Clinical trial NCT04094870
Conditions: Perinatal Depression HIV-1-infection
Keywords: perinatal depression HIV Antiretroviral Treatment Interpersonal psychotherapy
Sponsor: University of North Carolina, Chapel Hill
Start date: 2019-10-30; Completion date: 2020-10-30
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study will evaluate, through quantitative and qualitative methods, whether different treatments for postpartum depression are feasible and acceptable in postpartum HIV infected women on antiretrovirals (ART). The study will take place at several clinics in Lusaka, Zambia.

Detailed description:
The standard of care for treating postpartum depression in the US is antidepressants, psychotherapy or both. Little data exist on the best method for treating perinatal depression (PND) in Sub-Saharan Africa. This is a mixed method study including a pilot randomized controlled trial (RCT) of antidepressant medication (ADM) versus interpersonal psychotherapy (IPT) and qualitative semi-structured interviews (SSIs). The study will enroll 100 pregnant HIV infected women over the age of 18 seeking postnatal care and continuing antiretroviral therapy in pregnancy. An additional 20 women enrolled in the RCT will be invited to participate in SSIs. Each participant will be followed for 24 weeks.

Arms: arm 1: Daily self-administered selective serotonin reuptake inhibitor (SSRI) Sertraline 25 mg table arm 2: Up to 11 planned therapy sessions over a 24-week period beginning the day of randomization
Interventions: intervention 1: Sertraline intervention 2: Interpersonal therapy
Intervention descriptions: intervention 1: daily SSRI (Sertraline 25mg) intervention 2: 11 sessions over a 24-week period

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 31 
 
 
 
 
 
 
 
 
 
A Pilot Trial of Perinatal Depression Treatment in HIV infected Women 
 
 
 
Protocol version 2.0 
26 June 2019 
 
 
 
Funded by: 
US National Institute of Mental Health 
1R21MH115806 
 
 
 
Protocol Co-Chairs:  
Bellington Vwalika, MBChB, MSc, MMed 
Elizabeth M. Stringer, MD, FACOG 
 
Trial Registration: 
ClinicalTrials.gov 
NCT04094870  
 
 


 
 
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TABLE OF CONTENTS 
INVESTIGATORS AND SCIENTIFIC TEAM ....................................................................... 4 
ABBREVIATION LIST ............................................................................................................ 6 
PROTOCOL SUMMARY ......................................................................................................... 7 
1.0 
INTRODUCTION .......................................................................................................... 9 
2.0 
STATEMENT OF THE PROBLEM .............................................................................. 9 
3.0 
RATIONALE .................................................................................................................. 9 
4.0 
LITERATURE REVIEW ............................................................................................... 9 
5.0 
SPECIFIC OBJECTIVES ............................................................................................. 12 
5.1 
Primary objective ...................................................................................................... 12 
5.2 
Secondary objectives ................................................................................................. 12 
5.3 
Tertiary objectives ..................................................................................................... 12 
6.0 
STUDY OUTCOMES .................................................................................................. 12 
6.1 
Primary outcomes ...................................................................................................... 12 
6.2 
Secondary/tertiary outcomes ..................................................................................... 12 
7.0 
METHODOLOGY ....................................................................................................... 13 
7.1 
Study design .............................................................................................................. 13 
7.2 
Study sites and study population ............................................................................... 13 
7.3 
Study intervention ..................................................................................................... 14 
7.3.1 
Study drug pharmacological information .......................................................... 14 
7.4 
Pilot randomized trial procedures ............................................................................. 15 
7.4.1 
Recruitment ........................................................................................................ 15 
7.4.2 
Antenatal EPDS screening ................................. Error! Bookmark not defined. 
7.4.3 
Postnatal EPDS and study screening ................................................................. 15 
7.4.4 
Study randomization .......................................................................................... 16 
7.4.5 
Study follow-up ................................................................................................. 16 
7.4.6 
Retention ............................................................................................................ 17 
7.5 
Qualitative activities .................................................................................................. 18 
7.6 
Biological specimen collection and testing ............................................................... 19 
7.7 
Data security and management ................................................................................. 19 
7.8 
Statistical considerations ........................................................................................... 19 
7.8.1 
Pilot randomized controlled trial sample size and analysis ............................... 19 
7.8.2 
Qualitative analysis ............................................................................................ 21 
7.9 
Dissemination of Findings ........................................................................................ 22 
8.0 
ETHICAL CONSIDERATIONS .................................................................................. 22 
8.1 
Informed consent ....................................................................................................... 22 
8.2 
Potential risks to participants .................................................................................... 23 
8.3 
Potential benefits to participants and others .............................................................. 24 
8.4 
Participant follow up once the study is completed .................................................... 24 
9.0 
SAFETY MONITORING ............................................................................................. 25 
9.1 
Data Safety Monitoring Board (DSMB) ................................................................... 25 
9.2 
Trial safety reporting ................................................................................................. 25 
10.0 BUDGET (1 USD = 10 ZMW) ..................................................................................... 26 
11.0 TIMELINE .................................................................................................................... 27 
12.0 REFERENCE LIST ...................................................................................................... 28 
 


 
 
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INVESTIGATORS AND SCIENTIFIC TEAM 
Co-Principal Investigators: 
Bellington Vwalika, MBChB, MMed, MPH 
Consultant and Head of Department 
Department of Obstetrics and Gynaecology 
University of Zambia School of Medicine 
Lusaka, Zambia 
Email: vwalikab@gmail.com 
 
Elizabeth M Stringer, MD, FACOG 
Associate Professor of Obstetrics and Gynecology 
Department of Obstetrics and Gynecology 
University of North Carolina at Chapel Hill 
Campus Box 7570, Chapel Hill, NC 27599 
Email: Elizabeth_stringer@med.unc 
 
Investigator of Record (IOR) and co-investigator 
Margaret Kasaro, MBChB, MSc 
UNC Global Projects - Zambia 
348 Independence Avenue 
Lusaka, Zambia 
Email: Maragaret.Kasaro@UNCLusaka.org 
 
Co-Investigators 
Samantha Meltzer-Brody, MD 
Associate Professor Department of Psychiatry  
University of North Carolina at Chapel Hill 
Campus Box 7570, Chapel Hill, NC 27599 
E-mail: samantha_meltzer-brody@med.unc.edu 
 
Ravi Paul, MD, M.B.B.S 
Head, Department of Psychiatry 
University Teaching Hospital 
Lusaka, Zambia 
Email: ravipaul35@gmail.com  
 
Crystal Schiller, PhD 
Assistant Professor Department of Psychiatry  
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599 
E-mail:  crystal_schiller@med.unc.edu 
 
Jennifer Winston, PhD 
Research Analyst 
Division of Global Womens Health 
University of North Carolina 


 
 
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Email: jen_winston@med.unc.edu 
 
 


 
 
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ABBREVIATION LIST 
AE 
 
 
Adverse event 
ADM  
 
Antidepressant medication 
ANC  
 
Antenatal care 
AOR  
 
Adjusted odds ratio 
ARR  
 
Adjusted relative risk 
ART   
 
Antiretroviral therapy 
ARVs  
 
Antiretrovirals 
CGI 
 
 
Clinical Global Impression 
CI 
 
 
Confidence interval 
DSM-V 
 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
EPDS  
 
Edinburgh Postnatal Depression Scale 
FWA  
 
Federal Wide Assurance 
HIV   
 
Human immunodeficiency virus 
LTFU  
 
Loss to follow up 
IPT 
 
 
Interpersonal therapy 
KHC  
 
Kamwala Health Centre 
OHRP  
 
Office for Human Research Protections  
PND   
 
Perinatal depression  
RCT 
 
 
Randomized controlled trial 
RR 
 
 
Risk ratio 
SAE 
 
 
Severe adverse event 
SSI 
 
 
Semi-structured interview 
SSRI  
 
Selective serotonin uptake inhibitor 
UNC  
 
University of North Carolina 
UTH  
 
University Teaching Hospital 
WHO  
 
World Health Organization 
 
 


 
 
