C/SOAP: Study of Effectiveness and Safety of Azithromycin-based Extended-spectrum Prophylaxis to Prevent Post Cesarean Infection

• Sponsor: Alan Tita (Other)
• Overall Status: Completed
• CT.gov ID: NCT01235546
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), University of Texas (Other), University of North Carolina (Other), Mission Hospital (Other), Ochsner Health System (Other), The University of Texas Health Science Center, Houston (Other), Columbia University (Other), University of Utah (Other), University of Mississippi Medical Center (Other)
• Enrollment: 2,013
• Locations: 9
• Arms: 2
• Duration (Months): 55
• Patients Per Site: 223.7
• Patients Per Site Per Month: 4.1

Study Details

Study Description

Brief Summary

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) study is a large pragmatic multi-center randomized clinical trial designed to evaluate the comparative effectiveness and safety of azithromycin-based extended-spectrum antibiotic prophylaxis (azithromycin plus standard narrow-spectrum cephalosporin) relative to standard single-agent cephalosporin (preferably prior to surgical incision) to prevent post-cesarean infection.

Hypothesis: Compared to narrow-spectrum prophylaxis (i.e. cefazolin alone, or clindamycin if cephalosporin allergy) prior to surgical incision, the addition of extended-spectrum prophylaxis (azithromycin + cefazolin) reduces the incidence of post-cesarean infection.

Condition or Disease	Intervention/Treatment	Phase
Endometritis; Wound Infection; Abscess; Surgical Site Infection	Drug: Azithromycin and standard of care; Drug: Placebo and standard of care	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 2013 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Cesarean Section Optimal Antibiotic Prophylaxis Trial
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo and standard of care 250 cc normal saline	Drug: Placebo and standard of care; 250 cc normal saline, plus standard of care (cephazolin or clindamycin); Other Names: normal saline
Experimental: Azithromycin and Standard of care 500 mg Azithromycin in 250 cc normal saline	Drug: Azithromycin and standard of care; 500 mg in 250 cc normal saline 1 time dose plus standard of care (cephazolin or clindamycin); Other Names: Zithromax

Outcome Measures

Primary Outcome Measures

1. Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery) [Up to 6 weeks after delivery]

   Endometritis was defined as the presence of at least two of the following signs with no other recognized cause: fever (temperature of at least 38°C [100.4°F]), abdominal pain, uterine tenderness, or purulent drainage from the uterus. Wound infection was defined as the presence of either superficial or deep incisional surgical-site infection characterized by cellulitis or erythema and induration around the incision or purulent discharge from the incision site with or without fever and included necrotizing fasciitis. Wound hematoma, seroma, or breakdown alone in the absence of the preceding signs did not constitute infection.

Other Outcome Measures

1. Neonatal Morbidities (Listed Below) [Up to 3 months after birth]

   morbidities include: death, Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Periventricular Leukomalacia (PVL) suspected or proven sepsis, Necrotizing Enterocolitis (NEC) Intraventricular Hemorrhage (IVH) and systemic inflammatory response syndrome

2. Neonatal Intensive Care Unit (NICU) Admission [Up to 3 months after birth]

   Neonates who are admitted to the NICU due to morbidities diagnosed from birth and up to three months of life. Morbidities as defined in the Neonatal morbidities outcome measure.

3. Neonatal Readmission [Up to 3 months after birth]

4. Maternal Fever [Up to 6 weeks after delivery]

5. Maternal Postpartum Readmission or Unscheduled Visit [Up to 6 weeks after delivery]

   Maternal postpartum unscheduled visit or readmission to the hospital

6. Maternal Postpartum Antibiotic Use [Up to 6 weeks after delivery]

   Maternal postpartum use of antibiotics

7. Maternal Serious Adverse Events [Up to 6 weeks after delivery]

   All maternal serious adverse events

8. Neonatal Serious Adverse Events [Up to 3 months after birth]

   Composite for all neonatal serious adverse events

9. Infant Pyloric Stenosis [up to 3 months after birth]

   Any diagnosis of pyloric stenosis based on clinical presentation and radiological and/or surgical confirmation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Pregnant Women aged 14 years and over at ≥ 24 weeks' viable gestation who will undergo unscheduled/non-elective cesareans with either:

