Improving Care Through Azithromycin Research for Infants in Africa (ICARIA)

Evaluation of the Impact on Childhood Mortality of Azithromycin Plus Intermittent Preventive Treatment Administered Through the Expanded Program on Immunization in Sierra Leone

Infectious diseases are among the most common causes of mortality in the over 2.5 million children under 5 years of age (U5) who died in 2018 in sub-Saharan Africa (SSA). New approaches to treatment and prevention of these diseases are needed to increase child survival. Sierra Leone has one of the highest rates of under-five child mortality in the world. It is estimated that 32,000 children die each year, the leading causes being neonatal conditions, malaria, pneumonia and diarrhea. In Sierra Leone, the available information on malaria indicates that it accounts for 38% of deaths among under-five children. Reducing the prevalence and impact of the disease among the general population is a major priority of the Ministry of Health and Sanitation (MoHS) of Sierra Leone .

Intermittent Preventative Treatment in infants (IPTi) - the administration of a full course antimalarial treatment to infants at individual timepoints regardless of infection status- has been shown to reduce clinical malaria and anemia in infants in the first year of life . When delivered alongside the Expanded Program on Immunization (EPI), IPTi with Sulphadoxine-pyrimethamine (SP) is a highly cost-effective intervention. . Sierra Leone is currently the only country that implements nationwide the World Health Organization's (WHO) IPTi guideline, which is administered within the first year of life. However, its benefit when expanded into the second year of life remains unknown. Taking the advantage of the inclusion in the EPI program of a booster dose of measles vaccine at 15 months of age, the ICARIA trial will also assess the efficacy of adding a dose of IPTi-SP at this age.

Recent studies show that azithromycin (AZi) - a macrolide antibiotic with some antimalarial effect- is associated with a significant reduction in childhood mortality when used in mass drug administration (MDA) for trachoma elimination in areas of sub-Saharan Africa (SSA) with child mortality rates far beyond Sustainable Development Goals , . However, despite the potential benefit of the intervention several fundamental scientific questions need to be answered before it can be recommended for large-scale implementation.

Study Overview

• Status: Recruiting
• Conditions: Child Mortality
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

Detailed Description

In order to generate the conclusive evidence needed to inform policy and accelerate the implementation of this intervention, we propose to carry out a large-scale clinical trial on the impact on all-cause mortality up to 18 months of age of AZi administration through EPI. The potential development of antibiotic and SP resistance, AZi and SP interactions with routine immunizations, as well as the safety and the impact on the health system will be all assessed in the ICARIA trial.

To provide the evidence needed to inform policy and practice and to accelerate the implementation of this intervention, a large-scale clinical trial on the impact on all-cause mortality up to 18 months of age of AZi administration through the World Health Organisation Expanded Program on Immunisation (EPI) will be carried out in Sierra Leone. The clinical trial will be individually randomised, placebo-controlled with a factorial design whereby AZi will be administered alongside routine preventive health interventions of the EPI, such as immunisations and Intermittent Preventive Treatment in infants (IPTi), which is recommended by the WHO for malaria prevention in this age group. The potential development of antibiotic resistance, the interactions with routine immunisations, the safety and the impact on the health system of AZi administration will be all assessed in this trial.

• Study Type: Interventional
• Enrollment (Estimated): 20560
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Haily Chen, MSc.; Phone Number: 2319 +34 932275400; Email: haily.chen@isglobal.org
• Study Contact Backup: Name: Anna Luca, MSc.; Phone Number: 1805 +34 932275400; Email: anna.lucas@isglobal.org

Study Locations

• Sierra Leone
  • Freetown, Sierra Leone
    • Recruiting
    • College of Medicine and Allied Health Sciences
    • Contact: Samai Mohamed, Doctor; Phone Number: +23278841262; Email: dhmsamai@yahool.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 1 year (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Parents/guardians have signed the informed consent
• Permanent residence in the study area-health facility catchment area
• Without known allergies to or contraindications to macrolides
• Without known allergies to or contraindications to SP
• Agreement to complete the EPI scheme at the recruitment health facility
• Parents/guardians agree to participate

Exclusion Criteria:

• Residence outside the study area or planning to move out in the following 12 months from enrolment
• Known history of allergy or contraindications to macrolides and/or SP
• Known history of allergy or contraindications to SP
• With signs of any acute illness at the time of recruitment
• Participating in other intervention studies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1; AZi at DTP-1 visit at 6 weeks of age, AZi (plus IPTi) at measles visit at 9 months of age and AZi (plus IPTi) at measles booster visit at 15 months of age.	Drug: Azithromycin; Administration of azithromycin during the first 15 months of life through the Expanded Program on Immunisation; Other Names: AZi; Sumamed
Placebo Comparator: Group 2; Placebo at DTP-1 visit at 6 weeks of age, placebo (plus IPTi) at measles visit at 9 months of age and placebo (plus IPTi) at measles booster visit at 15 months of age.	Drug: Placebo; Administration of placebo during the first 15 months of life through the Expanded Program on Immunisation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rate of all-cause mortality	all-cause mortality rate at 18 months of age	18 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The cause-specific mortality rate	Cause-specific mortality rate at 18 months of age	18 months of age
Malaria related mortality	Malaria related mortality at 18 months of age	18 month of age
Incidence of all-cause hospital admissions	Incidence of all-cause hospital admissions	Through study completion, 36 months
Incidence of all-cause outpatient attendances	Incidence of all-cause outpatient attendances at the health facilities	Through study completion, 36 months
Incidence of confirmed (RDT positive) malaria hospital admissions	Incidence of confirmed (RDT positive) malaria hospital admissions at all health facilities	Through study completion, 36 months
Incidence of confirmed (blood smear positive/RDT positive) malaria hospital admissions	Incidence of confirmed (blood smear positive/RDT positive) malaria hospital admissions at all health facilities	Through study completion, 36 months
Frequency and severity of drug adverse reactions	Frequency and severity of drug adverse reactions throughout the trial	Through study completion, 36 months
Prevalence of macrolide resistance in nasopharyngeal isolates	Prevalence of macrolide resistance in nasopharyngeal isolates	Through study completion, 36 months
Prevalence of macrolide resistance in the gut bacteria	Prevalence of macrolide resistance in the gut bacteria	Through study completion, 36 months
Proportion of children with protective antibody responses to specific routine EPI immunizations (measles and yellow fever)	Proportion of children with protective antibody responses to specific routine EPI	Through study completion, 36 months

Collaborators and Investigators

• Sponsor: Barcelona Institute for Global Health
• Collaborators: Bill and Melinda Gates Foundation; University of Sierra Leone; Ministry of Health and Sanitation, Sierra Leone
• Investigators: Study Chair: Clara Menendez, MD, PhD, Barcelona Institute for Global Health

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2021
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: January 17, 2020
• First Submitted That Met QC Criteria: January 17, 2020
• First Posted (Actual): January 22, 2020

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Malaria; Infant; Azithromycin; U5; Intermittent preventive treatment for infants; Expanded Program on Immunization; Sulphadoxine-pyrimethamine
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: ICARIA; OPP1196642 (Other Grant/Funding Number: Bill & Melinda Gates Foundation)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes