Clinical trial NCT03431168
Conditions: HIV Pregnancy Malaria Sexually Transmitted Infection
Keywords: STI Prevention Cameroon sub-Saharan Africa HIV pregnancy Malaria in pregnancy
Sponsor: University of Alabama at Birmingham
Start date: 2018-03-07; Completion date: 2022-01-01
Enrollment: 308 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
More than 3 billion people worldwide are at risk of acquiring malaria and pregnant women living with HIV in Africa are at particular risk. An effective prophylaxis regimen capable of preventing malaria and other common perinatal infections would have great potential to improve adverse birth outcomes. The purpose of this randomized controlled trial is to evaluate a new combination prophylaxis regimen in pregnant women with HIV in Cameroon to determine its efficacy and safety.

Detailed description:
The World Health Organization (WHO) recommends malaria prophylaxis for all pregnant women living in endemic areas in order to reduce maternal anemia, low birth weight and perinatal mortality by 25-45%. The most commonly used regimen is intermittently dosed sulfadoxine-pyrimethamine (SP).Unfortunately, SP prophylaxis is contraindicated for HIV-infected pregnant women since co-administration with TMPS (trimethoprim-sulfamethoxazole) causes serious adverse events. TMPS (Bactrim or Cotrimoxazole) is an effective, well-tolerated, low-cost antibiotic that is used as prophylaxis in HIV-patients with low CD4 counts. It has anti-malarial activity with prophylactic efficacy that is comparable to SP (30-90%). Daily TMPS is recommended as malaria prophylaxis in pregnant women with HIV in many African countries (including Cameroon) but malaria infection rates are high even when medication compliance is excellent; thus, new and improved options are urgently needed. Azithromycin (AZ) is a macrolide antibiotic with activity against malaria, a good safety profile in pregnancy and proven utility as a part of combination malaria prevention regimens (such as SP-AZ). It also has activity against sexually transmitted infections (STI) and perinatal pathogens, including chlamydia (CT), gonorrhea (GC), syphilis and GBS (Streptococcus agalactiae or Group B Streptococcus), a potential but understudied contributor to high rates of newborn sepsis and death in Africa. SP-AZ prophylaxis in HIV-uninfected pregnant women has been reported to reduce prevalence of low birth weight (RR 0.74, 95% confidence interval (CI) 0.6-0.9) and preterm delivery (RR 0.66, 95% CI 0.48-0.91) compared to SP alone.

Thus, the central hypothesis is that a TMPS-AZ combination will be more effective than standard TMPS malaria prophylaxis in pregnant women with HIV, and that it will also decrease STI coinfection. Investigators plan a test-of-concept of the central hypothesis by conducting a double blinded, Phase II randomized controlled trial (RCT).

Arms: arm 1: Azithromycin 1 gm po daily x 3 days at enrollment and at each 4 week follow up visit.

TMPS double strength 1 tablet po daily. arm 2: Azithromycin placebo 1 gm po daily x 3 days at enrollment and at each 4 week follow up visit.

TMPS double strength 1 tablet po daily.
Interventions: intervention 1: Azithromycin/TMPS intervention 2: Placebo/TMPS
Intervention descriptions: intervention 1: 2 tabs po daily x 3 days at enrollment and at each monthly follow up visit intervention 2: 2 tabs po daily x 3 days at enrollment and at each monthly follow up visit

Protocol documents:
Prot_SAP_ICF_000.pdf: 
1 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
 
 
 
STUDY PROTOCOL 
 
 
 
  
 
 
A Novel Regimen to Prevent Malaria and STI in Pregnant Women with HIV: 
The PREMISE Trial 
 
 
 
 
 
Version 1.1 
05 September 2018 
 
 
 
 
 
 
 
 
 


2 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
TABLE OF CONTENTS 
Table of Contents………………………………………………………………………………….2 
Investigator Roster………………………………………………………………………………. 4 
Role of Investigators…………………………………………………………………………........5 
 
I. 
Introduction…………………………………………………………………………..6 
a. Study Abstract……………………………………………………………………..6 
b. Primary Hypothesis………………………………………………………………..6 
c. Protocol Summary………………………………………………………………...6 
 
II. 
Background…………………………………………………………………………..7 
 
III. 
Study Objectives……………………………………………………………………..9 
a. Primary Outcomes………………………………………………………………...9 
b. Secondary Outcomes……………………………………………………………...9 
 
IV. 
Study Design………………………………………………………………………...10 
 
V. 
Study Enrollment …………………………………………………………………..10 
a. Screening for Eligibility………………………………………………………….10 
b. Participant Inclusion Criteria…………………………………………………….10 
c. Participant Exclusion Criteria……………………………………………………11 
d. Randomization Procedures and Masking………………………………………...11 
 
VI. 
Study Intervention………………………………………………………………….12 
a. Study Product Description and Storage………………………………………….12 
b. Administration of Study Product………………………………………………...12 
c. Assessment of Participant Compliance with Study Intervention………………..12 
d. Concomitant Medications/Treatments…………………………………………...12 
 
VII. 
Study Schedule and Procedures…………………………………………………...13 
a. Visit 1 – Screening and Enrollment/Baseline Visit (<28 weeks GA)…………...14 
b. Follow up Scheduled Visit (14-35 weeks GA)...………………………………...14 
c. Unscheduled Visit/Sick Call (14-35 weeks GA)………….……………………..14 
d. End of Pregnancy Visit (35-42 weeks GA)…...…………………………………15 
e. Labor and Delivery Visit………………………………………………………...15 
f. Postpartum Follow Up Visit or Call……………………………………………..16 
g. List of Study Forms……………………………………………………………...17 
 
VIII. Training and Quality Assurance…………………………………………………..17 
 
IX. 
Monitoring of Adverse Events…………………………………………………......18 
a. Reporting…………………………………………………………………………..18 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
b. Safety Oversight (DSMB)…………………………………………………………18 
 
X. 
Specimen Collection and Processing……………………………………………....19 
 
XI. 
Sample Size Considerations………………………………………………………..20 
 
XII. 
Data Analysis and Management…………………………………………………...20 
 
XIII. Study Timetable…………………………………………………………………….22 
 
XIV. Ethical Considerations……………………………………………………………..22 
a. IRB……………………………………………………………………………….22 
b. Informed Consent Process……………………………………………………….23 
c. Participant Confidentiality……………………………………………………….23 
d. Study Costs and Participant Compensation……………………………………...23 
Appendix A – Design Summary…………………………………………………………...24 
Appendix B - Consent Form……………………………………………………………….25 
References…………………………………………………………………………………...30 
Protocol Changes…………………………………………………………………………...36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
 
Investigator Roster 
 
Jodie Dionne-Odom, MD 
Principal Investigator 
Assistant Professor of Medicine, Division of Infectious Diseases 
University of Alabama at Birmingham 
 
Jeanne Marrazzo, MD, MPH 
Co-Investigator 
Professor of Medicine 
Director of the Division of Infectious Diseases 
University of Alabama at Birmingham 
 
Alan T.N. Tita, MD, PhD 
Co-Investigator 
Professor of OB/GYN/MFM 
University of Alabama at Birmingham 
 
Eric Achidi, PhD 
Co-Investigator 
Professor of Laboratory Medicine 
University of Buea, Cameroon 
 
Barbara Van Der Pol, PhD, MPH 
Co-Investigator 
Associate Professor of Medicine, Director of the UAB STI Research Laboratory 
University of Alabama at Birmingham 
 
Andrew Westfall, MS 
Co-Investigator 
Administrative Director, CFAR Analytics Core 
University of Alabama at Birmingham 
 
Rahel Mbah  
Study Coordinator 
Cameroon Health Initiative at the University of Alabama (CHI-UAB) 
 
Edward Ndze Ngah 
Study Pharmacy 
CBCHS Central Pharmacy, Mutengene 
 


5 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
 
Roles of Investigators 
 
Name 
Title 
Responsibility for the Protocol 
Jodie Dionne-Odom 
Principal Investigator 
Principal Investigator 
Jeanne Marrazzo 
Co-Investigator 
Co-Investigator 
Alan Tita 
Co-Investigator 
Co-Investigator 
Eric Achidi 
Co-Investigator 
Laboratory - Cameroon 
Barbara Van Der Pol 
Co-Investigator 
Laboratory - UAB 
Andrew Westfall 
Co-Investigator 
Statistical Analysis 
Edward Ndze 
Study Pharmacist 
Central Pharmacy for Study Drug  
Rahel Mbah 
Study Coordinator 
Site Coordination in Cameroon 
Guy Molesa 
Study Physician 
Medical Supervision - Douala 
Seraphine Pekwarake 
Study RN  
Local Procedures - Douala 
Rita Fubam 
Study RN 
Local Procedures - Douala 
Caesar Madimba 
Site Physician 
Medical Supervision - Mutengene 
Anthony Fondzeyuf 
Study RN 
Local Procedures - Mutengene 
Edwan Kencho 
Study RA 
Local Procedures - Mutengene 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
 
I. 
INTRODUCTION 
 
a) Study Abstract 
More than 3 billion people worldwide are at risk of acquiring malaria and HIV-infected pregnant 
women in Africa are at particular risk. An effective prophylaxis regimen capable of preventing 
malaria and other common perinatal infections would have great potential to improve adverse 
birth outcomes. The purpose of this randomized controlled trial is to evaluate a new combination 
prophylaxis regimen in pregnant women with HIV in Cameroon to determine its efficacy and 
safety. 
b) Primary Hypothesis 
A novel regimen of trimethoprim-sulfamethoxazole (TMPS) in combination with azithromycin 
(AZ) compared to the standard of care (TMPS) will be more effective in preventing infection 
with Plasmodium falciparum (malaria), Treponema pallidum (syphilis), Chlamydia trachomatis 
(CT), Neisseria gonorrhoeae (GC), and Streptococcus agalactiae (GBS) in HIV-infected 
pregnant women in Cameroon, Central Africa. 
c) Protocol Summary 
We plan a test-of-concept of our central hypothesis by conducting a randomized, placebo-
controlled, double-blinded, Phase II trial with the following 3 aims: 
Aim 1: Test the efficacy of a combination malaria prophylaxis regimen (TMPS-AZ) compared to 
the standard of care regimen (TMPS) in reducing malaria in HIV-infected pregnant women. The 
goal is to determine whether the addition of azithromycin has an impact on the proportion with 
submicroscopic parasitemia at delivery.  
Approach: Pregnant women with HIV will be randomized to the intervention (TMPS-AZ) or to 
usual care (TMPS) with monthly follow-up visits to receive medications. Blood collected at 
delivery will be tested by PCR to assess for infection with Plasmodium falciparum.  
Aim 2:  Measure the reduction in prevalence of curable bacterial STIs and GBS colonization 
after 35 weeks gestation (or at delivery) in the intervention and usual care groups. The goal is to 
measure the impact of monthly AZ prophylaxis on the prevalence of pathogens that are 
associated with adverse birth outcomes (Neisseria gonorrhoeae, Chlamydia trachomatis, 
Treponema pallidum, Streptococcus agalactiae). 
Approach: Participants will have vaginal and anogenital swabs in late pregnancy or at delivery 
for GC/CT/GBS nucleic acid amplification testing. Blood will be collected simultaneously for 
syphilis testing.  
Aim 3: Determine the fetal/neonatal safety and adherence/tolerability of TMPS-AZ compared to 
TMPS.  The goal is to collect safety, adherence and tolerability data for this novel regimen used 
in HIV-infected pregnant women.  


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
Approach: Birth outcomes will be captured by chart review and women will fill out a validated 
questionnaire to assess medication adherence and tolerance at each visit. The first dose of 
medication at each visit will be given under directly observed therapy.  
II. 
BACKGROUND 
HIV and malaria coinfection in pregnancy is a major public health problem in sub-
Saharan Africa. 
Up to 40% of the world’s population is at risk of malaria, including 25 million pregnant women in 
sub-Saharan Africa. The parasite Plasmodium falciparum transmitted by the anopheline mosquito 
causes most serious malaria infections with peak mortality rates in pregnant women and children 
under 5 years. P falciparum is the etiology of 96% of malaria infections in Cameroon with a mean 
entomological inoculation rate of 3.9 infective bites per person each night.(1-3) HIV, malaria and 
pregnancy are considered the “triple threat” in terms of maternal morbidity and mortality in 
Africa.(4) Pregnancy is a risk factor for acquiring malaria, particularly among primigravidae 
because of parity-dependent development of protective immunity to placental antigens.(5-7) (8) 
Women with HIV have elevated malaria acquisition risk (RR 1.8), irrespective of parity, and lower 
rates of malaria specific immunity.(9) Women with HIV also have a 70% increased risk of 
placental infection and more severe clinical disease than HIV-uninfected pregnant women. (10-
13) (14) Studies in pregnancy (including those from our collaborators in Cameroon) among HIV-
uninfected pregnant women have documented peripheral parasitemia in 22-82% of women.(15-
19) Placental malaria is associated with a two-fold increased risk of low birthweight but effective 
prevention improves maternal severe anemia, low birthweight and perinatal mortality by 27-
43%.(6, 20, 21) Malaria also leads to a transient elevation in HIV viral load (7 fold for symptomatic 
disease) and an increased risk of mother to child HIV transmission which is independent of 
maternal HIV viral load. (RR 7.9, p=0.025). (11, 22-24)  
 
Curable bacterial STIs are common in pregnant women with HIV in Africa and an 
important cause of maternal and neonatal morbidity.  
 
Accumulating evidence supports infection as a major cause of spontaneous preterm labor, 
particularly when it occurs before 30 weeks gestation.(25) The underlying pathogenesis is under 
study, but proinflammatory cytokines IL-6, TNF, IL-1, metalloproteinase-9 and alternations in the 
maternal microbiome contribute to uterine activation.(26-30) HIV prevalence in pregnancy is 
elevated in Africa (10% in urban Cameroon) and antenatal screening suggests a high rate of STIs 
in women with HIV.(31, 32) In one study, 38% of pregnant women with HIV had CT (compared 
to 7% in HIV-uninfected), 10% had GC (compared to 3%) and 36% had syphilis (compared to 
11%). Up to 90% of pregnant women with early syphilis transmit Treponema pallidum to the fetus 
which can lead to stillbirth, neonatal deaths, congenital syphilis and low birth weight. There are 
an estimated 200,000 adverse pregnancy outcomes attributable to syphilis in sub-Saharan Africa 
each year and adequate prevention could reduce stillbirths by 80% worldwide.(33, 34) Although 
GC/CT infections are generally confined to the lower genital tract, GC acquisition in pregnancy 
has been associated with preterm birth (aOR 2.1, 95% CI 1.02-3.97) and CT infection with low 
birthweight (aOR 2.07, 95% CI 1.01-4.24).(35, 36)  
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
More effective prevention tools for malaria and sexually transmitted infections are needed 
for the high-risk population of HIV-infected pregnant women.  
Since ART is increasingly available, and HIV-associated mortality rates have fallen, more 
pregnant women with HIV are in need of malaria prophylaxis.(37) The prevalence of malaria 
among pregnant women in sub-Saharan Africa ranges from 25-50% despite available 
prophylaxis.(15-17) The concept of intermittent prophylaxis during pregnancy is to prevent 
infection and treat asymptomatic infections before negative consequences can occur. Prevention 
of infection in pregnancy is an attractive concept since antibiotics are only administered during a 
defined period of exposure and even timely treatment of infection often occurs too late to reverse 
deleterious inflammatory processes.(38) Although intermittent sulfadoxine-pyrimethamine (SP) is 
recommended as malaria prophylaxis for many pregnant women, this option is not available for 
pregnant women with HIV taking TMPS. Co-administration of dual antifolate therapy with TMPS 
and SP is contraindicated because of side effects including 100-fold higher risk of severe rash. 
Given this important interaction, in many African countries (including Cameroon), daily TMPS is 
recommended for malaria prophylaxis in pregnant women with HIV. Available evidence shows 
that TMPS is as effective as SP (30%-90% efficacy).(39-42) While SP efficacy is jeopardized by 
emerging resistance, TMPS has good activity against malaria to date.(43, 44)  
 
