Clinical trial NCT03248297
Conditions: Postpartum Sepsis Postpartum Endometritis Postpartum Fever
Sponsor: University of Alabama at Birmingham
Start date: 2018-01-12; Completion date: 2020-10-01
Enrollment: 756 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study, performed over a course of 3 years in 5 collaborating hospitals in Cameroon, Africa, will randomize 750 women in labor with prolonged rupture of membranes ≥ 8 hours or prolonged labor ≥ 18 hours to identical oral regimens of 1 gram of azithromycin, 1 gram of azithromycin+2 grams of amoxicillin or placebo. Women will be followed to ascertain maternal infectious outcomes and perinatal outcomes.

Detailed description:
This 3-arm study is a large randomized clinical trial designed to evaluate the comparative effectiveness and safety of single dose oral azithromycin or combined azithromycin+amoxicillin compared to placebo for the prevention of peripartum infections and sepsis in laboring women. We have previously shown the effectiveness of azithromycin for extended spectrum antibiotic prophylaxis in addition to the standard cephalosporin alone for reduction of post-cesarean infections. In LICs, the fraction of maternal infection and sepsis from cesarean delivery is minimal. Therefore, it is necessary to evaluate strategies aimed at reducing these morbidities in women who have vaginal births. There is an increased risk of infection in women who have prolonged labor or prolonged rupture of membranes. Drawing from our findings with azithromycin-based extended antibiotic prophylaxis for cesarean delivery, we propose to adapt the intervention and evaluate a single oral dose of azithromycin (with or without oral amoxicillin) to prevent maternal peripartum infection and sepsis. This study, performed over a course of 3 years in 5 collaborating hospitals in Cameroon, Africa, will randomize 750 women in labor with prolonged rupture of membranes ≥ 8 hours or prolonged labor ≥18 hours to 1 gram of oral azithromycin, 1 gram of azithromycin+2 grams of amoxicillin, compared to usual care (placebo). Women will be followed to ascertain maternal infectious outcomes and perinatal outcomes.

Arms: arm 1: Patients in this arm will receive 1 gram oral azithromycin as a single dose and amoxicillin placebo. arm 2: Patients in this arm will receive 1 gram oral azithromycin and 2 grams oral amoxicillin in a single dose. arm 3: This arm will consist of routine care at the clinical sites (which is usually no antibiotic). They will receive placebo (for azithromycin) and placebo (for amoxicillin)
Interventions: intervention 1: Azithromycin intervention 2: Azithromycin and amoxicillin intervention 3: Placebo
Intervention descriptions: intervention 1: Azithromycin tablet intervention 2: azithromycin and amoxicillin intervention 3: Placebo tablet

Protocol documents:
Prot_SAP_000.pdf: 
MISP Protocol and Procedures 
1 
Final Version: 10/08/2018 
 
 
 Investigator Studies Program(MISP)Protocol and Procedures
 
 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
  
The title of the protocol should include study design, indication and, where applicable, 
dosage, dosage form, and comparative agent(s). 
 
Single oral dose of azithromycin1 gm with or without 
amoxicillin2 gm to prevent peripartum infection and sepsis in 
laboring high-risk women: 3-Arm RCT 
 
Request Date: 
 
11/20/2015; Updated 6/13/2017; 10.1.2017; 11.28.17; 10/20/2018 
Institution Name 
 
University of Alabama at Birmingham/Cameroon Health Initiative 
Investigator Contact 
Information: 
- Full address 
- Phone No. 
- Fax  No. 
- e-mail address 
Alan T.N. Tita, MD, PhD 
Professor, Department of Obstetrics and Gynecology 
Director, Center for Women’s Reproductive Health & Maternal-Fetal 
Medicine Division 
10270K Women & Infants Center 
1700 6th Avenue South 
Birmingham Alabama 35233 
Phone: 205-934-9616 
Fax: 2059759858 
Email: atita@uab.edu 
 
 
 
 
 
 


MISP Protocol and Procedures 
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Final Version: 10/08/2018 
 
Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
Primary Objective: To test the effectiveness of a single adjunctive oral dose 
of a) 1g of azithromycin  and b) 1g of azithromycin + 2g of amoxicillin, each 
compared to c) usual care alone (placebo group)in reducing maternal 
peripartum infections and sepsis in at-risk laboring women in a LIC setting. 
Hypothesis #1: A single, oral dose of a) 1g azithromycin or b) 1g 
azithromycin+2g amoxicillin given for prolonged labor or prolonged 
membrane rupture in term pregnant women will reduce the risk of peripartum 
infections and sepsis. 
 
