Innovative Contact Tracing Strategies for Detecting TB in Mobile Rural and Urban South African Populations
Phase: NA
Conditions: Tuberculosis, Hiv
Sponsor: Johns Hopkins Bloomberg School of Public Health

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INNOVATIVE CONTACT TRACING STRATEGIES FOR DETECTING TB IN MOBILE 
RURAL AND URBAN SOUTH AFRICAN POPULATIONS 
Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
DMID Funding Mechanism: 
R01 AI147681 
Industrial Support Provided by: 
N/A 
NCT04520113
Principal Investigator: 
David W. Dowdy 
DMID Clinical Project Manager 
 Karen Lacourciere 
Draft or Version Number: 
5.0 
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Statement of Compliance 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
• 
ICH GCP E6 
• 
Completion of Human Subjects Protection Training 
• 
NIH Clinical Terms of Award 
Refer to:  http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46. 
http://www.fda.gov/cder/guidance/959fnl.pdf 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html 
http://cme.cancer.gov/c01/ 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator: David Dowdy 
 
 
 
Signed: 
 
Date: 
8 Oct 2019 
 
David Dowdy, MD, PhD 
Assistant Professor 
Department of Epidemiology 
Johns Hopkins Bloomberg School of Public Health 
 
 
 
 
 
Site Investigator: Neil Martinson 
 
 
 
Signed: 
 
Date: 
 
8 Oct 2019 
 
Neil Martinson, MBChB, MPH 
Chief Executive Director 
Perinatal HIV Research Unit (PHRU) 
 
 
 
 
 
Site Investigator: Khatija Ahmed 
 
 
                                                                                                           Date:  
Signed: 
                                             
 
        8 Oct 2019 
 
 
 
Khatija Ahmed, MBChB, MMED, FcPath(Micro) 
Executive Director 
Setshaba Research Centre 
 
 
 

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Table of Contents 
 
 
 
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iii 
Statement of Compliance ................................................................................................................. i 
Signature Page ................................................................................................................................ ii 
List of Abbreviations ........................................................................................................................ v 
Protocol Summary .......................................................................................................................... vi 
 
1 
Key Roles ............................................................................................................................... 9 
2 
Background Information and Scientific Rationale ............................................................... 12 
2.1 
Background Information ........................................................................................... 12 
2.2 
Rationale .................................................................................................................. 14 
2.3 
Potential Risks and Benefits .................................................................................... 15 
2.3.1 
Potential Risks ............................................................................................. 15 
2.3.2 
Known Potential Benefits ............................................................................. 15 
3 
Objectives ............................................................................................................................ 16 
4 
Study Design ........................................................................................................................ 17 
5 
Study Population .................................................................................................................. 20 
5.1 
Selection of the Study Population............................................................................ 20 
6 
Study Procedures/Evaluations ............................................................................................ 22 
6.1 
Study Procedures .................................................................................................... 22 
6.2 
Laboratory Evaluations ............................................................................................ 24 
6.2.1 
Laboratory Evaluations/Assays ................................................................... 24 
6.2.2 
Special Assays or Procedures ..................................................................... 25 
6.2.3 
Specimen Collection, Preparation, Handling and Shipping ........................ 25 
7 
Study Schedule .................................................................................................................... 26 
7.1 
Screening and Enrollment ....................................................................................... 26 
7.2 
Enrollment/Baseline, if applicable ........................................................................... 26 
7.3 
Follow-up and Final Visits, if applicable .................................................................. 26 
7.4 
Early Termination Visit, if applicable ....................................................................... 26 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject (or a Cohort), if applicable 27 
8 
Assessment of Outcome Measures .................................................................................... 28 
8.1 
Specification of the Appropriate Outcome Measures.............................................. 28 
8.1.1 
Primary Outcome Measure .......................................................................... 28 
8.1.2 
Secondary Outcome Measures ................................................................... 28 
9 
Safety assessment and reporting ........................................................................................ 30 
9.1 
Definition of Adverse Event (AE) ............................................................................. 30 
9.2 
Definition of Serious Adverse Event (SAE) ............................................................. 30 
9.3 
Reporting Procedures .............................................................................................. 30 
9.3.1 
Serious Adverse Event Detection and Reporting ........................................ 30 
9.3.2 
Reporting of Pregnancy ............................................................................... 30 

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9.3.3 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .......................................................... 30 
9.3.4 
Type and Duration of the Follow-up of Subjects After Adverse Events ...... 31 
10 
Clinical Monitoring Structure ................................................................................................ 32 
11 
Statistical Considerations .................................................................................................... 33 
11.1 
Study Outcome Measures ....................................................................................... 33 
11.2 
Sample Size Considerations ................................................................................... 34 
11.3 
Participant Enrollment and Follow-Up ..................................................................... 35 
11.4 
Analysis Plan............................................................................................................ 36 
11.5 
Blinding .................................................................................................................... 39 
12 
Access to Source Data/Documents ..................................................................................... 40 
13 
Quality Control and Quality Assurance ............................................................................... 41 
14 
Ethics/Protection of Human Subjects .................................................................................. 42 
14.1 
Declaration of Helsinki ............................................................................................. 42 
14.2 
Institutional Review Board ....................................................................................... 42 
14.3 
Informed Consent Process ...................................................................................... 42 
14.3.1 Informed Consent/Assent Process (in Case of a Minor or others unable to 
consent for themselves) ............................................................................... 43 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 43 
14.5 
Subject Confidentiality ............................................................................................. 43 
14.6 
Future Use of Stored Specimens ............................................................................ 44 
15 
Data Handling and Record Keeping .................................................................................... 45 
15.1 
Data Management Responsibilities ......................................................................... 45 
15.2 
Data Capture Methods ............................................................................................. 45 
15.3 
Types of Data ........................................................................................................... 45 
15.4 
Timing/Reports ......................................................................................................... 45 
15.5 
Study Records Retention ......................................................................................... 46 
15.6 
Protocol Deviations .................................................................................................. 46 
16 
Publication Policy ................................................................................................................. 47 
17 
Literature References .......................................................................................................... 48 
 
 

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ACF 
AE 
Active Case Finding 
Adverse Event 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case Report Form 
DHHS 
DMID 
United States Department of Health and Homeland Security 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
HIV 
Good Clinical Practice 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
NICD 
National Institutes of Health 
National Institute For Communicable Diseases  
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
SOP 
TB 
Standard Operating Procedure 
Tuberculosis 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 

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Title: 
Innovative contact tracing strategies for detecting TB in mobile rural and 
urban South African populations 
 
Population: 
4,800 male and female newly diagnosed TB cases age 0-99 years and 
their estimated 9,600 household contacts in Limpopo, North West and 
Gauteng provinces, South Africa  
 
Number of Sites: 
See Section 1/Appendix 
 
Study Duration: 
5 years total (2.5 years of enrollment) 
 
Subject Duration: 
Single visit (30-45 minutes) 
 
Objectives: 
 
Primary: 
To measure the comparative effectiveness of two novel household-based TB contact investigation 
strategies: 1) tracing on holidays in rural areas; 2) tracing on evenings and weekends in urban 
areas versus tracing during working hours (standard household contact tracing). 
 
Secondary: 
To compare the implementation, effectiveness, cost-effectiveness and potential impact of rural 
holiday and urban off-peak contact investigation against standard contact investigation in South 
Africa 
a) Assess the effectiveness of each novel strategy compared to standard contact tracing by 
setting (rural versus urban). 
b) Examine metrics of acceptability, feasibility, fidelity and sustainability for each novel strategy 
relative to standard contact investigation. 
c) Measure costs of each intervention and estimate cost-effectiveness (incremental cost per 
disability adjusted life year averted) and budget impact. 
d) Evaluate associations between mobility and TB transmission using whole-genome 
sequencing. 
e) Project the potential reduction in population-level TB five-year incidence achievable through 
holiday-time rural screening and off-peak urban screening, using an individual-based 
transmission model. 
f) To inform bioethical analysis by describing the experiences, attitudes, and preferences of 
patients with TB and their household contacts regarding household contact investigation. 