Azithromycin (AZ) is a useful agent for co-prophylaxis given its broad coverage, favorable 
pharmacokinetics, track record of safety in pregnancy and association with improved birth 
outcomes.  
AZ has anti-inflammatory and immunomodulatory properties and it has been shown to prevent 
LPS-associated pregnancy loss in a murine model.(45, 46) It concentrates in tissues and has proven 
efficacy and safety for malaria prevention when used as part of a combination regimen 
(recommended by WHO to reduce the risk of parasite resistance).(47) AZ has a prolonged half-
life (68 hours) and good oral bioavailability (34-52%). Pharmacokinetic studies have shown that 
increased AZ dosing in pregnancy is not necessary and the AZ dosing schedule with demonstrated 
efficacy for malaria prophylaxis is 1 gram daily for 3 days.(47-49) One recent study of HIV-
uninfected women in Papua New Guinea suggested a reduction in low birthweight (RR 0.74, 95% 
CI 0.6-0.9) and preterm delivery (RR 0.62, 95% CI 0.4-0.9) with the addition of monthly AZ to 
SP.(50) SP-AZ also significantly improved low birthweight and infant growth parameters at 12 
months in Malawi compared to SP alone.(51, 52) For STI prophylaxis, monthly AZ in Kenyan sex 
workers lowered the incidence of GC by 64% and CT by 62% compared to placebo.(53)AZ 1gm 
is CDC recommended therapy for CT (97% efficacy).(54, 55) Combination therapy including AZ 
1gm is recommended for GC treatment but a single 2 gram dose of AZ has shown 99.2% 
efficacy.(56) A recent CDC analysis showed 99.6% GC sensitivity to AZ and response rates 
averaged 96% worldwide.(57, 58) Given more limited exposure to macrolides, GC response rates 
to AZ are similar or better in Africa.(59) For syphilis treatment, AZ 1-2gm has similar efficacy as 
benzathine penicillin in certain populations, but AZ resistance has been documented and penicillin 
remains the treatment of choice.(60) (54) AZ also has activity against other genital tract pathogens 
which may contribute to birth outcomes (i.e. Ureaplasma urealyticum (95%), Mycoplasma 
genitalium (70%)) and Streptococcus agalactiae (GBS) (70%).(53, 61, 62) Anogenital GBS 
colonization during pregnancy is a primary preventable cause of neonatal pneumonia, meningitis 
and sepsis and HIV-exposed infants are at higher risk of invasive disease.(63) GBS colonization 
rates range from 20-30% worldwide but antenatal screening is not routine in Africa. (64, 65) We 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
have an active study to document rates of maternal GBS colonization and capture birth outcomes 
for exposed infants in Cameroon given the paucity of data. (127) 
 
Both TMPS and Azithromycin are effective for malaria prophylaxis with favorable safety 
profiles individually in pregnancy, but additional data on the combination is needed.  
A recent review of malaria prophylaxis regimens in pregnancy discussed the need to capture safety 
outcomes for new combinations.(66) TMPS is a well-tolerated, inexpensive, widely prescribed, 
FDA “category C” drug with efficacy against parasitic and bacterial pathogens. It has good 
pregnancy safety and is part of the WHO-recommended therapy for HIV-infected pregnant 
women.(67, 68) Azithromycin is a “category B” agent with a favorable safety profile in all 
trimesters and efficacy against STIs. (48, 69) TMPS/AZ are commonly administered together as 
prophylaxis in HIV patients and there are no published reports of malaria resistance to TMPS or 
AZ in Africa.(70)  
 
III. 
STUDY OBJECTIVES 
As resistance spreads, new options are needed to prevent malaria during pregnancy, particularly 
among women with HIV-infection.  The combination of TMPS and Azithromycin has not yet 
been studied for efficacy in terms of preventing malaria and other STIs that contribute to adverse 
birth outcomes. 
a) Primary Outcomes 
Aim 1 Proportion of women with Plasmodium falciparum peripheral parasitemia by microscopy 
or PCR. 
Aim 2 Prevalence of a composite STI measure (GC, CT, syphilis infections) will be measured in 
both groups in late pregnancy (>35 weeks gestation) or at delivery and compared between the 
two groups.  
Aim 3 a) Mean infant birthweight; b) Proportion with adverse birth outcomes, including  low 
infant birthweight (<2500 gm), miscarriage (<28 weeks), preterm delivery (<37 weeks), small 
for gestational age (SGA), stillbirth (>28 weeks), congenital anomaly at birth, early neonatal 
mortality (within 7 days); and c) maternal adherence to and tolerance of the prophylactic regimen 
(vomiting, rash/allergic reactions, dizziness, weakness).   
b) Secondary Outcomes 
Aim 1 a) Episodes of symptomatic malaria during study period; b) geometric mean parasite 
density at delivery; c) Proportion with placental malaria (impression smear, available on a 
subset); d) Proportion with anemia at delivery (hgb <11 g/dL); e) Proportion with adverse birth 
outcomes, including preterm delivery (<37 wks), stillbirth, low birth weight (<2500g) or early 
neonatal death (<7 days); f) Proportion of infants with poor growth at 6 and 12 months of age. 
Aim 2 a) Proportion with anogenital GBS colonization after 35 weeks GA or at delivery; and b) 
Maternal puerperal and/or neonatal infections prior to hospital discharge c) Proportion with 
infection with Mycoplasma genitalium (M gen), Trichomonas vaginalis (T vag), and bacterial 
vaginosis (BV). 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
IV. 
STUDY DESIGN 
 
 
 
V. STUDY ENROLLMENT  
a) Recruitment and Screening for Eligibility 
Women will be recruited for the study by study nurses from the waiting room for the antenatal 
care clinic at one of 2 CBCHS facilities; Mboppi Hospital in Douala and the Baptist Hospital in 
Mutengene. Study eligibility will be assessed using a standardized form by study nurses with 
review of the medical record and discussion with the patient in a private room. Subjects will be 
consented prior to any study procedures. 
If the patient appears to meet the criteria for enrollment and expresses interest in the study, she 
will be told more details about the study and asked to sign the informed consent. The consent 
form will be available in English and in French. For patients who only understand Pidgin English 
or are not literate, the study will be explained verbally by the study nurse and the consent will be 
read aloud.  A support person or family member will be allowed to help with the consent process 
if the patient prefers this option. 
b) Participant Inclusion Criteria 
• Confirmed HIV-infection (documented in medical record) 
• Age ≥16 years 
• Confirmed pregnancy, <28 weeks estimated gestational age (by best obstetric 
estimate which may include ultrasound or fundal height and LMP)  
• Live singleton pregnancy  


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
• Receiving prenatal care at Mboppi Hospital or Mutengene Hospital 
• Plan to receive follow up prenatal care and deliver at study facility 
• Capable of providing written informed consent 
• Able and agree to come to facility for febrile episodes or acute illness during 
pregnancy (with reimbursement of transportation costs). 
• Agree to avoid antimalarial medications outside of study protocol. 
• Women receiving standard therapy for HIV infection (any antiretroviral regimen) 
and standard malaria prophylaxis medications (cotrimoxazole) will be eligible to 
participate. 
• Women with HIV-infection who are not taking antiretrovirals (for any reason) are 
eligible to participate in the trial if all other study criteria are met. 
• Participants will be eligible to participate irrespective of prior or active malaria 
infection detected at the time of study enrollment. 
 
c) Participant Exclusion Criteria 
• Severe anemia (last hemoglobin <6) 
• History of severe adverse reaction to co-trimoxazole or azithromycin  
• Active medical problem requiring inpatient evaluation at the time of screening 
• Intention of moving far away from the facility during pregnancy or not likely to 
return for follow up care or delivery  
• Signs or symptoms of early or active labor 
• Known congenital anomalies 
• History of severe cardiac disease (including congestive heart failure, severe 
valvular disease or arrhythmias). 
 
d) Randomization Method and Masking 
Consenting women will be assigned to one of two prophylaxis groups with a computer generated 
variable size (2, 4, 6) block randomization sequence prepared in advance by a co-investigator at 
the University of Alabama at Birmingham.  The active and placebo study medication will be 
indistinguishable in appearance and packaged according to the randomization sequence so that 
the patient is randomized when she is assigned to the next available individual supply of study 
medication.  The study is double masked; neither the patient nor the clinical staff will be aware 
of the assigned prophylaxis. 
Randomization will be stratified by clinical center to assure balance between the two study 
groups with respect to anticipated differences among the clinic populations and possible 
differences in patient management. A unique study ID will be provided to each patient after they 
are randomized (starting with 5001D for the Douala site, starting at 9001M for the Mutengene 
site). 
The PI and all staff responsible for assessing outcomes (laboratory and clinical) will be blinded 
to the randomization arm.  
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
VI. STUDY INTERVENTION 
a) Study Product Description and Storage 
The medications are to be taken orally as pills. They are stable at room temperature in 
Cameroon.  The supply will be maintained by the study nurse on site.  The TMPS will be 
acquired in Cameroon per routine procurement pathways at CBCHS. The CBCHS Pharmacy has 
internal policies and procedures to verify the quality of the antibiotics administered on site. The 
azithromycin and matching azithromycin placebo will be created by a US Pharmaceutical 
Company (Goderich Pharmacy, Houston, TX) and shipped to the Central Pharmacy in 
Mutengene, Cameroon where the study drugs will be packaged for dissemination. 
b) Administration of Study Product 
Study nurses will have 30 day supply of medications prepared in advance for each subject 
according to their study ID. TMPS (1 DS tab 160/800 mg po QD) is routinely offered in clinic 
and this will be provided for women in both groups. Women will also receive a 1 gram dose (two 
500 mg pills) of azithromycin (AZ) or AZ placebo under directly observed therapy and this will 
be recorded.  Subjects will be observed for 5 minutes for adverse events. Women will be sent 
home with 4 additional azithromycin or placebo pills with written instructions on the bag to take 
2 pills on the morning of day #2 and 2 pills on the morning of day #3 after the study visit.  The 
azithromycin has a 2-year shelf life at room temperature. 
c) Assessment of Participant Compliance with Study Intervention 
Study subjects will be reminded that they will be asked about adherence, tolerance and side 
effects at the subsequent visit.  They will complete a medication adherence questionnaire (MAQ) 
at subsequent visits.  
d) Concomitant Medications/Treatments 
Subjects will be encouraged to continue daily antiretroviral therapy throughout pregnancy.  They 
will be advised not to take any outside medications to treat or prevent malaria without discussing 
it with the study nurse.  Antipyretics and any other medications without antimicrobial properties 
are allowed.  All medications taken will be captured at each follow up visit. 
 
 
 
 
 
 
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
VII. STUDY SCHEDULES AND PROCEDURES 
 
Screen 
and 
Enroll 
Follow 
up Visit  
(1-6) 
Sick 
Visit 
(1-9) 
 Term 
Visit 
(1) 
Delivery 
Visit 
(1) 
Postpartum  
(if no Delivery 
Visit) 
Follow 
Up Call 
Infant Follow 
Up Call or 
Visit 
Timing of Visit/Call 
4-28 
weeks 
Every 4 
weeks 
As 
Needed 
35-42 
weeks 
At Delivery 
Within 14 days  
of delivery¹ 
Within 6 
weeks  
3, 6, 9, 12 
months 
FORMS² 
Screening Log (Form 1) 
X 
 
 
 
 
 
 
 
Eligibility (Form 2) 
X 
 
Consent and Randomize (Form 3,4) 
X 
Baseline Survey (Form 5) 
X 
Follow Up Survey (Form 6) 
X 
X 
X 
X 
 
Med Adherence (Form 7) 
X 
X 
X 
X 
X 
Sick Call Survey (Form 8) 
 
 
X 
 
 
 
 
Outcomes and Labs (Form 9) 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events (Form 10) 
 
X 
X 
X 
X 
X 
x 
 
Postpartum Phone Call (F 11) 
 
 
 
 
 
 
X 
 
Participant Contact Info (Form 12) 
X 
X 
X 
X 
X 
X 
X 
 
Infant Follow Up (Form 13) 
 
 
 
 
 
 
 
X 
CLINICAL AND SAMPLING 
Vitals and Exam 
X 
X 
X 
X 
X 
X 
Venipuncture 
X 
X 
X 
X 
X 
Finger stick 
X 
X 
X 
X 
X 
X 
Vaginal Swab 
X 
X 
X 
X 
Placental biopsy 
X 
Directly Observed Therapy 
X 
X 
X 
X 
 
 
 
LAB TESTING² 
CBC and differential 
X 
X 
X 
X 
CD4 Count 
 
 
 
X 
 
 
 
HIV Viral Load 
 
 
 
X 
 
 
 
Thick smear  
X 
X 
X 
X 
RDT 
 
X 
X 
X 
 
 
 
DBS for PCR 
X 
X 
X 
X 
X 
X 
Syphilis (RPR/TPHA) 
X⁴ 
X 
X 
X 
Xpert GC/CT & GBS NAAT 
 
 
 
X 
X 
X 
 
SUPPLIES PROVIDED 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
Bed Net  
X 
Condoms 
X 
X 
X 
X 
30 day med supply  
X 
X 
X 
X 
¹ Samples collected at postpartum visit only if they were not collected at prior visits 
² Lab testing to be performed on site. Additional testing at UAB is not part of this table. 
³ In cases of fever or clinical suspicion of malaria. 
⁴ RPR testing will be performed for women with a positive treponemal test on enrollment if it has not been done. 
 
a) Enrollment Visit 
Following the provision of informed consent, study subjects will be randomized to one of 
two arms.  A baseline survey will be administered by study nurses, vital signs will be 
collected and a brief exam will be performed. The medical chart will be reviewed for 
additional information.  A 30 day supply of medications will be provided by study nurse. 
Contact information will be collected for the woman and a back-up person (with 
permission) and women will be given an appointment to return in 30 days. Bed nets, 
condoms and safe sex counseling will be provided.  Partner HIV testing will be 
recommended, discussed with all women and facilitated, as necessary. Questions will be 
asked by study staff and entered into a RedCAP database. All forms will be labeled with 
the unique study ID, visit number and date. 
 
Testing: CBC, thick smear and DBS. RPR confirmatory testing for those with + ANC 
syphilis screen. Vaginal swab for GC/CT and store. pH. Slides and store. 
 
Treatment: For malaria peripheral parasitemia:  
1st trimester – Quinine. 
National Guidelines: Three doses of Parenteral Quinine base at 8.3mg/kg x 3 every 8 
hours for 24 hours. Each infusion should run for 4 hours. This is relayed by Oral Quinine 
(tablets) for 3 days if patient can tolerate) and a maximum dose of 1.5 per day of Quinine 
base. The treatment is for 7 days. If the woman develops contractions on quinine, 
administer tocolytics. 
 
2nd or 3rd trimester - Artesunate.  
Per National Guidelines: Injectable Artesunate IV or IM: 2.4mg/kg at 0, 12, and 24 hours. 
This is continuous once every 24 hours until the patient can take the oral with ease. This 
is relayed with Artemether -Lumefantrine for 3 days if she can swallow. 
 
1st dose of study medications will be given under directly observed therapy (DOT). 
 
b) Scheduled Follow Up Visit 
Subjects will have vitals and brief exam. If they are noted to be febrile (axillary T>37.5), 
RDT will be collected.  Survey about medication adherence for ART, TMPS, 
AZ/placebo, pill count, tolerance of prophylaxis and ART, interim treatment, ITN usage. 
Transportation costs, 30 day medication supply and follow up appointment will be 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
provided.  Contact information will be verified.  Questions will be asked by study staff 
and entered into a RedCAP database. 
 
Testing: DBS for all. RDT if febrile.  
Treatment (dosing in section a)):  
Malaria with positive RDT: Quinine during the 1st trimester, Artesunate IV during 2nd or 
3rd trimester. STI rx from enrollment visit if needed. Syndromic management of STI per 
routine. DOT ppx meds. Condoms and safe sex counseling will be provided. 
 
c) Unscheduled Sick Call Visit 
Per routine 24/7 in maternity unit. Vitals and brief exam. Management will be per routine 
with RDT for fever. Transportation costs will be covered. 
If scheduled appointment had been missed – if possible, administer survey about 
medication adherence and tolerance and outside medications. Provide medications for 30 
days. Questions will be asked by study staff and entered into a RedCAP database. 
 