Secondary Objectives: 1. To collect and story specimens to estimate the 
prevalence of mycoplasma and ureaplasma in the genital tract, placenta and 
chorioamnion and assess whether their presence is associated with 
peripartum infection in LICs. 
Hypothesis #2: The presence of genitalureaplasma and mycoplasmas in the 
placenta and chorioamnion of laboring women will be strongly associated 
with maternal peripartum infections (similar to our findings in the US). 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Maternal bacterial infection and sepsis during pregnancy and the 
puerperium accounts for approximately 10% of the global burden of maternal 
deaths. This places it among the top 5 causes.1 The appropriate use of 
antibiotic prophylaxis for cesarean delivery and antiseptic agents are among 
the most effective preventive interventions as highlighted by the recent WHO 
guidelines for maternal peripartum infections (access guidelines at: 
http://www.who.int/reproductivehealth/publications/maternal_perinatal_health
/peripartum-infections-guidelines/en/).1 Cesarean delivery is the strongest risk 
factor for maternal peripartum infection including endometritis, wound infection 
and sepsis (increasing risk by at least 5 to 10 times compared to vaginal 
delivery).2 Antibiotic prophylaxis, preferably prior to incision, in particular, 
among several strategies, effectively reduces the risk of infection and 
associated high health care and personal costs.1,3-5 In a recently completed 
multicenter US randomized clinical trial (abstract attached), we have 
demonstrated a further 50% reduction in the risk of maternal peripartum 
infection by adding a single 500mg intravenous dose of azithromycin to the 
standard prophylactic regimen (a single intravenous dose of cefazolin 1-2g or 
ampicillin) in the highest-risk group of women who undergo cesarean delivery 
following labor or membrane rupture for at least 4 hours(see trial registration 
at: https://clinicaltrials.gov/ct2/show/NCT01235546?term=tita&rank=2). This 
work builds on, and is supported by, over 20 years of research on maternal 
infections at UAB and elsewhere.6-17Azithromycin provides coverage against 
the most common pathogens identified in association with peripartum 
infections including genital mycoplasmas and ureaplasmas (when specific 
methods are utilized to identify them). In sum, the use of a single dose of 
cefazolin or ampicillin for cesarean delivery is associated with a 50% reduction 
in risk of infection/sepsis. Adding azithromycin to this standard regimen further 
reduces post-cesarean infection risk by 50%. It is unknown whether the effect 
of azithromycin alone would be similar to azithromycin plus cefazolin or 
ampicillin.  
While the role of antibiotic prophylaxis for cesarean delivery is well-
established, in most low income countries, the fraction of maternal infection 


MISP Protocol and Procedures 
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and sepsis attributable to cesarean delivery is minimal because of the low 
cesarean delivery rate of 5-10% or lower (compared with 20-30% or higher in 
the US and many high income countries).18 Therefore, strategies that address 
maternal peripartum infection and sepsis in the developing world should focus 
on identifying and preventing (or treating) infection in high-risk women who 
have a vaginal birth (or abortion). There is an increased risk of infection in 
women who undergo prolonged labor ≥18-24 hours (at least 2 fold) or 
membrane rupture ≥8-12 hours (2-3 fold in our study) compared to women 
who do not experience these risk factors. These risk factors identify a large 
group of women who are at the highest risk for maternal peripartum infections 
(chorioamnionitis and endometritis) and sepsis after a vaginal delivery. Indeed, 
the recent WHO Guidelines articulated the following among research priorities: 
what are the benefits of initiating prophylactic antibiotics after prolonged 
rupture of membranes?1Furthermore, a recent JHPIEGO consultative 
meeting on enhancing the focus on maternal infections suggested that 
"Attention to identification and prompt management of prolonged labor 
and prolonged rupture of membranes is critical to reduce disease and 
death due to maternal sepsis". 
Therefore, drawing from our findings with the azithromycin-based 
extended antibiotic prophylaxis strategy for cesarean delivery in the US, we 
propose to adapt the intervention and evaluate the role of a single oral dose of 
azithromycin (with or without oral amoxicillin) to prevent maternal peripartum 
infection and sepsis in women planning a vaginal delivery who have prolonged 
labor  (≥18 hours) or prolonged membrane rupture (≥8 hours). The current 
global standard of care (including at the proposed study sites) is that antibiotics 
are not given solely for these risk factors. 
Azithromycin is available as a generic agent. It has a bimodal half-life 
of up to 70 hours in the non-pregnant population; although it is not as well 
studied in the pregnant population. Azithromycin covers a broad spectrum of 
bacteria 
(including 
gram-positive 
cocci, 
genital 
ureaplasmas 
and 
mycoplasmas and certain gram-negative bacilli and anaerobes) that are 
associated with maternal infections, which are often polymicrobial 
(chorioamnionitis, endometritis and perineal wound infection) and sepsis. 
Amoxicillin mirrors the standard penicillin or cephalosporin recommended for 
prophylactic use for cesarean delivery and is also commonly available in LICs 
as a generic agent.1The use of single prophylactic doses minimizes the 
likelihood of antimicrobial resistance (although this will need to be monitored). 
Azithromycin is currently recommended to treat or prevent several infections 
in pregnancy including gonorrhea (1g po), chlamydia (1 g po) and 
mycobacterium avium complex prophylaxis (600mg twice/week or 1.2 g 
weekly po). It is sometimes used for perioperative prophylaxis in patients at 
risk for endocarditis (500mg po). Considering our success with 500mg IV for 
cesarean prophylaxis, the 40% bioavailability of oral azithromycin and the 
approved doses for treatment of infections, we will use 1g po of azithromycin 
for the proposed intervention. Similarly, amoxicillin has a bioavailability of 80-
90% and is used to treat several infections at doses of 500mg-2g po. 
Considering that ampicillin is used at a dose of 1-2g for cesarean prophylaxis, 
a 2g optimal dose of amoxicillin will be used for the study intervention. 
The best approach to this evaluation in order to influence future uptake 
into clinical practice is a randomized trial of these simple regimens vs. the 
usual standard of care (including antibiotic prophylaxis after 18 hours of 


