Azithromycin for Premature Birth

(ALEC Trial)

Not currently recruiting at 1 trial location

Overseen By Rupsa Boelig, MD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: Thomas Jefferson University

Must not be taking: Antibiotics, Indomethacin

Disqualifiers: HIV, Prolonged QT, Congenital anomalies, 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: 1

Duration: 26 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding the antibiotic azithromycin can help extend pregnancy for women needing a cerclage (a stitch in the cervix to prevent early birth). Researchers aim to determine if azithromycin, which fights certain bacteria linked to preterm birth, can make a difference. The trial compares women receiving azithromycin with those receiving standard treatments, cefazolin and indomethacin, without azithromycin. Pregnant women with a single baby who need a cerclage might be suitable for this study. As a Phase 4 trial, this research involves an FDA-approved treatment and seeks to understand how it can benefit more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken indomethacin or any antibiotics in the 7 days before joining the study.

What is the safety track record for these treatments?

Research has shown that azithromycin is generally safe for people. One study found that a single oral dose of azithromycin significantly reduced the risk of serious infections or death in women planning a vaginal birth. This indicates that azithromycin is usually well-tolerated by pregnant women. Other studies have found that higher doses of azithromycin can lower the chances of maternal fever and early birth. Additionally, azithromycin has been safely used in infants at high risk for lung problems. Overall, these findings support the safety of azithromycin in various situations, including during pregnancy. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about azithromycin for preventing premature birth because it offers a unique approach compared to standard treatments. Unlike other options primarily focusing on managing symptoms or complications, azithromycin targets bacterial infections that may contribute to early labor. Its potential to directly address underlying bacterial causes could lead to more effective prevention of premature births. Additionally, azithromycin is often well-tolerated, making it a promising candidate for this critical condition.

What evidence suggests that azithromycin might be an effective treatment for preterm birth?

Research has shown that azithromycin can help reduce preterm births. In this trial, one group of participants will receive azithromycin along with cefazolin and indomethacin. Studies have found that using azithromycin in pregnant women is linked to fewer early deliveries and improved survival rates for newborns. This antibiotic effectively fights bacteria often associated with early births. When a mother's water breaks early, azithromycin has been shown to delay delivery, extending the pregnancy and giving the baby more time to develop. ^{1 3 4 5 6}

Who Is on the Research Team?

Rupsa C Boelig, MD

Principal Investigator

Thomas Jefferson University

Jenani S Jayakumaran, MD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

This trial is for pregnant women over 18 years old with a single pregnancy, less than 24 weeks along, who need a cerclage (a stitch to keep the cervix closed). Participants must understand and agree to the study's procedures. Those with HIV, certain heart conditions, major fetal anomalies, fever, previous cerclage in current pregnancy or recent use of indomethacin/antibiotics cannot join.

Inclusion Criteria

Pregnant women with singleton pregnancies

I am eligible for a stitch to prevent premature birth.

I understand the study's purpose and agree to follow its protocol.

Exclusion Criteria

I have a diagnosed heart condition that affects my heart's electrical activity.

I have not taken indomethacin or antibiotics in the last 7 days.

I cannot take indomethacin due to health reasons.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azithromycin, cefazolin, and indomethacin perioperatively with cerclage placement

26 weeks

Regular visits for medication administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cervicovaginal cytokine analysis and neonatal outcomes

4 weeks

1-2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin

Trial Overview The study tests if adding azithromycin (an antibiotic) before placing a cervical stitch can extend pregnancy duration and prevent premature birth. It compares outcomes between standard treatment with cefazolin and indomethacin versus the addition of azithromycin.

How Is the Trial Designed?

Group I: Cefazolin and Indomethacin Experimental Treatment 1 Intervention

Control arm- perioperative cefazolin and indomethacin

Group II: Azithromycin + control Experimental Treatment 2 Interventions

perioperative azithromycin, cefazolin and indomethacin

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?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

Published Research Related to This Trial

Azithromycin therapy may reduce the risk of bronchopulmonary dysplasia (BPD) or death in preterm infants who test positive for Ureaplasma, based on a meta-analysis of five randomized clinical trials.

However, the overall evidence quality is low, and azithromycin did not show significant benefits for all preterm infants, indicating that its efficacy may be limited to those with Ureaplasma infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin for preventing bronchopulmonary dysplasia in preterm infants: A systematic review and meta-analysis. Razak, A., Alshehri, N.[2021]

In a study involving 2,297 pregnant women in Southern Malawi, routine prophylaxis with a single dose of azithromycin did not significantly reduce the incidence of preterm birth compared to a placebo, with rates of 16.8% in the azithromycin group versus 17.4% in the placebo group.

The findings suggest that antibiotics like azithromycin are not effective as a routine preventive measure for preterm birth in high-risk populations, indicating a need for alternative strategies to address this issue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The APPLe study: a randomized, community-based, placebo-controlled trial of azithromycin for the prevention of preterm birth, with meta-analysis. van den Broek, NR., White, SA., Goodall, M., et al.[2022]

Maternal treatment with azithromycin effectively eradicated Ureaplasma parvum infection from the amniotic fluid within 4 days, leading to a 90% culture-negative rate in placenta and fetal tissues at delivery.

The azithromycin regimen significantly delayed preterm delivery and mitigated fetal lung injury, providing a crucial opportunity to improve fetal health despite some residual inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. Grigsby, PL., Novy, MJ., Sadowsky, DW., et al.[2021]

The AZTEC trial is a large-scale study involving 796 infants born before 30 weeks' gestation, aiming to determine if a 10-day course of intravenous azithromycin can reduce the rates of chronic lung disease of prematurity (CLD) compared to a placebo.

