Child MortalityPhase 3ICARIANCT04235816
Improving Care Through Azithromycin Research for Infants in Africa
A Phase 3 study testing Azithromycin in people with Child Mortality, run by Barcelona Institute for Global Health at 1 site in Sierra Leone.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 6 to 8 weeksHealthy volunteers can take part
- Conditions the study is for
- Child Mortality
- What is being tested?
- Azithromycin
- Type of treatment
- Vaccines
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20,560 participants
- Where
- 1 siteSierra Leone
- Study dates
- 15 Mar 2021to 30 Apr 2026
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 8 weeks
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Sierra Leone1 site
College of Medicine and Allied Health Sciences
Freetown
About this study
Official title: 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.
Read the 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.
- Conditions
- Child Mortality
- Being tested
- Azithromycin, Placebo
- Keywords
- Infant, U5, Azithromycin, Intermittent preventive treatment for infants, Expanded Program on Immunization, Malaria, Sulphadoxine-pyrimethamine
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzithromycinDrug
Also called AZi, Sumamed
Administration of azithromycin during the first 15 months of life through the Expanded Program on Immunisation
PlaceboDrug
Administration of placebo during the first 15 months of life through the Expanded Program on Immunisation
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Active comparator | 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. Receives: Drug: Azithromycin |
| Group 2 | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The rate of all-cause mortality
all-cause mortality rate at 18 months of age
Measured: 18 months of age
Secondary outcomes (10)
The cause-specific mortality rate
Cause-specific mortality rate at 18 months of age
Measured: 18 months of age
Malaria related mortality
Malaria related mortality at 18 months of age
Measured: 18 month of age
Incidence of all-cause hospital admissions
Incidence of all-cause hospital admissions
Measured: Through study completion, 36 months
Incidence of all-cause outpatient attendances
Incidence of all-cause outpatient attendances at the health facilities
Measured: 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
Measured: 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
Measured: Through study completion, 36 months
Frequency and severity of drug adverse reactions
Frequency and severity of drug adverse reactions throughout the trial
Measured: Through study completion, 36 months
Prevalence of macrolide resistance in nasopharyngeal isolates
Prevalence of macrolide resistance in nasopharyngeal isolates
Measured: Through study completion, 36 months
Prevalence of macrolide resistance in the gut bacteria
Prevalence of macrolide resistance in the gut bacteria
Measured: 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
Measured: Through study completion, 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2020
- Study start15 Mar 2021
- Primary completion11 Sep 2025
- Study completion30 Apr 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Child MortalityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 2-arm individually randomized placebo-controlled clinical trial of AZi administration in young children from Sierra Leone.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20,560 participants (actual)
Sponsor and investigators
- Lead sponsor
- Barcelona Institute for Global Health
- Sponsor type
- University, hospital or other
- Collaborators
- University of Sierra Leone, Bill and Melinda Gates Foundation, Ministry of Health and Sanitation, Sierra Leone, La Caixa Foundation
- Responsible party
- Sponsor
- Investigators
- Clara Menendez, MD, PhD, Principal investigator, Barcelona Institute for Global Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04235816
- Sponsor's protocol ID
- ICARIA
- Other IDs
- OPP1196642
- Acronym
- ICARIA
- Status last verified
- Nov 2026
- First submitted
- 17 Jan 2020
- Last updated
- 6 Nov 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Chen H, Montero-Vale M, Owusu-Kyei K, Lara-Munoz A, Rubio-Garcia E, de Pedro-Jove R, Guiral E, Chileshe MN, Williams J, Bofill A, Samai M, Casals-Pascual C, Vila J, Menendez C. Early-life carriage and antibiotic resistance of Streptococcus pneumoniae in infants from Sierra Leone. Front Microbiol. 2026 May 22;17:1822296. doi: 10.3389/fmicb.2026.1822296. eCollection 2026.
PubMed 42254515Chen H, Owusu-Kyei K, Fombah AE, Williams J, Garcia-Fernandez C, Rovira-Vallbona E, Bofill A, Quinto L, Figueroa-Romero A, Mac-Abdul F, Samai M, Mayor A, Menendez C. Prevalence of Molecular Markers of Resistance to Antimalarial Drugs Three Years After Perennial Malaria Chemoprevention in Sierra Leone. Gates Open Res. 2025 Oct 8;9:81. doi: 10.12688/gatesopenres.16367.1. eCollection 2025.
PubMed 41080970Owusu-Kyei K, Chen H, Chileshe M, Quinto L, Sibley M, Figueroa-Romero A, Llach M, Ramirez M, Bofill A, Samai M, Menendez C; ICARIA Trial Team. Impact of oral azithromycin and intermittent preventive treatment with sulfadoxine-pyrimethamine regimen on child mortality in Sierra Leone: trial protocol for a randomised, two-arm, double-blinded, placebo-controlled clinical trial (ICARIA). Trials. 2024 Sep 27;25(1):626. doi: 10.1186/s13063-024-08443-9.