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Overall Anticipated Study TImeline: 
 
 
 
Activity 
2019 
2020 
2021 
2022 
2023 
2024 
Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 
Protocol development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB & local/provincial approval  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Database development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hire & train study staff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment of participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data collection & cleaning 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Empirical costing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole genome sequencing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epidemiological data analysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bioethics data collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dissemination of findings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
KEY ROLES 
For questions regarding this protocol, contact Karen Lacourciere (lacourcierek@niaid.nih.gov) 
Individuals:  
DMID Program Officer/Clinical Project Manager 
Karen Lacourciere 
Respiratory Disease Branch/DMID/NIAID  
5601 Fishers Lane, Room 8E29 
Rockville, MD 20852-9825 
Phone:  (240) 627-3297  
E-mail:  lacourcierek@niaid.nih.gov 
 
 
Principal Investigator:   
David Dowdy, MD PhD 
Associate Professor 
Johns Hopkins Bloomberg School of Public Health 
615 N. Wolfe St., E6531 
(410) 614-5022 (phone), (410) 614-0902 (fax) 
ddowdy1@jhmi.edu 
 
South African Co- Principal Investigators:  
Neil Martinson, MBChB DCH MFGP MPH 
 
 
 
 
 
 
 
Chief Executive Director 
 
 
 
 
 
 
 
Perinatal HIV Research Unit 
 
 
 
 
 
 
Chris Hani Baragwanath Hospital 
  
 
 
 
 
 
Soweto, South Africa 
 
 
 
 
 
 
+27 11-989-9762 (phone) 
 
 
 
 
 
 
martinson@phru.co.za 
 
 
 
 
 
 
 
 
Khatija Ahmed, MBChB MMED FCPATH 
 
 
 
 
 
 
 
Executive Director 
 
 
 
 
 
 
 
Setshaba Research Centre 
 
 
 
 
 
 
 
Soshanguve, South Africa 
 
 
 
 
 
 
 
+27 12-799-2422 (phone) 
 
 
 
 
 
 
 
kahmed@setshaba.org.za 
 
Co-Investigators 
 
 
 
 
Colleen Hanrahan, PhD 
Johns Hopkins Bloomberg School of Public 
Health 

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Bareng Aletta Sanny Nonyane, PhD 
Johns Hopkins Bloomberg School of Public 
Health 
 
Limakatso Lebina, MBChB 
Perinatal HIV Research Unit 
 
Mookho Malahleha, MBChB 
Setshaba Research Centre 
 
Shapo Annah Pitsi, MBChB 
Setshaba Research Centre 
 
Barun Mathema, PhD 
Columbia University Mailman School of 
Public Health 
 
Shaheed Vally Omar, MSc 
National Institute of Communicable 
Diseases 
 
Institutions:  
Johns Hopkins Bloomberg School of Public Health 
 
 
615 N Wolfe St, Baltimore, MD 21205 USA 
 
 
David Dowdy, MD, PhD 
 
 
410-614-5022 (phone) 
 
 
410-614-0902 (fax) 
 
 
ddowdy1@jhmi.edu 
 
 
 
 
Perinatal HIV Research Unit 
 
 
Chris Hani Baragwanath Hospital, Soweto, South Africa 
 
 
Neil Martinson, MBChB MPH 
 
 
+27 11-989-9762 (phone) 
 
 
+27 11-989-9762 (fax) 
 
 
martinson@phru.co.za 
 
 
 
 
Setshaba Research Centre 
 
 
Soshanguve, South Africa 
 
 
Khatija Ahmed, MBChB, MMed, FC(path) 
+27 12-799-2422 (phone) 
 
 
+27 12-799-2685 (fax) 

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kahmed@setshaba.org.za 
 
 
 
 
Columbia University Mailman School of Public Health 
 
 
 
722 W 168th St, Room 812J New York, NY 10032 USA 
 
 
 
Barun Mathema, PhD 
 
 
 
212-342-0167 (phone) 
 
 
 
bm2055@columbia.edu 
 
 
 
 
National Institute of Communicable Diseases 
 
 
 
Johannesburg, South Africa 
 
 
 
Shaheed Vally Omar, MSc 
 
 
 
+27 11 885 5309 (phone) 
Naziri@nicd.ac.za 
 
 
 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Tuberculosis (TB) remains a global health emergency, responsible for 10 million new cases in 
2017.1,2 It is the world’s leading infectious disease killer, causing 1.3 million deaths annually,1 
despite the availability of cheap curative treatment for the vast majority of cases.3 Worldwide, 
TB incidence has been declining since 2004 at a rate of only 2% per year.1 The global 
community has recognized that this rate of progress – with declines in incidence nearly matched 
by population growth – is unacceptable for a curable disease, and the World Health 
Organization (WHO) has set very ambitious targets for ending the global TB epidemic.4 To meet 
interim milestones, including a 50% reduction in TB incidence by 2025, novel approaches are 
urgently needed.5 
Arguably, the greatest impediment to achieving marked reductions in TB incidence and 
transmission is delayed (or entirely missed) detection of individuals with active TB in high-
burden settings. An estimated 3.6 million people with incident TB (>30% of all cases) were 
“missed” – i.e., never reported to public health authorities – in 2017.1 Furthermore, national 
prevalence surveys suggest that the average duration of culture-detectable TB (as estimated by 
the incidence/prevalence ratio) is one year or more.6 The inability of more sensitive diagnostic 
tests (such as Xpert MTB/RIF7) to substantially reduce TB morbidity8-12 suggests that, even with 
available highly sensitive tests, patients with TB are being diagnosed very late in their disease 
course. This hypothesis is supported by evidence of declining TB mortality in most countries 
(suggesting better diagnosis and treatment), but without a corresponding decline in incidence or 
prevalence (suggesting that treatment is occurring too late to prevent transmission).1,13 
TB transmission is demographically heterogeneous14 – including three dimensions that are 
highly consistent across epidemiological settings. First, in high-burden settings (particularly 
those in sub-Saharan Africa), the majority of TB disease occurs in young adults (ages 15-49)15; 
even in low-burden countries like the United States, where the elderly face higher TB rates 
because of greater exposure to TB in the past,16 the longitudinal risk of TB over the lifespan is 
greatest during the young adult.17 Second, it is increasingly recognized that men account for a 
preponderance of TB in nearly every country6 – a gender gap that may partially reflect poorer 
access to healthcare (or lower willingness to access healthcare), but that also likely reflects 
differential social mixing patterns,15 higher likelihood of living in congregate settings (particularly 
prisons18), and other poorly characterized (e.g., biological7) factors.19 Third, TB is the 
quintessential disease of poverty; more impoverished individuals almost universally experience 
higher rates of TB.20,21 As with the gender and age gaps, some of this disparity can be explained 
by known factors (e.g., malnutrition,22 crowding23), but other unknown factors likely also play an 
important role. Regardless of the mechanistic causes of these three sources of demographic 

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heterogeneity, they result in an unfortunate reality, namely that the populations most likely to 
have and to transmit TB are also the populations (young adult, male, poor) that are hardest to 
reach through existing interventions that rely on the routine healthcare system. 
A hallmark of these high-TB-risk demographic groups is their high level of mobility and 
migration. While the motivations for human movement are diverse, two major patterns include 
migration to urban centers for employment and return to homelands to spend time with families. 
Such mobility is common in many developing country settings,24,25 and can result in temporary 
population spikes in “destination” areas of 125%.26 South Africa is emblematic of these patterns, 
with a recent net population shift from rural to urban areas,27 a population of temporary migrants 
overwhelmingly comprised of males age 20-45 years,28 and the majority of its tourism 
representing trips for visiting family and relatives.29 Internal migration has been linked with HIV 
(a major risk factor for TB): in KwaZulu Natal, South Africa, the prevalence ratio for HIV, 
comparing migrants to non-migrants in the same neighborhood, was 1.65 and increased with 
the number of moves.30 Recent migrants are less likely to utilize health services in South 
Africa,31 and are at higher risk of all-cause mortality as well as mortality due specifically to 
HIV/TB.32 Recent studies have shown that migration likely plays an important role in the 
transmission of extensively drug resistant TB (XDR-TB)—among 1084 genomically linked case-
pairs in KwaZulu Natal, the median distance between case-pairs was 108 km, and half of all 
case-pairs resided in Durban, the urban center of the province, while the other half resided in 
rural areas.33 Finally, studies from China and Tajikistan show that migrants are less likely to be 
appropriately treated for TB, and at higher risk for loss from care, treatment failure and death 
than non-migrant counterparts.34,35 Given the strong demographic correlation between mobility 
and TB disease risk, co-location of major TB risk factors (e.g., HIV) among migrants, and poorer 
TB treatment outcomes associated with migration, better understanding of the spatial and 
temporal dynamics of TB transmission – including the design of effective interventions – among 
highly mobile populations will be essential if we are to make substantive progress toward ending 
TB in high-burden settings. In South Africa, which bears the fifth-largest burden of incident TB in 
the world, household contact investigation is recommended as a key component of the national 
TB strategic plan for HIV, TB, and sexually transmitted infections.36 Household contact 
investigation entails visits by healthcare workers to the homes of individuals diagnosed with TB, 
in order to identify household members who may have TB infection or disease.37 As high-burden 
countries pursue increasingly ambitious goals for ending TB, the importance of household 
contact investigation is likely to increase worldwide.38 Furthermore, household contact 
investigation provides an ideal opportunity to offer HIV counseling and testing.39 However, the 
practice of household contact investigation also presents both logistical and ethical challenges. 
For example, one must weigh the deontological value of protecting confidentiality to prevent 
stigma and blame of the individual diagnosed with TB against the utilitarian perspective of 
protecting the household and broader community health against infection.40  
Our unique research collaboration can provide novel insights into migration and TB 
transmission. To better understand the interplay between mobility and TB transmission, it is 
important to compare patterns of TB disease and transmission in representative rural and urban 
settings. Our research infrastructure is ideally placed to make this comparison. Specifically, for 