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PROTOCOL SUMMARY 
Background: Depression is the single largest contributor to global disability. Perinatal depression 
(PND) is defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-V) as an episode of moderate or severe depression that either begins during pregnancy or 
within 4 weeks of delivery. The severity of PND symptoms typically peaks at 2-4 months 
postpartum corresponding to the riskiest time for breastfeeding HIV transmission and is thus a 
critical time for optimal adherence to antiretroviral therapy (ART). Multiple studies suggest that 
rates of PND are high in HIV infected women in sub-Saharan Africa and that depression is a risk 
factor for suboptimal medication adherence among HIV infected individuals. The standard of care 
for treating postpartum depression in the US is antidepressants, psychotherapy or both. Little data 
exist on the best method for treating PND in Sub-Saharan Africa.  
Objectives: In preparation for a possible full-scale efficacy trial, this pilot study will evaluate, 
through quantitative and qualitative methods, whether different treatments for postpartum 
depression are feasible and acceptable in postpartum HIV infected women on antiretrovirals. Our 
study hopes to contribute to reducing barriers to medication adherence with an ultimate public 
health goal of decreasing intergenerational HIV transmission in low-resource regions. 
Design: Mixed method study including a pilot randomized controlled trial (RCT) of antidepressant 
medication (ADM) versus interpersonal psychotherapy (IPT) and qualitative semi-structured 
interviews (SSIs)  
Study Arms: Daily self-administered selective serotonin reuptake inhibitor (SSRI) Sertraline 25 
mg tablet versus IPT in a 1:1 ratio commenced between six and 8 weeks postpartum and continued 
through 30 weeks postpartum.  
Population: 150 pregnant HIV infected women over the age of 18 seeking postnatal care and 
continuing antiretroviral therapy in pregnancy will be enrolled in the pilot RCT; an additional 20+ 
eligible women who decline to participate in the RCT will be invited to participate in semi-
structured interviews (SSIs) and 20 women enrolled in the RCT will be invited to participate in 
SSIs. 
Study Sites: Kamwala Health Centre (KHC) and University Teaching Hospital (UTH), Lusaka, 
Zambia 
Duration and Follow up: Women will be screened and enrolled over a period of 5-12 months.  
Each participant will be followed for 24 weeks. Total duration of the study is 24 months.      
Endpoints: The pilot RCT will measure feasibility including: screening uptake with EPDS, the 
prevalence of perinatal depression, study uptake, and study retention, as well as preliminary 
efficacy of the study intervention as a secondary outcome. Semi-structured interviews will evaluate 
acceptability of a study of treating PND to improve adherence to ART and identify barriers and 
facilitators to study enrollment, study adherence to study interventions and study retention. 
Relevance: More than 1.5 million HIV-infected women become pregnant each year. 
Approximately half have access to ART, but all are at increased risk of PND.  Identifying and 
treating PND is a potentially promising intervention to improve maternal adherence to ART and 
improve maternal and infant outcomes in the postnatal period. This pilot study will provide critical 
insight into the feasibility of a phase III trial by determining whether women are willing to 
participate, to adhere to study drug, and to complete follow-up.  


 
 
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Statement of Problem: Perinatal depression is a significant and unrecognized problem in many 
parts of the world. HIV infected women are known to be less adherent to ART in the postnatal 
period increasing their risk for drug failure and potentially exposing their infants to HIV through 
breastfeeding. Determining the best treatment of depression in the postnatal period among HIV-
infected women is a health care priority.  
 


 
 
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1.0 INTRODUCTION 
Depression is the leading cause of disability worldwide1,2. In Lusaka, Zambia, where our group 
has worked since 2001, as many as 1 in 5 pregnant and recently postpartum women meet criteria 
for perinatal depression (PND)3. This staggering rate coincides with another, equally staggering 
one: HIV prevalence among pregnant women in Lusaka exceeds 20%.4. As combination 
antiretroviral therapy (ART) has become available to an ever-growing number of pregnant women 
around the world, perinatal HIV transmission rates have plummeted5. To capitalize on both the 
maternal and neonatal gains that have been made with the widespread scale up of antiretrovirals, 
mothers must adhere to their prescribed antiretroviral therapy.6 Many of the hallmark features of 
depression, such as sadness, fatigue, and withdrawal, work frustratingly against a woman’s ability 
to adhere to her prescribed medication and keep her appointments.7  
This study will use a formative mixed-methods approach to assess feasibility, acceptability, and 
preliminary efficacy for treating depression in postpartum clinics in Lusaka. We have chosen a 
formative mixed-methods approach that involves both the implementation of a pilot trial and a 
qualitative assessment of participation in it. The pilot will precisely quantify key indices of trial 
feasibility while also providing estimates of the baseline PND prevalence and preliminary 
efficacy and safety of treatment. A set of concurrent, qualitative activities will seek a more 
nuanced understanding of the personal, social, psychosocial, behavioral and structural barriers to 
trial participation that will be used to design the larger study. 
2.0 STATEMENT OF THE PROBLEM 
Treatment of depression in non-pregnant adults has been found in randomized trials to improve 
HIV outcomes8,9,10 . We hypothesize that treatment of PND in recently postpartum women will 
improve maternal health and protect the infant from breastfeeding HIV transmission. However, 
we are concerned about the feasibility of a full-scale efficacy trial, given the lack of knowledge in 
sub-Saharan Africa concerning depression and its treatment.  
3.0 RATIONALE 
While treatment of depression has been studied in HIV-infected individuals in industrialized 
countries9, interventional data from low resource countries are lacking.   This study focuses on 
exploring the diagnosis and treatment of PND as a potential way to improve not only the health 
of a new mother, but also the health of her child. This pilot study is setting the stage for an 
innovative phase III trial where depression screening and treatment will be undertaken to 
improve maternal and child outcomes among HIV infected women. The primary outcome in the 
future study will focus on “program failure” – defined as the proportion of women who have 
died, are lost to follow-up, have been switched to second-line antiretroviral therapy (ART), or 
who have a plasma viral load > 50 copies / mL at 12 months postpartum. Additional outcomes 
will be rates of mother-to-child HIV transmission, infant morbidity, infant anthropometry, 
breastfeeding practices, measures of maternal-infant bonding and infant neurodevelopment. We 
anticipate that the feasibility study will provide information on choice of treatment design 
details. 
4.0 LITERATURE REVIEW 
Major depressive disorder is among the most common ailments faced by women during pregnancy 
and the postpartum period.11 Postpartum depression is defined in the DSM-V12 as an episode of 
moderate or severe depression that either begins during pregnancy or within 4 weeks of delivery.12 


 
 
