MOD 00009 RE TB SVCS WITH CDC TBESC.PDF

Steve Chucri
Chairman, Maricopa County Board of Supervisors
ATTEST: APPROVE AS TO FORM:
_____________________________________ _____________________________________
Clerk of the Board Date Attorney for Maricopa County Date

SECTION B SUPPLIES OR SERVICES AND PRICES/COST
Option 8 Option Period 8 Items:
ITEM SUPPLIES/SERVICES -17/UNIT UNIT PRICE EXTENDED PRICE
0009 TBESC Research lEach $325,002.00 $325,002.00
Tuberculosis Epiclemiologic Studies
Consortium (TBESC) Research
entitled, "Improving the Diagnosis
and Treatment of Latent TB
Infection" and in accordance with
Section C, Statement of Work
(SOW).
Performance Period:
September 29, 2018 through
September 28, 2019
Line(s) Of Accounting:
939ZR0U 2555 2018 75-18-0950
5610411101 $325,002.00
STATEMENT OF WORK
For 6/19/2018 13, pgs
Task Order 1
Title of Project: "Prospective Comparison of the Tuberculin Skin Test (TST) vs. Interferon Gamma
Release Assays (IGRAs) in Diagnosing Latent Tuberculosis Infection (LTBI) and in Predicting Progression
from LTBI to Active Tuberculosis Disease"
I. Project Identification
This Request for Task Order Proposal (RFTOP) is to contract with research sites to participate in the
Tuberculosis Epidemiologic Studies Consortium (TBESC) research study named "Prospective Comparison of the
Tuberculin Skin Test (TST) vs. Interferon Gamma Release Assays (IGRAs) in Diagnosing Latent Tuberculosis
Infection (LTBI) and in Predicting Progression from LTBI to Active Tuberculosis Disease."
II. Background and Need
Tuberculosis (TI3) is the world's second leading cause of death from infectious disease, killing an estimated 1.7
million people a year. Its reservoir is the estimated one third of the world's population who are infected with
Mycobacterium tuberculosis but have no symptoms and cannot transmit the infection. One in ten of these persons

with latent TB infection (LTB1) will eventually develop active disease and, on average, spread the infection to an
additional 10 to 15 people before dying or recovering.' In the United States, where an estimated 11 million people
have LTBI, identification and treatment of those persons most likely to progress to active TB is a key component of
TB prevention and control.
Risk of LTBI and TB
From an operational point of view, LTB1 may best be defined as a state of persistent immune response to
previously acquired M. tuberculosis antigens without evidence of clinically manifest TB. Based on this definition,
individuals with LTBI carry an increased risk of progression to active TB disease. However, an unknown (but
large) proportion of those with LTHI will not develop active TB disease because: a) their immune systems
persistently control the dormant living mycobactcria; b) they are no longer infected; or c) they received curative
therapy.
Persons at risk of TB infection and of progression to active disease constitute two distinct but overlapping
groups. Persons at increased risk for Mycobacterium tuberculosis infection include: close contacts of persons
known or suspected to have active TB; foreign-born persons from areas that have a high incidence of active TB
(e.g., Africa, Asia, Eastern Europe, Latin America, and Russia); persons who visit areas with a high prevalence of
active TB, especially if visits are frequent or prolonged; residents and employees of congregate settings whose
clients are at increased risk for active TB (e.g., correctional facilities, long-term care facilities, and homeless
shelters); healthcare workers who serve persons who are at increased risk for active TB; populations defined locally
as having an increased incidence of latent M. tuberculosis infection or active 1'I3, possibly including medically
underserved, low-income populations, or persons who abuse drugs or alcohol; and infants, children, or adolescents
exposed to adults who are at increased risk for latent M. tuberculosis infection or active TB. 1,2
It is well established that only a small proportion of individuals who are infected with M. tuberculosis will ever
develop TB. The risk of progression to active TB is not evenly distributed among persons with LT13.1. It is highest
in the first two years after infection, and drops exponentially thereafter. In the first two years, the cumulative risk is
approximately 2%-5% or one per 100 person-years. 34 The subsequent risk of about one in 1,000 person-years
accumulates to a lifetime risk of 10% •-15% if infection occurs at a relatively young age. 5-7 1-lowever, lifetime risk is
strongly dependent on co-factors, such as the presence of other diseases. Persons with LTBI who also have
HIV/AIDS have a 5% to 15% annual risk of progression. Risk also is increased among persons with a history of
untreated or inadequately treated active TB, including persons with fibrotic changes on chest radiograph consistent
with prior active TB; persons with silicosis, diabetes mellitus, chronic renal failure, leukemia, lymphoma, or cancer
of the head, neck, or lung; and persons who have had a gastrectomy or jejunoileal bypass.". Treatment with
immunosuppressive drugs also increases the risk of progression, including treatment following organ transplantation
and treatment with tumor necrosis factor-alpha (TNF-a) antagonists and systemic corticosteroids equivalent to >15
mg of prednisone per day.' 1° Behaviors that increase risk of progression include cigarette smoking and alcohol and
drug abuse.
Identification of persons with urBi
Two methods are available for diagnosis of LTB1: the in vivo tuberculin skin test (TST) and the ex vivo
interferon gamma release assay (IGRA), both of which identify an adaptive immune response to mycobacterial
antigens. 12-14.
1) Tuberculin skin test
The TST, the most widely used screening test, has been in use for over a century. 12,14 It measures cell-mediated
immunity in the form of a delayed-type hypersensitivity (0TH) response to the most commonly used purified
protein derivative (PPD) of tuberculin. TST reactions in humans are measured by the diameter of induration 48-.72
hours after PPD injection.
The TST has well-known problems with sensitivity and specificity. Its sensitivity varies by the chosen cut point
for determining El positive result (5, 10, or 15 mm of induration). Tuberculin PPD is a crude mixture of antigens,