MISP Protocol and Procedures 
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membrane rupture). The key primary outcomes will include any maternal 
bacterial infection (sepsis, chorioamnionitis, endometritis, or other wound 
infection) and/or maternal death prior to discharge from the hospital. 
The primary endpoint is the incidence of maternal peripartum infections that 
lead to sepsis and death. For this study we will assume an effect size of 50% 
which mirrors the minimum effect size observed with standard antibiotic 
prophylaxis for cesarean delivery. The baseline risk of infection with prolonged 
membrane rupture or labor is not well defined and ranges from 15-30%. We 
assume a baseline risk of 20% for the composite and this test of concept will 
also help better quantify baseline risks.  
2.3 Study Design 
 
Study design:3-arm randomized controlled trial. The investigational regimens 
are 1g of azithromycin and 1g azithromycin+2g amoxicillin; the common 
control arm is usual care at sites + placebo. We will design placebo for each, 
amoxicillin and azithromycin, with the assistance of the CBCHS Central 
Pharmacy, using identical capsules containing each antibiotic or matching 
placebo (non-antimicrobial agent e.g. starch) to accomplish blinding: 1 g 
azithromycin/placebo for amoxicillin, 1 g azithromycin/2 g amoxicillin vs. 
placebo for azithromycin /placebo for amoxicillin. 
Study location:4 6 hospitals with approximately 8,000 deliveries in total per 
year in Cameroon. These hospitals belong to (or are affiliated with) the 
CBCHS, a well-established major local partner of our UAB Cameroon Health 
Initiative (CHI UAB).  CHI UAB is collaboration between a multidisciplinary 
group at UAB (multiple schools and departments) and major health 
organizations in Cameroon including the CBCHS, major medical schools and 
the Ministry of Health to improve health care through research, education and 
service delivery. CHI UAB has a dedicated in-country program coordinator 
based at the CBCHS with a background in laboratory sciences (MSc) and 
public health (MPH). The CBCHS is a very well organized system with 7 major 
hospitals and over 80 health care units providing maternity care in 6 of the 10 
regions of Cameroon. We will start at BBH, MBH, BHM and Mboppi and add 
a 5th site later if necessary. 
 
Inclusion criteria: Pregnant women with singleton pregnancy in labor at term 
≥37 weeks who plan to deliver vaginally and have a) prolonged membrane 
rupture (≥ 8 hours) or prolonged labor (≥18 hours)*The study is restricted to 
those at term because those who are preterm may be more likely to receive 
antibiotics for other reasons and per recommendations. 
Exclusion criteria: Evidence of chorioamnionitis or other infection requiring 
antibiotics at time of eligibility, allergy to azithromycin or amoxicillin or any 
ingredients in the placebo, or plan for cesarean delivery prior to 
enrollment.Interventions:1g po Azithromycin/ placebo for amoxicillin, 1g po 
Azithromycin+ 2 g po Amoxicillin, and placebo for amoxicillin/placebo for 
azithromycin.  Subjects will be stratified by enrollment site. 
 
Outcomes: The primary endpoint is the percentage of women that 
develop maternal peripartum infection or death prior to discharge from 
the hospitalup to 6 weeks postpartum defined as one or more of:  
a) Chorioamnionitis: Fever (>100.4F/38C on two occasions 30 minutes apart 
or ≥102F/39C on one occasion) in addition to one or more of the following: 
fetal 
tachycardia 
>160bpm, 
maternal 
tachycardia>100bpm, 
uterine 
tenderness or purulent lochia prior to delivery, or diagnosis by a clinician. 