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this proposed research, we will combine three research sites: two in rural Limpopo province 
(located in northern South Africa along the border with Botswana, Mozambique and Zimbabwe) 
and one in the Soshanguve township of urban Tshwane and surrounding areas. Relative to 
other provinces in South Africa, Limpopo is more representative of sub-Saharan Africa as a 
whole, with a low (<50/km2) population density, a lower – though still extremely high – TB 
prevalence (300 per 100,000), and the lowest per capita gross domestic product ($3,500 
USD).41 Johns Hopkins University (JHU) and the Perinatal HIV Research Unit (PHRU) of the 
University of the Witwatersrand have been conducting studies of active TB case finding in 
Limpopo Province since 2014.42 Many residents of Limpopo migrate south toward Tshwane and 
Johannesburg for work. Tshwane Municipality is the northernmost urban area in Gauteng 
Province, and has a TB incidence rate of 330/100,000). One Tshwane township in particular, 
Soshanguve, (the name of which is itself a concatenation of ethnic groups from Limpopo) is 
densely population (1,100 residents/km2) has a large number of immigrants and migrants from 
Limpopo. Setshaba Research Centre has been located and working in Soshanguve since 2004 
and has conducted over 30 clinical and social science studies in the area, with a focus on HIV 
and TB.43-61 Setshaba has developed long-term partnerships with local government 
representatives and community leaders in the area which will facilitate recruitment and 
enrollment of the proposed study population. Our research collaboration is therefore uniquely 
placed to answer questions about TB transmission and mobility by combining high-quality 
infrastructure in a rural homeland province with that an urban settlement to which many 
residents migrate. 
2.2 
Rationale 
It is not sufficient merely to understand TB transmission patterns; we must also design and 
evaluate interventions to find the “missing” cases of TB in these high-risk mobile populations. 
Although the household setting does not account for all (or even the majority of) TB 
transmission in South Africa,62 households remain the highest-yield location for TB systematic 
screening.63 Characteristics of effective case-finding interventions will include: (a) ability to 
identify cases who are not found (or found only very late) by the routine healthcare system; (b) 
feasibility of implementation;64 (c) cost-effectiveness65 and (d) potential to reduce TB incidence 
at the population level.66 Taking these considerations into account, we propose to evaluate the 
effectiveness, implementation, cost-effectiveness and potential impact of two innovative 
approaches to TB case detection in a highly mobile South African population: holiday-based 
contact investigation in rural homelands and “off-peak” (evening/weekend) household screening 
in an urban township. We will investigate associations between mobility patterns and TB 
transmission using a multidisciplinary approach that includes detailed epidemiological 
investigation, genomic epidemiology, and transmission modeling; this will be combined with a 
rigorous evaluation of the interventions themselves, including both their effectiveness in 
identifying additional cases and each intervention’s implementation in terms of reach, feasibility, 
fidelity, cost-effectiveness, and maintenance. This research has the potential to transform our 
approach to finding the “missing 3.6 million” TB cases by recognizing a major sociodemographic 

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driver of missed and delayed diagnosis – human mobility – and implementing solutions that are 
tailored to the needs of the highly mobile populations that bear a disproportionate burden of TB 
morbidity and likely also generate a disproportionate share of TB.  
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
Our surveys are designed to pose only minimal risk to participants. The primary risk to 
patients in this study is a breach of confidentiality. Participants will be asked to provide 
potentially sensitive information (e.g., participant home address, socioeconomic status, 
patient TB status), and while every effort will be made to maintain those data in 
confidential and secure fashion, it is possible that such data could become known by 
individuals other than study personnel. Participants will be informed of this risk and given 
the opportunity to decline participation without any negative impact on their clinical care. 
Patients will also be offered HIV testing, which carries a risk of emotional distress with a 
positive result. All study staff who perform HIV testing will first be trained in appropriate 
HIV Testing and Counseling (HTC); no HIV tests will be performed, nor results provided, 
without appropriate corresponding counseling. Patients (for example, those testing newly 
HIV positive) who require additional clinical care will be promptly referred to routine 
clinical services for management. Patients may also experience inconvenience due to 
the time required to complete the survey, including a sense of intrusion from household 
visits. We will thoroughly train data collection staff to maintain discretion during 
participant interactions and to respect the privacy of each participant. Data collection 
activities will be ceased immediately if requested by the participant at any point during 
the study. For participants who take part in focus group discussions, although we will 
stress confidentiality, we cannot assure it due to the group nature of this interaction. 
 
2.3.2 Known Potential Benefits 
The proposed research may provide a direct benefit to household contacts who are 
enrolled in this study, as it may facilitate more rapid diagnosis of TB or HIV, which would 
in turn facilitate more rapid treatment, thus improving survival and reducing additional 
transmission to loved ones. Index cases are unlikely to derive direct benefit from 
participating in the study, but their families may benefit as above. We also aim to 
conduct this research in such a way as to provide maximum benefit to the community; 
we will actively disseminate our results to decision-makers within our study districts in 
Limpopo and North West and Gauteng provinces, and anticipate that our findings may 
influence policy, enabling the implementation of interventions that can reduce TB 
incidence in the affected communities. Our research is specifically designed to evaluate 
the potential benefits to these communities, in terms of acceptability, effectiveness in 
finding new cases of TB (and starting them on treatment), and impact on incidence at 
the population level. 

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3 
OBJECTIVES 
Primary: 
To measure the comparative effectiveness of two novel household-based TB contact investigation 
strategies: 1) tracing on holidays in rural areas; 2) tracing on evenings and weekends in urban 
areas: each of these compared to tracing during working hours (standard household contact 
tracing). 
 
Secondary: 
1. To compare the implementation, effectiveness, cost-effectiveness and potential impact of rural 
holiday and urban off-peak contact investigation against standard contact investigation in South 
Africa 
a) Assess the effectiveness of each novel strategy compared to standard contact tracing by 
setting (rural versus urban). 
b) Examine metrics of acceptability, feasibility, fidelity and sustainability for each novel strategy 
relative to standard contact investigation. 
c) Measure costs of each intervention and estimate cost-effectiveness (incremental cost per 
disability adjusted life year averted) and budget impact. 
d) Evaluate associations between mobility and TB transmission using whole-genome 
sequencing. 
e) Project the potential reduction in population-level TB five-year incidence achievable through 
holiday-time rural screening and off-peak urban screening, using an individual-based 
transmission model. 
2. To inform bioethical analysis by describing the experiences, attitudes, and preferences of 
patients with TB and their household contacts regarding household contact investigation 
a) Assess participants’ experiences of inconvenience and stigma (personal and 
family/community), attitudes toward confidentiality and importance of contact 
investigation, motivation to participate in household contact investigation, and 
preferences for disclosure.  
b) To evaluate the degree to which offering routine HIV testing influences beliefs about 
TB/HIV co-morbidity and affects thinking about stigma, blame, and duty to others’ health 
during household contact investigation. 
 

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4 
STUDY DESIGN 
In this study, we will evaluate two innovative approaches to household contact investigation, 
namely holiday-time contact investigation in a largely rural province (Limpopo) and evening-time 
contact investigation in a peri-urban township (Soshanguve in Gauteng province and 
surrounding areas within North West province). These approaches leverage known patterns of 
movement and migration in sub-Saharan Africa and throughout the world, namely that younger 
working individuals (i.e., those at greatest risk of TB and TB transmission) often immigrate from 
rural to urban areas, spending evenings after work in their urban homes, and returning to their 
rural family homesteads for major holidays. We will compare each of these approaches to each 
other and to standard household contact investigation during business hours from 8 am to 4 pm 
Monday through Friday in each setting, with a primary outcome of the number of additional 
cases of TB identified per index case and secondary outcomes of implementation, cost-
effectiveness and transmission, thus identifying feasible strategies that can be more efficient 
(per dollar invested) in finding additional cases of TB.  
 