1. Labor (spontaneous or induced): active labor (ongoing contractions and at least 4cm dilated or contractions for at least 4 hours with documented cervical change of ≥1cm dilatation or ≥50% effacement), or

2. Membrane rupture (standardized to duration of at least 4 hours prior to randomization).

Exclusion Criteria:

• Patient unwilling or unable to provide consent

• Multiple pregnancy

• Known azithromycin (or other macrolide) allergy

• Vaginal delivery

• Elective or scheduled cesarean prior to labor or membrane rupture.

• Azithromycin, erythromycin or other macrolide antibiotic use within 7 days of enrollment.

• Clinical chorioamnionitis or any other active bacterial infection (e.g. pyelonephritis, pneumonia, abscess) at time of randomization.

• Patient is unable or unlikely to follow-up after delivery (e.g. no prenatal care or a non-resident patient)

• Fetal demise or major congenital anomaly

• Significant liver disease defined as known cirrhosis or elevated transaminases of at least 3-fold upper limit of normal

• Significant renal disease defined as serum creatinine known to be >2.0 mg/dl or on dialysis.

• Active congestive heart failure (EF<45%) or pulmonary edema

• Active diarrhea at time of delivery

• Any patient with significant electrolyte abnormalities such as hypokalemia or hypocalcemia

• Any patient with structural heart disease or arrhythmias, or taking any medications known to prolong the QT interval

• Patient currently being treated with efavirenz, nelfinavir or fluconazole

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
3	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
4	Columbia University	New York	New York	United States	10032
5	Mission Hospital	Asheville	North Carolina	United States	28801
6	University of North Carolina	Chapel Hill	North Carolina	United States	27599-7516
7	University of Texas Medical Branch	Galveston	Texas	United States	77555-0587
8	University of Texas Health Science Center at Houston	Houston	Texas	United States	77225
9	University of Utah	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• Alan Tita
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• University of Texas
• University of North Carolina
• Mission Hospital
• Ochsner Health System
• The University of Texas Health Science Center, Houston
• Columbia University
• University of Utah
• University of Mississippi Medical Center

Investigators

• Principal Investigator: Alan TN Tita, MD, PhD, University of Alabama at Birmingham

Study Documents (Full-Text)

None provided.

More Information

Publications

• Andrews WW, Hauth JC, Cliver SP, Savage K, Goldenberg RL. Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis. Obstet Gynecol. 2003 Jun;101(6):1183-9.
• Tita AT, Hauth JC, Grimes A, Owen J, Stamm AM, Andrews WW. Decreasing incidence of postcesarean endometritis with extended-spectrum antibiotic prophylaxis. Obstet Gynecol. 2008 Jan;111(1):51-6. doi: 10.1097/01.AOG.0000295868.43851.39.
• Tita ATN, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review. Obstet Gynecol. 2009 Mar;113(3):675-682. doi: 10.1097/AOG.0b013e318197c3b6. Review.

• Responsible Party: Alan Tita, Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT01235546
• Other Study ID Numbers: F090323006; NIH 1R01HD064729-01A1
• First Posted: Nov 5, 2010
• Last Update Posted: Jul 28, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Alan Tita, Professor, University of Alabama at Birmingham: Pregnancy; Cesarean section; Antibiotic; Infections
• Additional relevant MeSH terms: Infections; Communicable Diseases; Surgical Wound Infection; Wound Infection; Endometritis; Azithromycin

Study Results

Participant Flow

Recruitment Details	Patients were randomly assigned to receive either azithromycin (at a dose of 500mg in 250 ml of saline, one time dose) or an identical-appearing saline placebo and the standard of care (cephazolin or clindamycin)
Pre-assignment Detail	The addition of azithromycin and the standard of care (cephazolin or clindamycin) for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin prophylaxis and the standard of care in women undergoing nonelective cesarean section.