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The severity of symptoms, however, usually peaks at 2-4 months postpartum13,corresponding to 
the riskiest time for breastfeeding HIV transmission14 and thus a critical time for optimal ART 
adherence. While the prevalence of postpartum depression in the United States is estimated to be 
15%,15 numerous recent studies suggest that the prevalence in sub-Saharan Africa is much higher. 
Bangsberg and colleagues report that 39% of HIV infected women in Uganda screened positive 
for depressive symptoms, a proportion that seemed to remain constant throughout non-pregnancy, 
pregnancy, and postpartum periods.16 A systematic review of 21 studies in 8 countries across the 
African continent reported a prevalence of 18.3% (95% CI: 17.6, 19.1%), and suggested a marked 
geographic disparity, where the prevalence was considerably higher in southern African countries, 
compared to West Africa.1 In Zambia, 229 postnatal women at the University of Zambia Teaching 
Hospital were screened with the Edinburgh Postnatal Depression Scale (EPDS) between 2 and 6 
weeks postpartum and 28% met criteria for PND (defined in this study as EPDS>12). The 
prevalence did not differ by HIV infection status.3 In a study of 210 HIV infected and uninfected 
postnatal women in nearby Zimbabwe, 64 (33%) met criteria for depression (defined by the authors 
as EPDS>10).17 (Note: as detailed below, we will use EPDS > 10 as a cut off to offer further 
diagnostic testing for PND in our study.) 
Depression is a known risk factor for suboptimal adherence to ART in many different studies, 
including those in low resource countries.18-21 Byakika-Tusiime et al. found that depression 
(defined as a Beck Depression Inventory score > 14) was a risk factor for < 95% adherence using 
a 30-day visual analog scale in their “MTCT Plus” cohort in Uganda (AOR 0.32; 95%CI: 0.11-
0.93). Two systematic reviews also show that depression has a negative impact on ART adherence. 
Mayston and colleagues conducted a review of all articles addressing mental health, HIV, and low 
resource countries.22 Of the six prospective studies that assessed a relationship between depression 
and adherence, five showed a relationship between depression and poor ART adherence.18,21,23 
Nakimulu-Mpungu performed a similar review of the literature, including over 10,000 adults, to 
examine the relationship between depression and ART adherence and found that depressed 
individuals had a 55% (95% CI 0.31-0.66) lower odds of achieving optimal ART adherence.24 In 
an analysis of the Nutrition for Healthy Living Study (a US cohort), 22% of participants developed 
incident depression over the course of up to 2.5 years of follow-up; of these, 45% had concurrent 
poor adherence (defined as missing >5% of ART doses in the prior 7 days) compared to 26% 
among those who did not become depressed (p=<0.01). Further, among those with optimal 
baseline adherence, those with incident depression were nearly twice as likely to develop 
suboptimal adherence during follow-up (ARR: 1.8; 95% CI: 1.1, 3.0).25  
The science behind the recent policy and program shift to lifelong antiretroviral therapy for HIV-
infected pregnant women (Option B+) offers – for the first time since the beginning of the HIV 
epidemic – a pathway to an AIDS-free generation.26 Currently available antiretrovirals (ARVs) are 
so potent and well tolerated as to extend an essentially normal lifespan to those who are able to 
adhere27, and if the medicine is started early in pregnancy and continued uninterrupted through 
breastfeeding, the risk of mother-to-child HIV transmission approaches zero.28,29 Yet, in most 
developing world settings, the promise of universal lifelong maternal ART has not been fully 
realized. Health systems are over-stretched and under-resourced. Providers are over-worked. 
Patients have a variety of competing issues (including mood disorders, as we detail below) that 
prevent them from remaining in care and adhering consistently to their prescribed ARVs. 
Our group has argued in a variety of contexts that poor ART medication adherence and loss to 
follow-up (LTFU) are by far the two largest threats to prevention of mother-to-child HIV 


 
 
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transmission (PMTCT) and ART program effectiveness.30 Adherence rates below 95% correlate 
strongly with detectable viral load,31 and almost every published estimate for postpartum ART 
adherence falls far short of this.32 In a meta-analysis of 49 studies that examined ART adherence 
during and after pregnancy in low, middle, and high income countries, only 74% of women overall 
achieved >80% adherence during pregnancy, and rates during the postnatal period were even lower 
(53%; 95% CI: 33%-73%).32 Consistently reported barriers to adherence in the postpartum period 
include postpartum depression , emotional stress, physical distance from pharmacy, economic 
hardship, and excessive pill burden.33,34  
LTFU (completely dropping out of care) presents an equally serious problem. In Lusaka, where 
our proposed trial will take place, of 6,572 women starting ART in pregnancy or shortly thereafter, 
23% (95%CI: 22%, 23%) had dropped out of care by 12 months and 37% (95%CI: 36%, 38%) 
were lost by 24 months. Similarly, in Malawi, where Option B+ was adopted well before the 2012 
WHO recommendations, retention among 1757 women who started ART either antenatally or 
during breastfeeding was 70% at 6 months (95% CI: 67%-72%) and 67% at 12 months (95% CI: 
65%-70%).33 These proportions are consistent with reports from the US.35  
Multiple instruments exist to screen women for perinatal depression; some have been studied more 
than others in developing world settings. The EPDS is the most widely studied perinatal depression 
screening instrument worldwide, and arguably the gold standard.7,36,37 It was specifically 
developed to assess postpartum depression and minimize confounding of the somatic symptoms 
of the disorder associated with parenting an infant (e.g. insomnia), but has now been validated in 
pregnancy as well.37 A 10-item questionnaire with each response 0 to 3 on a Likert scale, EPDS 
scores > 10 are consistent with PND.38 It can be self-administered or read to the patient by a clinic 
worker. The EPDS has been validated in a number of low resource settings, including Zambia. In 
1998, Lawrie and colleagues in South Africa validated the EDPS against the DSM-IV. Using a 
cut-point EPDS score of 12, 100% of postpartum women with major depressive disorder and 70% 
of women with a minor depressive disorder were identified.39 In 2013, Chibanda and colleagues 
validated the EPDS among HIV-infected and uninfected pregnant women in Zimbabwe and found 
that a cut-off of 12 had 88% sensitivity and 74% positive predictive value compared to structured 
clinical interviews.40 Most experts suggest screening at 4-6 weeks postpartum because of the onset 
of depressive symptoms and worldwide women typically present for a six-week postpartum visit. 
Postpartum depression is responsive to the same therapies that are used to treat major depressive 
disorder in the general population.8 Pharmacologic therapy is a mainstay of postpartum treatment 
in industrialized countries and is potentially a more scalable approach to postpartum treatment in 
low-resource settings than individual psychotherapy.9,10 The most commonly used antidepressant 
medications (ADMs) are selective serotonin uptake inhibitors (SSRIs) because of their tolerability 
and favorable safety profiles. SSRI side effects are usually minor and will manifest in the first few 
weeks of initiation allowing for dosing changes or termination as indicated.41 Standard protocols 
exist on how to titrate these medications when determining a patient’s optimal dose.  SSRIs have 
proven to be safe in breastfeeding because only small amounts of the drug transfer into breast 
milk.42 Most experts agree that current evidence does not support significant medication 
interactions between ARVs and most antidepressants and that the benefits of giving an ADM for 
depression outweighs the potential interaction risks.43,44  
Psychotherapy is effective for the treatment of major depressive disorder, and different types of 
psychotherapy seem equally effective.45 A meta-analysis comparing interpersonal therapy (IPT), 
cognitive behavioral therapy, and non-directive counseling for PND showed no differences in 


 
 
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success.46 IPT is a time limited, problem focused therapy that frames depression as a medical 
illness occurring within a social context. IPT is evidence based, typically lasts 12-20 weeks, and 
can be administered individually or in a group.45,47 IPT has been used successfully and adapted in 
low-income countries in Africa.48  
Horberg and colleagues examined the effects of SSRIs for depression on ART adherence and 
clinical outcomes. Patients who took their SSRIs had improved ART adherence and improved viral 
load suppression that was comparable to patients who were not depressed.49 Yun also found similar 
results showing that depressed HIV infected patients who were adherent to their antidepressant 
therapy were more likely to be adherent to their ART.50 
 
5.0 SPECIFIC OBJECTIVES 
5.1 
Primary objective 
• To determine the feasibility of treating PND in HIV infected women on ART by measuring 
(1) screening uptake with EPDS; (2) the prevalence of perinatal depression; (3) study uptake; 
(4) and study retention.  
5.2 
Secondary objectives  
• To assess and compare response to therapy at 24 weeks after enrollment in each arm of the 
study  
• To assess acceptability of a randomized clinical trial of depression treatment among women 
agreeing to trial participation and among those who choose not to participate. 
• To describe antenatal PND characteristics in this population of women  
5.3 
Tertiary objectives 
• To evaluate clinical outcomes in study participants including maternal viral load at study 
completion, medication toxicity, medication adherence, adherence to IPT sessions; and 
worsening depression.  
6.0 STUDY OUTCOMES 
6.1 
Primary outcomes 
Study feasibility as measured by  
1) Screening uptake at six weeks postpartum– the proportion of women who agree to be 
screened for depression when offered  
2) PND prevalence – the proportion of screened women who are EPDS and MINI + at 6 
weeks postpartum   
3) Study uptake – the proportion of trial eligible women who agree to be randomized 
4) Study retention – the proportion of randomized women who complete follow-up through 
week 24  
6.2 
Secondary/tertiary outcomes 
• Depression treatment response – defined as the mean decline in the 10-item EPDS at 30 
weeks postpartum. We will also investigate the proportion of patients in each treatment 
arm in whom the Clinical Global Impression (CGI) improves by at least 1 point.  