MISP Protocol and Procedures 
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b) Endometritis: Fever (>100.4F/38C on two occasions 30 minutes apart or 
≥102F/39C on one occasion) in addition to one or more of uterine tenderness 
or purulent lochia or diagnosis by a clinical provider.  
c) Sepsis–a clinical diagnosis of infection in association with standard clinical 
criteria suggestive of a sepsis syndrome.19The WHO Definition: Suspected or 
confirmed infection plus signs of mild to moderate organ dysfunction 
(tachycardia, low BP, tachypnea, altered mental status, and reduced urinary 
output) will be used. The specific identification criteria put out by WHO will be 
used. Other components of peripartum infection also include chorioamnionitis, 
endometritis or wound infection and abscess as defined in the manual and will 
be ascertained as defined below. 
d) Maternal death due to any reason 
 
Other endpoints: will include the following: 
a) the incidence of Ureaplasma and mycoplasma colonization of the placenta 
and chorioamnion (PCR and culture testing of a specimens obtained after 
delivery from all participants) 
ab) The incidence of the primary endpoint (above) within 6 weeks of 
deliveryprior to discharge from the hospital. 
bc)  Maternal readmission for any reason within 6 weeks of delivery 
cd) Neonatal morbidity requiring prolonged hospital stay >3 days. 
 
Sample size: It is estimated that up to15-30% of women who have prolonged 
labor or membrane rupture will have one or more infections included in the 
primary endpoint. We assume a baseline risk of 20%. To demonstrate a 50% 
reduction in peripartum infections in the high-risk group of laboring women (of 
the same order as the minimum effect size observed in high risk group who 
have cesarean) with each of the antibiotic prophylaxis regimens (azithromycin 
alone and azithromycin+amoxicillin compared separately to placebo with 80% 
power and two-sided alpha of 0.025 for each comparison (0.05 total), 241 
women per group are needed.  Thus, approximately 750 women will be 
needed for the 3-arm comparison. 
All enrolled will have specimen collection from the placenta and chorioamnion 
and will be followed for outcome ascertainment up to 6 weeks postpartum. Of 
note, the oral regimens will include an identical placebo capsule with the 
azithromycin and 2 placebo capsules for the no treatment group. 


MISP Protocol and Procedures 
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2.4 Study Flowchart 
 
2.5 Study 
Procedures 
1. Screening: Routine care at each hospital will be given to patients by their 
clinical maternity providers who will be blinded to the study interventions. 
Patient admitted to L&D for delivery 
Has labor≥18hrs or membrane rupture≥8hrs. 
Research Team Screens and Consents Patient: 

Viable singleton pregnancy ≥ 37 weeks with plan to deliver vaginally 

Exclude those on antibiotics or with allergy to medications/placebo 
Usual care at each site + 
Randomization on L&D (according to protocol) 
Azithro1g/Placebo 
Placebo/Placebo 
Delivery 

Chorioamnion swab and biopsy of placenta for organism 
 
PCR/culture (including Ureaplasma). Store in freezer. 

Ship to UAB  
Trained research nurses ascertain maternal/neonatal outcomes- by 
chart review as indicated 

Prior to discharge (primary endpoint) and up to 6 weeks (call) 
Data entry online/Transmission to Data Coordination Center for 
data management. No confidential information/identifiers 
PI’s review/confirm 
primary & key secondary 
endpoints 
DSMB Interim/Final 
Review 
 
DCC Monitors and 
Analyzes Data 
Azithro1g/Amox2g 


MISP Protocol and Procedures 
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Final Version: 10/08/2018 
Trained research staff in maternity outcomes reporting at each center (also 
blinded to study medications) will be responsible for all screening and research 
data abstraction from patient medical records with the help of clinical 
investigators and staff. Each hospital will have a designated investigator 
physician. Research nurses will undergo centralized specific training to screen 
and ascertain study outcomes. Screening will occur on labor and delivery in the 
selected CBCHS units and will be conducted by dedicated trained study staff 
with the assistance of clinical staff. The screening form will be used and 
completed for each patient screened. Potential subjects will be approached by 
trained research staff for written consent in English or French. Patients who 
cannot read will have the consent form read to them. Those that indicate they 
do not understand will be excluded. Study subjects will be randomized only 
after eligibility criteria have been confirmed and the patient has consented to 
participate by signing the informed consent form. The randomization form will 
be used to complete randomization 
 
2. Randomization and Drug allocation concealment: Enrolled subjects will be 
randomly assigned in a 1:1:1 ratio to one of the two prophylactic oral regimens 
or to no treatment/placebo using either a web-based randomization sequence 
with varying block sizes and stratified by study site. Alternatively, considering 
challenges to internet access, a computer-generated randomization scheme 
with appropriate sequence of use of the interventions will be confidentially 
maintained in the pharmacy at each site and used to accomplish the random 
allocation of consecutive patients.  
Blinding: As previously discussed we will plan to accomplish blinding with 
placebo by working with the CBCHS central pharmacy to accomplish identical 
capsules with and without the active medications. These medications will be 
packaged according to the predefined sequence into opaque envelopes 
containing the designated medication. All packages will have capsules that 
represent azithromycin or placebo and amoxicillin or placebo. The envelopes 
will be stored in sequential order until a patient is ready for randomization, 
 
3. Medication distribution: The allocated therapy will be provided by the 
pharmacy staff. Clinical supplies will be received by a designated person at 
the study site, handled and stored safely and properly, and kept in a secured 
location for use in study participants as above. Clinical supplies will be 
dispensed in accordance with the protocol. The pharmacy is responsible for 
keeping accurate records of the clinical supplies, the amount dispensed for 
use by the patients, and the disposition at the end of the study. 
The allocated therapy will be provided by the pharmacy staff to study staff for 
distribution.  
The patient is considered randomized once the medication is dispensed 
from the pharmacy and sequential number posted on the patient specific 
randomization form. The study medication will be initiated immediately 
(prior to delivery). 
 
