Azithromycin for Child Mortality

(MIRAMA Trial)

Not currently recruiting at 2 trial locations

Overseen By Djeinam Toure

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, San Francisco

Must not be taking: Macrolides

Disqualifiers: Allergy to macrolides, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if administering the antibiotic azithromycin, along with vitamin A, can reduce child mortality rates in Burkina Faso. Researchers will compare communities where children receive azithromycin to those where they receive a placebo. Children aged 1 to 11 months in participating communities are eligible, as long as they do not have a known allergy to macrolide antibiotics. The trial also examines whether using azithromycin impacts antibiotic resistance in the community. As a Phase 4 trial, this research seeks to understand how the already FDA-approved and effective treatment can benefit more patients.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What is the safety track record for azithromycin and placebo?

Research has shown that azithromycin can reduce death rates in children. Studies found that fewer children died when they received azithromycin compared to those who did not. However, widespread use can lead to increased bacterial resistance, reducing the medicine's effectiveness.

Azithromycin is generally safe for children. Previous studies did not identify any major side effects, so serious reactions are uncommon. Since this trial is in a later stage, strong evidence supports the treatment's safety. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the use of azithromycin for reducing child mortality because it represents a unique approach compared to traditional methods. Unlike standard treatments that primarily focus on vaccination and nutritional supplementation, azithromycin is an antibiotic that may help prevent infections that are a major cause of death in young children. This treatment is particularly promising because it's administered biannually alongside child health initiatives, potentially improving overall community health outcomes. Additionally, this approach could offer a dual benefit of reducing both mortality rates and antimicrobial resistance through careful monitoring, which is not typically a focus of existing child health strategies.

What evidence suggests that azithromycin might be an effective treatment for reducing child mortality?

Research has shown that azithromycin can help reduce child deaths. In one study, children aged 1 to 59 months who took azithromycin had a 14% lower chance of dying from any cause compared to those who did not take it. Another study found a 13.5% decrease in deaths among children who received azithromycin. In this trial, some participants will receive biannual mass oral azithromycin alongside child health days, while others will receive a placebo. These findings suggest that regularly administering azithromycin can effectively lower the risk of death in young children. The evidence supports azithromycin's potential to improve survival rates in children under five. ^{2 6 7 8 9}

Who Is on the Research Team?

Thomas Lietman, MD

Principal Investigator

University of California, San Francisco

Georges Dimithe

Principal Investigator

Helen Keller International

Are You a Good Fit for This Trial?

This trial is for babies aged 1 to 11 months living in certain regions of Burkina Faso. It's part of a program that includes vitamin A supplementation and malnutrition checks. Babies with known allergies to macrolides or those from communities unsafe for the study team cannot participate.

Inclusion Criteria

Community eligibility criteria: Located in one of the three selected regions: SudOuest, Centre-Ouest, Hauts-Bassins

gave us a sense of what it means to be a part of a community that is focused on improving the health of its members

I am under 1 year old.

Exclusion Criteria

Community exclusion criteria: Inaccessible or unsafe for the study team

My child is allergic to macrolide antibiotics.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Census

Conduct a baseline census of the study areas for treatment coverage estimations

2 weeks

Treatment

Biannual mass distribution of azithromycin or placebo to children aged 1-11 months, paired with Vitamin A distribution

24 months

Biannual visits (door-to-door)

Resistance Monitoring

Collect rectal and nasal swabs from children to monitor antimicrobial resistance

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin
• Placebo

Trial Overview The trial tests if giving azithromycin, an antibiotic, can reduce infant mortality when added to 'Child Health Days' activities versus a placebo. Children will receive either azithromycin or a placebo alongside vitamin A and nutrition screening.

How Is the Trial Designed?

Group I: Biannual mass oral azithromycin + child health days Active Control 1 Intervention

Bi-annual Mass Azithromycin distribution to all children 1-11 months old in participating communities paired with the Child Health Days Vitamin A distribution platform

Group II: Resistance Sub Study: Azithromycin + Child Health Days Active Control 1 Intervention

Antimicrobial resistance will be monitored in a parallel study of communities from the target study area. 60 communities will be randomly selected among eligible communities, and randomized in a 1 : 1 fashion

Group III: Resistance Sub Study: Placebo + Child Health Days Placebo Group 1 Intervention

Antimicrobial resistance will be monitored in a parallel study of communities from the target study area. 60 communities will be randomly selected among eligible communities, and randomized in a 1 : 1 fashion

