Mortality Reduction After Oral Azithromycin: Morbidity Study

NCT02048007 | Completed Phase 4 DMC FDA Drug

• 1 other identifier: OPP1032340-B
• Study Type: interventional
• Target: 72,000
• Locations: 5 countries
• Sites: 6

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 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.

Conditions

Childhood Mortality

Keywords

Childhood mortality; Azithromycin; Mass treatment; Infection; Bacterial infections; Trachoma; Chlamydia infections; Malaria; Diarrhea; Respiratory Infections; Antibiotic resistance; Verbal Autopsy; Microbiome

Outcome Measures

Primary Outcomes (6)

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (23)

• Density of asexual stages and gametocytes, in children 1-60 months

  Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months

• Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months

  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

  24 months

• 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

  24 months

• Rates of acute respiratory illness among children 1-60 months.

  6-24 months after baseline

Study Arms (2)

Biannual mass oral azithromycin

ACTIVE COMPARATOR

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 placebo

PLACEBO COMPARATOR

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

Interventions

Azithromycin DRUG

Biannual mass oral azithromycin to children

Also known as: Zithromax

Biannual mass oral azithromycin

Placebo DRUG

Biannual mass oral placebo to children

Biannual mass oral placebo

Eligibility Criteria

• Age: 1 Month+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Individuals:
• Pregnant women
• All those who are allergic to macrolides or azalides

Sponsors & Collaborators

• University of California, San Francisco: lead
• Bill and Melinda Gates Foundation: collaborator
• Johns Hopkins University: collaborator
• London School of Hygiene and Tropical Medicine: collaborator

Study Sites (6)

UCSF Proctor Foundation

San Francisco, California, 94143-0944, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

College of Medicine at the University of Malawi, Blantyre

Blantyre, Malawi

Location

The Carter Center, Niger

Niamey, Niger

Location

Kongwa Trachoma Project

Kongwa, Tanzania

Location

London School of Hygiene & Tropical Medicine

London, United Kingdom

Location

Related Publications (13)

• Arzika AM, Abdou A, Maliki R, Lebas E, Cook C, Vanderschelden B, O'Brien KS, Cotter SY, Varnado NE, Callahan EK, Bailey RL, West SK, Rosenthal PJ, Porco TC, Lietman TM, Keenan JD; MORDOR-Niger Study Group. Biannual Mass Azithromycin Distributions for Preschool Children and Malaria Parasitemia: A Secondary Analysis of the MORDOR Cluster Randomized Trial. JAMA Netw Open. 2025 Aug 1;8(8):e2527148. doi: 10.1001/jamanetworkopen.2025.27148.

  PMID: 40824641 DERIVED

• Liu J, Brennhofer SA, Zhang J, Stroup S, Pholwat S, Arzika AM, Maliki R, Abdou A, Lebas E, O'Brien KS, Arnold BF, Keenan JD, Lietman TM, Platts-Mills JA, Rogawski McQuade ET, Houpt ER. Effect of biannual azithromycin on respiratory pathogens among symptomatic children: results from the randomised Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) I trial. BMJ Glob Health. 2025 Feb 10;10(2):e016043. doi: 10.1136/bmjgh-2024-016043.

  PMID: 39929535 DERIVED

• 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.

  PMID: 35997979 DERIVED

• 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.

  PMID: 35190534 DERIVED

• 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.

  PMID: 35156069 DERIVED

• 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.

  PMID: 34967883 DERIVED

• 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.

  PMID: 34559801 DERIVED

• 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.

  PMID: 31237871 DERIVED

• 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.

  PMID: 30950493 DERIVED

• 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.

  PMID: 30419040 DERIVED

• 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.

  PMID: 30151409 DERIVED

• 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.

  PMID: 28402408 DERIVED

• 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.

  PMID: 25858004 DERIVED

MeSH Terms

Conditions

Infections; Bacterial Infections; Trachoma; Chlamydia Infections; Malaria; Diarrhea; Respiratory Tract Infections

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Conjunctivitis, Bacterial; Eye Infections, Bacterial; Chlamydiaceae Infections; Gram-Negative Bacterial Infections; Eye Infections; Conjunctivitis; Conjunctival Diseases; Eye Diseases; Corneal Diseases; Sexually Transmitted Diseases, Bacterial; Sexually Transmitted Diseases; Communicable Diseases; Genital Diseases; Urogenital Diseases; Protozoan Infections; Parasitic Diseases; Mosquito-Borne Diseases; Vector Borne Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Tom M Lietman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Elodie J Lebas, RN

  University of California, San Francisco

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2014
• First Posted: January 29, 2014
• Study Start: November 1, 2014
• Primary Completion: August 27, 2020
• Study Completion: August 27, 2020
• Last Updated: March 17, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); NI (1); GB (1); TA (1); MA (1)