Implementation of a Combination Intervention for Sustainable Blood Pressure Control in KwaZulu-Natal, South Africa (IMPACT-BP)
Phase: NA
Conditions: Hypertension
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
 
36 
 
 
Final Trial Protocol 
 
IMPACT-BP: 
Implementation of a Combination Intervention for Sustainable Blood Pressure Control in Rural 
KwaZulu-Natal, South Africa 
 
Version 5: February 15, 2024 
 
Africa Health Research Institute 
Brigham and Women’s Hospital 
Massachusetts General Hospital 
 
 
 
ClinicalTrials.gov registration Number: NCT05492955

 
 
 
 
 
 
37 
 
ABBREVIATIONS 
 
AHRI 
ART 
Africa Health Research Institute 
Antiretroviral therapy 
BP 
Blood pressure 
CBPM 
CHW 
Community Blood Pressure Monitor 
Community Health Worker 
CDS 
Clinical Decision Support 
CMIR 
Conceptual Model of Implementation Research 
CKD 
Chronic Kidney Disease 
CVA 
Cerebrovascular accident 
CVD 
Cardiovascular disease 
DALY 
Disability adjusted life year 
DBP 
Diastolic blood pressure 
DM 
Diabetes Mellitus 
DoH 
Department of Health 
GFR 
Glomerular Filtration Rate 
HBPM 
Home-based Blood Pressure Management 
HTN 
ICERs 
KZN 
Hypertension 
Incremental cost-effectiveness ratios 
KwaZulu-Natal 
MI 
Myocardial infarction 
NCD 
NHLBI 
PCCs 
Non-communicable disease 
National Heart, Lung, and Blood Institute 
Primary care clinic(s) 
PHC 
POC 
SA 
Primary health center 
Point of care 
South Africa 
SBP 
SOC 
SOP 
QALYs 
Systolic blood pressure 
Standard of care 
Standard operating procedure 
Quality adjusted life years 
 

38 
 
 
TABLE OF CONTENTS 
 
I. 
INVESTIGATORS AND INSTITUTIONS ........................................................................................ 42 
II. 
STUDY FUNDING AND REGISTRATION ..................................................................................... 43 
III. 
PROJECT SUMMARY AND SPECIFIC AIMS ........................................................................... 44 
IV. 
AIM 1: READINESS AND ACCEPTABILITY ASSESSMENT ................................................... 46 
A. 
Methods ......................................................................................................................................... 46 
B. 
Study Outcomes ........................................................................................................................... 47 
C. 
Eligibility Criteria Rationale ......................................................................................................... 47 
a. 
Key Informants ............................................................................................................................ 47 
b. 
Health Workers ........................................................................................................................... 47 
c. 
Patients/Eligible Study Participants ............................................................................................ 47 
D. 
Recruitment ................................................................................................................................... 47 
E. 
Enrollment ..................................................................................................................................... 47 
a. 
Inclusion Criteria for Key Informants ........................................................................................... 47 
b. 
Inclusion Criteria for Health Care Workers ................................................................................. 47 
c. 
Inclusion Criteria for Participant Focus Groups .......................................................................... 48 
F. 
Sample Size ................................................................................................................................... 48 
G. 
Informed Consent ......................................................................................................................... 48 
H. 
Data Collection and Analysis ....................................................................................................... 48 
a. 
Data Collection ............................................................................................................................ 48 
b. 
Data Analysis .............................................................................................................................. 48 
I. 
Risks, Protection from Risks and Benefits to Study Participation in Aim 1 ........................... 49 
a. 
Risks and Protections ................................................................................................................. 49 
b. 
Benefits ....................................................................................................................................... 49 
V. 
AIM 2: IMPLEMENTATION CLINICAL TRIAL .............................................................................. 50 
A. 
Aim 2 Overview ............................................................................................................................. 50 
Figure 1. Study Schema ....................................................................................................................... 50 
B. 
Eligible Study Population ............................................................................................................. 51 
C. 
Eligibility Criteria .......................................................................................................................... 51 

39 
 
 
a. 
Inclusion Criteria ......................................................................................................................... 51 
b. 
Exclusion Criteria ........................................................................................................................ 51 
D. 
Subject Recruitment ..................................................................................................................... 51 
a. 
Participant Identification .............................................................................................................. 51 
E. 
Informed Consent ......................................................................................................................... 52 
F. 
Randomization .............................................................................................................................. 52 
G. 
Aim 2 Study Procedures .............................................................................................................. 52 
a. 
Blood Pressure Monitoring Procedures by Study Arm ................................................................ 52 
i. 
SOC: Baseline Visit for Clinic-Based Standard of Care Participants (Figure 2) .................. 52 
ii. 
Intervention 1: Community Blood Pressure Monitor Model (CBPM) (Figure 3) ................... 53 
iii. 
Intervention 2: Enhanced Community Blood Pressure Monitor-based with mobile health 
blood pressure monitoring model (eCBPM+) (Figure 4) ............................................................. 54 
b. 
Study Visit Schedule ................................................................................................................... 55 
i. 
Visit 1: Enrollment ................................................................................................................ 55 
ii. 
Visit 2: 6-month BP Measurement Assessment and Medication Use .................................. 55 
iii. 
Visit 3: 12-month BP Measurement Assessment and Evaluation of BP Device Function ... 55 
iv. Extension phase and additional study visits: 18 and 24-month BP Measurement 
Assessment and Evaluation of BP Device Function ................................................................... 56 
v. 
Missing and Late Appointments ........................................................................................... 56 
Table 1. Summary of Study Visit Procedures ...................................................................................... 56 
H. 
Data Systems and Management .................................................................................................. 56 
a. 
Data Systems .............................................................................................................................. 56 
i. 
REDCap Study Database ................................................................................................... 56 
ii. 
Hypertension Management Application .............................................................................. 57 
b. 
Data Protection and Confidentiality ............................................................................................. 57 
c. 
Data Sharing ............................................................................................................................... 57 
d. 
Specimen Collection and Testing ............................................................................................... 57 
e. 
Data Monitoring and Quality Control ........................................................................................... 58 
I. 
Study Monitoring and Regulatory Oversight ............................................................................. 58 
a. 
Staff Training ............................................................................................................................... 58 
i. 
Research Staff .................................................................................................................... 58 
ii. 
Provider Staff ...................................................................................................................... 58 
b. 
Regulatory Oversight and Safety Monitoring .............................................................................. 58 
i. 
Safety Monitoring: ............................................................................................................... 58 
ii. 
Adverse and Unexpected Event Reporting: ........................................................................ 59 
J. 
Statistical Considerations and Analyses .................................................................................... 59 
a. 
Sample Size ................................................................................................................................ 59 
Table 2. Differences in change from baseline that can be detected with 80% power ........................ 60 
Table 3. Hypertension visits and patients at clinics in the study catchment area (2020) .................... 60 
K. 
Study Outcomes ........................................................................................................................... 60 

40 
 
 
a. 
Primary Outcome of Clinical Trial: .............................................................................................. 60 
b. 
Secondary Outcomes: ................................................................................................................ 60 
c. 
Safety Measures ......................................................................................................................... 60 
L. 
Aim 2 Analysis Plan ...................................................................................................................... 61 
M. Risks, Protection from Risks and Benefits to Study Participation in Aim 2 ........................... 61 
a. 
Risks and Protections ................................................................................................................. 61 
b. 
Benefits ....................................................................................................................................... 62 
VI. 
AIM 3 .......................................................................................................................................... 63 
A. 
Methods ......................................................................................................................................... 63 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 63 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 63 
B. 
Study Outcomes ........................................................................................................................... 64 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 64 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 64 
Table 4. Summary of acceptability, fidelity, and sustainability outcome measures for Aim 3a ............ 65 
C. 
Data Sources ................................................................................................................................. 66 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 66 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 66 
D. 
Recruitment ................................................................................................................................... 66 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 66 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 66 
E. 
Enrollment ..................................................................................................................................... 66 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability ......................................................................... 66 
i. 
Inclusion Criteria for Key Informants ................................................................................... 66 
ii. 
Inclusion Criteria for Health Care Workers .......................................................................... 66 
iii. 
Inclusion Criteria for Participants ........................................................................................ 66 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 67 
F. 
Sample Size ................................................................................................................................... 67 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 67 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 67 
G. 
Informed Consent ......................................................................................................................... 67 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 67 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 67 
H. 
Data Collection .............................................................................................................................. 67 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 67 
b. 
(Aim 3b) Cost-effectiveness ........................................................................................................ 67 

41 
 
 
I. 
Analysis ......................................................................................................................................... 68 
a. 
(Aim 3a) Fidelity, Sustainability, and Acceptability ...................................................................... 68 
b. 
(3b) Cost and Cost-effectiveness ................................................................................................ 68 
J. 
Risks, Protection from Risks and Benefits to Study Participation in Aim 3a and 3b ............. 69 
a. 
Risks and Protections ................................................................................................................. 69 
a. 
Benefits ....................................................................................................................................... 69 
VII. 
REFERENCES ........................................................................................................................... 70 
 
 

42 
 
 
I. INVESTIGATORS AND INSTITUTIONS 
 
Thomas A. Gaziano, MD MSc 
 
Co-Principal Investigator  
Harvard Medical School  
 
 
Massachusetts General Brigham 
Tel: +1-617-432-4348 
 
           Email: tgaziano@bwh.harvard.edu 
 
Mark J. Siedner, MD MPH 
 
Co-Principal Investigator  
Harvard Medical School  
 
 
Massachusetts General Brigham 
Tel: +1-617-726-4686 
 
 
Email: msiedner@mgh.harvard.edu  
 
Max Bachmann, MD PhD MSc 
 
Co-Investigator 
Norwich Medical School 
 
 
University of East Anglia 
Tel: +44 (0)1603-59 1220  
 
Email: M.Bachmann@uea.ac.uk 
 
Nombulelo Magula,   
 
Co-Investigator 
MBChB, MSc, FCP(SA), PhD 
Nelson R Mandela School of Medicine University of KwaZulu-Natal 
Tel: +27 31 260 4238 
 
 
Email: magulan@ukzn.ac.za 
 
Joanna Orne-Gliemann, PhD MPH 
Co-Investigator 
Bordeaux University 
Tel: +33 (0) 5.57.57.45.17  
 
Email: Joanna.Orne-Gliemann@u-bordeaux.fr 
 
 
 

43 
 
 
 
II. STUDY FUNDING AND REGISTRATION 
 
Sponsor: National Heart, Lung, and Blood Institute (NHLBI) 
Grant Number: NIH R01 HL144848 
FAIN: R01HL144848 
Study Period: September 04, 2020 – August 31, 2025 
ClinicalTrials.gov registration Number: NCT05492955 
 
 
 
 
 

44 
 
 
III. PROJECT SUMMARY AND SPECIFIC AIMS 
 
Uncontrolled hypertension is the primary risk factor for stroke and hypertensive heart disease, 
which are the leading causes of non-communicable disease (NCD) deaths in South Africa, and 
of disability adjusted-life years lost globally [1-3]. Yet, there is a large knowledge-
implementation gap between efficacy literature on hypertension control   and effectiveness of 
health systems to provide hypertension care [4]. This is particularly true in resource-limited 
settings. In rural KwaZulu-Natal (KZN), we recently found that approximately one in six adults 
over 18 years old have hypertension, and fewer than one in four of those with hypertension 
have disease control [5]. 
 
The South African (SA) Department of Health (DoH) in its “Strategic Framework 2019-2024” 
has set a goal to increase life-expectancy through universal health coverage [6]. KZN Health 
has outlined its strategic goals to be consistent with the National goals to reduce morbidity and 
mortality through increased screening, treatment, and control of NCDs [7]. These goals will be 
achieved through an enhanced community-based care program, that will further integrate 
community health workers (CHWs) into the public health system, strengthen clinics, and 
implement a digital health strategy. The basic structure of the community-based program is the 
linkage of Ward Based Primary Care Outreach teams that are linked to the primary health 
center (PHC) facility and consists of a team of CHWs lead by an outreach team leader who is 
a trained nurse. The COVID-19 pandemic has accelerated the need for these changes which 
would allow community members to receive a greater portion of their care in their homes 
limiting overcrowding of clinics and decreasing infection risk.  
 