many of which are shared by a number of nontuberculous mycobacteria that can cause cross-reactions. A negative
TST is difficult to interpret in individuals who are immunocompromised from underlying disease, such as HIV, or
from drug treatment for cancer and other diseases. However, the most problematic issue for TST usc in the United
States is false positives caused by cross-reactivity with Bacille Calmette-Guerin (BCG) vaccine, widely used abroad
to protect newborns against TB meningitis and other severe forms of TB. More than 37 million foreign-born
persons live in the United States as permanent residents or visitors. Each year since 2002, foreign-born persons
have accounted for the majority of newly-diagnosed TB cases, with the proportion increasing each year. In 2009,
60% of newly-diagnosed TB cases occurred among foreign-born persons. An estimated 6.9 million foreign-born
persons who are permanent residents of the United States have LTBI. Improvements in TB prevention and control
in the foreign-born population will require a test for LTBI that is more specific than the TST.
2) Interferon Gamma Release Assays
IGRAs were developed in response to the limitations of TST. IGRA testing is based on the hypothesis that T-
eens of individuals sensitized by M. tuberculosis will produce interferon gamma (IFN-y) when they re-encounter
mycobacterial antigens. Specific IFN-y production in response to mycobacterial antigens, therefore, is presumed to
be indicative of M. tuberculosis infection."
IGRAs measure in vitro IFN-y production by circulating T-cells after 16-20 hours of stimulation in response to
specific M. tuberculosis antigens. The specific antigens used in IGRAs are produced by genes (ESAT-6 and CFP-
10) not found in BCG or in most environmental mycobacteria.'.' Therefore, IGRAs may produce fewer false
positives in persons previously vaccinated with BCG or who come from countries where nontuberculous
mycobacterial infections are common. 17' In 2001, the Food and Drug Administration approved the first IGRA,
QuantiFERON-TB test (Cellestis Limited, Carnegie, Victoria, Australia) for diagnosing M. tuberculosis infection.
The two IGRAs currently marketed in the United States are the QuantiFERON-T13 Gold-in-tube test (INT-GIT)
(Cellestis Limited, Carnegie, Victoria, Australia) and the T-SPOT.TB test (T-Spot) (Oxford Immunotec Limited,
Abingdon, United Kingdom).
3) TST vs. IGRA
The predictive value of a positive TST (i.e., the probability that the patient will develop TB in the near future) is
generally poor, while the negative predictive value (i.e., the probability that a person with a negative TsT will not
develop TB in the future) is high. The positive predictive value of an IGRA may be better than the TST because of
the higher lest specificity and similar, or probably higher, sensitivity.' 2'
For testing of immunosuppressed persons, evidence suggests that IGRAs have superior sensitivity compared to
TS'. This is because conditions in vitro may be optimized through incubation time and/or adjustment of cell
numbers to potentially adjust for immunosuppression (e.g., a longer incubation period or use of a larger number of
cells in someone with neutropenia). A specific advantage of in vitro (IGRA) testing is that stimulation reactions
with negative and positive (i.e., mitogcn stimulus) controls are conducted in parallel to evaluate test performance vs.
background signals or general T-cell responsiveness. In persons with immune suppression, an impaired mitogen
response may serve as an indirect measure of the overall degree of immunosuppression. Thus, unlike the TST, in
vitro IGRA tests may be able to better discriminate true negative responses from anergy. In addition, such IGRA
quantitation may be useful in estimating the degree of individual imtnunosuppression.
Based on evaluation of studies to date, the CDC in 2005 and 2010 published guidelines supporting the
equivalence of TSTs and IGRAs in most situations, and a preference for 1GRAs in certain situations, including
screening of foreign-born persons. 3'' 31 However, no large-scale population-based studies have been done to
compare the abilities of the two tests to (1) identify persons with LTBI, overall and in important subpopuIations, and
(2) determine which persons with LTBI are most likely to progress to TB. In addition, a positive TST or IGRA
could mean "lasting TB immune response" but not necessarily true "latent tuberculosis infection" with viable
bacilli and potential risk of developing active TB disease. A study that develops a way to identify the group of
individuals with true LTBI who are at greatest risk of progressing to active TB disease would greatly improve the
efficiency and cost-effectiveness of TB control efforts.