On labor anddelivery,achorioamnion swab will be collected by trained research 
staff into storage tubes with appropriate medium and stored in a dedicated 
study freezer. Maternal blood will also be collected into the tube provided and 
frozen as well. Specimens will be shipped to UAB and kept in a biorepository 


MISP Protocol and Procedures 
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for future testing (shipped in batches as boxes get full). Of note all CBCHS 
facilities have back-up generators to ensure continuous power.  
 
Data Collection: Research staff will use data collection forms to collect patient 
information including contact information, characteristics and clinical 
outcomes. In addition to outcomes at time of discharge, participants will be 
followed-up at 6 weeks in person at their postpartum visit or by phone. They 
will be asked about any post-delivery problems and admissions for them or 
their baby and records will be reviewed to validate the outcomes. Complete 
baseline and outcome data will be collected by trained study nurses by direct 
interview and chart review using the forms provided. Contact and other 
confidential information will be known only to the local staff at each site. No 
confidential information will be entered into the database. 
Outcome adjudication:  We will review and validate primary outcomes centrally 
in a blinded fashion – 2 investigators will review de-identified records to confirm 
that the pre-defined criteria are met and agree on the diagnosis. Any initial 
disagreement will be resolved by consensus of the reviewers. If necessary a 
final adjudication will be made by the study PI. 
Data Management: A study statistician and data manager located at UAB will 
be responsible for coordinating overall data management for the trial. A 
designated in-country site PI will be responsible for day-today supervision of 
data management, with everyone using the same standardized data collection 
tools.  Data management at each site includes procedures for data entry, data 
editing, and compilation; data transmittal and quality control, data verification, 
confidentiality and security.  Data will be collected and managed with Research 
Electronic Data Capture (REDCap), an established, secure web-based data 
capture and management tool developed at Vanderbilt University and 
supported by the Data team at UAB. We have been able to use REDCap for 
remote capture of data entered in Cameroon into the database at UAB in our 
ongoing survey of infection practices. Data quality will be assessed monthly 
by the data manager, and remedial measures, including re-abstraction of data 
and retraining of staff and edits will be used as needed to enhance data quality. 
Overview of study management: Dr. Tita will be PI and will coordinate with 
and local project director, Pr. Tih to provide local study oversight in 
collaboration with other team members of CHI UAB and the Weltys. Mrs. Rahel 
Mbah will be project coordinator. Physicians at each site will be designated as 
site PIs and the central pharmacy will be responsible for packaging 
medications. The CHI-UAB research assistant team will help with 
implementation at each site. The study will be discussed every 2 weeks at UAB 
during the CHI UAB Meeting with the Weltys. Dr. Tita will correspond with Mrs. 
Mbah on a weekly basis and she will oversee the research assistants. Dr. Tita 
or a team member investigator from the US will visit Cameroon every 4-6 
months and tour all sites to ensure the proper implementation. UAB has 
established a subcontract to CBCHS for management purposes. 
6. Study Administration 
This study will be conducted at 4 6 hospitals with approximately 8,000 deliveries in total 
per year in Cameroon. These hospitals belong to (or are affiliated with) the CBCHS, a 
well-established major local partner of our UAB Cameroon Health Initiative (CHI UAB).  
CHI UAB is collaboration between a multidisciplinary group at UAB (multiple schools 


MISP Protocol and Procedures 
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Final Version: 10/08/2018 
and departments) and major health organizations in Cameroon including the CBCHS, 
major medical schools and the Ministry of Health to improve health care through 
research, education and service delivery. CHI UAB has a dedicated in-country program 
coordinator based at the CBCHS with a background in laboratory sciences (MSc) and 
public health (MPH). The CBCHS is a very well organized system with 7 major hospitals 
and over 80 health care units providing maternity care in 6 of the 10 regions of 
Cameroon. We will start at BBH, MBH, BHM and Mboppi and add a 5th site later. 
Table 1: Study sites, key investigators and roles 
Clinical Sites 
Members 
Role 
UAB 
Alan Tita, MD, PhD  
Akila Subramaniam, MD, MPH 
Lorie Harper, MD 
Jodie Dionne-Odom, MD 
Jeff Szychowski, PhD 
PI/PD  
Co-I  
Co-I/DSMB 
Co-I 
Biostatistician 
 
