Prevent TB: Application of Choice Architecture to Implement TB Preventive Therapy in South Africa
Phase: NA
Conditions: HIV/AIDS, Tuberculosis
Sponsor: Johns Hopkins University

 
 
 
 
 
 
NCT04466488 
 
Prevent TB: Application of choice architecture to implement TB 
preventive therapy in South Africa 
 
 
 
Protocol Date: 13 May 2024 
 
 
 
 
 
 
 
 
 

 
 
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Prevent TB: 
Application of choice architecture to implement TB preventive 
therapy in South Africa  
 
 
Short title: Prevent TB 
Protocol version: 4.0 dated 13 May 2024 
Funder: National Institute of Allergy and Infectious Diseases, USA (Grant# 
1R01AI150432) 
Implementing Partner: PHRU, South Africa 
Principal Investigators: Christopher Hoffmann 
South African Principal Investigator: Limakatso Lebina 
 
 

 
 
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Statement of Compliance 
The study will be carried out in accordance with the design and specific provisions of this 
Human subjects ethics-approved protocol, with the ethical principles that are consistent with 
Good Clinical Practice (GCP) and the applicable regulatory requirements by the following: 
• 
Declaration of Helsinki 
• 
ICH GCP E6 
• 
Completion of Human Subjects Protection Training 
The Principal Investigator will assure that no deviation from, or changes to, the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
Human Research Ethics Committee, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. The Principal Investigator will promptly report to Human 
Research Ethics Committee any changes in research activity and all unanticipated problems 
involving risk to human subjects or others. 
 
 
 
 
 
 

 
 
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STUDY SUMMARY 
Background: Clinical guidelines and policies often fail to achieve high levels of delivery of 
intended clinical interventions. The difference in what we know works and what is actually 
delivered at the clinic-level to patients, is known as the “science-to-service gap.”1 In the 
realm of tuberculosis (TB) prevention, this gap is reflected in <20% of TB preventive therapy 
(TPT) -eligible persons living with HIV (PLWH) being offered or initiated on isoniazid 
preventive therapy (IPT) in many settings.2-5 Recent innovation in TPT have brought new 
pharmacological options allowing for shorter courses, intermittent dosing, or both. For 
example, a 12-dose once-weekly rifapentine and isoniazid (3HP) regimen has been 
demonstrated to be effective and well tolerated.6,7  The science-to-service gap is likely to 
persist despite improved TPT options. 
 
The overarching goal of this study is to identify a generalizable approach to overcome 
current barriers to delivery of TPT in order to achieve high levels of TPT delivery during 
routine care in public clinics. Multiple approaches are in standard use to change prescribing 
behavior including in service training, audit and feedback, clinical mentoring, the use of 
clinical decision aids, and “academic detailing.”8,9 Each of these approaches has an evidence-
base for improvement in delivery (sometimes limited to a specific setting).  However, the 
overall change is generally modest. For example separate Cochrane Reviews of audit and 
feedback and academic detailing reported a median increase in service delivery of about 
5%.10,11  To achieve a substantial increase in TPT delivery (from current approximately 20% 
to 60-80%) will require a fundamental change in the approach to selecting patients for TPT – 
a redesign of the choice architecture of TPT prescribing.12 
 
 
Aims: To identify a pragmatic approach using choice architecture to increase TPT prescribing to 
PWH. 
 
Methods: We are proposing a choice architecture that makes prescribing TPT the “default” 
or standard option and that for TPT not to be prescribed will require a choice by a clinician to 
“opt-out” of TPT for a specific patient. This will be implemented through combined 
prescribing stationary or stamps (as appropriate for the context) to make TPT part of ART 
prescribing or re-prescribing. 
 
We are proposing a cluster randomized design to test the choice architecture approach to 
increasing delivery of TPT. Clinics will be randomized to one of two strategies: (1) standard 
implementation and (2) choice architecture default TPT. Because of the clinic-level nature of 
the implementation strategies, all PLWH receiving care at a clinic will be exposed to the 
standard implementation or TPT routinization implementation. Clinical process data will be 
used to assess the effectiveness of each strategy to determine the proportion of PLWH (1) 
screened for TPT, (2) eligible for TPT, and (3) prescribed TPT.  

 
 
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The primary objective is to test whether this choice architecture approach of a “default” to 
prescribing TPT substantially increases TPT prescribing. Identifying a pragmatic approach will 
lead the way for improving TPT prescribing across the study sites. It will furthermore 
contribute to implementation science at large in describing implementation strategies that 
may be applied to clinic-level implementation of other innovations. 
 
Significance: TB is the leading cause of death among PWH in South Africa and elsewhere on the 
continent. TPT is a proven intervention to reduce mortality among PWH but is not widely 
prescribed. This study seeks to identify an implementation strategy to reach optimal TPT 
prescribing.  
 
 
 
 

 
 
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Key Personnel 
 
Name 
Responsibility 
Contact 
PHRU 
Limakatso Lebina 
Site Principal Investigator  
 
Study design, protocol writing, 
study management, study 
implementation, data analysis, 
report writing, managerial 
oversight and support at the 
sites. Will lead the study and 
manage the study team. 
Mobile: +27 82 554 4548 
Email: likamatso.lebinal@ahri.org 
Neil Martinson 
Co-Investigator  
 
 
Project oversight, stakeholder 
engagement, dissemination and 
manuscript preparation. 
Phone: +27 11 989 9836 
Mobile: +27 82 331 6756 
Email: martinson@phru.co.za 
Leisha Genade 
Responsible for study management, 
study implementation, and field 
team oversight 
Phone : +27 11 989 9714 
Mobile : +27 61 629 9748 
Email : genadel@phru.co.za 
Maxine Nunu 
Responsible for study management, 
study implementation, and field 
team oversight. 
Phone : +27 11 989 9714 
Email : nunum@phru.co.za 
JOHNS HOPKINS UNIVERSITY 
Christopher Hoffmann 
Principal Investigator 
 
Developing procedures, protocol, 
project management, stakeholder 
engagement, dissemination and 
manuscript preparation. 
Phone: +1 (410) 614-4257   
Mobile: +1 (443) 602-2210 
Email: choffmann@jhmi.edu 
Jonathan Golub 
Co-Investigator 
Responsible for contribution to 
design and analysis of RCT 
components. 
Phone: +1 (443) 287-2969 
Email:  jgolub@jhmi.edu 
Richard Chaisson 
Co-investigator 
Responsible for contributing to 
design of RCT and to stakeholder 
engagement 
Phone: +1 (410) 955-1755 
Email: rchaiss@jhmi.edu 
Jill Owczarzak 
Co-investigator 
Responsible for overall input in 
study implementation and all 
qualitative and behavioral 
assessments 
Phone: +1 (410) 502-0026 
Email: jillowczarzak@jhu.edu 
Bareng Aletta Nonyane 
Statistician 
Responsible for study design, 
statistical analysis plan, and 
Phone: +1 (410) 955-3934 
Email: bnonyan1@jhu.edu 

 
 
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conducting analyses for interim 
reports and manuscript 
preparation  
Letha Varughese 
Statistician 
 
Responsible for assisting with 
statistical analysis plan and 
conducting analyses for interim 
reports and manuscript 
preparation 
Phone: N/A 
Email: lvarugh1@jhu.edu 
Kate Shearer 
Co- Investigator 
Responsible for study design, 
protocol writing, study 
management, and oversight 
Phone: +27 60-876-0192 
Email: ksheare5@jhu.edu 
Laura Steiner 
Research Coordinator 
Responsible for protocol writing, 
study management, study 
implementation and oversight 
Phone: +1 410-4248445 
Email: lsteine5@jhmi.edu 
 
 
 

 
 
