Tuberculosis Clinical Trial
Official title:
Delivering Community-based Interventions and Disease Management Tools Across a Digital Platform in Order to Increase TB Treatment Adherence in LMICs
Each year, 10.4 million patients are diagnosed with and 1.8 million people die from
Tuberculosis (TB). Despite the availability of highly effective and accessible medications in
the developing world where TB is endemic, the 6-18 month treatment regimen is often thwarted
as patients fail to comply due to a lack of knowledge about the disease, desire for privacy,
and/or stigma avoidance. Inappropriate medication use leading to multi-drug resistant (MDR)
TB infects 5% of all TB patients, yet accounts for a significant proportion of all spending.
In Kenya, the burden of TB is among the highest in the world with a prevalence rate of 558
cases per 100,000 people. There is a great need for the development of alternative protocols,
which reduce the costs of treatment and burden of adherence, and more effectively motivate
patients to adhere to the program. A substantial and growing literature in the social
sciences demonstrates the potential of behavioral interventions for generating large
increases in contributions to public goods.
This 1200 participant, Randomized Controlled Trial (RCT) explores the capacity of Keheala, a
feature-phone and Internet-based digital platform that uses Unstructured Supplementary
Service Data (USSD) technology, to deliver behavioral interventions for improving treatment
adherence, outcomes and quality of life for TB patients in Nairobi, Kenya. Keheala taps into
this underutilized potential by developing a powerful, cost-effective platform for better
engaging patients' sense of responsibility to their community in order to increase adherence.
Tuberculosis (TB) is the deadliest infectious disease in the world. The latest estimates
suggest there were 10.4 million cases in 2015 and 1.8 million TB deaths. Despite the
availability of highly effective medications for treating TB in the developing world, lack of
adherence to the treatment regimen remains the driving influence leading to multi-drug
resistant (MDR) TB, morbidity and mortality. Conventional treatment is a lengthy process
which depends heavily on patient adherence in seeking and then carrying out the prescribed
treatment. Recognizing this challenge, the World Health Organization has developed a protocol
for treating TB called Direct Observation of Treatments, Short-course (DOTS), but it is
expensive and difficult to institute on a large-scale in resource-constrained regions,
evidenced by its use in only 30% of all cases. This protocol also further burdens TB patients
who are already some of the most marginalized individuals in society by requiring them to
take time off from work in order to travel to the TB clinic for treatment verification. The
patient may find this embarrassing if there is a stigma surrounding the disease in the
community, or at the least, an unwelcomed intrusion into one's privacy. There is therefore
great need for the development of alternative protocols, which reduce the costs of treatment
and burden of adherence, and more effectively motivate patients to adhere to the program.
TB is spread through the air when people who are sick with TB excrete the causative bacillus,
Mycobacterium tuberculosis mainly through coughing. Left untreated, a single patient can
infect between 12 and 15 persons per year, a stark contrast to an Ebola patient who will only
infect between 1.5 and 2.5 persons. When a patient adheres to the treatment regime, she makes
it less likely that others will become sick, contributing to the health of her family and
community. Adherence is thus a contribution to a public good--a personally costly action that
benefits others. A substantial and growing literature in the social sciences demonstrates the
potential of behavioral interventions for generating large increases in contributions to
public goods, yet this potential has largely been left untapped in the treatment of TB.
Keheala taps into this underutilized potential by developing a powerful, cost-effective
platform for better engaging patients' sense of responsibility to their community in order to
increase adherence.
Keheala is a feature-phone and Internet-based digital platform that uses text message-like
interactions to deliver behavioral interventions that have been demonstrated as remarkably
effective in the social sciences literature on altruism. A patient who participates in the
program is assigned a support-sponsor who receives alerts about the patient's adherence,
allowing a dialogue of support or problem solving. For the pilot RCT, these support-sponsors
will be hired and trained by Keheala. An automated system sends motivational messages and
regular prompts for patients to self-verify their treatment. Messages include reminders about
the community benefits of adherence and a measure of the patient's adherence performance
relative to successful peers. If a patient fails to correctly verify her compliance, the
system automatically alerts the support-sponsor, who then intervenes with a supportive
dialogue. Clinicians can view individual or aggregate patient histories to leverage limited
resources. Combining powerful behavioral interventions with the functionality needed to
lessen the burden of disease on everyday life, Keheala uniquely and comprehensively overcomes
the barriers to appropriate treatment adherence.