II. Project Purpose
The purpose of this study is to compare the performance of IGRAs and TSTs in a large and heterogeneous
cohort of patients in order to identify the method that best predicts progression to TB disease, overall and in
important subgroups of patients.
The results of this project should have a major impact on CDC recommendations for the detection of persons
with urm or TB disease and for follow-up and treatment of persons with LTBI.
III. Scope of Work
Project identification
This request is to support the TBESC in conducting a study to compare TST and IGRAs in diagnosing LTBI
and in predicting progression from LTBI to TB disease.
Study Population
Potential study participants are persons at high-risk group for LTBI or TB disease including:
a) Close contacts of persons known or suspected to have active TB.
b) Immigrants and refugees with Class 131 and B2 TB notification status.
c) Foreign-born persons from areas that have a high incidence of active TB who have lived in this
country for less than two years.
d) Residents and employees of congregate settings whose clients are at increased risk for active TB (e.g.,
correctional facilities, long-term care facilities, and homeless shelters).
e) Populations defined locally as having an increased incidence of LTBI or active TB, possibly including
medically underserved persons, low-income populations, or persons who abuse drugs or alcohol.
f) Persons with human immunodeficiency virus (HIV) infection.
Persons who are receiving immunosuppressive therapy, such as tumor necrosis factor-alpha (TNF-a)
antagonists, systemic corticosteroicls equivalent to >15 mg of preclnisone per day, or immune
suppressive drug therapy following organ transplantation.
h) Persons with a history of untreated or inadequately treated active TB, including persons with fibrotic
changes on chest radiograph consistent with prior active TB.
Study Overview
This study is a prospective comparison of TST and IGRAs in diagnosing LTBI and in predicting progression
from LTBI to TB disease (See Diagram 1).
All persons at high-risk of TB infection or of progression to active disease (see Study Population section) are
eligible to participate and will be tested using the TST and the Quaritiferon TB Gold In-Tube (QFT-GIT) assay. The
inclusion of an additional IGRA (T-Spot) is an optional activity under consideration.
Those testing negative by each test will be entered into the study database but not followed. These who test
positive by either TST or QFT-GIT test will be entered into the study database and followed for two years. Those

followed will include persons who are and who arc not candidates for LT.BI preventive therapy. Those who are
candidates for LTBI preventive therapy will be offered treatment. Those accepting LTBI treatment will have a
repeat OFT-GIT at completion of LTBI therapy. For those declining or not completing LTBI preventive therapy,
the OFT-GIT will be repeated on the date treatment was supposed to be completed.
All patients who tested positive by TST or OFT-GIT will be evaluated for signs and symptoms of TB disease
every 6 months (i.e., a16, 12,18, and 24 months) after the diagnosis of LTBI.
A serum specimen thr a serum bank will be obtained on all patients diagnosed with LTBI or TB disease.
Collection of a blood sample for a cell bank is an optional activity under consideration.
Comparative cost-effectiveness, outcome, and economic analyses will be conducted as part of this study.
Research sites will act as sources of and collection sites for data related to cost, process, and outcome measures
necessary to conduct these analyses.
Final analysis of the combined data from all sites will be performed by the CDC.
The CDC will conduct periodic matches between the study database and state TB registries to identify persons
entered into the study who have progressed from LTBI to TB disease.