The scientific goals of this project are to inform best practices for implementation of 
interventions targeting health systems and individual barriers to effective hypertension care in 
rural KwaZulu-Natal. We have selected a combination of interventions, effective in clinical trials 
but without widespread successful health system translation in resource-limited settings, that 
target both the health system and the individual to attain improved blood pressure control. Our 
intervention design specifically reflects support for community-based delivery of care for 
chronic diseases, that has been established to be effective in HIV care [8], increasingly 
prioritized in light of the COVID-19 pandemic [9] and is promoted by the South Africa 
Department of Health Non-Communicable Disease Control Program Policy Statements [10]. 
We will conduct a randomized trial to evaluate community-based hypertension control 
programs based on three primary components: a) community-based disease management 
with home-blood pressure measurements; b) a nurse champion for program oversight, and c) 
use of a clinical decision support system. Community blood pressure monitors (CBPMs) will be 
employed to execute study activities, in a capacity that is equivalent to that of CHWs in the 
DoH Ward Based Primary Care Outreach teams.   
 
We will evaluate the implementation of two community-based, technology-supported programs 
to improve blood pressure control in South Africa, guided by the Conceptual Model for 
Implementation Research [11], with a focus on acceptability (Aim 1), effectiveness (Aim 2) and 
feasibility, cost- effectiveness and sustainability (Aim 3). We will leverage a 20-year 
partnership with the Department of  Health, a multidisciplinary team of experts, and a recent 
health screening of approximately 18,000 individuals in the catchment area [5] to accomplish 
the above goals, and to accomplish the following aims: 
 
 

45 
 
 
Aim 1  
Evaluate the acceptability and conduct a readiness assessment for implementation, of 
community-based hypertension, technology-supported interventions to reduce blood 
pressure in rural.   
Guided by the Conceptual Model of Implementation Research (CMIR), we will use mixed 
methods to assess organizational, healthcare worker, and participant readiness for 
implementation of the interventions. We will use results of the readiness assessments to refine 
final implementation strategies for the intervention.  
 
Aim 2 
Determine the effectiveness of a community-based, technology-supported intervention 
to reduce systolic blood pressure and increase blood pressure control among 
individuals with uncontrolled hypertension in rural South Africa.  
 
We will conduct a trial using CBPMs in conjunction with in-home BP monitoring among 
approximately 774 adults randomized to one of three different arms of hypertension care: 1) 
clinic-based standard of care model (SOC); 2) community blood pressure monitor-based blood 
pressure monitoring model (CBPM); 3) and enhanced community blood pressure monitor-
based model, including mobile health blood pressure monitoring (eCBPM+). 
 
Aim 3 
Determine the fidelity, sustainability, acceptability, and cost-effectiveness of 
community-based, technology-supported hypertension interventions to reduce blood 
pressure in rural KwaZulu-Natal.   
 
The use of the CMIR (Aim 1) will be extended to evaluate the fidelity and sustainability of the 
intervention. A microsimulation model (CVD PREDICT) that uses individual-level risk factor 
data and health cost inputs will be used to determine the cost-effectiveness of the intervention. 
 
 
 
 

46 
 
 
IV. AIM 1: READINESS AND ACCEPTABILITY ASSESSMENT 
 
Evaluate the acceptability and conduct a readiness assessment for implementation, of 
community-based hypertension, technology-supported interventions to reduce blood pressure 
in rural KwaZulu-Natal.   
 
A. Methods 
Guided by the Conceptual Model for Implementation Research [11] and the Theoretical 
Framework for Acceptability [12], we will use qualitative methods to assess organizational, 
healthcare worker, and patient acceptability of and readiness for the implementation of the 
intervention.  
 