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline Standard of care (cephazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and standard of care (cephazolin or clindamycin)
Period Title: Overall Study
STARTED	994	1019
COMPLETED	992	1018
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Placebo With Standard Prophylaxis	Azithromycin (Zithromax) With Standard Prophylaxis	Total
Arm/Group Description	Placebo: 250 cc normal saline Standard Prophylaxis: standard cephalosporin prophylaxis	Azithromycin: 500 mg in 250 cc normal saline 1 time dose Standard Prophylaxis: standard cephalosporin prophylaxis	Total of all reporting groups
Overall Participants	994	1019	2013
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	28.4 (6.5)	28.2 (6.1)	28.3 (6.3)
Sex: Female, Male (Count of Participants)
Female	994 100%	1019 100%	2013 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	994 100%	1019 100%	2013 100%
Smoking Prevalence (Count of Participants)
Count of Participants [Participants]	122 12.3%	97 9.5%	219 10.9%

Outcome Measures

1. Primary Outcome

Title	Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery)
Description	Endometritis was defined as the presence of at least two of the following signs with no other recognized cause: fever (temperature of at least 38°C [100.4°F]), abdominal pain, uterine tenderness, or purulent drainage from the uterus. Wound infection was defined as the presence of either superficial or deep incisional surgical-site infection characterized by cellulitis or erythema and induration around the incision or purulent discharge from the incision site with or without fever and included necrotizing fasciitis. Wound hematoma, seroma, or breakdown alone in the absence of the preceding signs did not constitute infection.
Time Frame	Up to 6 weeks after delivery

Outcome Measure Data

Analysis Population Description

The specific characteristics related to the cesarean delivery, including indications for cesarean delivery, receipt of standard prophylaxis, timing of receipt of study medication, and type of surgical skin preparation, were similar in the two groups.

Arm/Group Title	Placebo	Azithromycin
Arm/Group Description	250 cc normal saline Placebo: 250 cc normal saline	Azithromycin: 500 mg in 250 cc normal saline 1 time dose
Measure Participants	992	1018
Count of Participants [Participants]	119 12%	62 6.1%

2. Other Pre-specified Outcome

Title	Neonatal Morbidities (Listed Below)
Description	morbidities include: death, Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Periventricular Leukomalacia (PVL) suspected or proven sepsis, Necrotizing Enterocolitis (NEC) Intraventricular Hemorrhage (IVH) and systemic inflammatory response syndrome
Time Frame	Up to 3 months after birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline and standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and Standard of Care (cefazolin or clindamycin
Measure Participants	992	1018
Count of Participants [Participants]	135 13.6%	146 14.3%

3. Other Pre-specified Outcome

Title	Neonatal Intensive Care Unit (NICU) Admission
Description	Neonates who are admitted to the NICU due to morbidities diagnosed from birth and up to three months of life. Morbidities as defined in the Neonatal morbidities outcome measure.
Time Frame	Up to 3 months after birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	250 cc normal saline Placebo: 250 cc normal saline and Standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and Standard of care (cefazolin or clindamycin)
Measure Participants	992	1018
Count of Participants [Participants]	169 17%	171 16.8%

4. Other Pre-specified Outcome

Title	Neonatal Readmission
Time Frame	Up to 3 months after birth

Outcome Measure Data

Analysis Population Description

Hospitalization after discharge

Arm/Group Title	Placebo With Standard Prophylaxis	Azithromycin (Zithromax) With Standard Prophylaxis
Arm/Group Description	Placebo: 250 cc normal saline Standard Prophylaxis: standard cephalosporin prophylaxis	Azithromycin: 500 mg in 250 cc normal saline 1 time dose Standard Prophylaxis: standard cephalosporin prophylaxis
Measure Participants	992	1018
Count of Participants [Participants]	43 4.3%	39 3.8%

