Azithromycin for Premature Birth

(ALEC Trial)

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

50 Participants Needed

Trial Summary

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 data supports the effectiveness of the drug azithromycin for preventing premature birth?

Research shows that azithromycin can improve birth weight and gestational age at birth, reduce neonatal infections, and delay preterm delivery in certain settings. It is also effective against infections like Ureaplasma, which are linked to preterm birth. ^{1 2 3 4 5}

Is azithromycin generally safe for humans?

Azithromycin is generally considered safe for humans, with common side effects like diarrhea and abdominal pain being mild or moderate. Serious side effects are rare, occurring in less than one percent of patients, and it is well tolerated across various ages and conditions. ^{6 7 8 9 10}

How is the drug azithromycin unique for preventing premature birth?

Azithromycin is unique because it is easier to administer, has a better side effect profile, and is less expensive compared to erythromycin, which is often used for similar conditions. Additionally, azithromycin has strong anti-inflammatory properties and is effective against certain infections, which may help improve outcomes in preterm infants. ^{3 6 11 12 13}

What is the purpose of this trial?

Azithromycin is an antibiotic that is effective against bacteria that been associated with preterm birth (PTB). The purpose of this study is to evaluate if the addition of azithromycin prior to exam indicated cerclage prolongs gestation. A cerclage is a suture placed in the cervix to prolong gestation.

Research Team

Rupsa C Boelig, MD

Principal Investigator

Thomas Jefferson University

Jenani S Jayakumaran, MD

Principal Investigator

Thomas Jefferson University

Eligibility Criteria

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.

Allergy to both penicillin and clindamycin

Timeline

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

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]

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 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]

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]

References

1. England 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. [2023]

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

Azithromycin for Eradication of Ureaplasma and Prevention of Bronchopulmonary Dysplasia in Preterm Neonates in the Neonatal Intensive Care Unit. [2023]

3. England 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. [2021]

4. United States 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. [2022]

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

Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. [2021]

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

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

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

Clinical toleration and safety of azithromycin. [2022]

8. China pubmed.ncbi.nlm.nih.gov

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

9. India pubmed.ncbi.nlm.nih.gov

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

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

Pregnancy outcome following gestational exposure to azithromycin. [2020]

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

Azithromycin vs erythromycin for the management of preterm premature rupture of membranes. [2020]

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

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

13. Japan pubmed.ncbi.nlm.nih.gov

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