Azithromycin for Reducing Infections After C-Section

(PRECEDE Trial)

Recruiting at 13 trial locations

Overseen By Maged Costantine, MD

Age: Any Age

Sex: Female

Trial Phase: Phase 3

Sponsor: The George Washington University Biostatistics Center

Must not be taking: Macrolides, QT prolonging drugs

Disqualifiers: Chorioamnionitis, Bacterial infection, others

Stay on Your Current Meds You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 2

Duration: 1 day

8000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This is a phase-III multi-center double-blind randomized controlled trial of 8,000 individuals undergoing a scheduled or prelabor cesarean delivery who are randomized to either adjunctive azithromycin prophylaxis or to placebo. Both groups also will receive standard of care preoperative antibiotics (excluding azithromycin). The primary endpoint is a maternal infection composite defined as any one of the following up to 6 weeks postpartum: endometritis, wound infection, abscess, septic thrombosis, sepsis, pneumonia, pyelonephritis and breast infection.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking medications that prolong the QT interval (a heart rhythm measurement), you may not be eligible to participate.

Is azithromycin generally safe for humans?

Azithromycin is generally safe for humans, with side effects occurring in about 12% of patients, which is less than with other antibiotics. Common side effects include mild to moderate diarrhea and abdominal pain, and serious side effects are rare. ^{1 2 3 4 5}

How is the drug azithromycin unique for reducing infections after C-section?

Azithromycin is unique because it is added to standard antibiotic regimens to further reduce infection rates after cesarean delivery, especially in unscheduled cases. It has a long half-life, excellent tissue penetration, and additional immunomodulatory effects, which may enhance its effectiveness compared to other antibiotics. ^{1 2 5 6 7}

What data supports the effectiveness of the drug Azithromycin for reducing infections after C-section?

Research shows that adding azithromycin to standard antibiotics for cesarean deliveries can significantly reduce the rate of postoperative infections, with one study noting about a 50% decrease in infection rates for women who received azithromycin. ^{1 2 5 6 8}

Who Is on the Research Team?

Monica Longo, MD PhD

Principal Investigator

Eunice Kennedy Shriver NICHD

Rebecca G Clifton, PhD

Principal Investigator

The George Washington University Biostatistics Center

Alan T.N. Tita, MD PhD

Principal Investigator

University of Alabama at Birmingham

Kim Boggess, MD

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

This trial is for individuals scheduled for a cesarean delivery (C-section) without labor. Participants must be willing to take additional medication or placebo alongside standard preoperative antibiotics and can't have conditions that exclude them from the study.

Inclusion Criteria

Scheduled or prelabor cesarean delivery

Singleton or twin gestation

I am at least 23 weeks pregnant according to ACOG guidelines.

Exclusion Criteria

Chorioamnionitis

Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, do not have to be excluded.

I have experienced a fetal loss or my baby has a significant birth defect.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 500mg of intravenous azithromycin or placebo prior to cesarean delivery, along with standard preoperative antibiotics

1 day

1 visit (in-person)

Follow-up

Participants are monitored for maternal and neonatal outcomes, including infection rates, up to 6 weeks postpartum

6 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin

Trial Overview The trial tests if adding azithromycin to usual pre-surgery antibiotics reduces postpartum infections in those having C-sections. It's a large study where participants are randomly given either azithromycin or a placebo, without knowing which one they receive.

How Is the Trial Designed?

Group I: Azithromycin prophylaxis and standard of care preoperative antibiotics Experimental Treatment 2 Interventions

500mg of intravenous azithromycin administered up to 1 hour prior to cesarean incision (or as soon as feasible after incision) and infused over one hour per FDA infusion recommendations for azithromycin. Additionally patients will received standard of care preoperative antibiotics (excluding azithromycin) prior to incision.

Group II: Placebo and standard of care preoperative antibiotics Placebo Group 2 Interventions

Normal saline administered up to 1 hour prior to cesarean incision (or as soon as feasible after incision) and infused over one hour in addition to standard of care preoperative antibiotics (excluding azithromycin) prior to incision.

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?

The George Washington University Biostatistics Center

Lead Sponsor

Trials

27

Recruited

111,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Published Research Related to This Trial

In a study of 242 women undergoing non-elective cesarean delivery, the addition of 500 mg intravenous azithromycin to standard antibiotic prophylaxis significantly reduced the incidence of cesarean scar defect (CSD) from 46.3% to 32.7%.

The results suggest that adjunctive azithromycin may be an effective strategy to lower the risk of CSD, highlighting its potential role in improving postoperative outcomes for women after cesarean sections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive azithromycin prophylaxis protects women from uterine cesarean scar defect: A randomized controlled trial. Huang, D., Chen, S., Cai, Y., et al.[2022]

In a study involving 2,013 women undergoing nonelective cesarean deliveries, adding azithromycin to standard antibiotic prophylaxis significantly reduced the risk of postcesarean infections.

However, the addition of azithromycin did not lead to a statistically significant reduction in noninfectious wound complications, such as seromas and hematomas, indicating that while it helps with infections, it may not impact other types of wound issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Azithromycin-Based Extended-Spectrum Antibiotic Prophylaxis on Noninfectious Cesarean Wound Complications. Ausbeck, EB., Jauk, VC., Boggess, KA., et al.[2020]

In a study of 2,339 women undergoing cesarean delivery, adding azithromycin to standard preoperative antibiotics did not significantly reduce the overall rate of postoperative infections compared to standard prophylaxis alone.

The results suggest that while azithromycin may have benefits for certain groups (like women in labor), its effectiveness may be limited, especially for women not in labor, indicating that the practice change may not yield the expected benefits in all cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical effectiveness of adding azithromycin to antimicrobial prophylaxis for cesarean delivery. Pierce, SL., Bisson, CM., Dubois, ME., 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]

In a study of 2,867 women undergoing prelabor cesarean births, the addition of 500 mg intravenous azithromycin to standard antibiotic prophylaxis significantly reduced the odds of postpartum infections from 4.8% to 3.3%.

The implementation of azithromycin also led to lower rates of specific complications such as wound infections and seromas, indicating its efficacy in improving postoperative outcomes without affecting neonatal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive Azithromycin Prophylaxis for Prelabor Cesarean Birth. Ruzic, MF., Blanchard, CT., Cozzi, GD., et al.[2023]

In a study involving 29,278 women planning vaginal delivery, a single 2-g oral dose of azithromycin significantly reduced the risk of maternal sepsis or death compared to placebo (1.6% vs. 2.4%), indicating its efficacy in preventing maternal infections during labor.

However, azithromycin did not significantly impact the rates of stillbirth, neonatal death, or neonatal sepsis, suggesting that while it is beneficial for maternal health, it does not improve outcomes for newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. Tita, ATN., Carlo, WA., McClure, EM., et al.[2023]

In a study of 2013 women undergoing nonelective cesarean delivery, the addition of azithromycin to standard antibiotic prophylaxis significantly reduced the rate of postoperative infections, with only 6.1% of women in the azithromycin group experiencing infections compared to 12.0% in the placebo group.

Azithromycin also led to lower rates of specific infections such as endometritis and wound infections, while showing no significant difference in serious neonatal complications, indicating its safety and efficacy as an adjunctive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. Tita, AT., Szychowski, JM., Boggess, K., et al.[2022]

Azithromycin is an effective broad-spectrum antibiotic with a long half-life and good tissue penetration, making it suitable for treating various infections, including respiratory and sexually transmitted infections.

While azithromycin has beneficial immunomodulatory effects for chronic respiratory diseases, it carries risks of serious side effects like cardiovascular arrhythmias and hearing loss, and there are concerns about macrolide resistance and drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescribing azithromycin. McMullan, BJ., Mostaghim, M.[2023]

Citations

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

Adjunctive Azithromycin Prophylaxis for Prelabor Cesarean Birth. [2023]

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

Impact of Azithromycin-Based Extended-Spectrum Antibiotic Prophylaxis on Noninfectious Cesarean Wound Complications. [2020]

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

Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. [2023]

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

Clinical effectiveness of adding azithromycin to antimicrobial prophylaxis for cesarean delivery. [2022]

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

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. [2022]

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

Clinical toleration and safety of azithromycin. [2022]

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

Adjunctive azithromycin prophylaxis protects women from uterine cesarean scar defect: A randomized controlled trial. [2022]

8. Australia pubmed.ncbi.nlm.nih.gov

Prescribing azithromycin. [2023]