PubMed 39334260
Study at a glance
From the registry record, last updated by the sponsor on 6 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Impact on Childhood Mortality of Azithromycin Plus Intermittent Preventive Treatment Administered Through the Expanded Program on Immunization in Sierra Leone
- ClinicalTrials.gov ID
- NCT04235816
- Acronym / sponsor ID
- ICARIA / ICARIA
- Conditions
- Child Mortality
- Keywords
- Infant, U5, Azithromycin, Intermittent preventive treatment for infants, Expanded Program on Immunization, Malaria, Sulphadoxine-pyrimethamine
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20,560 participants (actual)
- Lead sponsor
- Barcelona Institute for Global HealthUniversity, hospital or other
- Collaborators
- University of Sierra Leone, Bill and Melinda Gates Foundation, Ministry of Health and Sanitation, Sierra Leone, La Caixa Foundation
- Study start
- 15 Mar 2021 (actual)
- Primary completion
- 11 Sep 2025 (actual)
- Study completion
- 30 Apr 2026 (actual)
- First posted
- 22 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- 2-arm individually randomized placebo-controlled clinical trial of AZi administration in young children from Sierra Leone.
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Active comparator | Drug: AzithromycinAZi 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. |
| Group 2 | Placebo comparator | Drug: PlaceboPlacebo 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. |
Who may qualify
- Ages
- 6 to 8 weeks
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzithromycinAlso: AZi, SumamedAdministration of azithromycin during the first 15 months of life through the Expanded Program on Immunisation | Drug | Group 1 |
| PlaceboAdministration of placebo during the first 15 months of life through the Expanded Program on Immunisation | Drug | Group 2 |
Primary outcome
The rate of all-cause mortality
Time frame: 18 months of age
all-cause mortality rate at 18 months of age
10 secondary outcomes
The cause-specific mortality rate
Time frame: 18 months of age
Malaria related mortality
Time frame: 18 month of age
Incidence of all-cause hospital admissions
Time frame: Through study completion, 36 months
Incidence of all-cause outpatient attendances
Time frame: Through study completion, 36 months
Incidence of confirmed (RDT positive) malaria hospital admissions
Time frame: Through study completion, 36 months
Incidence of confirmed (blood smear positive/RDT positive) malaria hospital admissions
Time frame: Through study completion, 36 months
Frequency and severity of drug adverse reactions
Time frame: Through study completion, 36 months
Prevalence of macrolide resistance in nasopharyngeal isolates
Time frame: Through study completion, 36 months
Prevalence of macrolide resistance in the gut bacteria
Time frame: Through study completion, 36 months
Proportion of children with protective antibody responses to specific routine EPI immunizations (measles and yellow fever)
Time frame: Through study completion, 36 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2026.
- Derived from this study: PubMed 42254515Chen H, Montero-Vale M, Owusu-Kyei K, Lara-Munoz A, Rubio-Garcia E, de Pedro-Jove R, Guiral E, Chileshe MN, Williams J, Bofill A, Samai M, Casals-Pascual C, Vila J, Menendez C. Early-life carriage and antibiotic resistance of Streptococcus pneumoniae in infants from Sierra Leone. Front Microbiol. 2026 May 22;17:1822296. doi: 10.3389/fmicb.2026.1822296. eCollection 2026.
- Derived from this study: PubMed 41080970Chen H, Owusu-Kyei K, Fombah AE, Williams J, Garcia-Fernandez C, Rovira-Vallbona E, Bofill A, Quinto L, Figueroa-Romero A, Mac-Abdul F, Samai M, Mayor A, Menendez C. Prevalence of Molecular Markers of Resistance to Antimalarial Drugs Three Years After Perennial Malaria Chemoprevention in Sierra Leone. Gates Open Res. 2025 Oct 8;9:81. doi: 10.12688/gatesopenres.16367.1. eCollection 2025.
- Derived from this study: PubMed 39334260Owusu-Kyei K, Chen H, Chileshe M, Quinto L, Sibley M, Figueroa-Romero A, Llach M, Ramirez M, Bofill A, Samai M, Menendez C; ICARIA Trial Team. Impact of oral azithromycin and intermittent preventive treatment with sulfadoxine-pyrimethamine regimen on child mortality in Sierra Leone: trial protocol for a randomised, two-arm, double-blinded, placebo-controlled clinical trial (ICARIA). Trials. 2024 Sep 27;25(1):626. doi: 10.1186/s13063-024-08443-9.
Related trials for Child Mortality
RecruitingObservational study
National, Non Interventional Study of Invasive Pneumococcal Disease in Children and Newborns
Pneumococcal Infections, Pneumococcal Conjugate Vaccine
Not yet recruitingObservational study
Frequency of Metabolic Acidosis in the Pediatric Intensive Care Unit
Metabolic Acidosis, Acid-Base Imbalance
RecruitingPhase 4
Azithromycin for Child Survival in Niger II
Mortality, Antimicrobial Resistance
Active, not recruiting
Enhancing Intergenerational Health in Nigeria: Peripartum as Critical Life Stage for Cardiovascular Health
Hypertension in Pregnancy, Hypertension
Not yet recruiting
Perinatal Mortality Outcomes Through Household Infection Pathways
Stillbirth and Neonatal Mortality, Perinatal Mortality
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clara Menendez, MD, PhD principal investigator
Barcelona Institute for Global Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Azithromycin in people with Child Mortality, run by Barcelona Institute for Global Health at 1 site in Sierra Leone.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sierra Leone. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The rate of all-cause mortality (time frame: 18 months of age). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04235816, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2026.