Azithromycin for Child Mortality

(MIRAMA Trial)

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

694400 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will investigate the supplementation of azithromycin distribution to the "Child Health Days" platform in Burkina Faso for child mortality reduction. This distribution will pair door-to-door administration of vitamin A and azithromycin or placebo with acute malnutrition screening among children 1-11 months old.

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 data supports the idea that Azithromycin for Child Mortality is an effective drug?

The available research shows that Azithromycin can be effective in reducing child mortality. For example, the MORDOR trial in Niger found that giving Azithromycin to children under 5 years old twice a year reduced overall child deaths by 18%. In Malawi, the same trial suggested a 9% reduction in mortality in communities treated with Azithromycin compared to those given a placebo. The study also indicated fewer deaths from diseases like pneumonia and diarrhea in the Azithromycin-treated groups. These findings suggest that Azithromycin can help lower child mortality rates, especially in areas with high baseline mortality. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Azithromycin in reducing child mortality?

Research from the MORDOR trial shows that giving azithromycin to young children twice a year reduced overall child deaths by 18% in Niger and 9% in Malawi. The drug may help by reducing deaths from conditions like pneumonia, diarrhea, and possibly HIV/AIDS. ^{1 2 3 4 5}

What safety data is available for azithromycin in children?

Several studies have evaluated the safety of azithromycin in children. A systematic review focused on neonates identified adverse drug reactions associated with azithromycin. Another meta-analysis investigated its safety in pediatric infectious diseases, finding it generally safe. A randomized placebo-controlled trial in preschool children reported that adverse events were rare and mild, with vomiting being more common in the azithromycin group. A clinical safety analysis showed fewer side effects in azithromycin-treated children compared to other antibiotics, with gastrointestinal issues being the most common. Overall, azithromycin appears to be safe for use in children. ^{6 7 8 9 10}

Is azithromycin safe for children?

Azithromycin is generally safe for children, with rare and mild side effects. In a study, 20% of children experienced at least one mild adverse event, with vomiting being slightly more common in those who took azithromycin compared to a placebo. ^{2 6 7 8 10}

Is the drug Azithromycin a promising treatment for reducing child mortality?

Yes, Azithromycin shows promise in reducing child mortality. Studies from the MORDOR trial in Malawi and Niger suggest that mass distribution of Azithromycin to children can lower death rates, particularly from diseases like pneumonia, diarrhea, and HIV/AIDS. In Niger, it reduced overall child mortality by 18%. ^{2 5 11 12 13}

How does the drug azithromycin differ from other treatments for reducing child mortality?

Azithromycin is unique in its use for reducing child mortality through mass drug administration, which has shown potential in lowering deaths from conditions like pneumonia and diarrhea in children under five. Unlike other treatments, it is administered biannually to entire communities, which may contribute to its effectiveness in reducing overall child mortality rates. ^{2 5 11 12 14}

Research Team

Thomas Lietman, MD

Principal Investigator

University of California, San Francisco

Georges Dimithe

Principal Investigator

Helen Keller International

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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 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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effect of Mass Azithromycin Distributions on Childhood Growth in Niger: A Cluster-Randomized Trial. [2022]

2. United States 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Effect Modification by Baseline Mortality in the MORDOR Azithromycin Trial. [2021]

4. England pubmed.ncbi.nlm.nih.gov

The impact on malaria of biannual treatment with azithromycin in children age less than 5 years: a prospective study. [2020]

5. England 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. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Use and safety of azithromycin in neonates: a systematic review. [2022]

7. China pubmed.ncbi.nlm.nih.gov

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

8. United States 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of azithromycin in the treatment of respiratory infections in children. [2012]

11. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic and clinical evaluation of azithromycin in the pediatric field]. [2016]

12. England pubmed.ncbi.nlm.nih.gov

Azithromycin use in paediatrics: A practical overview. [2021]

13. England 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. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Azithromycin in upper respiratory tract infections: a clinical trial in children with otitis media. [2013]