Form Form
:LTBI:Treatrnent
Closing
Foll ...........
Treatment
LIBI. Recurring YES-4.; .. •,
....... .• results
IZ) . L..,,,.. lab e
F0 Add
IGRA
Form
Close-out
•
for Recurring Registry Match
Candidate Treatment Algorithm •• . i
11.1
Recurring
p
NO I Year lowL1
TB 2 Fol
Form for
Fortin Form
LTBI
TS-VIGRA results Follow-up
lab
1 Add (-)
Bank
log Senum TSTAGRA Test All Negative
Declined
•
Form
YES Begin Enrollment
Entry
:
Study
Form
Pm-enrollment
Diagram Population Risk) Form
(High Disease
Study
TB

200-2011-41279/0001 00009
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Project Objective
The main objective of this study is to compare the accuracy and cost-effectiveness of the 1ST and IGRAs in 1)
identifying persons with LTBI, and 2) identifying persons with LTB1 who progress to TB disease.
Other questions to be addressed by this study include:
a) What is the accuracy of IGRAs in the diagnosis of LTBI in special populations including children,
individuals with EIIV infection, and individuals on imrnunosuppressive therapy?
b) What is the incidence of TB disease in persons with TST-/IGRA-, TST÷/fGRA+, TST-/IGRA+, and
TST+/IGRA- results?
c) Are higher IFN-y responses associated with a greater risk for developing TB disease?
d) What causes variation in IGRA results?
e) How common are IGRAs reversions/conversions?
f) What is the clinical/epiderniologic significance of IGRAs conversion and reversion?
g) What factors, including treatment, baseline IFN-y levels, and variability around cut-offs, are associated
with IGRAs conversion/reversion?
h) How do IGRA results change during and after treatment for LTBI? Do IGRAs have a role in monitoring
response to LTBI treatment?
i) Will treatment of IGRA+ persons reduce the incidence of TB disease?
j) Which patient or population subgroups are most likely to benefit from the use of IGRAs?
k) Can sensitivity and specificity of IGRAs be improved by different interpretation criteria?
I) What is the ability of IGRAs to detect new infection/re-infection?
in) How much time is required after exposure for an IGRA to become positive?
n) What are the accuracy and utility of screening strategies that use combinations of TST and IGRAs (e.g.,
first screen with the TST then confirm positive results with IGRAs)?
o) How do TST and IGRAs compare in effectiveness, outcome, and economic analyses?
IV. Technical Reciuirernents
Contract Requirements
The contractor shall conduct the research study outlined above, in accordance with the study's protocol. In
summary, the contractor shall recruit patients at high risk for LTBI/TB disease and for each patient shall (1) obtain
and process the QFT-GIT, (2) apply and read the TST, (3) evaluate the person for TB, (4) offer and provide CDC-
recommended LTBI preventive therapy, and (6) perform patient follow-up for TB disease every six months for a
total of two years from the time of the initial LTBI diagnosis.' 41
Specific requirements are listed below. The contractor shall:
1. Follow up all patients receiving LTBI therapy for adverse effects of treatment.
2. Follow up all patients for signs and symptoms of TB disease at six-month intervals (e.g., at 6, 12, 18, and
24 months) for two years after the initial LTBI diagnosis.
3. Complete the following study forms:
a. LTB1 Treatment Follow-up Form
i. Signs or symptoms of LTBI preventive therapy toxicity, including drug-related symptoms

200-2011-41279/0001 00009
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If toxicity is established, the plan for addressing the toxicity
For those discontinuing or currently receiving LTBI preventive therapy:
number of doses of each LTBI preventive treatment dispensed
number of doses of each LTBI preventive treatment remaining, and
number of doses of each LTBI preventive treatment taken.
b. LTBI Treatment Closing Form for those declining, prematurely interrupting or completing preventive
therapy:
Number of LTBI preventive therapy doses of each medication received
Signs or symptoms of TB disease, and
Whether the patient has developed TB disease.
c. Follow-up Form for TB that records:
i. Signs or symptoms of TB disease; and
Whether the patient has developed TB disease.
d. For any LTBI patient progressing to TB disease, complete a TB Disease Form:
i. Signs and symptoms of TB disease
Laboratory data
Genotype of the TB strain
iv. Risk factor for TB disease.
e. Close-out Form to be completed at the end of the 2-year follow-up period for all patients.
4. Enter and submit data into the CDC-developed data entry system using a password-protected entry system.
5. Perform quarterly quality assurance (QA) data checks for completeness, use of valid variables and
responses, and logical consistency. The contractor shall correct data errors discovered during QA checks.
6. Respond to any OA issues noted by the COTR. The contractor shall investigate all QA issues and respond
with written documentation containing a description of: (1) all the issues that were identified; (2) issues that
were resolved and (3) issues that could not be resolved and why. The errors shall be revised in the data
entry system within two weeks after notice of QA issue.
7. Respond to any issues noted by the COTR concerning patient enrollment, management and follow-up. The
contractor shall investigate all these issues and respond with written documentation containing a
description of: (1) all issues that were identified; (2) issues that were resolved and (3) issues that could not
be resolved and why. The contractor will provide an immediate action plan on how the issues will be
corrected.