To do so, we will first host a series of key informant interviews and meetings, with 
representatives from the national DoH and other key stakeholders, which will allow us to 
assess pre-intervention implementation acceptability and readiness at the organizational level. 
These interviews/meetings will be designed to assess how the intervention aligns with health 
policy goals, current practice guidelines and services for hypertension, and institutional 
resources available to support the project.  
 
Then group discussions will allow us to assess patient, nurse, CHW, and nurse supervisor 
perceptions about, and acceptability of, the intervention. We will explore areas such as 
workers’ attitudes and beliefs about providing effective care to their patients (including self-
efficacy), understanding of the intervention and expected effectiveness, relationships between 
workers and the primary care system (including perceived burden); we will also investigate 
patient perceptions of and need for hypertension care provided at the clinics.  
 
These meetings and group discussions will be conducted approximately three months prior to 
study implementation. This approach allows for in-depth assessment of the initial acceptability 
of the intervention and to identify potential barriers and facilitators to the intervention and its 
implementation.  
 
We will conduct selective (purposive) sampling of potential participants at the trial clinics, 
divided evenly between those who have controlled blood pressure and those who have 
uncontrolled blood pressure, and include both sexes and a range of ages for maximum 
variation. Health care workers will be selected from clinics that are included in the study. 
Participation in the health care worker groups will be determined by role, to encourage 
participants to share their opinions freely, given the strong hierarchical structure in clinical 
practice settings.   
 
A major theme of the interviews will be readiness of the system infrastructure to support the 
intervention will also be assessed through an assessment of the capacity to support the 
interventions, including available cell phone coverage in the study area, data transfer capacity 
and processes, and piloting of the blood pressure monitoring app component of the 
intervention with nurses.  
 
Added support for this intervention will be negotiated with community leadership structures 
such as the traditional leadership or Ward Councillor. Public health interventions have been 
shown to have more positive health and psychosocial outcomes when there is community 

47 
 
 
engagement [13]. This community engagement process will be incorporated into the 
Conceptual Model for Implementation Research and the Theoretical Framework for 
Acceptability.  
 
These data will lead to a review the design of the intervention, if relevant, to refine its 
implementation through adaptations in the randomized clinical trial (Aim 2).  
 
B. Study Outcomes 
• Intervention acceptability, readiness, potential barriers and facilitators 
• Potential intervention design modifications 
 
C. Eligibility Criteria Rationale 
a. Key Informants: partners at the KZN DoH who are familiar with provincial and national 
health care policies, goals, and systems. These partners will provide important feedback 
on the alignment and fit of the proposed intervention with the current health priorities, 
goals, and availability of resources for hypertension care. Community leadership will 
also be interviewed as key informants in order to assess how the proposed intervention 
can be supported in community structures.   
 
b. Health Workers: clinic-based professional nurses, operational managers, outreach 
team leaders, physicians, CHWs, and pharmacists employed at clinics included in the 
trial.  Each of these workers will provide rich data about their experiences providing 
specific components of clinical care to participants with hypertension, which will help 
with refining the implementation strategies, including adaptations, for the intervention.  
 
c. Patients/Eligible Study Participants: are expected to be receiving care for 
hypertension at the clinics included in the trial. Their experiences will be used to identify 
needs, potential barriers and facilitators to the intervention implementation, which will be 
considered when designing the implementation strategies of the study.  
 
D. Recruitment 
Key informants will be identified and contacted by study investigators at Africa Health 
Research Institute (AHRI) from current and prior collaborators working on improving health 
care in this rural population. Health care workers will be identified from personnel records at 
the study clinics and be invited to participate in the group discussions by study investigators, in 
agreement with DoH and AHRI policy for conducting research among health care 
professionals. Participants for group discussions will be identified from clinic registers for 
hypertensive patients.  
 