Problem Statement TB treatment adherence rates suffer due to the burdensome six-month
duration of treatment. During this period, patients endure severe side effects from drug
cocktails, while regular clinical visits often necessitate distant, time-consuming travel and
absenteeism from work. However, non-adherence not only threatens the individuals' health--70%
of those who aren't treated will die within 10 years --it is also a public health concern:
adherence reduces the risk of transmission, usually to nearly zero within less than two
weeks, whereas treatment cessation can lead to recurrence and high transmission rates,
threatening the well-being of affected communities. Keheala's goal is to increase adherence
for the benefit of the infected individual and the community as a whole.
Justification The Keheala solution is based on extensive primary and secondary research.
Interviews with relevant and experienced stakeholders ensured that the functionality provided
is what actually is needed in order to overcome the social drivers of failed treatment
adherence. Additionally, the functionality is designed with principles from the social
sciences literature showing the potent impact invoking an individual's sense of
responsibility to her community can have on affecting behavior. These principles are
well-supported and understood in other contexts, however, exactly how effective these
principles can be at invoking treatment adhering behavior in the resource-constrained TB
context remains to be tested.
Null Hypotheses Ha1: Patients enrolled in the Keheala program achieve a greater proportion of
'Cured' outcomes by at least 7.5%.
Ho1: Patients enrolled in the Keheala program achieve a greater proportion of 'Cured'
outcomes by no more than 7.5%.
Ha2: Patients enrolled in the Keheala program achieve an improvement of at least 7.5% on one
of the following outcomes: 'Treatment Completed,' 'Dying while on Treatment,' Out of Control
or Loss to Follow Up' and 'Failing'.
Ho2: Patients enrolled in the Keheala program achieve an improvement of no more than 7.5% on
one of the following outcomes: 'Treatment Completed,' 'Dying while on Treatment,' Out of
Control or Loss to Follow Up' and 'Failing'.
General Objectives The goal of the research is to establish the potential of Keheala's
behavioral intervention for positively impacting the process of care and treatment outcomes
for a TB patient and healthcare providers.
Additional Qualitative Objectives
- Measure and compare the frequency and duration of treatment interruption
- Measure and compare perception of 'trust' for the healthcare system, as well as the
doctor-patient relationship
- Measure and compare the perception of community stigma
Design and Methodology Study site The burden of TB in Kenya is among the highest in the world
with a prevalence rate of 558 cases per 100,000 people. Mortality from TB in Kenya is also
above the global average at 21 deaths per 100,000.
Symptomatic patients are identified either in health clinics or by Community Health
Volunteers (CHVs), laypersons employed to screen for TB in the community. Individuals who
show up to the clinic usually do so because they are experiencing a sickness or have been
referred to the clinic. In rural communities, regularly scheduled meetings organized by local
chiefs or administrative officials are used as opportunities to educate the community about
TB and to sometimes distribute questionnaires probing symptoms of TB. Questionnaire
respondents who demonstrate signs of symptoms of TB are requested to give a sputum sample,
which will be tested at a health clinic and feedback given to the CHV in order to communicate
the results back to the individual and link them to a specific clinic if treatment is needed.
There are times, however, when finding the individual is not always possible. Additionally,
these CHVs will sometimes attend market days or go home to home in order to identify sick
individuals in the general population.
Symptoms of TB include coughing for three weeks or longer, chest pain, coughing up blood or
sputum (phlegm from deep inside the lungs), weakness or fatigue, weight loss, appetite
suppression, fever and chills. Diagnosis is accomplished with sputum smears and sometimes
x-rays. Any individuals started on TB medication are entered into a paper log at each health
facility. Sub-county TB coordinators compile all of the paper logs every one to four weeks,
transferring them to a cloud-based digital form.
Treatment duration is either six months (first-time patients) or eight months (repeat
patients). During the first two to three months when daily treatment is required, medications
are given for a week at a time or with special permission for longer than a week. For the
latter four or five months of treatment patients are required to return to the clinic every
two weeks for medication refills. Patients are supposed to visit clinics for medication
refills with their treatment supporter - a friend or relative who watches the patient take
their medication. However, clinicians do not go to the full-extent necessary to ensure the
sponsor has been observing a patient's adherence. Follow-up smears are given after two, five
and six months for patients who were initially smear positive. Upon completion of the
prescribed treatment regimen and a negative sputum smear, patients are released from
treatment and told only to come back if symptoms reappear.