We propose to conduct a four-arm parallel randomized trial, using the following strategies (See 
study schematic below):  
1. Routine contact investigation in rural Limpopo. Study staff will perform routine 
contact investigation of TB cases diagnosed in study hospitals in Limpopo, throughout 
the year. Contact investigation will be performed on weekdays during business hours.  
2. Holiday contact investigation in rural Limpopo. At the time of diagnosis, study staff 
will ask TB cases diagnosed in Limpopo study hospitals for consent to perform deferred 
household contact investigation over a three week period during the Easter holiday (for 
cases diagnosed between January 1 and Easter) or a five week period during the 
Christmas holiday (for cases diagnosed between Easter and December 31). These 
holiday periods will align with the public school holidays in South Africa as detailed 
by the National Education Policy Act School Calendar. 
3. Routine contact investigation in urban Soshanguve and surrounding areas. Study 
staff will perform routine contact investigation of TB cases diagnosed in study clinics in 
Soshanguve, throughout the year. Contact investigation will be performed on weekdays 
during business hours.  
4. Off-peak contact investigation in urban Soshanguve and surrounding areas. Study 
staff will perform contact investigation of TB cases diagnosed in study clinics in 
Soshanguve, throughout the year. Contact investigation will be performed during 
evenings and weekends.  
 
Bioethics sub-study 
We will perform a mixed-methods investigation of the ethics of household contact investigation 
for TB among participants from the parent study (both TB index cases and their household 
contacts) after they complete TB evaluation. This investigation will include a combination of 
focus group discussions (six groups of 10 participants each), in-depth interviews (24 interviews), 
and quantitative surveys (300 participants). Each of these investigations will follow a 2x3 
factorial design, including equal representation of household contacts and index patients across 

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each of the three study districts. 

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Study Schematic 
 

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5 
STUDY POPULATION 
5.1 
Selection of the Study Population 
Sample Size 
We anticipate enrolling a total of 14,400 participants. We make no exclusions based on sex, age 
or race for enrolment, therefore we expect that our final enrolled study population will be roughly 
representative of those living within the study area.   
 
These 14,400 will include: 
- 1600 index cases in the routine contact investigation arm in Limpopo 
- 1600 index cases in the routine contact investigation arm in Soshanguve and surrounding 
areas 
- 800 index cases in the holiday contact investigation arm in Limpopo 
- 800 index cases in the off-peak contact investigation arm in Soshanguve and surrounding 
areas 
- 9,600 contacts (a mean of two contacts per case, accounting for some cases who will not have 
any contacts, based on our enrollment of household contacts in our recent trial in Limpopo) 
Study Population Sources 
Index cases will represent a sample of consecutive consenting individuals diagnosed with  
pulmonary TB (including microbiological and/or chest x-ray diagnosis) from twelve hospitals in 
Vhembe and Capricorn Districts of Limpopo, and 33 primary health care clinics and two district 
hospitals in Soshanguve and surrounding areas. The only exclusion criteria will be a plan not to 
pursue treatment within the study district (as this would make contact investigation infeasible in 
the programmatic setting), and being on TB treatment for longer than one month (as these 
cases will likely be negative by liquid culture in order to identify transmission links between 
cases using whole genome sequencing). Note that contacts do not have the same requirement 
of planning to pursue treatment within the district; thus, it is possible – and expected – that 
holiday contact investigation in Limpopo will yield cases from outside the district, for example. 
Individuals who later decline to have contact investigation performed (or who, for example, 
provide false contact information thus making contact investigation infeasible) will still be 
included in the study sample and in the denominator for all analyses. Our aim is to make the 
population of this study as representative as possible as the target population for the proposed 
intervention. Eligible participants in the bioethics sub-study will include all individuals who were 
enrolled in the parent study and completed follow-up for the primary outcome (including those 
who declined or were ineligible to participate in household contact investigation). We will enroll 
consecutive eligible participants in each district until our desired sample size (64 evaluable 
index cases and 64 evaluable household contacts from each district) has been attained. 

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Eligibility Criteria 
Subjects in each of the below participant categories must meet each eligibility criteria for that 
category: 
 
TB index cases: 
Inclusion criteria: 
• 
Age 0-99 years (Including those recently deceased) 
• 
Diagnosed with pulmonary TB at a study hospital or clinic (microbiological and/or chest 
x-ray diagnosis) 
 
Exclusion criteria: 
• 
Unwilling/unable to provide informed consent (including next of kin, for those recently 
deceased) 
• 
Plan not to pursue TB treatment within the study district 
• 
Unwilling/unable to comply with study procedures 
 
Contacts: 
Inclusion criteria: 
• 
Age 0-99 years (18-99 for the bioethics sub-study) 
• 
Currently resides with or visiting eligible TB index case 
   
Exclusion Criteria: 
• 
Unwilling/unable to provide informed consent 
• 
Unwilling/unable to comply with study procedures 

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6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
Study Procedures 
 
Recruitment  
Within Limpopo Province, we will have two study sites, one in Vhembe and one in Capricorn 
district and these sites will recruit participants from a total 12 hospitals. In Tshwane (across both 
North West and Gauteng provinces) we will have one site in Soshanguve, and this will recruit 
participants from 33 clinics and two district hospitals. Within each site and clinic/hospital, we will 
seek to enroll all consecutive patients meeting the following inclusion criteria: (a) diagnosed with 
pulmonary TB at one of the study health facilities (including microbiological and/or chest x-ray 
diagnosis); (b) plan to pursue treatment within the study district; (c) willingness to provide 
informed consent and comply with study procedures. We will also include those patients who 
are recently deceased from the hospital register. Eligible participants will be identified by weekly 
review of the presumptive TB and TB treatment registers in each location, also in close 
collaboration with healthcare staff in each study health facility. We will approach all potentially 
eligible participants for informed consent at their treatment location within two weeks of 
diagnosis, making phone calls as necessary to contact participants who have been lost to 
follow-up between diagnosis and treatment initiation. For patients who are recently deceased, 
the next of kin will be contacted and asked if they can consent for the patient’s information to be 
included in the study. Next of kin will also be asked to provide temporary consent for index 
patients who are too ill to consent at the time of enrollment. (These patients will be re-
approached for consent once they have recovered to the extent of being able to complete the 
consent process.) After providing informed consent, participants will be randomized via a 
computer-generated algorithm to either routine or novel (holiday or off-peak) household contact 
investigation. Of note, participants who after consent and randomization, decline to accept 
household contact investigation – or who cannot be located at home at the time of home visit, 
will be included in the primary analysis as not resulting in a secondary case detected. 
Recruitment will be continued until 2400 participants are enrolled in each arm (expected to be 
completed within 28 months). For the bioethics sub-study, eligible participants will include all 
individuals who were enrolled in the parent study and completed follow-up for the primary 
outcome (including those who declined or were ineligible to participate in household contact 
investigation). For this sub-study, we will enroll consecutive eligible participants in each district 
until our desired sample size (˜64 index cases and ˜64 evaluable household contacts from each 
district) has been attained.  
 
Data Collection: Contact tracing and interviews  
Upon enrollment, we will conduct a detailed interview of all index cases, based on our current 
case report forms used in Limpopo. These interviews will include demographic, socio-economic 
and clinical characteristics, detailed data on mobility and migration, the preceding diagnostic 
cascade and symptom history, and extensive assessment of costs (including catastrophic health 
expenditures). Experience suggests that we can collect these data in 30 minutes. For patients 

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who are deceased or too ill to participate, the next of kin will complete the interview to the best 
of their ability. We will also collect a sputum sample from each living index case which will be 
sent for liquid MGIT culture in order to perform whole genome sequencing. After completing the 
interview, for cases assigned routine or off-peak contact investigation, an appointment time in 
the next two weeks will be arranged for the household visit. Cases allocated to holiday-time 
investigation will be asked for contact information and will be called within two weeks of the 
holiday to remind them of the study and set an appointment time for the household visit.  
 
Study teams (2 in Limpopo and 2 in Soshanguve) consisting of a nurse and a research assistant 
trained in HIV counselling and testing will visit the household of each consenting index case (or 
legal guardian, in the case of minors).  At the household, teams will recruit all available 
household members of all ages. For each enrolled participant, the team will conduct a similar 
interview to the index case on demographic, socio-economic, mobility/migration, health seeking 
behavior and clinical characteristics. Specifically, mobility questions will focus on spatial and 
temporal movement patterns over the previous year and will include: number and duration of 
trips away from primary residence, total duration of time away, destination and purpose of trips, 
longest distance travelled, longest trip duration, length of time living at primary residence and 
total number of lifetime moves. Each participant will be screened for TB as described above. 
Results on Xpert testing will be monitored by study staff using the electronic NICD laboratory 
system (tier.net), and participants will be notified either by phone or in person at a household 
visit if they have tested positive for TB and referred to the nearest public-sector clinic for 
treatment.  
 