E. Enrollment 
d. Inclusion Criteria for Key Informants  
• age 18 and over.  
• representative of the KZN DoH for involved in management of primary care delivery 
programs. 
• Ward Councillor or traditional leadership (Induna) in the community. 
 
e. Inclusion Criteria for Health Care Workers  
• age 18 and over.  
• currently functioning as a health care worker (physician, nurse, CHW, pharmacist, 

48 
 
 
clinic administrator/operational manager) at one of the study clinics. 
 
f. Inclusion Criteria for Participant Focus Groups 
• age 18 and over. 
• diagnosed with both controlled and uncontrolled hypertension. 
 
F. Sample Size  
Final sample sizes for each of the participant groups will be driven by saturation of themes and 
in the following ranges: 
• Key informants interviews/meetings: 8-10 
• Group discussions with health care workers: approximately 2 or until saturation 
achieved 
• (number of participants per group: 8-10) 
• Group discussions with patients/eligible future participants: approximately 2 or until 
saturation achieved 
• (number of participants per group: 8-10) 
 
 
G. Informed Consent 
Key informants will be invited to participate in interviews/meetings to discuss about the 
planned study and their participation will be taken as consent to participate. Study research 
assistants will recruit participants enrolled in the study and health care workers to participate in 
the group discussions. The research assistants will explain the activities of the study, how 
confidentiality will be maintained, and explain the informed consent form, as well as answer 
any questions. Those who agree to participate will be asked to sign two copies of an informed 
consent form. One copy will be given to the participant for his/her records and the other will be 
retained as part of the study record. For those who cannot sign their name, a thumb print will 
be obtained. If remote participation in group discussions are necessary due to the COVID-19 
pandemic restrictions on in-person activities, verbal consent will be obtained and recorded 
prior to the start of the discussion.    
 
H. Data Collection and Analysis 
a. Data Collection 
Names of key informants and data from key informants’ interviews meetings will be kept 
confidential and will not be recorded. No personally identifiable data from these meetings 
will be used in publication or dissemination activities in any form. Data from both study 
participants and health care workers will be collected from group discussions. A Zulu-
speaking research assistant with training in qualitative methods will facilitate the group 
discussions, which will be held in a private setting to ensure confidentiality and encourage 
maximum participation. The discussions will be recorded using digital audio. Health care 
workers and study participants will be asked to complete a short 5-10 item questionnaire 
and a generic study identification number will be assigned to each person completing the 
survey. Interviewers and focus group facilitators will use guides with open-ended questions 
to collect data. Discussions will cover pre-designated core topics such as understanding, 
perceptions and attitudes towards the planned intervention, any anticipated barriers, and 
opportunities for implementation. 
 
b. Data Analysis 
Group recordings will be transcribed and translated into English. Manual thematic analysis 

49 
 
 
will be performed using a combination of theory-led (deductive) and  data-led (inductive) 
coding. The study team will collaboratively review the data in both isiZulu and English to 
identify emerging codes and capture the richness of the data. Research assistants will 
conduct the primary coding of interview data. Their work will be supervised by at least 2 
senior researchers who will perform double coding and review a subset of the research 
assistants’ work to ensure uniformity and quality of the coding process. The senior 
researchers will review all the coded data and will create thematic summaries. Data 
management software package (NVivo) will be used to code and explore themes. Data on 
the acceptability of the intervention will be organized into the seven component constructs 
of the Theoretical Framework of Acceptability [12], which includes affective attitude, 
burden, ethicality, intervention coherence, opportunity costs, and perceived effectiveness.  
 
Findings will contribute to identify key areas of the intervention implementation that will 
need specific attention for effective implementation. These results will be shared with the 
study team to identify processes in the randomized clinical trial protocol that may need to 
be adapted prior to implementation. Final training materials for health care workers 
participating in the trial will be updated to reflect these refinements in implementation.  
 
