Mortality Reduction After Oral Azithromycin: Mortality Study (MORDORIMort)

• ClinicalTrials.gov Identifier: NCT02047981
• Recruitment Status: Completed
• First Posted: January 29, 2014
• Results First Posted: January 3, 2020
• Last Update Posted: November 8, 2022
• Sponsor: University of California, San Francisco
• 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

Tracking Information

• First Submitted Date: January 24, 2014
• First Posted Date: January 29, 2014
• Results First Submitted Date: August 29, 2019
• Results First Posted Date: January 3, 2020
• Last Update Posted Date: November 8, 2022
• Study Start Date: December 2014
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 2, 2020)

• All-cause Mortality Rate in Children Aged 1-60 Months [ Time Frame: 24 Months ]
  This is a single multi-site trial, with each country as a secondary analysis. Also, an interim analysis of efficacy and futility will be conducted according to a pre-specified plan in the Statistical Analysis Plan.
• All-cause Mortality Rate in Children Aged 1-60 Months [ Time Frame: 36 months ]
  This was a pre-specified contingency study in Niger only in which all communities were treated with mass azithromycin during the third year of the study following the primary 24-month endpoint.

Original Primary Outcome Measures (submitted: January 24, 2014)

All-cause Mortality Rate in children aged 1-60 months [ Time Frame: 24 Months ]

This is a single multi-site trial, with each country as a secondary analysis. Also, an interim analysis of efficacy and futility will be conducted according to a pre-specified plan in the SAP.

Current Secondary Outcome Measures (submitted: October 11, 2022)

• Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) [ Time Frame: 24 Months ]
  Deaths were assessed via biannual population census. A pre-specified outcome was cause of death, assessed by verbal autopsy.
• Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death [ Time Frame: 24 months ]
  Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death during the 24 month phase
• All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children [ Time Frame: 24 months ]
  We recorded clinic visits one year prior the study and during the first year of the study and collected outcomes of these visit.
• Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) [ Time Frame: 24 Months ]
  At 6-monthly intervals a census of the communities was conducted, and for child deaths a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. Mortality due to pneumonia or diarrhea by age group and arm are shown in the outcome measure data table below.
• Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) [ Time Frame: 24 Months ]
  Cause-specific mortality by intention-to-treat for the four main inferred causes of death in the study area.

Original Secondary Outcome Measures (submitted: January 24, 2014)

• Cause-specific Mortality Rate in children aged 1-60 months, as assessed from verbal autopsy [ Time Frame: 24 Months ]
• Cost-effectiveness of mass azithromycin administration, per averted childhood death [ Time Frame: 24 months ]
• All-cause and cause-specific health clinic visits in 1-60 month-old children [ Time Frame: 24 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mortality Reduction After Oral Azithromycin: Mortality Study
• Official Title: Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Mortality Trial
• Brief Summary: Our long-term goal is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood mortality. We propose a single multi-site (multi-country), cluster-randomized trial comparing communities randomized to oral azithromycin with those randomized to placebo. We hypothesize that mass azithromycin treatments will reduce childhood mortality.

Detailed Description

We will assess childhood mortality over three years, comparing communities where children aged 1-60 months receive biannual oral azithromycin ("Azithromycin" arm) for two years, to communities where the children receive biannual oral placebo ("Control" arm) for two years. During the third year at the Niger site only, everyone will receive azithromycin.

This is a cluster-randomized trial; at each site, communities within a contiguous area of 300,000 to 600,000 individuals will be randomized to azithromycin or placebo using simple random sampling.

Niger contingency study: In the event that mass distributions of oral azithromycin are proven to reduce mortality in 1-60 month-old children, then we will treat all communities in Niger with mass azithromycin distributions to test whether the intervention continues to reduce childhood mortality after the initial 2 years of mass treatments.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Childhood Mortality

Intervention

• Drug: Azithromycin
  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. In Niger during year 3, all communities will be offered azithroymcin.
  Other Name: Zithromax
• Drug: 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. In Niger during year 3, all communities will be offered azithroymcin.

Study Arms

• Active Comparator: Biannual mass oral azithromycin

  Comparison of childhood mortality 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.

  In Niger during year 3, all communities will be offered azithroymcin.

  Intervention: Drug: Azithromycin
• Placebo Comparator: Biannual mass oral placebo

  Comparison of childhood mortality 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

  In Niger during year 3, all communities will be offered azithroymcin.