Procedures
The investigators will approach clinics in Nairobi in order of size. Clinics will be included
if there is substantial support for the program by the staff and the investigators believe
the intervention can be implemented with local support. The investigators will be randomizing
subjects into a treatment and control group within each clinic. The following clinics will be
approached:
1. Kasarani Health Centre
2. St. Mary's Mission Hospital
3. Riruta Health Centre
4. Kangemi Health Centre
5. Kibera South (MSF Belgium) Dispensary
6. Kayole II Sub-District Hospital
7. Dandora II Health Centre
8. Baraka Medical Centre (St. Stephen)
9. Mukuru MMM Clinic
10. Rhodes Chest Clinic
11. Embakasi Health Centre
12. Ngara Health Centre (City Council of Nairobi)
13. Umoja Health Centre
14. Kibera DO
15. Mathare North Health Centre
16. Kahawa West Health Centre
17. Kamiti Prison Public Hospital (not for inmates)
At each clinic, 50% of all TB patients will be randomly selected to join the treatment group:
- Existing patients will be ordered by date and time admitted, and selected so that every
other patient is included in the treatment group (block design).
- New patients will be similarly selected so that every other new patient is included in
the treatment group (block design).
The control and treatment groups will thus each be made up of half the patients in the
clinics. Overall, the investigators expect the control and treatment group to be comprised of
600 subjects, each. Patients will not be offered a stipend for participation so as not to
introduce any unnecessary bias into the study.
Data Management A. Data collection and reduction Clinics will provide paper or digital copies
of patient medical records for Keheala staff to consolidate and digitize. Anonymous platform
usage data and analytics will be obtained from a dashboard.
Qualitative data will be obtained from a digitally administered survey across the mobile
platform and/or through focus group discussions and interviews.
B. Statistical Analysis The simplest possible statistical approach is illustrated in the
power calculations. In this approach, the investigators simply compare outcome rates at the
end of treatment for subjects in the treatment and control groups. This comparison can be
done using a t-test or using an ordinary least squares regression, which can include controls
for time trends, patient demographics, and clinic characteristics.
The investigators will also employ a more sophisticated (and slightly more statistically
powerful) analysis of hazard rates. The hazard rate is estimated daily as the probability
that a patient who is currently adhering continues to adhere. It is estimated using a
logistical regression of whether the patient adhered on a given week on whether the patient
adhered in all previous weeks and whether the patient is in the treatment group. The
regression can also include controls for time period, patient demographics, and clinic
characteristics. Note that the investigators have based the power calculations on the simpler
regressions of final outcomes on treatment.
C. Data Storage During the study patient names and clinics are kept in an encrypted and
password protected 'Master Document'. At the end of the pilot, all personal identifying
information will be redacted and patients will be uniquely identified by a randomly generated
identification number. No documents or data containing patient identifying information (name
and/or address) will be available to outside parties.
Ethical Considerations
The investigators recognize that dealing with human subjects necessitates the highest level
of respect for persons. Accordingly, in order to ensure the autonomy of the individual, each
patient will receive a full disclosure of the nature of the study, the risks, benefits and
alternatives, with an extended opportunity to ask questions. Patients with diminished
autonomy (children) will not be coerced to participate. Instead, they will be duly protected
through co-consent of the parent and child. No patient will be permitted to participate in
the study without having signed an Informed Consent waiver.
The investigators have given forethought to the maximization of benefits and reduction of
risks that might occur from the research. The equitable selection and fairness in
distribution of participants is only limited by funding; no benefit to which a person is
entitled is denied without good reason or when some burden is imposed unduly.
Study limitations As with any study of this nature, focusing on a particular subset of
clinics, and excluding some patients limits the generalizability of the results to the
population at large (external validity). However, our within-clinic randomization procedure
ensures robust internal validity and maximizes statistical power, so that we can maximize the
value of this assessment.
Further, the study is limited to a single treatment group, making it impossible to tease
apart the impact of Keheala's various elements, evaluate different messages, or different
frequency of contact. This decision was made to streamline logistics--these questions are
left for a follow-up assessment.
Study Implications A successful pilot would demonstrate the potential of Keheala's low-cost
mobile platform to increase compliance and save lives. The investigator's goal is to
demonstrate this potential, and also to learn from the implementation in order to maximize
the impact of future iterations of the platform.
TB is a particularly ripe use-case for Keheala's platform due to onerous and extended
treatment, the limits of existing programs (e.g., the WHO's DOTS program), TB's highly
infectious nature, the risk of disease-resistant strains, and its severity. However, Keheala
could eventually be applied to address other public health concerns, such as HIV, which
shares many of these features. A successful pilot would pave the way for such applications.
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