 
 
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• Reported knowledge, attitudes, and practices related to HIV, ART, postnatal depression, 
and participation in RCTs, as well as attitudes about medications and counseling for the 
treatment of PND 
• Antenatal PND characteristics: (1) the PND screening rate in pregnancy, (2) the screen 
positive rate in pregnancy, (3) the proportion of women who screen EPDS+ in pregnancy 
that are MINI+ at postpartum week 6 (4) the proportion of women who are EPDS 
negative in pregnancy who are MINI+ at postpartum week 6  
• Maternal viral load at study initiation and completion,  
• ADM medication toxicity (ADM arm only) 
• ADM medication adherence, assessed by pharmacy pill count and patient report 
• Adherence to IPT sessions 
• Worsening depression as assessed by CGI and/or hospital admission.  
 
7.0 METHODOLOGY 
7.1 
Study design 
This will be a mixed method study to evaluate the feasibility and acceptability of a trial of 
depression treatment among postpartum HIV-infected Zambian women. To assess the feasibility 
of a full-scale clinical trial, we will implement a pilot two-arm, trial of ADM vs IPT among HIV-
infected women seeking postnatal care in Lusaka, Zambia. Participants will be randomly assigned 
to either a daily self-administered SSRI or IPT starting at their six-week postpartum visit. In this 
pilot study, we will be able to estimate screening uptake, prevalence of PND, study uptake, 
adherence to study medication, IPT, and protocol, and study retention. To assess the acceptability 
of a trial to test treatment of depression among HIV-infected postpartum women in Zambia, we 
will employ a qualitative approach of longitudinal semi-structured interviews among women 
agreeing to trial participation and one-time SSIs among those who decline to participate. 
Schema of the study design:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Eligible and 
agreed to enroll 
IPT 
Ineligible/eligible 
but refuse to enroll 
ADM 
SSI 
Randomization 1:1 


 
 
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7.2 
Study sites and study population 
Participants will be recruited from  two antenatal clinics in Lusaka, Zambia: The Women’s and 
New Born Hospital, University Teaching Hospitals (UTH) clinic and the Kamwala District Health 
Clinic (KHC).  
Inclusion criteria: 
1. 18 years of age or older 
2. Documentation of confirmed HIV-1 infection 
3. Six to eight weeks postpartum 
4. Currently taking ART treatment  
5. Able and willing to provide written informed consent 
6. Willing to adhere to study visit schedule 
7. PND diagnosis confirmed by Mini-International Neuropsychiatric Interview 
Exclusion criteria: 
1. Taking an ADM in the prior 12 months prior to enrollment 
2. Actively suicidal  
3. Known or suspected allergy or contraindication to first line Sertraline  
4. any other condition (social or medical) which, in the opinion of the study staff, would 
make trial participation unsafe or complicate data interpretation.  
Two groups of participants will be eligible for participation in the qualitative activities of this 
study. Women who decline enrollment into the randomized trial will be invited to participate in a 
one-time face-to-face SSI, while women enrolled and randomized into the placebo-controlled trial 
will be randomly selected to be followed longitudinally with three serial SSIs. 
7.3 
Study intervention 
Participants will be randomized 1:1 to one of two arms in the pilot randomized controlled trial. 
The first arm will a self-administered daily SSRI (Sertraline 25mg) while the other arm will be 
IPT. SSRIs will be administered at enrolment per an evidence-based treatment algorithm based on 
the Massachusetts Child Psychiatry Access Project (MCPAP)51  that is currently used at UNC. The 
Sertraline dose will be titrated up to receive treatment effect. The study nurses administering the 
ADMs will be overseen by study psychiatrists. The IPT arm will be treated according to an 
evidence-based IPT structured manual. Patients will have up to 11 planned sessions over a 24-
week period beginning the day of randomization. Any patient who needs to be seen for crisis 
intervention regardless of randomization arm will be seen and referred to the teaching hospital.  
7.3.1 Study drug pharmacological information 
First line drug: Sertraline 
Pharmacologic Category: Selective serotonin reuptake inhibitor 
Chemistry: Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral 
administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following 
chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine 
hydrochloride. It is a white crystalline powder that is slightly soluble in water and isopropyl 
alcohol, and sparingly soluble in ethanol  


 
 
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Mechanism of Action: The mechanism of action of sertraline is presumed to be linked to its 
inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man 
have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In humans, 
following oral once-daily dosing over the range of 25mg to 200 mg for 14 days, mean peak 
plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The 
average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this 
pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after 
approximately one week of once-daily dosing. As might be predicted from its primary site of 
metabolism, liver impairment can affect the elimination of sertraline. The use of sertraline in 
patients with liver disease must be approached with caution. If sertraline is administered to 
patients with liver impairment, a lower or less frequent dose should be used. Thus, sertraline 
multiple dose pharmacokinetics appear to be unaffected by renal impairment.  
Clinical indication for use: Sertraline has been used to treat Major Depressive Disorder, 
Obsessive Compulsive Disorder, Panic Disorder, Post traumatic stress disorder, and Social 
Anxiety Disorder 
Formulation: Oral tablet 
Strength: The standard dose range is 25mg to 150 or 200 mg once per day.  The dose will be 
titrated up in increments of 25 or 50 mg per day, every one to four weeks to achieve treatment 
response. 
The accountability procedures for the investigational products are outline in the pharmacy SOP 
number 11. 
7.4 
Pilot randomized trial procedures 
7.4.1 Recruitment 
Recruitment activities will begin with community sensitization including education for health staff 
at the recruiting clinics and other community stakeholders in consultation with community 
advisory board (CAB) members. Study staff will sensitize the general community though various 
methods for example; door-to-door education, drama performances, and one to one discussions at 
health centers to promote messages about HIV testing, mental health,  what postpartum depression 
is, and the purpose of the study. Drama performances at public markets, infant growth monitoring 
points, and water pumps/collection sites within the community will be held to raise awareness and 
encourage women to learn more about the study.  
Trained study staff will also conduct health talks each morning at antenatal clinics and the mother’s 
shelter. Health talks will focus on the importance of antenatal care, mental health, and overall 
wellbeing. 
7.4.2 Postnatal EPDS and study screening  
Trained staff will conduct EPDS screening as part of standard of care at two to seven weeks 
postnatally and record aggregate numbers of decliners, screen positives, and screen negatives. 
Those who screen positive for depression (i.e. EPDS >6) will be referred to the study site to learn 
more about the study and complete the informed consent process if interested prior to the 
completion of any study specific screening or enrollment activities. Postpartum women may also 
be referred for study screening from other ongoing studies in which the EPDS is conducted. No 
identifiable information about individual women will be recorded for study purposes until after 


 
 
