Simplified Isoniazid Preventive Therapy (SPIRIT) Strategy to Reduce TB Burden
Phase: NA
Conditions: Tuberculosis, HIV/AIDS
Sponsor: University of California, San Francisco

SPIRIT Protocol, version date: March 4th, 2022  
Page 1 of 30 
  
 
 
Simplified Isoniazid Preventive Therapy (SPIRIT) Strategy to Reduce TB Burden  
 
 
A study of the: 
 
Makerere University – University of California, San Francisco (MU-UCSF) Research 
Collaboration 
 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
NCT03315962 
 
 
 
 
 
Protocol version: 6.0 
Version Date: March 4th, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: Diane V. Havlir, MD 
University of California, San Francisco 
 
 
Protocol Vice Chairs: 
Moses R. Kamya, MBChB, MMed, MPH, PhD 
Gabriel Chamie, MD, MPH 
 
Protocol Statistician 
Laura Balzer, PhD, MPhil 
 
 
 
 
 
 

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Table of Contents 
STUDY INVESTIGATORS ............................................................................................................................................ 4 
GLOSSARY OF KEY TERMS ..................................................................................................................................... 6 
1. Introduction ................................................................................................................................................................. 7 
1.1 Study Synopsis ..................................................................................................................................................................... 7 
1.2 Background & Rationale.................................................................................................................................................... 8 
2. Study Objectives ..................................................................................................................................................... 10 
3. Study Site & Population ....................................................................................................................................... 11 
3.1 Study Setting ........................................................................................................................................................................ 11 
3.2 Study Population ................................................................................................................................................................ 11 
4. Study Design ............................................................................................................................................................. 12 
5. The SPIRIT Intervention Trial ............................................................................................................................. 12 
5.1 Recruitment & Enrollment of Study Participants ................................................................................................. 12 
5.1.1 Recruitment ...................................................................................................................................................................................... 12 
5.1.2 Consent Process ........................................................................................................................................................................... 12 
5.1.3 Screening for Enrollment ........................................................................................................................................................... 12 
5.2 Randomization ..................................................................................................................................................................... 12 
5.3 The SPIRIT Intervention ................................................................................................................................................... 12 
5.3.1. SPIRIT-1: The Teaching Collaborative ............................................................................................................................. 13 
5.3.2. SPIRIT-2: The Toolkit ................................................................................................................................................................ 13 
5.3.3. SPIRIT-3: The Reporting Collaborative ............................................................................................................................ 13 
5.4 The Control Condition ...................................................................................................................................................... 14 
5.5 INH Provision ........................................................................................................................................................................ 14 
5.6 Measures ................................................................................................................................................................................ 14 
5.6.1 Outcomes measurements: ........................................................................................................................................................ 14 
5.6.2 Mixed methods assessment of intervention mechanisms and implementation processes ..................... 15 
5.7 Statistical Analysis ............................................................................................................................................................ 15 
5.7.1 Data Collection & Management ............................................................................................................................................. 16 
5.7.2 Sample Size & Accrual ............................................................................................................................................................... 17 
6. IPT Adherence & TB Incidence in the SPIRIT Trial ................................................................................... 18 
6.1 IPT Registry Sampling Approach ................................................................................................................................ 18 
6.2 IPT Completion .................................................................................................................................................................... 18 
6.2 Active TB Incidence ........................................................................................................................................................... 18 
6.3 Antiretroviral therapy (ART) Adherence ................................................................................................................... 18 
6.4 Data Management & Statistical Considerations .................................................................................................... 18 
6.4.1 Data Collection & Management ............................................................................................................................................. 18 
6.5.2 Analysis .............................................................................................................................................................................................. 18 
6.5.2.1 IPT completion: ........................................................................................................................................................................... 18 
6.5.2.2 TB incidence: ............................................................................................................................................................................... 19 
6.5.3 Sampling Approach & Sample Size Considerations.................................................................................................... 20 
7. Evaluate the impact of business and leadership training on management and leadership 
skills among SPIRIT intervention vs. control DHOs. .................................................................................... 21 
7.1. Teaching Mini-Collaborative Business Leadership and Management training ...................................... 21 
7.2. Measures ............................................................................................................................................................................... 21 
7.3. Outcomes .............................................................................................................................................................................. 21 
7.4. Data Management & Statistical Considerations .................................................................................................. 21 
7.4.1. Data Collection & Management ............................................................................................................................................ 21 
7.4.2. Analysis ............................................................................................................................................................................................. 21 

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8. Costs & Cost-Effectiveness of SPIRIT ........................................................................................................... 22 
8.1 Costs ........................................................................................................................................................................................ 22 
8.2 Costs Analysis ..................................................................................................................................................................... 22 
8.3 Health Effects ....................................................................................................................................................................... 22 
8.4 Cost-effectiveness Analysis .......................................................................................................................................... 23 
9. SPIRIT Enhanced Business Training & “Training-of-trainers” curriculum ......................................... 23 
9.1. Objective ................................................................................................................................................................................ 23 
9.2. Eligibility criteria ................................................................................................................................................................ 23 
9.2.1. Inclusion criteria ............................................................................................................................................................................ 23 
9.2.2. Exclusion criteria .......................................................................................................................................................................... 23 
9.3. Enhanced Business Training ....................................................................................................................................... 23 
9.4. “Training-of-trainers” curriculum intervention .................................................................................................... 23 
9.4 Measures ................................................................................................................................................................................ 23 
9.5. Outcomes .............................................................................................................................................................................. 23 
9.6. Data Management & Statistical Considerations .................................................................................................. 24 
9.6.1. Data Collection & Management ............................................................................................................................................ 24 
9.6.2. Analysis ............................................................................................................................................................................................. 24 
10. “Training-of-trainers” curriculum impact on district-level management and health outcomes
 ............................................................................................................................................................................................. 24 
10.1 Objective ............................................................................................................................................................................... 24 
10.2 Recruitment & Enrollment of District Health Team (DHT) members ......................................................... 24 
10.2.1 Recruitment ................................................................................................................................................................................... 24 
10.2.2 Consent Process ......................................................................................................................................................................... 24 
10.2.3 Screening for Enrollment ........................................................................................................................................................ 24 
10.2.3.2. Exclusion criteria .................................................................................................................................................................... 24 
10.3 Outcome Measures............................................................................................................................................................ 24 
10.3.1 Leadership and Management Measures .............................................................................................................................. 24 
10.3.2 District Level Health Measures ................................................................................................................................. 25 
10.4. Data Collection .................................................................................................................................................................. 25 
10.5 Analysis ................................................................................................................................................................................. 25 
11. Human Subjects .................................................................................................................................................... 26 
11.1 Risks to Human Subjects ............................................................................................................................................. 26 
11.2 Adequacy of Protection against risks ..................................................................................................................... 26 
11.2.1 Informed Consent ....................................................................................................................................................................... 26 
11.2.2 Risk of HIV/Suspected TB disclosure ............................................................................................................................... 26 
11.2.3 Data Security ................................................................................................................................................................................ 26 
11.2.4 Institutional Review Board Approval ................................................................................................................................. 26 
11.3 Potential benefits of the proposed research to the participants and others ......................................... 26 
11.4 Importance of the knowledge to be gained .......................................................................................................... 27 
12. Publication of Research Findings ................................................................................................................. 28 
13. References ............................................................................................................................................................... 28 
 
 
 

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STUDY INVESTIGATORS 
 
Principal Investigator: 
 
Diane V. Havlir, MD 
 
Professor of Medicine 
 
Chief of the Division of HIV, Infectious Diseases & Global Medicine 
 
Zuckerberg San Francisco General Hospital 
 
University of California, San Francisco 
 
UCSF Box 0874, 995 Potrero Avenue 
 
San Francisco, CA  94110, USA 
 
Phone: (415) 476-4082, ext. 400 
 
Email: Diane.Havlir@ucsf.edu  
 
Uganda Co-Investigators: 
 
Uganda Principal Investigator/Protocol Co-Vice-Chair 
Moses R. Kamya, MBChB, MMed, MPH, PhD 
 
Professor of Medicine  
Dean, Makerere Medical School 
Makerere University 
Plot 4B, Kololo Hill Drive 
 
P.O. Box 7972, Kampala, Uganda   
 
Phone: +256-414-533200 
 
Fax: +256-414-540524 
Email: mkamya@infocom.co.ug 
 
United States Co-Investigators 
Protocol Statistician  
Laura Balzer, PhD, MPhil 
Assistant Professor 
Department of Biostatistics & Epidemiology 
School of Public Health & Health Sciences 
University of Massachusetts – Amherst 
416 Arnold House, 715 North Pleasant St. 
Amherst, MA 01003-9304, USA 
Phone: (413) 545-9464 
Email: lbalzer@umass.edu 
 
Carol S. Camlin, PhD, MPH 
Associate Professor in Residence 
Department of Obstetrics, Gynecology & Reproductive Sciences 
University of California, San Francisco 
ANSIRH Program, 1330 Broadway, Suite 1100 
Oakland, CA 94612, USA 
Tel. (510) 986-8981 
Email: Carol.Camlin@ucsf.edu 
 
 
Protocol Co-Vice Chair:  
Gabriel Chamie, MD, MPH 
 
Associate Professor of Medicine 
 
Division of HIV, Infectious Diseases & Global Medicine 
 
San Francisco General Hospital 
 
University of California, San Francisco 
 
UCSF Box 0874, 995 Potrero Avenue 
 
San Francisco, CA  94110, USA 

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Phone: (415) 476-4082, x445 
 
Email: Gabriel.Chamie@ucsf.edu 
 
 
Monica Gandhi, MD, MPH 
Professor of Medicine  
Division of HIV, Infectious Diseases & Global Medicine 
 