 
Robin Steele, MPH 
Victoria Chapman, RN, MPH 
Wally Carlo, MD 
Data Manager 
Analyst 
DSMB 
 
CBCHS 
 
Pr. Pius Tih, PhD, MPH 
 
Cameroon PD 
 
 
Rahel Mbah, MSc, MPH 
Leopold Tchokote, MD 
Dr. Datouo 
Edward Ndze 
Edith Welty 
TBN 
TBN 
Coordinator 
Co-I MBHD 
Co-I MBH 
Pharmacist 
Co-I 
Co-I BHM 
Co-I BBH 
UB 
Gregory Halle-Ekane, MD 
 
Co-I and ObGyn 
 
 
Overview of training: Dr. Tita will oversee the training of staff and clinical 
providers at all sites in coordination with Ms. Mbah. As relevant training will 
cover the ethical conduct of research, study overview (why is the study being 
done?), training in implementing study procedures, training in collecting and 
entering date into database, training in reporting of adverse events. Mrs. Mbah 
will be invited to come to the US to receive a 1 week training in the conduct of 
clinical research prior to the start of the study and she will be expected to train 
and supervise the assistants with research. Our staff are already familiar with 
data collection at CBCHS facilities and entry into our database with over 1000 
enrolled in the Moyo evaluation and 220 in the GBS study as well as 140 in a 
malaria study in Mutengene. 
 Screening and randomization will occur as previously described together with 
specimen collection. 
 Maternal outcomes will be ascertained in the hospital following (on an 
ongoing basis until discharge) and at the follow-up 6 weeks after delivery. 


MISP Protocol and Procedures 
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 Patients will be educated about the signs and symptoms of infection and 
other study outcomes and encouraged to notify the provider or come to the 
hospital after discharge with any concerns. If possible, records of visits (to any 
hospital or health facility) prior to the routine postpartum call will be obtained and 
reviewed to ascertain study outcomes (treating providers may also be called if 
clarifications are needed).  
 All newborn outcomes will be ascertained until hospital discharge and with 6 
week follow-up or death through review of hospital discharge records 
supplemented by maternal questionnaire at 6 week phone follow-up. 
Readmissions and related diagnoses for infants will be validated through history 
and record review.  
 Several data collection forms will be used during these processes, including 
forms for maternal outcomes, newborn outcomes, NICU outcomes, and 
postpartum clinic/hospital outcomes. Data on these forms devoid of personal 
identifiers will be securely sent to the DCC through web-based entry.  
 As a validity check a second abstraction of all study forms will be performed 
on a random sample of 5% of all subjects by a different research staff and 
compared for concordance (inter-rater agreement).  
 
4.5. Follow-up 
 Through discharge and then up to 6 weeks as previously described.  
 
4.5.1 Withdrawals: Patients who withdraw from the study after randomization will be 
excluded from further follow-up. Outcomes ascertained up until the time of withdrawal 
will be reported in intent to treat fashion. Those who withdraw prior to the 6-week 
window for ascertaining the primary outcome will be accounted for by randomizing an 
equal number of additional patients.  
 
2.6 Study Duration 
3 years 
2.7 Statistical 
Analysis and 
Sample Size 
Justification 
Data Management 
Data management: A study statistician and data manager located at UAB will be 
responsible for coordinating overall data management for the trial. A designated in-
country site project director and staff will be responsible for day-today supervision of 
data management, with everyone using the same standardized data collection tools.  
Data management at each site includes procedures for data entry, data editing, and 
compilation; data transmittal and quality control, data verification, confidentiality and 
security.  Data will be collected and managed with Research Electronic Data Capture 
(REDCap), an established, secure web-based data capture and management tool 
developed at Vanderbilt University and supported by the Data team at UAB. We have 
been able to use REDCap for remote capture of data entered in Cameroon into the 
database at UAB in our ongoing survey of infection practices. Data quality will be 
assessed monthly by the data manager, and remedial measures, including re-
abstraction of data and retraining of staff and edits will be used as needed to enhance 
data quality. 


