-
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London, Storbritannia
- London School of Hygiene & Tropical Medicine
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-
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Kongwa, Tanzania
- Kongwa Trachoma Project
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Deltakelseskriterier
Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
1 måned og eldre (Barn, Voksen, Eldre voksen)
Tar imot friske frivillige
Ja
Kjønn som er kvalifisert for studier
Alle
Beskrivelse
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)
Studieplan
Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Firemannsrom
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
|---|---|
|
Aktiv komparator: 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
Andre navn:
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Placebo komparator: 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
|
Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
|
Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 36 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
|
|
Prevalence of macrolide resistance in the stool as determined by genetic determinants or phenotypic testing
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
|
Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months
Tidsramme: 24 months
|
MORDOR Malawi and Niger.
Please note: Each outcome will be analyzed separately for each study site.
|
24 months
|
|
Height over time in children aged 1-60 months
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
|
Weight for Height over time in children aged 1-60 months
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
Density of asexual stages and gametocytes, in children 1-60 months
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
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Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
|
Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 7-12 years of age
Tidsramme: 24 months
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MORDOR Niger
|
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
Tidsramme: 24 months
|
MORDOR Malawi, Tanzania and Niger.
Please note: Each outcome will be analyzed separately for each study site.
|
24 months
|
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Rates of acute respiratory illness among children 1-60 months.
Tidsramme: 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
Tidsramme: 24 months
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MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately for each study site.
|
24 months
|
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Rates of diarrhea among children (1-60 months)
Tidsramme: 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
Tidsramme: 6-24 months after baseline; Niger will also report outcomes at 48 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
|
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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.
Tidsramme: 6-24 months after baseline
|
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
Tidsramme: 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
Tidsramme: 5 x over 24 weeks after baseline
|
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
Tidsramme: 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
Tidsramme: Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
|
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
|
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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
Tidsramme: 24 months
|
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.
Tidsramme: 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. 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
Tidsramme: 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. 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
Tidsramme: 24 months
|
MORDOR Malawi
|
24 months
|
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Head circumference over time in children aged 1-60 months
Tidsramme: 24 months
|
MORDOR Malawi
|
24 months
|
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Knee-heel length over time in children aged 1-60 months
Tidsramme: 24 months
|
MORDOR Malawi
|
24 months
|
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Resistance (in E.coli phenotypically or genetic determinants) in stool of children aged 1-60 months.
Tidsramme: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 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
|
|
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
Tidsramme: Baseline
|
MORDOR Malawi
|
Baseline
|
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Prevalence of helicobacter pylori of children aged 1-60 months
Tidsramme: Baseline
|
MORDOR Malawi
|
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
Tidsramme: Niger will report outcomes at 36, 48 and 60 months
|
MORDOR Niger
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Niger will report outcomes at 36, 48 and 60 months
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Samarbeidspartnere og etterforskere
Det er her du vil finne personer og organisasjoner som er involvert i denne studien.
Samarbeidspartnere
Etterforskere
- Studieleder: Elodie J Lebas, RN, University of California, San Francisco
Publikasjoner og nyttige lenker
Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.
Generelle publikasjoner
- 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.
Studierekorddatoer
Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.
Studer hoveddatoer
Studiestart (Faktiske)
1. november 2014
Primær fullføring (Faktiske)
27. august 2020
Studiet fullført (Faktiske)
27. august 2020
Datoer for studieregistrering
Først innsendt
24. januar 2014
Først innsendt som oppfylte QC-kriteriene
24. januar 2014
Først lagt ut (Anslag)
29. januar 2014
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
17. mars 2021
Siste oppdatering sendt inn som oppfylte QC-kriteriene
15. mars 2021
Sist bekreftet
1. mars 2021
Mer informasjon
Begreper knyttet til denne studien
Nøkkelord
Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- OPP1032340-B
Plan for individuelle deltakerdata (IPD)
Planlegger du å dele individuelle deltakerdata (IPD)?
NEI
Legemiddel- og utstyrsinformasjon, studiedokumenter
Studerer et amerikansk FDA-regulert medikamentprodukt
Ja
Studerer et amerikansk FDA-regulert enhetsprodukt
Nei
produkt produsert i og eksportert fra USA
Nei
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