Empirical Assessment of Costs  
We will conduct an empirical costing and associated cost-effectiveness analysis of the four 
contact investigation strategies from the societal perspective. Costs will be measured 
prospectively from study data and will comprehensively include those related to both health 
systems and patients. Health systems costs will be captured using an “ingredients” through a 
combination of budgetary review, key informant interviews (e.g., administrative staff), direct 
observation (e.g., time-motion studies of patients and study staff), and prospective logbooks 
kept by study staff and other relevant personnel (e.g., clinic nurses) Patient-level costs will be 
measured through patient interview, using the WHO Handbook on Tuberculosis Cost Surveys 
as a guide. We will also include other costs incurred by society, including additional costs to the 
national disability grant system (for which most TB patients are eligible), costs to the community 
“safety net” associated with having to perform contact investigation outside of regular business 
hours (e.g., any security concerns, childcare and other expenses for healthcare staff), and costs 
to caregivers to help patients complete the process of initiating TB treatment (for contacts who 
test positive). Costs from this “ingredients” approach will be compared (as a check) to a “top-
down” approach in which we estimate large cost items (e.g., annual staff salaries) and divide 
those costs by the number of new TB cases identified and starting treatment under each 
strategy. We will also perform additional calculations for budget impact analysis, including 
estimating the size of the eligible population, the current number receiving contact investigation 
and the expected number receiving contact investigation after introducing novel implementation 
strategies, and any changes expected in TB-related costs following the introduction of this 
intervention. 
 
Bioethics sub-study  

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Quantitative surveys 
After obtaining written informed consent, trained data collectors will meet with participants either 
at their homes or in study clinics according to participant preference. Surveys will be conducted 
in the participant’s choice of English or the local language in each district, and answers will be 
entered directly into an electronic database by study staff using mobile tablets. The interview will 
be pilot tested by study staff and designed to last a maximum of 30 minutes. Surveys will 
include participants’ level of agreement with importance of household contact investigation; 
willingness to participate in household contact investigation; preferences for TB/HIV status 
disclosure; if (and to what extent) HIV testing contributes to the misconception that all people 
with TB have HIV; and whether HIV testing affects willingness to participate in household 
contact investigation. Question formats will include Likert scales, discrete choice experiments, 
best-worse scales, contingent valuation, and validated multi-item instruments (e.g., van Rie 
stigma scale25). All data will be securely transmitted into a password protected REDCap 
database. The study data manager will routinely check all uploaded records daily for 
completeness, will run in- depth queries on a weekly basis, and ensure that all queries are 
resolved.  
 
Qualitative interviews/focus group discussions 
Each semi-structured, in-depth interview will be approximately one hour in length and will cover 
the following domains: TB/HIV disclosure preference, perceived stigma/blame, importance of 
household contact investigation, willingness to participate in household contact investigation, 
family invasiveness, community stigma/blame, duty to others health, and beliefs about TB/HIV 
confection. Six focus groups of ten participants each will be conducted in a private room at a 
central hospital in each district. Focus group discussions will last approximately two hours and 
will feature discussions on community-level perceptions and norms regarding the ethics of 
household contact investigation. No personal identifiers will be collected or used during the 
discussion. All in depth interviews and focus group discussions will be audio recorded, 
transcribed, translated as needed, and coded using Atlas.ti or NVivo. Thematic content analysis 
will be conducted to explore and document themes relating to participants’ experiences, 
attitudes, and preferences in each domain. 
 
 
6.2 
Laboratory Evaluations 
6.2.1 Laboratory Evaluations/Assays 
Liquid MGIT culture 
Liquid MGIT culture is a mycobacterial growth assay that detects the presence of 
Mycobacterium tuberculosis directly from sputum. Xpert MTB/RIF assays will be carried 
out on sputum samples collected from participants.  This assay will not be conducted 
under research conditions, but as part of routine South African standard of care, by the 
National Institute For Communicable Diseases (NICD). Sputum samples collected from 

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participants will be couriered by team couriers to NICD central laboratory for MGIT 
testing (see 6.2.3.2).  
6.2.2 Special Assays or Procedures 
Whole Genome Sequencing (WGS) 
During the period of enrollment, we will work with the National Health Laboratory 
Services to perform culture and whole genome sequencing on all positive sputa. 
Bacterial isolates from standard culture will have total DNA extracted by staff at the 
NICD laboratory. WGS will be performed on the Illumina NextSeq platform. Nextera XT 
kit will be used to prepare libraries. Paired-end sequencing will be done with read-
lengths of 250 bp at >50x coverage. Alignment to a reference strain (H37Rv), variant 
filtering, and variant comparison will flow through a pipeline of five open-source tools 
(FastQC, BWA, Samtools, Freebayes, and Bedtools) following criteria commonly used in 
genomic analyses. 
6.2.3 Specimen Collection, Preparation, Handling and Shipping 
6.2.3.1 
 Instructions for Specimen Preparation, Handling, and Storage 
Sputum collection is a routine clinical procedure that does not place the participant at 
any risk, and will be conducted by study staff only at household visits—the remainder of 
sputum collection for the study will be conducted by local clinic staff according to the 
standard of care.  The participant will be instructed to go outside to provide the sputum 
sample. They should take several deep breaths, and hold each for 5 seconds, then 
cough such that sputum, if any, comes into their mouth. The participant then spits the 
sputum into the sputum collection jar and seals the lid on top, before handing to the 
study staff who then labels the specimen with participant details according to South 
African Department of Health standard procedures and places it inside of a sealed 
plastic bag then into a cooler until it is handed off to the NICD courier for transport to the 
NICD laboratory.  At the laboratory, the sputum is processed immediately and tested by 
the Xpert MTB/RIF assay. No specimen is retained by the laboratory after testing 
6.2.3.2 
Specimen Shipment 
Sputum specimens in closed vials inside of a sealed bag are transported by NICD 
courier to the central NICD laboratory according to standard NICD procedures.  This 
occurs 1-2 times on each weekday, and the timing is variable by clinic.  Specimens are 
kept at 4°C in a cooler until reaching the laboratory. Specimens for WGS will be 
transported by NICD courier to the NICD headquarters in Johannesburg as above, on a 
bi-weekly basis by courier. 

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7 
STUDY SCHEDULE 
7.1 
Screening and Enrollment 
Within Limpopo Province, we will have two study sites, one in Vhembe and one in Capricorn 
district, while in Tshwane municipality we will have one site covering Soshanguve and 
surrounding areas. Within each site, we will seek to enroll all consecutive patients meeting the 
eligibility criteria. Potential eligibility will be assessed weekly review of the presumptive TB and 
TB treatment registers at each study facility, in close collaboration with healthcare staff in each 
hospital. We will approach all potentially eligible participants for informed consent at their 
treatment location within two weeks of diagnosis, making phone calls and/or home visits as 
necessary to contact participants who have been lost to follow-up between diagnosis and 
treatment initiation. 
All individuals present at the household at the time of a household study visit will be considered 
eligible for enrollment as contacts, and all adults approached during the timing of the bioethics 
sub-study will be considered eligible for enrollment into that sub-study. 
7.2 
Enrollment/Baseline, if applicable 
See above. 
7.3 
Follow-up and Final Visits, if applicable 
Not applicable, unless the participant is a household contact who is diagnosed with TB or 
selected for the bioethics sub-study. For household contacts, we will perform a follow-up visit to 
relay results and refer for treatment, however no other study-specific procedures will be 
performed at this visit. For the bioethics sub-study, all procedures will be completed during a 
single follow-up visit (during which no personal identifiers will be recorded). 
7.4 
Early Termination Visit, if applicable 
Not applicable. 
 

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7.5 
Criteria for Discontinuation or Withdrawal of a Subject (or a 
Cohort), if applicable 
Participants may withdraw from the study voluntarily at any time, but there are no further criteria 
for discontinuation or withdrawal. 

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8 
ASSESSMENT OF OUTCOME MEASURES  
8.1 
Specification of the Appropriate Outcome Measures 
8.1.1 Primary Outcome Measure 
The effectiveness of contact tracing, measured as the number of secondary cases 
identified and started on treatment per index case, comparing households in the novel 
arm to households in the standard arm. 
8.1.2 Secondary Outcome Measures 
 
1. The TB prevalence ratio, comparing highly mobile to less mobile 
individuals, measuring mobility on two scales (neighborhood/intra-urban and 
regional/intra-national).  
2. Relative acceptability of each novel strategy, compared against routine 
contact investigation. We will create a continuous score from the acceptability 
interview questions (provided to a randomly selected 15% of the population), with 
a higher score indicating greater acceptability of the contact tracing strategy.  
3. Feasibility of each strategy as the proportion of potentially eligible index cases 
for whom a household visit was conducted.  
4. Relative fidelity of each novel strategy using a process checklist for each 
index case and household, including whether the household visit was offered and 
accepted, whether the visit was attempted, whether the visit was successful (i.e., 
enrolled at least one contact), whether symptom screening and sputum collection 
were completed and whether newly identified TB cases were notified and 
referred for treatment.  
5. Sustainability of each novel strategy by reporting the primary outcome and 
fidelity measures according to six-month time period over the course of the study.  
6. Incremental cost-effectiveness ratio for each novel strategy. defined as (cost 
of contact tracing strategy 2 – cost of strategy 1)/(effectiveness of strategy 2 – 
effectiveness of strategy 1), where effectiveness is modeled as the number of 
disability-adjusted life years (DALYs) averted by the intervention. The primary 
cost-effectiveness measures will be the incremental cost per DALY averted using 
novel strategies (holiday and off-hours contact tracing) compared to routine 
contact tracing in each setting separately.   