Testing: RDT for fever per routine, DBS for malaria testing (PCR) 
Treatment (dosing in section a)):  
Malaria with positive RDT: Quinine during the 1st trimester, Artesunate IV during 2nd or 
3rd trimester. STI syndromic management. Other antibiotics per routine if recommended 
by provider and this will be captured as an outcome. DOT of prophylaxis medications if 
provided. 
 
d) 35-42 Week Visit 
Vitals and brief exam.  
Testing: CBC, RDT, DBS and store, vaginal swab for GC/CT and store, anogenital swab 
for GBS, vaginal pH, slides and store, rapid syphilis test with RPR confirmation. 
Questions will be asked by study staff and entered into a RedCAP database. 
 
Treatment:  
Malaria with positive RDT: Artesunate IV (dosing above). GC/CT/Syphilis (same day if 
possible). DOT of prophylaxis medications. Condoms and safe sex counseling will be 
provided. 
 
e) Labor and Delivery Visit 
Vitals and brief exam. 
Testing (if not performed at 35-42 weeks): CBC, thick smear, DBS and store, vaginal  
swab for GC/CT and store, anogenital swab for GBS, vaginal pH, slides and store, rapid 
syphilis test with RPR confirmation. Collect placentas, OK to refrigerate overnight.  
Biopsy specimen placed in formalin and can be stored on site. Questions will be asked by 
study staff and entered into a RedCAP database. 
 
Treatment:  


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
Malaria with positive RDT or peripheral parasitemia: Artesunate IV. GC/CT/syphilis if 
not yet treated from prior visit or newly detected. Ampicillin IV for GBS positive (late 
pregnancy screen or L+D screen). Treat maternal/neonatal infection per routine. 
 
Survey: FU survey with questions about medication adherence, tolerance, interim 
medications and source.   
 
Study RN: outcome assessment form including infant weight with electric scale, GA, 
maternal/neonatal infection, surface examination for major congenital anomalies.   Verify 
contact information – plan to call after 7 days to ask about neonatal mortality. 
Recommend infant HIV testing. 
 
f) Postpartum visit – 0-14 days with baby 
For women who did not deliver at the facility.   
Testing: if not done prior (35-42 wk or at delivery) - CBC, thick smear, DBS and store, 
vaginal swab for GC/CT and store, anogenital swab for GBS, vaginal pH, slides and 
store, rapid syphilis test with RPR confirmation.  No testing if it was done previously. 
Questions will be asked by study staff and entered onto paper forms for later entry into a 
RedCAP database.  
 
Treatment: infection detected on current testing or prior testing if not yet treated. 
 
Survey: Follow-up survey about medication adherence, tolerance, interim meds and 
source. 
 
Study RN: outcome assessment form – review patient medical record (document source 
of info) and capture birth weight.  Ask about maternal/neonatal infections.  Perform 
surface exam for major congenital anomalies.  Verify contact information – may need to 
come back for treatment if testing performed and any new infections noted. 
 
g) Follow Up Phone Call – within 6 weeks 
Women will be contacted by telephone to check in to see how mom and baby are doing 
and to document any new outcomes on the study outcomes form including 
hospitalizations and deaths. 
 
h) Follow Up Phone Call or Visit for Infant Outcomes – Every 3 months until 1 year 
Women will be contacted by phone every three months to ask how the baby is growing. 
Information from medical visits about the baby’s height and weight will be asked as well 
as any information about infant hospitalizations or sick clinic visits or death.  Women 
will be encouraged to bring the baby to the clinic for a visit at 6 months and 12 months to 
measure height, weight and head circumference. 
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
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Study Forms  
 
Form 
# 
Form Name 
0 
Forms List 
1 
Screening Log 
2 
Eligibility Assessment 
3 
Consent  
4 
Randomization Data Form 
5 
Enrollment Visit Baseline Survey  
6 
Follow Up Visit Questionnaire 
7 
Medication Adherence Questionnaire 
8 
Sick Call Visit Questionnaire 
9 
Study Outcomes Including Labs 
10 
Adverse Event Form 
11 
Postpartum Check In Form 
12 
Participant Follow Up and Call Log 
13 
Infant Follow Up Form 
 
VIII. TRAINING AND QUALITY ASSURANCE 
Study staff (RN, data manager, study coordinator) must have the human subject’s protection 
training certificate.  New staff members will undergo training on research ethics. Additional 
training will occur on site prior to study initiation related to study procedures, forms, data entry, 
sample collection and subject follow up. Specific training will be provided to midwives about 
how to assess for congenital anomalies at birth. 
The participating site is responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance. The site PI 
will provide direct access to all trial-related sites, source data/data collection forms, and reports. 
The site PI will ensure all study personnel are appropriately trained and applicable 
documentations are maintained on site. 
Data QC checks will be run on the database. Any missing data or data anomalies will be 
communicated to the site(s) for clarification and resolution. 
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
IX. MONITORING OF ADVERSE EVENTS 
 
a)  Reporting  
Adverse Event: 
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical 
product regardless of its causal relationship to the study treatment. The occurrence of an AE may 
come to the attention of study personnel during study visits and interviews of a study recipient 
presenting for medical care. 
All AEs not meeting the criteria for SAEs should be captured on the appropriate form. 
Information to be collected includes event description, clinician’s assessment of severity, 
relationship to study product, and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
Any medical condition that is present at the time that the subject is screened should be 
considered as baseline and not reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to study product. 
Severity of Event: All AEs will be assessed by the clinician using a grading system.  
Mild: events require minimal or no treatment; do not interfere with the subject’s daily activities. 
Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures; may cause some interference with functioning. 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug therapy or 
other treatment; are usually incapacitating. 
Relationship to Study Products: The clinician’s assessment of an AE's relationship to the study 
drug is part of the documentation process. 
• Related – There is a reasonable possibility that the study drug caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study drug and the AE. 
• Not Related – There is not a reasonable possibility that administration of the study drug 
caused the AE. 
Serious Adverse Event (SAE): 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator, it results in any of the following outcomes: 
• Maternal death 
• Neonatal death 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
• Stillbirth 
• Congenital anomalies 
• Unanticipated or prolonged maternal hospitalization (longer than expected) 
• Prolonged neonatal hospitalization (longer than expected based on gestational age 
at birth) 
All SAEs will be: 
• Assessed for severity and relationship to study product and alternate etiology by a study 
physician. 
• Recorded on the appropriate form 
• Followed through resolution by a licensed study physician. 
• Reviewed and evaluated by the DSMB and the IRB.  
 
b) Data Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety. The DSMB members will be separate and independent of study 
personnel participating in this trial and should not have scientific, financial, or other conflict of 
interest related to the study. The DSMB will consist of three members with appropriate expertise 
to contribute to the interpretation of the data from this trial: malaria in pregnancy, maternal-fetal 
medicine and biostatistics.   
The DSMB will review and approve the study protocol and safety plan prior to initiation of the 
trial. It will be convened when 50% of the planned subjects have been enrolled for a review of 
interim data. The PI will review safety data weekly and report any serious adverse events to the 
DSMB and IRB and to NIH/NICHD. The DMSB and NIH will receive quarterly adverse event 
reports and the interim report will include the following information: recruitment, withdrawals, 
loss to follow up, adverse events, and medication tolerance. The DSMB will also review efficacy 
and safety data after all subjects have been enrolled in a final closeout meeting, held at the end of 
the study. As an outcome of each review/meeting, the DSMB will make a recommendation as to 
the advisability of proceeding with study and to continue, modify, or terminate the study. 
X. SPECIMEN COLLECTION AND PROCESSING 
All samples will be collected under practices outlined in SOPs and they will be labeled with 
unique study ID, visit number and date. Malaria testing: Blood will be collected by fingerstick 
for thick smear microscopy and dried blood spots (DBS) will be collected on filter paper for PCR 
testing later. Blood will also be collected by venipuncture for CBC, differential and RPR testing, 
as indicated. RPR will be performed on women with a prior positive treponemal test during 
antenatal care if not performed previously.  Microscopy, CBC, and syphilis testing will be 
performed at the facility laboratory but same day results cannot be guaranteed.  Subjects will be 
called by telephone with positive results that return after they have left the facility along with 


20 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
specific follow up instructions. Filter paper with DBS will be stored in the freezer (-20 degrees 
C) with regular transportation to the University of Buea for long term storage and PCR testing.  
Placental biopsies will be collected on as many women as possible at the time of facility 
delivery. Slides will be created with impression smears and placental blood will be collected on 
filter paper for PCR testing. 
STI testing: Vaginal swabs will be collected at enrollment for storage and at the 35-42 week or 
delivery or post-delivery visit (whichever comes first) for GC/CT NAAT testing as well as an 
anogenital swab for GBS NAAT testing per SOPs. pH indicator sticks will be used to collect a 
sample from the lateral vaginal wall. Slides will be prepared from a vaginal swab at the late 
pregnancy visit.  
Vaginal Swab specimens for Future Testing: Vaginal swabs will be stored in transport media 
using buffer in a -20 freezer until they can be transported to the UAB STI laboratory for later STI 
testing. Participants will be asked to sign a consent specifically for their agreement to have these 
samples stored and shipped to UAB for future analysis.  For those who do not consent, the 
samples will be destroyed at the end of the study. Before specimens leave the clinic, they will be 
assigned a unique code.  Specimens stored for future research will be shipped to the UAB STI 
Research Laboratory at the University of Alabama at Birmingham (UAB) (Dr. Van Der Pol Lab, 
Dr. Ken Waites Mycoplasma/Ureaplasma Laboratory) where they will be stored according to 
GCLP by the Laboratory Managers. 
XI. SAMPLE SIZE CONSIDERATIONS 
AIM 1: To test the hypothesis that the addition of AZ to standard preventive therapy in pregnant 
women with HIV will be associated with a lower proportion of women with peripheral 
parasitemia detected by microscopy or PCR at delivery, we assumed a 30% prevalence of 
parasitemia in the TMPS arm based on prior studies and 15% prevalence in the TMPS/AZ arm. 
A sample size of 134 pregnant women per arm has 80% power at a two-sided significance level 
of 0.05 using a chi-square.  
We will plan for 15% loss to follow up (LFU) and will recruit 154 women per arm (308 women 
total).  
AIM 2: Based on the sample size of 308 evaluable participants at the time of delivery and an 
expected prevalence of 30% for one or more STIs (CT 20%, GC 5%, syphilis 5%) there will be 
>80% power at a two-sided significance level of 0.05 to detect a 50% lower STI prevalence in 
the intervention arm. 
XII. DATA ANALYSIS AND MANAGEMENT 
Data management and analysis will be led by the University of Alabama at Birmingham under 
the supervision of the study PI (Dr. Dionne-Odom).  
The primary analysis will be by intention to treat for women who are randomized and receive at 
least 1 dose of study medication. 


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05 September2018 
The “per protocol” analysis will be performed on women who came to at least one follow up 
visit following the enrollment visit, reported excellent (>90%) medication adherence, and had 
outcomes captured (ie – not lost to follow up). 
Statistical Analysis: Descriptive statistics will be used to compare the study participants between 
each arm and the primary analysis will be intention-to-treat for the primary outcome of 
proportion of women with parasitemia. The analysis plan for categorical outcomes is chi-square, 
Fisher’s exact tests as needed for small sample sizes and we plan to use t-test and Wilcoxon 
Rank-Sum tests for continuous outcomes. Women will be considered lost to follow up if they do 
not have a study visit after 35 weeks or at delivery for outcome ascertainment.  
For the secondary outcomes, the significance of differences in proportion will be explored using 
the Pearson’s χ2 test or Fisher’s exact test. Multivariable regression modeling will be used to 
evaluate baseline factors associated with parasitemia if there is imbalance between the arms 
despite randomization. Potential covariates include age, parity, educational level, monthly 
income, marital status, history of negative birth outcomes, CD4 count, ART adherence, bed net 
usage, malaria treatment received and number of study visits. All analyses will be performed in 
SAS v 9.3. 
Data Management: Data will be collected in clinic on paper forms to be entered into a password-
protected, secure, web-based, electronic database (REDCap). Information will be stored locally 
on the device, then transferred to a server located at the University of Alabama at Birmingham 
when the internet access is adequate. On site, the paper forms will be kept in a locked cabinet in 
a room with the study staff and the computer for data entry will be password protected.  During 
the conduct of the study, periodic data checks will occur to systematically evaluate for any 
missing data or unanticipated problems. The site staff will receive feedback to improve the 
process as indicated. Adverse events will be reviewed weekly by the PI who will be blinded to 
study arm randomization. The final data analysis will occur after all participants have been 
enrolled and procedures completed at both sites. 
REDCap (Research Electronic Data Capture) is a secure, Web-based application designed to 
support data capture for research studies. For multi-center studies, Data Access Groups may be 
set up to allow users access only to their site’s data.  For quality control purposes, REDCap 
offers real-time range checking during data entry.  There are also data visualization tools to assist 
in data cleaning and evaluation.  The Data Export Tool includes methods for data de-
identification and exports some or all data to Excel, SAS, SPSS, R, S-Plus, and Stata.  
The REDCap database is hosted at the UAB Department of Medicine’s secure data center, which 
will be used as a central location for data storage, processing, and management. The servers are 
protected by an aggressive firewall and a log monitoring system. All web communications are 
protected via SSL encryption. Only IRB approved research team members will have access to 
the REDCap. Access is granted according to “the principle of least privilege.” Each team 
member will be granted access to the REDCap data system through a secure login. 
The protocol has been registered on clinicaltrials.gov with the study ID number NCT03431168.  


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
XIII. STUDY TIMETABLE 
 
2017 
2018 
2019 
2020 
IRB Approval 
X 
 
 
 
Hire Study Staff 
X 
 
 
 
Training 
X 
 
 
 
Enrollment 
 
X 
X 
 
Subject Follow Up 
 
X 
X 
 
Data Processing 
 
X 
X 
 
Data Analysis  
 
 
 
X 
 
a) IRB Approval – see ethical considerations in subsequent section (Section XIV). 
b) Study Staff – One study nurse and one data manager will be hired at each facility and the 
current CHI-UAB Coordinator will assume the duties of study coordination at both sites. The 
study PI will be onsite several times a year for 1-2 months at a time during the study period.  She 
will also be on site during training, study initiation and enrollment. 
c) Training – Before the trial begins, study nurses, coordinators, physician co-investigators and 
laboratory staff will undergo training on study procedures and data collection, including 
standardized testing methods for malaria and sexually transmitted infections and how to perform 
a surface examination for congenital anomalies at birth and collect placental biopsies. 
d) Enrollment and Follow Up – In 2014, Mboppi Hospital in Douala had more than 15,000 
antenatal care visits and 4000 deliveries. Approximately 400 new pregnant patients are seen each 
month in clinic and approximately 24 women are HIV-infected (seroprevalence 5.9%). At the 
Baptist Hospital in Mutengene (BHM), the HIV seroprevalence is 10.2%, and there are 10 new 
HIV-infected women seen each month in clinic. Approximately 20% of women present for ANC 
care during their 1st trimester and 75% during the second trimester. Pregnant women routinely 
have 4 prenatal visits and clinic attendance rates are high with 80% facility delivery rates.  
We plan to enroll approximately 18 women each month (12 in Douala, 6 in Mutengene) over an 
18 month enrollment period to reach the 308 women needed.  This will allow us to have 268 
women with evaluable outcomes according to the power calculation stated above (this assumes 
15% loss to follow up but we will strive for >95% subject retention).  
e) Data Processing and Analysis – After a three-month period for completion for data entry for 
the trial, the dataset will be locked and available for analysis. Approximately six months will be 
required to complete the final report and submit it for publication. Group meetings will be held 
to determine which manuscripts will be written and the appropriate team members for submitted 
abstracts and publications. 
XIV. ETHICAL CONSIDERATIONS 
a) The protocol will be reviewed by the Institutional Review Board in Cameroon at CBCHS 
(Cameroon Baptist Convention Health Services).  This is an active and long-standing 
IRB group that meets regularly and reviews all research protocols for work proposed to 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
take place at CBCHS facilities.  The protocol will also be reviewed by the IRB at the 
University of Alabama at Birmingham but the primary IRB will be located in Cameroon. 
Any changes or edits to the protocol will be submitted to both IRB groups and both will 
be informed of any serious adverse events that occur during the study. 
 
b) Informed Consent Process: Women will be invited to participate and provide informed 
consent. Anyone 16 years of age or older will be eligible to participate according to 
Cameroon law which grants “mature minor” status to girls during pregnancy and this 
allows them to consent without parental involvement.   
 