200-2011-41279/0001 00009
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8. Participate to the extent needed for co-authorship, in the development of topics for papers to present study
findings, drafting and publication of papers.
9. At the completion of the study, submit a final summary report to the Consortium's DMC. The report shall
include: (1) a summary of all persons enrolled; 2) results of TST and IGRA testing; 3) interpretation of the
positive and negative predictive values of the TST and/or IGRAs in detecting LTBI and for predicting
progression from LTBI to active TB, including stratification by risk groups or innmunocompetent vs.
immunocompromised status; (4) a description of the strengths and weaknesses of the study, barriers
encountered during the study, and factors which helped facilitate the study, and (3) recommendations for
future studies.
10. Throughout the duration of this contract, the contractor shall participate fully as a member of the TBESC.
In particular, as an active member of the consortium, the contractor shall:
a) participate in efforts to develop, implement, monitor and update the TBESC research agenda
b) adhere to the policies, procedures, and research protocols that guide all aspects of the TBESC
activities and operations
c) participate as appropriate in protocol development
d) participate actively and as appropriate in TBESC committee activities
e) participate fully in TBESC quality assurance activities
cooperate with the TBESC site monitoring program
g) abide by the TBESC policies and procedures for the publication of data
h) participate in TBESC scheduled weekly or biweekly teleconferences and e-mail communications
i) attend two TBESC meetings per year and stay until the end of each meeting.
Each contractor shall, as an independent organization and not as an agent of the Government, furnish all the
necessary services, qualified personnel, material, equipment, and facilities to perform this study. At the study sites,
data must be available for external checking against the original source documentation as required by U.S. Federal
regulations. Either DTBE-CDC staff or an external Contract Research Organization (CRO) site monitor will
evaluate good clinical practice, data collection and reporting, regulatory compliance, accurate protocol
implementation, internal quality management, and test product accountability. Site visits will be performed
approximately twice a year, or as needed to review selected protocols, provide training on protocol conduct, review
internal quality assurance plans, or document error resolution.
V. Period of Performance: The period of performance of this task order will be consist of a 6- month
base period, 6-month option period, and eight (8) option periods with a 12- month period of performance per
optional periods.
VI. Specific Tasks: Ongoing tasks
Option Period 1 (6 months)
Option Period 2 (12 months)

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1. For all persons with LTBI receiving preventive therapy perform follow-up every 30 days while on therapy and
complete the LTBI Treatment Follow-up Form at each clinic visit.
2. For all patients diagnosed with LTBI, the patient's case manager, nurse, physician, or other appropriate
professional shall meet with or contact the patient at 6, 12, 18, and 24 months after study entry (i.e., diagnosis of
LTBI) and complete the Follow-up Form for TB to assess (A) development of TB disease signs or symptoms and
(B) development of TB disease.
3. When the patient completes LTBI preventive therapy, a case manager, nurse, or study professional shall fill out a
LTBI Treatment Closing Form (for those declining, and those completing partial or complete courses of preventive
therapy).
4. Complete the Close-out Form for all patients ending the 2-year follow-up period.
5. The contractor shall enter the data from all patient forms into a database provided by the CDC or upload the forms
to an FTP location designated by the CDC.
6. The contractor shall participate fully as a member of the TBESC as described above.
Option Period 3 to 7 (12 months each)
The contractor shall continue the, preventive treatment, follow-up, observation, data collection, and data
analysis of LTBI patients as described in the option period 2.
The contractor shall participate fully as a member of the TBESC as described above.
In addition to the tasks listed above the contractor shall also perform the following:
I. BRIEF DESCRIPTION OF PROJECTS
Project One:
Prospective Comparison of the Tuberculin Skin Test and Interferon-Gamma Release Assays in Diagnosing
Infection with Mycobacterium tuberculosis and in Predicting Progression to Tuberculosis
Objectives:
(1) Evaluate the agreement between the tuberculin skin test and the two commercially available interferon-
gamma release assays (IGRAs) for LTBI, overall and in important subgroups
(2) Determine the ability of each test to predict progression to TB disease, overall and in important subgroups.
Project Two:
Strengthening Public Health Surveillance for Latent Tuberculosis Infection
Objectives:
(1) Improve public health surveillance for LTBI within TBESC programs