Group IV: Biannual mass placebo + child health days Placebo Group 1 Intervention

Bi-annual Mass placebo distribution to all children 1-11 months old in participating communities paired with the Child Health Days Vitamin A distribution platform

Azithromycin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in United States as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in Canada as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Bill and Melinda Gates Foundation

Collaborator

Trials

428

Recruited

23,060,000+

Helen Keller International

Collaborator

Trials

32

Recruited

742,000+

Centre de Recherche en Sante de Nouna, Burkina Faso

Collaborator

Trials

19

Recruited

818,000+

Published Research Related to This Trial

A meta-analysis of nine studies involving 3,597 pediatric patients found that azithromycin has a statistically significant lower risk of adverse events compared to other antibiotics, indicating its relative safety in treating infectious diseases in children.

While azithromycin is generally safe, caution is advised with higher dosages, suggesting that careful monitoring is necessary to avoid potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of azithromycin in pediatric infectious diseases: a clinical systematic review and meta-analysis. Li, D., Wang, Y.[2022]

A cluster-randomized trial involving 3936 children in Niger found that biannual mass distributions of azithromycin did not significantly increase overall childhood growth in height or weight compared to a placebo over a 4-year period.

However, among the shortest children at baseline, azithromycin was associated with a small increase in height, suggesting that while the overall growth benefit was not evident, there may be specific advantages for children who are initially shorter.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Mass Azithromycin Distributions on Childhood Growth in Niger: A Cluster-Randomized Trial. Arzika, AM., Maliki, R., Ali, MM., et al.[2022]

In the MORDOR trial involving over 130,000 person-years of follow-up, communities treated with azithromycin showed a 9% lower mortality rate compared to placebo communities, suggesting a potential benefit of the drug in reducing child mortality.

The analysis indicated that azithromycin may specifically reduce deaths from HIV/AIDS and pneumonia, with significant findings showing a 30% reduction in HIV/AIDS deaths and a 42% reduction in pneumonia deaths, highlighting its potential efficacy in addressing these critical health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial. Hart, JD., Kalua, K., Keenan, JD., et al.[2022]

In a 2-year trial involving 594 community clusters in Niger, biannual mass distribution of azithromycin to children under 5 years reduced all-cause mortality by 18%, particularly lowering deaths from malaria, pneumonia, dysentery, and meningitis.

Despite the reduction in mortality, the distribution of causes of death was similar between the azithromycin and placebo groups, suggesting that azithromycin's broad-spectrum antibiotic properties may have contributed to the overall decrease in child deaths from infectious diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Keenan, JD., Arzika, AM., Maliki, R., et al.[2021]

In a study involving 35 children aged 9 months to 12 years, azithromycin (AZM) demonstrated a high efficacy rate of 93.9% in treating various pediatric infectious diseases, including pharyngotonsillitis and pneumonia.

The treatment was generally safe, with only a few cases of elevated liver enzymes reported and no significant clinical adverse reactions observed, indicating that AZM can be a reliable option for pediatric infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic and clinical evaluation of azithromycin in the pediatric field]. Kitamura, K., Kamiya, H., Nakano, T., et al.[2016]

Azithromycin is an effective antibiotic for treating respiratory infections in children, but it should be used cautiously due to concerns about antibiotic resistance, particularly with pneumococcal bacteria.

It is generally not recommended for certain conditions like acute pharyngitis, acute otitis media, or pneumococcal community-acquired pneumonia in children, especially in those at high risk for bacteremia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin use in paediatrics: A practical overview. Ovetchkine, P., Rieder, MJ.[2021]

A new age-based dosing strategy for azithromycin in children 1-11 months old was found to be highly effective, with 89%-93% of doses falling within safe tolerance limits, compared to only 70% with the existing height-based method.

The proposed two-tiered dosing approach (80 mg for 1-2 months and 160 mg for 3-11 months) simplifies administration while ensuring safety, making it more efficient for mass distribution in trachoma control programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simplified dosing of oral azithromycin for children 1-11 months old in child survival programmes: age-based and height-based dosing protocols. Hu, H., Arzika, AM., Sie, A., et al.[2022]

Azithromycin significantly reduces the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates, with a relative risk of 0.83 based on a review of 11 studies involving 473 neonates.

While azithromycin is associated with various adverse events, including respiratory and gastrointestinal issues, there was no significant increase in liver enzyme levels compared to placebo, indicating a relatively safe profile for this medication in neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use and safety of azithromycin in neonates: a systematic review. Smith, C., Egunsola, O., Choonara, I., et al.[2022]

A study involving 450 children in Burkina Faso found that a single dose of azithromycin resulted in mild and rare adverse events, with no significant difference in adverse events between the azithromycin and placebo groups.