  Intervention: Drug: Placebo

Publications *

• Pickering H, Hart JD, Burr S, Stabler R, Maleta K, Kalua K, Bailey RL, Holland MJ. Impact of azithromycin mass drug administration on the antibiotic-resistant gut microbiome in children: a randomized, controlled trial. Gut Pathog. 2022 Jan 6;14(1):5. doi: 10.1186/s13099-021-00478-6.
• Arzika AM, Maliki R, Abdou A, Mankara AK, Harouna AN, Cook C, Hinterwirth A, Worden L, Zhong L, Chen C, Ruder K, Zhou Z, Lebas E, O'Brien KS, Oldenburg CE, Le V, Arnold BF, Porco TC, Keenan JD, Lietman TM, Doan T. Gut Resistome of Preschool Children After Prolonged Mass Azithromycin Distribution: A Cluster-randomized Trial. Clin Infect Dis. 2021 Oct 5;73(7):1292-1295. doi: 10.1093/cid/ciab485.
• Doan T, Worden L, Hinterwirth A, Arzika AM, Maliki R, Abdou A, Zhong L, Chen C, Cook C, Lebas E, O'Brien KS, Oldenburg CE, Chow ED, Porco TC, Lipsitch M, Keenan JD, Lietman TM. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. N Engl J Med. 2020 Nov 12;383(20):1941-1950. doi: 10.1056/NEJMoa2002606.
• O'Brien KS, Arzika AM, Maliki R, Manzo F, Mamkara AK, Lebas E, Cook C, Bailey RL, West SK, Oldenburg CE, Porco TC, Arnold B, Keenan JD, Lietman TM; MORDOR Study Group. Biannual azithromycin distribution and child mortality among malnourished children: A subgroup analysis of the MORDOR cluster-randomized trial in Niger. PLoS Med. 2020 Sep 15;17(9):e1003285. doi: 10.1371/journal.pmed.1003285. eCollection 2020 Sep.
• Doan T, Hinterwirth A, Arzika AM, Worden L, Chen C, Zhong L, Oldenburg CE, Keenan JD, Lietman TM. Reduction of Coronavirus Burden With Mass Azithromycin Distribution. Clin Infect Dis. 2020 Nov 19;71(16):2282-2284. doi: 10.1093/cid/ciaa606.
• Keenan JD, Arzika AM, Maliki R, Elh Adamou S, Ibrahim F, Kiemago M, Galo NF, Lebas E, Cook C, Vanderschelden B, Bailey RL, West SK, Porco TC, Lietman TM; MORDOR-Niger Study Group. Cause-specific mortality of children younger than 5 years in communities receiving biannual mass azithromycin treatment in Niger: verbal autopsy results from a cluster-randomised controlled trial. Lancet Glob Health. 2020 Feb;8(2):e288-e295. doi: 10.1016/S2214-109X(19)30540-6.
• Bloch EM, Munoz B, Mrango Z, Weaver J, Mboera LEG, Lietman TM, Sullivan DJ Jr, West SK. The impact on malaria of biannual treatment with azithromycin in children age less than 5 years: a prospective study. Malar J. 2019 Aug 23;18(1):284. doi: 10.1186/s12936-019-2914-8.
• Doan T, Arzika AM, Hinterwirth A, Maliki R, Zhong L, Cummings S, Sarkar S, Chen C, Porco TC, Keenan JD, Lietman TM; MORDOR Study Group. Macrolide Resistance in MORDOR I - A Cluster-Randomized Trial in Niger. N Engl J Med. 2019 Jun 6;380(23):2271-2273. doi: 10.1056/NEJMc1901535. No abstract available.
• Keenan JD, Arzika AM, Maliki R, Boubacar N, Elh Adamou S, Moussa Ali M, Cook C, Lebas E, Lin Y, Ray KJ, O'Brien KS, Doan T, Oldenburg CE, Callahan EK, Emerson PM, Porco TC, Lietman TM. Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa. N Engl J Med. 2019 Jun 6;380(23):2207-2214. doi: 10.1056/NEJMoa1817213.
• Porco TC, Hart J, Arzika AM, Weaver J, Kalua K, Mrango Z, Cotter SY, Stoller NE, O'Brien KS, Fry DM, Vanderschelden B, Oldenburg CE, West SK, Bailey RL, Keenan JD, Lietman TM; Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) Study Group. Mass Oral Azithromycin for Childhood Mortality: Timing of Death After Distribution in the MORDOR Trial. Clin Infect Dis. 2019 May 30;68(12):2114-2116. doi: 10.1093/cid/ciy973.
• Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, Kalua K, Mrango Z, Ray KJ, Cook C, Lebas E, O'Brien KS, Emerson PM, Porco TC, Lietman TM; MORDOR Study Group. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018 Apr 26;378(17):1583-1592. doi: 10.1056/NEJMoa1715474.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 2, 2020): 190238
• Original Estimated Enrollment (submitted: January 24, 2014): 227000
• Actual Study Completion Date: September 2018
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Eligibility 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 - All children aged 1-60 months (up to but not including the 5th birthday), as assessed via biannual census.

Exclusion Criteria:

Individuals

- Refusal of village chief (for village inclusion), or refusal of parent or guardian (for individual inclusion)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 60 Months (Child)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Malawi, Niger, Tanzania, United Kingdom, United States

Administrative Information

• NCT Number: NCT02047981
• Other Study ID Numbers: OPP1032340-A
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of California, San Francisco
• Original Responsible Party: Same as current
• Current Study Sponsor: University of California, San Francisco
• Original Study Sponsor: Same as current

Collaborators

• 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: Elodie J Lebas, RN; University of California, San Francisco

• PRS Account: University of California, San Francisco
• Verification Date: October 2022