Primary Prophylaxis for Prevention of TB in Prison's Populations
Phase: PHASE4
Conditions: Tuberculosis, Pulmonary, Antibiotic Prophylaxis
Sponsor: Federal University of Mato Grosso

FEDERAL UNIVERSITY OF MATO GROSSO DO SUL 
DOCTORATE PROGRAM IN INFECTIOUS AND PARASITIC DISEASES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROPHYLAXIS FOR PRIMARY PREVENTION OF TUBERCULOSIS IN PRISONERS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CAMPO GRANDE-MS, BRAZIL 
JUNE/2018

 
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ADMINISTRATIVE INFORMATIONS 
Public title: Prophylaxis for Primary Prevention of Tuberculosis in Prisoners 
Public acronym: PCL 06/2017 
Evaluation Record: ClinicalTrials.gov, Identifier: NCT03028129 
Protocol Version: 6 of 06/12/2018 
Financing: National Council for Scientific and Technological Development (Process 420672/2017-
6 and Process 401824/2016-0) 
Sponsor Name and Contact Information: Clinical Research Platform, Vice Presidency of 
Research and Biological Collections of the Oswaldo Cruz Foundation. Phone: + 55 21 3882-9238 / 
+55 21 3882-9239. Email: pesquisaclinica@fiocruz.br 
 

 
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LIST OF ABBREVIATIONS 
 
ALT 
Alanate Aminotransferase 
AST 
Aspartate Aminotransferase 
AUDIT 
Alcohol Use Disorder Identification Test 
BCG 
Bacillus Calmette-Guérin 
CEP 
Research ethics committee 
DNA 
Deoxyribonucleic Acid 
AE 
Adverse Event 
SAE 
Serious advers event 
HIV 
Human Imunodeficiency Virus 
INH 
Isoniazid 
IGRA 
Interferon gamma realease assay 
LPCS/UFGD 
Research Laboratory in Health Sciences/Federal university of Grande 
Dourados 
MDR 
Multidrug-resistant 
MS 
Ministry of Health 
Mtb 
Mycobacterium tuberculosis 
WHO 
World Health Organization 
PED 
State Penitentiary of Dourados 
SOP 
Standard Operational Procedure 
PPD 
Purified Protein Derivative 
TB 
Tuberculosis 
TCLE 
Informed consent form 
DOT 
Directly Observed Treatment 
UEMS 
State University of Mato Grosso do Sul 
XDR 
Extensively Drug-resistant 
 
 

 
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LIST OF FIGURES 
 
Figura 1 - Schedule, second quarters, of research activities. The parentheses indicate that the 
procedures are optional. ................................................................................................................. 16 
Figura 2 - Sample table of the sample values in both groups (intervention and control), based on the 
primary outcome. ............................................................................................................................ 17 

 
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SUMMARY 
 
ADMINISTRATIVE INFORMATIONS .......................................................................... 1 
LIST OF ABBREVIATIONS ........................................................................................ 2 
LIST OF FIGURES ...................................................................................................... 3 
1 INTRODUCTION ...................................................................................................... 5 
2 BACKGROUND ........................................................................................................ 6 
2.1 Mycobacterium tuberculosis ............................................................................... 6 
2.2 Epidemiology ...................................................................................................... 7 
2.3 The relation prison and tuberculosis .................................................................. 7 
2.4 Prophylactic use of isoniazid .............................................................................. 8 
2.5 Isoniazid in the treatment of latent TB ................................................................ 9 
3 RATIONALE ........................................................................................................... 10 
4 AIMS ....................................................................................................................... 11 
4.1 General ............................................................................................................. 11 
4.2 Especifics ......................................................................................................... 11 
5 OUTCOMES ........................................................................................................... 12 
5.1 Primary outcome .............................................................................................. 12 
5.2 Secondary outcome ......................................................................................... 12 
6 METHODOLOGY ................................................................................................... 13 
6.1 Study designer ................................................................................................. 13 
6.2 Inclusion criteria ............................................................................................... 14 
6.3 Exclusion criteria .............................................................................................. 14 
6.4 Indications for premature exclusion .................................................................. 14 
6.5 Conducting the study ........................................................................................ 15 
6.6 Estatistical analysis .......................................................................................... 16 
6.7 Interim analysis ................................................................................................ 17 
6.8 Study interruption ............................................................................................. 17 
6.9 Ethical aspects ................................................................................................. 17 
6.10 Quality control ................................................................................................ 18 
6.11 Potential risks ................................................................................................. 18 
6.12 Expected benefits ........................................................................................... 19 
REFERENCES .......................................................................................................... 20 
 
 

 
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1 INTRODUCTION 
Despite being a disease known to humanity for more than 9,000 years ago, tuberculosis (TB) 
still represents a serious public health problem in developing countries. 
TB is an infectious, airborne disease that can present in both active and latent forms. Despite 
the biological aspect of transmission, unhealthy environmental conditions (eg, environment without 
direct sunlight, poor ventilation, overcrowding, etc.) and individual factors (malnutrition, 
immunosuppression, use of alcohol, other drugs, etc.) have a significant influence on the 
transmissibility and infectivity of the disease. 
With the discovery of active drugs against Mycobacterium tuberculosis, a reduction in the 
incidence of the disease was seen worldwide. Despite this decreasing incidence, the World Health 
Organization (WHO) classified TB as a global public health problem, due to the appearance of 
multidrug resistant or extensively resistant tuberculosis disease, resistant to treatment. In addition 
reactivation of latent TB was consistently observed with the advent of HIV. 
Several studies have shown a direct relationship between the incidence of TB and the prison 
environment. The presence of prison units in a locality raises the incidence of the disease, 
suggesting tuberculosis transmission between the prison and the community. 
To date, TB control in prisons is based on screening individuals with active and/or latent TB 
and their treatment. To identify individuals with active disease, diagnostic algorithms using 
respiratory symptoms (mainly cough), sputum culture, and chest radiography are used. Regarding 
the search of individuals with latent tuberculosis, the skin test with the PPD can be performed. 
Prisoners in Brazil have short incarceration terms, usually leaving prison within one to two 
years. Therefore, an intervention that protects prisoners from acquiring recent infection during prison 
stay may be adequate for long-term tuberculosis control in these prisons. Although there is a large 
body of empirical evidence demonstrating that isoniazid prevents progression to active tuberculosis, 
whether isoniazid prevents primary infection is unknown. 
The aim of this study was to determine the efficacy of primary prophylaxis in the prison 
population in order to gather new scientific evidence that would bring accessible methods for the 
control of TB in prisons. 
 

 
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2 BACKGROUND 
2.1 Mycobacterium tuberculosis 
M. tuberculosis was discovered by Robert Koch in 1882. It is an immobile, aerobic bacterium 
of the Mycobacterium tuberculosis complex. This complex is formed by several species of 
mycobacteria, causal agents of TB in different hosts: M. tuberculosis, M. africanum, M. canetti (affect 
humans); M. microti (infect mice); M. bovis (affect cattle); M. pinnipedi (found in seals and sea lions); 
M. caprae (infect sheep and goats) and BCG vaccine strain(1). Different bacterial strains of the M. 
tuberculosis complex are closely related, with 99.9% genetic similarity and strong host 
specificity(2,3). 
M. tuberculosis is primarily responsible for most TB cases in humans. The main 
characteristics of M. tuberculosis aree the high content of guanine-cytosine in its DNA; the long 
generation time (cell division between 12 to 24 hours under favorable conditions) and the special 
cell wall, shared by all species of the Mtb complex. The structure of this wall is its composition: highly 
cross-linked peptideoglycans and mycolic acid, making the bacterium highly hydrophobic and acid-
resistant, a characteristic that is used to diagnose the disease(4,5). The lipid-rich cell wall forms the 
basis for the intrinsic resistance of Mtb to most antibiotics(6). 
TB is transmitted primarily through aerosols. Aerosols are tiny droplets containing bacteria, 
formed when a patient with active TB coughs or sneezes. If these droplets are inhaled by another 
susceptible person (or animal), the bacteria enter the lung where they are phagocytosed by the 
macrophages. In other words, Mtb must be active to be transmitted. A person with active TB can 
infect an average of 10 to 15 people within a year(7). However, the amount of bacilli present, its 
virulence, health status (co-infections, immunosuppression), the individual's age, and adequate 
environmental factors such as ventilation and exposure to sunlight (ultraviolet light) have a great 
influence on infectivity. Yet, theoretically, TB is infectious for a long time while bacteria are viable in 
the sputum. If a patient is under treatment, it takes about 4 to 8 weeks until no more bacteria are 
detected in his sputum(4). As the first organ affected is the lung, most cases of TB are called 
pulmonary TB. Even so, TB can affect other parts of the body, in this case called extrapulmonary 
TB. In these occasions, the individual is usually not infectious, since the bacterium is not expelled 
through the aerosols, however, may present clinical of the disease. 
Once the bacteria entered the lung they are phagocytosed by alveolar macrophages. Mtb 
can grow within macrophages by inhibiting the fusion of phagosomes with lysosomes, thus avoiding 
their digestion. Granulomas are formed - aggregation of infected phagocytes (macrophages, 
neutrophils, monocytes and dendritic cells) and surrounded by B and T lymphocytes(8). At first three 
scenarios are possible: first, the immune system overcomes bacteria, which are killed and 
eliminated completely; Second, bacteria outgrow the immune system and multiply in the lung, 
causing disease; Third, there is a balance between the bacteria and the immune system, which are 
in a dormant state called latent TB. When the individual has latent TB, the infection remains clinically 
silent and the bacteria do not spread. In 90-95% of cases the bacteria remain dormant and never 
reactivate. In the remaining 5-10% reactivation of bacteria occurs after a few years, leading to 
clinical disease, called secondary TB(9). 
The hypotheses described above must be seen as a result of a dynamic transmission system, 
in which the course depends on both host and bacterial factors(10). One reason for the reactivation 
of latent TB is HIV co-infection. CD4 lymphocytes play a key role in the formation of granulomas, as 
they produce cytokines (eg, IL-12 and IFN-γ) that activate macrophages. CD4 lymphocyte count is 
generally low with the advancement of HIV infection, patients living with HIV are at high risk (over 
40 times) of becoming infected with TB and progressing to TB(11,12). 

 
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The most common symptom of TB is productive and persistent cough for several weeks, thus 
serving as an indicator for TB screening in endemic countries. It is often accompanied by other 
nonspecific symptoms such as fatigue, fever, night sweats and later weight loss, chest pain and 
difficulty breathing(7). 
2.2 Epidemiology 
TB and humans have coexisted for a long time. Estimates suggest that this relationship 
occurs at least 70,000 years(13). Physical evidence of bacteria in humans has been found in two 
9,000-year-old bodies from Haifa, Israel, and from Egyptian mummies dating from 1550 to 1080 
BC(14,15). However, TB only appeared epidemic in Europe and North America in the 18th and 19th 
centuries, declining with the introduction of isolation and chemoprophylaxis and reemerging again 
in the 1980s and early 1990s as a result of the HIV pandemic and increased resistance to drugs 
used in treatment(16,17). 
In 1993, WHO declared TB a global emergency, given the rise in multi-drug resistant cases 
and the HIV epidemic(18). As a consequence, the DOT strategy was developed and, after a few 
years, the STOP TB Strategy was formed, a network of public and private organizations from several 
countries, with the participation of governments and collaborators, whose purpose is to reduce 
drastically the burden of disease worldwide(19,20). 
TB remains the leading global health problem today. One third of the global population is 
infected and 8.6 million people developed the disease, resulting in 1.3 million deaths in 2012(7). 
Most TB cases are found in Southeast Asia (29%), Africa (27%) and Western Pacific Region (19%). 
The 22 countries with the highest burden of disease represent 82% of the reported cases in the 
world, with India and China alone representing 39% of this. TB affects more men than women and 
yet causes one in three deaths in this population, especially those living with HIV. All age groups 
are affected by the disease, but most cases occur in the economically active population. TB in 
children has been neglected for a long time, since they do not represent the most infectious cases. 
However, children are an indicator for active transmission and in 2012 accounted for 6% of the total 
cases detected(7). 
To reduce the global burden of TB, the STOP TB Strategy formulated several targets to be 
achieved by 2015, in line with the Millennium Development Goals(21). Although the overall mortality 
rate has dropped by 45 per cent and the prevalence by 37 per cent since 1990, several of the targets 
proposed, for example the goal of reducing the prevalence of active TB by 50 per cent, have 
probably not been met by 2015, especially in Africa and European region formed by the countries 
of the Soviet Union, where mortality and prevalence remain high(22). Large numbers of people with 
latent infection, HIV pandemic and increased bacterial resistance challenge the achievement of 
targets to eliminate TB as a public health problem by 2050. Every year about 450,000 new cases of 
MDR are detected, with the estimated global rate of 9.6% in new cases and 92 countries have 
reported at least one case of XDR TB so far (7,23). Less than 25% of estimated MDR TB cases 
worldwide are detected and only 50% of cases initiating therapy are successfully treated. 
2.3 The relation prison and tuberculosis 
The world prison population is currently estimated at 10.2 million people(24). Brazil has the 
third largest population in the world, with 688,759 individuals in 1,449 establishments, and the 
incidence of TB in this population has increased in the last seven years(25). Although prisoners 
represent only 0.3% of the country's population, an increase in the prison population over this period 
has resulted in almost double the proportion of all TB cases among prisoners (4.1% in 2007, 8% 
1% in 2013). 

 
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The prison environment contributes greatly to the transmission of TB. Prisons are an ideal 
environment for the transmission of the disease, since they bring together individuals who use 
tobacco and alcohol in high doses, in addition to drug abuse, in overcrowded cells, with little 
ventilation and with limited access to care. health and diagnosis of TB. Urrego et al.(26) collected 
architectural and ventilation data in a southern prison in Mato Grosso do Sul and, using a modified 
Wells-Riley model for indoor TB transmission, projected TB transmission rates within each cell , 
provided that an infectious case was present. They estimated that 53-70% of cell mates would be 
infected after four months of exposure. 
In a case-control study associated with molecular methods, Sacchi and cols.(27) examined 
the role of prison in TB burden in the population of Dourados. Among 240 cases of TB reported over 
a 46-month period, 180 (75%) occurred in the general population and 60 (25%) in the prison 
population, showing a 40-fold increased risk (incidence) among prisoners of TB. Among the TB 
cases of the general population, 23% occurred among residents who were previously incarcerated. 
Previous incarceration was the strongest risk factor for TB in the community (adjusted OR, 28.5). 
Among 97 isolates for which restriction fragment polymorphism (IS6110) genotyping was performed, 
79 could be classified into 17 groups. Ten of these 17 sets, comprising 82% of the clustered isolates, 
involved two prisoners and community members, including the former detainees. These results 
demonstrate a high degree of linkage between lineages in prisons and in the community; and 
indicate that the approach to TB transmission in prisons will be critical to disease control among the 
general population. 
Carbone et al.(28) carried out a cross-sectional study to estimate the prevalence of active 
and latent TB and associated risk factors among 3,380 prisoners (2,861 men, 519 women) from the 
12 penitentiaries in Mato Grosso do Sul. The prevalence of active TB was calculated as 917 cases 
per 100,000 inmates and the latent one, at 21%. Comparing the prevalence and annual reports of 
TB, the mean infection time was estimated at 4.8 months. 
2.4 Prophylactic use of isoniazid 
The discovery of INH was based on the activity of nicotinamide against TB bacilli in an animal 
model, observed by Chorine in 1945, and the rearrangement of chemical groups in 
thiosemicarbazone. INH represents an important milestone in TB chemotherapy because it is highly 
active against bacilli, low cost and without significant side effects. 
In 1952 it was proved that the drug had tuberculostatic activity, however, the target of action 
was unknown(29,30). Subsequently, it has been found that INH inhibits the synthesis of mycolic 
acids, α-alkyl β-hydroxy and higher chain fatty acids that cover the surface of the mycobacteria. The 
main molecular target of action of INH is the inhA gene, which encodes the enzyme inhA. This 
enzyme catalyzes the transfer of a hydrogen atom to the substrate at its catalytic site using NADH, 
which is a reducing agent found in numerous biochemical processes in living beings as a source of 
hydrogen(31). 
Due to the bacterial resistance to streptomycin (discovered in the previous decade) the use 
of INH in the treatment of TB started successfully. Although it was generally well tolerated by 
patients, cases progressing with pruritus and hepatitis were recorded(32). Salpeter(33), in a review 
covering 20,212 individuals who started chemoprophylaxis with INH, estimated the incidence of 
hepatitis at 1%, with 8,700 individuals being 35 years of age or older. 
In 1963 Hanson, Comstock, and Haley(34) conducted a community-based clinical trial in 
Alaska using chemoprophylaxis with INH in half a population (about 9,000 subjects) who received 
a daily dose of the drug (5mg / kg) for 12 months. The intervention was performed based on the 
epidemiological picture of the region, whose TB incidence was 20 times higher than the North 

 
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American population, in addition to conditions considered propitious for transmission (small, 
overcrowded, poorly ventilated and malnourished individuals). The results showed the occurrence 
of 32 cases of TB in the control group, compared to 1 case in the treatment. 
The conditions described by Hanson, Comstock and Haley in the Alaskan population are 
similar to those currently found in the prison system in developing countries. However, in this review, 
no studies were found on the prophylactic use of INH in prisons, and its use was restricted to cases 
of latent TB. 
2.5 Isoniazid in the treatment of latent TB 
In 1999, Smieja et al(35), in a review to identify the efficacy of INH in non-HIV subjects, found 
that the relative risk of acquiring TB after 6 months of prophylaxis with 300mg of the drug was 0.40 
(95% CI 0.31 -0.52), with an absolute risk reduction of 0.01, ie, it would take 100 treatments to avoid 
1 case of active TB. The most frequent adverse reactions were mild and transient headache, 
nausea, dizziness. The occurrence of hepatitis was 0.12% in the controls and 0.52% in the 
treatments, having as risk factors age greater than 45 years and alcohol use. 
Sharma et al.(36) in a review comparing regimens with rifamycin (and its derivatives, 
including rifapentine) and INH, conclude that regimens using rifamycin alone are longer, have a 
lower completion rate, and do not present advantages over the INH regimen alone. 
Epidemiological conditions conducive to high TB transmission are currently found in the 
prison system (26). Macintyre et al.(37) conducted a cohort study in 16 of the 23 prisons in Maryland 
and concluded that the use of INH prophylaxis reduced the risk of progression to active TB in 
individuals reacting to the skin test by 50%. Al-Darraji; Kamarulzaman and Altice(38) have shown, 
through a systematic review covering 18 publications (between cohort and transverse studies) that 
the efficacy in cases of latent TB is about 60% in non-HIV individuals and 36% in individuals with 
HIV, using INH for 6 months. The hepatotoxicity rate was on average 6%. Approximately two-thirds 
of these studies were conducted in countries with low endemicity for the disease. In view of this, the 
authors recommend that further studies should be conducted, but in countries highly endemic for 
the disease, to explore the efficacy and safety of INH in closed prisoners. 
Two randomized clinical trials showed an 83.8% and 69% adherence rate with an isolated 
INH regimen and a hepatotoxicity of 2.4% and 2.7%(39,40). It is noteworthy that in the 
aforementioned studies all the individuals allocated in the treatment group had latent TB diagnosed 
through the skin test with PPD. 
 

 
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3 RATIONALE 
Despite advances in TB diagnosis and treatment, it is the third leading cause of death from 
infectious diseases in the world(41). In 2015, WHO estimated that 9.6 million new TB cases 
worldwide occur, with about 1.1 million deaths. For Brazil, the incidence of 44 cases per 100,000 
inhabitants(42) was estimated. The incidence of TB has decreased by around 2% per year. 
Brazil occupies the 22nd place in the WHO ranking with an annual rate estimated in 83,310 
cases of the disease (42). Over the past seven years, it has been estimated that the incidence 
declined only 0.7% (per year). A key factor in this slow progress in TB control in Brazil and in other 
emerging countries is the existence of high-risk subpopulations, including favelas and prisons, which 
serve as reservoirs and amplifiers for the transmission of the disease(43,44). A recent systematic 
review has shown that the average incidence of TB in the prison population may be up to 23 times 
that recorded in the general population(45). 
With the third largest population of prisoners in the world, the increase in the incidence of TB 
among prisoners in the last seven years is observed in Brazil. Although prisoners represent only 
0.3% of the country's population, an increase in the prison population over this period has resulted 
in almost double the proportion of all TB cases among prisoners (4.1% in 2007, 8% 1% in 2013). 
Prisons are an ideal environment for TB transmission, since they bring together high-dose 
tobacco and alcohol users, as well as drug abuse, in overcrowded, poorly ventilated, and limited 
access health and diagnosis of TB. Currently, the Ministry of Health recommends the active search 
for TB at the entrance to the prison and once a year, through the chest X-ray. Due to cost and 
logistics, most prisons do not adhere to this recommendation. There is also a clear recommendation 
not to use the tuberculin test or to perform treatment for latent TB. Whether procedures for active 
case detection and / or prophylactic treatment would impact on the high transmission of the disease 
in prisons is an issue that remains open(38). 
The concentration of TB cases in prisons may represent both an obstacle and an opportunity 
for disease control, depending on the effectiveness of the interventions performed in these settings. 
Preliminary studies show a high annual rate of TB infection (26%) among the prison 
population of 12 penitentiaries in Mato Grosso do Sul. In addition to the large burden of disease in 
this population, the dispersion of TB from prisons to the community is significant(27). Cross-
sectional studies show a high yield of annual screening for TB, however, the effectiveness of this 
measure associated with other interventions has not yet been clarified(46–52). Because of the 
combination of the high force of infection in prisons and the short period of incarceration, primary 
prophylaxis can be an effective intervention. 
This approach has not yet been evaluated in the context of prisons in middle- and low-income 
countries. Thus, in order to assess the impact of program strategies for TB control and primary 
prophylaxis, longitudinal data will be essential. Given the infrastructure that has been created for 
prospective long-term studies in Brazil, there is an excellent opportunity to close the fundamental 
knowledge gaps that have been barriers to effective implementation of TB control in high-
transmission prisons. 
 

 
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4 AIMS 
4.1 General 
To determine the efficacy of primary prophylaxis with INH 900mg twice weekly in innmates 
in a closed regimen. 
4.2 Especifics 
• Determine the impact of INH use on the incidence of active and latent TB in the prison 
population; 
• To quantify the occurrence of adverse events, including hepatotoxicity, due to the use of INH; 
• Evaluate residual protective effect until the 12th month after intervention; 

 
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5 OUTCOMES 
5.1 Primary outcome 
Reduction of 50% in latent TB in the treatment group after 12 months of intervention, estimated by 
IGRA QuantiFERON TB Gold Plus – Qiagen. 
5.2 Secondary outcome 
Reduction of 50% in active TB in the treatment group after 12 months of intervention, estimated by 
sputum positive culture. 
 

 
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6 METHODOLOGY 
6.1 Study designer 
Phase IV, randomized, double-blind, placebo-controlled clinical trial with innmates serving 
time in a closed regimen. 
6.1.1 Sample and population of the study 
This research will be carried out at one prison unit, located in the city of Dourados, in the 
state of Mato Grosso do Sul. Currently, this prison unit has approximately 2,300 inmates, with a 
mean age of 31.5 ± 9.4 years; an average of 9.7 (± 4.2) individuals per cell, who remain in a closed 
regimen, about 20.8 (± 24.1) months. The TB indicators show a tuberculin test serocoversion rate 
of 26% (23-26) and incidence, 2.45 / 100,000(28). 
The sample was calculated for a significance level of 5%, detection power of 90%, 
considering a percentage of occurrence of latent TB of 20% in the control group after one year of 
follow-up and 10% in the experimental group. For these parameters, 560 individuals will be needed 
for the study, however, 30% will be added for possible losses, ending the sample in 728 participants. 
Memory calculation available at https://www.sealedenvelope.com/power/binary-superiority/. 
6.1.2 Randomization and masking 
Two groups, called intervention (INH) and control (placebo), respectively, each composed of 
364 participants, will be formed from a simple randomization process using the True Random 
Number Service developed by the School of Computer Science and Statistics in Dublin, Ireland and 
available at <www.random.org>. The sequence generator mode used by the principal investigator 
will produce 728 random alpha-numerical codes, composed of three digits each, that will be 
delivered to the pharmacist for individual randomization (intervention vs control) containing only the 
identifying code. 
The study pharmacist will be responsible for randomization of the participants and 
organization of INH-containing bottles or placebo for dispensing during DOT visits. As this is a 
double-blind study, the other team members are blind and do not have access to the randomization 
list. The study participants will also not know in which group they are allocated. The description of 
the pharmacist's activities in the clinical trial are detailed in specific SOP. 
The use of placebo was a strategy because there is no clinical trial of primary prophylaxis for 
TB. 
6.1.3 Blinding Break 
In the event of any significant AE, the sigil will be broken to identify in which group the 
participant was allocated. The request for blinding should be made by the study coordinator or lead 
investigator to the study pharmacist. 
In case of breach of blinding, the sponsor must be notified within 48 hours, and the 
justification for the early breakdown is informed in detail. The reason for the rupture of the blinding 
should be described in the participant's chart. 
At the end of the study randomization will be opened, thus allowing for statistical analysis. 

