GXT - GeneXpert or Chest-X-ray or Tuberculin Skin Testing for Household Contact Assessment: a Cluster Randomized Trial
Phase: NA
Conditions: Latent Tuberculosis
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
1 
GXT – GeneXpert or chest-X-ray or Tuberculin skin testing for household contact assessment: 
a cluster randomized trial 
Main objective:  
To compare across three different strategies for contact investigation the proportion of 
household (HH) contacts treated for active and latent tuberculosis (TB), time to treatment 
initiation, adverse events, as well as costs from the perspective of the health system and 
patient.   
 
Summary of the 3 strategies compared:  
Children under 5 years old in Benin and people living with HIV (known or detected through study 
procedures) will be excluded from this study as they should receive an expedited strategy as 
recommended by WHO. Adults older than 50 years old will also be excluded; they will be 
investigated and treated for LTBI on an individualized basis by their provider after judging the 
balance of risks and benefits. All children, regardless of age, can be included in the study in 
Brazil. 
 
Study participants will be randomized to: 
1. Standard care (control arm): Participants will receive symptom screening and tuberculin skin 
testing (TST). If symptom screen positive and/or TST positive, they undergo chest x-rays (CXR). If 
CXR abnormal, they undergo microbiological investigation. If CXR normal or if microbiological 
investigation negative, TST positive receive latent TB infection (LTBI) treatment. If 
microbiological investigation is positive they will be offered treatment for active TB. For 
children under 5 years of age in Brazil, sputum induction will be performed for bacteriological 
investigation. 
 
2. GeneXpert (GX): Participants follow an algorithm similar to the standard care, however 
participants with positive symptom screen and/or positive TST will receive GX (i.e., GX replaces 
CXR in standard care algorithm). GX positive are considered to have active TB. TST positive and 
GX negative receive LTBI treatment.  If an individual is not able to provide sputum, they will 
undergo a CXR.    
 
3. CXR for all/NoTST: Participants will receive symptom screening and CXR. No TST will be 
performed. If CXR abnormal or symptom positive, they undergo microbiological investigation. If 
the CXR is normal, and/or microbiological investigations negative – they receive LTBI treatment 
as per national guidelines. If microbiological investigation is positive they will be offered 
treatment for active TB. 
 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
2 
 
 
 
Specific objectives: 
To compare outcomes that result from three different strategies for the management of HIV 
uninfected persons aged 0-50 years who are HH contacts of newly diagnosed microbiologically 
confirmed active pulmonary TB.  
 
Primary Outcome:    
Among HH contacts of patients with newly diagnosed active pulmonary TB (index TB patient), 
who are eligible (measured or estimated) for LTBI therapy, the proportion starting LTBI therapy 
within 3 months of the index TB patient starting active TB treatment. 
Rationale: The primary endpoint will be the number of HH contacts who start latent TB therapy 
within 3 months of the date of start of active TB treatment in the index TB patient (the member 
of their household who was diagnosed with active TB and because of whom the contact 
investigation was performed). Because household contacts are at risk to progress to active TB 
within months after exposure and infection, all TB programs recommend that contact 
investigation is completed, and contacts started on latent TB therapy rapidly - as soon as 
possible once active TB has been excluded. For this study we will use a benchmark that contacts 
should begin LTBI therapy within 3 months of the date of start of treatment of the Index HH 
member who has active TB. The date when the index case TB patient is started on active TB 
treatment is easy to identify and standardized, whereas the date of diagnosis of active TB can 
be difficult to establish as it depends on the modality of diagnosis.   
 
Secondary outcomes: 
1. Societal costs (health system and patient costs) of the full cascade of care - from initial 
identification to LTBI therapy completion. 
2. Prevalence of microbiologically confirmed and clinically diagnosed active TB  – detected as 
part of the initial contact investigation, who initiate LTBI treatment within 3 months of the 
index TB patient starting active TB treatment. 
3. Prevalence of positive TST (>5 mm or >10 mm) – overall, and by age group.  
4. Incidence of grade 1-4 adverse events related to LTBI therapy. 
5. Completion of LTBI therapy – defined as having taken at least 80% of doses in 120% of 
allowed time. 
6. Sensitivity and specificity of CXR reading by usual providers in each study site (reference 
standard will be readings by an external review panel). 
7. Prevalence of active TB  diagnosed using CXR in participants who cannot produce a sputum 
sample. 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
3 
8. Applicable for Brazil only: To evaluate the applicability and performance of material for 
bacteriological investigation obtained from induced sputum in children under 5 years of age. 
 
Background and rationale for the study: 
 
Impact of latent TB infection 
There are several unique features of the pathogenesis of TB that make global eradication of this 
disease very challenging. TB is transmitted through the airborne route from a person with 
active and contagious pulmonary TB to an uninfected person in close proximity. If infection is 
acquired during this exposure, then in more than 95% of persons, disease does not develop 
right away. Instead the newly infected person will develop latent or dormant infection, which 
can reactivate to cause active disease months to decades later. It has been estimated that one 
quarter of the world’s population has latent or dormant tuberculosis [1]. This acts as a huge 
reservoir from which active symptomatic and contagious TB develops. Active TB that is 
untreated is fatal in a high proportion of individuals, although if diagnosed and treated, 
mortality is much lower. However, substantial morbidity can occur despite treatment: several 
studies in low and middle-income countries (LMIC) demonstrated that persons who recovered 
from active TB had an average loss of lung function of 25% – equivalent to the effects of heavy 
cigarette smoking for more than 25 years. Hence, prevention of TB, through treatment of LTBI, 
could provide very important potential individual benefits – by preventing this morbidity and 
mortality. TB prevention could also provide important public health benefits. In a modelling 
study, officials at the World Health Organization (WHO) estimated that treatment of LTBI was 
essential to achieve long-term reductions in global TB incidence [2]. In view of the individual 
and public health benefits, a recent United Nations high level conference on TB set a target that 
more than 30 million individuals should be treated for LTBI over the next 5 years. This 
ambitious goal will require massive scaling up of LTBI diagnosis and treatment – which will be 
challenging, if not impossible, with current approaches to diagnosis and treatment of latent TB. 
 
Diagnosis of latent TB infection (LTBI) 
The diagnosis of LTBI relies upon detection of an immune response to antigens from M. 
tuberculosis, the microorganism that causes TB. Two tests are available to detect antigens: the 
Tuberculin Skin Test (TST), first introduced in 1908, and the interferon gamma release assays 
(IGRA), which have been in clinical use for the past 15-18 years. The IGRA’s measure the 
immune reaction to more specific TB antigens and are ex-vivo tests. Despite its relative 
antiquity, the TST remains the most commonly used test for LTBI diagnosis in the world. The 
advantages of the TST include its low cost and feasibility in resource-poor settings because 
there is no need for complex laboratory equipment or procedures, nor for highly trained 
technicians, although trained health care personnel and a functioning cold chain are necessary. 
One disadvantage is that the TST is less specific, but two meta-analyses have summarized that 
TST can be used to predict benefit of LTBI therapy [3, 4]. Although there are some 
inconsistencies, the majority of the published studies have demonstrated that in those who are 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
4 
TST positive, LTBI therapy is significantly beneficial, but is not beneficial when given to those 
who are TST negative.  
 
Despite this, the current WHO recommendations allow TB programs in resource-poor settings 
to give LTBI therapy to persons living with HIV, and children under five years – even in the 
absence of TST [5]. This reflects the high risk of disease in these two populations if LTBI 
treatment is not given, and the operational challenges of performing the TST in LMIC. These 
include the difficulties of training and quality assurance of TST administration and reading, and 
a global shortage of tuberculin material. This last problem was due in part to production 
problems of a major supplier – Statens Serum Institut (SSI) in Copenhagen. The production 
problems are now resolved, but the global shortage remains, and because of this, the price of 
tuberculin test material (PPD) has risen considerably. The problems of quality assurance of TST 
are well recognized – although considered a reliable test ‘in good hands’ – those good hands 
require training and ongoing supervision – as with any diagnostic test. Brazil adopted these 
WHO recommendations for people living with HIV. However, children under five years old who 
are investigated for LTBI  should receive TST and chest X-ray before LTBI treatment 
initiation.But, the most important limitation is that only about 10% of those with a positive TST 
will ever develop active disease. Hence, ten persons with presumed LTBI must be treated to 
prevent one from developing disease. 
 
The IGRA’s have become increasingly popular over the past 15 years – due in large part to their 
improved specificity – a major advantage in high income, low prevalence settings.  However, 
the unit costs for these assays are higher than for the TST and are less accessible than TST in 
most resource-limited settings due to the need for complex laboratory equipment and well-
trained technicians. In addition, the IGRA’s are equally inefficient as the TST for predicting who 
will develop disease. Several meta-analyses and large prospective studies have shown the 
IGRAs to have little or no difference in their ability to predict future active TB [6-9]. Current 
WHO recommendations state that IGRA or TST may be used, although several potential 
advantages of TST for resource-limited settings are listed in the same document [5].  
 
Treatment of LTBI 
The inefficiency of LTBI diagnosis would be less important if treatment of latent TB was quick, 
inexpensive and safe. However, for the vast majority of persons treated for LTBI in LMIC, 
current treatment has none of these characteristics. The current standard treatment, 
recommended by the WHO, is 6 months Isoniazid (6H). This is obviously long and also can lead 
to serious side effects including potentially fatal liver toxicity, particularly in older adults. Even 
in high income settings with close monitoring and follow-up, liver failure (requiring liver 
transplantation) and deaths still occur [10, 11]. In addition to these problems (or perhaps 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
5 
because of them), less than 50% of persons complete 6H or 9H as prescribed, under routine 
conditions in many programs [12]. 
 
These problems with INH have motivated considerable work in the past 20 years to develop 
and test new, shorter regimens. Most of these regimens have included rifampin or rifapentine – 
which have greater bactericidal activity, allowing shortening of active TB treatment.  Three 
rifamycin-based regimens have been shown, in randomized trials, to have at least as good 
efficacy for TB prevention as 6 or 9 months INH. The regimen of 3-4 months INH and rifampin 
(3HR) has the same efficacy and adverse event profile as 6 months INH [13]. A regimen of 3 
months INH and rifapentine (3HP) given once weekly for 12 doses had non-inferior efficacy 
compared to 9H, and similar safety in large scale randomized trials [14]. In these trials, the 
overall rate of grade 3-4 adverse events, or adverse events requiring regimen change, were 
more frequent with 3HP than with 9H [14, 15], but liver toxicity was significantly less with 3HP 
[14]. The third alternative is 4 months daily rifampin. In recent trials, when compared to 9H, this 
regimen has been shown to have non-inferior efficacy for TB prevention in largely HIV 
uninfected adults [16] and children [17]. Very importantly, this is the only LTBI regimen that has 
consistently shown significantly lower rates of grade 3-4 adverse events (or drugs stopped due 
to adverse events) when compared to the standard 9H [16-18]. On the basis of these trials, and 
associated meta-analyses, in LMIC WHO has recommended use of 6INH or either 3HR or 3HP, 
and country National TB Programs (NTP’s) have started adopting them. WHO also 
recommended these regimens, as well as 9H, and 4R in high income countries [5]. 
Importance of household contacts  
HH contacts are well recognized to be at high risk for active TB. This includes prevalent active 
TB – detected at the time of initial contact investigation – and incident active TB that occurs 
within the next 2 to 5 years. In systematic reviews, among HH contacts in LMIC, the prevalence 
of active TB ranges from 3% to 5% [19, 20]. For this reason, screening HH contacts for active TB 
is considered a high priority for virtually all TB control programs in all LMIC as this is a very high 
yield active case finding strategy. Treatment of LTBI among these HH contacts may also have an 
important potential benefit as the prevalence of LTBI exceeds 50% in LMIC [19, 20]. Hence, 
identification and investigation of contacts is a high-yield activity, for detection and treatment 
of active as well as LTBI.  
The investigation and treatment of all the HH contacts has other important advantages – this 
approach can provide important health and financial benefits to the entire family. The 
occurrence of TB can have very serious effects on the family including the well described 
catastrophic costs related to loss of income and costs for care. [21, 22]. By investigating and 
detecting both active and latent TB – further catastrophic costs will be avoided, and the 
amplified health consequences due to occurrence of TB in other HH members prevented. 
Hence this approach is in line with a more holistic ‘family health’ approach. In addition, this 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
6 
approach is much more efficient – TB care can be provided to all HH members at once, during 
the period of time the index TB patient is still receiving care – maximizing the impact and cost-
effectiveness of health system interventions, such as home visits, or minimizing patient costs 
due to travel for follow-up visits. 
 
 
The cascade of care in LTBI – Methods and problems of contact Investigation  
The diagnosis and treatment of LTBI – in HH contacts or others with LTBI - represents a complex 
cascade of care. In a recent systematic review, we demonstrated that substantial losses and 
dropouts occur throughout that cascade [12], substantially reducing the potential benefit of 
LTBI management. Of all those with LTBI in the studies included in the review, only 18% 
completed investigation and therapy appropriately.  
 
Two aspects of management of LTBI – need for CXR and need for TST - are controversial, as 
both can create important barriers to LTBI initiation, thereby reducing the individual as well as 
public health benefits. WHO updated its guidelines for LTBI management in 2018 [5]; this 
included detailed recommendations for investigation to exclude active TB  which is important 
to avoid inadvertent mono-therapy of patients with undiagnosed active TB, as this can lead to 
the emergence of resistance. The algorithm suggested in HIV negative persons aged 5 and older 
is based on extensive experience in randomized trials. In these trials, patients underwent 
screening to exclude active TB including symptom assessment and CXR. Although not 
necessarily 100% sensitive to detect all prevalent active TB, this testing was sufficient to 
prevent the development of resistance in those who received INH treatment [23, 24]. This is 
the fundamental objective – if a screening algorithm is sufficient to identify (and therefore 
exclude) those who will develop resistance if given INH mono-therapy, there is no justification 
for further testing. Symptom screen has acceptable sensitivity to detect prevalent active TB 
among HIV infected individuals who are not treated with anti-retroviral therapy (ART) [25] and 
child contacts aged less than 5 years old [5]. However, symptom screen alone is less than 50% 
sensitive to detect active TB in adults and children aged 5 and older who are HIV uninfected, or 
HIV infected person on ART [5, 26]. In these same populations, CXR screening has sensitivity as 
high as 98%, if any abnormality triggers further investigation. This may explain why the current 
algorithm is sufficient to avoid development of INH resistance. However, CXR services are not 
accessible in many settings and even if accessible, the cost for a CXR often falls on patients [27] 
and is often prohibitively expensive. For example, in the proposed study sites in Benin, the NTP 
and government health services do not cover the full costs for CXR; therefore, patients must 
bear all or part of the cost. In Benin patients pay the equivalent of 10 Euros for one CXR. In a 
family with 6 HH contacts, the cost of CXR for all contacts will exceed the average one-month 
salary for an unskilled worker. This is clearly not affordable, particularly as part of a preventive 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
7 
strategy. Hence the requirement of a CXR as part of the pre- LTBI treatment algorithm results in 
a major barrier preventing HH contacts from starting on potentially beneficial LTBI treatment.  
 
An alternate strategy is to use GeneXpert equipment, with the Xpert MTB/Rif test (hereafter 
labelled GX) to replace CXR to exclude prevalent active TB. This will make the algorithm less 
complex (fewer steps), and may increase the number of patients who successfully complete all 
steps in the algorithm. GX, a recent addition to the tuberculosis diagnostic armamentarium, is a 
cartridge-based test that utilizes nucleic acid amplification techniques (nested PCR) to detect 
M. tuberculosis DNA in sputum samples within 2 hours. This test also can detect rifampin 
resistance if tuberculosis is present. The availability of this test has steadily increased over the 
last 10 years in LMIC. Sensitivity is better than that of direct microscopic examination of a 
sputum for acid fast bacilli (AFB smear), although less than TB liquid culture. GX is also less 
sensitive, but more specific than CXR, and the result is much more reproducible. Since the GX 
cost is always covered by TB programs, from a patient perspective, this is more attractive than 
CXR. In addition, the high sensitivity and 2-hour turnaround time means that this can be used as 
a rapid rule out test in HH contacts.  
 
Disadvantages to this strategy include the lower sensitivity of GX in patients with minimal active 
disease (so called pauci-bacillary disease), raising concerns about giving therapy for latent TB 
infection to patients with negative GX but minimal active disease. However, based on earlier 
studies of latent TB therapy there appears to be a considerable margin of safety. The first 
United States public health study conducted in 1958-1962, randomized children with 
parenchymal infiltrates and hilar lymphadenopathy to placebo or INH monotherapy. Children 
with these findings on CXR nowadays would be considered to have active disease. Despite this 
evidence of significant active TB, children treated with INH alone had very high success rates 
and no reported emergence of resistance [28]. Another group would be patients with symptoms 
who are unable to produce sputum. This could raise concerns about missing minimal active TB, 
so a CXR will be done for all patients with TB symptoms who cannot produce a sputum sample. 
For all those under 5 years of age, a sputum sample will be obtained for bacteriological analysis 
through sputum induction with 5% hypertonic saline solution. Another disadvantage is false 
positives since prevalence is low. 
 
Prior relevant research by the team 
Completion, safety and efficacy of 4 months rifampin (4R) vs 9 months INH (9H): Between 2001 
and 2018, we conducted a series of three clinical trials to compare treatment completion, 
serious adverse events and efficacy in TB prevention of 4R and 9H. The phase 2 and phase 3 
studies (completed in 2007 and 2018 respectively) were conducted in Brazil and Benin among 
other sites. In these studies, we demonstrated that in these 2 countries, patients’ acceptance of 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
8 
LTBI diagnosis and treatment was high, their tolerance and completion of both treatments were 
good, although completion and safety were significantly better with 4R. These findings 
suggested that latent TB management was well accepted by providers and patients in these 
settings. The results of these trials were fundamental for the current WHO recommendations. 
A cluster randomized trial of a public health intervention to improve the Cascade of care in LTBI 
(ACT4): During the conduct of the 4Rvs9H trial, a number of major challenges in the LTBI 
cascade of care were identified. These motivated ACT4 – a cluster randomized trial of a public 
health intervention to improve the latent TB cascade of care at health facilities in Benin, Ghana 
and Brazil, as well as in Canada, Indonesia and Vietnam. Initial cascade of care analyses in Benin 
and Brazil revealed that almost no HH contacts were initiating LTBI treatment (let alone 
completing it). The ACT4 study revealed different problems at each study site; as part of the 
study, local solutions were identified and implemented by stakeholders at each site. These 
were successful in resolving barriers to LTBI diagnosis and treatment, and when these potential 
barriers were identified and removed, we found that HH contacts in these settings were 
enthusiastically adherent to the various steps in the cascade of care in latent TB, resulting in 
substantially greater uptake of LTBI therapy in all settings. 
However, at most sites the performance of TST and access to CXR prior to initiating LTBI 
therapy were problems that were very difficult to resolve. The TST was not performed in most 
settings – in part based on the recommendations of WHO, and in part because of cost and 
complexity (and also a global shortage of tuberculin testing material). Hence staff at the sites 
had to be trained and a quality assurance program initiated to maintain high quality 
performance of TST. The CXR was also an important additional barrier, because even if 
available, CXR was not paid by the TB programs, so costs had to be borne by TB patients or their 
contacts. For the ACT4 project, CXR were paid by research funds, but this is clearly not 
sustainable. In other settings, a waiting list for CXR delayed substantially LTBI treatment 
initiation. Therefore, either the CXR has to be abandoned as an integral part of LTBI 
investigation or WHO must adopt a policy that CXR are an essential service to be provided for 
TB patients and their contacts. 
Summary of evidence 
In summary, current WHO recommendations allow TB programs in resource-poor settings to 
manage latent TB without testing in under five child contacts and HIV infected of all ages. This is 
because the guidelines group considered that the risks from not receiving LTBI treatment in 
those with latent TB outweighed the risks of unnecessary therapy in those without LTBI 
treatment. We believe the same argument can be applied to all contacts under 50 years – as 
this group is also at high risk to develop disease. Current policy and practice in many LMIC is 
that HIV uninfected HH contacts aged 5 years and older do not receive LTBI treatment. This is 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
9 
because incorporation of TST and CXR into the test and treat algorithm for this group has had 
the unintended effect of reducing the likelihood that HH contacts with LTBI are treated at all. In 
a nutshell, the current policy has deprived a high-risk group of significant potential benefits, 
because of concerns about potential harms from overtreatment or misdiagnosis (i.e. treating 
for LTBI when it is in fact active TB). From our prior research studies in these settings, we know 
that LTBI treatment is well accepted with high rates of completion among HH contacts. 
However, the difficulties of access to affordable CXR and high quality reliable TST in these 
settings are major impediments to long term success of our previous findings. We believe the 
balance of benefits and risks will favor LTBI treatment of HH contacts in the absence of TST, and 
also that GX may be a very satisfactory replacement for CXR. However, the advantages and 
disadvantages of the different approaches we propose to test in this study may vary depending 
on the resources available at each setting, as well as the prevalence of LTBI and age structure in 
the populations of HH contacts.  
 
STUDY DESIGN, INTERVENTIONS AND RATIONALE 
This will be a cluster randomized trial with three arms of equal size; clusters will be defined as 
all the household contacts of patients with newly diagnosed active pulmonary TB. The first 
eligible member of the HH who provides signed informed consent to participate will be 
randomized to one of the three strategies. All subsequently enrolled members of the same HH 
will be assigned to the same arm. In all strategies, if the treating team believes that there is 
sufficient clinical, radiologic and microbiologic evidence for the diagnosis of active TB, the HH 
contact will receive treatment for active TB. If other respiratory diseases  (ie. pneumonia, 
asthma etc) are suspected, then these will be investigated and treated by the primary provider.  
 
As mentioned above, HH contacts who are <5 years old in Benin only, and/or HIV infected 
should complete expedited investigations as recommended by WHO and so will be excluded 
from the study. All potential study participants will be asked about known HIV infection, as well 
as current therapy with ART. As well contacts may be tested for HIV infection – those found to 
be positive will be excluded – including post randomization. Other members of the HH aged 0-50 
years will receive LTBI treatment as per national algorithms. HIV uninfected HH contacts aged 
over 50 years will also be excluded, as LTBI treatment would not be given routinely to them – to 
enhance safety. On an individualized basis the provider may recommend therapy if they judge 
that the risks of disease outweigh risks of adverse events. 
 
Rationale for cluster study design   
A family-based approach to TB control is proposed, as we see this as the most feasible next step 
in TB endemic areas to truly begin to prevent future cases of active disease.  This has the 
advantage of being a highly feasible strategy, for active case finding, and LTBI detection and 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
10
treatment compared to population level testing. This is because the TB programmes in most 
countries, and certainly in the participating countries, already identify and screen HH contacts 
of newly diagnosed patients with active TB – hence the proposed activities are an extension of 
those activities, rather than entirely new ones. 
 
Strategy ONE: Standard: This strategy is based on the current WHO recommended algorithm 
for HH contacts that are HIV negatives and age > 5 years in Benin. TST and microbiologic testing 
are generally paid by the TB program, but in Benin, in normal practice, the HH contacts pay for 
CXR. For study participants, these CXR costs will be paid by research funds.  
In Brazil, this strategy is based on the algorithm currently recommended by the WHO for 
immunocompetent contacts up to 50 years of age. It is also the standard strategy recommended 
by the Brazilian NTP . 
  
Symptom screen and TST at the time of the first interview. (An IGRA would be an acceptable 
alternative, but in the 2 countries where this study will be conducted, IGRA testing is not 
accessible in the public health system).   
If no symptoms: participants with negative TST will be discharged. The cut-point for 
negative/positive TST will be according to NTP policy in each country. If positive TST, then CXR  
will be done.  
If symptom screen is positive (cough, sputum, fever, anorexia/weight loss), participants will 
undergo a CXR. (Note: In all situations in Strategies 1 & 3, when a CXR is indicated for a female 
HH contact of child bearing age, she will be questioned regarding possible pregnancy, and if 
confirmed (or possible) will undergo CXR with appropriate shielding). If the CXR is abnormal, 
the HH contact will have microbiologic investigations. These microbiological investigations will 
comply with NTP policy and procedures in each country. In Benin, when pulmonary tuberculosis 
is suspected, two sputum samples are taken – the first sample is taken immediately on the 
spot, and the second is collected by the patient at home the next day upon waking. Refer to 
appendix 1 for details of procedures in Brazil, where this will also be standardized for all study 
participants. If the CXR is normal, and symptoms have resolved after a week – then TST 
negative will be discharge and TST positive will be recommended to start LTBI therapy. If the 
CXR is normal but TB symptoms persist, then microbiological testing will be done. If the 
microbiological tests are negative for active TB, then participants will be discharged if TST 
negative, or recommended to start LTBI therapy (if TST positive). 
 
IF a CXR was done before the randomization for any other reason, we can use that result if:  
(1) CXR was done within 3 months before enrolment (in the study) but BEFORE the date of diagnosis of 
the index TB patient;  
(2) That earlier CXR was normal;  

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
11
(3) The participant does not have persistent TB symptoms currently; 
(4) The CXR film must be available to review (and to take a picture for the study documents) not just the 
report. 
 
If all four conditions are met - the prior CXR can be used. Otherwise the CXR must be repeated. 
NOTE: If a CXR was done on the same day or after the date of diagnosis of the index TB patient - this 
HHC is excluded. 
 
IF TST (or IGRA) indicated, (Note: for Strategy 1&2 persons with history of prior treatment for 
active TB will not have TST, but will have a CXR to exclude active TB).  
TST negative - will have no further investigation. (Brazilian guidelines recommend a second TST 
8 weeks later. This will not be mandated by the study protocol – to be consistent in all countries 
and with WHO guidelines. However, if providers wish to do this second TST – this can be done 
and therapy given if the second TST is positive). 
TST positive - will have a CXR (if not done already). If CXR abnormal they will have 
microbiological testing as above. If CXR normal, and no history of prior TB treatment, they will 
be recommended to start LTBI therapy.  
For Strategy 1 and 2 – the use of the TST may be new in some clinics and for some HCWs. 
Training will be done for TST administration and reading, during initial site training. The “mTST 
tool”  will be used as part of the quality assurance for the TST – at all sites (see link for video on 
mTST instructions https://www.youtube.com/watch?v=xmCRJ44TmpQ, and appendix 2 for 
instruction manuals for mTST). 
 
Figure 1: SCHEMATIC OF STRATEGY 1: Standard (based on Algorithm in WHO LTBI guidelines 
2018) 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
12
 
 
* For Brazil, if participant under 5 years old, sputum collection must be performed using the induced sputum method. 
 
STRATEGY TWO: GX & TST Strategy:   
The main difference from Strategy 1 above is that GX replaces CXR everywhere that CXR would 
normally be done. TB program pays for all TST and GX. 
Symptom screen at the time of the first interview.  
No symptoms will have TST (or IGRA, but as described above this will be TST in study sites) 
Positive symptom screen (cough, sputum, fever, anorexia/weight loss) will undergo a GX.  
GX positive – treat active TB  
GX negative - TST (or IGRA) 
IF TST (or IGRA): 
TST negative - will have nothing further.  
TST positive - will have a GX (if not done already).  
GX positive – will have a chest-x-ray as part of an assessment of the diagnosis 
and need for treatment of active TB. Treatment will be at the discretion of 
treating clinician/team (see below – for rationale).  

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
13
GX negative - will be recommended to start LTBI therapy.  
 
It is predicted that even after careful training, approximately 40% of adolescents and adults 
would not be able to produce a spot sample of sputum and an even higher proportion of 
children aged 5 to 10 years will be unable to produce a sample sputum. In these participants 
this may result in missed active TB with the GX strategy. However, for children under 5 years of 
age, spontaneous sputum collection is d an alternative. Therefore, for this age group, we will 
collect material using inducing sputum with 5% hypertonic saline. Studies comparing the results 
of culture and molecular biology testing demonstrated better yield of material collected by 
induced sputum when compared to gastric lavage and nasal aspirate in any of the  available 
detection methods. In the Vietnamese ACT3 population-based study, sensitivity of GX to detect 
pulmonary active TB among household contacts was only 40%, compared to a reference 
standard of 2 sputum samples sent for liquid TB culture. Hence, there is a real risk that active 
TB can be missed with the GX strategy, although an argument could be made that this will likely 
be minimal active TB. We think it better to ascertain this through a secondary procedure with 
appropriate secondary analysis. Participants who are randomized to the GX strategy and are 
unable to produce a sputum sample (between 5 and 10 years) - after standard efforts, will have 
a CXR. If the CXR is abnormal and judged possibly or probably active TB such that microbiologic 
investigations are necessary, these will be done following procedures outlined for the other two 
arms. In a planned secondary analysis, we will examine the proportion of participants in the GX 
arm who are unable to produce sputum and: (i) are judged to have possible or probable active 
TB on CXR; or, (ii) are treated for active TB ; or, (iii) have positive sputum cultures.   
Similarly, CXR and other investigations can be performed at the discretion of the treating 
physician/team if other respiratory diagnoses are suspected. Or, if CXR abnormal or CXR normal 
plus symptoms, but microbiologic investigations are negative, then medical evaluation can be 
done to exclude other respiratory illnesses. (Indeed, in all three strategies, the investigations 
mandated by the protocol are the minimum required. But the treating team can, at any time, 
order additional investigations and prescribe non-TB related treatment, if they feel these are 
clinically warranted). All non-protocol mandated investigations and treatment will be recorded, 
and the costs added in the calculation of total costs for each strategy, regardless of whether 
these added costs are borne by the public health system or the patient.  
Figure 2: SCHEMATIC OF STRATEGY 2: GX replaces CXR 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
14
 
*In Brazil, if participant under 5 years old, sputum collection must be performed using the induced sputum method.  
 
Rationale for GX intervention:  
The unit cost of GX is similar to that for CXR, but in all countries the cost for this test is borne by 
the TB program – an important advantage to patients. This strategy may prove to be more 
expensive for the TB program/health system, but will also be more rapid and efficient in 
detecting active disease as this skips the step of CXR which is then followed by microbiologic 
investigations. From the TB program’s perspective, GX offers the advantage of good sensitivity 
(better than AFB smear). For this study, GX is already available at proposed sites in Benin and 
Brazil. If participants have symptoms but are unable to produce sputum it is plausible that these 
procedures may miss some cases. However, studies have demonstrated that training of health 
care staff about how to obtain sputum from patients will enhance yield [29]. (refer to appendix 
3 for example patient instructions from Zimbabwe; this will be adapted for use in the two 
countries). If staff have been trained in instructing patients, and no sputum is produced, then 
active TB is unlikely in asymptomatic patients; however, we will routinely obtain a CXR in all 
these HHC from 5 years old (see above).  For those under 5 years of age, a material collection 
strategy will be used with sputum induction by 5% hypertonic saline solution. Induced sputum 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
15
has been used safely in children of any age in high-prevalence and resource-poor settings such 
as South Africa. For the investigation of active pulmonary TB, the use of molecular biology 
techniques such as the Gene X-pert MTB/RIF Ultra in expectorated or induced sputum have 
shown greater sensitivity in children when compared to conventional techniques and may 
become an important tool for the use in public health in Brazil. In addition, providers will be 
encouraged to exercise their clinical judgement in care of symptomatic HH contacts. Therefore, 
they may decide to treat such patients with antibiotics or other therapy – based on their clinical 
judgement. This would be in accordance with current WHO recommendations for patients with 
“TB symptoms” but negative microbiologic investigations. If, after 1-2 weeks, the symptoms 
have resolved then LTBI therapy can be started. If the HH contact is still symptomatic, then 
another attempt will be made to obtain a sputum sample. If no sputum sample is obtained, 
then providers may decide to order other investigations such as a CXR, or other treatment. 
On the other hand, if the GX is positive, we must consider possible false positive results as GX 
has a specificity of 98%. If the contact has a positive GX and TB symptoms – the GX will be 
considered true positive, given the higher pre-test likelihood disease. However, if the contact 
has no symptoms and a positive GX they will also have a CXR routinely to assist in the clinical 
decision making. This is because GX has a 2% false positive rate. In asymptomatic HH contacts – 
the expected prevalence of active TB is low – estimated to be less than 2%. In these persons the 
positive predictive value might be less than 50%. Hence a CXR will be mandated – to assist in 
the clinical assessment of these contacts, and reduce the risk that contacts with a falsely 
positive GX receive unnecessary treatment for active TB.   
 
STRATEGY 3: CXR ALL, no TST:   
This group will undergo CXR regardless of presence of symptoms. If the CXR is abnormal, or CXR 
normal and symptoms then microbiologic investigations will be done. These investigations will 
be as per national TB policy and procedures, as above. If CXR abnormal or CXR normal plus 
symptoms, but microbiologic investigations are negative, then medical evaluation will be done 
to exclude other respiratory illnesses. If no sputum is obtained for microbiologic investigations, 
then usually this will be considered a negative microbiologic result. However, this will be up to 
the treating team/provider – if they agree – then LTBI therapy can be started. But if they feel 
that additional investigations are warranted, then they may follow the current WHO algorithm 
for TB suspects – which is to treat for an alternative diagnosis (usually oral antibiotics for 7-10 
days for a respiratory tract infection) with repeat evaluation after 14 days. If persistent 
symptoms, then repeat sputum examinations are recommended. If at any time TB is confirmed 
or considered likely by the treating team/provider, then active TB treatment is started. Once 
active TB is considered excluded by the treating team, then the HH contact will be 
recommended to start LTBI therapy. All microbiologic tests are paid by the TB program, but in 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
16
Benin, in normal practice the HHC pays CXR cost. Study participants: CXR will be paid by 
research funds.  
 
IF a CXR was done before the randomization for any other reason, we can use that result if:  
(1) CXR was done within 3 months before enrolment (in the study) but BEFORE the date of 
diagnosis of the index TB patient;  
(2) That earlier CXR was normal;  
(3) The participant does not have persistent TB symptoms currently; 
(4) The CXR film must be available to review (and to take a picture for the study documents) not 
just the report. 
 
If all four conditions are met - the prior CXR can be used. Otherwise the CXR must be 
repeated. 
NOTE: If a CXR was done on the same day or after the date of diagnosis of the index TB 
patient - this HHC is excluded. 
 
Figure 3: SCHEMATIC OF STRATEGY 3 (CXR all, no TST) 
 *
 
*If participant under 5 years old, sputum collection must be performed using the induced sputum method. 
 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
17
Rationale for CXR all/no TST intervention:  
In this strategy CXR will be performed for all HH contacts – so persons with prevalent active TB 
will not be missed. However, the overall program costs will be higher, due to costs related to 
the CXR. For ethical reasons the study must bear costs of CXR for participants, however if this 
arm were shown to be best strategy the cost implications (i.e. need for publicly funded CXR) 
would need to be addressed. Since the CXR has long been discouraged by WHO policy this study 
findings would be presented to WHO, and the National TB programme managers in the 
participating countries, as part of the knowledge translation efforts.  
The other disadvantage of this strategy is that HH contacts without LTBI are treated – which 
results in unnecessary costs (patient and health system) and risks to patients from adverse 
events without potential benefits. However, this approach warrants consideration for several 
reasons: 1) TST may be inaccurate due to poor technique – due to lack of trained personnel, 
and/or lack of a quality assurance program; 2) Stock-outs of tuberculin test material due to 
recurrent global shortages make TST frequently unavailable; 3) Delays and dropouts plus added 
costs are associated with TST, due to need for multiple patient visits for TST administration and 
reading. Without need for a TST, LTBI therapy can be started the same day as symptom screen 
and CXR (one stop shop); 4) Among the highest risk groups of child contacts aged <5 years, and 
HIV infected persons the WHO recommends TST, but makes it clear that if TST cannot be 
performed, for any of the reasons listed above, that LTBI therapy should be given – since the 
benefits of therapy outweigh the risks in these groups. It may be argued that the same is true 
for all HH contacts.  
A further consideration is the expected prevalence of positive TST among HH contacts; 
as prevalence increases the no-TST strategy becomes more advantageous. One systematic 
review estimated the pooled prevalence of LTBI among HH contacts in LMIC to be 51% [19, 20]. 
However, data from previous work at our study sites shows that prevalence of positive TST 
among HH contacts of all ages is 51% in Brazil (M Bastos unpublished), and 72% in Benin (M 
Adjobimey unpublished). This means that the number unnecessarily treated would be less in 
these high TB incidence/ high LTBI prevalence study settings. In addition, the HH contacts most 
likely to have a negative TST are the youngest. This is the group who are also the least likely to 
have any serious side effects with any of the LTBI regimens [10, 30, 31]. Hence, the risk of 
unnecessary side effects from treating LTBI in persons who do not have LTBI should be low.  
Another way that we have reduced the risk to participants is that we have limited 
routine provision of LTBI treatment to HH contacts aged younger than 50 years, as the rates of 
adverse events is higher in those aged over 50 years [30, 31] although providers can 
recommend therapy if they feel the benefits outweigh the risks on an individual basis. A final 
mechanism to reduce risks as well as time and cost burden on study participants will be to 
introduce shorter regimens such as 4R, 3HP or 3HR instead of 6H as standard LTBI treatment. In 
this way, all HHC treated within this study would receive the same shorter regimen –i.e. the 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
18
regimen would not be randomized. This has been accepted by the National TB Program in each 
country, as this will provide pilot programmatic experience to demonstrate the advantages – to 
patient and programs - of use of shorter rifamycin based LTBI therapy.  
In Benin, 3HR will be used – as the fixed dose combination formulations for adults and 
children are available in all health centres. As reviewed earlier, 3HR has better completion rates 
than 6INH, which should result in better effectiveness, and lower program as well as patient 
costs, since fewer follow-up visits are necessary. This would help compensate for the increased 
workload of more contacts being treated. An added advantage of 3HR is that it’s easy to 
implement in all settings as the formulations – for adults and children are already available in 
all settings, and staff are familiar with dosing and administration, as they are used for 
treatment of patients of all ages with active TB. In Brazil, 4R may be used – as this is approved 
for use by the National Programme. Of all the currently recommended short regimens tested in 
randomized trials, only 4R has had significantly lower overall rate of all serious adverse events, 
or of hepato-toxicity than 9H or 6H. Hence use of 4R should reduce time and cost burden on 
patients and staff, plus reduce risk of AE. 
 
STUDY POPULATION  
Study site (clinic) selection 
We will use a checklist (refer to appendix 4) for each health facility that will focus on the 
number of index TB patients diagnosed at the facilities, and their capacity to conduct all the 
steps of the LTBI cascade of care. These include contact investigation, Tuberculin skin testing 
and reading, performance and interpretation of CXR, performance of GeneXpert and of 
subsequent microbiologic testing, LTBI treatment initiation and follow-up. For a clinic to be 
selected, they do not necessarily need to have CXR or GeneXpert facilities on site, but they 
must make arrangements that CXR and/or GeneXpert can be performed on household contacts 
in a nearby health facility. This means they will have an explicit agreement (not necessarily a 
signed MOU or contract, but at least well known to staff and agreed upon by clinic 
management) that patients from their clinic can go to a nearby health facility and obtain these 
tests within a reasonable delay. Reasonable is defined as the delay that would normally be 
incurred at health facilities that have these procedures on site. As well they must agree to 
perform contact investigations including Tuberculin skin testing and reading - if materials and 
training are provided.  
We will select clinics that are representative of the diagnostic facilities and capacities available 
in clinics in the country. This means that clinics may be selected that have all diagnostic facilities 
on site, but others may be selected that do not have either chest-x-ray or GeneXpert, but have 
made administrative arrangements with nearby health facilities for the performance of these 
tests  in their patients. 
 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
19
Inclusion criteria 
Index TB patients:  
1. New diagnosis of pulmonary microbiologically confirmed (smear, GX or culture) active 
TB within 30 days of treatment initiation.  
For Brazil: a new diagnosis of clinically pulmonary active is eligible. 
2. Must have at least one identified household contact, and HHC investigation has not 
been started already.  
3. Must agree to allow research team to access their medical history and approach their 
household contacts. 
Household contacts:  
1. Age 5-50 years for Benin and Age 0-50 years for Brazil.  
2. On average in the past 3 months – slept in the same house, at least one night per week, 
or spent at least one hour per day for 5 days per week.  
3. Pregnant woman can be included.  
4. People with prior active TB or latent TB therapy will be included. These participants will 
be assessed for prevalent active TB, although they will not be treated for LTBI. Hence 
they will be included in the analyses of yield of active case finding, but excluded from 
analyses of numbers diagnosed and treated for LTBI. 
 
Exclusion criteria 
Index TB patients:   
1. Known drug-resistant TB (INH resistant, multidrug resistance or rifampin resistance) may 
be excluded – after discussion in each country with TB program officials. If the TB 
programme’s policy is to screen contacts of MDR cases for active TB only and not 
provide any LTBI therapy, then index TB patients with MDR will be excluded as well as 
their HHCs. However, if the national TB program policy is to treat such individuals with 
standard LTBI therapy (since some HHCs of MDR patients will develop TB with drug-
sensitive isolates later), then these index TB patients and their HHCs will be eligible. 
Hence, this will be a country-specific exclusion criterion.  
2. Index TB patient with previous history of active TB (because their HHC may have 
undergone investigation before – which may change their need for study interventions, 
and also potentially change their perceptions and behaviours in the study).  
3. Only has extra-pulmonary TB.  
4. No identified household contacts.  
Household contacts:   
1. Members of the household, but do not meet the minimum time definitions for HH 
contacts.  
2. Had TST/IGRA within 3 months. 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
20
3. Had a CXR on the same day of after the date of diagnosis of the index TB patient. 
4. People living with HIV. In most TB programs, HH contacts have unknown HIV status; HIV 
testing is recommended by WHO only if the index TB patient is known to have HIV co-
infection. Contacts will be asked if they have been previously diagnosed to have HIV 
infection, and also asked if they are taking anti-retroviral therapy (if patients are 
receiving any medications, these will be checked carefully to verify what these are, and 
in particular if they are on anti-retroviral therapy). Both questions will be asked because 
some patients may be on therapy, but are not aware of the indication, or they may not 
wish to divulge their HIV status. If HHC are on anti-retroviral therapy and/or provide a 
history of previous HIV diagnosis, then they will be excluded, because the WHO 
recommended algorithm for investigation of household contacts who are HIV infected is 
different from that followed in the study arms. All index TB patients should undergo HIV 
testing based on national algorithm. If the index TB patient is found to be HIV positive,  
partner notification services will be recommended to the person living with HIV. The 
children of women who are HIV-infected should also undergo HIV testing. HIV testing 
will be offered to these household contacts (ie children and partners of an HIV infected 
index TB patient) who have not been HIV-tested within the last 6 months. If any 
household contact is found to be HIV-infected, they will be excluded pre-randomization. 
If there is a significant delay between identification of the household contacts and 
obtaining the HIV result, the HHCs can be randomized and then excluded post-
randomization. These HHCs will be excluded from the modified intention to treat 
analysis, which will be the primary analysis. All HHCs identified to have HIV-infection will 
undergo investigations and treatment following national guidelines for HIV-infected 
household contacts. 
5. If one member family refuses to participate to the study and has no objection to have 
the other HH members to participate in the study, then we can proceed with the 
consent process with the other HHC. But if one household contact refuses to participate 
and objects to other HH members to take part of the study, then none of the HHC in this 
family can participate in the study. It is not necessary that all of the HHC signed consent 
but simply that no one objects.  At any time a participant can refuse any test, or have 
other investigations - as ordered by their doctor/nurse or if they prefer).  
 
Consent and enrolment 
The first step in enrolment will be to explain the study to all newly identified index TB patients 
with active pulmonary TB. Those that agree will provide the names of their HH contacts to 
study personnel, who will approach each HH contact (or their parent / guardian if a child aged 
up to -17 years) for individual signed informed consent. We will not seek informed consent 
from the index TB patients, since they do not actively participate in any study procedures. 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
21
Members of the same HH do not have to all agree to participate, as the interventions are 
directed to each individual.  
 
 
Randomization 
If one or more HH contact agrees to participate and provides signed informed consent, then the 
first member of the HH will be randomized to one of three arms. All other consenting members 
of the HH will be assigned to the same arm, as long as they are enrolled within 14 days after the 
first HH member was randomized. 
Randomization will be computer generated and stratified by randomization units within each 
country, in blocks of variable length. Randomization units will be defined on the basis of 
expected number of eligible index TB patients, and availability on-site of CXR facilities.   
Registration of participants, entry of information to verify eligibility, and randomization will be 
done via a web-based programme, that will be developed and housed by the Laboratoire de 
Télématique Biomédicale (LTB) du Réseau en santé respiratoire du Québec (RSR), with whom 
we have worked for similar data entry and randomization programs for more than a decade. 
 
SAMPLE SIZE CONSIDERATIONS 
  
LTBI treatment initiation: 
We will base total sample size on the proportion of identified HH contacts who start LTBI 
treatment in each strategy. We are interested to detect a difference between the proportion of 
HH contacts starting LTBI therapy in those randomized to the standard algorithm and each of 
the alternative regimens. The proportion starting LTBI during phase 2 of ACT4, at the same 
study site, when solutions had been implemented and the barriers of TST and CXR had been 
resolved will be used as the likely proportion in the Standard arm. We consider that accepting 
to start treatment will likely be strongly influenced by other household members. We do not 
have an estimate of the cluster effect of HH on starting, so will use the “cluster effect” of study 
therapy completion which was observed in the 4V9 trial in the same sites. This gave an ICC of 
0.33. Based on that and an average of three HH contacts aged 0-50 years (observed in ACT4), 
we can estimate the design effect as (1+household size)*ICC. We will not adjust for clustering at 
the level of the health facility, but instead will balance key characteristics within each country 
by stratifying randomization by characteristics of the health facility (CXR on-site), plus group 
facilities into randomization units of equal numbers of active TB patients. 
 
 
 
 
 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
22
 
 
 
Table 1: Sample size required to detect superior initiation of LTBI therapy with either one of 
the experimental arms compared to standard arm 
 
* alpha = 0.05. The intra-class correlation coefficient (ICC) or clustering effect of households on LTBI 
treatment initiation was estimated from the ICC for completion in the adult trial comparing 4R with 9H 
[16], among study subjects who had at least one other family member in the study – i.e. from 
participants in families of size >1. We expect the average number of household contacts to be 3 (based 
on our just completed ACT4 study). 
** In the Standard and GX arms, all children <5 years, and older HH contacts who are TST positive will be 
eligible to initiate therapy. We estimate this will be about 50% of all HH contacts, resulting in the lower 
overall expected initiation rate among all HHC – as cannot exceed the expected proportion eligible for 
LTBI therapy. In the no TST arm we expect a higher proportion of HH contacts will start therapy, but we 
will estimate the number eligible based on prevalence of positive TST in the same age groups at the same 
centres in the other two arms; the number required in the no TST arm is therefore the same - based on 
this estimation.  
*** Total is based on 80% power. 
 
In the ACT4 trial, 60% of eligible HH contacts started an LTBI regimen once the TST and CXR 
problems were resolved. We assume that 50% of HH contacts will be eligible for LTBI therapy, 
and that 60% of eligible HH contacts in the Standard arm will start therapy – for an overall 
initiation rate of 30% with Standard arm in this trial. To detect an improvement such that 85% 
LTBI Initiation rate – among all 
HH Contacts identified 
Number required per group to detect significant 
difference*, accounting for clustering by household 
Standard 
Experimental 
(GX or noTST)** 
N per arm – 80% 
power 
N per arm –60% 
power 
Total N*** 
(3 arms) 
40% 
45% 
3046 
1901 
9138 
 
50% 
766 
478 
2298 
 
 
  
  
 
35% 
40% 
2921 
1823 
8763 
 
42.5% 
1311 
818 
3933 
 
45% 
742 
464 
2226 
 
47.5% 
477 
298 
1431 
 
 
 
 
 
30% 
35% 
2734 
1706 
8202 
 
40% 
703 
439 
2109 
 
42.5% 
455 
284 
1365 
 
45% 
318 
199 
954 
 
 
  
  
 
25% 
30% 
2484 
1551 
7452 
 
35% 
649 
405 
1947 
 
40% 
297 
186 
891 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
23
of eligible start therapy in the GX arm, for an overall initiation rate of 42.5% we would need to 
enrol 455 participants into each arm. Allowing for 5% withdrawal, or otherwise not analyzable 
participants, this would inflate the number per arm to 478, so we plan to enrol a total of 1434 
participants. If the LTBI treatment initiation rate among eligible is 80%, providing an overall 
initiation rate that is only 10% better than Standard – then 1371 participants would still provide 
60% power to detect a significant difference. Power will be greater if the initiation rate in the 
Standard arm is lower; for example, if only 50% of eligible HH contacts or 25% overall initiate 
therapy, as seen in Table 1.  
 
Patient and health system costs: 
Costs associated with the different study arms will be carefully measured. We expect that 
significant differences exist between sites in terms of costs – from perspective of health 
systems and patients. Hence, we have calculated study power for each country. For power 
calculations costs are based on estimates from the WHO CHOICE database and data gathered as 
part of prior studies (ACT4). As seen in Table 2, the number enrolled to each arm in each 
country should provide more than 90% power to detect a significant difference in costs. 
 
Table 2: Sample size required to detect significant difference in costs between Standard and 
GX arms – in each country 
 
Estimated costs associated with 
Standard* CAD$ 2017  
 Estimated costs associated with GX** 
CAD$ 2017  
Power to detect effect sizes***  
(Effect size = the detectable difference/SD)  
Patient  
perspective^ 
Health 
System 
perspective 
Total 
Patient 
perspective^  
Health 
System 
perspective 
Total 
0.3 
0.33 
0.5 
Benin 
 
20 
121 
141  
16 
111 
127 
0.72 
0.8 
0.99 
 
 
 
 
 
 
 
 
 
Brazil 
 
36 
319 
355  
28 
278 
306  
0.72 
0.8 
0.99 
 
 
 
 
 
 
 
 
 
 
* For Standard Scenario: Assume that HH contact has two visits for TST (administration and reading). 
Half have three more visits for medical evaluation and CXR, and 20% of these have an added two more 
visits to collect sputum samples. 25% have all of the above, plus 1 visit for LTBI treatment initiation and 3 
more visits for LTBI treatment follow-up.  
** For GX scenario: Assume that HH contact has two visits for TST (administration and reading). Half 
have one more visit for medical evaluation and GX. One quarter also have one visit for LTBI treat 
initiation and 3 more visits for LTBI treatment follow-up. 
^Costs from the Patient Perspective: Expenses associated with medical visits assumed to be $4.00 per 
visit in Benin, and $7.50 per visit in Brazil. This accounts for travel costs and additional expenses during 
travel or at medical visit. 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
24
***To estimate power, we assume alpha = 0.05, and 455/3=152 analyzable subjects per group in each 
country, and we considered the effect size (detectable difference/SD).  We do not know the standard 
deviation, but can estimate approximate costs, based on prior work in each country. As an example, 
based on costs collected previously in Ghana (neighbouring country to BENIN, that also participated in 
our prior RCT of 4RIF vs 9INH), we expect a difference in total costs of $28 between standard and GX 
arms. If the standard deviation is $84, then the effect size will be ($28/$84) = 0.33. After accounting for 
clustering by household, assuming an ICC of 0.33 and 4 subjects per household this effect size will result 
in estimated power of 80%.  If the SD is actually smaller (SD=$56), then for the same expected difference 
in costs, we will have an effect size=0.5, providing 99% power to detect a significant difference. 
 
LTBI Treatment completion: 
The power to detect a significant difference in treatment completion is determined primarily by 
the expected number who start LTBI therapy in each arm, and the expected completion rates in 
the Standard arm. The expected number who will start is taken from Table 1. In the 4R trial 
completion of 9H overall was 62% among adults, and 80% in children, compared to 75% and 
90% completion rates for 4R respectively. Hence, we anticipate overall completion rates in 
these same sites with the Standard strategy to be similar – i.e. close to 70%. As seen below we 
will have more than 67% power to detect a significant difference in LTBI completion rates.  
Table 3: Power for various detectable differences in completion of LTBI therapy with GX or 
noTST arms (numbers based on 455 analyzable subjects per arm, and initiation rates of 42.5% 
(GX or no TST arm) and 30% (standard arm), as shown in Table 1 above) 
LTBI completion rate (of those who start) 
Standard 
GX or noTST 
Estimated Power 
50% 
60% 
0.26 
 
65% 
0.52 
 
70% 
0.78 
 
 
 
60% 
70% 
0.29 
 
75% 
0.57 
 
80% 
0.83 
 
 
 
70% 
80% 
0.34 
 
85% 
0.67 
 
90% 
0.92 
* alpha = 0.05. The intra-class correlation coefficient (ICC) or clustering effect of households on LTBI 
treatment completion was estimated from the ICC for completion in the adult trial comparing 4R with 9H 
[16], among study subjects who had at least one other family member in the study – i.e. from 
participants in families of size >1. We expect the average number of household contacts to be 3 (based 
on our recently completed ACT4 study). 
 
Prevalent Active TB among HH contacts 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
25
In two systematic reviews, the prevalence of active TB among HH contacts, at the time of initial 
investigation, was 3-5% [19, 20]. We assume that any difference in detection of prevalent active 
TB will be the result of an increased number of HH contacts who complete the investigation 
algorithm, and not because of inherent differences in test characteristics (for example a 
difference in sensitivity between GX and CXR). Hence, extrapolating from Table 1, if the 
difference in proportion starting LTBI therapy is equivalent to the difference in the proportion 
completing the investigation – then we expect a difference that about 10% of HH  contacts will 
complete the investigation algorithm with GX or CXR/no TST – which would mean a difference 
in detection of prevalent active TB of 10% of 5% or 0.5% or one more active case detected per 
200 HH contacts enrolled. Given the anticipated enrolment and follow-up of only 455 per arm, 
it is unlikely that we will detect significantly more cases of active TB. However, we plan to 
maintain this as a secondary outcome – given the strong current global interest in methods to 
enhance active case detection. As well, power may be greater - if the prevalence of active TB is 
higher, or the differences between standard and experimental arms are greater than expected. 
DATA GATHERING: 
Pre-randomization (baseline) 
For the index TB patient, we will collect information regarding demographics, results of AFB 
smear, GX, and/or cultures, and CXR. 
For each HH contact identified, we will gather information regarding age, sex, co-morbid 
illnesses, relationship to the index TB patient, nights per week sleeping in the house or hours 
per week spent in the house. We will also gather information regarding prior history of 
tuberculosis, prior treatment for latent or active TB as well as any prior testing for tuberculosis, 
including TST or IGRAs. 
 
Post-enrolment and randomization - Investigation of HHC 
For consenting HH contacts, we will gather information on the investigations performed – 
including those mandated by the protocol (symptom screen, CXR or GX, TST or IGRA) and as 
well document all other investigations performed at the discretion of the treating team. One 
particular concern is the potential for errors made by the treating team in conducting 
investigations not mandated per protocol, due to their desire that HH contacts get certain tests 
even if not part of the strategy to which the HH was randomized. All investigations including 
dates performed and results will be recorded.  
 
To measure one of the secondary outcomes, the sensitivity and specificity of CXR interpretation 
by the study site staff will be estimated from a second reading of a copy of the film (or digital 
file) by an independent reviewer. This reviewer will be a chest specialist with experience in TB, 
or a radiologist. The reviewer will judge if the CXR is normal or abnormal, and if abnormal - 
whether the abnormalities are consistent with active TB (yes/no) or suspicious enough for 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
26
active TB to warrant further microbiologic investigations (yes/no). A fourth question will ask if 
there are additional respiratory diagnoses suggested by the CXR (yes/no). These finding will be 
used to estimate sensitivity and specificity of CXR reading by local staff. Missed minor 
abnormalities may result in commencement of treatment inappropriately in the CXR and 
standard arms.  On the other hand, over-diagnosis (especially among children under -10) also 
may have occurred. The CXR re-readings will not be done ‘in real time’ and the results will not 
be used clinically. However, results will be returned to the original CXR readers’ as a quality 
improvement measure. 
 
Follow-up during LTBI treatment 
If patients are recommended to take LTBI treatment by the treating team, this will be recorded 
and also whether the patient accepts and begins treatment. The definition of LTBI treatment 
started will be a prescription given or pills dispensed. Follow-up during LTBI treatment will not 
be mandated by protocol. This is a pragmatic trial, and the LTBI treatment is not part of the 
interventions to which participants are randomized. Hence, we cannot impose a burden on the 
participants, meaning that follow-up during LTBI treatment will follow local/national 
recommendations and norms, and that we will accept the treating team’s definitions of 
treatment completion or non-completion. As part of site staff training at the time of study 
initiation, we will review national and international recommendations for follow-up, as well as 
definitions of completion/non-completion, and seek a consensus among providers as to the 
optimal methods of follow-up for their site, that balance need for patient safety with feasibility 
and costs – for patients and the health system.  All patient visits will be recorded and at these 
visits, we will request (or study staff will perform) pill counts.  
To measure the secondary outcome of treatment completion, pills dispensed at each visit, as 
well as counts of pills remaining on return visits will be recorded and used to calculate 
treatment adherence and completion. Treatment completion will also be defined as having 
taken 80% of doses within 120% of allowed time; this definition will be used in secondary 
analyses.  
 
End of treatment – documentation 
End of treatment forms will be competed for all HHCs enrolled who start LTBI therapy. These 
will be completed when LTBI is stopped – either because treatment was completed (as defined 
above), or not completed – due to patient decision, provider decision due to adverse event, 
death, or other outcome. 
 
Health system costs and patient costs 
Differences in health system costs between the three strategies will focus on the costs related 
to the different tests being used, and related management of results of these tests.  Each cost 
will be estimated using relevant cost components and an ingredients approach.  The actual 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
27
activities, investigations, supplies and services used for the investigation and treatment of all 
HHC, including follow up will be tabulated. Drug costs and all costs related to adverse event 
management will be included. The cost components required for each test are summarized in 
Table 4.  Health personnel time is a key component of total test cost.  The health personnel 
time for various LTBI management activities, including tuberculin skin test administration and 
reading, medical evaluation and initiation of treatment, will be taken from time and motion 
(TAM) studies completed during ACT4. The WHO CHOICE tool will be used to estimate health 
facility overhead costs and international suppliers such as Global Drug Facility (GDF) for the cost 
of materials where relevant (see below for specific details and references).  
Table 4:  Cost components and potential sources of cost data for tests performed  
UNIT COST AND COMPONENTS 
SOURCE / METHOD TO OBTAIN / DATA COLLECTION TOOL 
TB CONTACT INVESTIGATION 
 
HCW Time to Perform 
TAMS and/or reported fees paid from ACT4 
HIV Test 
From UNAIDS Agreement 
Outpatient Visit 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
TB SYMPTOM SCREEN 
 
HCW Time to Perform 
TAMS and median salaries from ACT4 
Outpatient Visit 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
CHEST X-RAY 
 
Cost of CXR and Personnel 
Derived using an allocation key applied to healthcare facility overhead and personnel¶ 
CXR-Related Patient Costs 
The cost charged to the patient for the CXR (patient subsidizes CXR cost in Benin) 
Non-CXR Related Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
INTERFERON-GAMMA RELEASE ASSAY 
 
Phlebotomist time to take blood 
Collected through TAMS during study; median salary collected during study 
Laboratory fee 
Derived from healthcare facility fees 
Outpatient Visit 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
TUBERCULIN SKIN TEST 
 
Materials: syringe, tuberculin 
Collected through ACT4 
HCW Time to Perform and Read 
TAMS and median salaries from ACT4 
Two Outpatient Visits 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
GENE XPERT 
 
Materials: Cartridge, Sputum Cup 
From Global Drug Facility Diagnostics Catalogue 
HCW Time to Take Sputum 
Collected through TAMS during study; median salary from ACT4 
Laboratory Personnel Time to Run GX 
TAMS and median salaries from ACT4 
Running Costs for Laboratory 
Derived using an allocation key applied to healthcare facility overhead† 
Outpatient Visit 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
SPUTUM AFB* 
 
Materials: Sputum Cups 
From Global Drug Facility Diagnostics Catalogue 
HCW Time to Take Sputum 
Collected through TAMS during study; median salary from ACT4 
Laboratory Personnel Time to Perform Smear 
Collected through TAMS during study; median salary from ACT4 
Running Costs for Laboratory 
Derived using an allocation key applied to healthcare facility overhead† 
Outpatient Visit 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
SPUTUM CULTURE* 
 
Materials: Sputum Cups 
From Global Drug Facility Diagnostics Catalogue 
HCW Time to Take Sputum 
Collected through TAMS during study; median salary from ACT4 
Laboratory Personnel Time to Perform Culture 
Collected through TAMS during study; median salary from ACT4 
Running Costs for Laboratory 
Derived using an allocation key applied to healthcare facility overhead† 
Outpatient Visit 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
LTBI TREATMENT (3HR, 3HP, 4R, 6H) 
 
Materials: Drugs 
From Global Drug Facility Medications Catalogue 
Lab Monitoring: Blood Tests (LFT, HIV, etc.) 
Derived from fees paid to local laboratory 
HCW Time During Treatment Initiation and Follow-
up (Physician, Nurse, Administrative) 
Collected through TAMS during study; median salary from ACT4 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
28
Adverse Event Management 
Algorithm collected during study, with cost components collected throughout 
Outpatient Visits 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
ACTIVE TB TREATMENT 
 
Materials: Drugs 
From Global Drug Facility Medications Catalogue 
Lab Monitoring: Blood Tests (LFT, HIV, etc.) 
Derived from fees paid to local laboratory 
HCW Time During Treatment Initiation and Follow-
up (Physician, Nurse, Administrative) 
Collected through TAMS during study; median salary from ACT4 
Adverse Event Management 
Algorithm collected during study, with cost components collected throughout 
Outpatient Visits 
WHO-CHOICE tool – tailored to healthcare facility specifications 
Patient Costs 
Modified version of patient cost questionnaire geared toward LTBI 
TAMS: Time and Motion Study; TB: tuberculosis 
¶Chest x-ray is subsidized in Benin meaning the patient pays for a chest x-ray, but some of the cost is still covered 
by the healthcare system. To determine the healthcare system cost of CXR we will use a top-down approach with 
an allocation key derived based on proportion of manpower assigned to the radiology department who are 
required to perform CXR. The running costs of the radiology department would then be approximated by the 
proportion of healthcare facility overhead—excluding staff salaries (as they are already considered) and other 
unnecessary items for day-to-day function. Using the manpower allocation required to perform CXR, we can use 
median salaries of radiologists and radiology technicians to arrive at annual personnel related costs. We will sum 
the overhead and personnel costs and divide this value by the annual number of CXR performed at the facility to 
determine the cost per CXR performed. 
†Allocation key derived based on proportion of manpower assigned to the laboratory compared to total 
manpower in the healthcare facility. The running costs of the laboratory would then be approximated by this 
proportion of healthcare facility overhead—excluding staff salaries (as they are already considered) and other 
unnecessary items for day-to-day function. 
*For these unit costs, fees from the laboratory may be used as proxy measures of cost. 
 
Key References for Table 4:  GDF (http://www.stoptb.org/gdf/;  WHO-CHOICE (https://www.who.int/choice/cost-
effectiveness/en/) and Patient Cost Questionnaire; 
http://www.stoptb.org/wg/dots_expansion/tbandpoverty/assets/documents/Tool%20to%20estimate%20Patients'
%20Costs.pdf 
 
Patient costs must be carefully considered in LTBI management because this condition is 
asymptomatic, and treatment is for prevention of a disease that may never occur anyway. 
Willingness to pay is likely to be lower than for symptomatic conditions, and so patient out-of-
pocket costs and time may be crucial barriers to successful completion of each step in the LTBI 
cascade of care. Patient direct and indirect costs will be measured for all household members; 
this includes time and travel costs for visits for investigation and treatment, and all out of 
pocket expenses, particularly for the time, travel and any other expenses related to the TST and 
CXR (even if the patients do not pay for the actual tests – these may require separate visits to 
the health facility just to complete them – and this requires time, and out-of-pocket 
expenditures).  
 
We will adapt a standardized interviewer administered questionnaire developed used 
previously by us to measure patient and family costs associated with active TB [32-35]. We will 
include a small number of items on this questionnaire regarding patient experience and 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
29
acceptability of study procedures. This questionnaire will be administered to patients in the 
third month post-randomization, meaning they will have undergone most investigations by that 
time. Hence, they should have a good perspective on their experience with tuberculin skin 
testing and reading, performance of CXR, and provision of sputum samples and performance of 
GeneXpert or microbiologic testing, while still being recent enough to avoid recall difficulties. 
(refer to appendix 5 for draft patient cost questionnaire) 
 
Data Analysis 
Modified Intention to treat: We will include all patients in this analysis, except for who were 
randomized but found to have exclusion criteria post-randomization – which may occur if index 
TB patients are found to have DR-TB, or HHCs are found to have HIV infection. Some HHCs may 
have additional of the three key tests (CXR, GX or TST) – that were not part of the algorithm to 
which they were randomized but were considered necessary by their provider. These HHCs will 
be included in the MITT analysis – according to the strategy to which they were originally 
assigned.  
Per protocol analysis: This will include only HHCs who underwent the key investigations (CXR or 
GX or TST), according to the strategy to which they were randomized, but did not have other of 
the three investigations of interest in this study.  
Interim analyses/monitoring 
We will monitor for problems related to study investigations, as well as LTBI treatment. If 
differences in enrolment or drop-out rates between the arms are noted, we will investigate to 
ensure the site health care staff are not trying influence allocation of HH contacts to different 
arms, and that there are no cross-over problems – in which HH contacts randomized to one arm 
are investigated with an algorithm for a different arm. Early in the trial these may occur 
randomly due to errors caused by health system staff due to their understanding and 
application of the investigation algorithms in the three arms. Errors in the investigation 
algorithms that are detected will be reviewed as part of ongoing in-service training of the staff 
involved. If differences in enrolment to the 3 arms persist, we will investigate the potential 
reasons for this and provide further in-service training to reinforce study procedures. 
 
Final analyses 
Primary analysis 
The primary outcome is the proportion starting LTBI therapy of those eligible (measured or 
estimated) for latent TB therapy. ‘Eligible’ will be defined as: aged 5-50 years, HIV uninfected 
and TST >5mm. For the no TST arm, the expected prevalence for HIV uninfected HH contacts 
aged 5 years and older will be estimated from age-specific prevalence of positive TST among HH 
contacts tested in the other two arms. This expected prevalence will be used to estimate the 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
30
proportion ‘eligible’ for LTBI therapy in the no TST arm. Treatment initiation will be defined as 
being given a prescription for LTBI therapy, or dispensed the first month of pills needed for LTBI 
therapy. Since this is a dichotomous outcome, the primary analysis will be a logistic regression, 
using an identity link, and estimated via generalized estimating equations (GEE) to account for 
clustering by household. An exchangeable correlation structure and empirical standard errors 
will be used.  The proportion starting LTBI therapy within 3 months of the index TB patient 
starting active TB treatment will be compared in each experimental arm against the standard 
arm.[C1] 
 
Secondary analyses 
1. Societal costs (health system and patient costs) of the full cascade of care - from initial 
identification to LTBI therapy completion will be considered. Using all relevant cost components 
(Table 4) and an ingredients approach, differences in health system costs will be assessed for 
each of the strategies. Patient time will be valuated based on an assumption of income 
equivalent to the average per capita income in the country. Health care personnel time will be 
valuated based on average salaries from information provided by facility management in each 
setting. 
 
2. Prevalence of microbiologically confirmed and clinically diagnosed active TB  – detected as 
part of the initial contact investigation, who initiate LTBI treatment within 3 months of the 
index TB patient starting active TB treatment, will be compared between all three arms. 
 
3. Prevalence of positive TST (5 mm or 10 mm cut-points) by age group – 0-4 (for Brazil only), 5-
10, 11-17, 18-24, 25-34 years, and older in Standard and GX Strategies. This is simple 
descriptive analysis – and will be presented as overall prevalence in the specified age groups, 
plus stratified by country. 
 
4. Incidence of serious adverse events related to LTBI therapy. Adverse events are relatively 
rare dichotomous outcomes. As such, Poisson regression will be used to compare the 
occurrence of the adverse events between each of the two experimental arms and the 
conventional arm. To account for clustering by household, we will use GEE, with an 
exchangeable correlation structure and empirical standard errors.  We will compare in the 
same way - the occurrence of grade 1-2 adverse events reported by study investigators. 
  
5. Completion of LTBI therapy –we will use the definition of completion/non-completion of the 
providers and the TB programs in each country, but in secondary analysis we will also define 
completion as taking at least 80% of doses in 120% of allowed time. (For 6H this means taking 
at least 144 doses within 216 days; for 4R this means 96 doses within 144 days, and for 3HR – 
72 doses within 108 days.) Since this is a dichotomous outcome, the primary analysis will use 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
31
logistic regression, with an identity link, and estimated via GEE to account for clustering by 
household. An exchangeable correlation structure and empirical standard errors will be used. 
We will compare the proportion completing treatment in each experimental arm against the 
standard arm.   
 
6. Sensitivity and specificity of CXR reading by usual providers in each study site. For this 
analysis, the reference standard will be the readings by the external CXR review. 
 
7. Active TB – defined as treatment initiated for active TB – detected only as a result of the CXR 
done in persons who could not produce a sputum sample. 
 
Ethical considerations 
The most important ethical considerations are the risks of treating undetected active TB with 
LTBI therapy and the risks of adverse events from LTBI therapy, particularly in participants who 
may not have latent TB infection. 
To protect participants from inadvertent LTBI therapy of undetected active TB, we will follow 
guidelines from the WHO by using symptom screening, as well as CXR or GX screening in all 
HHC. GX is a sensitive test for detection of active TB, and several studies have demonstrated 
that GX can be used to replace CXR for detection of active TB in other populations. These 
studies suggest that GX will fail to detect only patients with minimal active TB, and in these 
persons, there is evidence that LTBI therapy is in fact adequate [28, 36]. In addition, we will 
review CXR independently, and provide quality assurance reports every quarter to CXR readers 
at each site. This feedback should help to enhance local proficiency in CXR reading, but if we 
detect substantial rates of missed diagnoses, then we will take corrective action in an ongoing 
fashion.  
The issue of over-treatment of latent TB in study participants in the no-TST arm is addressed in 
detail in the rationale for interventions section above. Briefly, we are safeguarding the 
participants by undertaking the study in settings where almost 2/3 of household contacts have 
evidence of latent TB infection and so would likely receive LTBI therapy if they underwent TST. 
In addition, those who are most likely to be treated in the absence of LTBI are those aged 0-20 
years as they have lower prevalence of positive TST [37, 38] but also least risk of adverse events 
from LTBI therapy. Additional safeguards are the use of the shorter regimens which will reduce 
burden, and risk of adverse events, and to exclude those aged over 50 years (although these 
persons could be tested and evaluated on an individualized basis only), as adverse events are 
more common in adults above this age limit. 
  
This study will place additional burden on study participants, as with any research trial. 
However, we believe the benefits to participants outweigh the burden because all potential 
study participants are at high-risk of having active TB – either at the time of enrolment or within 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
32
2 years after. Participants in this this study should benefit from a reduced risk of morbidity and 
mortality from TB, besides the added benefit of reduced risk of further transmission within the 
household. All direct costs for study interventions (TST, GX or CXR) will be covered by the TB 
program, if usually covered, or by research funds. Therefore, study participants will not pay 
direct costs, such as for CXR. Other costs, and patient time for the health care facility visits for 
investigations or treatment would normally be incurred anyway. As well, these are important 
outcomes in their own right - high costs or significant loss of time would represent important 
barriers for future uptake of the results in these settings. Hence, patient out-of-pocket costs 
(e.g. for travel, or food), and time will be carefully measured. We will not compensate patients 
for these costs because this would potentially influence the study outcomes and are important 
outcomes for future generalizability of the study results. 
 
All participants will provide signed informed consent, before randomization. For children aged 
0-17 years, we will obtain parental signed consent, and for children aged 10-17 years, we will 
also ask the child to sign assent forms. This consent will include agreement that the digital file 
of the CXR can be stored in a de-nominalized database for later use to assess software for 
computer aided diagnosis of active TB. We will not ask index TB patients to provide consent, as 
they are not undergoing any study procedures, although they must agree verbally to allow 
research staff to approach their HH contacts. Individual members of each HH can decide 
independently to participate; it is not necessary for all HH members to participate together – as 
the study interventions are directed to each individual and not to the household itself.  
 
This protocol as well as consent and parental/assent forms will be reviewed by an ethics review 
board of the RI of the MUHC. After approval by this board, it will be reviewed by research ethics 
committees at all participating centres. 
 
Trial management 
Scientific Advisory Committee (SAC)  
The responsibilities of the SAC are to provide advice and recommendations regarding scientific 
aspects of the studies, particularly study design, interventions and outcomes as well as the 
statistical analysis plan. We have already formed a SAC for all projects within the CIHR 
Foundation grant.  
Members of the SAC are: Dr. Hailey Getahun, responsible for anti-microbial resistance now, but 
until June 2018 was responsible for latent TB at the World Health Organization in Geneva, 
Switzerland; Dr. Bill Burman, director of Denver Public Health and long-standing member of TB 
Trials Consortium; Dr. Andy Vernon, director of Science, TB division, Centre for Disease Control, 
Atlanta, Georgia and director of TB Trials Consortium; Dr. Ben Marais, professor of University of 
Melbourne, Australia – considered the global authority on pediatric tuberculosis.  
 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
33
 
Data Safety and Monitoring Board (DSMB) 
The DSMB will be responsible to review any unusual or unexpected events and make 
recommendations regarding continuing or stopping enrolment to study arms (or the overall 
study). They also will review on an ad-hoc and immediate basis any serious adverse events that 
are unexpected, as well as any deaths that are judged possibly or probably related to therapy of 
LTBI. Note that certain adverse events are expected as these occurred in our prior trials with 4R 
and 9H, and in published studies using the different LTBI regimens that may be used in this trial. 
These will not be brought to the attention of the DSMB when they occur, but will be included in 
all safety analyses, plus they are mentioned in the consent, and will be explained to the 
potential participants’ during the consent process. Ad-hoc reviews of unexpected serious 
adverse events will be whenever needed. DSMB recommendations following any ad hoc 
meetings will be sent to the research ethics committees at all participating sites. 
 
Trial steering committee 
The trial steering committee will review progress of the ongoing trial, including enrolment and 
randomization, pragmatic problems such as difficulties with enrolment or withdrawal of 
consent, as well as need for study amendments. The trial steering committee will also review 
recommendations of the SAC and the DSMB. The trial steering committee will be responsible 
for the final decision regarding stopping enrolment to any study arm, or the study. If such a 
decision is taken, the research ethics committees at all participating sites will be notified. 
 
This committee will be comprised of the principal investigator (Dr. Menzies), the Foundation 
project manager (Dr. Oxlade), the trial biostatistician (Dr. Benedetti) as well as the principal 
investigators from each site (Benin and Brazil).  
 
REFERENCE 
1. 
Houben RM and Dodd PJ, The Global Burden of Latent Tuberculosis Infection: A Re-estimation 
Using Mathematical Modeling. PLOS Med, 2016. 13(10): p. e1002152. 
2. 
Dye, C., et al., Trends in tuberculosis incidence and their determinants in 134 countries. Bull. 
World Health Organ, 2009. 87: p. 683-691. 
3. 
Bucher, H.C., et al., Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of 
randomized controlled trials. AIDS, 1999. 13(4): p. 501-507. 
4. 
Akolo, C., et al., Treatment of latent tuberculosis infection in HIV infected person ( Review0. The 
Cochrane Coolboration, 2010. 1: p. 1-50. 
5. 
World Health Organization, Latent TB Infection : Updated and consolidated guidelines for 
programmatic management. 2018: https://www.who.int/tb/publications/2018/latent-
tuberculosis-infection/en/. 
6. 
Rangaka, M.X., et al., Predictive value of interferon-gamma release assays for incident active 
tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis, 2012. 12(1): p. 45-55. 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
34
7. 
Auguste, P., et al., Comparing interferon-gamma release assays with tuberculin skin test for 
identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review 
and meta-analysis. BMC Infect Dis, 2017. 17(1): p. 200. 
8. 
Abubakar, I., et al., Prognostic value of interferon-gamma release assays and tuberculin skin test 
in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study. 
Lancet Infect Dis, 2018. 18(10): p. 1077-1087. 
9. 
Sester, M., et al., Risk assessment of tuberculosis in immunocompromised patients. A TBNET 
study. Am J Respir Crit Care Med, 2014. 190(10): p. 1168-76. 
10. 
Garibaldi, R.A., et al., Isoniazid-associated hepatitis. Report of an outbreak. Am Rev Respir Dis, 
1972. 106(3): p. 357-65. 
11. 
Kabbara, W.K., A.T. Sarkis, and P.G. Saroufim, Acute and Fatal Isoniazid-Induced Hepatotoxicity: 
A Case Report and Review of the Literature. Case Rep Infect Dis, 2016. 2016: p. 3617408. 
12. 
Alsdurf, H., et al., The cascade of care in diagnosis and treatment of latent tuberculosis infection: 
a systematic review and meta-analysis. Lancet Infect Dis, 2016. 16(11): p. 1269-1278. 
13. 
Ena J and Valls V, Short-course therapy with rifampin plus isoniazid, compared with standard 
therapy with isoniazid, for latent tuberculosis infection: a meta-analysis. Clin Infect Dis, 2005. 
40(5): p. 670-676. 
14. 
Sterling TR, et al., Three months of rifapentine and isoniazid for latent tuberculosis infection. 
New Engl J Med, 2011. 365(23). 
15. 
Sterling TR, et al., Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly 
Rifapentine plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the 
PREVENt Tuberculosis Study. Clin Infec Dis, 2015. 61(4): p. 527-35. 
16. 
Menzies, D., et al., Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis 
in Adults. N Engl J Med, 2018. 379(5): p. 440-453. 
17. 
Diallo, T., et al., Safety and Side Effects of Rifampin versus Isoniazid in Children. N Engl J Med, 
2018. 379(5): p. 454-463. 
18. 
Menzies D, et al., Adverse events with 4 months rifampin or 9 months isoniazid as therapy for 
latent TB infection: results of a randomized trial. Annals of Internal Medicine, 2008. 149: p. 689-
697. 
19. 
Fox GJ, et al., Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur 
Respir J, 2013. 41: p. 140-156. 
20. 
Morrison J, Pai M, and Hopewell P, Tuberculosis and latent tuberculosis infection in close 
contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a 
systematic review and meta-analysis. Lancet Infect Dis, 2008. 8: p. 359-368. 
21. 
Tanimura, T., et al., Financial burden for tuberculosis patients in low- and middle-income 
countries: a systematic review. Eur Respir J, 2014. 43(6): p. 1763-75. 
22. 
Wingfield, T., et al., Defining catastrophic costs and comparing their importance for adverse 
tuberculosis outcome with multi-drug resistance: a prospective cohort study, Peru. PLoS Med, 
2014. 11(7): p. e1001675. 
23. 
Balcells, M., et al., Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect 
Dis, 2006. 12(5): p. 744-751. 
24. 
Samandari, T., et al., A randomized placebo-controlled trial of 6 versus 36 months Isoniazid 
tuberculosis preventive therapy for HIV-infected adults in Botswana. Lancet, 2011. 377: p. 1588-
1598. 
25. 
Getahun, H., et al., Development of a Standardized Screening Rule for tuberculosis in People 
Living with HIV in Resource Constrained Settings: Individual participant Data Meta-analysis of 
Observational Studies. PLOS Medicine, 2011. 8(1): p. e1000391. 

Dr Dick Menzies - McGill University Health Centre 
GXT: GeneXpert or chest-X-rays or Tuberculin skin testing Protocol. Version 3: 14 March 2022 
Protocol Version 3 – 14 March 2022 
35
26. 
van't Hoog, A.H., et al., Screening strategies for tuberculosis prevalence surveys: the value of 
chest radiography and symptoms. PLoS One, 2012. 7(7): p. e38691. 
27. 
Pedrazzoli, D., et al., Can tuberculosis patients in resource-constrained settings afford chest 
radiography? Eur Respir J, 2017. 49(3). 
28. 
Mount, F.W. and S.H. Ferebee, Preventive effects of isoniazid in the treatment of primary 
tuberculosis in children. N Engl J Med, 1961. 265: p. 713-21. 
29. 
Corbett EL, et al., Comparison of two active case-finding strategies for community-based 
diagnosis of symptomatic smear-positive tuberculosis and control of infectious tuberculosis in 
Harare, Zimbanwe (DETECTB): acluster-randomised trial. Lancet, 2010. 376: p. 1244-1253. 
30. 
Kopanoff DE, Snider DE, and Caras GJ, Isoniazid-related hepatitis. Am Rev Respir Dis, 1978. 117: 
p. 991-1001. 
31. 
Salpeter, S.R., et al., Monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 
35 years of age: A risk-benefit and cost-effectiveness analysis. Ann Intern Med, 1997. 127(12): p. 
1051-1061. 
32. 
R, S., et al., Patients costs and cost -effectiveness of tuberculosis tretment in DOTS and non-DOTS 
facilities in Rio de Janeiro, Brazil. Plos ONE, 2010. 5(11): p. e14014. 
33. 
Rouzier, V.A., et al., Patient and family costs associated with tuberculosis, including multidrug-
resistant tuberculosis, in Ecuador. Int J Tuberc Lung Dis, 2010. 14(10): p. 1316-1322. 
34. 
KR, J., et al., Costs Incurred by Patients with Pulmonary Tuberculosis in Rural India. Int J Tuberc 
Lung Dis, 2009. 13(10): p. 1281-1287. 
35. 
Aspler A, et al., Cost of tuberculosis (TB) diagnosis and treatment from the patient perspective in 
Lusaka, Zambia. Int J Tuberc Lung Dis, 2008. 12(8): p. 928-935. 
36. 
Ferebee SH, Controlled chemoprophylaxis trials in tuberculosis. Adv Tuberc Res, 1969. 17: p. 28-
106. 
37. 
Menzies, R., The determinants of the prevalence of tuberculous infection among Montreal 
schoolchildren, Thesis for M.Sc. in Epidemiology and Biostatistics. 1989, Montreal: McGill 
University. 
38. 
Menzies, R., B. Vissandjee, and D. Amyot, Factors associated with tuberculin reactivity among 
the foreign-born in Montreal. Am Rev Respir Dis, 1992. 146: p. 752-756.