MISP Protocol and Procedures 
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Analyses: Data analyses will follow the CONSORT guidelines. Analyses will 
be by intention-to-treat in which subjects will be analyzed in the group to which 
they were randomized, regardless of whether or not they received the 
assigned intervention.  Analyses will be performed at the Center for Women’s 
Reproductive Health, University of Alabama at Birmingham. 
The key analyses for this study are the comparisons reflected by the primary 
and secondary aims. The primary analysis will compare the incidence of the 
composite peripartum infection outcome between each of the active groups 
and the control groups – a chi-square p-value as well as the relative risk and 
95% CI will be computed for each comparison. The secondary outcomes will 
be similarly compared. Student’s t-test comparisons of continuous outcomes 
will be done. Standard comparisons of covariate characteristics at baseline 
between groups will be done. It is anticipated that the randomization scheme 
will balance the groups for these covariates; however, secondary analyses of 
relevant outcomes using logistic regression adjustments will be implemented 
to account for any suggested confounding. A secondary comparison will 
examine the 2 active groups relative to each other. The data from the 
ureaplasma/mycoplasma testing will be similarly compared with the 
understanding that the baseline colonization rate will be reflected by the 
findings in the no-treatment/placebo group.  
Sample Size Calculation, Primary Outcome: This has been previously 
presented above and is shown here as a reminder. 
Sample size: Up to15-30% of women who have prolonged labor or membrane 
rupture will have one or more infections included in the primary endpoint. We 
assume a baseline risk of 20%. To demonstrate a 50% reduction in peripartum 
infections in the high-risk group of laboring women (of the same order 
observed in high risk group who have cesarean) with antibiotic prophylaxis 
with 80% power and alpha of 0.025 per primary comparison (0.05 total), 241 
women per group are needed.  Thus 750 women will be needed for the 3 arm 
comparison. 
In a sub-study of our US trial 1/3 (30%) of patients had colonization with 
ureaplasma or mycoplasma. For the cohort of 600, a sample size of 195 will 
be needed to estimate a prevalence of 25% (±5%) with 95% confidence. Thus, 
we will have sufficient study population to estimate the prevalence of 
colonization with ureaplasmas by PCR methods and to assess its role as a 
risk factor for infection. Testing of the 200 receiving placebo/placebo will 
provide baseline prevalence whereas the results from the antibiotic-exposed 
groups 
will 
allow 
us 
to 
explore 
whether 
the 
prevalence 
of 
ureaplasma/mycoplasma colonization is influenced by the exposure between 
randomization and delivery (when specimens are collected and stored in 
appropriate media). 
2.8 Specific Drug 
Supply 
Requirements  
The study drugs and identical placebos will be provided with the assistance of 
the CBCHS Central pharmacy which is responsible for procuring and 
supplying medications to over 90 CBCHS facilities in Cameroon. Medications 
will either be purchased through the CBCHS Central Pharmacy or at a certified 
pharmacy in the US.  
The CBCHS pharmacy investigator will be responsible for the destruction of 
the supplies at the study center pursuant to the ICH/GCP Guidelines, local 
regulations and the investigator’s institutional policies. Clinical supplies will be 
received by a designated person at the study site, handled and stored safely 


MISP Protocol and Procedures 
12 
Final Version: 10/08/2018 
and properly, and kept in a secured location for use in study participants. 
Clinical supplies will be dispensed in accordance with the protocol. The 
pharmacy is responsible for keeping accurate records of the clinical supplies, 
the amount dispensed for use by the patients, and the disposition at the end 
of the study. 
 
2.9 DSMB and 
Adverse Experience 
Reporting 
Detailed information concerning adverse events (AEs) will be collected and 
evaluated throughout the trial. An AE is any event that is serious, deemed 
related to the study and/or unexpected in nature, severity, or frequency. 
Reporting of these events will be as follows: 
• For any maternal, fetal or neonatal deaths or other life-threatening events: 
 
 An Adverse Event Report will be sent by fax/email within 24 hours of 
knowledge to the DCC, who will assure that the event is reported to 
the DSMB as indicated.   
 
 A copy of the patient’s medical record should be made (with all of the 
patient identifiers removed or completely obscured) in case it is later 
required by the Data and Safety Monitoring Board (DSMB). These will 
be reviewed by the site study physician and Dr. Halle Ekane who will 
make the determination regarding information to submitted on the 
form and relatedness. 
• Any other events that are serious and/or unexpected in nature, severity, or 
frequency. 
 
Promptly complete an Adverse Event Report and send to the DCC. 
The DSMB will review all AEs and other interim safety data and will provide a 
report to the study leadership and the IRBs. 
 
DSMB) will be constituted to assist with safety monitoring. The DSMB will 
review safety (safety outcomes will include drug reactions, perinatal 
death and maternal death or severe morbidity warranting prolonged 
maternal or neonatal hospital stay or readmission. Institutional Review 
Board (IRB) approval for the study will be obtained at UAB and CBCHS 
IRBs. Adverse events will be reported locally to the IRB, to the UAB IRB and 
to the DSMB. DSMB members will have expertise in Epidemiology/Statistics, 
OB/maternal-fetal medicine (Dr. Lorie Harper, MD) and 
pediatrics/neonatology (Dr. Wally Carlo) and will be appointed prior to study 
starting enrollment. 
Given the small size of the study, no stopping rules for effectiveness have been 
developed. However the DSMB may recommend to stop for safety. 
Given our experience with the prior study of azithromycin in the US, this is a 
low-risk study and we anticipate few severe adverse events 
2.10 Itemized Study 
Budget  
See attached separately 
2.11 References 
1. WHO. WHO recommendations for the prevention and treatment of 
maternal peripartum infections. World Health Organization, Geneva; 
2015http://www.who.int/reproductivehealth/publications/maternal_perinat
al_health/peripartum-infections-guidelines. 
2. Gibbs RS. Clinical risk factors for puerperal infection. Obstet Gynecol. 
1980;55(5 Suppl):178S-184S. 


