Clinical trial NCT04235816: Improving Care Through Azithromycin Research for Infants in Africa
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Child Mortality
Keywords: Infant
U5
Azithromycin
Intermittent preventive treatment for infants
Expanded Program on Immunization
Malaria
Sulphadoxine-pyrimethamine
Lead sponsor: Barcelona Institute for Global Health
Sponsor class: OTHER
Collaborators: name: University of Sierra Leone
name: Bill and Melinda Gates Foundation
name: Ministry of Health and Sanitation, Sierra Leone
name: La Caixa Foundation
First posted: 2020-01-22
Enrollment: 20560
Sex: ALL
Minimum age (years): 6
Maximum age (years): 8
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2-arm individually randomized placebo-controlled clinical trial of AZi administration in young children from Sierra Leone.
Primary purpose: PREVENTION

Brief 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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: The rate of all-cause mortality
timeFrame: 18 months of age
Secondary outcomes:
measure: The cause-specific mortality rate
timeFrame: 18 months of age
measure: Malaria related mortality
timeFrame: 18 month of age
measure: Incidence of all-cause hospital admissions
timeFrame: Through study completion, 36 months
measure: Incidence of all-cause outpatient attendances
timeFrame: Through study completion, 36 months
measure: Incidence of confirmed (RDT positive) malaria hospital admissions
timeFrame: Through study completion, 36 months
measure: Incidence of confirmed (blood smear positive/RDT positive) malaria hospital admissions
timeFrame: Through study completion, 36 months
measure: Frequency and severity of drug adverse reactions
timeFrame: Through study completion, 36 months
measure: Prevalence of macrolide resistance in nasopharyngeal isolates
timeFrame: Through study completion, 36 months
measure: Prevalence of macrolide resistance in the gut bacteria
timeFrame: Through study completion, 36 months
measure: Proportion of children with protective antibody responses to specific routine EPI immunizations (measles and yellow fever)
timeFrame: Through study completion, 36 months
Other outcomes:
Locations:
city: Freetown
country: Sierra Leone
facility: College of Medicine and Allied Health Sciences
Study officials:
affiliation: Barcelona Institute for Global Health
name: Clara Menendez, MD, PhD
role: STUDY_CHAIR
References: