Azithromycin for Pediatric Health

(AVENIR Trial)

Overseen By Sandrine Kyane

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, San Francisco

Must not be taking: Macrolides

Disqualifiers: Allergy to macrolides, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of azithromycin, an antibiotic, in reducing child mortality when administered twice a year to infants aged 1-11 months. The researchers aim to determine if distributing azithromycin in areas with high child death rates can save lives while monitoring antibiotic resistance. Families in certain regions of Niger with children aged 1-11 months who do not have a known allergy to macrolides (a type of antibiotic) might be suitable for this trial. As a Phase 4 trial, this study involves an FDA-approved treatment and seeks to understand its benefits for more patients.

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?

Research has shown that azithromycin is usually safe for children, but some important considerations exist. Azithromycin is safer than many other antibiotics, but high doses require caution. Studies also indicate that its safety for children under 6 months old is not fully known. Therefore, while azithromycin is a common antibiotic, parents should be mindful of these points, especially for very young children. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard of care, which often involves antibiotics administered in response to specific infections, azithromycin in this trial is given proactively to children aged 1-11 months. This biannual oral administration by community health workers aims to reduce the incidence of infections before they start. Researchers are excited because this approach could potentially lower overall infection rates and improve health outcomes in young children, offering a preventive strategy rather than just a reactive one.

What is the effectiveness track record for azithromycin in reducing child mortality?

Research has shown that azithromycin effectively treats various infections in children, achieving a 94.4% success rate, including for conditions like pneumonia. Studies have found that azithromycin works well for respiratory infections, which are common in kids. The World Health Organization recommends azithromycin for widespread use in areas with high child mortality rates. In this trial, community health workers will administer biannual oral azithromycin to one group of participants. However, a large study in Burkina Faso found that giving azithromycin through the healthcare system did not reduce infant deaths. The effectiveness of azithromycin in lowering child mortality seems to depend on children's proximity to healthcare services. ^{1 6 7 8 9}

Who Is on the Research Team?

Kieran O'Brien, PhD, MPH

Principal Investigator

University of California, San Francisco

Tom Lietman, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

The trial is for children aged 1-11 months in Niger, specifically from Dosso, Tahoua, Maradi, Zinder, or Tillabéri regions. Caregivers must consent to participation. Children previously in MORDOR trials or with known macrolide allergies cannot join.

Inclusion Criteria

At the community-level: Location in Dosso, Tahoua, Maradi, Zinder, or Tillabéri regions

I am between 1-59 months or 7-12 years old, or I am the caregiver of an eligible child.

At the community-level: Verbal consent of community leader(s)

Exclusion Criteria

At the individual-level: Not on list of randomly selected participants from the census

At the community-level: Inaccessible or unsafe for study team

At the individual-level: Known allergy to macrolides

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Biannual oral azithromycin administration to children aged 1-11 months distributed by community health workers

2 years

Biannual visits for azithromycin distribution

Monitoring

Mortality and antimicrobial resistance monitored through birth histories and community/clinic visit data

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin

Trial Overview

Azithromycin for Oral Suspension is being tested to see if it can reduce child mortality when given twice a year to infants. The study will also monitor the impact on antibiotic resistance within programmatic settings.

How Is the Trial Designed?

Group I: Programmatic azithro 1-11 Active Control 1 Intervention

Biannual oral azithromycin administration to children aged 1-11 months distributed by community health workers

Group II: no intervention Active Control 1 Intervention

No additional intervention.

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+

Ministry of Health, Niger

Collaborator

Trials

3

Recruited

1,356,000+

Published Research Related to This Trial

A meta-analysis of 14 studies showed that azithromycin (AZM) has a significantly lower incidence of adverse reactions (24.20%) compared to control treatments (48.05%), indicating a better safety profile for pediatric respiratory disease treatment.

AZM demonstrated fewer adverse reactions across various administration methods, including sequential therapy, intravenous, and oral routes, making it a safer and more appealing option for treating children with respiratory conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profiles and adverse reactions of azithromycin in the treatment of pediatric respiratory diseases: A systematic review and meta-analysis. Sun, YW., Cen, YH., Chen, MH., et al.[2023]

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 (AZM) was effective in treating various pediatric infections, achieving a success rate of 94.4% in 36 patients, including those with pneumonia and bronchitis.

The treatment was well-tolerated with no observed adverse reactions or abnormal laboratory changes in a safety evaluation of 43 patients, indicating its safety for use in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical evaluation of a new macrolide antibiotic, azithromycin, in the pediatric field]. Meguro, H., Terashima, I.[2016]

Single-dose azithromycin (30 mg/kg) demonstrated a high clinical success rate of 88% in treating children with otitis media, based on data from four clinical trials involving 619 patients.