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Contents 
 
Statement of Compliance .............................................................................................................. 3 
1 
INTRODUCTION .................................................................................................................. 11 
1.1 
Background ..................................................................................................................... 11 
1.2 
Study objectives .............................................................................................................. 14 
1.3 
Significance ..................................................................................................................... 15 
2 
METHODS .......................................................................................................................... 15 
2.1 
Study design ................................................................................................................... 15 
2.2 
Study setting ................................................................................................................... 16 
2.2.1 
Description of the geographical areas of study implementation 
16 
2.2.2 
Rationale for selecting geographical areas of study implementation 
17 
2.3 
Study Population............................................................................................................. 17 
2.3.1 
Inclusion and exclusion criteria 
17 
2.4 
Sampling scheme ............................................................................................................ 17 
2.4.1 
Clinic selection 
17 
2.4.2 
Clinic level baseline data abstraction 
17 
2.4.3 
Randomization 
17 
2.4.4 
Choice architecture arm 
20 
2.4.5 
Standard of care arm 
21 
2.5 
Study outcomes .............................................................................................................. 21 
2.5.1 
CRT primary and secondary effectiveness outcomes 
21 
2.5.2 
Assessment of clinic implementation of choice architecture 
22 
2.5.3 
Patient initiation and completion of TPT 
25 
2.5.4 
TB Patient Care 
27 
3 
Analysis: Descriptive  statistics will be generated to describe availability and utilization of services for 
TB patients.Data Management..................................................................................................... 27 
3.1 
Data collection tools ....................................................................................................... 27 
3.2 
Database ......................................................................................................................... 28 
3.2.1 
Structure of the database 
28 

 
 
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3.2.2 
Database access 
29 
3.2.3 
Locking of final database 
29 
3.2.4 
Data security 
29 
3.2.5 
Study limitations 
29 
4 
Appropriate care in response to study-specific findings ......................................................... 30 
5 
Protection of human participants ......................................................................................... 30 
5.1 
Regulatory approvals ...................................................................................................... 30 
5.2 
Risks and benefits ........................................................................................................... 30 
5.3 
Clinical trials registration ................................................................................................ 31 
5.4 
Confidentiality ................................................................................................................ 31 
5.5 
Data safety and monitoring ............................................................................................ 32 
6 
Project Governance and Management ................................................................................. 32 
6.1 
Research team ................................................................................................................ 32 
6.2 
Publication policy ............................................................................................................ 33 
6.3 
Performance monitoring ................................................................................................ 33 
7 
Participant reimbursement .................................................................................................. 33 
8 
Funding .............................................................................................................................. 33 
9 
References ......................................................................................................................... 34 
 
 
 
 

 
 
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Glossary of Terms 
AIDS 
 
Acquired Immuno-deficiency Syndrome 
ART 
 
Antiretroviral Therapy 
CAU 
 
Care as Usual 
CBO 
 
Community Based Organization 
CCMDD 
Central Chronic Medicine Dispensing and Distribution (system or service) 
CRF 
 
Case Report Form 
DOH 
 
South African Department of Health 
HIV 
 
Human Immunodeficiency Virus 
LTFU  
loss to follow up 
NIH 
 
National Institutes of Health 
PHC 
 
Primary Health Clinic 
PIS 
 
Participant Information Sheet 
RCT 
 
Randomized Clinical Trial 
SA 
 
South Africa 
STI 
 
Sexually Transmitted Illnesses 
TB  
 
Tuberculosis 
 
List of Tables 
 
Table 1. Number of clinics required for 80% power to detect a difference in proportion initiating 
ART and TPT  between the two study arms................................................................................... 20 
Table 2. Aim 1 outcomes & analysis approach .............................................................................. 22 
Table 3. Power calculation for patient initiation and completion ................................................. 25 
Table 4. List of data collection tools and intended use ................................................................. 27 
 
List of Figures 
 
Figure 1. TPT choice architecture aid ............................................................................................ 21 
Figure 2: Project Management Structure ...................................................................................... 32 
 
 
 

 
 
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1 INTRODUCTION 
1.1 Background  
A.1. Overview. Despite being a preventable and treatable disease, tuberculosis (TB) kills 1.5 
million people annually and is the leading cause of death in people with HIV (PWH).5 TB 
preventive therapy (TPT) is an evidence-based approach to reducing TB disease and mortality 
that has been embraced in international and national policies and guidelines. Yet TPT remains 
woefully under-implemented. We propose to test a choice architecture based strategy to 
increase initiation of TPT among people with HIV (PWH) in South Africa. Increasing TPT 
initiation, as called for by global bodies and the South African Department of Health, has the 
potential to reduce death among PWH receiving antiretroviral therapy (ART).13,14 
A.2. HIV associated mortality and TB disease in LMIC.TB is the leading cause of death due to an 
infectious agent worldwide.5,15 Among PWH in low and middle income countries (LMIC), TB 
represents the leading cause of mortality among PWH.16 South Africa is particularly affected by 
the syndemic of HIV and TB with an estimated HIV prevalence in 2017 of 7.2 million and TB 
incidence of 567/100,000 population with over 60% of TB cases among PWH.5,17,18 There were 
an estimated 78,000 deaths from TB in South Africa in 2017; 56,000 of the deaths among PWH.5 
Findings from our group suggest this is likely an underestimate of true TB disease and TB 
related mortality.19  
A.3. TB preventive therapy reduces TB disease and mortality. For the past 30 years isoniazid 
based TPT has been known to reduce the risk of TB among PWH.20,21 Multiple studies have 
subsequently confirmed and strengthened this finding. Following cohort studies conducted in 
South Africa and Brazil by our team that showed marked reductions in TB incidence for PWH, 
clinical trials of isoniazid preventive therapy have reported up to a 70% reduction in TB 
incidence among PWH.22-24 A study conducted in Cote d’Ivoire randomized participants to one 
of four groups: deferred ART, deferred ART plus TPT using isoniazid preventive therapy (IPT), 
early ART, and early ART plus IPT. Among over 2000 participants, 175 met the 30 month 
primary endpoint of mortality, AIDS defining illness, cancer, or invasive bacterial disease. The 
percentage of participants per group meeting this endpoint was 14% in the deferred ART, 8.8% 
in the deferred ART plus IPT, 7.4% in the early ART only, and 5.7% in the early ART plus IPT 
group.13 Another study from Africa randomized children and adults with CD4 counts <100 
cells/mm3 to ART or ART plus TPT, fluconazole, azithromycin, albendazole, and cotrimoxazole.25 
Among participants in the standard ART arm, 12.2% had died by 24 weeks compared to 8.9% in 
the enhanced prophylaxis arm (p=0.03).25 TB disease was reduced from 13% to 8.9% 
(p=0.007).26   
A.4. TPT has been embraced by international and national guidelines. In recognition of the role 
of TPT to reduce TB disease and mortality, the WHO recommended TPT for PWH in 1998.27 
These recommendations have been revised several times since.28 Multiple national HIV 
program guidelines and TB control programs also recommend TPT. Current South African 
Department of Health guidelines recommend TPT to all PWH (without assessment for latent TB 
infection) stating to “ensure linkage to TPT for all eligible PLHIV” and “initiate IPT at ART 
initiation for all eligible patients.”29.  

 
 
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A.5. Current delivery of TPT to PWH is anemic. Despite the evidence and guidelines supporting 
TPT, current delivery of TPT is anemic. Reports from South Africa (and preliminary data by 
members of this investigative team) have observed between 14% and 35% of eligible patients 
are prescribed TPT.2 Other countries in sub-Saharan Africa have similarly low initiation. A study 
of 102 clinical facilities and 16,433 PWH in Ethiopia reported 3,230 (19.6%) initiated TPT.3 In 
Kenya, a report by the national TB program reported only 3.6% of adult ART patients initiated 
TPT.4 In Nepal, 32% of eligible patients were prescribed TPT.30 In 2017, TPT initiation, as 
reported in the 2018 WHO Global TB Report ranged from 1 to 53% for high burden African 
countries.5 South Africa reports higher rates of TPT initiation compared to the rest of the 
continent, but progress has plateaued and current initiation levels are insufficient for impact.5,31 
Furthermore, our data suggest that the South African national reporting overestimates actual 
TPT initiation (see Preliminary Studies). 
A.6. Patient adherence is good when TPT is prescribed. In contrast to low levels of TPT initiation, 
a large proportion of patients who receive TPT take it. Among patients who receive TPT in 
LMICs, adherence ranges from 71-97%.30,32-35  
A.7. Limited (but real) risks with use of TPT. Increased drug resistance is a potential 
consequence of inappropriate use of any anti-microbial agent. In practice, isoniazid resistance 
has not increased in communities with higher TPT use and clinical trials of TPT have not 
identified an increase in drug resistant TB among participants diagnosed with TB while receiving 
TPT.36-38 Best evidence indicates that the risk of substantially increasing drug resistant TB is very 
low with use of TPT, even when patients with TB disease receive TPT prior to TB diagnosis. 
Notably, excessive efforts to exclude TB disease can be counterproductive. An intensive 
screening before TPT study from Botswana compared TB screening with chest X-ray to 
symptom-only based screening. The strategy using chest X-ray identified more TB cases, but 
also had 13% more deaths. These deaths were attributed to delays in TPT initiation and lower 
overall initiation of TPT.39  
Drug induced liver injury (DILI) is another important, but exaggerated, concern. The risk of fatal 
DILI from isoniazid TPT is estimated to be between 0.001% and 0.06%. This is similar to the 
range of DILI risk (fatal and non-fatal) from the commonly prescribed antibiotic amoxicillin-
clavulanate.40 Underlying liver disease, advanced age, and heavy alcohol consumption increase 
the risk of DILI. In a RCT of TPT in Botswana, there was no difference in side effects (including 
DILI) between study arms.39 In another RCT in South Africa, 2.9% of participants in the TPT arm 
experienced a side effect compared to 1.5% in the placebo arm; none of the side effects were 
severe and the proportion stopping active drug or placebo due to side effects was similar by 
study arm.41 In a cluster randomized trial in South Africa involving 24,221 participants, there 
were 17 (0.07%) cases of clinical DILI with only one fulfilling criteria for a severe adverse 
reaction.42 Importantly, discontinuation of TPT if causing symptomatic DILI generally leads to 
resolution.43 
Painful peripheral neuropathy is another potential complication of isoniazid-based TPT. 
Fortunately, it can be prevented with pyridoxine (vitamin B6) supplementation44 – as is 
recommended in South African and WHO guidelines. Notably, both untreated HIV and the ART 
agent stavudine pose higher risks for peripheral neuropathy than does isoniazid.45-47 Earlier 
initiation of ART among PWH, a change in regimens away from stavudine, and inclusion of 

 
 
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pyridoxine with isoniazid have all led to a reduction in peripheral neuropathy in global HIV 
programs. 
A.8.Current barriers to TPT delivery. Key factors leading to low TPT initiation are (1) lack of 
provider confidence in definitively ruling-out active TB, (2) concerns about increasing drug 
resistant TB, (3) understanding appropriate screening for TB disease, (4) concerns for DILI, (5) 
the complexity of prescribing guidelines, (6) misperceptions regarding which patients may 
benefit, (7) not understanding the benefit of TPT, (8) assumption that patients will not adhere 
to TPT, and (9) the increased work-load of TPT initiation.3,34,48-50 All of these factors contribute 
to the cognitive load of TPT initiation, some also add to the workload. Drug stock-outs in some 
settings have also posed a barrier to initiation.3  
A.9. Approaches that have been studied to improve TPT delivery. The majority of studies on TPT 
have focused on patient adherence to therapy.51 Two studies from South Africa sought to 
increase TPT initiation in public clinics. One study sought to integrate HIV and TB services using 
extra nurses as integration officers.52 The other sought to make screening for latent TB a 
routine part of HIV care (although latent TB testing is not currently required in South Africa).53 
Neither study achieved statistical significance in increasing TPT initiation. Single site studies 
from Papua New Guinea and Nigeria have reported increased TPT initiation through quality 
improvement approaches and job aids.8,9 Notably, similar job aids have been implemented in 
South Africa without resulting in reaching goal TPT initiation [Aurum Institute, personal 
communication]. An ongoing study in Uganda is testing a co-formulation of isoniazid and 
cotrimoxazole (a preventive medication for a variety of infections that is more widely 
prescribed than TPT) [SPIRIT Trial – clinicaltrials.gov]. Another ongoing study is evaluating nurse 
training and mentoring to increase TPT initiation.54  
A.10. TPT regimens. The standard TPT regimen is 6 to 12 months of isoniazid (isoniazid 
preventive therapy; IPT). Two new options for TPT have been developed: (1) three months of 
weekly rifapentine and isoniazid (3HP) or (2) one month of daily rifapentine and isoniazid (1HP). 
These two regimens are better tolerated, of shorter duration, and non-inferior to isoniazid only 
regimens.6,7 In recognition of potential advantages, the regimen of three months of weekly 
rifapentine and isoniazid was endorsed by the World Health Organization and the US PEPFAR 
program in 2019 and the 1HP regimen is expected to be added in the near future. We propose 
to follow the South African Department of Health TPT regimen that is in use in at the time of 
the study. Twelve months of daily isoniazid is the current recommendation for PWH in South 
Africa [DoH Circular, September 2018] but 3HP is expected to be rolled out country-wide in 
2020. Thus the flexibility of the proposed implementation strategy is a strength. Should it prove 
successful in one setting and with one regimen, the approach is highly feasible to adapt to 
other settings and other TPT regimens. 
A.11. HIV and TPT care system in South Africa 
South Africa has adopted a model of ART care with ART initiation and maintenance in primary 
care clinics and community health centers. Within these facilities, nurses are empowered to 
initiate ART and manage follow-up. In addition to ART, cotrimoxazole and isoniazid TPT are 
available and can be prescribed by primary care nurses providing HIV care. TB screening is 
based on asking the WHO four symptom screen (any of cough, fever, night sweats, or weight 
loss). Patients with a positive symptom screen are meant to receive further evaluation by 

 
 
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sending sputum to a government laboratory for microbiologic analysis using the Cepheid 
GeneXpert MTB/Rif nucleic acid amplification system. TB disease is usually managed separately 
from HIV, usually by nurses trained in TB management. Supply chains for ART, isoniazid, 
cotrimoxazole, and TB medications are reasonably robust, with stock-outs of medications the 
exception. Prescriptions are written or stamped into the patient’s paper chart by the 
prescribing nurse or doctor. At the time of prescribing, medications are dispensed either at an 
in-clinic pharmacy or by the provider in the consulting room. Subsequent refills (up to 6 months 
after original prescription) are filled either at the pharmacy, a “fast-lane” refill station, 
community distribution, or by a primary care nurse in a consulting room. 
A.12. Choice architecture and TPT delivery. Choice architecture is a behavioral economics 
approach that is used to improve decision making.12,55 Choice architecture involves deliberate 
consideration of how options are presented and what follows from each options, including 
what happens if no active decision is made (sometimes referred to as passive selection or the 
“default” setting). Choice architecture can reduce time and complexity required for decision 
making leading to a reduction in the cognitive load.56 Lower cognitive load can improve 
decisions; high cognitive load leads to poorer decisions.56,57  
Examples of choice architecture approaches to improve medical decision making include 
agreeing to deceased donor organ donation, increasing influenza vaccination, increasing 
appropriately targeting Cryptococcus screening, improved opioid prescribing, and increasing 
generic medication prescribing.12,58 In each example, the “default” was altered to enable an 
individual or provider to select the (usually) most appropriate choice with the least cognitive 
load. Notably, the alternative decision could be taken as well – allowing for the provider, in 
shared decision making with the patient, to take the action most appropriate for the individual 
patient. Making what should usually be the best or most appropriate option the default reduces 
cognitive load and normalizes the default option (making it okay to do it rather than it being 
exceptional).  
Currently TPT initiation requires an active process to select TPT and a passive (neglecting to 
consider TPT) process for not initiating. The current active process required for TPT initiation 
includes at least four steps: (1) consider TPT, (2) evaluate reasons for not initiating, this includes  
potential concerns for undiagnosed TB and the presence of liver disease, (3) weigh the risks and 
benefits of TPT, (4) consider patient adherence, and (5) write the TPT prescription. These steps 
require consideration (cognitive load) and time. Both cognitive load and time compete with 
other priorities of a complex clinical encounter. As a result, clinicians may “defer” consideration 
to the “next” visit or turn to rules of thumb to justify deferring or not initiating TPT. Given that 
the vast majority of ART patients in South Africa would benefit from TPT, the use of choice 
architecture making TPT the “default” could improve provider decision making and safely 
increase TPT initiation.  
1.2 Study objectives 
The overarching goals of this proposal are to test a low-cost and context appropriate approach 
to translating TPT policy into on-the-ground TPT delivery. We are proposing a cluster-
randomized trial (CRT) to measure the effectiveness of a choice architecture-based TPT 
initiation strategy versus usual prescribing (Figure 1). We anticipate a substantial increase in 

 
 
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TPT initiating, potentially increasing from approximately 35% to 60-80% of ART initiators. This 
can be achieved through choice architecture and a decrease in cognitive load. We will assess 
the effectiveness, implementation measures, and patient-level delivery and acceptability to 
providers. 
  
 
The primary objectives of this study are: 
1. To compare the proportion of patients newly starting ART also initiating TPT within 90 
days between the choice architecture and usual prescribing arms 
2. To characterize the processes of TPT implementation by study arm including: 
o Provider adoption 
o Fidelity 
o Provider acceptability 
o Intervention maintenance 
o Provider cognitive load of TPT prescribing 
o Clinic workflow integration 
3. To describe patient-level characteristics associated with initiating TPT and adhering to 
TPT 
 
The secondary objectives of this study are: 
1. The proportion of patients already on ART initiating TPT within 90 days of a re-
prescribing visit 
2. The proportion of eligible patients newly starting ART also initiating TPT within 90 days 
3. The proportion of eligible patients already on ART initiating TPT within 90 days of a re-
prescribing visit 
4. The proportion of patients who initiate TPT and discontinue TPT prior to completion 
 
1.3 Significance 
TB is the leading cause of death among people with HIV in South Africa and much of the world. 
TPT is a proven approach to reduce mortality. This study has the potential of identifying an 
approach to markedly increase TPT prescribing. 
 
2 METHODS 
2.1 Study design 
We are proposing a clinic-level cluster randomized trial of a strategy to increase the delivery of 
evidence-based care. Clinics will be randomized to the novel choice architecture strategy arm 
or usual prescribing arm with analysis based on the clinic-level proportion of TPT initiated. This 
study will further assess implementation outcomes, the underlying theory of change (the effect 
of choice architecture on cognitive load), provider experiences with the novel strategy, and 
patient experiences with TPT by study arm. 

 
 
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2.2 Study setting 
The proposed research will be conducted by PHRU in two districts:  the Kenneth Kaunda district 
in the North West Province of South Africa and Mangaung District in the Free State Province. 
Kenneth Kaunda district has a population of 742,000 59 and is served by 36 public-sector clinics 
(primary care clinics and community health centers) providing HIV care (ART, TPT, TB 
treatment). Mangaung District has a population of 747,431 and is served by 45 public clinics.  
Both districts have urban, peri-urban, and large rural areas. Both districts are also settings with 
high HIV and TB prevalence with which the team is very familiar, has a working relationship 
with the local Department of Health, and has completed prior research on TB and TPT delivery. 
2.2.1 Description of the geographical areas of study implementation 
The proposed study will be conducted in 36 public clinics that provide antiretroviral therapy 
(ART).  Clinics will be located in rural and peri-urban areas in Kenneth Kaunda especially around 
Matlosana and JB marks  and urban and rural areas of Mangaung, especially around 
Botshabelo, Bloemfontein and Thaba Nchu.(See clinics) 
 
Kenneth Kaunda District 
Mangaung District 
SUBDISTRICTS 
ClinicName 
SUBDISTRICTS 
ClinicName 
Matlosana 
Marcus Zenzile PHC  
Botshabelo 
Itumeleng (M) 
 
Matlosana 
Kanana PHC  
Botshabelo 
Dr Pedro (K) 
 
Matlosana 
Khuma PHC  
Botshabelo  
Daniel Ngatane (F) 
 
Matlosana 
Tigane CHC 
Botshabelo  
Maletsatsi Mabaso(B) 
 
Matlosana 
RB Nzima Satellite 
Botshabelo  
TS Mahloko ( C) 
 
Matlosana 
Stilfontein PHC  
Botshabelo 
Pule Sefatsa (U) 
 
Matlosana 
Delekile Khoza 
Thaba Nchu  
Mefane 
 
Matlosana 
Tsholofelo PHC  
Bloemfontein  
Opkoms 
 
Matlosana 
Empilisweni PHC  
Bloemfontein  
Thusong 
 
Matlosana 
Botshabelo CHC 
Botshabelo 
Industrial 
 
JB Marks 
Top City Clinic 
Botshabelo 
Potlako Motlohi (L) 
 
Matlosana 
Majara Sephapo PHC 
Bloemfontein  
Mmabana 
 
JB Marks 
Steve Tshwete Clinic 
Botshabelo 
Winnie Mandela (J) 
 
JB Marks 
Lesego Clinic 
Botshabelo 
Herry Gwala(N) 
 
Matlosana 
Gateway NM Pretorius PHC 
Thaba Nchu  
Gaongalelwe 
 
Matlosana 
Orkney PHC  
Botshabelo  
Jazzman Mokhothu (E) 
 
Matlosana 
Alabama Clinic 
Botshabelo  
Molefi Tau (H) 
 
JB Marks 
Boiki Thlapi 
Thaba Nchu  
Thaba Nchu 
 
 
 

 
 
Prevent TB/Fedisa TB Protocol v4.0 13 May 2024 
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2.2.2 Rationale for selecting geographical areas of study implementation 
We selected these two areas based on a long-standing working relationship between the team 
and the DoH in these locations and established PHRU research infrastructure in both locations.   
2.3 Study Population 
The study is a cluster-randomized trial with clinics as units of randomization and the primary 
outcome measured at the clinic level. The strategy arm seeks to improve delivery of guideline-
mandated services to the clinic population.  Thus the strategy clinics may have greater 
prescribing of TPT and anticipated improved health outcomes, but clinic patients will not 
perceive any differences in care nor will any individual randomization or patient-level consent 
occur for the primary outcome of the proportion of patients who receive TPT. 
2.3.1 Inclusion and exclusion criteria 
The unit of analysis and unit of randomization is the clinic. Due to the clinic-level nature of the 
implementation strategies, all people living with HIV receiving care at a clinic will be exposed to 
the standard implementation or choice architecture default TPT implementation. All adult (≥18 
years old) patients initiating ART or already on ART and coming for ART re-prescribing will be 
used as denominators for (1) the proportion of ART initiators receiving TPT at the clinic and (2) 
the proportion of current ART patients receiving TPT at the time of ART re-prescribing.  
 
 
2.4 Sampling scheme 
2.4.1 Clinic selection 
Baseline data collection will be completed for a stratified randomization. Key clinic 
characteristics used for stratification will be measured during a pre-study initiation baseline 
assessment in the study clinics prior to randomization and will include clinic-level characteristics 
of patient volume, staffing, and monthly ART initiation.   
2.4.2 Clinic level baseline data abstraction 
Prior to randomization, data on TPT prescribing, ART initiation, ART maintenance, and clinic 
staffing will be obtained for the prior 12 months. These data will be abstracted as monthly 
aggregates from electronic and paper clinic reporting systems (tier.net and clinic registers).  No 
patient level data or identifiers will be abstracted. 
2.4.3 Randomization 
We will conduct a covariate-constrained randomization to balance the allocation of clinics 
between the two study arms, ensuring validity of the randomization process (Moulton L.H. 
Covariate-based constrained randomization of group-randomized trials. Clinical Trials. 2004; 
1(3):297-305). Implementation will be staggered over time with 4 clinics (two from each of the 
arms) entering the study phase every 1-2 months which will provide contemporaneous 
comparison data (see study implementation timeline). If only a couple of covariates and entry 

 
 
Prevent TB/Fedisa TB Protocol v4.0 13 May 2024 
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month /quarter are considered for balance in randomization (i.e. study site and clinic volume of 
ART patients), a computer-generated stratified randomization sequence based on these 
covariates will be generated by the study statistician. If multiple covariates are considered for 
balance, randomization sequences that satisfy the balance and validity criteria across all 
covariates will be generated and one of those will be randomly selected.  
 
 

 
Study implementation timeline 
 
Y1 
Y2Q1 
Y2Q2 
Y2Q3 
Y2Q4 
Y3Q1 
Y3Q2 
Y3Q3 
Y3Q4 
Y4Q1 
Y4Q2 
Y4Q3 
Y4Q4 
Y5 
Protocol development 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
DSMB meeting 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study initiation 
activities 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinic 1-2 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Clinic 3-4 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Clinic 5-6 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Clinic 7-8 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Clinic 9-10  
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Clinic 11-12 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Clinic 13-14 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Clinic 15-16 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Clinic 17-18 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinic 19-20 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinic 21-22 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinic 23-24 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinic 25-26 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinic 27-28 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinic 29-30 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Clinic 31-32 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Clinic 33-34 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Clinic 35-36 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Data analysis and 
write-up 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 

 
Sample Size Justification. The primary outcome is the proportion of adult patients newly 
initiating ART who are also initiated on TPT. We hypothesize that 35% of eligible patients in the 
standard strategy approach will receive TPT as found in the TEKO study completed by Dr Golub 
and Martinson53 while the proposed opt-out intervention will increase this proportion to 50-
60% of eligible patients. Historical data indicate that the annual number of eligible patients (i.e. 
initiating ART) will be 200 per clinic.53 Table 1 illustrates different scenarios of the coefficient of 
variation (CV) which was found to be between 0.4 and 0.5 in prior work that involved only 14 
clinics by the study team in one of the proposed study districts. For this trial, a larger number of 
clinics and stratification by important baseline covariates is expected to reduce the CV. A total 
of 36 clinics (18 per arm) is feasible within the available resources and it will enable us to detect 
a meaningful difference of 20 percentage points with 80% power at a 5% level of significance. 
We will stratify the randomization by the clinics’ annual visits and other available covariates 
(TPT prescribing, ART initiation, ART maintenance, and clinic staffing for the prior 12 months) in 
order to control the between-clinic coefficient of variation and to improve the efficiency of the 
estimates. 
 
 
Table 1. Number of clinics required for 80% power to detect a difference in proportion 
initiating ART and TPT  between the two study arms  
Proportion initiating TPT 
in standard approach  
Proportion initiating TPT 
in opt-out arm 
Coefficient of 
variation 
Required Number 
of clusters per 
arm  
35 
50 
0.3 
14 
35 
55 
0.3 
9 
35 
60 
0.3 
7 
35 
50 
0.4 
23 
35 
55 
0.4 
15 
35 
60 
0.4 
11 
35 
50 
0.5 
35 
35 
55 
0.5 
23 
35 
60 
0.5 
17 
2.4.4 
Choice architecture arm 
In the choice architecture implementation strategy, all opt-out clinic providers and pharmacists 
will be trained on the approach. The fundamental tenant of this approach is that TPT will be 
prescribed with any ART initiation and any ART re-prescribing for 3-12 months of TPT (adherent 
to current guidelines) if TPT has not been previously prescribed or if there is uncertainty 
regarding previous prescribing. This will be facilitated by co-prescribing ART and TPT. That is 
when ART is being prescribed, TPT is meant to be prescribed at the same time of the clinic visit.  

 
 
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The simultaneous prescribing will be facilitated through the introduction of an ink stamp or pre-
printed sticker to use for quick entry of the ART prescription along with TPT and cotrimoxazole 
(Figure). This stamp/sticker will be available in the consulting rooms and will be pre-
stamped/applied by file clerks to files when retrieved. The stamp/sticker for ART prescription, 
the prescription for TPT and for cotrimoxazole will be “automatically” included. Active canceling 
of these prescriptions (and indicating the reasons) will be needed to not have TPT dispensed.  
The stamp/sticker design and content will be finalized in consultation with the clinicians and the 
PHC nurses working in those districts to ensure that it is aligned with the latest guidelines and 
stationery being utilized in the health facilities. If necessary, the design and size might vary 
between the two provinces. 
 
Figure 1. TPT choice architecture aid 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.5 Standard of care arm 
The standard TPT implementation is for a clinician to screen for TB and to consider TPT for 
those who do not have “presumptive TB”. Clinicians in the study district (and most districts in 
South Africa) have received training and job aids to assist in appropriate application of the TPT 
initiation algorithm. Prescribing for TPT and ART is done by writing, by hand, the prescription in 
the patient’s paper file. As part of this study, all study clinic providers will have access to 
standard Department of Health printed material and clinical training. 
2.5 Study outcomes 
2.5.1 CRT primary and secondary effectiveness outcomes 
The primary outcome is the proportion of ART initiators also initiating TPT. This includes 
patients who are ART naïve and those re-initiating ART after a lapse in therapy. Secondary 
outcomes are the proportion of already on-ART patients initiated on TPT, the proportion of 

 
 
Prevent TB/Fedisa TB Protocol v4.0 13 May 2024 
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eligible patients initiated on TPT (with ART initiators and re-prescribing reported separately), 
and the proportion of patients initiated on TPT with a subsequent discontinuation prior to 
completing the course of therapy. Adjustment for sex and age strata, as a clinic proportion, will 
be conducted as a secondary analysis. TPT initiation will be ascertained from all available data 
sources in the clinics, including but not limited to paper files, clinic registers, pharmacy records, 
DHIS2, and the electronic HIV health information reporting system (tier.net). Similarly the total 
number of ART initiations and ART re-prescription, and age and sex distribution will be 
ascertained from the same data sources. Analytic approaches for Aim 1 are described in Table 
2.  A detailed statistical analysis approach will be contained in the study Statistical Analysis Plan. 
 
 
Table 2. Aim 1 outcomes & analysis approach 
 
 
Outcomes 
Data source 
Statistical Test 
Primary 
Proportion of ART 
initiators initiated on TPT 
Paper files, clinic 
registers, pharmacy 
records, DHIS2, 
Tier.Net 
The primary analysis will apply 
the unpaired t-test of the 
cluster-level proportions,  
keeping with the randomized 
nature of the design. Residual 
confounding by stratification 
variables used in the 
randomization, entry month 
/quarter and other clinic 
characteristics will be adjusted 
for using a log-binomal 
regression with robust variance 
estimation to account for 
clustering by clinic. 60 
Secondary 
Proportion of already on 
ART patients initiated on 
TPT  
Paper files, clinic 
registers, pharmacy 
records, DHIS2, 
Tier.Net 
Secondary 
Proportion of TPT 
“eligible” patients 
initiated on TPT (ART 
initiators and ART re-
prescribing, separately) 
Paper files, clinic 
registers, pharmacy 
records, DHIS2, 
Tier.Net 
Secondary 
Proportion of patients 
started on TPT with 
subsequent 
discontinuation 
Paper files, clinic 
registers, pharmacy 
records, DHIS2, 
Tier.Net to identify 
noted stopping for 
possible adverse effect 
2.5.2 Assessment of clinic implementation of choice architecture 
Implementation measures: Adoption will be assessed as the proportion of visits in which the 
choice architecture strategy was used (as measured by use of the pre-printed/stamped 
prescription), regardless of the clinician’s initiation decision. Fidelity will be assessed through 
the proportion of visits for which the clinician opts not to prescribe and has indicated a reason 
for not initiating. Maintenance will be assessed by evaluating the adoption of the choice 
architecture approach by month from start to end of the study implementation in each choice 
architecture strategy clinic. The twelve month implementation period is sufficient to observe 
desensitization toward a strategy among providers and thus assess maintanence.61 A decline in 
use of the choice architecture strategy along with a decline in TPT initiation will suggest a 
potential problem with maintaining the strategy over time.  