Page 16 of 31 
 
study informed consent has been provided.  Once participants sign the informed consent, we will 
obtain a copy of their ANC card and record the EPDS score from ante and/or postnatal care if 
available.  
Those who meet preliminary eligibility criteria who are interested in participating will complete 
an informed consent process in English, Nyanja, or Bemba, depending on their language 
preference. Trial participation will be offered to all HIV-infected women who are determined to 
meet the listed inclusion and exclusion criteria. 
After consenting for participation, study staff will document the EPDS score and confirm the 
clinical diagnosis of major depression with the Mini-International Neuropsychiatric Interview 
(MINI).52,53 The MINI has several modules. We will use the following mood modules to 
diagnose depression and coexisting morbidities: (a) major depression past and present, (b) PTSD, 
and (c) anxiety. We will also administer a standardized assessment of domestic violence/gender-
based violence.  Study staff will then verify antenatal and HIV history data from participants’ 
postnatal cards and HIV clinic charts and collect a blood sample for baseline Viral Load testing. 
7.4.3 Study randomization 
Women who have been confirmed to be eligible for the study will undergo randomization into one 
of two study arms between six and eight weeks postpartum.  The trial will use REDCAP for 
randomization with a paper-based system of sealed envelopes as a backup when the electricity is 
out to assign women 1:1 to either the ADM arm or the IPT arm.  A statistician from the UNC 
Center for AIDS Research Biostatistics Core not otherwise associated with the study will design 
the scheme using random permuted blocks.  
Study medication will be obtained locally.  Participants will be instructed to begin daily self-
administration of study medication from the day of randomization. Women will be instructed on 
the importance of adherence at the enrollment visit and at additional study visits, as needed. Study 
medication will initially be dispensed at 1- week intervals which will then be spaced out to coincide 
with study visits that will be spaced out over time. Sertraline will be titrated up to achieve treatment 
effect. (SEE SCHEDULE OF EVALUATIONS) At each visit, medication will be given and an additional 
7 to 14-day buffer to be replenished as needed at subsequent study visits. Each participant will be 
asked to return any leftover medications at follow-up visits.  
Participants randomized to the IPT arm will receive weekly IPT for the first month and then 
biweekly for the next two months and then monthly until the exit visit. All participants will have 
the same number of face to face visits with clinic staff regardless of study arm. We plan to adapt 
existing IPT modules to the local context. We have been consulting with a team of researchers 
who have adapted IPT to improve medication adherence and reduce depression in patients with 
HIV in South Africa, which they have disseminated to community health clinics across the 
country, including both rural and urban settings. Their protocol, Mental Health Integration 
Programme (MhiNT), includes sessions explicitly focused on medication adherence, poverty, 
social isolation, experienced stigma/discrimination and rejection, and internalized and perceived 
stigma as they relate to depression. We have spoken to their team about adapting their model for 
Zambia, and they have agreed to continue consulting on the project to help tailor all elements to 
the women in our clinics. 
7.4.4 Study follow-up 
Women will be screened and enrolled over a period of 5-12 months.  Each participant will be 


 
 
Page 17 of 31 
 
followed for 24 weeks. Total duration of the study is 24 months.   Routine postnatal and HIV care 
will be provided to all participants following Zambian standard of care guidelines at KHC and 
UTH. Study staff will conduct follow-up clinical visits at approximately 8 and 16 weeks after 
enrollment which will occur in addition to the scheduled IPT visits and visits to collect ADM. At 
these visits, the medical history will be updated by the clinic staff and an EPDS as well as 
appropriate MINI modules will be completed. Our study staff will work with participants to ensure 
follow-up visits coincide with scheduled infant visits which occur at 6, 10 and 14 weeks of life to 
reduce burden on participants with regards to time and travel.  
Finally, all participants presenting to the final study visit will have an EPDS, a MINI evaluation 
as well as an exit survey performed. The study nurse will collect a blood sample at the final visit 
for Viral Load testing. Visit procedures are summarized in the Table 1 below.  
Table 1: Schedule of Evaluations 
 
 
7.4.5 Retention 
  
Scr 
Enr 
Follow-up 
Final 
 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Weeks postnatal 
6 
6 
7 
8 
9 
10 
12 
14 
16 
18 
22 
26 
30 
Administrative/Regulatory Procedures 
 
Informed consent 
• 
• 
  
  
  
  
  
  
  
  
  
  
 
Locator information 
  
• 
  
  
  
  
  
  
  
  
  
  
 
Eligibility confirmation 
  
• 
  
  
  
  
  
  
  
  
  
  
 
Randomization 
  
• 
  
  
  
  
  
  
  
  
  
  
 
Qualitative Procedures 
 
Decliner interview 
• 
  
  
  
  
  
  
  
  
  
  
  
 
Longitudinal interviews 
• 
  
  
  
  
  
  
  
  
  
  
 
• 
Study Assessments/Interventions 
 
EPDS 
• 
  
 • 
•  
 • 
• 
 • 
•  
• 
 • 
• 
• 
• 
MINI 
  
• 
  
  
  
  
  
  
  
  
  
 
  
GBV assessment 
  
• 
  
  
  
  
  
 
  
  
  
 
  
CGI 
  
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
ADM administration 
  
• 
• 
• 
• 
• 
• 
•  
• 
  
• 
• 
  
IPT session 
  
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
Adherence assessment 
  
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Collection of medical and 
behavioral data 
• 
• 
  
  
  
  
  
•  
 
  
• 
 
• 
Exit survey 
  
  
  
  
  
  
  
  
  
  
  
 
• 
Viral load  
  
• 
  
  
  
  
  
  
  
  
  
 
• 


 
 
Page 18 of 31 
 
Once a participant is enrolled in the trial, the study team will make reasonable efforts to retain her 
in follow-up to minimize bias associated with loss to follow-up. The study team will track retention 
rates and address any issues related to retention. Strategies may include:  
• Thorough explanation of the study visit schedule and procedures during informed consent, 
and re-emphasis at each study visit. 
• Encouragement of participants to discuss potential study participation with their 
husbands/partners and other influential family members before agreeing to enrol in the study.  
• Collection of detailed locator information at screening, and review and updating of this 
information at each study visit. 
• Use of appropriate and timely visit reminder mechanisms (including phone calls and text 
messages, if participants specifically agree). 
• Follow-up on missed visits, including home or other off-site visits if agreed upon. 
• Mobilization of trained outreach workers to complete in-person contact with participants at 
their homes and/or other locations. 
 
Procedures for when and how to withdraw participants are specified in our Retention and 
Assessing Suicidality and Need for Discontinuation from the study SOPs.  
7.5 
Qualitative activities 
Women who decline enrollment into the randomized trial will be invited to participate in a one-
time, face-to-face SSI to assess the following subject areas: (1) perceptions of depression; (2) 
health beliefs about and attitudes towards HIV, ART, and depression and towards treatment for 
depression; (3) acceptability of a daily medicine for treatment of depression as well as acceptability 
of IPT; and (4) attitudes towards participation in a randomized trial for treatment of depression. 
We aim to sequentially interview at least 20 women who decline enrollment, with the goal of 
thematic saturation of data. Prior to the qualitative interviews, a series of five qualitative interviews 
will be conducted to inform the questions that will be asked in the official pilot. 
Additionally, women who are enrolled into the RCT will be randomly selected to be followed 
longitudinally with two serial SSIs, to be held at enrollment, and at the final study visit. We aim 
to conduct interviews with women enrolled in the study to address the same domains outlined 
above, in addition to barriers and facilitators to: (1) adherence to an antidepressant or IPT sessions; 
(2) returning unused pills– i.e. protocol adherence; and (3) retention in the study. If our random 
sample does not include women from the full range of adherence levels, we will apply purposeful 
sampling to capture women of underrepresented adherence levels for a single interview mid-study.  
Our expected sample size for this group will be 20 women (10 from each arm of the study), based 
on expectations regarding saturation of qualitative themes.  
All interview sessions will be facilitated by a staff member trained in qualitative data collection 
techniques, in a private location on-site and are expected to last 30 minutes each. Sessions will be 
audio-recorded and transcribed, with approval provided by participants via informed consent. 
Where translations are needed, we will have independent reviewers review to ensure accuracy. 
Women participating in interviews for the qualitative analysis will also complete a consent process 
prior to completion of any study activities.  