The treatment was found to be safe, with mostly mild and temporary side effects, and showed excellent compliance rates of 99-100%, making it a suitable alternative for pediatric patients, especially in areas with low macrolide resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose azithromycin for the treatment of children with acute otitis media. Soley, CA., Arguedas, A.[2006]

In a study involving 32 pediatric patients, azithromycin (AZM) demonstrated a high efficacy rate of 96.7% in treating various bacterial infections, with 18 patients rated as having 'excellent' outcomes.

While AZM was generally well-tolerated, with only mild side effects reported, it is important to note some patients experienced slight changes in laboratory test results, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical studies on azithromycin in pediatrics]. Okamoto, T., Sekiguchi, T.[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]

This systematic review aims to comprehensively evaluate the safety of azithromycin in children of all ages by analyzing various study types, including randomized controlled trials and cohort studies, to identify any adverse drug reactions (ADRs).

Concerns about the safety of azithromycin, particularly in young children, will be addressed through meta-analyses and subgroup analyses based on age and dosage, ensuring a thorough assessment of its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of azithromycin in paediatrics: a systematic review protocol. Xu, P., Zeng, L., Xiong, T., et al.[2023]

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]

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]

In a randomized controlled trial involving 56 children with cystic fibrosis, both low (5mg/kg/day) and high (15mg/kg/day) doses of azithromycin did not show significant differences in improving lung function (FEV1) or reducing pulmonary exacerbations over 12 months.

While children tolerated both doses well without significant side effects, the study found that stopping azithromycin led to an increase in pulmonary exacerbations, indicating that the benefits of the treatment may diminish shortly after discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term daily high and low doses of azithromycin in children with cystic fibrosis: a randomized controlled trial. Kabra, SK., Pawaiya, R., Lodha, R., et al.[2010]

In a study of 15 pediatric patients aged 1 to 10 years, azithromycin (AZM) demonstrated a high efficacy rate of 92.9% in treating various respiratory tract infections, including pneumonia and bronchitis.

The treatment was generally well-tolerated, with only one case of moderate diarrhea reported, indicating that AZM is a safe option for pediatric patients with respiratory infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic and clinical evaluations of azithromycin in the pediatric field]. Okada, T., Machida, Y., Fujieda, M., et al.[2016]

In a review of 45 studies involving 4,499 children aged 6 months to 16 years, azithromycin was found to be safe for treating acute bacterial infections, with only 8.7% of children experiencing mild to moderate adverse events, primarily gastrointestinal.

The incidence of adverse events was similar between azithromycin and comparator treatments, with only 1.3% of azithromycin-treated children discontinuing treatment due to side effects, indicating its comparable safety profile to other antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paediatric safety of azithromycin: worldwide experience. Treadway, G., Pontani, D.[2019]

Citations

1.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2309495

Azithromycin during Routine Well-Infant Visits to Prevent ...

In this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7661415/

Safety of azithromycin in pediatrics: a systematic review and ...

One prospective study where children received weekly azithromycin for 6 months reported statistically significant QT prolongation [35]. QT ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6598555/

Safety of azithromycin in paediatrics: a systematic review ...

It is effective in respiratory infections, which are common in children. The WHO recommends 3–5 years of annual mass azithromycin distribution ...

4.

withpower.com

withpower.com/trial/phase-4-morality-5-2022-e8a15

Azithromycin for Pediatric Health (AVENIR Trial)

Azithromycin (AZM) was effective in treating various pediatric infections, achieving a success rate of 94.4% in 36 patients, including those with pneumonia and ...

5.

jamanetwork.com

jamanetwork.com/journals/jamanetworkopen/fullarticle/2812967

Distance to Health Centers and Effectiveness of ...

The effectiveness of azithromycin mass administration to reduce child mortality varied significantly by distance to the nearest primary health center.

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2021/050670s036,050710s051,050711s050,050784s037lbl.pdf

ZITHROMAX (azithromycin) Label - accessdata.fda.gov

The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established.

7.

mayoclinic.org

mayoclinic.org/drugs-supplements/azithromycin-oral-route/description/drg-20072362

Azithromycin (oral route) - Side effects & dosage

Children weighing 34 kilograms (kg) or more—Dose is based on body weight and must be determined by your doctor. The dose is usually 2 grams once ...

8.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2012/050797s016lbl.pdf

Zmax Label - accessdata.fda.gov

Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been established. Community-Acquired Pneumonia: The safety and ...

9.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8578745/

Safety of azithromycin in pediatric infectious diseases

Compared with other antibiotics, the clinical safety of azithromycin is relatively good, but care should be taken when the dosage is high in treating some ...