Malaria detected as part of the study (whether a screening test or a test done in the setting 
of a fever work up) will be treated with quinine per clinical routine.  Positive tests for 
STIs (GC/CT and syphilis) identified at the end of pregnancy will be treated per CDC 
recommendations. GBS colonization will be treated with ampicillin IV during labor and 
delivery for women with facility deliveries.  The cost of treatment for infections detected 
or adverse events as a result of testing or treatment performed for the study will be 
covered as a part of study expenses but hospitalization and other diagnostic and treatment 
costs will not be covered. 
 
Women will have the option in the consent of whether or not to submit samples to long 
term storage and later testing on dried blood spots, vaginal swabs and placental biopsies 
and infant follow up procedures. No blood or samples will be collected from infants. 
 
c) Participant confidentiality.  Given the personal and serious nature of working with a 
population of pregnant subjects with HIV infection, study related conversations will 
occur in private although participants will be invited to include a support person in the 
discussion if they prefer. Subjects will have code numbers and will not be identified by 
name.  The staff at CBCHS is very well versed in caring for women with HIV-infection 
and they prioritize confidentiality at the highest level in all clinical and research activities 
and documentation. Subjects will have code numbers and will not be identified by name.  
d) Participant Costs.  Subjects will be told that they will be provided with study related 
medications and testing at no cost.  They will be treated for infections diagnosed on site 
and this antibiotic therapy will be provided for free as well.   
 
Compensation. Participants will be reimbursed for transportation (2000 CFA per visit) for 
routine visits and sick call visits.  They will also be provided with a phone card (1000 
CFA per visit) at each visit to allow them to call the study nurse if they have questions or 
illness. Women who deliver at the facility will receive a small token for the baby and 
there will be follow up phone calls from the study staff to check on how the baby is 
doing. 
 
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
Appendix A – DESIGN SUMMARY 
 
 
 
Registered at Clinical Trials Website (clinicaltrials.gov): NCT03431168  
 
 
 
 
 
 
 
 
 
 
 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
Appendix B (03 April 2018) 
CONSENT FORM 
 
TITLE OF RESEARCH: 
The PREMISE Trial: A Novel Regimen to Prevent Malaria and STI 
in Pregnant Women with HIV 
IRB PROTOCOL NO.: 
IRB-300001112 
PRINCIPAL INVESTIGATOR: Jodie Dionne-Odom, MD 
SPONSOR: 
National Institute of Child Health and Human Development 
 
National Institutes of Health, United States of America 
 
Purpose of the Research 
This consent form may contain words you do not understand.  Please ask the study staff to explain any 
words or information you do not clearly understand. 
 
We are asking you to take part in a research study because you are pregnant. This research is to look for 
ways to prevent infections including malaria and certain sexually transmitted infections (STI) in pregnant 
women who are infected with HIV.  Malaria and STIs are common in Cameroon and pregnant women 
with HIV are at particular risk of becoming infected.  You are eligible to participate if you are taking or 
will take standard medications to prevent malaria during pregnancy. 
 
This is a double blind, randomized placebo controlled trial.  A randomized controlled trial is where study 
participants are put into one of two groups at random (like flipping a coin).  People in each group receive 
different treatments to study if one treatment is better than the other. Double blind means that neither you 
nor the study staff will know which treatment group you are in and the antibiotic pills will be packaged to 
look the same. 
 
The medication recommended to prevent malaria in pregnant women with HIV in Cameroon is a pill 
called co-trimoxazole. This is called the standard of care medication. The PREMISE study will look to 
see if combination therapy with co-trimoxazole and azithromycin is better at preventing infection in 
pregnancy compared to co-trimoxazole alone. One group of women will receive cotrimoxazole + 
azithromycin and the other group will receive cotrimoxazole + placebo (sugar pill.)  
 
This study is funded by the National Institutes of Health in the United States and we plan to  enroll 
approximately 310 pregnant women living with HIV from two Cameroon Baptist Convention Health 
Services (CBCHS) facilities in Mutengene (105 women) and Douala (205 women), Cameroon.  
 
Explanation of Procedures 
If you enter the study, you will have the following research procedures according to the visit schedule that 
follows. 
 
Enrollment Visit 
This visit will take about 3 hours.  
• 
You will have a brief physical exam to look at your skin, listen to your heart and lungs 
and abdomen and your temperature will be taken. 
• 
You will complete a survey including questions about your background, your medical 
history, malaria prevention, HIV history, and current medications. 
• 
You will receive the first dose of study medication. 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
• 
Your blood will be drawn (fingerstick and 1 teaspoon of blood from your vein) for 
malaria and STI testing. Testing will be performed in Cameroon. 
• 
A vaginal swab will be collected by the study nurse. This is a swab that is inserted a few 
inches into your vagina and then removed. This will be tested at UAB. 
• 
You will be given  a mosquito bed net if you do not have one and condoms. 
• 
You will be provided with a 30-day supply of medications and a follow up visit for 30 
days from the baseline visit. 
 
Follow Up Visit(s) – scheduled for every 30 days after the enrollment visit until delivery. 
This visit will take about 30 minutes. 
• 
You will have a brief exam and your temperature will be taken. 
• 
You will be asked about symptoms. 
• 
You be asked to complete a survey about your medications. 
• 
You will receive the next dose of study medication. 
• 
Your blood will be drawn (fingerstick) for malaria testing. Testing will be performed in 
Cameroon at the end of the study. 
• 
Your blood will be drawn by fingerstick for malaria testing at the CBCHS facility if you 
have fever. 
• 
You will receive treatment for malaria if the test is positive.  If the test returns positive 
after you have left the clinic, you will be contacted by phone with results. 
• 
You will be offered condoms. 
• 
You will be provided with a 30-day supply of medications and a follow up visit. 
 
Sick Call Visit(s) 
This visit will take 30-60 minutes, depending on your symptoms. 
• 
You will have a brief exam and your vital signs will be taken. 
• 
You will be asked about symptoms 
• 
You be asked to complete a survey about your medications. 
• 
Your blood will be drawn (fingerstick) for malaria testing. Testing will be performed in 
Cameroon at the end of the study. 
• 
Your blood will be drawn by fingerstick for malaria testing at the CBCHS  facility if you 
have fever. 
You will receive treatment for malaria if the test is positive.  If the test returns positive after you have left 
the clinic, you will be contacted by phone with results. 
• 
You will be provided with a 30-day supply of medications if you have run out. 
• 
You will receive additional testing and/or treatment if recommended by CBCHS staff 
depending on your clinical findings. 
 
Near/at Term Visit (35-42 weeks) 
This visit will take about 30 minutes. 
• 
You will have a brief exam and your vital signs will be taken. 
• 
You will be asked about symptoms. 
• 
You be asked to complete a survey about your medications. 
• 
Your blood will be drawn by fingerstick for malaria testing at CBCHS if you have fever. 
Your blood will also be drawn by vein for additional testing in Cameroon 
• 
You will have a vaginal swab collected and an anogenital swab collected for testing at 
Mboppi Hospital in Douala. 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
• 
You will be provided with a 30-day supply of medications and a follow up visit. 
• 
You will receive treatment for malaria if the test is positive.  If the test returns positive 
after you have left the clinic, you will be contacted by phone with results.  
 
Delivery Visit 
This visit will take 30 minutes. 
• 
You will have a brief exam and your vital signs will be taken. 
• 
You will be asked about symptoms. 
• 
You will be asked to complete a survey about your medications. 
• 
Your blood will be drawn by fingerstick for malaria testing at CBCHS if you have fever. 
Your blood will also be drawn by vein for additional testing in Cameroon 
• 
You will have a vaginal swab collected and an anogenital swab for group B streptococcus 
testing (if not previously provided at 35-42 weeks). This is a swab that is inserted 2 
inches into your vagina and then your rectum to look for bacteria. Testing will be 
performed at Mboppi Hospital in Douala. 
• 
A sample will be taken from the placenta for malaria testing at a later date and will be 
tested in Cameroon 
• 
You will receive treatment for group B streptococcus colonization if the test returns 
positive and results are available prior to delivery 
• 
You will receive treatment for malaria if the test is positive. The baby will not be tested.   
• 
You will receive additional treatment if needed for infections detected at the 35-42 week 
(or other) visit that have not been treated. 
• 
Information will be collected about the baby’s weight, age, and appearance, including an 
examination for any congenital anomalies (birth defects). 
 