5. Other Pre-specified Outcome

Title	Maternal Fever
Time Frame	Up to 6 weeks after delivery

Outcome Measure Data

Analysis Population Description

Postpartum Fever

Arm/Group Title	Placebo With Standard Prophylaxis	Azithromycin (Zithromax) With Standard Prophylaxis
Arm/Group Description	Placebo: 250 cc normal saline Standard Prophylaxis: standard cephalosporin prophylaxis	Azithromycin: 500 mg in 250 cc normal saline 1 time dose Standard Prophylaxis: standard cephalosporin prophylaxis
Measure Participants	992	1018
Count of Participants [Participants]	81 8.1%	51 5%

6. Other Pre-specified Outcome

Title	Maternal Postpartum Readmission or Unscheduled Visit
Description	Maternal postpartum unscheduled visit or readmission to the hospital
Time Frame	Up to 6 weeks after delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline Standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose Standard of care (cefazolin or clindamycin)
Measure Participants	992	1018
Count of Participants [Participants]	123 12.4%	83 8.1%

7. Other Pre-specified Outcome

Title	Maternal Postpartum Antibiotic Use
Description	Maternal postpartum use of antibiotics
Time Frame	Up to 6 weeks after delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline and Standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and Standard of care (cefazolin or clindamycin)
Measure Participants	992	1018
Count of Participants [Participants]	166 16.7%	126 12.4%

8. Other Pre-specified Outcome

Title	Maternal Serious Adverse Events
Description	All maternal serious adverse events
Time Frame	Up to 6 weeks after delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline and Standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and Standard of care (cefazolin or clindamycin)
Measure Participants	992	1018
Count of Participants [Participants]	29 2.9%	15 1.5%

9. Other Pre-specified Outcome

Title	Neonatal Serious Adverse Events
Description	Composite for all neonatal serious adverse events
Time Frame	Up to 3 months after birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline and Standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and Standard of care (cefazolin or clindamycin)
Measure Participants	992	1018
Count of Participants [Participants]	5 0.5%	7 0.7%

10. Other Pre-specified Outcome

Title	Infant Pyloric Stenosis
Description	Any diagnosis of pyloric stenosis based on clinical presentation and radiological and/or surgical confirmation
Time Frame	up to 3 months after birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo and Standard of Care	Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline and Standard of care (cefazolin or clindamycin)	Azithromycin: 500 mg in 250 cc normal saline 1 time dose and Standard of care (cefazolin or clindamycin)
Measure Participants	992	1018
Count of Participants [Participants]	1 0.1%	2 0.2%

Adverse Events

Time Frame	Up to 6 weeks after delivery
Adverse Event Reporting Description	Maternal serious adverse events (maternal safety composite outcome) included death, suspected allergic reactions (including anaphylaxis or generalized skin rash), any serious adverse event leading to the discontinuation of a study medication or suspected to be due to the medication, and any other reported serious adverse complication, including pulmonary embolism, admission to an intensive care unit (ICU), and cardiac events.
Arm/Group Title	Placebo and Standard of Care		Azithromycin and Standard of Care
Arm/Group Description	Placebo: 250 cc normal saline and Standard of care (cefazolin or clindamycin)		Azithromycin: 500 mg in 250 cc normal saline and Standard of care (cefazolin or clindamycin)
All Cause Mortality
	Placebo and Standard of Care		Azithromycin and Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/992 (0%)		0/1018 (0%)
Serious Adverse Events
	Placebo and Standard of Care		Azithromycin and Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/992 (2.9%)		15/1018 (1.5%)
Immune system disorders
Severe allergic reaction	29/992 (2.9%)	29	15/1018 (1.5%)	15
Other (Not Including Serious) Adverse Events
	Placebo and Standard of Care		Azithromycin and Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/992 (1.4%)		9/1018 (0.9%)
General disorders
ICU admission	14/992 (1.4%)	14	9/1018 (0.9%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.