San Francisco General Hospital 
 
University of California, San Francisco 
UCSF Box 0874 San Francisco, CA, 94143-0874  
Phone: (415) 476-4082, x127 
Fax: (415) 476-6953 
Email: Monica.Gandhi@ucsf.edu  
 
Elvin Geng, MD, MPH 
Professor of Medicine  
Institute for Clinical and Translational Sciences 
 
Institute for Public Health 
 
Washington University in St. Louis 
Northwest Tower 4990 Children’s Place St. Louis, MO 63110  
Email: Elvin.Geng@wustl.edu  
 
 
 
Carina Marquez, MD, MPH 
 
Assistant Professor of Medicine 
Division of HIV, Infectious Diseases & Global Medicine 
 
San Francisco General Hospital 
 
University of California, San Francisco 
UCSF Box 0874 San Francisco, CA, 94143-0874 
Phone: (415) 476-4082, x331 
Fax: (415) 476-6953 
Email: Carina.Marquez@ucsf.edu  
 
Starley Shade, PhD, MPH 
 
Associate Professor 
 
Center for AIDS Prevention Studies 
 
University of California, San Francisco 
550 16th Street 
San Francisco CA 94158 
Phone: (415) 476-6362 
Email: Starley.Shade@ucsf.edu  
 
Study Pharmacist (Uganda): 
Bishop Opira 
Clinical Trials Pharmacist 
Infectious Diseases Research Collaboration 
2C Nakasero Hill Road 
Kampala, Uganda 
Phone: +256-312-281-479 
Email: opibish@idrc-uganda.org  
 

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GLOSSARY OF KEY TERMS 
 
ART 
 
Antiretroviral therapy 
DHO  
District Health Officer 
DTLS  
District TB/Leprosy Supervisor  
FGD 
 
Focus Group Discussion 
HIV 
 
Human Immunodeficiency Virus 
INH 
 
Isoniazid 
IPT 
 
Isoniazid Preventive Therapy 
KII 
 
Key Informant Interview  
LFTs  
Liver Function Tests 
MoH 
 
Ministry of Health 
PLWHIV 
Persons living with HIV  
RCT 
 
Randomized, controlled trial 
RRF 
 
Reduced Refill Frequency 
SMS 
 
Short Message Service (i.e. “texting”) 
SPC 
 
Single Pill Combination 
SPIRIT 
Simplified Isoniazid Preventive Therapy 
SSA 
 
Sub-Saharan Africa 
TMP-SMX 
Trimethoprim-Sulfamethoxazole 
 
 
 

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1. Introduction 
 
The failure to use isoniazid (INH) preventative therapy (IPT) in HIV-infected individuals in Sub-Saharan Africa 
represents one of the single biggest implementation gaps between evidence and practice in today’s response 
to the HIV epidemic. IPT reduces TB incidence by 40%.1,2 Yet today, in Africa, less than 2% of eligible 
individuals receive IPT3 and TB remains the largest killer of HIV-infected persons.4 Given the existence of both 
clear guidelines recommending IPT from international organizations and national health ministries in Africa, as 
well as simple symptom-based clinical algorithms for identifying persons eligible for IPT that can be applied by 
front line health care workers,5 a remaining critical requirement for IPT scale-up is strengthening the link – 
mediated by middle management in most health systems – between health ministry policy and clinics.  
In the Republic of Uganda, the 112 local District Health Officers (DHOs) are the highest-ranking health officials 
based in the field and outside of the capital city, and serve as key middle managers working at the nexus 
between policy and implementation. In Uganda, <1% of eligible HIV-infected patients have initiated IPT.3 Our 
preliminary work has identified three barriers among DHOs to IPT uptake. First, knowledge of scientific 
evidence of the efficacy of IPT has not diffused among DHOs (and downstream to providers). Second, the 
system is already perceived as operating at capacity, and adding yet another two pills (INH and Vitamin B6) to 
prevent a long-term outcome is not prioritized. Third, geographic remoteness and poor infrastructure (e.g. 
roads and internet) dilute managerial efficacy and accountability between DHOs and the front line workforce.  
To catalyze IPT implementation across Uganda, we propose to test a multi-component “SPIRIT” (Simplified 
INH Preventive Therapy) intervention targeting DHOs – whom we view as critical dissemination agents – in two 
geographical regions in Uganda. Our intervention is based on the empirically-validated PRECEDE model,6 
which suggests that health promotion strategies are most effective when they combine: (1) “predisposing 
factors” comprised of knowledge, attitudes or beliefs that affect behavior; (2) “enabling factors” that facilitate 
change by making the behavior “easier”; and (3) “reinforcing factors” which include anticipated consequences 
following a behavior.7   
The SPIRIT intervention therefore, first, convenes intervention groups of DHOs into mini-collaboratives to 
disseminate knowledge about efficacy of IPT and to predispose them towards deployment of IPT. Small-world 
network theory suggests that random links between mini-collaborative members will speed diffusion of this 
predisposing information and accelerate attitude change towards IPT within the group.8 Theories of social 
influence and persuasion suggest that, because of their authority and influence, attitude change among DHOs 
will result in changes in practice among the front line providers they oversee.9 Second, we will also deploy a 
two-way SMS system for DHOs and health care workers, based on local input and a behavioral construct, to 
facilitate communication between “hub” and “spoke.” Third, we will provide DHOs data on their district IPT 
uptake and share these data with their peers in the collaborative, thereby using a reputational approach to 
reinforce implementation of IPT. 
1.1 Study Synopsis 
We will evaluate the effect of the SPIRIT intervention on provider prescription and patient use of a 6-month 
course of IPT among all adults in HIV care in Uganda. SPIRIT is a multicomponent intervention based on the 
PRECEDE model of behavioral change targeted primarily at the level of the DHO. The SPIRIT intervention 
deploys predisposing (teaching collaborative); enabling (SMS); and reinforcing (reporting collaborative) 
components. The study design is a cluster randomized trial where the unit of randomization is a group of 4-6 
DHOs: seven groups randomized to the intervention and seven to the current country standard of care. The 
primary endpoint of the study is the rate at which eligible HIV-positive adults (defined by the Ugandan Ministry 
of Health) receive a prescription for INH in health facilities overseen by DHOs participating in the SPIRIT trial. 
Secondary endpoints include: a) IPT completion measured through analyzing successful INH refill patient-
visits; b) DHO and health worker attitudes towards IPT; c) TB incidence; d) DHO leadership and management 
skills and e) costing and cost-effectiveness. The overall goal of the proposal is to test the effectiveness of a 
scalable approach to increasing IPT uptake through a behavioral change model targeting DHOs (middle 
managers) within the Uganda health infrastructure. In a second phase of the trial (Phase 2: Years 4-5), we will: 
a) evaluate the impact of enhanced business management training, focused on SPIRIT intervention DHOs in 

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the Southwestern Uganda region, on IPT initiation in the region during Phase 2; and b) implement a training of 
trainers (ToT) curriculum among DHOs enrolled in the SPIRIT trial from the southwestern region of Uganda to 
determine if DHO-provided business management training of their District Health Team (DHT) members can 
improve the management skills of the DHT members.  Figure 1 provides a schematic overview of the SPIRIT 
study: 
 
 
 
 
1.2 Background & Rationale 
 
Tuberculosis (TB) remains a major cause of death among persons living with HIV; yet, proven 
prevention strategies such as isoniazid preventive therapy (IPT) that can reduce TB by 40% are not 
being fully deployed.3 The data to support efficacy of IPT for TB prevention in HIV-infected adults are 
extremely robust.10-14 Randomized trials and cohort studies conducted in both high and low TB prevalence 
settings show that IPT reduces the incidence of active TB by approximately 40 percent,1,2 is safe to 
administer,13,15 and is not associated with an increase in isoniazid resistance among TB breakthrough cases.16 
IPT provides independent protection against TB among persons receiving antiretroviral therapy (ART), even at 
high CD4 cell counts.17 In a recent post-trial extension study of a large randomized trial of IPT among HIV-
infected adults with high CD4 cell counts in Africa, IPT recipients had significant reductions in mortality 
compared to IPT non-recipients, independent of ART.18 WHO guidelines recommend IPT for all persons living 
Figure 1. SPIRIT study schema. For illustration we show 10 DHO groups per arm with 5 DHOs per group. The trial will 
enroll 14 DHO Groups: 7 intervention and 7 control. In Years 4 and 5 (Phase 2), the trial will be limited to the 14 
districts in the Southwestern region of Uganda. 

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with HIV (PLWHIV), regardless of the results of reactive tuberculin skin testing, a marker for highest TB risk.5 
Yet despite these compelling data, the 2014 Global TB report showed that globally, fewer than 2% of PLWHIV 
in Africa are receiving IPT.3 
 
Some of the reasons for poor uptake of IPT in Africa in the past - no country policy and lack of 
protocols for providers to rule out active TB disease - are no longer barriers. Based on data cited above, 
IPT is recommended for TB prevention by the WHO and at the country level. From a provider perspective, the 
inability to exclude active TB in IPT candidates (posing a risk for single drug treatment of undiagnosed active 
TB) has been a legitimate concern for the widespread uptake of IPT. However, there are now evidence-based 
country protocols for ruling out active TB supported by existing and new data,19 and from trials in HIV-infected 
patients with both high CD4 cell counts (TEMPRANO study)17 and low CD4 counts (REMEMBER study),20 
showing that simple clinical algorithms with or without the addition of new diagnostics, such as the Xpert 
MTB/RIF assay, can identify a high proportion of PLWHIV who are candidates for IPT.  
 