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(2) Promote partnerships between TBESC TB programs and local community providers who care for
populations at high risk for LTBI
(3) Identify reasons why high-risk populations are not screened for LTBI, why persons with LTBI do not start
treatment, and why patients with LTBI who start treatment do not complete treatment.
Other questions to be addressed by this study include:
a) Which community clinics and private providers serve populations at hii2,11 risk of LTBI?
b) What are current practices related to LTBI testing and treatment, both among TBESC members and
selected local partners?
c) Are high-risk populations, particularly persons born outside the Unit,ecl States, being tested and treated for
LTBI?
cl) What are the magnitude and location of gaps in the delivery and uptake of TB prevention services?
e) What instruments and processes can community providers use to assess their LTBI practices?
Project Three
Identifying barriers to LTBI testing and treatment in local health departments and among partner
community providers.
Objectives:
(1) To identify barriers to LTBI screening, testing, and treatment at health departments and their partner
community clinics.
(2) To identify facilitators to LTBI screening, testing, and treatment at health departments and their partner
community clinics.
(3) To design multi-faceted strategies to remove barriers and/or expand facilitators to LTBI testing and
treatment at health departments and their partner community clinics.
Project Four
Six weeks of daily rifapentine vs. a comparator arm of 12-16 week rifamycin-based treatment of latent M.
tuberculosis infection: assessment of safety, tolerability and effectiveness
Objectives:
(1) Compare the safety of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment (3HP,
3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.
(2) If safe, compare the effectiveness of daily 6wP to a comparator arm of 12-16 week rifamycin-based
treatment (3HP, 3HR, or 4R) for the prevention of TB in persons > 12 years old with LTBI.
Other questions to be addressed by this study include:
What is the proportion among those treated with 6wP vs the comparator arm with treatment completion?
g) What is the proportion among those treated with 6wP vs the comparator arm with drug discontinuation for
any reason?
h) What is the proportion among those treated with 6wP vs the comparator arm with any grade 3, 4, or 5 (Le.,
death) adverse event associated with study drug?
i) What is the proportion among those treated with 6wP vs the comparator arm who have died for any reason?
i) What is the proportion among those treated with 6wP vs the comparator arm with hepatitis and non-
hepatotoxic systemic drug reactions.
k) What is the proportion among those treated with 6wP vs the comparator arm with culture-confirmed or
clinical TB regardless of age?

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1) What is the proportion among those treated with 6wP vs the comparator arm with TB among those who
complete therapy (efficacy)?
m) What is the safety, tolerability, and effectiveness in human immunodeficiency virus (HIV) - infected
participants?
III. Technical Requirements
Contract Requirements
The contractor shall conduct the research studies outlined above in accordance with each study protocol
(attached).
V. Specific Tasks
A. Option period 8 (12 months)
During Option Period 8, the contractor shall perform the following activities for each of the listed projects:
1. Prospective Comparison of the Tuberculin Skin Test and Interferon-Gamma Release Assays in
Diagnosing Infection with Mycobacterium tuberculosis and in Predicting Progression to
Tuberculosis (see attached protocol).
The contractor shall perform the following activities during this option period:
a. Conduct registry matches every six months to identify TB cases that might have occurred among
enrolled participants, as described in option period 2.
h. Respond to questions from CDC about participants who have been enrolled in the study.
c. Continue 12 month, 18 month, and 24 month follow-up of participants, as described in option period 2.
d. Fill out and submit appropriate paperwork for any participants who develop TB during the option
period, as described in option period 2.
e. Complete all data entry for participants and submit appropriate closing forms, as described in option
period 2.
f. For those sites whose Pis have agreed to review uploaded chest radiographs, review the radiographs
and enter the appropriate documentation in the online Data Management System.
g. Participate in analysis of data and development and writing of manuscripts.
h. Participate in review of proposals for manuscripts and abstracts and manuscripts written by other
TBESC members.
i. When possible (i.e., abstract has been accepted for presentation), attend regional and national
conferences to present the results of analyses related to this protocol.
2. Strengthening Public Health Surveillance For Latent Tuberculosis Infection (see attached protocol)
The contractor shall perform the following activities during the option period:
a. Use data entered into the Surveillance for TB Elimination Management System (STEMS) to assess the
site's LTBI activities; specifically, to calculate at least two LTBI Cascade to Cure graphics to assess
points in the care continuum where patients drop out of care:
i. An overall cascade that describes the number of patients who are tested, the number
or proportion who test positive for LTBI, the number or proportion diagnosed with
LTB1, the number or proportion offered treatment, the number or proportion placed
on treatment, and the number or proportion who finish treatment.
ii. A cascade that includes only foreign-born persons. To calculate this cascade, sites
will use a TBESC-developed algorithm to calculate the estimated number of foreign-
born persons in the site's jurisdiction who have LTBI, the number or proportion who
are tested at the health department, the number or proportion who test positive for
LTBI, the number or proportion diagnosed with LTBI, the number or proportion