 
 
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Population: All study clinics and all ART prescribing encounters at these clinics will be used to 
assess the implementation measures. 
Analysis: We will use descriptive statistics to characterize each of the implementation 
outcomes. Adjusted chi-squared statistics (Reed 2004;  Jeph Herrin, 2002. "CLTEST: Stata 
modules for performing cluster-adjusted chi-square and t-tests," Statistical Software 
Components S424901, Boston College Department of Economics, revised 03 Feb 2012.) that 
account for clinic clustering  will be used to compare proportions by and by population of 
interest. 
Acceptability evaluation: Acceptability will be assessed among providers in the choice 
architecture strategy arm using a researcher administered and self-completed (mixed) 
acceptability questionnaire. The questionnaire will be based on the theoretical framework of 
acceptability developed by Sekhon et al.62 This framework has seven core constructs: attitude 
(how an individual feels about the strategy), burden (effort required for the strategy), ethics 
(concurrence with value system), coherence (how well the strategy is understood), opportunity 
costs, perceived effectiveness, and self-efficacy (confidence in using the strategy). The 
acceptability scores will be interpreted in the context of the study efficacy results with a general 
threshold of the majority of participants scoring the constructs as acceptable (responses on 
Likert scale). Findings from the acceptability questionnaire will be further explored through in-
depth interviews in a sequential explanatory mixed methods approach (described as follows). 
Population: We will invite all HIV care providers at the study clinics, who have spent 3 or more 
months at the study clinic, to complete the acceptability assessment. 
Analysis: Acceptability will be scored as a mean (if normally distributed, otherwise median) per 
domain with 95% confidence intervals (if normally distributed, otherwise inter-quartile range). 
Hypothesis testing will be used to compare the score to a neutral (3 on a 5-point Likert scale) 
response. Scores will be interpreted with a general threshold for acceptability if mean or 
median score favors acceptability.  
Cognitive Load Assessment.  
We will use instruments self-completed by providers with support from the study staff to assess 
cognitive load. Cognitive load theory was developed in educational psychology to explain 
learning of complex tasks63 and has been extended to understand decision making in medical 
care. Several instruments have been developed for measuring cognitive load. The Paas scale,64 
is among the earliest and most heavily used, including in healthcare applications.  
Population for cognitive load assessment. All health care workers who prescribe ART at each of 
the study facilities (3-4 providers per facility) will be invited to complete these instruments 
through self-administration with support from the study staff (to reduce social desirability bias). 
We will ask health care workers to complete these instruments during breaks during an ART 
prescribing day. We anticipate approximately three or four healthcare workers per facility, for a 
minimum sample size of approximately 60-70 providers per arm .  We follow a conservative 
approach and assume that 50% of the providers in the standard arm will express moderate or 
very high cognitive load in a typical assessment question. If we assume a design effect of 1.5, 
the effective sample size ~80  overall would enable us to estimate the overall prevalence with 
an 11 point margin of error (95% CI width of 22); and it would provide 82% power to detect a 

 
 
Prevent TB/Fedisa TB Protocol v4.0 13 May 2024 
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reduction of 20 percentage points in the more strategy arm (n=40 per arm). A higher design 
effect of 2 would provide 69% power to detect this difference. 
Procedures for measuring cognitive load. We propose to include three separate brief scales of 
cognitive load and task load: the Paas scale, the Klepsch scale, and the NASA Task Load Index. 
We have selected these instruments because they each measure slightly different aspects of 
cognitive load and all three have been used to assess decision making or task performance in 
medical settings.63-66 The Paas scale uses a Likert scale with a single question, the Klepsch scale 
uses 7 items, each with a 5-point Likert scale; two of the items map to intrinsic cognitive load, 
two to extraneous cognitive load, and three to germane cognitive load. The NASA Task Load 
Index (TLX) has six questions each rated with a scale and is focused on task complexity and 
difficulty in completing (Appendix B).65 We will calculate a composite score for each instrument 
to have three cognitive load scores. 
Cognitive load analysis: We will assess each scale independently and then assess inter-scale 
consistency across scales (Cronbach’s alpha). The analysis will be in two parts. For each 
assessment question / subscale rating, we will compare the proportions of participants who 
report moderate to high load between the two study arms using log-binomial regression with 
robust variance to account for within-clinic clustering, and the resultant p-values will be 
adjusted for multiple testing to control the Type-1 error rates due multiple testing. We will then 
use exploratory factor analysis to generate cognitive load score for each scale, and this load 
score will be  compared  between the two study arms using either the Kruskal-Wallis test, a 
non-parametric method, or t-test if the results are normally distributed.67  
Workflow integration and congruence assessment: We will conduct semi-structured interviews 
among providers. We will use an interview guide developed based on the constructs of 
Normalization Process Theory.68 These are interactional workability, relational integration, skill-
set workability, and contextual integration and acceptability constructs. The interview guide will 
be further informed by findings from the process measures, acceptability questionnaire, and 
cognitive load measures. Interviews will be conducted in a private setting in the language of 
choice of the provider (generally English) and digitally audio-recorded. Audio-recordings will be 
transcribed and translated (as needed). 
Population: We will seek to recruit 15-20 providers from each of the choice architecture and 
usual prescribing arms (total 30-40). We will seek to maximize diversity and representativeness 
among levels of providers (primary care nurses and doctors) through purposively selecting a 
range of ages, men and women, and duration of practice. A randomization scheme stratified by 
the above characteristics will be generated among all prescribers present at the 9-18 month of 
study implementation time, who have been providing ART care for at least 2 months at the 
study clinic. A random selection of providers, by random number generation, will then be 
invited to participate in the structured interviews. 
Analysis: Transcripts of audio-recordings will be uploaded into MaxQDA software for the 
purposes of coding and analysis. Our approach to the qualitative data will involve thematic 
analysis and employ both inductive and deductive coding techniques.69,70 We will first develop 
an a priori code book that reflects key analytic concepts of the Normalization Process Theory. 
During the process of reading and coding of transcripts using this initial coding scheme, 
additional codes may be added to document emerging themes of interest.  

 
 
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Analysis will be led by Owczarzak and will be assisted by the experienced qualitative PHRU 
team. Qualitative analysis will proceed by first exploring broad patterns and experiences of 
clinicians, and then assessing possible similarities and differences in experiences between 
providers (including different ages, sex, and level of training.).  
2.5.3 Patient initiation and completion of TPT 
Aim: to evaluate factors associated with TPT initiation and completion. These factors will 
include sex, advanced HIV (CD4 <100 cells/mm3) compared to less advanced HIV, younger (aged 
<35 years old) compared to older patients; ART initiation and regimen; economic factors (e.g. 
employment) and clinical factors (e.g.  close contact TB history). A subset of the enrolled 
participants will be invited for in-depth interviews to assess experience with TPT .  
Setting & Population. ART initiators and established ART patients will be 
a) Recruited by study staff using a convenience sampling method inboth choice 
architecture and usual prescribing clinics. Study staff will inform eligible patients about 
the study as they are waiting for their consultation. 
b) Clinic staff will refer individuals for further information from the study team and 
enrollment.  
Potential partcipants identified through this process will be provided study information and 
undergo the consent process in a private area in the clinic. The consent process and the 
subsequent participant interview will be conducted in a private area to assure confidentiality. 
TB and HIV will not appear in any prominent places on any of the documents and all study 
forms (aside from the informed consent document) will be identified by study identification 
number. 
Between 3 and 12 months from the time a patient could have initiated and may still be 
receiving TPT (3-9 months after ART initiation or 3-12 months after a re-prescribing visit) 
patients will be invited to participate. Consent will be sought for both clinical record abstraction 
and a structured interview.  
We propose to enroll an equal number (n=20) of participants per clinic in order to reduce 
between cluster size variability, for a total of approximately 720. Assuming a null prevalence of 
35% to 50% initiation for a given group defined by a category within any of the factors being 
evaluated (e.g. males vs females), and moderate to high design effects due to similarity in the 
intiation rates within clinics, this sample size will provide more than 80% power to detect a 20 
percentage point difference in the outcome (Table 3). We anticipate >3,600 ART initiators at 
clinics in each study arm during the duration of study implementation making the proposed 
sample size highly feasible to recruit. 
Table 3. Power calculation for patient initiation and completion 
Null prevalence of 
TPT initiation 
Design effect 
Detectable difference Power 
0.35 
2 
0.15 
0.82 
0.35 
2 
0.2 
0.97 