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7. Experiences of inconvenience, attitudes toward confidentiality, motivation 
to participate, and preferences for disclosure, assessed through both 
thematic analysis of in-depth interviews and focus group discussions and 
quantitative analysis of discrete choice experiments and best-worst scaling. 

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9 
SAFETY ASSESSMENT AND REPORTING 
9.1 
Definition of Adverse Event (AE) 
As our intervention is the implementation and observation of routine South African standard of 
care (contact tracing of newly identified TB cases), we do not anticipate any medical adverse 
events which may occur as a result of this research study. Therefore, AEs (including SAEs) will 
not be recorded and reported for this study. 
9.2 
Definition of Serious Adverse Event (SAE) 
N/A—see 9.1 “Definition of Adverse Event” 
9.3 
Reporting Procedures 
N/A—see 9.1 “Definition of Adverse Event” 
9.3.1 Serious Adverse Event Detection and Reporting 
N/A—see 9.1 “Definition of Adverse Event” 
9.3.2 Reporting of Pregnancy 
This is a cross-sectional study which makes no attempt to exclude pregnant women. 
Pregnancy does not represent a complication within the context of this research study. 
Pregnancy status of any enrolled participant will be documented. 
9.3.3 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
TB cases detected through this study are referred for care to their closest public health 
clinic for further evaluation and treatment, according to the South African standard of 
care.  As TB is a measured outcome of this study, and detection of TB is the overall 
goal, it is not considered an AE or SAE. 

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9.3.4 Type and Duration of the Follow-up of Subjects After Adverse Events 
 
N/A—see 9.1 “Definition of Adverse Event” 
 

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10 
CLINICAL MONITORING STRUCTURE 
Site monitoring is conducted to ensure that the human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that the study is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures. DMID, the funder of the project, or its designee may conduct 
site-monitoring visits. 
Site visits may be made at standard intervals and may include, but are not limited to, review of 
regulatory files, informed consent forms, laboratory reports, and protocol and GCP compliance. 
Site monitors will have access to the study site, study personnel, and all study documentation. 
Study monitors will meet with site principal investigators to discuss any problems and actions to 
be taken and document visit findings and discussions. 
 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Outcome Measures 
Primary Outcome Measure: 
Our primary effectiveness outcome will be the ratio of the number of secondary TB 
cases identified and started on treatment per index case, comparing index cases 
allocated to the novel strategy (off-peak screening in Soshanguve and holiday screening 
in Limpopo) to those receiving standard contact investigation.  
 
Secondary Outcome Measures: 
 
1. The TB prevalence ratio, comparing highly mobile to less mobile 
individuals, measuring mobility on two scales (neighborhood/intra-urban and 
regional/intra-national). For the former, we will estimate the number of kilometers 
traveled on a daily basis (secondary analysis: amount of time spent in transit), 
truncating long excursions at 50km (one hour).  
2. TB strain relatedness using maximum likelihood transmission trees.  We 
will integrate TB natural history, epidemiological, and WGS-derived phylogenetic 
data into a statistical modeling framework to draw probabilistic conclusions about 
the likelihood of transmission between persons. “Transmitters” will be defined as 
individuals from whom at least one secondary case most likely originated. 
3. Relative acceptability of each novel strategy, compared against routine 
contact investigation. We will measure acceptability of the intervention among 
index cases and contacts using a short questionnaire given to a randomly 
selected participant at a randomly selected 15% of the households visited. The 
interview will cover acceptability of the visit timing, notification, visit activities (TB 
screening, HIV testing) and study team interaction among others.  
4. Feasibility of each strategy as the proportion of potentially eligible index cases 
for whom a household visit was conducted. We will also record all reasons why 
visits were unable to be conducted (e.g. could not find household, no one ever 
home, visit not conducted during expected off-peak period).  
5. Relative fidelity of each novel strategy using a process checklist for each 
index case and household, including whether the household visit was offered and 
accepted, whether the visit was attempted, whether the visit was successful (i.e., 

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enrolled at least one contact), whether symptom screening and sputum collection 
were completed and whether newly identified TB cases were notified and 
referred for treatment.  
6. Sustainability of each novel strategy by reporting the primary outcome and 
fidelity measures according to six-month time period over the course of the study.  
7. Incremental cost-effectiveness ratio for each novel strategy.  defined as 
(cost of contact tracing strategy 2 – cost of strategy 1)/(effectiveness of strategy 
2 – effectiveness of strategy 1), where effectiveness is modeled as the number of 
disability-adjusted life years (DALYs) averted by the intervention. The primary 
cost-effectiveness measures will be the incremental cost per DALY averted using 
novel strategies (holiday and off-hours contact tracing) compared to routine 
contact tracing in each setting separately. 
8. Experiences of inconvenience, attitudes toward confidentiality, motivation 
to participate, and preferences for disclosure, assessed through both 
thematic analysis of in-depth interviews and focus group discussions and 
quantitative analysis of discrete choice experiments and best-worst scaling. 
 
 
 
11.2 Sample Size Considerations 
 
We estimate our sample size based on the assumption that 3% of household contacts will have 
tuberculosis (half the 6% prevalence seen in a previous study led by Dr. Martinson),64 and that 
an average of two contacts per case will be screened in the routine arm (based on our ongoing 
trial in Limpopo). Thus, in the routine arm, we anticipate a mean of 0.06 secondary cases per 
index case. Given the additional complexity of holiday-time or off-peak screening, we power our 
analysis under the a priori belief that such interventions will not be reasonably implemented 
unless they result in a yield that is twice that under routine contact investigation. Assuming an 
average of two to five contacts per household and a high (0.68) between-household coefficient 
of variation of the outcome as found in 64, a comparison of n=1600 households (index cases) in 
the routine arm and 800 households (index cases) in the novel arm would have more than 99% 
power to detect this difference. If only half of the expected index cases are enrolled, the 
minimum power (two contacts per household) would be 84%. A maximally conservative 
estimate of sample size – assuming complete clustering of these cases at the household level, 
two contacts per household, and only 50% as many household cases as found previously – is 
described by a Poisson distribution of 0.06 secondary cases per index case.  

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We have selected our sample size to give more than 90% power to detect this most 
conservative difference. The table below provides estimates of our power to detect a statistically 
significant difference in the primary outcome. 
 
Table. Power calculations. The power to detect each difference is given in italics; the primary 
comparison is between finding 0.06 secondary cases per index case  in the routine arm and 
0.12  in the novel screening arm.  
 
 
Mean number of secondary cases per index case, novel approach 
Mean 
number of 
secondary 
cases per 
index case 
, routine 
approach 
 
0.08 
0.1 
0.12 
0.18 
0.24 
0.02 
>0.99 
>0.99 
>0.99 
>0.99 
>0.99 
0.04 
0.99 
>0.99 
>0.99 
>0.99 
>0.99 
0.06 
0.54 
0.97 
>0.99 (primary) 
>0.99 
>0.99 
0.08 
- 
0.44 
0.93 
>0.99 
>0.99 
 
Randomization 
 
Randomization will be performed using computer-generated random permuted blocks of varying 
sizes, with an allocation ratio of 2 (routine):1 (novel: holiday or off-peak). Randomization will be 
conducted separately for Limpopo and Soshanguve and surrounding areas (i.e., two separate 
randomization sequences will be generated for each site); and within Limpopo, randomization will 
be further stratified by district, thus ensuring 2:1 allocation within each district as well. The 
randomization schedules will be uploaded into the REDCap system, which will automatically output 
an allocation every time a new consented patient is added and the interview is completed. In 
Limpopo, randomization will be performed throughout the year; those patients who are allocated to 
holiday timing will undergo household contact investigation during Easter if they are enrolled 
between February 1 and the end of the two-week Easter holiday, whereas those patients enrolled 
between the end of the Easter holiday and December 31 will undergo contact investigation during 
Christmas.  
11.3 Participant Enrollment and Follow-Up 
We anticipate enrolling a total of 14,400 participants: 
 
- 1600 index cases in the routine contact investigation arm in Limpopo 
- 1600 index cases in the routine contact investigation arm in Soshanguve 
- 800 index cases in the holiday contact investigation arm in Limpopo 
- 800 index cases in the off-peak contact investigation arm in Soshanguve 
- 9,600 contacts (a mean of two contacts per case, accounting for some cases who will not have 
any contacts, based on our enrollment of contacts in our current trial in Limpopo) 

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Among adults from the above groups, 384 individuals (192 index cases and 192 contacts) will 
be selected to participate in the bioethics supplement. 
 
We plan a single visit to each participant, so follow-up is not considered in this study. 
11.4 Analysis Plan 
Primary Outcome: 
Our primary effectiveness outcome will be the ratio of the number of secondary TB 
cases identified and started on treatment per index case in the novel strategy arm (off-
peak screening in Soshanguve and holiday screening in Limpopo) compared to index 
cases receiving standard contact investigation. We will conduct separate analyses for 
each site (rural Limpopo and peri-urban Soshanguve). For the primary analysis we will 
conduct an unpaired t-test for the hypothesis that the difference between the number of 
secondary TB cases per index case is the same in the two study arms.  A secondary 
analysis will be performed to adjust for index case demographics, socio-economic 
factors, self-reported health seeking behavior, and clinical characteristics such as HIV 
status and history of TB. As the majority of the index cases are expected to have no 
secondary cases, this will be conducted using a zero-inflated Poisson regression with 
robust standard errors to account for household and enrollment site clustering. 
 
Secondary outcome measures: 
1. The TB prevalence ratio, comparing highly mobile to less mobile index 
patients, measuring mobility on two scales (neighborhood/intra-urban and 
regional/intra-national). For the former, we will estimate the number of kilometers 
traveled on a daily basis (secondary analysis: amount of time spent in transit), 
truncating long excursions at 50km (one hour). Based on exploratory data 
analysis and consideration of generalizable numbers (e.g., multiples of 5 and 10), 
we will consider a binary measurement of “highly mobile” versus “less highly 
mobile” at a natural break near the midpoint of the data. We will then use log-
binomial regression to adjust for a priori potential confounders that will include 
age, sex, socioeconomic status, and HIV status, and robust variance estimation 
to account for clustering by households. Analyses will be stratified by site. We will 
perform a similar analysis for regional/intra-national mobility, taking as the 
primary exposure variable the self-reported number of trips per year greater than 
50km (secondary analysis: number of nights spent away from primary 
residence). For each measure of mobility, we will explore additional methods of 
modeling the exposure variable, including continuous (linear), using restricted 
cubic splines (which may yield less interpretable estimates of effect but more 
flexible incorporation of complex patterns in the data), and as a categorical 
(“dummy variable”) exposure – again at natural breaks in the data. 

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2. TB strain relatedness using maximum likelihood transmission trees.  Along 
with standard genetic thresholds (i.e. SNP differences of <5) for assessing whether 
strains are related by transmission, we will construct a maximum-likelihood 
phylogenetic tree using RAxML and other tree estimation packages. We will then 
employ a Bayesian approach to infer transmission.65,66 After separating the data 
into distinct putative transmission clusters using a probabilistic approach combining 
SNPs, timing, and location information, we will generate timed phylogenetic trees 
for each cluster using Bayesian Evolutionary Analysis Sampling Trees (BEAST).116 
We will then use a stochastic, continuous-time Monte Carlo Markov Chain (MCMC) 
representing a branching transmission model. We will model within-host evolution 
of Mtb assuming a neutral coalescent process and generate transmission trees 
using an MCMC approach.65,67 We will weight candidate transmission trees based 
on likely or unlikely linkages (e.g., household contacts). This method integrates TB 
natural history, epidemiological, and WGS-derived phylogenetic data into a 
statistical modeling framework to draw probabilistic conclusions about the 
likelihood of transmission between persons. “Transmitters” will be defined as 
individuals from whom at least one secondary case most likely originated. 
3. Relative acceptability of each novel strategy.  We will create an acceptability 
score from the interview questions, with a higher score indicating greater 
acceptability of the contact tracing strategy. We will use multivariable generalized 
linear regression model with a suitable link to model the acceptability score, with 
the primary exposure of interest being each novel contact investigation strategy 
(i.e off-hours tracing in Soshanguve, holiday tracing in Limpopo), relative to 
standard contact investigation in each setting. Analyses will be stratified by site 
4. Feasibility of each strategy as the proportion of potentially eligible index cases 
for whom a household visit was conducted. We will also record all reasons why 
visits were unable to be conducted (e.g. could not find household, no one ever 
home, visit not conducted during expected off-peak period). Analyses will be 
stratified by site 
5. Relative fidelity of each novel strategy using a process checklist for each 
index case and household, including whether the household visit was offered and 
accepted, whether the visit was attempted, whether the visit was successful (i.e., 
enrolled at least one contact), whether symptom screening and sputum collection 
were completed and whether newly identified TB cases were notified and 
referred for treatment. We will model fidelity as a binary outcome, using log-
binomial regression, with the primary exposure of interest being novel versus 
standard contact investigation (separately in each setting), adjusting for potential 
confounders (for example, socio-demographic and clinical factors)  and 
enrollment site as with the acceptability outcome and robust standard errors for 
multiple outcomes per household. Analyses will be stratified by site 

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6. Sustainability of each novel strategy will be accomplished by incorporating an 
indicator variable for the six-month time windows of the study period into the 
multivariable regression models of acceptability and fidelity outcomes described 
above, and evaluating for interactions between this time window indicator and the 
primary exposure variable (i.e. investigation arm).   
7. Cost-effectiveness ratio for each novel strategy. Outcome measures will be 
derived by combining study data on patient characteristics (e.g., demographics, 
HIV status) and intervention effectiveness with literature estimates on key 
parameter values (e.g., disability weights,68 sensitivity of Xpert Ultra,69 and 
notified data on treatment outcomes1) to construct a Markov model of a 
population of individuals who are eligible for TB screening under each strategy.  
In performing this evaluation, we will follow standard guidance for economic 
evaluation, including inflation using South Africa’s GDP deflator, conversion to a 
common currency (US dollars) and year, discounting of all future costs and 
effectiveness, and measurement of costs as economic (opportunity) costs.70,71 
We will conduct one-way sensitivity analyses of all model parameters and multi-
way sensitivity analyses of those parameters found to be most influential, in order 
to provide insight into the major drivers of cost-effectiveness and the settings in 
which each contact tracing strategy is likely to be preferred. We will also perform 
a probabilistic sensitivity analysis (using beta distributions for parameters with 
defined upper and lower bounds and gamma distributions for parameters defined 
from zero to infinity) to generate 95% uncertainty ranges around all estimates. 
We will construct cost-effectiveness acceptability curves, using as a reference 
South Africa’s per-capita gross national income of $5,430 as a willingness to pay 
per DALY averted72 but also considering revealed thresholds for potentially 
competing interventions (e.g., the estimated cost-effectiveness of treatments for 
MDR-TB for which the government of South Africa has revealed a willingness to 
pay). 
8. Experiences of inconvenience, attitudes toward confidentiality, motivation 
to participate, and preferences for disclosure. Outcome measures will be 
assessed via Likert scales which will be evaluated via multivariable regression, 
adjusting for demographic characteristics, district, study arm, and household 
characteristics (e.g., size). Responses will be dichotomized based on exploratory 
data analysis and conduct log-binomial regression, comparing these results to 
those of linear regression performed after assigning a numerical value to each 
response level. Our generic (e.g. unlabeled) discrete choice experiment (DCE) 
will be based on five different attributes (disclosure of index case TB status, 
routine vs off-peak evaluation, inclusion of routine HIV testing, use of official vs 
unmarked cars, provision of monetary reimbursement for time), each with two 
different levels. The DCE will utilize a fractional factorial design created to 
estimate the main effects alone. Results from the DCE for certain characteristics 

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will be compared against a double-bounded contingent valuation survey in which 
we will evaluate participants’ willingness to accept household CI (with different 
characteristics) with and without monetary reimbursement of different levels (to 
compensate for household members’ time). 
11.5 Blinding 
The US-based PI (David Dowdy), the South African-based co-PIs (Neil Martinson and Khatija 
Ahmed) and NIH sponsors will be blinded to all primary and secondary outcomes during 
conduct of the study through the completion of data cleaning and analysis. 
 
 
 

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12 
ACCESS TO SOURCE DATA/DOCUMENTS 
Research records for this study will be kept in a centralized study office in each district, in 
compliance with Section 4.9 of ICH E6 GCP, and regulatory and institutional requirements for 
the protection of confidentiality of subjects.  As part of participating in a DMID-funded,   study, 
each site will permit authorized representatives of the funder, DMID, and regulatory agencies to 
examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.  