 
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6.2 Inclusion criteria 
• Age above 18 and under 45 at the time of inclusion; 
• Sign the informed consent form. 
6.3 Exclusion criteria 
• Be indigenous; 
• Active TB or previous use of INH; 
• Sscore AUDIT ≥15. 
• Reactive serology for HIV, hepatitis B and C; 
• Reactive result for IGRA, considering as positive the result of TB1 Tube and / or TB2 
Tube above 0.2 IU/mL(53); 
• Liver enzymes (AST and ALT) three times the upper limit; 
• History or treatment for epilepsy; 
6.4 Indications for premature exclusion 
The participant may be withdrawn from the clinical trial at any time for the reasons listed 
below: 
• at the request of the participant (withdrawal or withdrawal of consent); 
• non-compliance with the protocol; 
• interruption of treatment or sum of temporary interruptions of intervention ≥90 days, either 
by decision of the participant or at medical discretion; 
• transfer to another prison unit or early release; 
• Clinical or laboratory AE requiring permanent discontinuation of medication (according to 
study-specific SOP); 
• any exclusion criterion according to item 5.3 that, incidentally, arises during the follow-up 
(both recently diagnosed and not previously recognized); 
• use of acetaminophen, valproic acid, carbamazepine, cycloserine, ethionamide, 
corticosteroids, diazepam, triazolam, disulfiram, phenytoin, aluminum hydroxide and rifampicin 
which, at the discretion of the investigator, are used in a dose that may interfere with the efficacy of 
INH as medication; 
• another reason, at the discretion of the principal investigator or study coordinator. 
At the time of the participant's withdrawal, a premature exclusion visit with clinical evaluation, 
evaluation of AE and blood and / or sputum collection should be performed according to the clinical 
judgment, according to the study schedule (figure 1). 
In addition, for cases in which treatment has been interrupted by decision of the participant 
or at medical discretion, as of 6 months from the start of the DOT, the participant will have two 
options: to remain in the study without the intervention (DOT), but with the accomplishment of all 
the visits anticipated in the protocol or to leave completely of the study without the realization of 

 
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additional collections and other accompaniments. For the latter case, follow-ups will be carried out 
only if the participant presents some AE at the time of their withdrawal. 
6.5 Conducting the study 
Participants will be invited to participate in the clinical trial through the consent process and 
will agree to participate in the study by signing the ICF. 
In the recruitment interval, prior to any intervention, participants will respond to the AUDIT 
questionnaire - which assesses various levels of alcohol use, from safe use to likely dependence - 
and eligibility criteria will be checked. In the recruitment interval, participants will have a 9mL sample 
of peripheral blood collected for testing of IGRA (QuantiFERON® TB GOLD PLUS kit - Qiagen, HIV, 
hepatitis B (HBsAg) and C (Anti-HCV) and serum levels of liver enzymes (AST and ALT). 
After the results of these initial tests (HIV, hepatitis B and C, IGRA, AST and ALT), if eligible, 
the participant will answer questionnaires containing socioeconomic, medical and criminal history 
and have a sample of sputum collected for culture. 
The participant will be included in the study without the result of the culture and, in case of a 
positive result for Mtb, the intervention will be suspended, the same will be excluded from the study 
and treated according to the MS protocol. If the sputum culture is contaminated, a new sample 
should be collected within 30 days after the result. 
The recruitment interval will last 20 to 45 days. 
On the day of initiation of DOT (D0), each participant will receive a supervised dose (three 
oral tablets) of INH (900mg) or placebo. The same will happen twice a week for 12 months. During 
the DOT the participant will be asked about AE. 
Blood samples will be collected every three months after D0 to measure hepatic enzyme 
levels (AST and ALT), as well as clinical evaluation and verification of AE, as shown in figure 1. 
At six months and at the end of the intervention (12th month), all participants will have a 
sample of sputum collected for culture and a blood sample for detection / quantification of interferon 
gamma. The same evaluation will be repeated in the 24th month counted from D0, that is, one year 
after the end of the intervention. 
At follow-up visits of 6, 12 and 24 months, if the interferon gamma result is indeterminate, the 
participant remains in the clinical trial and a new sample is collected within 30 days. If the IGRA 
result is positive (result standardized according to the package insert of the Qiagen®), the participant 
will suspend the medication (in the case of the 6-month visit), will be excluded from the study and 
treatment for latent TB. 
If the sputum culture is positive for Mtb, the participant will be excluded from the study and 
treatment for active TB according to MS will be offered. If the sputum culture is contaminated, a new 
sample should be collected within 30 days after the result. 
In the occurrence of hepatotoxicity, diagnosed through hepatic enzyme levels (elevation 
greater than five times the upper limit of the test if the individual is asymptomatic) and / or clinical 
examination (presence of jaundice, right upper quadrant pain, dark urine, fever, asthenia, myalgia), 
the intervention will be interrupted and the participant will be led to clinical care by the project team, 
according to the project's SOP. In this study, the following values will be used as laboratory 
parameter: AST: 8-40 IU / mL and ALT: 5-30 IU / mL(54,55). Other laboratory tests may be 