A study of IPT implementation targeting the “middle managers” of the health system - the 112 District 
Health Officers (DHOs) responsible for public health in Uganda - is likely to have the highest impact at 
scale. Although the behavior of health care workers has often been the focus of implementation interventions, 
for public health interventions in which adoption at scale is a crucial goal, targeting the “middle managers” of 
the health system – the DHOs – may achieve a greater overall impact, because each DHO oversees 
budgetary, education and operational aspects of public health over a catchment area of >300,000 residents. In 
light of the heterogeneity in disease burden between districts, an intervention targeting DHOs vs a single 
intervention for all health providers in Uganda creates potential efficiency by influencing the highest level of 
regional authority and permitting flexibility for DHOs to facilitate implementation within their region. 
 
Birken reports four major “points of influence” of a middle manager in a theoretical framework where 
health policy moves (or not) to implementation and effectiveness.21 These points of influence include 1) 
information diffusion; 2) synthesis of data; 3) day-to-day activity; and 4) “selling” of implementation. In 
designing SPIRIT, we used formative data to conceive of an intervention to overcome current barriers (real or 
perceived) to IPT implementation at the DHO level. The SPIRIT intervention is based on the PRECEDE model 
of behavioral change6 and exploits specific “points of influence” within the DHO’s role as middle manager. 
Some components of the intervention, such as making a single pill combination of INH/B6/septrin available, 
also serve as “enablers” for front line providers and patients for IPT uptake, thus mitigating the risk of reliance 
on one level of the health system in our intervention strategy. 
 
Social network analysis assumes interpersonal connections rather than individual “rational agent” 
characteristics drive the spread of behaviors,22-26 including practice patterns of health care 
professionals. Sociologists have long observed that new ideas and practices – from adoption of 
contraceptives to new farming practices – spread through interpersonal contact.27 The importance of 
interpersonal contact in dissemination extends, perhaps exquisitely so, to health care provider behavior. A 
seminal study in diffusion science from the 1950’s and still cited today found that opinion leaders in a 
community of physicians drove uptake of a new antibiotic through interpersonal contact.28 Since then, 
numerous studies have documented the effect of social networks on issues ranging from reducing 
unnecessary caesarian sections to uptake of novel diagnostic and treatment strategies.29-32 Although 
pharmaceutical companies commonly use network principles to influence drug sales,33 public health research 
has not fully exploited these principles to promote dissemination of evidence-based interventions. The SPIRIT 
intervention will utilize the social networks of DHOs as an agent of behavioral change to catalyze IPT uptake. 
 
The SPIRIT intervention incorporates contemporary understandings of relational influences on attitude 
change, namely that attitude change is motivated not only by absorption of new knowledge, but by normative 
concerns for ensuring coherent and favorable evaluations of the self (resolving cognitive dissonance, or a 
conflict between one’s knowledge and behaviors), and satisfactory relations with others given the 
rewards/punishments they can provide.9 We posit that DHOs will catalyze IPT uptake via their roles both as 
credible sources of clinical expertise for front line providers, and as key actors in health systems empowered 
with oversight (dispensing rewards and punishments e.g. hiring, firing, retrenchment) of providers. The SMS 
messaging component will facilitate the influence of DHOs via enhancing their communication with providers. 
 

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Examining cost-effectiveness and resource utilization of any intervention is critical to evaluate value 
and sustainability in an era where resources are being stretched to treat PLWHIV patients new to and 
already in care. Modeling studies support the investment in IPT as cost-effective.34-36 Preventing a TB case is 
not only cost saving in terms of potential mortality and downstream effects, but also in the morbidity associated 
with the disease. SPIRIT is designed to test an intervention that is intentionally “simple” by targeting DHOs, 
mobilizing existing systems, inserting IPT into ongoing ART care structures, and facilitating patient adherence 
via an SPC. However, there are costs associated with DHO training, introducing a new medication (the SPC 
INH/B6/septrin) on the formulary, as well as maintaining stocks of the SPC. Our proposal includes a specific 
costing domain that will measure these processes and provide useful information for countries considering 
using the SPIRIT strategy to achieve countrywide scale-up of IPT.  
 
Scale up of IPT is long overdue, and research such as that proposed here is needed to assess how to 
effectively achieve roll out at the country level. Uganda is an ideal location for this study given: a) a high TB 
burden and large population of PLWHIV; b) government policies supporting IPT use in PLWHIV; c) DHO 
authority and residence within the community; d) high uptake of TB screening already achieved in ART clinics; 
and e) high level stakeholder “buy-in” for a sustainable IPT program. The benefit is clear: Testing an 
intervention that could improve worldwide delivery of IPT for PLWHIV in high TB burden countries 
could dramatically reduce global morbidity and mortality from TB. 
2. Study Objectives 
Aim 1: Determine if the SPIRIT intervention increases IPT initiation.  We will form 14 groups of 4-7 District 
Health Officers and randomize half to the SPIRIT intervention and half to control (country standard) in a cluster 
randomized trial. The primary outcome will be the rate at which eligible HIV-infected adults receive a 
prescription for INH in health facilities overseen by DHOs participating in the SPIRIT trial. In all DHO groups 
the primary outcome will be measured over the 12-36-month period following the intervention initiation to 
account for INH stockouts and intervention start up time. We will use health information systems already in 
place to collect data about visits, IPT eligibility and IPT initiation. For secondary outcomes, we will conduct pre-
/post-intervention surveys, focus group discussions, and key informant interviews to assess changes in 
knowledge, attitudes and practices regarding IPT among the DHOs and front line health workers in intervention 
and control groups, to assess mechanisms through which the intervention achieves outcomes. 
Aim 2: Evaluate the effect of the SPIRIT intervention on IPT completion and TB incidence. Even if the 
intervention increases IPT initiation, quantifying actual use of IPT by patients and downstream effects on 
population health status (e.g. reduction in TB incidence) are important to assess impact and thereby enable 
policy makers to prioritize this intervention more widely. A subset of adult patients who received a prescription 
for IPT will be randomly sampled to measure IPT completion through patient chart review. TB incidence will 
also be measured on the overall population of HIV-positive adults in care at health facilities overseen by the 
DHOs. 
Aim 3: Evaluate the impact of business training on leadership and management skills among SPIRIT 
intervention vs. control DHOs. At the completion of the 36-month period following SPIRIT intervention 
initiation, we will evaluate leadership and management skills, assessed by cross-sectional leadership and 
management survey measures, among SPIRIT intervention DHO groups who participated in business training 
within the SPIRIT intervention and control DHO group members. 
Aim 4: Evaluate the cost and cost-effectiveness of SPIRIT. Using effectiveness measures obtained in Aims 
1 and 2, and standard time and motion and costing methods, we will estimate the cost and cost-effectiveness 
of SPIRIT vs. standard of care in our sampled population from Aim 2. Outcomes of interest will include 
program costs per: a) IPT initiation b) IPT completion and c) TB case averted.  
 
Aim 5: To evaluate the effect of enhanced business training among DHOs in the southwestern Uganda 
region on IPT initiation during years 4-5 of trial follow-up (Phase 2). Building on business training 
introduced within the SPIRIT intervention, we will provide additional management training (“Gap Analysis”) to a 
subset of SPIRIT intervention DHO groups, in the southwestern Uganda region, in order to evaluate the impact 
of enhanced business training on ongoing IPT initiation, at quarterly business training meetings. 
 

SPIRIT Protocol, version date: March 4th, 2022  
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Aim 6: To determine if having DHOs provide business leadership and management training to their 
District Health Teams (DHTs) can improve district-level management practices and health outcomes. 
We will implement a “training of trainers” (ToT) curriculum during Phase 2 of the trial, in which we will provide 
intervention group DHOs from Southwestern Uganda with training on how to provide business leadership and 
management training (modeled after the business training the SPIRIT intervention DHOs received in the first 
phase of the trial) to their DHT members. DHOs oversee and lead District Health Team members (i.e., 
assistant health officers and disease-specific focal persons) in addressing public health priorities for each 
district in Uganda. At the completion of Phase 2, we will determine whether DHO-provided training of DHTs 
impacted management practices and health outcomes at the district level, in districts in SPRIT intervention vs. 
control DHO groups in the Southwestern Uganda region. 
 
Our overall objective is to determine if a multi-component implementation intervention (SPIRIT) that targets 
DHOs can increase IPT initiation and completion among HIV-infected persons, and decrease TB incidence, as 
compared to country standard practices, in a cluster randomized trial in Uganda. 
3. Study Site & Population 
3.1 Study Setting 
This study is evaluating the impact of the SPIRIT intervention on the implementation of IPT in two major 
geographic regions of Uganda: the Southwest, East and Eastern-Central regions (with the exception of 
Kampala and Wakiso (Kampala’s surrounding suburb)). There are an estimated 1.5 million PLWHIV in 
Uganda.37 Following ART scale-up over the last decade, Uganda’s ART program, supported by a combination 
of PEPFAR funding (CDC and USAID), the Global Fund, the Ugandan government and other NGOs, now 
offers HIV care to 800,000 persons (~570,000 persons on ART) at 1,500 facilities. The MoH is the governing 
body of the Uganda Health System. The MoH is responsible for coordination and provision of technical 
guidance for the public health system; within the MoH, the AIDS Control Program coordinates service delivery 
in public and private facilities and public health programs. Within the MoH are District Health Officers (DHOs) 
who oversee health facilities and health budgets in their assigned districts (112 total in Uganda as of 2017) and 
bear overall responsibility for the training and oversight of providers and implementation of MOH policy. DHOs 
are responsible for coordination of various HIV Implementing Partners (IPs), including the Private not for 
Profits, and ensure that linkages and referral mechanisms between IPs and other district entities are functional 
in offering comprehensive services for HIV treatment and prevention. 
3.2 Study Population 
Aim 1: IPT Initiation: The target population for the SPIRIT trial intervention is DHOs, the DHOs’ TB support 
staff, and the health facilities they oversee in the geographic regions participating in SPIRIT (the Southwest, 
East and East-central regions). The target population for the trial’s primary outcome is all HIV+ adult (≥15 
years) patients who are eligible for IPT by Uganda Ministry of Health Guidelines (in each pair-matched DHO 
group), and in care at a facility overseen by DHOs participating in the SPIRIT trial. 
Aim 2: IPT Completion & TB Incidence: Adherence and TB incidence will be measured in a sub-sample of 
HIV+ adults prescribed IPT at a facility overseen by the DHOs (N=800), using patient chart review. TB 
incidence will also be measured among all HIV+ adults in care at health facilities overseen by the DHOs 
participating in the SPIRIT trial based MoH TB Registry entries.  
Aim 3: The Aim 1 study population.  
Aim 4: Cost and Cost-effectiveness: The study population for Aim 4 will be the sub-sample from Aim 2. 
Aims 5 & 6: The target populations for the Phase 2 intervention period are DHOs and their respective District 
Health Team (DHT) members included in the training-of-trainers (ToT) curriculum and evaluation from the 
Southwestern Uganda region of SPIRIT. DHOs oversee all health aspects of a district and manage DHTs, 
comprised of a group of 6-8 health care professionals including the TB, HIV, Malaria and Laboratory focal 
persons, clinic in-charges, district biostatistician, and maternal and child health officer. The target population 
for Phase 2 leadership and management outcomes are the DHT members. The target population for Phase 2 
health outcomes are district residents in the Southwestern region districts participating in the SPIRIT trial.  

SPIRIT Protocol, version date: March 4th, 2022  
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4. Study Design 
The overall study design is a pair-matched cluster randomized trial. In Phase 1, the clusters correspond to 
groups of DHOs and are pair-matched within region on predictors of the primary outcome (IPT uptake). The 
primary outcome of IPT initiation as well as key secondary outcomes of IPT completion and TB incidence, and 
will be measured among providers and patients in facilities overseen by the DHOs. A sub-sample of adults 
prescribed INH will be followed longitudinally and assessed for adherence, TB incidence, and costing 
outcomes (Aims 2 and 4). In Phase 2, we will evaluate the impacts of enhanced business training among 
Phase 1 SPIRIT intervention DHOs from Southwestern Uganda on IPT initiation (Aim 5) and determine the 
effect of DHO-provided business training (following DHO participation in a training of trainers’ curriculum) on 
the leadership and management skills of the District Health Team (DHT) members they supervise and health 
outcomes that DHTs oversee in Southwestern Uganda (Aim 6).   
5. The SPIRIT Intervention Trial 
5.1 Recruitment & Enrollment of Study Participants 
5.1.1 Recruitment  
Prior to the start of the study, Dr. Kwarisiima (Uganda PI), the SPIRIT Project Coordinator and study research 
assistants, will work with the Uganda Ministry of Health to obtain contact information for all Uganda DHOs and, 
whenever possible, for their respective District TB Supervisors.  SPIRIT study staff will initiate contact with the 
DHOs’ offices and/or the District TB Supervisors’ Offices by email, phone or in-person, to recruit for 
participation in the trial. 
5.1.2 Consent Process 
Upon contacting the DHOs’ offices, the SPIRIT Uganda PI or Project Coordinator will describe the SPIRIT trial, 
and screen for enrollment. All eligible DHOs and/or District TB Supervisors (or other DHO-appointed TB focal 
person) that agree to participate will provide written consent prior to randomization. If a DHO or TB supervisor 
departs for a new position, we will consent the incumbent DHO or TB supervisor for study participation.  
5.1.3 Screening for Enrollment 
Study staff will screen all DHOs and/or District TB Supervisors reached during recruitment (5.1.1 above) for the 
exclusion criteria noted below.  
5.1.3.1 Inclusion Criteria 
(a) District Health Officer or District TB Supervisor (or other DHO-appointed TB focal person) in Uganda. 
(b) By definition, the DHO or District TB Supervisors in Uganda are all ≥18 years of age 
5.1.3.2 Exclusion Criteria 
(a) Planned departure from position as DHO or TB District Supervisor prior to randomization. 
5.2 Randomization  
The SPIRIT trial investigators will form up to 14 groups of 4-7 DHOs (Figure 1). When possible, groups will be 
formed based on geographic, socio-demographic, and health systems characteristics. The groups will be pair-
matched on geographical, socio-demographic and health systems characteristics to improve statistical 
efficiency. For both the creation of the groups and construction of matched pairs, geographic proximity will be 
optimized to facilitate DHO mini-collaboratives in the SPIRIT intervention and minimize contamination between 
arms. Randomization will be performed using a random number generator in standard statistical software, and 
overseen by the study statistician. One group in each of the 7 matched pairs will be randomized to the 
intervention, and one to the control condition.  
5.3 The SPIRIT Intervention  
The SPIRIT Intervention package will be offered to DHOs in intervention groups. The SPIRIT package is based 
on the empirically validated PRECEDE framework and informed by theories of social networks, social influence 
and behavior change. We segment the intervention into three components: SPIRIT-1, SPIRIT-2, and SPIRIT-3. 

SPIRIT Protocol, version date: March 4th, 2022  
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5.3.1. SPIRIT-1: The Teaching Collaborative 
Study staff will form up to 7 mini-collaboratives directly from the intervention groups of 4-7 DHOs each (Figure 
1), along with any support staff the DHOs may bring, including the District TB Supervisor. Each mini-
collaborative of DHOs will be led by an opinion leader (“coach” - selected by the SPIRIT investigators) with HIV 
and TB expertise, to spread new scientific knowledge about IPT and the clinical ability to rule out TB, and to 
facilitate discussion between DHOs. Additional training at the Teaching Collaboratives (and the Reporting 
Collaboratives – see below) may include skills, such as business and management training provided by 
business leaders, that aim to assist the DHOs and the District TB Supervisors, in overseeing any new or 
ongoing initiatives to improve IPT implementation. This additional training may also act to incentivize DHOs 
and District TB Supervisors to continue engaging in SPIRIT intervention mini-collaborative meetings (both 
Teaching and Reporting) for their personal and professional development.   
The rationale for this approach is that research on the link between implementation and program outcomes 
show that outcomes may not be achieved by didactic training alone and that “coaching” is critical for success.38 
Coaching can facilitate: a) “buy in” from participants; b) sharing of best practices; and c) a productive 
environment for accountability. By creating a collaborative, the SPIRIT intervention seeks to enable a group to 
form bonds so that perspectives in favor of IPT can spread within the group.39  
Implementation: We will hold these meetings twice a year for three years during the SPIRIT intervention, with 
1-2 additional meetings in the first year of the intervention period. At each meeting, the group may generate 
ideas about how best to implement the SPIRIT intervention (see 5.3.2. SPIRIT-2 below), and to discuss 
lessons learned from the use of novel components of the intervention. We will also be communicating with the 
DHOs and District TB Supervisors with phone calls using a pre-specified script up to two times between each 
of these meetings to discuss progress toward IPT implementation.  
5.3.2. SPIRIT-2: The Toolkit 
The rationale for this approach is that by investigating a “toolkit” of options to ease IPT implementation, we will 
support DHOs to scale up IPT through the study of the comparative effectiveness of material contributions to 
their day-to-day function of managing front line providers and clinics. These contributions to improve IPT 
implementation may include:  
1) SMS interventions: Following initiation of DHO mini-collaboratives, a text messaging strategy using local 
input into behavior constructs will be developed and implemented, to allow text messaging between DHOs, 
clinic directors, front-line health care workers, and/or clinic patients. Based on pilot work, message domains 
may include: Informational, motivational, social monitoring and problem solving components. SMS 
interventions will enhance DHO influence on provider behavior and provider communication with DHO offices, 
by crossing boundaries of time and space that normally limit communication between DHOs and facilities. For 
example, messages might read:  “Remember that TB can be latent for years!” (informational); “TB is the 
leading killer of HIV patients” (motivational); “Are you making progress with IPT dispensing to HIV+ patients? 
Please let me know how it’s going” (social monitoring); or “Hope all is well at the facility” (social support). 
SPIRIT study staff may provide technical guidance and support for SMS implementation in SPIRIT intervention 
communities, in contrast to SPIRIT control communities. DHO SMS message costs related to the study will be 
covered by the study. DHOs will receive instruction that no personal health information should be transmitted 
through SMS.   
2) Comparative delivery/refill strategies of INH/B6 (or INH/B6/TMP-SMX SPC), including Community 
Adherence Groups (CAGs), pharmacy only visits (POVs), 90-day supply (vs. 30-day supply) of INH/B6 to 
reduce refill frequency, or other strategies developed or discussed in the teaching collaboratives.  
3) Adherence and side effect monitoring strategies, including mobile phone monitoring of clinic patients, point-
of-care liver function testing, or other strategies developed in the collaboratives;  
4) Clinic-based patient education strategies. 
5.3.3. SPIRIT-3: The Reporting Collaborative 
By creating 7 mini-collaboratives of 4-7 DHOs each, defining targets as a group, and reconvening every 6 
months for 3 years (with the additional option of 36 months for a final report back), each collaborative has an 
opportunity to share progress and results. Incentives in this schema will work through a reputational 
mechanism. The coach will prepare summaries of data about progress and uptake at each site with the DHOs 
before the meeting and then present a comparative report showing results across all districts. The coach will 
provide a trusting and non-critical environment where comparisons can be used to gently reinforce behavior. In 

SPIRIT Protocol, version date: March 4th, 2022  
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addition, the gaps or differences between sites will allow and prompt discussion of problem solving. This 
intervention is based conceptually on the IHI Breakthrough Collaboratives Series,40 but differs in notable ways 
such as the use of much smaller groups and the focus on a predetermined outcome. 
5.4 The Control Condition 
The only intervention for DHOs in the control groups will be the guaranteed provision of both printed and 
electronic versions of Uganda Guidelines for IPT. These 7 “groups” created for the purpose of the 
randomization will have no required group meetings and will follow usual country standards for IPT. 
5.5 INH Provision 
INH and B6 will be provided by the Uganda Ministry of Health (MoH), at the request of the Districts, susceptible 
to drug availability. INH/B6 supply may also be supplemented and distributed by Implementing Partners, with 
support from the study.  
5.6 Measures 
For collection of the primary outcome of IPT uptake in eligible patients, we will leverage existing health 
information systems. All patients (≥15 years of age) with HIV in Uganda receive clinical documentation through 
MOH form 257 (the “Blue Card”). This card documents basic demographics, clinical and laboratory 
characteristics, TB screening, and prescription of all medications including INH.  Although this routine data 
collection may be sub-optimal in completeness and accuracy, we have extensive experience in strengthening 
accurate data collection within routine health systems in Uganda, including investments in data entry, quality 
control mechanisms such as sampling charts, and asking clinicians for reconciliation when data are missing. 
These data are the basis of clinic-level measures of IPT initiation and TB cases, documented in the registries, 
which will be used to evaluate the primary outcome and key secondary endpoints. In the primary outcome, we 
will rely on registry data, and in IPT completion sub-study (Aim 2), we will take a census-based approach, 
using all de-identified individual level data available from sampled participants (N=800). We will also measure 
Aim 1 implementation processes as guided by Proctor’s approach to implementation outcomes.41 We will 
measure fidelity to Aim 1 procedures through quantitative assessments of each of the SPIRIT components 
(Table 1). 
 
Table 1. Process Measures of fidelity to the SPIRIT intervention 
Intervention component  
 Process measures  
SPIRIT 1:  
Teaching Collaborative 
 
1. Proportion of scheduled trainings for DHOs completed and DHO attendance 
2. DHO knowledge about efficacy and delivery of IPT pre- and post-training  
3. Number of DHO-led trainings for front line providers conducted (as fraction of planned) and attendance 
SPIRIT 2: 
Toolkit: (e.g. SPC, SMS) 
1. SMS delivery (technical); frequency and content (e.g. motivational, informational, problem solving)  
2. Provider action derived from SMS interaction 
3. Occurrence/frequency of drug stock outs at health facilities 
SPIRIT 3: 
Reporting Collaborative 
1. Attendance of DHOs at the reporting collaboratives 
2. Number of IPT uptake reports generated 
3. Number of reports discussed and actions derived and enacted from collaborative discussions  
5.6.1 Outcomes measurements: 
The primary outcome of IPT uptake is the rate at which eligible HIV-infected adults who receive a prescription 
for INH at a health facility overseen by DHOs participating in the SPIRIT trial. IPT initiation will be measured 
among the two largest clinics in each district and over the 24-month period, beginning 12 months after the 
intervention start in each pair-matched DHO group. The 12-month lead-in is to account for ramp-up of the 
SPIRIT intervention and for INH stock-outs. The denominator of this rate is the person-time-at-risk of starting 
IPT, accounting for prior starts and other changes in the active care population. The numerator is the number 
of HIV-infected adults prescribed INH. In other words, the primary outcome is the incidence rate of IPT 
prescriptions among eligible HIV-positive patients. The primary outcome will be compared between SPIRIT 
intervention and control groups. 
 
Secondary outcomes will include: 
1) Changes in DHO and providers’ knowledge and attitudes related to IPT in both intervention and control arms 
over time, as measured by quantitative surveys and data from focus group discussions (FGDs) within 
intervention districts and Key Informant Interviews (KIIs) within control districts. We will compare these 
changes across study arms.  

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2) In addition, for frontline providers, we will compare measures of social influence of DHOs on their own 
attitudes and practices in the intervention vs. control arms. These measures include perceptions of DHO 
credibility, salience of information from DHOs, and level of exposure to DHO influence (via assessment of 
quality and quantity of communications from DHOs).  
3) Additional clinical secondary outcomes will include: a) IPT completion - as measured by sufficient INH refill 
visits to complete 180 doses of INH in a nine-month period, recorded on IPT registry or “blue card” clinical data 
from clinics overseen by DHOs participating in the SPIRIT cluster randomized trial; and b) TB incidence, as 
measured from government TB registry data from each district. We will compare these outcomes (IPT 
completion and TB incidence) by study arm, within the sub-sample described for Aim 2 (below).  
 
The schedule of evaluation for outcome measures is shown in Table 2. 
 
Table 2. SPIRIT Trial - Schedule of Evaluations 
 
 
Baseline 
2-4 
Months 
6 Months 
12 Months 
18 
Months 
24 Months 
30 Months 
36 Months 
Interventio
n 
DHOs & TB 
support staff 
 
- Pre-test 
- Teaching 
Mini-
collaborative 
- Quantitative 
survey 
- 
Reporting 
Mini-
collaborati
ve 
- 
Reporting 
Mini-
collaborati
ve 
 
- Reporting 
Mini-
collaborative 
- FGDs 
(sample) 
- 
Reporting 
Mini-
collaborati
ve 
- Reporting 
Mini-
collaborative 
- FGDs 
(sample) 
Reporting 
Mini-
collaborativ
e 
- Post-test 
- FGDs 
(sample) 
Frontline 
provider 
sample 
Quantitative 
survey 
 
 
Quantitative 
Survey 
 
Quantitative 
Survey 
 
Quantitative 
Survey 
Control  
DHOs & TB 
support staff 
 
- Pre-test 
- Distribute 
MoH IPT 
Guidelines 
- Quantitative 
survey 
 
 
- Distribute 
MoH IPT 
Guidelines 
- KIIs 
 
- Distribute 
MoH IPT 
Guidelines 
- KIIs 
 
- Post-test 
- KIIs 
Frontline 
provider 
sample  
Quantitative 
survey 
 
 
Quantitative 
survey 
 
Quantitative 
survey 
 
Quantitative 
survey 
5.6.2 Mixed methods assessment of intervention mechanisms and implementation processes 
1) We will conduct quantitative surveys of intervention and control DHOs and a sub-sample of providers at 
baseline and three times following the intervention to measure knowledge, attitudes and practices related to 
IPT. Among providers, surveys will ask additional questions regarding perceptions of DHOs’ credibility, 
salience of information from DHOs, and level of exposure to DHO influence (including quantity and quality of 
interpersonal communications).  
2) We will collect qualitative data through 2-3 Focus Group Discussions (FGDs) in sub-samples of DHOs (e.g., 
combining 2 to 3 DHO groups per FGD) annually during the intervention and following the intervention. The 
FGD guide will be designed to elicit, in the intervention arm, DHOs’ perceptions of intervention content and 
impact on attitudes and practices. In the control arm, IPT-related secular trends, including perceptions of 
change in policy, policy communications, attitudes, and practices in the absence of intervention will be 
measured through KIIs in a sample of DHOs/DTLSs. 
 
DHOs/DTLSs and frontline providers selected to participate in quantitative surveys, FGDs, and KIIs will provide 
written informed consent prior to participation. All data collection will be conducted in local languages and/or 
English, depending on interviewee preference. 
5.7 Statistical Analysis 
Overview of statistical analyses for IPT uptake: The target population for the primary outcome is all HIV+ adult 
(≥15 years) patients who are eligible for IPT within 36 months of intervention start (in each pair-matched DHO 
group), and in care at a facility overseen by DHOs participating in the SPIRIT trial. The analytic population for 
the primary outcome is all adults in active HIV care in the largest two clinics in each district of the trial. The 
primary outcome (Section 5.6.1 above) for each randomized group is the rate at which these patients receive a 
prescription for INH over the 12-36 month period following the intervention start. In the primary analysis, we will 
account for prior INH starts and changes in the analytic population. All DHO groups are followed for three 
years total.  
 

SPIRIT Protocol, version date: March 4th, 2022  
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Estimation of the impact of the SPIRIT intervention on this outcome will be based on a two-stage analysis. In 
the first stage we will estimate IPT uptake for each DHO group. IPT uptake will then be compared between 
SPIRIT intervention and control arms with targeted maximum likelihood estimation (TMLE), adjusting using a 
pre-specified algorithm, and accounting for the pair-matched design and limited numbers of independent 
units.42 As a secondary analysis, we will implement the unadjusted effect estimator. Hypothesis testing will be 
based on a two-sided test at the α=0.05 significance level. We also propose to examine possible effect 
modifiers and mediators (e.g. HIV prevalence, TB screening, loss to follow-up rates, study time, drug shortages 
and drug availability). 
 
Analyses of secondary quantitative outcomes (IPT completion, TB incidence: see Aim 2) will be implemented 
analogously.  
 
Analyses of qualitative data: Focus group facilitators and key informant interviewers and recorders will be 
engaged to participate in coding and interpretation of data in collaboration with Camlin and other investigators. 
Team members will prepare and load translated FGD and KII transcripts into Atlas.ti software43 for coding and 
interpretation. An initial analytical code list will be defined by Camlin on the basis of theory and initial empirical 
data, with iterative refinement as new data are loaded. At defined stages of the analysis process, codes and 
definitions will be refined or expanded as needed. In team meetings, members will discuss coding of rich or 
difficult segments of text to achieve consensus, and Camlin will lead training exercises to ensure consistency 
in the application of codes to the data. Code query reports will be generated to explain patterns and identify 
emergent themes in the FGD and KII data. 
5.7.1 Data Collection & Management 
SPIRIT-1 and -3 Collaboratives Data: 1) Audio transcripts of participant (DHO/TB supervisor) discussions 
during mini-collaboratives (SPIRIT-1 and SPIRIT-3) may be obtained following enrollment and randomization, 
for analysis of both fidelity of training by coaches, as well as for evaluation of intra-collaborative communication 
and content. 2) DHO/TB Supervisor knowledge as measured by pre- and post-training testing. 3) DHO/TB 
Supervisor attendance and participation in training. 
 
Health Center (Clinic-level) Data: All data, including data on INH prescribing and refills, will be obtained either 
from encounter forms (“blue cards”) at local health centers and recorded onto standardized case record forms 
by study staff, or from centralized Uganda MoH health registries. Data will also be obtained from MoH TB 
Registries at the clinical level. Afterwards, the forms will be entered directly into an electronic database. Data 
integrity checks will be written into the database to limit the entry of incorrect data and ensure entry of data into 
required fields. Data may be double entered to verify accuracy of entry. The database will be transferred 
regularly via a secure electronic transfer to the data center facility in Kampala and stored on a secure server.  
 
Qualitative Data: Staff will record interviews on audio devices using study IDs (not participant names), and 
transcribed interviews and translations will be data entered into appropriate software on password-protected 
study computers. Data from interviews will be transferred via a secure electronic transfer to our data center 
facility in Kampala and stored on a secure server.  

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5.7.2 Sample Size & Accrual 
Sample size considerations for the primary outcome of IPT uptake:  In the control condition (standard of care), 
we anticipate 10% of eligible individuals will receive IPT. We anticipate that 50% of eligible individuals will 
receive IPT in the intervention condition. Assuming 12 DHO groups per arm and an extremely conservative 
matched pair coefficient of variation km of 0.4, this study will be powered at >95% (Figure 2).44 If we more than 
double the anticipated rate of IPT use in the control condition to 25% (vs. 50% in the treatment condition), the 
power remains at >90%. Of note, unlike a traditional sample 
size calculation where the investigators must “enroll” to reach 
a desired sample size, we use routine health systems data 
and therefore calculate anticipated power from a fixed 
sample size based on the number of DHO groups. As 
shown in Figure 2, these power calculations are not 
sensitive to the number of patients enrolled in each DHO 
group. We expect 1,000-25,000 patients in each DHO 
group.   
 
 
Figure 2 (right): Power calculations for the primary 
outcome of IPT uptake, assuming 12 DHO groups 
per arm and varying the outcome among the 
standard of care (SoC) and the number of patients 

SPIRIT Protocol, version date: March 4th, 2022  
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6. IPT Adherence & TB Incidence in the SPIRIT Trial 
 
Rationale: The population health impact of our DHO intervention aimed at reducing TB depends not only on 
IPT prescribing, but also on adherence and completion of IPT by patients. Thus, to understand the 
implementation pathway, it is important to measure an adherence outcome, which we propose to assess 
through the analyses of INH refill visits, as metrics of long-term pill consumption. Because ART use can both 
affect risk for TB in HIV+ persons, and be indirectly affected by our DHO intervention, we will also measure 
ART refills in our sampled subset of Aim 2. As another secondary outcome, TB incidence contributes to 
quantifying the magnitude of the public health effect of SPIRIT. 
6.1 IPT Registry Sampling Approach 
Aim 2 will employ a sampled approach for adherence measurement through INH refill visit measurements, as 
measured by review of MoH IPT refill registries. In the sampling approach (see details below in 6.6.3. Sampling 
Approach & Sample Size Considerations), de-identified INH refill data will be collected from approximately 800 
HIV+ adults prescribed INH in Uganda (400 from SPIRIT Intervention groups, and 400 from control groups).  
 
Additional measures of TB incidence (through MoH TB registry data) will be measured on the broader 
population of HIV-positive adults in care at health facilities overseen by the DHOs via MoH TB case registry 
counts. 
6.2 IPT Completion 
There is no gold standard for IPT completion in the field and prior studies have utilized patient self-report, pill 
counts, INH refill visits, and or blood/urine measures of INH metabolism.  
 
INH refill visits will be measured from “blue card” clinic data or MoH IPT registries in the Aim 2 sub-sample 
(see Section 5.6.1. above). INH refill visit measurements will include both the number of refill visits (i.e. 5, if 
prescribed monthly), and the number of pills dispensed. INH completion by INH refill visit measurement will be 
defined as dispensation of 180 pills of INH within 9 months of INH initiation. 
6.2 Active TB Incidence 
HIV-associated TB case detection will be obtained from the standard reporting system where local case entry 
is catalogued in MoH TB clinic registries and submitted through the DHO to central TB control. We will collect 
TB incidence data from MoH TB registries in all districts participating in the SPIRIT trial. We will compare HIV-
associated TB incidence in SPIRIT intervention vs. control groups, as described above (see Section 5.7 
above).  
6.3 Antiretroviral therapy (ART) Adherence 
We will record ART regimen, viral load, and ART adherence status during IPT registry and “blue card” review 
during IPT Registry sampling for Aim 2. We will compare ART adherence and viral suppression (<400 
copies/mL) by SPIRIT intervention vs. control district status to test the hypothesis that the SPIRIT intervention 
increases ART adherence and viral suppression, as a result of promoting daily pill taking by intervening to 
improve INH adherence. 
6.4 Data Management & Statistical Considerations 
6.4.1 Data Collection & Management 
Staff will record all Aim 2 study de-identified data, obtained from IPT registry and  “blue card” data (re: INH 
refills), and TB disease evaluation data (e.g. sputum microscopy results or x-ray results) using either paper lab 
logs, or password-protected study computers. Data from these logs or devices will be entered and transferred 
via a secure electronic transfer to our data center facility in Kampala and stored on a secure server.  
6.5.2 Analysis 
6.5.2.1 IPT completion: 
Primary outcome: We will examine INH completion, defined as an indicator of dispensation of 180 pills of INH 
within 9 months of INH initiation, as the primary outcome of Aim 2 among sampled patient charts in 
intervention and control groups (see Section 6.5.3. below). The effect of SPIRIT on INH completion will be 

SPIRIT Protocol, version date: March 4th, 2022  
Page 19 of 30 
estimated with TMLE, analogously to the primary endpoint of IPT uptake (see Section 5.7 above). We will 
account for clustering by randomization group and by DHO within randomization group.  In all analyses, we will 
adjust for the sampling probability to make inferences about the target population of IPT-prescribed, HIV-
infected persons in Uganda. 
 
Figure 3 shows the effect size that we are powered to detect when IPT completion (as measured by hair 
levels) is 30-50% in the control arm. These calculations assume 30-40 patients sampled per DHO group, 12 
DHO groups per arm, and a matched pair coefficient of variation km=0.2. Assuming IPT completion is 44% 
under the standard of care, we anticipate at least 80% power to detect a 40% increase in IPT completion due 
to the SPIRIT intervention (Figure 3).44   
 
Additional secondary analyses: We will examine the effect 
of SPIRIT on ART adherence and viral suppression in the 
sub-sample of patients for Aim 2. 
Qualitative analysis: Data collection and analyses will be 
similar to those described for Aim 1.  
 
 
6.5.2.2 TB incidence: 
Primary outcome: We will examine the impact of the 
SPIRIT intervention on the incidence rate of TB among all 
HIV-positive adults at a health facility overseen by DHOs 
participating in the SPIRIT trial. The analysis of TB incidence in the 
overall 
population will mirror the primary analysis of Aim 1. Assuming an incidence rate 200 cases per 100,000 
person-years in the standard of care,45 and 10% completion of IPT (which conservatively reduces TB incidence 
by 40%,1,2 the incidence density method suggests a two-year cumulative incidence of approximately 0.38% in 
the control arm. Figure 4 shows the effect size that we are powered to detect when the control cumulative 
incidence is 0.35-0.40%.44 Since the outcome is rare, these calculations are more sensitive to the number of 
patients per DHO group. However, we are relying on existing data collection systems (“blue card” forms and 
MoH TB clinic registries). Therefore, we anticipate capturing TB case reports on at least 3000 patients per 
DHO group. Assuming a control incidence of 0.38%, at least 2800 eligible patients in each DHO group, 12 
DHO groups per arm, and a matched pair coefficient of variation km=0.2, we will be powered to detect 40% 
reduction in TB incidence in the overall population.   
 
The analysis of TB incidence in the sub-sample of Aim 2 will mirror the analysis of IPT completion (Section 
6.5.2.1). We will adjust for clustering and the sampling probability to make inferences about the target 
population of IPT-prescribed, HIV-infected persons in Uganda.  
 
Figure 4: Effect size (in percent decrease in TB incidence) detected with at least 80% varying the incidence under the standard of care 
(SoC) and number of HIV-positive adults per DHO group. We assume 12 DHO groups per arm and a matched pair coefficient of 
variation km=0.2. 
30
32
34
36
38
40
35
40
45
50
Effect Size Detected with 80% Power 
 Varying the Number of Sampled Patients 
 and the IPT Completion in the Standard of Care (km=0.2)
Number of Patients Sampled per DHO group
Effect Size (in % Increase) Detected with 80% Power
SoC: 30% completion
SoC: 35% completion
SoC: 40% completion
SoC: 45% completion
SoC: 50% completion
Figure 3 (right): Effect size (in percent increase in IPT completion) 
detected with at least 80% varying the completion under the 
standard of care (SoC) and number of patients sampled per DHO 
group. We assume 12 DHO groups per arm and a matched pair 
coefficient of variation km=0.2. 

SPIRIT Protocol, version date: March 4th, 2022  
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6.5.3 Sampling Approach & Sample Size Considerations 
In our sampling approach for adherence measures and intensified TB case finding, we first stratify on the DHO 
randomization group. Then within DHO groups we will sample a minimum of thirty patients who are prescribed 
INH. To preserve generalizability, the sampling of patients may be further stratified by facility characteristics 
(e.g. size, DHO, SPC availability) and may be staggered across study time. We aim to perform chart review 
among 800 patients total, 400 per SPIRIT trial arm.  
 
 
 

SPIRIT Protocol, version date: March 4th, 2022  
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7. Evaluate the impact of business and leadership training on management and leadership 
skills among SPIRIT intervention vs. control DHOs. 
Rationale: The SPIRIT intervention seeks to increase routine, appropriate use of isoniazid at the clinic 
systems level, in part by providing leadership and management training during teaching mini-collaboratives. As 
a result we hypothesize that self-reported confidence in DHO leadership and management skills will be greater 
in intervention than control DHOs. 
7.1. Teaching Mini-Collaborative Business Leadership and Management training 
As noted in the SPIRIT-1 intervention (see Section 5.3.1.), additional training at the Teaching Collaboratives 
(and the Reporting Collaboratives) includes business and management training provided by business leaders, 
that aim to assist the DHOs and the District TB Supervisors in overseeing any new or ongoing initiatives to 
improve IPT implementation. DHOs are trained as clinicians and public health officers, but their qualifications 
and training do not include formal leadership and management training. Through additional business training, 
the SPIRIT intervention seeks to increase DHO leadership and management competency, thus improving 
implementation of IPT.  
7.2. Measures 
Measures obtained will include:  
1. The Leadership Business Description Questionnaire (LBDQ),46 adapted for the DHOs to provide self-
reported quantitative assessment of their leadership and management skills, and measured at the completion 
of the SPIRIT trial, Phase 1.  
2. Qualitative Key Informant Interviews (KIIs): Management and Leadership assessments, using interview 
guides based on the World Management Survey47, implemented among DHOs participating in qualitative 
interviews at the completion of the SPIRIT trial, Phase 1. 
7.3. Outcomes 
The primary outcome for the analysis of business training is the quantitative assessment of leadership and 
management skills as measured by the Leadership Business Description Questionnaire in intervention vs. 
control DHO groups at the completion of the SPIRIT trial, Phase 1. Qualitative outcomes will include DHOs’ 
perceptions of business training content and impact of the business training on attitudes and practices. 
7.4. Data Management & Statistical Considerations 
7.4.1. Data Collection & Management 
Staff will conduct the adapted LBDQ survey and KIIs at the completion of the SPIRIT Trial, Phase 1. Data from 
these surveys will be entered and transferred via a secure electronic transfer to our data center facility in 
Kampala and stored on a secure server. 
7.4.2. Analysis 
Analyses will evaluate the impact of the SPIRIT Phase 1 intervention on LBDQ scores between randomization 
arms using TMLE, implemented analogously to the primary endpoint of IPT uptake (see Section 5.7 above).  
 
 

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8. Costs & Cost-Effectiveness of SPIRIT 
In order to generate evidence that can address key questions concerning optimal resource allocation and 
provide guidance to policymakers, we will use rigorous methods to determine the costs of the SPIRIT 
intervention and assess its cost-effectiveness – particularly the cost per person initiating and completing IPT as 
well as the costs per TB case averted and disability-adjusted life years (DALYs) averted.  
8.1 Costs 
We will use standard micro-costing techniques to measure the cost of each component of the SPIRIT 
intervention. This will include costing of training activities and efforts made to transfer knowledge to DHOs in 
meetings; costs associated with utilizing opinion leaders to teach DHOs; costs of the SPC for administering 
INH, SMS system development and implementation, and other communication efforts; and costs of biannual 
meetings held with DHOs. This costing process will quantify the resource and associated unit costs required to 
deliver each intervention step, organized in standard expenditure categories—personnel, supplies, equipment, 
services (e.g. electricity), space, and overhead. Costs will be allocated to each intervention step to the extent 
possible and review of the division of shared resources and staff time, noting and reporting uncertainties in 
these divisions. Information required to determine costs will be obtained through examination of expenditure 
records, discussion with program managers and staff including pharmacy, care delivery labs and observation 
of service delivery for a sample of patients. Focused “time and motion” studies to allocate staff time across 
tasks within and outside the intervention will also be carried out to properly account for health care workers’ 
time devoted to the intervention. Donated and subsidized resources will be appraised at market value. We will 
assess costs from the societal perspective, i.e. including costs to patients and their family members in the form 
of out-of-pocket expenditures and also lost productivity. To assess costs incurred by patients, we will 
administer short questionnaires to patients selected for participation in the Aim 2 sub-sample at intervention 
and control facilities that elicit their expenditures for transportation to receive treatment and the value of the 
time lost in accessing care by clients and accompanying family members and time lost due to illness. 
8.2 Costs Analysis 
Costs will be estimated as the sum of the product of resources (e.g. staff minutes) times unit costs (e.g. 
compensation levels). We will assess costs twice in each of the two Aim 1 trial arms: once before and once 
after adoption of SPIRIT, in order to compare costs of standard of care to SPIRIT. “Economic” costs (the true 
value of resources consumed or “opportunity cost”) will be assessed by identifying the value of subsidized or 
donated resources with information from data bases (e.g. wage rates) and donors, and, as needed, three price 
quotes from appropriate market sources. Costs for capital items (equipment) will be amortized on a straight-
line basis over expected useful life, and assuming no salvage value. We will further allocate expenditures 
across three areas: i) medications ii) service delivery iii) indirect costs consisting of intervention overhead and 
administration. If possible, we will document changes in unit cost over time as programs potentially achieve 
greater scale, experience, and efficiency. We will also estimate the changes in HIV medical care costs due to 
use of changes in TB case rates.  We will accomplish these calculations using projected costs for TB care. 
After computing the intervention cost per participant initiating and completing IPT, we will quantify net costs – 
i.e. program costs adjusted for added or averted health care costs. We will base changes in short-term health 
care costs on household surveys (household expenditures for illness episode and hospitalizations). Longer-
term health care costs will be projected using clinical simulation modeling, based on observed changes in 
health status (e.g. TB- or HIV-related morbidity), combined with estimates from the trial and published studies 
of the costs of managing these conditions. We will explore uncertainty in this measure with sensitivity analyses. 
8.3 Health Effects 
Health effects will be quantified in two ways. First, we will use directly measured study outcomes pertaining to 
health-related events (TB cases, deaths, hospitalizations). Second, we will integrate the health impact of 
averted TB cases using disability-adjusted life years (DALYs), including lost years of life and the collective 
disability effects of adverse events. DALY estimates will be for the short term (during the trial) and the long 
term (5, 10, and 20 years) using clinical modeling. We will estimate future changes in DALYs among infected 
individuals by projection duration of survival and morbidity given best estimates of projected IPT initiation rates 
and use of ART.  We will conduct extensive sensitivity analysis on our assumptions, to describe the range of 
probable DALYs averted. We will also calculate the DALYs averted due to each TB infection averted due to 
IPT, using data from our own ongoing studies and published estimates of TB transmission rates. 

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8.4 Cost-effectiveness Analysis 
We will calculate efficiency (CE) indicators, such as program cost per person starting IPT, per person 
completing IPT and per TB case averted. We will calculate the standard CE ratio, net cost per DALY averted, 
with net costs equal to program costs adjusted for changes in health care costs due to the intervention. We will 
calculate this ratio with and without the projected long- term effects. All future costs and health effects will be 
discounted at 3% per year, per standard practice. We will conduct extensive univariate and multivariate 
sensitivity analysis. Importantly, if the intervention yields net savings (i.e., negative net costs) as well as health 
benefits, the intervention is classified as “dominant” and no CE ratio is calculated. 
9. SPIRIT Enhanced Business Training & “Training-of-trainers” curriculum 
9.1. Objective 
Objective: To evaluate the effect of enhanced business training among intervention group DHOs from Phase 1 
(Years 1-3 of trial follow-up) in the southwestern Uganda region on IPT initiation during years 4-5 of trial follow-
up (Phase 2). We propose to extend the SEARCH-IPT study for two additional years which will occur during 
Years 4 and 5 post trial baseline enrollment (Phase 2).  
9.2. Eligibility criteria 
9.2.1. Inclusion criteria 
(a) District Health Officer or District TB Supervisor (or other DHO-appointed TB focal person) from the Phase 1 
Southwestern Uganda region which includes 2 intervention and 2 control DHO groups (of 5-10 DHOs/group) 
(b) By definition, the DHO and District TB Supervisors in Uganda are all ≥18 years of age 
9.2.2. Exclusion criteria 
(a) Planned departure from position as DHO or TB District Supervisor prior to enrollment. 
9.3. Enhanced Business Training 
Building on business training introduced within the SPIRIT intervention, we will provide additional management 
training (using a technique referred to as “Gap Analysis”48) to a subset of SPIRIT intervention DHO groups, in 
the southwestern Uganda region, in order to evaluate the impact of enhanced business training on ongoing IPT 
initiation at quarterly meetings.  
9.4. “Training-of-trainers” curriculum intervention 
The “Training-of-trainers” (ToT) curriculum will include materials to support business training including slides 
and information materials that cover leadership and management skills taught to SPIRIT intervention-group 
DHOs over the first 3 years (Phase 1) of teaching mini-collaboratives. The ToT program will be designed such 
that intervention DHOs will provide business management and leadership training quarterly to their respective 
District Health Teams (DHT).  
9.4 Measures 
9.4.1. Measures to evaluate the effect of enhanced business training will include changes in IPT initiation (as 
measured in Phase 1: see section 5.6.1), change in self-assessed leadership and management skills as 
measured by the modified LDBQ (see section: 7.2) and qualitative interviews (see section 7.2), as well as  
measures of attendance during enhanced business training sessions among intervention group DHOs. 
9.4.2. Measures of implementation of the ToT intervention will include DHO fidelity to the training curriculum 
materials when DHOs provide quarterly business training to their respective DHTs, as measured by 
participation observation during meetings by our study staff and time spent on training at quarterly meetings. 
9.5. Outcomes 
The outcomes for this study aim will include changes in IPT initiation rates in Phase 2 intervention vs. control 
districts (see section 5.6.), and fidelity to implementation of the ToT program as defined by completion of 
trainings covering the full ToT curriculum. 