200-2011-41279/0001 00009
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offered treatment, the number or proportion placed on treatment, and the number or
proportion who finish treatment.
b. Begin or continue outreach to focal providers outside the health department who serve persons at high
risk of LTBI. This shall include development of a toolkit that summarizes TBESC experience with
outreach activities for use by other jurisdictions, health departments, and providers. This toolkit will
include an overall summary of activities, instructions on ways to identify appropriate partners,
suggestions for outreach activities, algorithms for calculation of the LTBI Cascade to Cure,
spreadsheets for calculation of local LTBI prevalence in high-risk populations, and other useful
documents.
c. Collect aggregate data from one or more local providers to calculate LTBI cascades to cure that will
help identify places in the care continuum where private-care patients drop out of care.
d. Participate in analysis of data and development and writing of manuscripts.
e. Attend regional and national conferences to present the results of analyses related to this protocol (i.e.,
abstract has been accepted for presentation).
Participate in review of proposals for manuscripts and abstracts and manuscripts written by other
TBESC members.
g. Provide a report to CDC by the end of the option period, 2018 or earlier that describes the site's
progress on meeting the goals of project 2 objectives. This should include a description of outreach
activities and collaborations with providers outside the health department.
3. Identifying barriers to LTBI testing and treatment in local health departments and among partner
community providers (see attached protocol).
Select contractors shall perform the following activities during the option period:
a. Obtain patient-specific information from private partners and/or the health department TB program
that will permit record-level construction of LTBI Cascades to Cure. Use this information to identify
places where persons at high risk of un3i are likely to fall out of care.
b. Conduct formative research within the health department and/or with outside partners to identify
facilitators and barriers to improvement of the LTBI Cascade to Cure, in order to increase the
proportions of patients tested for LTBI and treated to cure.
c. Identify one or more local strategies to improve the LTBI Cascade to Cure in order to increase the
proportions of patients tested for LTBI and treated to cure.
d. Participate in analysis of data and development and writing of manuscripts.
e. When possible, (i.e., abstract has been accepted for presentation), attend regional and national
conferences to present the results of analyses related to this protocol.
f. Send a project coordinator or principal investigator to one or more trainings related to formative
research and implementation science.
g. Participate in review of proposals for manuscripts and abstracts and manuscripts written by other
TBESC members.
h. Provide a report to CDC by the end of the option period, or earlier, that summarizes the site's progress
on meeting project 3 objectives.
At the discretion of specific sites, and with the agreement of CDC, the following activities may be
substituted for activities a through g:

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a. Work with local partners to evaluate billing practices with the goal of improving partners'
abilities to obtain reimbursement for LTBI services.
b. Produce a document that summarizes the site's findings and contains suggestions for
improving reimbursement.
4. Six weeks of daily rifapentine vs. a comparator arm of 12-16 week rifamycin-based treatment of latent
M. tuberculosis infection: assessment of safety, tolerability and effectiveness (see attached protocol)
Select contractors shall perform the following activities during the option period:
a. Provide to CDC a plan for implementation of the safety and tolerability aspects of the clinical trial
at the local site. This plan should include description of
i. measures taken to ensure maintenance of drugs at constant temperature.
specific tests required by the protocol that sites do not normally perform before
placing a patient on LTBI treatment.
other materials needed to fulfill the protocol requirements, including patient
followup.
iv. The number of patients the site expects to enroll annually
b. Compare the safety of daily 6wP to a comparator arm of 12-16 week rifamycin- based treatment
(311P, 3HR, or 4R) for the prevention of TB in person's? 12 years old with latent M. tuberculosis
infection.
c. Compare the tolerability of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment
(3HP, 31-IR, or 4R) for the prevention of TB in person's? 12 years old with latent M. tuberculosis
infection.
d. Among those treated with 6wp, compare
i, treatment completion with an alternative regimen after discontinuation of study therapy
ii. Resistance to rifamycins or isoniazid among persons who develop TB.
c. If safe, compare the effectiveness of daily 6wP to a comparator arm of 12-16 week rifarnycin-based
treatment (3HP, 31-1R, or 4R) for the prevention of TB in person's? 12 years old with LTBI.
f. Participate in CDC trainings as necessary, this may require travel.
B. Option period 9 (12 months)
During Option Period 9, the contractor shall perform the following activities for each of the listed projects:
I. Prospective Comparison of the Tuberculin Skin Test and Interferon-Gamma Release Assays in
Diagnosing Infection with Mycobacterium tuberculosis and in Predicting Progression to
Tuberculosis (see attached protocol)
2. Strengthening Public Health Surveillance for Latent Tuberculosis Infection (see attached protocol)
a. The contractor shall provide to each partner with which the site has established a relationship a report
describing key activities and goals that have been accomplished. A copy of this report shall be
provided to CDC.
3. Identifying barriers to LTBI testing and treatment in local health departments and among partner
community providers (see attached protocol).
4. Six weeks of daily rifapentine vs. a comparator arm of 12-16 week rifamycin-based treatment of latent M.
tuberculosis infection: assessment of safety, tolerability and effectiveness (see attached protocol)

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a. Compare the safety of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment (3HP,
3HR, or 4R) for the prevention of TB in person's ? 12 years old with LTBI.
b. Compare the tolerability of daily 6wP to a comparator arm of 12-16 week rifamycin-based treatment
(3HP, 31-IR, or 4R) for the prevention of TB in person's ? 12 years old with LTBI.
c. Among those treated with 6wp, compare
i. treatment completion with an alternative regimen after discontinuation of study therapy
ii. Resistance to rifamycins or isoniazid among persons who develop TB.
d. If safe, compare the effectiveness of daily 6wP to a comparator arm of 12-16 week rifamycin-based
treatment (311P, 31-ER, or 4R) for the prevention of -rB in person's ? 12 years old with LTBI.
e. If safe, continue enrollment to compare the effectiveness of 6wP vs. SOC.
f. Participate in CDC trainings as necessary, this may require travel.
Option Period 10 (12 months)
During Option Period 10 the contractor shall perform the following activities for each of the listed projects:
1. Prospective Comparison of the Tuberculin Skin Test and Interferon-Gamma Release Assays in
Diagnosing Infection with Mycobacterium tuberculosis and in Predicting Progression to
Tuberculosis (see attached protocol)
a. At the close of Option Period 10, the contractor shall provide a report to CDC that summarizes the
contractor's activities and accomplishments related to this project.
2. Strengthening Public Health Surveillance for Latent Tuberculosis Infection (see attached protocol)
a. The contractor shall provide to each partner with which the site has established a relationship a report
describing key activities and goals that have been accomplished. A copy of this report shall be
provided to CDC.
b. At the close of Option Period 10, the contractor shall provide a report to CDC that summarizes the
contractor's activities and accomplishinents related to this project.
5. Identifying barriers to LTBI testing and treatment in local health departments and among partner
community providers (see attached protocol).
a. At the close of Option Period 10, contractors shall provide a report to CDC that summarizes the
contractor's activities and accomplishments related to this project.
6. Six weeks of daily rifapentine vs. a comparator arm of 12-16 week rifamycin-based treatment of
latent M. tuberculosis infection: assessment of safety, tolerability and effectiveness (see attached
protocol)
These contractors shall:
a. Participate in analysis of data and development and writing of manuscripts.
b. When possible, (i.e., abstract has been accepted for presentation), attend regional and national
conferences LO present the results of analyses related to this project.
c. Participate in review of proposals for manuscripts and abstracts written by other 'TBESC members.
d. At the close of Option Period 10, provide a report to CDC that summarizes the contractor's
activities and accomplishments related to this project.
e. Participate in CDC trainings as necessary, this may require travel.