 
Version 6, 06/12/2018 
16 
requested from the research participants, according to the clinical judgment of the physician 
responsible for the care of the AE and according to the specific SOP of the project. 
IGRA, smear culture, and serology for HIV, hepatitis B and C are performed LPCS / UFGD. 
The AST/ALT exams and other laboratory tests, when necessary, are performed in an external 
laboratory. 
During the course of the study, the Notification of Injury Information System will be used to 
identify the occurrence of active TB cases in both groups. 
The box below summarizes the activities to be developed at each stage of the protocol. 
 
Enrollment 
DOT 
start 
(D0) 
1st visit 
(3 mo± 
15 d) 
2nd visit 
(6 mo± 
15 d) 
3rd visit 
(9 mo± 
15 d) 
4th visit 
(12 mo± 
30 d) 
5th visit 
(24 mo± 
30 d) 
Early 
exclusion 
visit 
Consent process 
X 
 
 
 
 
 
 
 
Verification of 
inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
AUDIT 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Criminal history 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
DOT star 
 
X 
 
 
 
 
 
 
DOT end 
 
 
 
 
 
X 
 
 
IGRA 
X 
 
 
X 
 
X 
X 
(X) 
ALT, AST 
X 
 
X 
X 
X 
X 
 
(X) 
Another 
laboratory exams 
(X) 
 
(X) 
(X) 
(X) 
(X) 
 
(X) 
Anti-HIV, HBsAg 
e Anti-HCV 
X 
 
 
 
 
 
 
(X) 
Sputum coleccion 
X 
 
 
X 
 
X 
X 
(X) 
Clínical evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
Adverses events 
evaluation 
 
 
X 
X 
X 
X 
X 
X 
DOT = Directly Observed Treatment, mo = months, d = days 
Figura 1 - Schedule, second quarters, of research activities. The parentheses indicate that the procedures are optional. 
6.6 Estatistical analysis 
Data on demographic, socioeconomic, medical and criminal history, as well as on pre, intra 
and post-intervention laboratory tests will be stored online at REDCap, available at 
<http://www.matogrossodosul.fiocruz.br/redcap/>, where each researcher is identified by single 
user and password, guaranteeing restricted and confidential access. Statistical analysis will be done 
with IBM® SPPS Statistics software. 
The incidence will be calculated on the basis of the new cases detected during the follow-up 
period, per 100 person-years. It will be considered a new case of TB individuals, regardless of the 
group, who present bacilloscopy or positive culture. For latent TB, a seroconversion will be 
considered for individuals who exhibit interferon gamma levels above the upper limit considered by 
the manufacturer of the QuantiFERON® TB Gold Plus commercial test in the 12th or 24th month. 
The effect of the intervention will be calculated through Relative Risk (RR), considering a 
Confidence Interval of 95% (95% CI). To determine the effectiveness of the intervention will be used 
Relative Risk Reduction (RRR) and Absolute Risk Reduction (RAR). In addition, to measure the 
impact of the intervention, the Number Needed to Treat (NNT) will be calculated. 

