MORDORIMort: Mortality Reduction After Oral Azithromycin: Mortality Study

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT02047981
• Collaborator: Bill and Melinda Gates Foundation (Other), Johns Hopkins University (Other), London School of Hygiene and Tropical Medicine (Other)
• Enrollment: 190,238
• Locations: 6
• Arms: 2
• Duration (Months): 45
• Patients Per Site: 31706.3
• Patients Per Site Per Month: 704.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Childhood Mortality	Drug: Azithromycin; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 190238 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Mortality Trial
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Sep 1, 2018
• Actual Study Completion Date: Sep 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
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.	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 Names: Zithromax
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.	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.

Outcome Measures

Primary Outcome Measures

1. All-cause Mortality Rate in Children Aged 1-60 Months [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.

2. All-cause Mortality Rate in Children Aged 1-60 Months [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.

Secondary Outcome Measures

1. Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) [24 Months]

   Deaths were assessed via biannual population census. A pre-specified outcome was cause of death, assessed by verbal autopsy.

2. Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death [24 months]

3. All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children [24 months]

4. Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) [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.

5. Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) [24 Months]

   Cause-specific mortality by intention-to-treat for the four main inferred causes of death in the study area.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Month to 60 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Proctor Foundation	San Francisco	California	United States	94143
2	Johns Hopkins University	Baltimore	Maryland	United States	21205
3	College of Medicine at the University of Malawi, Blantyre	Blantyre		Malawi
4	The Carter Center, Niger	Niamey		Niger
5	Kongwa Trachoma Project	Kongwa		Tanzania
6	London School of Hygiene & Tropical Medicine	London		United Kingdom

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: Catherine A Cook, MPH, University of California, San Francisco

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 15, 2019
• Study Protocol - Jun 27, 2018

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02047981
• Other Study ID Numbers: OPP1032340-A
• First Posted: Jan 29, 2014
• Last Update Posted: Sep 9, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of California, San Francisco: Childhood mortality; Azithromycin; Mass treatment; Infection; Verbal Autopsy
• Additional relevant MeSH terms: Azithromycin

Study Results

Participant Flow

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo
Arm/Group Description	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. 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.	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. 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.
Period Title: MORDOR Stage I Year 1-2
STARTED	97047	93191
COMPLETED	87650	84474
NOT COMPLETED	9397	8717
Period Title: MORDOR Stage I Year 1-2
STARTED	37497	33294
COMPLETED	34611	30931
NOT COMPLETED	2886	2363

Baseline Characteristics

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo	Total
Arm/Group Description	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. 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.	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. 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.	Total of all reporting groups
Overall Participants	97047	93191	190238
Age, Customized (Count of Participants)
1-5 months	7135 7.4%	6870 7.4%	14005 7.4%
6-11 months	12777 13.2%	12318 13.2%	25095 13.2%
12-23 months	18557 19.1%	17886 19.2%	36443 19.2%
24-59 months	58578 60.4%	56117 60.2%	114695 60.3%
Sex: Female, Male (Count of Participants)
Female	47901 49.4%	46019 49.4%	93920 49.4%
Male	49146 50.6%	47172 50.6%	96318 50.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	97047 100%	93191 100%	190238 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Niger	40345 41.6%	35747 38.4%	76092 40%
Malawi	39386 40.6%	39534 42.4%	78920 41.5%
Tanzania	17316 17.8%	17910 19.2%	35226 18.5%
Number of communities (communities) [Number]
Number [communities]	762	750	1512

Outcome Measures

1. Primary Outcome

Title	All-cause Mortality Rate in Children Aged 1-60 Months
Description	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.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo
Arm/Group Description	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. 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.	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. 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.
Measure Participants	97047	93191
Number [deaths per 1000 person-years]	14.6	16.5

2. Primary Outcome

Title	All-cause Mortality Rate in Children Aged 1-60 Months
Description	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.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo
Arm/Group Description	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. 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.	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. 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.
Measure Participants	37497	33294
Number (95% Confidence Interval) [deaths per 1000 person-years]	23.3	24.0

3. Secondary Outcome

Title	Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only)
Description	Deaths were assessed via biannual population census. A pre-specified outcome was cause of death, assessed by verbal autopsy.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo
Arm/Group Description	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. 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.	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. 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.
Measure Participants	40345	35747
Injury	0.22	0.23
Malnutrition	0.39	0.42
AIDS	0.12	0.12
Measles	0.30	0.28
Meningitis	0.82	1.22
Dysentery	0.74	1.14
Diarrhea	3.01	3.60
Pertussis	0.04	0.04
Pneumonia	3.27	3.96
Malaria	5.60	7.22
Hemorrhagic fever	0.08	0.06
Other infection	4.24	5.06
Unspecified	1.43	1.81
Total	22.3	27.3

4. Secondary Outcome

Title	Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only)
Description	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.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo
Arm/Group Description	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. 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.	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. 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.
Measure Participants	17316	17910
Age group Mortality: 1- 5 months	0.46	0.90
Age group Mortality: 6- 11 months	0.47	0.56
Age group Mortality: 12 - 23 months	0.29	0.29
Age group Mortality: 24 - 59 months	0.15	0.10

7. Secondary Outcome

Title	Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only)
Description	Cause-specific mortality by intention-to-treat for the four main inferred causes of death in the study area.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Biannual Mass Oral Azithromycin	Biannual Mass Oral Placebo
Arm/Group Description	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. 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.	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. 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.
Measure Participants	39386	39534
Pneumonia	1.15	1.40
Malaria	3.68	3.84
HIV/AIDS	1.06	1.54
Diarrhoea	0.67	0.72

Adverse Events

Time Frame	36 months.
Adverse Event Reporting Description	A SAE is any adverse event that: Results in death Is life-threatening (i.e., causes an immediate risk of death) Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability or incapacity Results in a congenital anomaly or birth defect Or that is considered to be: · An important medical event SAE reporting excludes mortality as measured for the primary outcome.
Arm/Group Title	Biannual Mass Oral Azithromycin		Biannual Mass Oral Placebo
Arm/Group Description	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. 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.		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. 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.
All Cause Mortality
	Biannual Mass Oral Azithromycin		Biannual Mass Oral Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3262/97047 (3.4%)		3392/93191 (3.6%)
Serious Adverse Events
	Biannual Mass Oral Azithromycin		Biannual Mass Oral Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3273/97047 (3.4%)		3400/93191 (3.6%)
Gastrointestinal disorders
Suspected ileus	1/97047 (0%)	1	0/93191 (0%)	0
Diarrhea	0/97047 (0%)	0	1/93191 (0%)	1
General disorders
Suspected dehydration	0/97047 (0%)	0	2/93191 (0%)	2
Coma	1/97047 (0%)	1	0/93191 (0%)	0
	4/97047 (0%)	4	0/93191 (0%)	0
Death	3262/97047 (3.4%)	3262	3392/93191 (3.6%)	3392
Infections and infestations
Malaria	4/97047 (0%)	4	3/93191 (0%)	3
Respiratory, thoracic and mediastinal disorders
ARI	0/97047 (0%)	0	2/93191 (0%)	2
Pneumonia	1/97047 (0%)	1	0/93191 (0%)	0
Other (Not Including Serious) Adverse Events
	Biannual Mass Oral Azithromycin		Biannual Mass Oral Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97047 (0%)		0/93191 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.