An Evaluation of Traditional Directly Observed Therapy (DOT) and Electronic DOT for TB Treatment

Tuberculosis (TB) is among the most common infectious diseases and cause of death worldwide.
The bacteria that causes TB, Mycobacterium tuberculosis (Mtb), is spread when a person with
TB disease of the lungs or throat coughs, speaks, or sings. These bacteria can float in the
air for several hours, depending on the environment. Persons who breathe in the air
containing these TB bacteria can become infected.

The World Health Organization (WHO) estimates that 9.6 million became ill with TB in 2014.
Among this group, approximately 480,000 persons became ill with multidrug-resistant TB (MDR
TB), which is TB caused by bacteria that are resistant to at least isoniazid and rifampin,
the two most potent TB drugs used to treat persons with TB disease. Extensively drug
resistant (XDR) strains of TB were reported by 105 countries in 2015. As such, the National
Strategy for Combatting Antibiotic Resistant Bacteria (CARB) has designated Mtb a SERIOUS
threat level pathogen.

Completion of treatment by persons with TB disease represents the optimal path to the
prevention of morbidity and mortality, cure of the patient, interruption of transmission, and
prevention of acquired drug resistance. The single best intervention in this regard has
proven to be directly observed therapy (DOT).

DOT provides frequent interactions between the patient and the patient's healthcare team.
This enables better monitoring and efficient response to medication side effects. This is
especially important as medication side effects are among the top reasons patients are lost
to follow-up during treatment therapy.

Experience in the U.S. in the 1990s demonstrated the efficacy of this intervention in the
prevention and control of drug-resistant tuberculosis.Studies in the past 15 years in
international settings have challenged the utility of DOT, but have been criticized for
imperfect to poor design or implementation.

DOT entails a trained "observer" acceptable to both the patient and the health system being
present to monitor treatment adherence as patients swallow anti-TB drugs. In the United
States, DOT remains a cornerstone of TB control. While DOT represents the treatment standard,
the implementation of DOT has been modified by some programs in an effort to reduce costs and
conserve program resources. In the U.S., efforts recently have sought to utilize advances in
communication technology to facilitate the implementation of DOT.

This study will evaluate traditional approaches to DOT compared to DOT by electronic methods.
The study will be based within, and primarily conducted by the New York City Department of
Health and Mental Hygiene (NYC DOHMH), Bureau of Tuberculosis Control (BTBC) clinics. This
will enable the study to be to be conducted in a programmatic setting and reflect "real-life"
situations.

Hypothesis: Directly observed therapy (DOT) that employs electronic communication methods
(eDOT) is a non-inferior approach to monitor treatment adherence, compared to traditional
forms of DOT, in which a trained person is in the physical presence of patients as anti-TB
drugs are ingested (ipDOT).

Design: This will be a U.S.-based, 1 site (with 4 clinic settings), randomized, cross-over,
2-arm, non-inferiority trial with randomization to either traditional in-person DOT (ipDOT)
or electronic DOT (eDOT)*, at the time outpatient treatment begins within participating
health department clinics.

*Secondary analyses will evaluate DOT conducted in "real time" or "live" (eDOT-live) compared
to DOT that uses a recorded video (eDOT-recorded).

Population:Patients newly diagnosed with drug-sensitive or non-rifamycin resistant TB.

Site: Four clinics of the New York City Department of Health and Mental Hygiene, Bureau of
Tuberculosis Control.

Study Duration: Duration per participant is approximately 6 months.

Description of Intervention: After providing written informed consent, participants will be
randomly assigned to one of the following DOT study group assignments: (1) traditional
in-person DOT (ipDOT) or (2) electronic DOT (eDOT).

Note: Patients and their providers will discuss and choose the type of eDOT they will use.
The two options are: (2a) eDOT conducted "live" in which TB program staff interact with
patients in real-time via a computer or phone application as they ingest their medication
(eDOT-live), and (2b) eDOT in which patients record themselves ingesting their TB medication
using "time-stamped, recorded" videos for TB program staff to review within 1 business day
(24 hours), and verify that patients ingested their medication doses as scheduled
(eDOT-recorded).

Following 20 observable medication doses under an initial DOT study group assignment
participants will be assigned (crossed-over) to the opposite DOT method to collect data on
another 20 observable medication doses. Specifically, participants who initially received
ipDOT will switch to eDOT. Participants initially assigned to eDOT will switch to ipDOT.

At the conclusion of this Cross-Over Period with 40 observable medication doses, participants
will continue treatment using their preferred DOT method.

Inclusion Criteria:

Individuals must meet the following inclusion criteria in order to participate in this
study:

1. All TB patients (both those with a confirmed diagnosis and those with a clinical
diagnosis), started on treatment for non-rifamycin resistant TB, and eligible to
receive DOT.

2. Physician determines the patient may be treated with any treatment regimen for
non-rifamycin resistant TB approved by the NYC DOHMH TB program.

3. Individuals found to have Isoniazid (INH) resistant disease are eligible for
inclusion.

4. Age >18 years or older

5. Age 12 to 17 years, with the consent of a parent or legal guardian

6. An address or residence location that is readily accessible for visiting, and
willingness to inform the study team of any change of address during the treatment and
follow-up period.

7. No plans to move out of the catchment areas of the participating TB program sites
within 9 months of enrollment.

8. Willingness to comply with study procedures and provide written informed consent prior
to study enrollment.

9. Individuals for whom a diagnosis of TB has been made clinically are eligible for study
inclusion. Data may be collected from these patients related to all objectives with
the exception of culture conversion.

Exclusion Criteria:

An individual meeting any of the following exclusion criteria at the time of enrollment
will be excluded from study participation:

1. At the time of enrollment, the patient's Mtb isolate is already known to be resistant
to rifamycin or prescribed a non-rifamycin treatment regimen.

2. Prescribed any injectable, anti-TB medication as part of an outpatient treatment
regimen.

3. Adverse reaction to initial doses of anti-TB medication (per NYC protocol) of
sufficient severity that in the judgement of the clinician makes study participation
not in the individual's best interest.

4. A cognitive or physical disability that prevents full participation in eDOT (e.g.,
vision, hearing, physically challenged, inability to swallow medications). NOTE:
Exceptions will be made for those patients who crush pills in order to swallow the
medication, or have a member of their household or a caregiver who can assist them for
the duration of the study.

5. Less than 12 years of age.

6. Patients 12-17 years of age, whose parents or legal guardians refuse to provide
consent.

7. Incarceration, institutionalization, or other involuntary detention.

8. Plans to move out of the catchment areas of the participating TB program sites in less
than 9 months from the day of enrollment.

9. Previously enrolled in this study.

10. Currently enrolled in a clinical trial that prohibits enrollment in another study.

11. Other medical conditions that, in the investigator's or the clinic physician's
judgment, make study participation not in the individual's best interest.