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9.6. Data Management & Statistical Considerations 
9.6.1. Data Collection & Management 
Staff will record all attendance at meetings on paper lab logs, or password-protected study computers. Data 
from these logs or devices will be entered and transferred via a secure electronic transfer to our data center 
facility in Kampala and stored on a secure server. 
9.6.2. Analysis 
The statistical analyses of IPT uptake will use the same methods as described for Phase 1 (see Section 5.7), 
limited to the SPIRIT trial intervention and control districts from the Southwestern region of Uganda. However, 
the outcome will be evaluated by district, rather than the pair-matched DHO groups evaluated in Phase 1.  
10. “Training-of-trainers” curriculum impact on district-level management and 
health outcomes 
10.1 Objective 
Objective: To determine if having DHOs provide business leadership and management training to their District 
Health Teams (DHTs) can improve district-level management practices and health outcomes.  
10.2 Recruitment & Enrollment of District Health Team (DHT) members 
10.2.1 Recruitment  
The SPIRIT Project Coordinator and study research assistants will work with the DHOs participating in the 
SPIRIT trial from the Southwestern Uganda region to obtain contact information for their DHT members.  
SPIRIT study staff will initiate contact with the DHT members by email, phone or in-person, to recruit for 
participation Phase 2 of the SPIRIT study. 
10.2.2 Consent Process 
Upon contacting the DHT members, the SPIRIT Project Coordinator or study research assistants will describe 
the business training planned for Phase 2 and the objectives of the study, and screen for enrollment. All 
eligible DHT members that agree to participate will provide written consent. If a DHT members departs from 
his/her position, we will consent the incumbent DHT member for study participation.  
10.2.3 Screening for Enrollment 
Study staff will screen all DHOs and/or District TB Supervisors reached during recruitment (10.2.1 above) for 
the eligibility criteria noted below.  
10.2.3.1 Inclusion Criteria 
(a) District Health Team (DHT) member in Uganda from the Phase 1 Southwestern Uganda region districts  
(b) By definition, the DHT members in Uganda are all ≥18 years of age 
10.2.3.2. Exclusion criteria 
(a) Planned departure from position as DHT Member prior to enrollment. 
10.3 Outcome Measures 
10.3.1 Leadership and Management Measures 
We will use a mixed methods approach to evaluate self-perceived business leadership and management skills 
among DHT members in intervention and control districts that includes longitudinal self-assessment surveys 
with the modified LDBQ survey and focus group discussions (among intervention DHT members), key 
informant interviews (among control DHT members) guided by components of the World Management Survey, 
as described above (see Section 7.2). We will also conduct evaluation of implementation processes such as 
DHT attendance at DHO-led business training meetings and the number and content of health care quality 
improvement initiatives/actions taken by DHT members during Phase 2.  

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10.3.2 District Level Health Measures 
 
We will obtain publicly available health outcomes as measured by the Uganda Ministry of Health at the district 
level from all Phase 2 districts in Southwestern Uganda. Health outcomes will include the metrics shown in 
Table 3, supplemented by other District-level health outcomes measured by the Ministry of Health and 
selected by DHOs or study investigators.  
 
Table 3: District-level health measures 
 
District Health Team Member 
District-Level Health Metrics 
Assistant District Health Officer: Maternal and Child 
Health 
1st antenatal care (ANC) visit attendance during 1st 
trimester 
Cold chain technician  
DPT3 Immunizations 
District TB/Leprosy supervisor 
TB treatment completion or TB cure  
Malaria Focal Person 
Pregnant patients receiving intermittent preventive 
therapy for malaria (IPTp) 
HIV focal person 
ART Quarterly report: Missed visits (proportion of 
scheduled visits missed among patients living with 
HIV active in care) 
Health Facility In-Charges  
Out-patient Department (OPD) new patient 
attendance 
10.4. Data Collection 
Annual leadership and management surveys will be conducted at Phase 2 baseline (trial year 3) and years 4 
and 5 of follow-up. Focus group discussions and key informant interviews will be audio recorded and 
translations will be data entered into appropriate software on password-protected study computers. Data from 
interviews will be transferred via a secure electronic transfer to our data center facility in Kampala and stored 
on a secure server. District level health metrics (Table 3), all of which is de-identified (aggregate data at the 
District level) will be obtained by study staff in collaboration with the Ministry of Health via electronic data 
queries from the Ugandan District Health Information System (DHIS2). 
10.5 Analysis 
For analysis of our primary outcome of interest among DHT members in Phase 2, we will compare changes in 
self-reported proficiency in business and leadership skills from Phase 2 baseline to Year 5 of follow-up, as 
measured by LDBQ survey responses, among DHT members in intervention vs. control districts using the 
same methods as for Phase 1 (see Section 5.7). We will also compare secondary outcome measures, 
including district-level health metrics and the number of quality improvement initiatives, from Phase 2 baseline 
to Year 5, in intervention vs. control districts. Qualitative data analyses will employ qualitative assessment 
methods as described for Phase 1 above (Section 5.6.2). 
 
 
 
 

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11. Human Subjects 
11.1 Risks to Human Subjects 
Potential Risks to Human Subjects  
There are relatively few risks to study participants, as the proposed research intervention aims to improve 
implementation of recommended Uganda Ministry of Health IPT guidelines. There are no “experimental” drugs 
in this study. We will be measuring the uptake of standard and approved drugs-- isoniazid and B6 that will be 
provided through the Uganda health system. The primary risks involved in study participation are inadvertent 
disclosure of HIV or suspected TB status by study staff with associated stigma (Aim 2).  
11.2 Adequacy of Protection against risks 
11.2.1 Informed Consent 
Trained research staff will obtain informed consent, as follows: 
 
1. Aim 1 – Cluster randomized trial: Written informed consent will be obtained from DHOs and their TB District 
Supervisors or other DHO-appointed TB focal person, for participation in the SPIRIT Aim 1 cluster randomized 
trial, including behavioral surveys. 
2. Aim 1 – Behavioral surveys: Written informed consent will be obtained from frontline clinic providers 
participating in behavioral surveys.  
3. Aim 4&5 – ‘Training-of-trainers’ curriculum: Written informed consent will be obtained from District Health 
Team members.  
 
All consent forms will be translated into the local language and back translated into English to ensure correct 
use of language. Consent forms will be read aloud to participants by trained staff. The informed consent will 
describe the purpose of the study, all the procedures involved, and the risks and benefits of participation. 
Interviewers will ask participants to summarize the study and explain the reasons why they want to participate. 
Either a signature or a thumbprint (for those who cannot read) will be acceptable to confirm informed consent 
for participation in the study, in the case of written consent forms.  
11.2.2 Risk of HIV/Suspected TB disclosure 
Given the sensitive and private nature of HIV care and suspected TB evaluation data of participants collected 
during implementation of research Aim 2, extra cautions will be put in place to ensure maintenance of privacy, 
confidentiality, and security of the data obtained during chart review. Only deidentified data will be collected 
and recorded, minimizing any likelihood of inadvertent disclosure during chart review. Data collection and 
storage procedures will include the use of encrypted, password-protected devices and servers. 
11.2.3 Data Security  
All information will be recorded using study identification numbers, rather than participant names, and stored 
securely in locked offices at a study data center. All study computers will be password encrypted and kept in 
locked offices. 
11.2.4 Institutional Review Board Approval 
The proposed research study will be reviewed and approved by the IRBs of all the participating institutions in 
the U.S. and Uganda. This includes the UCSF Committee on Human Research (CHR), the Makerere 
University School of Medicine - Research and Ethics Committee (SOM-REC), the Uganda National Council of 
Science and Technology (UNCST), and the Uganda National Drug Authority (NDA).  All study staff are 
required to undergo training in human subjects’ research, and good clinical practice (GCP). 
11.3 Potential benefits of the proposed research to the participants and others 
The primary benefits of the proposed research are: a) the proven benefits of wide-scale adoption of isoniazid 
preventive therapy to patients accessing HIV care in Ugandan Ministry of Health associated clinics, with 
associated reductions in active TB and TB-associated mortality risk; b) improved access to health education for 
District Health Officers (DHOs) in the intervention arm of the study; c) the potential for improved 
communication between DHOs and their clinic staff via study SMS communications; and d) improved 
management and leadership skills among DHOs and their DHT members (in the southwestern region only) 

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among intervention participants. The public health benefits may include decreased TB incidence with 
subsequent decreased TB transmission. 
11.4 Importance of the knowledge to be gained 
The minimal risk in this study is far outweighed by the importance of knowledge to be gained. Given the public 
health importance of achieving higher uptake of IPT among HIV-infected persons in sub-Saharan Africa, it is 
vital to have a proven intervention that can be used to overcome IPT implementation barriers at a country level 
scale. Our study will provide information on the effectiveness of a multi-component intervention at the middle 
management, health systems level that can be adapted and deployed across countries and regions, and be 
utilized as new advances in TB prevention emerge. 
 
 

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12. Publication of Research Findings 
The findings from this study may be published in a medical journal. No individual identities will be used in any 
reports or publications resulting from the study. The researchers will publish results of the study in accordance 
with NIAID, UCSF, UNCST, and Makerere University guidelines. 
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