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
Details on all quality control and quality assurance procedures can be found in the associated 
DMID approved Clinical Quality Management Plan.  The participating site is responsible for 
conducting routine quality assurance (QA) and quality control (QC) activities to internally 
monitor study progress and protocol compliance. The site principal investigator will provide 
direct access to all study-related sites, source data/data collection forms, and reports for the 
purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. The site principal investigator will ensure all study personnel are appropriately 
trained and applicable documentations are maintained on site. 
The data management center will be maintained by PHRU with input from Setshaba Research 
Centre, and will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database within 2 days of mobile 
data capture. Cyclical queries will be communicated to the sites for clarification and resolution. 
Protocol compliance will be managed on a day-to-day basis by the study coordinator, and 
overseen by the PI and other study investigators.  The study coordinator will ensure proper 
training on study protocol of all study staff and will conduct routine field visits in order to monitor 
study compliance. Data quality will be monitored for missing values on a weekly basis by the 
study coordinator who will review case report forms and remediate errors or omissions with 
study staff.  In depth data quality checks will be made on a quarterly basis, managed by the 
data manager. 
A study monitor from PHRU will make periodic field visits to study sites to review study practices 
and documents in order to ensure compliance with ethical standards.   

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformity with the current 
revision of the Declaration of Helsinki, or with the International Conference for Harmonisation 
Good Clinical Practice (ICH-GCP) regulations and guidelines, whichever affords the greater 
protection to the subject. 
14.2 Institutional Review Board 
Independent ethics review of this study will be handled in South Africa by the Human Research 
Ethics Committee at the University of the Witwatersrand, which holds a current U.S. Federal-
Wide Assurance issued by OHRP, and in the United States by the Institutional Review Board at 
the Johns Hopkins Bloomberg School of Public Health. 
14.3 Informed Consent Process 
 
Written consent (and assent) 
Written consent will be obtained for all study participants. For children, written consent will first 
be obtained from the parent/guardian and followed with written assent from children 7 years and 
older. Consent will be conducted privately and one-on-one. Consent will be obtained using an 
easily-understood form (as the educational level of the target population is low). Risks and 
benefits of participation will be explained, with a clear alternative of no participation, and 
participants will be clearly informed that consent can be withdrawn at any time without adverse 
effects on their clinical care. Informed consent will be provided in the participant’s preferred 
language, including English and four local languages (Tshivenda, Sepedi, Tsonga and 
Setswana). Our experience in Limpopo Province is that, while a number of local dialects are 
spoken, almost all participants can communicate fluently in one of these languages. All informed 
consent documents, including a register thereof, will be maintained in a locked cabinet 
accessible only to study personnel. We anticipate that some of the participants are not literate, 
and hence not able to read the written consent. For such participants, we will read the consent 
document as described above, asking participants to make a mark on a corresponding form 
(and a witness who is not a member of the study staff to sign the form) after having the 
opportunity to ask any questions and being given the opportunity to decline enrollment with no 
adverse consequences on their clinical care. Enrollment of illiterate participants will be important 
to for proper representation of the study population. For these individuals, again, the scientific 
benefit increases if we are able to include all potential participants (not only those whom we 

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could consent with on-site staff), and this activity of screening for TB is already the existing 
standard of care.   
14.3.1 Informed Consent/Assent Process (in Case of a Minor or others 
unable to consent for themselves) 
In the case of minors, aged 7-18 years, we will seek written assent, using a separate 
form from that used for adults. The assent forms will be written in simpler language the 
details of the study, study procedures and risks.  In addition, we will seek 
parent/guardian informed consent for the participation of these minors. For children <7 
years, we will seek only parental informed consent. 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This study does not intend to exclude any of these special populations. 
14.5 Subject Confidentiality 
 
The risks faced by participants in this study relate to consequences due to breach of 
confidentiality.  Disclosure of any clinical information, including HIV and TB status, could be 
potentially damaging to the study participants.  Household visits by the study team may 
engender stigma by neighbors.  These risks will be minimized by ensuring that all study team 
members are trained in Good Clinical Practices and re-emphasizing the principles surrounding 
confidentiality on a regular basis in order to ensure that clinical information is handled with 
respect and in line with the highest research ethics standards. Recruitment, consent and 
interview of index cases (or next-of-kin) will be conducted in one-on-one in a private room.  
Household visits will be conducted using unmarked cars and non-uniformed staff. For safety 
purposes, household visits will be conducted in teams of at least 2 study staff, who will present 
identifying badges and ask permission before entering the household.   
Confidentiality cannot be assured in the presence of focus-group discussions, however we will 
take several precautions to maximize confidentiality: 1) Emphasize confidentiality at the 
beginning and end of focus group discussions; 2) Use of alternative name placards instead of 
actual participant names; 3) Conduct all individual-based activities (e.g. informed consent, 
reimbursement) in private. Although we will record focus groups as well as in-depth interviews, 
these recordings will not use participants’ names or other identifiers and will be destroyed once 
the interviews are transcribed/translated. 
All study materials will be kept in locked cabinets when not in use, and the study database and 
files containing transcribed focus groups and interviews will be password protected and stored 
on secure servers. All paper-based study data will be stored in locked cabinets in a locked 

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room.  Identifiers will be kept separately from all other study data, and will be coded using a 
unique study ID. The key for this study ID will likely be kept separately. The database will not 
contain participant identifiers, and will be password protected and stored on a secure database. 
Data will be accessed by JHU investigators through the secure online password protected 
database. All recorded interviews will be stored on a password protected secured hard drive 
and will be destroyed following completion of transcription/translation. 
14.6 Future Use of Stored Specimens 
The remainder of any sputum specimens not used for Xpert MTB/RIF and/or liquid culture will 
be stored at the central NICD laboratory for all those testing Xpert MTB/RIF positive, as well as 
a subset of 5% of all those testing Xpert MTB/RIF negative.  Specimens will be stored at -80C in 
a locked freezer, and will be identified by study ID only. Specimens will be held for the purpose 
of future testing using a novel diagnostic test for TB. Specimens will be held for 5 years 
following the close of enrollment (until 30 March 2027) and will then be destroyed. 

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15 
DATA HANDLING AND RECORD KEEPING 
15.1 Data Management Responsibilities 
 
 
Details of study data management can be found in the corresponding Data Management plan.  
In brief, data collection will be conducted by research assistants, interviewers and study nurses. 
 The study coordinator and data manager will be responsible for routine quality control of the 
data.  The principal investigator and other study investigators will be responsible for periodic 
data review, generating study materials and reports.   Our local partners, the Perinatal HIV 
Research Unit and the Setshaba Research Centre will be responsible for retaining source 
documents and records.    The PI and investigators will be responsible for data interpretation, 
analysis, as well as review of tables and listing. Reporting to the sponsor and ethics/IRB 
committees will be the responsibility of the PI and other investigators. 
15.2 Data Capture Methods 
We will use handheld mobile devices (phones and/or tablets) in order to collect data for this 
study.  We will utilize REDCap, a secure mobile data collection platform for this purpose.  Data 
from interviews and file reviews can be captured directly on the mobile device and either 
immediately uploaded to a secure online database, or uploaded later in case a good cellular 
signal is not available.  Data may also be captured on paper forms then later entered into 
REDCap if mobile devices are not available/functional. 
15.3 Types of Data 
Types of data collected will include those from chart and record review, participant interviews on 
above listed outcomes, and qualitative interviews for bioethics sub study. 
15.4 Timing/Reports 
Data review will occur on a quarterly basis in order to ensure enrollment targets are met, and 
that inclusion/exclusion criteria are followed.  Final data review will take place at the completion 
of each study phase. 

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15.5 Study Records Retention 
The investigator will maintain records pertaining to this study for a period of 5 years following 
the close of enrollment. Permission is not required prior to destruction of records. 
15.6 Protocol Deviations 
We will monitor data on a quarterly basis in order to ensure that there are no deviations from 
protocol.   
Protocol compliance will be managed on a day-to-day basis by the study coordinator, and 
overseen by the PI and other study investigators.  The study coordinator will ensure proper 
training on study protocol of all study staff and will conduct routine field visits in order to monitor 
study compliance. Additionally, he will review consent forms and study case report forms to 
identify potential areas for protocol violation, and conduct retraining as necessary.  The study PI 
and other investigators will make period study monitoring visits to ensure protocol adherence, 
and will conduct weekly teleconference calls with the study coordinator to review progress and 
address protocol issues in a timely fashion.  Likewise, the study coordinator will monitor day-to-
day compliance with ethical standards through training, review of practices, consents, 
enrollment logs and case report forms, as well as through periodic unannounced field visits.  
Additionally, study monitors from our local partners, the Perinatal HIV Research Unit and 
Setshaba Research Centre, in South Africa will make periodic field visits to review study 
practices and documents in order to ensure compliance with ethical standards.   

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16 
PUBLICATION POLICY 
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal, as well as present finings at international scientific conferences.  The 
International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
trials-registration policy as a condition for publication.  This policy requires that all clinical trials 
be registered in a public trials registry.  We will register this trial at ClinicalTrials.gov. 
. 

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17 
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