Vomiting was the only notable adverse event, occurring more frequently in the azithromycin group (7.2%) compared to the placebo group (1.9%), indicating that azithromycin is generally safe for preschool children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Clinic Visits following a Single Dose of Oral Azithromycin among Preschool Children: A Randomized Placebo-Controlled Trial. Sié, A., Dah, C., Bountogo, M., et al.[2022]

In a review of clinical trials involving 1,129 children, azithromycin was associated with significantly fewer side effects (7.6%) compared to standard treatments (13.8%), indicating a better safety profile.

The most common side effects in the azithromycin group were gastrointestinal issues, which occurred in 5.6% of patients, compared to 11.7% in those receiving comparator treatments, suggesting azithromycin is better tolerated overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety and tolerance of azithromycin in children. Hopkins, S.[2019]

In a study involving 30 communities in Tanzania, biannual treatment with single-dose azithromycin did not significantly reduce the prevalence of clinical malaria in preschool children compared to a placebo, suggesting limited efficacy against malaria.

While there was a decline in malaria positivity over time in both treatment groups, the placebo group showed a greater odds of decline in RDT-positivity, indicating that the effect of azithromycin on malaria may be temporary and not substantial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact on malaria of biannual treatment with azithromycin in children age less than 5 years: a prospective study. Bloch, EM., Munoz, B., Mrango, Z., et al.[2020]

Azithromycin demonstrated high clinical effectiveness in treating respiratory tract infections in children, with 89.1% of patients experiencing symptom relief after just 3 days and an overall effectiveness of 94.8% in the study of 156 children.

The treatment was associated with a low incidence of adverse events, with only 11.5% of patients reporting side effects, primarily mild issues like diarrhea and vomiting, indicating that azithromycin is a safe option for managing these infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of azithromycin in the treatment of respiratory infections in children. Lakoš, AK., Pangerčić, A., Gašparić, M., et al.[2012]

In the MORDOR clinical trial, azithromycin was found to reduce mortality rates more effectively in areas with higher baseline mortality risk, with an estimated additional reduction of 6-12% for each doubling of baseline mortality.

The analysis utilized Cox proportional hazards models to assess the interaction between baseline mortality risk and the effectiveness of azithromycin, indicating that the drug's impact varies based on child age and geographical site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect Modification by Baseline Mortality in the MORDOR Azithromycin Trial. Oron, AP., Burstein, R., Mercer, LD., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39167806/

Azithromycin to Reduce Mortality - An Adaptive Cluster- ... Azithromycin distributions to children 1 to 59 months of age significantly reduced mortality and was more effective than treatment of infants 1 to 11 months of ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2504644

Mass Administration of Azithromycin to Infants in Mali to ... Results of that trial showed a significant 13.5% lower incidence of death from any cause among children who received azithromycin than among ...

3. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2823798

Twice-Yearly Doses of Azithromycin Past Infancy Cut Child ... Communities assigned to twice-yearly distribution of azithromycin for children aged 1 to 59 months saw roughly 12 deaths per 1000 person-years ...

4. journals.plos.org journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0003875

Mass azithromycin for prevention of child mortality among ... The MORDOR study demonstrated a 14% reduction in all-cause childhood mortality with biannual mass azithromycin distribution. The largest effects ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02047981

Mortality Reduction After Oral Azithromycin: Mortality Study We will assess childhood mortality over three years, comparing communities where children aged 1-60 months receive biannual oral azithromycin ("Azithromycin" ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12204265/

Azithromycin mass drug administration to reduce child ... Trials have demonstrated that azithromycin mass drug administration (MDA) to children 1-59 months old reduces mortality, but increases antimicrobial resistance ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3106233/

Childhood Mortality in a Cohort Treated With Mass ... During a mass azithromycin campaign for trachoma, all-cause and infectious mortality rates were lower in treated children compared to untreated children.

8. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2836245

Spillover of Azithromycin Mass Drug Administration and ... Communities distributing azithromycin to all children aged 1 to 59 months saw lower mortality among those aged 1 to 11 months if those children had an older ...

9. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2312093

Azithromycin to Reduce Mortality — An Adaptive Cluster ... Azithromycin distributions to children 1 to 59 months of age significantly reduced mortality and was more effective than treatment of infants 1 to 11 months of ...