 
 
Page 19 of 31 
 
7.6 
Biological specimen collection and testing 
All samples will be obtained from study participants by trained study staff according to approved 
standard operating procedures. All samples will be processed for viral load testing according to 
the assay manufacturers’ specifications. With participant consent, leftover specimens will be 
primarily housed at the University Teaching Hospital, Department of Obstetrics and Gynecology. 
Use of stored specimens for testing that is not specifically designated in this protocol will require 
additional regulatory approval.  
7.7 
Data security and management 
Data collected on each participant will include sociodemographic information, relevant HIV and 
obstetrical history, recent pregnancy outcome, adherence to ART, and side effects of any 
medications. We will also collect data on adherence to ADM and IPT throughout the study, and 
qualitative data from semi-structured interviews. If data is missing, we will document why the data 
is missing. 
Study data management (e.g. data transmission, query resolution, storage and security, etc.) will 
follow site Data Management SOPs. Study identification numbers will be used on all forms, 
returned ADMs, and communications related to the study.  
A separate confidential register will link study identification numbers and participants’ names. All 
data instruments and registers will be securely stored. Data will be entered into a custom-built 
database and will be validated. Computers will be password protected and their access restricted 
to authorized study personnel. Backups of the data will be made on a weekly basis. Data may be 
transmitted electronically to the study investigators through secure cloud-based servers. Study 
information will not be released without written permission of the participant, except when 
necessary for monitoring by the relevant ethical committees or their designees.  
Data will be disposed of after completion of the study following sponsor guidelines as per Data 
Management SOPs. At that time, electronic records, including linkage codes and identifiers, will 
be permanently deleted.  
If a participant is withdrawn from study product, all the data except data for intervention (ADM 
and IPT), will be collected until the study termination. If the participant is withdrawn from the 
study then no further data will be collected from the participant.  
7.8 Statistical considerations 
7.8.1 Pilot randomized controlled trial sample size and analysis 
The primary objective of this research is to determine whether a phase III efficacy trial would be 
feasible by measuring four key indices of feasibility including screening uptake with EPDS, the 
prevalence of perinatal depression, study uptake, and study retention. Given concerns around 
increased the stigmatization of depression, non-adherence to ART in the postpartum period as well 
as suspected high rates of postpartum depression among HIV infected women, we have 
chosen feasibility as our primary outcome. As this is a feasibility study, our sample size is not 
based on a comparison,54,55  but rather on the minimum desired precision around our four 
quantitative measures of feasibility. Since study retention is at the end of the screening and 
evaluation cascade, it will have the fewest numbers available and thus the least precision. Also, 
we expect the primary outcome of the planned phase III trial to be a composite measure that we 
have previously defined as program failure56,57 (detectable maternal viral load, death, or loss-to-


 
 
Page 20 of 31 
 
follow-up). Retention is likely to be the driving factor in this composite metric. Thus, we have 
chosen study retention as the primary outcome for our pilot study. Based upon prior experience 
and the published PND literature, which suggests loss-to-follow-up is a major issue in PND trials,58  
we estimate that 30% of randomized women will be lost to follow-up over the 6-month study 
period (i.e., retention will be 70%).  
We used the normal approximation confidence limit approach to choose the sample size, with the 
exact binomial confidence interval (CI) as a sensitivity analysis. Using a 95% CI for the proportion 
of randomized patients retained in the study, n=150 provides a lower confidence limit above 60%. 
TABLE 2 presents the precision achieved for outcomes with an observed proportion of 50-95% 
given a total sample size of 150.  
Table 2: Anticipated precision with n=150 participants 
 
With a randomization sample size set at 150, we then calculated the number of women to whom 
we would need to offer enrollment into the study, by applying best estimates for attrition along the 
screening and follow-up cascade. Based on these estimates, we will need to screen 1130 women, 
of whom 10% will decline screening (estimate from ongoing prematurity cohort), leaving 1017 
evaluated by EPDS. Of these, we expect 70% to be EPDS negative3,17 and proceed to MINI 
screening. The specificity of EPDS to screen for clinically confirmed PND (i.e., MINI+) varies 
widely by study, but we have conservatively assumed 12% of EPDS positive women will be MINI 
positive for either major depression or anxiety, yielding 268 MINI positives. Of these, we estimate 
4% will report suicidal tendencies or otherwise be too ill to randomize and that 10% will be 
ineligible after applying exclusion criteria, leaving 231 to whom we will offer enrollment. Finally, 
we estimate from prior trial experience, that 35% of eligible women will decline participation in 
the study, leaving 150 who are consented and randomized. 
For our primary analyses, we will measure the quantitative feasibility outcomes in the entire trial 
cohort – (i.e., without accounting for randomization arm). This will involve screening uptake with 
EPDS, the prevalence of perinatal depression, study uptake, and study retention. All statistical 
estimates of population parameters will be tabulated along with corresponding confidence intervals 
(CIs). 
In a secondary analysis, we will investigate response to therapy at 24 weeks in each arm of the 
study. Depression treatment response – defined as the mean decline in the 10-item EPDS at 24 
weeks postpartum. Since this will be analyzed as a continuous variable, our study will have 80% 
power to detect a difference of 3 points in the EPDS between each of the intervention arms (alpha 
= 0.05; EPDS sd ± 5 points). We will also investigate the proportion of patients in each treatment 
arm in whom the CGI improves by at least 1 point. 
In other secondary analyses, we will quantify the following antenatal PND characteristics: (1) the 
PND screening rate in pregnancy; (2) the screen positive rate in pregnancy (3) the proportion of 
women who screen EPDS+ in pregnancy that are MINI+ at postpartum week 6 (4) the proportion 
of women who are EPDS negative in pregnancy who are MINI+ at postpartum week 6. In tertiary 
analyses of clinical outcomes, we will evaluate: (1) maternal viral load at study completion, (2) 


 
 
Page 21 of 31 
 
ADM medication toxicity (ADM arm only); (3) ADM medication adherence, assessed by 
pharmacy pill count and patient report; (4) adherence to IPT sessions (5) worsening depression as 
assessed by CGI and/or hospital admission.  
We will define uptake strictly as the proportion of women meeting initial (screening) eligibility 
criteria who are randomized in the trial. If uptake in the pilot is very low, enrollment of a large 
trial might not be feasible. Low uptake might also make us worry about external validity and 
whether the trial would be representative enough to be of real policy value. 
To quantify study retention, we will calculate the proportion of women randomized in the trial 
who complete the final visit. For the present study, we will require a clinic visit to define retention 
success.  
Univariate analyses will be performed to identify maternal demographic and health characteristics 
associated with adherence, uptake and retention; and adjusted associations will be analyzed with 
a multivariable log-binomial model as appropriate (for outcomes with a sufficient number of 
events). 
Other outcomes will include: (a) maternal viral load at study completion; (b) ADM medication 
toxicity; (c) ADM medication adherence, assessed by pharmacy pill count and patient report; (d) 
adherence to IPT sessions; (e) requirement of up titration of ADM; (f) worsening depression; (g) 
other maternal or neonatal adverse events. We will attempt to trace all participants who are lost to 
follow-up to determine obstetrical and neonatal outcomes. In an exploratory analysis of these 
outcomes, we will conduct descriptive statistics of participant demographic and clinical features, 
and of the proportion of patients experiencing the secondary outcomes of poor maternal and 
neonatal outcomes. Although our study is not powered for efficacy, we will perform univariate 
analyses to determine if a numerical difference in risk of these secondary efficacy and safety 
outcomes exists between women who were randomized to ADM compared to those randomized 
to the IPT arm. Sensitivity analyses will be used to investigate how limiting the analysis to high 
adherers impacts the estimated RR. The effect of participant demographic variables (and any 
additional potential measured confounders) will be explored in multivariable analyses using a log-
binomial model. Exploratory analyses will be stated as such and presented as pilot effect estimates 
with a 95% CI; such analyses will provide useful results for planning a full-scale trial. All 
hypothesis tests that are observed to be not statistically significant will be reported as being 
inconclusive.  
In sum, we expect this feasibility study to allow us to estimate the proportion of women who (a) 
are eligible to participate, (b) will agree to participate, (c) are able to comply with the visit 
schedule, (d) will adhere to prescribed study drug and therapy sessions, and (f) will remain in the 
study once enrolled. We will gain insight into the (g) baseline event rate, (h) preliminary effect 
size, and (i) rates of adverse events. Finally, the study will allow us to develop and test study-
specific SOPs and gain experience with randomization. 
We will report the proportion of missing baseline data as well as missing data for the primary 
outcome. Our main analysis will be intent to treat. We will perform a sensitivity analysis to 
quantify the effect of missing outcome data on study results. 
7.8.2 Qualitative analysis 
Our primary objective is to identify common facilitators and barriers to screening and treatment of 
depression in a clinical trial. We will first analyze data from women who decline enrollment 


 
 