MISP Protocol and Procedures 
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Final Version: 10/08/2018 
3. Mackeen AD, Packard RE, Ota E, Berghella V, Baxter JK. Timing of 
intravenous prophylactic antibiotics for preventing postpartum infectious 
morbidity in women undergoing cesarean delivery. Cochrane Database 
Syst Rev. 2014 Dec 5;12:CD009516 
4. Smaill FM, Grivell RM. Antibiotic prophylaxis versus no prophylaxis for 
preventing infection after cesarean section. Cochrane Database Syst Rev. 
2014 Oct 28;10:CD007482 
5. Gyte GM, Dou L, Vazquez JC. Different classes of antibiotics given to 
women routinely for preventing infection at caesarean section. Cochrane 
Database Syst Rev. 2014 Nov 17;11:CD008726 
6. Tita ATN., Rouse DJ., Blackwell S., Saade GR., Spong CY., Andrews WW.  
Evolving Concepts in Antibiotic Prophylaxis for Cesarean Delivery: A 
Systematic Review.   Obstet Gynecol. 2009;133(3):675-82.  (PMID: 
19300334) 
7. 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;101(6):1183-9.  (PMID: 12798523) 
8. Tita AT, Hauth JC, Grimes A, Owen J, Stamm AM, Andrews WW. 
Decreasing incidence of post-cesarean endometritis with extended-
spectrum antibiotic prophylaxis. Obstet Gynecol. 2008;111(1):51-6. (PMID 
18165392) 
9. Tita AT, Owen J, Stamm A, Hauth JC, Andrews WW. Impact of Extended-
Spectrum Antibiotic Prophylaxis on Incidence of Post-Cesarean Surgical 
Wound Infection.  Am J Obstet Gynecol 2008; 199(3): 303.e1-3. (PMID: 
18771992) 
10. Watts DH, Eschenbach DA, Kenny GE.Early postpartum endometritis: the 
role of bacteria, genital mycoplasmas, and Chlamydia trachomatis. Obstet 
Gynecol. 1989;73(1):52-60.  (PMID: 2783262) 
11. Hoyme UB, Kiviat N, Eschenbach DA. Microbiology and treatment of late 
postpartum endometritis. Obstet Gynecol. 1986;68(2):226-32.  (PMID: 
3737039) 
12. Emmons SL, Krohn M, Jackson M, Eschenbach DA.Development of 
wound infections among women undergoing cesarean section. Obstet 
Gynecol. 1988;72(4):559-64.  (PMID: 3419735) 
13. Roberts S, Maccato M, Faro S, Pinell P. The microbiology of post-cesarean 
wound morbidity. Obstet Gynecol. 1993;81(3):383-6.  (PMID: 8437791) 
14. Rosene K, Eschenbach DA, Tompkins LS, Kenny GE, Watkins H. 
Polymicrobial early postpartum endometritis with facultative and anaerobic 
bacteria, genital mycoplasmas, and Chlamydia trachomatis: treatment with 
piperacillin or cefoxitin. J Infect Dis. 1986;153(6):1028-37.  (PMID: 
3701114) 
15. Andrews WW, Shah SR, Goldenberg RL, Cliver SP, Hauth JC, Cassell GH. 
Association of post-cesarean delivery endometritis with colonization of the 
chorioamnion 
by 
Ureaplasma 
urealyticum. 
Obstet 
Gynecol. 
1995;85(4):509-14.  (PMID: 7898825) 
16. Keski-Nisula L, Kirkinen P, Katila ML, Ollikainen M, Suonio S, Saarikoski 
S. Amniotic fluid U. urealyticum colonization: significance for maternal 
peripartal infections at term. Am J Perinatol. 1997;14(3):151-6.  (PMID: 
9259918) 


MISP Protocol and Procedures 
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Final Version: 10/08/2018 
17. Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS. 
Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is 
associated with a robust host response in fetal, amniotic, and maternal 
compartments. Am J Obstet Gynecol. 1998;179(5):1254-60.  (PMID: 
9822511) 
18. WHO Statement on Caesarean Section Rates. Geneva: World Health 
Organization; 2015 (WHO/RHR/15.02). 
19. Barton JR, Sibai BM. Severe sepsis and septic shock in pregnancy. Obstet 
Gynecol. 2012 Sep;120(3):689-706. 
 
2.12 Publication 
Plan 
We plan at least 2 abstracts to reputable international obstetric meetings (e.g. 
SMFM, ACOG or FIGO) and 2 manuscripts within 6-12 months of completion 
of the primary data collection to high impact journals such as the New England 
Journal of Medicine, JAMA, the Lancet or BMJ. 
2.13 Curriculum 
Vitae 
 
Attached separately 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Formatted: Tab stops: Not at  1"