 
 
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0.35 
3 
0.15 
0.65 
0.35 
3 
0.2 
0.89 
0.50 
2 
0.15 
0.82 
0.50 
2 
0.2 
0.97 
0.50 
3 
0.15 
0.65 
0.50 
3 
0.2 
0.89 
 
Procedures 
Clinical assessment: Clinical records (paper and electronic records) for participants in this aim 
will be abstracted for key clinical characteristics including: ART initiation and regimen, CD4 
count results, HIV viral load results, hepatitis B test results, COVID-19 test results, clinical 
documentation of prior TB, prior TPT, alcohol use, liver disease, TPT initiation and medication 
pickups, TB screening, TB diagnoses after TPT initiation, medication discontinuations with 
reason when noted (e.g. suspected side effects), and documented potential side effects. This 
chart abstraction will occur as a single cross-sectional assessment.  
Structured interview: The structured quantitative patient interview will include closed-ended 
questions regarding demographics, food security, income, employment, prior TB history, close 
contact TB history, prior ART history, prior TPT, COVID-19 history, current smoking status and 
smoking history, current alcohol use, current known liver disease, awareness of TPT, receipt of 
TPT, adherence to TPT if prescribed, and experience with TPT if prescribed (e.g. suspected side 
effects).  
In depth interview: A subset of 30-45 patients among the 720 recruited for TPT assessment will 
be invited for participation in in depth interviews to explore understanding and experience with 
TPT. 
Analysis. Quantitative data from the clinical abstraction and structured interviews will be 
combined for analysis. Descriptive statistics will be used to characterize the population and 
attributes of patients in each of three outcome categories: participants who initiated and 
completed TPT, those who were initiated on but did not complete TPT, and those not initiated 
on TPT. Log-binomial regression with robust standard errors to adjust for clustering will be used 
to assess differences in TPT receipt by each factor, adjusting for the main effect of study arm. 
We will also conduct a similar analysis for factors associated with completing TPT. The factors 
to be evaluated will include advanced HIV (CD4 <100 cells/mm3) compared to less advanced 
HIV, sex, and younger (aged <35 years old) compared to older patients. We will evaluate 
whether study arm acts as a mediator (rather than a confounder) between these factors and 
initiation/completion of TPT using simple generalized structural equation models. Descriptive 
statistics will be used to characterize any reported side effects or other challenges with TPT. 
Mixed effects logistic or log-binomial regression (depending on prevalence of side effects) will 
be used to compare self-reported and clinical record documented side effects by study arm and 
other key characteristics, including age group and sex. 
 

 
 
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2.5.4 TB Patient Care 
Aim: to understand which services patients are offered during their TB treatment in both usual 
prescribing and choice architecture clinics.  
Setting & Population. In order to ensure accuracy of the information collected, a study team 
member will request to speak with a provider that has been providing TB care to patients for 
>=2 months at the study clinic. One or more TB healthcare providers will be selected to review 
the clinic TB stationary with study staff.  
Procedures 
Chart Review: People with TB are often co-afflicted with other health and socio-ecominc 
conditions that can potentially be screened for and treated/addressed during TB treatment. 
These co-morbidities include tobacco use, alcohol abuse, mental health issues, pre-diabetes or 
diabetes, hypertension, food insecurity, and lung impairment. We plan to review current 
screening and care practices at the study clinics in the North West province to determine what 
services are currently available for people with TB. We will review current forms used at TB 
screening and diagnosis with one or more TB care providers, ask what services are provided in 
the clinic, and which services are referred out of the clinic. The proposed activity is expected to 
take less than 15 minutes in each clinic. No identifying information will be collected from the 
health care providers, no preferences or opinions will be collected from the providers, and data 
will be entered into a de-identified REDCap database.  
3 Analysis: Descriptive  statistics will be generated to describe availability and 
utilization of services for TB patients.Data Management 
Data will be collected to review study associated outcomes in order to evaluate the extent to 
which the case management goals and objectives are being met. To achieve this, data will be 
collected in the pre- and intervention study periods. In addition to this, data will also be 
collected to assess actual programme performance against planned activities. 
3.1 Data collection tools 
Table 4. List of data collection tools and intended use 
Name of tool 
Purpose 
Schedule 
Study arm 
Clinic baseline ART 
and TPT 
characteristics & 
clinic characteristics 
(CL001) 
To describe record key clinic characteristics and 
ART initiation, ART maintenance, and TPT 
prescribing over the preceding 12 months 
Pre-
randomization 
Both 
Clinic baseline ART 
and TPT 
characteristics & 
clinic characteristics 
(CL002) 
To describe record key clinic characteristics and 
ART initiation, ART maintenance, and TPT 
prescribing over the current 12 months of study 
Post 
Randomization  
Both 
TPT001 
To abstract ART prescribing (new patients), ART 
re-prescribing (current patients), TPT prescribing, 
Monthly 
Both 

 
 
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and adoption of TPT assessment (choice 
architecture clinics only) 
Acceptability to 
health care workers 
(F002) 
Quantitative interview of acceptability domains 
9-18 months 
after study 
initiation 
Choice 
Architecture 
clinics only 
Intervention 
only 
Cognitive load for 
health care workers 
(F003) 
Measures of cognitive load to assess the overall 
cognitive load of clinical decision making and the 
specific burden of TPT prescribing 
9-18 months 
after study 
initiation 
Both 
Patient TPT use 
(PT001) 
Baseline demographic and health data collected 
from subset of patients 
3-12 months 
after TPT 
initiation (or 
potential TPT 
initiation) 
Subset of 720 
participants 
drawn from 
both arms 
Patient TPT clinical 
record review 
(PT002) 
Clinical data collected related to time of TPT 
initiation and 12 month follow-up 
12 months 
after TPT 
initiation (or 
potential TPT 
initiation) 
Subset of 720 
participants 
drawn from 
both arms 
Health care worker 
interview guide 
(IG001) 
Interview guide for assessing workflow 
integration of choice architecture TPT 
9-18 months 
after study 
initiation 
Both 
Patient interview 
guide (IG002) 
Interview guide for patient-level factors related 
to TPT. 
3-12 months 
after TPT 
initiation (or 
potential TPT 
initiation) 
Both 
TB Patient Care 
(PC001) 
To describe the services offered to patients 
during their TB treatment 
1-12 months 
after study 
initiation 
Both 
 
 
3.2 Database 
3.2.1  Structure of the database 
This study will rely on two databases within the secure web-based REDCapTM (Research 
Electronic Data Capture) system.  One will be used to capture participant-level demographic 
and clinical data obtained from clinical record abstraction and structured interviews 
(participant database).  The other database will be a clinic-level database used for collection of 
monthly data points (clinic database).   The Redcap database provides an intuitive interface for 
validated data entry; audit trails for tracking data manipulation and export procedures; 
automated export procedures for seamless data downloads to common statistical packages; 
and procedures for importing data from external sourcesWe will develop a separate database 

 
 
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form within REDCap for each paper case report form (CRF).  All fields will have appropriate 
range-checks for validation during data-entry.  Field numbers and names in the database will 
correspond to numbers and names on the CRF.  Trained data capturers or research assistants 
will either directly enter data into REDCap using tablets or will manually input all data into the 
electronic database from the paper CRFs.  
Data entry validation and automatic range checks will be incorporated in most data fields to 
reduce data entry errors.  In addition, a data monitor will compare approximately 10% of CRFs 
with data within the database.  This will help to identify systematic errors.  Such problems may 
lead to a review of a larger proportion of CRFs.   In addition, bi-weekly electronic checks for 
inconsistencies within and across forms will be performed followed by CRF review of any data 
queries that are generated.  
3.2.2 Database access 
Access to the database (data entry, reporting, and extraction) is controlled by the Data 
Manager, Study Manager, and the REDCap Database Administrator. Study personnel requiring 
access to the database must complete required documentation and training prior to receiving 
the necessary username and password. 
3.2.3 Locking of final database 
The final study database is locked to changes after the clean file form has been signed. Final 
storage of the database is with the production folder structure together with all the Metadata, 
source data and the user written programs and the version of the system used to produce the 
database. The folder is given a special icon to show it is locked and the available choices are 
restricted to reading the data. 
3.2.4 Data security 
All paper study records (e.g. consent forms, screening logs) will be kept in a secure location 
accessible only to authorized study staff, investigators, and monitors.  All CRFs will be identified 
with study ID numbers and will not contain personal identifiers.  
3.2.5 Study limitations 
The proposed implementation research has the following limitations: 
- 
Participant self-report regarding lapses in medications may introduce bias as participants 
may favour the most socially acceptable responses. Verification of self-reported adherence 
using clinic records will be conducted, where possible, for all participants.  
- 
Observation of providers in the intervention clinics may result in modified or improved TPT 
prescribing because of the fact that they are being studied 
- 
Patient loss to follow-up may hinder the study team’s ability to assess the outcomes of TPT 
adherence and TPT discontinuation. 
- 
The study team will be relying on routine clinical records to determine patient eligibility for 
TPT and the ability of the team to determine TPT eligibility may be hampered by incomplete 
documentation of patient eligibility. This may be a larger issue in the standard of care arm. 
 