Postpartum Visit (within 14 days after childbirth for women who did not deliver at CBCHS facility) 
This visit will take about 45 minutes. 
• 
You will have a brief exam and your vital signs will be taken. 
• 
You will be asked about symptoms. 
• 
You will be asked to complete a survey about your medications. 
• 
Your blood will be drawn by vein and fingerstick for malaria testing in Cameroon. 
• 
A vaginal swab and ano-vaginal swab will be collected for testing at Mboppi Hospital in 
Douala if not collected at the 35-42 week visit. 
• 
You will receive additional treatment if needed for infections detected at the 35-42 week 
(or other) visit that have not been treated. 
• 
Information will be collected about the baby’s weight, age, and appearance. 
• 
You will be contacted by phone if testing returns positive after you have left the clinic. 
 
Follow Up Phone Call (within 6 weeks of delivery) 
• 
You will be asked if you have had any fever or hospitalization since delivery. 
• 
You will be asked about how the baby is doing including any hospitalization or illness. 
 
Follow Up Phone Call or Visit for Infant Outcomes – Every 3 months until 1 year 
• 
You will be contacted by phone every three months to ask how the baby is growing. 
Information from medical visits about the baby’s height and weight will be collected as 
well as any information about infant hospitalizations or illness.  
• 
You will be encouraged to bring the baby to the clinic for a visit at 6 months and 12 
months to measure height, weight and head circumference. 


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PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
 
Some of the testing will be performed in Cameroon at CBC with results available to impact your clinical 
care. Other, later laboratory testing for research purposes will be performed in Cameroon at the 
University of Buea and/or the University of Alabama at Birmingham in the US.  You will not be 
contacted with these results. 
 
Risks and Discomforts 
There is a risk of loss of confidentiality. We will work hard to protect your personal information and only 
the information that is needed for the study will be collected. You will be assigned a unique study 
identification number for study paperwork instead of your name.  
 
This study will provide commonly used antibiotics to women with no history of allergy or adverse 
reaction to co-trimoxazole or azithromycin.  All women will receive daily co-trimoxazole as standard of 
care and some women will receive azithromycin for 3 days monthly. Azithromycin is an antibiotic that 
although there have been no adequate controlled studies in pregnant women, has been used in pregnant 
women for many years.  The antibiotic, co-trimoxazole has no controlled data in human pregnancy; 
however, it is part of the World Health Organization (WHO)-recommended therapy for HIV-infected 
pregnant women in Africa. The study nurse will be asking questions about how you tolerate the medicine 
and if you have any side effects. There is a risk of randomization since you will be assigned to one of two 
groups by chance. One group may prove to be less effective or have more side effects than the other 
group.. You will be asked to return to clinic for illness in between visits and not to take any medications 
for malaria not prescribed by your provider unless necessary.  
 
The most common side effects of azithromycin are diarrhea, nausea and occasionally pain in the abdomen 
or vomiting.  The common side effects of cotrimoxazole are diarrhea, nausea, vomiting, loss of appetite, 
skin rash and allergic reaction (itching, rash, difficulty breathing).  There are other rare side effects that 
have occurred.  If you feel you are having a side effect from the treatment contact your doctor 
immediately. There may be some side effects of the combined antibiotics that are not known at this time. 
We do not expect any harm to the baby as a result of participating in this study and no blood will be 
drawn from him/her. You may experience some discomfort, bruising or swelling associated with the 
collection of blood we will draw from you. You may also experience some minimal discomfort with 
vaginal swab collection.   
 
Benefits 
You may or may not benefit from taking part in this study.  If an infection is detected as part of the study, 
you will be offered treatment. This includes treatment for malaria, sexually transmitted infections, and 
group B streptococcus. This study may help us better understand how to prevent malaria and STIs in 
pregnant women in the future. 
 
Confidentiality 
Information obtained about you for this study will be kept confidential to the extent allowed by law.  The 
findings from the research may be published for scientific purposes; however, your identity will not be 
given out. All study paperwork will be stored on a password protected computer or in a locked cabinet 
and your name will not be listed on routine study forms. Information that will not include your name or 
other personal identifiers will be entered into a computer database that will be transmitted and read at the 
University of Alabama at Birmingham in the US.  
 


29 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
 
Voluntary Participation and Withdrawal 
Whether or not you take part in this study is your choice. There will be no penalty if you decide not to be 
in the study. If you decide not to be in the study, you will not lose any benefits you are otherwise owed. 
You are free to withdraw from this research study at any time. Your choice to leave the study will not 
affect your relationship with your provider or with the Cameroon Baptist Convention Health Services 
Organization (CBCHS). 
 
Cost of Participation 
There will be no cost to you for taking part in this study. The costs of your standard medical care will be 
billed to you in the usual manner.  
 
Payment for Participation in Research 
You will receive reimbursement for transportation to attend study visits including sick visits (2000 CFA 
per visit or $4 USD).  You will also be provided with a phone card (1000 CFA or $2 USD) so you can 
call the study team with questions or problems that may occur between or after study visits. You will 
receive a small gift at the time of delivery when you deliver at Mboppi or BHM facilities. 
 
Questions 
If you have any questions, concerns, or complaints about the research, you may contact Mrs. MBAH 
Rahel and she will inform Dr. Jodie Dionne-Odom, the Principal Investigator. You may also reach out to 
a local member of the CBCHS IRB group, Mrs. Grace Ndze.  
 
Rahel Mbah, MPH 
 
 
 
 
 
 
Mrs. Grace Ndze 
CHI UAB Program Coordinator  
 
 
 
 
CBC IRB 
237 670 671 378 
 
 
 
 
 
 
237 677 022 470 
 
Jodie Dionne-Odom, MD 
 
 
 
 
 
Seraphine Pekwerake 
Principal Investigator of PREMISE 
 
 
 
 
Research Nurse  
University of Alabama at Birmingham, USA 
 
 
 
Mboppi (MBHD) 
237 653 960 213 
 
 
 
 
 
 
237 670 332 709 
 
Legal Rights 
You are not waiving any of your legal rights by signing this informed consent document. 
 
Storage of Specimens for Future Use 
As part of this study, we would like to store some of the blood, vaginal swabs and placental biopsy 
collected from you for future research on malaria and sexually transmitted infections in pregnancy that is 
not planned in the current study. The future research may be conducted by Dr. Jodie Dionne-Odom or by 
other researchers that obtain approval for their research. The specimens will be labeled with a code that 
only Dr. Dionne-Odom can link back to your medical information. Results of any future research will not 
be given to you or your doctor, because that researcher will not have your name or contact information. 
You do not have to agree to allow your blood or vaginal swabs to be stored to be part of this future 
research. 
You may request at any time that your research samples be removed from storage and not be used for 
future research. If you decide you want your samples removed, you may contact Mrs. MBAH Rahel at 
237 670 671 378. Once the request is received, and if your samples have not already been used for other 


30 
 
PREMISE Trial Protocol, v 1.1 – Cameroon 
05 September2018 
research, they will be destroyed. If you do not make such a request, your specimens will be stored until 
they are no longer scientifically useful. 
Initial your choice below: 
____I agree to allow these samples to be kept and used for future research on infection in pregnancy. 
 
___ I do not agree to allow my samples to be kept and used for future research on infection in pregnancy.  
(List here separately which sample types should not be stored________________________) 
 
Infant Follow Up (every 3 months) 
Initial your choice below: 
____I agree to participate in the infant follow up portion of the PREMISE study. 
 
___ I do not agree to participate in the infant follow up portion of the PREMISE study. 
 
Signatures 
Your signature below indicates that you have read (or been read) the information provided above and 
agree to participate in this study. You will receive a copy of this signed consent form. 
 
Signature of Participant ________________________________ Date 
________ (MM/DD/YY) 
Signature of Person Obtaining Consent_________________________Date 
 
_(MM/DD/YY) 
 
 
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Protocol Changes 
Protocol 
Version 
Number 
Date 
Changes Made Since Prior Version 
1.1 
20 Aug 2018 
Added quarterly infant follow up study procedures. 
Added dried blood spot collection at every follow up visit. 
DSMB minutes, quarterly AE and SAE reports sent to NICHD.