 
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17 
Two protocols will be performed for statistical analysis: 1) intention-to-treat analysis and 2) 
per protocol. The sample calculation for the primary outcomes is based on intention-to-treat 
analysis. 
The intent-to-treat analysis will be performed for all subjects who complete at least 6 months 
of treatment. The participant may decide to withdraw the consent in whole or in part. In the case of 
withdrawal of partial consent IGRA will be withdrawn at the 12th or 24th month and the participant 
will remain in the study according to the initial randomization. 
Analysis by protocol will be performed only using the group of individuals who completed at 
least 80% of the predicted doses of the study. 
6.7 Interim analysis 
After a 6-month visit of at least 100 participants, in addition to the follow-up clinic-laboratorial 
evaluation (which includes blood collection for hepatic enzyme dosage and directed clinical 
examination), an evaluation of the effectiveness of the intervention will be carried out, through 
sputum culture and interferon-gamma dosing / quantification. It is estimated that there is a linear 
relationship between follow-up time and the risk of acquisition of latent TB. 
This evaluation intends to verify the feasibility of continuity of the study and adequacy of the 
sample calculation. The study will be discontinued if the primary endpoint is less than 2.5% as 
compared to the control group, or if the difference between the intervention group and the control 
group is greater than 12.5% according to the box below: 
 
Intervention (isoniazid) 
(N=162) 
Control (placebo) 
(N=162) 
Finale total number 
(N final+30%) 
Reference 
5.0% 
10% 
726 
Insufficient sample 
7.5% 
10% 
3357 
Insufficient sample 
10.0% 
12.5% 
3910 
Insufficient sample 
12.5% 
15.0% 
4555 
Insufficient sample 
15.0% 
17.5% 
5114 
Insufficient sample 
17.5% 
20.0% 
5361 
Sufficient sample 
5.0% 
17.5% 
172 
Sufficient sample 
7.5% 
20.0% 
187 
Sufficient sample 
10.0% 
22.5% 
213 
Sufficient sample 
12.5% 
25.0% 
218 
Sufficient sample 
15.0% 
27.5% 
229 
Figura 2 - Sample table of the sample values in both groups (intervention and control), based on the primary outcome. 
6.8 Study interruption 
The study may be terminated early according to the outcome of the interim analysis or at the 
discretion of the research team, which shall prepare written notices to the IRB and to the sponsor, 
detailing the reasons interruption of the study. 
Participants should be informed about early termination of the study, treatment discontinued, 
and premature exclusion visit according to figure 1. 
6.9 Ethical aspects 
 

 
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18 
Following the provisions of Resolution 466/12 of the National Health Council, the present 
study was sent to the IRB of the UEMS, having its first approval in the Opinion no. 1,677,965, CAAE 
no. 57333716.8.0000.8030. 
This study will use REDCap to capture data and it will be used as a source document of the 
information contained in it. A copy of the completed document will be printed and archived in the 
participant's folder. 
It is registered and approved in the Brazilian Registry of Clinical Trials, available at 
<http://www.ensaiosclinicos.gov.br/rg/RBR-4n67h3/> and in the Clinical Trials, available at 
<https://clinicaltrials.gov/ct2/home>, identifier NCT03028129. 
All individuals approached by the researcher and team should read and sign the TCLE to 
participate in the research. 
During the course of the experiment, participants will be monitored clinically and laboratorially 
for the occurrence of adverse effects, particularly hepatotoxicity, a more frequent event (1%) 
according to the literature(33). 
If the intervention results in greater than expected benefit, the team will discontinue the 
experiment and provide all participants with INH treatment. 
6.10 Quality control 
Sponsor will provide monitoring visits that will include reviewing forms, batch counting of 
drugs, checking laboratory data, monitoring adverse events, and documenting any violations or 
deviations from the protocol. 
This study may be subject to audit procedures in cases where the sponsor or the Brazilian 
regulatory agency (ANVISA) deems relevant. 
6.11 Potential risks 
1) The protocol will identify active and latent cases of TB among inmates. Although the diagnosis of 
TB provides the prisoner with situations that can be understood as benefits, such as admission to 
less busy wards and access to better services, the disease in Brazil, as in many countries, is 
potentially stigmatizing. 
2) During recruitment, cases of HIV and viral hepatitis (B and C) may be identified, which, although 
treatable, as well as TB, are potentially stigmatizing. 
3) Participants allocated to the experimental group will receive INH. Mild and serious adverses 
events including hepatotoxicity may occur. All participants will be monitored every three months 
through clinical consultation and blood tests when necessary. 
4) The study team will extract information about demographics, behaviors, and past medical history 
during interviews, so there is the potential risk of discomfort in answering questions and breach of 
confidentiality regarding personal information. 
5) Blood samples will be collected by venipuncture during the study, which, despite having minimal 
risks, may be associated with discomfort and bruising. 

 
Version 6, 06/12/2018 
19 
6) Innmates are inherently vulnerable populations who may feel compelled to participate in the study 
and may perceive that their involvement in the proposed study provides benefits or risks in relation 
to the conduct of officials and other prisoners. 
7) The study team is exposed to the risk of infections and work-related illnesses due to the high rate 
of TB transmission in the study sites (prison). 
6.12 Expected benefits 
1) Reduce the risk of becoming infected with TB or developing the disease during incarceration. 
2) Quantification of the risk / benefit of primary prophylaxis in subjects without tTB (active or latent), 
but strongly exposed to the risk of becoming infected with TB or developing the disease. 
3) Produce scientific evidence to modify the recommendations of the competent organs regarding 
primary prophylaxis in the prison system. 
 

 
Version 6, 06/12/2018 
20 
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