Azithromycin is expected to improve respiratory outcomes by targeting both Ureaplasma infections and inflammation, with secondary outcomes including monitoring for potential adverse effects and other complications like necrotizing enterocolitis and retinopathy of prematurity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants. Lowe, J., Gillespie, D., Hubbard, M., et al.[2021]

Azithromycin is highly effective against a range of bacteria, including Staphylococcus aureus and Haemophilus influenzae, showing particularly strong activity against H. influenzae compared to other macrolides.

After oral administration, azithromycin is well-absorbed and distributed throughout the body, achieving higher concentrations in infected tissues due to its selective delivery by phagocytes, leading to successful treatment outcomes for respiratory infections with a convenient 3-day dosing regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological and pharmacokinetic properties of azithromycin (Zithromac), a novel 15-membered ring macrolide antibacterial agent]. Matsunaga, T.[2019]

Azithromycin is generally considered a safe medication, with serious side effects like angioedema and cholestatic jaundice occurring in less than 1% of patients.

However, this report highlights a rare but severe case of dilated cardiomyopathy and significant liver toxicity leading to hepatic encephalopathy in a patient taking Azithromycin, suggesting that even commonly used medications can have unexpected serious effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin induced hepatocellular toxicity and hepatic encephalopathy in asymptomatic dilated cardiomyopathy. Das, BK.[2021]

Azithromycin has been shown to be more effective than placebo in eradicating Ureaplasma in preterm neonates, based on a review of 9 studies involving 388 neonates.

Despite its efficacy in Ureaplasma eradication, azithromycin did not significantly reduce the incidence of bronchopulmonary dysplasia (BPD) compared to placebo, and no serious adverse effects were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin for Eradication of Ureaplasma and Prevention of Bronchopulmonary Dysplasia in Preterm Neonates in the Neonatal Intensive Care Unit. Chang, E., Ballard, KE., Johnson, PN., et al.[2023]

In a study of 3,995 patients aged 2-94, azithromycin demonstrated a favorable safety profile, with only 12.0% of patients experiencing side effects, which is significantly lower than the 14.2% seen with other standard antibiotics.

The most common side effects were mild to moderate gastrointestinal issues, and only 0.7% of patients discontinued treatment due to side effects, indicating that azithromycin is well tolerated even among patients with various concurrent illnesses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical toleration and safety of azithromycin. Hopkins, S.[2022]

The SANTE trial, involving 49,600 pregnant women and their infants in rural Mali, aims to evaluate the effectiveness of azithromycin in preventing stillbirths and infant mortality over 6-12 months, using a randomized, placebo-controlled design.

The study will also assess the impact of administering azithromycin alongside routine vaccinations (Penta-1 and Penta-3) on infant survival, potentially influencing future healthcare guidelines for antenatal and infant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antenatal, intrapartum and infant azithromycin to prevent stillbirths and infant deaths: study protocol for SANTE, a 2×2 factorial randomised controlled trial in Mali. Driscoll, AJ., Haidara, FC., Tapia, MD., et al.[2023]

In a study of 453 women with preterm premature rupture of membranes, different dosing regimens of azithromycin did not show a significant difference in the time from rupture to delivery compared to erythromycin, suggesting that azithromycin can be a suitable alternative when erythromycin is unavailable.

However, the 5-day azithromycin regimen was associated with a higher incidence of respiratory distress syndrome in newborns compared to both the 1-day azithromycin and erythromycin groups, indicating a potential safety concern with longer azithromycin treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin vs erythromycin for the management of preterm premature rupture of membranes. Navathe, R., Schoen, CN., Heidari, P., et al.[2020]

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 369 pregnant women found that taking azithromycin during pregnancy does not increase the risk of major malformations in newborns compared to women taking other non-teratogenic antibiotics or agents.

The results support the safety of azithromycin in pregnancy, particularly during the first trimester, and suggest it can be a safe treatment option for conditions like chlamydia without raising concerns for fetal development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnancy outcome following gestational exposure to azithromycin. Sarkar, M., Woodland, C., Koren, G., et al.[2020]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2589933324001496

Azithromycin dosing and preterm premature rupture of ... CONCLUSION. Approximately 500 mg daily dosing of azithromycin maintains higher amniotic fluid concentrations and more consistently greater than common minimum ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11253273/

PeRinatal, neOnatal, and Maternal OuTcomEs with ... Initial trials showed that antenatal azithromycin use was associated with reduced preterm delivery, improved neonatal survival, and better ...

3. thelancet.com thelancet.com/journals/lanres/article/PIIS2213-2600(24)00079-1/fulltext

Azithromycin therapy for prevention of chronic lung disease ... A 2014 meta-analysis suggested potential benefit of prophylactic azithromycin therapy in preterm infants targeting Ureaplasma spp, pulmonary ...

4. dig.pharmacy.uic.edu dig.pharmacy.uic.edu/faqs/2024-2/january-2024-faqs/what-evidence-supports-the-use-of-azithromycin-for-ruptured-membranes-in-preterm-prelabor/

What evidence supports the use of azithromycin for ruptured ... Women who received azithromycin and amoxicillin had a longer median latency from time of membrane rupture to delivery compared to those who ...

5. bmcpregnancychildbirth.biomedcentral.com bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-022-05189-7

RETRACTED ARTICLE: Different azithromycin protocols for ... Azithromycin in the treatment of preterm prelabor rupture of membranes demonstrates a lower risk of chorioamnionitis and postpartum endometritis ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212111

Azithromycin to Prevent Sepsis or Death in Women ... Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death ...