 
 
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4 Appropriate care in response to study-specific findings 
Aggregate data will be collected for the primary CRT outcomes.  No specific patient level care 
will be able to be guided from these data.  Clinical data will be collected among a subset of 720 
individually enrolled participants.  However, these clinical data will be collected retrospectively. 
As a result, no specific response to care will be possible. Any increase in reported side effects in 
the intervention arm will be reported to the DSMB for review and guidance on course of action. 
 
5 Protection of human participants 
5.1 Regulatory approvals 
This study will be conducted according to Good Clinical Practice (GCP) guidelines and completed 
in compliance with international and local human subject research guidelines. Approvals will be 
sought from University of the Witwatersrand Human Research Ethics Committee, North West 
and Free State Provinces, and the Johns Hopkins University IRB. 
 
5.2 Risks and benefits 
- 
The primary goal of this study is to improve appropriate prescribing of TPT. The risks overall 
are no greater than risks from normal medical care.  
- 
Among patient participants recruited for additional evaluation there is a risk of inadvertent 
disclosure of HIV status. This risk will be addressed through training of study staff and 
secure storage of all study documents. 
- 
Among health care workers recruited for in depth interviews and quantitative surveys there 
is a risk of inadvertent release of comments about care proficiency.  All documents and data 
will be confidential and securely stored. No individual level results will be provided to other 
health care workers, clinic management, or other Department of Health personnel.  
 
1. No excessive inducements for participation. 
Participants will not receive specific remuneration for overall study participation. Any patient 
travel will be compensated for in depth interviews or other specific data collection activities at 
a value of R150. 
 
2. The information is presented in language that is understandable to the subject 
population. 
The Participant Information Sheet (PIS) and other study related communication is at the 
participant level. Additionally, the PIS will be translated into the appropriate common local 
languages spoken in the North West and Free State provinces. 
Written informed consent will be obtained from eligible patient participants and from health 
worker participants at times convenient to them. The consent process will be done in a private 
area to ensure confidentiality. Informed written consent, using Ethics Committee/IRB-approved 
consent forms, will be obtained by trained study personnel prior to performing any study-
specific procedures. Informed consent is a process that will be initiated prior to the individual’s 
agreeing to participate in the study and will continue throughout the individual’s study 

 
 
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participation. Potential participants will receive information about risks and possible benefits of 
study participation, study objectives and procedures. Informed consent requires the legally 
effective signature or mark of the subject. A copy of the signed and dated informed consent 
document will be offered to each participant for his or her records.  The rights and welfare of 
the subjects will be protected by emphasizing to subjects that the treatment by clinicians will 
not be adversely affected if they decline to participate in this study, and that they may 
withdraw consent at any time. The investigator will retain a copy of the signed consent forms, 
which may be inspected at the monitor’s/auditor’s request.  The investigator will promptly 
report to the Ethics Committee/IRB of all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, and will not make changes in the research 
without Ethics Committee/IRB approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 
The informed consent process will include a verbal review of the study, provision on participant 
information sheets in relevant languages, review of the information sheets, and answering any 
questions. Participants unable to read or write will be asked to make a mark or thumbprint in 
the presence of a witness (verbal consent will not be obtained).  Only written informed consent 
will allow for study participation. 
 
3. Health care worker participation 
Health service staff involved in TPT prescribing will be recruited for participation.  Selected staff 
members will be invited by a study team member to participate.  Study information will be 
provided to the potential staff participant. Staff willing to participate will be asked to sign a 
written informed consent document in duplicate.  One copy will be provided to the staff 
member and the other will be retained in study files.  
The consent process and decision regarding participation will remain confidential from clinic 
officials, the study PI, and study co-investigators.  Interviews among staff participants will be 
scheduled to take place in a private setting at a later time and date. 
 
5.3 Clinical trials registration 
The study will be registered with clinicaltrials.gov.  Key study information and results will have 
open-access availability on the clinicaltrials.gov website.  This is in accord with funder (NIH) 
regulations. 
5.4 Confidentiality 
All study records will be managed in a secure and confidential fashion. All records will be stored  
in research office space in locked filing cabinets and access to the records will be restricted to 
specified study team members. Case report forms and case management documents will be 
identified using the participant’s study number only, with locator information stored 
separately.   

 
 
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5.5 Data safety and monitoring 
A data safety and monitoring board will be established to review the protocol and monitoring 
plan prior to commencement of enrollment into the CRT and meet virtually prior to 
commencing enrollment and then every 6 months to review CRT progress, enrollment and 
outcomes data, and any potential adverse outcomes. The meetings will review safety to suggest 
procedural changes and study modifications. The DSMB will include 3-5 members including 
individuals with experience with HIV care, clinical outcomes research, clinical trials, and good 
clinical practice. 
 
6 Project Governance and Management 
6.1 Research team 
- Dr. Christopher Hoffmann, MD, MPH, MSc is a clinician scientist, Associate Professor at 
Johns Hopkins University. Dr. Hoffmann will provide overall leadership for study 
implementation. 
- Dr Limakatso Lebina MBChB, MPH is a clinician scientist and Director at the Perinatal HIV 
Research Unit. Dr Lebina is the South African PI and will oversee the implementation and 
operational aspects of the study.    
- Dr Neil Martinson MBBCh, MPH is a clinician scientist and Chief Executive Officer of the 
Perinatal HIV Research Unit. Dr Martinson is the South African Co-Investigator and will 
provide oversight to the South African team. 
 
The study team (PI, South African PI, and co-Is) will meet biweekly to review study progress.  
The team will meet weekly to discuss operational aspects of the study implementation. Dr 
Owczarzak will meet as needed for qualitative analysis components. The PI will make 3 – 4 visits 
annually to study sites. 
 
 
 
Figure 2: Project Management Structure 
Co-Is 
Golub 
Chaisson 
Owczarzak 
Churchyard 
Shearer 
 
Co-Investigator 
(Martinson) 
Research Field Team / 
Data management 
Principal Investigator 
(Hoffmann) 
DSMB Oversight 
Site – PI (Lebina) 
  
JHU study staff 
Nonyane (statistician) 
 Steiner 
(researchcoordinator) 

 
 
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6.2 Publication policy  
The research findings will be presented first to national stakeholders, and disseminated to 
stakeholders and participants in each province by means of local meetings. The results will be 
written up as one or more articles for submission to a suitable scientific journal.  
6.3 Performance monitoring 
The principal investigator will complete a monthly progress report that will facilitate monitoring 
of study progress and keeping the funders informed. These reports will capture vital 
information, such as IRB timelines, status of protocol development, enrolment figures, and any 
issues/delays that the PI may be experiencing. 
 
7 Participant reimbursement 
Participants will not receive payment for participation in the study.  Participants will receive 
reimbursements for time and or travel for in-depth interviews and other data collection 
requiring travel. 
 
8 Funding 
Funding for this study is provided by the National Institute of Mental Health, USA, Grant 
Number: 1R01AI150432. 
 
 

 
 
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