Page 22 of 31 
 
independently from data among those who enroll. Then, findings from common baseline domains 
evaluated in both assessment groups will be compared to identify commonalities or discrepancies 
between decliners and enrollees. The longitudinal data assessed from interviews with enrolled 
participants will be compared across time and between those randomized to ADM vs IPT. After 
translations and transcription, a team of coders with qualitative data analysis experience will use 
qualitative analysis software to organize the transcribed data. Transcript data will initially be 
organized based on the questions in the semi-structured guides. Coders will read and “memo” each 
transcript and compare memos to create a preliminary codebook. They will apply the codes to 
significant utterances, comparing their results periodically (such as every 4-5 interviews) to assess 
consistency between coders in order to refine a final codebook. They will examine codes and 
utterances for clusters of meaning to construct themes and maps reflecting categories and 
relationships among codes. They will then examine the themes identified from each dataset for 
contrasts and overlaps between them, which may lead to reconstructions of the existing themes or 
the emergence of new subthemes. A summary report of the analyzed SSI data will be created which 
will inform the development of the following materials for the planned full-scale efficacy and 
safety trial: study protocol, consent forms, adherence monitoring and counseling guide, and 
provider training materials. 
7.9 
Dissemination of Findings 
Study findings will be disseminated through appropriate local channels, including academic and 
public health research symposia. One or more publications will also be submitted to a peer-
reviewed journal. Our study team will plan to publish results whether positive or negative. The 
study participants’ privacy and confidentiality will be strictly maintained in all results 
dissemination or publication activities. 
8.0 ETHICAL CONSIDERATIONS 
The study protocol, informed consent, and all participant materials will be reviewed by relevant 
ethics committees maintaining Federal Wide Assurances (FWA) with Office for Human Research 
Protections (OHRP) approval. All staff who have contact with participants will receive training on 
the protection of human research participants prior to conducting any study activities and routinely 
thereafter.  
8.1 
Informed consent 
Discussions with prospective participants and informed consent procedures will be conducted in 
private to protect patient confidentiality. Where possible, a private room will be used to discuss 
the study and potential participant’s eligibility. If a private room is not available, a designated area 
far enough away from other patients such that they cannot hear the conversation will be used. The 
study nurse will obtain written informed consent from all participants. The study procedures, risks, 
and benefits will be discussed and the study nurse will answer all questions prior to obtaining 
consent. The consent forms will be translated into local languages (Nyanja and Bemba) and back-
translated into English to assure accurate translation. All versions of the consent forms will be 
approved by the relevant ethics committees prior to study initiation. For illiterate participants, a 
literate impartial witness will be present during the entire consent process to ensure that all of the 
relevant information has been provided and the participant voluntarily gives consent.  
Eligible women who do not wish to participate in this study will continue to receive postnatal care 
and treatment according to local clinical standards.   


 
 
Page 23 of 31 
 
8.2 
Potential risks to participants  
We expect participant risk to be minimal. We will exclude any woman with an initial EPDS >25 
and treat her accordingly. Any participant found to have active thoughts of suicide will be referred 
for immediate psychiatric care She will be accompanied to the referral by a study staff member. 
As the study will be conducted while the patient is at the clinic, she will have the opportunity to 
disclose any issues or concerns to the provider immediately during her participation in the study 
participation. In addition, investigators will be available to discuss acute psychiatric concerns by 
study staff as needed and to liaison with the psychiatric team in Zambia.  
A small number of women in the antidepressant medication arm may develop side effects or 
potential interactions with their ART, so we will closely monitor adverse events and document all 
concomitant medication use. We are not aware of any contraindications to potential treatment 
combinations but will maintain a laminated notebook with commonly prescribed medications and 
potential interactions with Sertraline. The book will be color coded and easily interpreted. All of 
the enrolled participants will be diagnosed with clinical depression. There is a possibility that these 
women will not respond to the therapies in our study and will need additional treatment. Any 
woman who experiences worsening depression based on an EPDS or a MINI or who has suicidal 
or homicidal ideations, will be withdrawn from the study and referred to UTH for further 
individualized management.  
We do not expect to uncover any incidental findings given that study assessments will be relatively 
limited. In the event this does occur, we will make assisted referrals by completing a referral form 
with all relevant information available and escorting the participant to the appropriate care 
provider. We will then follow up with both the participant and the provider routinely to ensure that 
she has received proper care 
Participation in clinical research includes the risks of loss of confidentiality and discomfort with 
the personal nature of questions, particularly when discussing HIV infection or mental health. At 
each step in the study, we will protect participant privacy and confidentiality to reduce these risks, 
such as not revealing all study inclusion criteria to participants or the community, consenting 
participants in a private setting, screening for risk factors that may increase the risk for social harm, 
carefully collecting locator information with details about how to communicate with participants, 
not including names on case report forms, and storing all research records securely. Although 
investigators make every effort to protect participant privacy and confidentiality, it is possible that 
participant involvement in the study could become known to others, and that social harms may 
result (i.e. as participants could become known as HIV infected). Should that occur, study staff 
will work with the participant and his/her family as appropriate to resolve the situation in whatever 
manner is preferred including additional counseling or referrals for community services for the 
participant and her partner/family.   
Risks to the participant will be minimized by thorough training and supervision of all staff. The 
confidentiality of all study records will be safeguarded to the extent legally possible. All study 
data, reports, laboratory specimens, and administrative forms will be identified by a coded number 
only to maintain participant confidentiality. All databases will be secured with password-protected 
access systems, and computer entries will be identified by coded number only. Forms, lists, 
logbooks, appointment books, audio-recordings, and any other listings or data forms that link 
participant ID numbers to other identifying information will be stored in a separate, locked cabinet. 
All data analysis will be done on datasets which have only the study number as a unique identifier. 


 
 
Page 24 of 31 
 
Clinical information with individual identifiers will not be released without the written permission 
of the participant. We expect these procedures to adequately protect participant confidentiality.  
The Victim Support Unit in the Zambia Police provides support to women who report domestic 
violence, and a number of non-governmental organizations work with women who are victims of 
gender based violence (GBV). All women who are screened for our study will be provided with 
pamphlets printed in local language outlining where women can receive care for gender-based 
violence, which will also be available in the clinic waiting room at all times. A few of the local 
organizations that support GBV are: World Vision, WILSA, ZCCP, and Lifeline-Childline Gender 
Based Violence Call Centre. We will also directly facilitate contact with any of these organizations. 
8.3 
Potential benefits to participants and others  
Individual participants in both arms of the study may benefit from treatment of depression if the 
intervention is found to be effective, but it is also possible that there will be no effect. We believe 
that equipoise exists between the study arms since neither treatment has been previously studied 
in HIV infected women receiving antiretroviral therapy in sub-Saharan Africa, and the exact risk 
for untreated PND unclear. All participants may benefit from close clinical monitoring. 
Knowledge generated from this study has the potential to inform future clinical trials on the best 
way to treat depression among HIV-infected women, which may enable policymakers worldwide 
to make informed decisions regarding effective interventions for treating PND among HIV 
infected individuals taking ART.  
At the clinic level, all staff involved in the study will receive refresher training on the diagnosis 
and treatment of PND59. Increased awareness about screening and treatment for PND may help to 
improve care overall at KHC and UTH. Additionally, our community sensitization activities may 
help to encourage more women to come for screening for PND earlier in pregnancy which is a 
known risk factor for depression in the postpartum period.  
In summary, we expect participant risk to be minimal. The knowledge generated from this study 
regarding the feasibility of diagnosing and treating PND among HIV-infected women is expected 
to outweigh the risks of participation. 
8.4 
Participant follow up once the study is completed 
Treatment for perinatal depression is typically offered for 6-12 months. Our study will follow up 
women for 24 weeks after enrollment. At the end of the 24 weeks, women will be assessed for 
depression. Women who are no longer depressed at the end of the study will be offered to 
discontinue the SSRI or to continue the SSRI for another 6 months, per patient preference. 
Women who desire to continue for another six months will follow up at UTH. Sertraline, the 
SSRI antidepressant medication we have chosen for our study, is on the Ministry of Health 
Essential Medicine list and is available to patients free of charge. Women who choose to 
discontinue their antidepressant will be followed up with a phone call 2-4 weeks after 
discontinuing the medication to ensure that they do not need a referral to UTH. Women in the 
IPT arm who remain depressed at the end of the study will be referred to UTH to start an 
antidepressant.  
Participants will be followed up until the end of trial if they are withdrawn from the 
investigational products. If the reason for withdrawal requires more follow up after the close of 
the study, the participant will continue to be seen and cared for by Dr. Ravi Paul in UTH 
Psychiatry department. 


 
 
Page 25 of 31 
 
 
9.0 SAFETY MONITORING 
At each study visit, study staff will evaluate participants for social harms and adverse events 
(AEs). A social harm will be defined as a non-medical untoward consequence of study 
participation, including: difficulties in personal relationships, stigma, or discrimination from 
family or community. An AE will be defined as any untoward medical occurrence in a study 
participant including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the individual’s participation in the research, 
whether or not considered related to participation in the research. In addition to events related to 
study procedures and ADM treatment, we can expect that this population of HIV-infected 
postpartum women to experience adverse events unrelated to study procedures, including 
opportunistic infections, side effects from ART or other medications, hospitalization, and death.  
The severity of study-related adverse events and social harms will be graded using the National 
Institute of Health’s Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events. We will also record information on all serious adverse events (SAEs) occurring 
in participants whether or not they are related to study participation or the study drug, including 
AEs that: 
1. Result in hospital admission (unless hospitalization is preplanned, i.e. for delivery) or 
prolongation of existing hospitalization  
2. Are immediately life-threatening, including drug reactions that necessitate discontinuation 
of study participation,  
3. Cause significant, persistent, or permanent harm or disability, either physical or 
psychological,  
4. Result in death to mother or infant 
9.1 
Data Safety Monitoring Board (DSMB) 
We will constitute a 5-member Data Safety and Monitoring Board (DSMB) through NC TraCS, 
the North Carolina Translation and Clinical Sciences Institute, to review the safety of the 
interventions, but its purpose would only be to monitor safety because there will be no stopping 
rules as this is not a comparative study. The three main outcomes that will be monitored are 1) 
interactions between antiretrovirals and antidepressants 2) side effects of antidepressants among 
participants requiring them to either switch antidepressant medication or discontinue the 
medication 3) worsening depression symptoms in either arm despite treatment. The DSMB will 
meet twice per year and additionally as needed, either in person or via conference call. The 
committee will discuss the project, review its progress, and assess unanticipated problems and 
adverse events. The DSMB members do not have any direct involvement in the study or conflict 
of interest with the study team.  
9.2 
Trial safety reporting 
For all enrolled participants, study staff will collect information on adverse events, adverse drug 
reactions/side effects, perceived social harms, and suicidal and homicidal ideations at each follow 
up visit. All events will be documented, assessed for seriousness / severity and relatedness, 
carefully monitored, and managed by the onsite investigators. Our trial will adhere to the NIMH 
reportable events reporting guidelines and will assess AEs following the current DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events. 


 
 
Page 26 of 31 
 
We can expect that this population of postpartum HIV infected women may experience adverse 
events unrelated to study procedures including new diagnoses of opportunistic infections, side 
effects from ART medications, hospitalization, and possibly death. Participant records will be 
carefully monitored internally by the Study Coordinator and investigators to ensure that no adverse 
events or social harms are missed. We will record relevant information about AEs, SAEs, social 
harms, and Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) in the study 
records.   
Participants in the ADM arm of the study may experience common side effects associated with 
this medication. We do not expect any participants to have major side effects, but if any do occur, 
we will evaluate the participant and potentially discontinue her use of the study drug. Any 
participants who develop active suicidal or homicidal ideation will be referred to the study 
psychiatrist for immediate care and may also be discontinued from their assigned intervention as 
needed.   
The site investigators and/or Study Coordinator will report all related serious adverse events, social 
harms, protocol violations, and UPIRSOs to the PI immediately within 24 hours of site awareness. 
The DSMB will be notified of any serious adverse events (related or unrelated) within 24 hours of 
site awareness.  If the investigators determine that study-related adverse events are occurring at an 
unexpected rate, the PI will facilitate re-training for study staff on clinical procedures or in 
protection of patient confidentiality as applicable and notify the DSMB and study sponsor as 
needed. AEs/SAEs, UPIRSOs, serious or continuing non-compliance, and protocol violations will 
be reported to all regulatory bodies and the NIMH following their requirements as outline in the 
Communication with Ethics and Regulatory Authorities SOP.  
If terminating the study trial, a DSMB will be convened. Recommendations to terminate the trial 
can be found in the DSMB charter. We will plan one interim test of SAEs or Adverse Drug 
Reactions after one half or 75 patients have been enrolled. The following SAEs or severe drug 
reactions will be assessed across both treatment arms: nausea, diarrhea, insomnia, agitation, mania, 
and active suicidal ideations. If after 75 participants are enrolled, there is a two-fold increase in 
SAEs or severe adverse drug reactions among women randomized to the ADM arm (20%) vs the 
IPT arm (10%), then the study should be suspended until further review.  
  
10.0 
BUDGET (1 USD = 11.5 ZMW) 
Year 1 
USD 
Year 1 
ZMW 
Year 2 
USD 
Year 2 
ZMW 
Total 
USD 
Total 
ZMW 
Personnel 
$60,511  
695,877  
$60,510 
695,865  
$121,021 
1,391,742  
Investigator 
$5,000  
57,500  
$6,000  
69,000  
$11,000  
126,500  
Study Coordinator 
$15,500  
178,250  
$14,500  
166,750  
$30,000  
345,000  
Research Nurse 
$10,500  
120,750  
$11,050  
127,075  
$21,550  
247,825  
Counselors 
$12,500  
143,750  
$13,200  
151,800  
$25,700  
295,550  
Data Staff 
$8,585  
98,728  
$7,340  
84,410  
$15,925  
183,138  
Support Staff 
$8,426  
96,899  
$8,420  
96,830  
$16,846  
193,729  
Travel 
$4,010  
46,115  
$4,010 
46,115  
$8,020 
92,230  
Supplies & materials 
$6,364  
73,186  
$3,505 
40,308  
$9,869 
113,494  
Office Supplies 
$2,855  
32,833  
$955  
10,983  
$3,810  
43,815  


 
 
Page 27 of 31 
 
Clinic Supplies 
$1,200  
13,800  
$1,200  
13,800  
$2,400  
27,600  
Study Drug 
$2,309  
26,554  
$1,350  
15,525  
$3,659  
42,079  
Participant Reimbursement 
$2,753  
31,660  
$2,692 
30,958  
$5,445 
62,618  
Full study visit - 50 ZMW 
$1,586  
18,239  
$1,640  
18,860  
$3,226  
37,099  
Intervention only visit - 25 
ZMW 
$1,167  
13,421  
$1,052  
12,098  
$2,219  
25,519  
Other 
$8,200  
94,300  
$2,520  
28,980  
$10,720 
123,280  
Admin costs (talk time, printing, 
shipping, utilities, etc) 
$2,200  
25,300  
$2,000  
23,000  
$4,200  
48,300  
Regulatory/Translation costs 
$4,000  
46,000  
$250  
2,875  
$4,250  
48,875  
Training/Community Outreach  
$2,000  
23,000  
$270  
3,105  
$2,270  
26,105  
TOTAL 
$81,838  
941,137  
$73,237  
842,226  $155,075 
1,783,363  
 
 
11.0 
TIMELINE 
Participants will be followed from enrollment through 30 weeks postpartum. We have allocated 6 
months to start-up activities and 3 months to wind-down activities. 
PHASE 
Year 1 
Year 2 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Pre-implementation 
 
 
 
 
 
 
 
 
Regulatory approvals 
X 
 
 
 
 
 
 
 
Site preparation and training 
X 
X 
 
 
 
 
 
 
Implementation 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
X 
X 
X 
 
 
 
Follow-up 
 
 
X 
X 
X 
X 
X 
X 
Data management, analysis & reporting 
 
 
 
 
 
 
 
 
Transcription and coding of interviews 
 
 
X 
X 
X 
X 
 
 
Data entry and management 
 
X 
X 
X 
X 
X 
X 
X 
Statistical analysis 
 
 
 
 
X 
X 
X 
X 
Publication and dissemination  
 
 
 
 
 
 
 
X 
 
 


 
 
Page 28 of 31 
 
12.0 
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