I. Risks, Protection from Risks and Benefits to Study Participation in Aim 1 
a. Risks and Protections 
i. 
The primary risk to participation is breach of confidentiality. We will not record 
names of any individuals taking part in interviews, nor will we report them in findings 
to be disseminated as part of this project. Given the low number of people in the 
study and the identification of participants (e.g., stakeholders in the Department of 
Health) it is possible that their identities could be inferred and we will make this risk 
clear during the consenting process. 
ii. 
A secondary risk of participation in this Aim is loss of time from participation in 
interviews and/or discomfort with the questions asked or nature of the conversations. 
All participation will be voluntary and participants will be free to pause, interrupt, or 
not respond to any questions or content areas that make them uncomfortable. 
b. Benefits 
i. 
Most study participants in Aim 1 will derive no direct benefit from participation in the 
study. 
ii. 
Some participants might gain a personal sense of pride from knowing they are 
contributing to development of a system that intends to improve hypertension care in 
their community, or for the opportunity to contribute to its design. 
iii. 
If one of the interventions is ultimately successful, this study might provide a benefit 
to the community by helping to guide development of an improvement system of 
hypertension care. 
iv. 
A financial incentive of R50 of airtime (telephonic), R50 in cash (in-person), or a R50 
food voucher will be provided to participants for their participation in discussion 
groups and interviews, subject to COVID-19 restrictions in place.  
 
 
 
 

50 
 
 
V. AIM 2: IMPLEMENTATION CLINICAL TRIAL 
Determine the effectiveness of community-based, technology-supported interventions 
to reduce systolic blood pressure and increase blood pressure control among 
individuals with uncontrolled hypertension in rural South Africa. 
 
A. Aim 2 Overview 
This is randomized clinical trial intended to identify the optimal strategy of blood pressure 
management in rural South Africa. Participants will be randomized into one of three arms of 
hypertension care: 1) clinic-based standard of care model (SOC); 2) community blood 
pressure monitor-based blood pressure monitoring model (CBPM); 3) an enhanced community 
blood pressure monitor-based model with mobile health blood pressure monitoring (eCBPM+). 
(Figure 1). Eligible participants will be recruited from prior community-based hypertension 
screening programs, CBPM-led hypertension screening activities, and/or from trial clinics 
where they are accessing care. Consenting participants will be randomized to one of the three 
study arms. Independent of clinical care, all participants will be seen at enrollment, at 6 
months, and at 12 months for BP monitoring and data collection by study nurses for outcome 
assessments.  
 
Figure 1. Study Schema 
 
 

51 
 
 
The primary effectiveness outcome will be assessed in an intention-to-treat analysis and 
defined as the change in systolic blood pressure (SBP) 6 months after enrollment. The 
secondary effectiveness outcome will be the proportion of participants with controlled blood 
pressure, as defined by an SBP <140 mmHg and a diastolic BP (DBP) <90 mmHg 6 months 
after enrollment. 
 
B. Eligible Study Population 
Residents living in the catchment area of publicly operated rural primary care clinics in the 
Umkhanyakude District in northern KwaZulu Natal. 
 
C. Eligibility Criteria 
a. Inclusion Criteria 
• Age greater than 18 years old. 
• Residing in uMkhanyakude District in northern KwaZulu-Natal in an area that is 
served by a CBPM. 
• Elevated blood pressure (blood pressure > 140/90 mmHg) on two measurements. 
 
b. Exclusion Criteria 
• Pregnant or breast-feeding women. 
• Severe, symptomatic hypertension with a measured blood pressure > 180/110 
mmHg. 
• Known, advanced chronic kidney disease. GFR < 60 ml/min/1.73 m2. 
• Current use of at least 3 different anti-hypertensive therapies at full dose. 
• Planning to move within the next 24 months. 
 
D. Subject Recruitment 
a. Participant Identification 
We will identify potentially eligible participant from three sources: 1) those presenting to 
the trial clinics with elevated blood pressure, 2) individuals who are diagnosed with 
hypertension during home visits by CBPMs, or 3) individuals with elevated blood 
pressure identifying through screening activities for hypertension conducted in the study 
catchment area, such as the Vukuzazi Study. Clinic and research staff from these 
activities will notify study nurses of potentially eligible participants who will then conduct 
eligibility assessments, either at the clinic, or in the case of notification after a home or 
community-based screening, at participant homes. Study nurses will describe the study 
and screening procedures, including the required screening for pregnancy and kidney 
function to confirm eligibility. Those who agree to be screened will have their eligibility 
determined by the nurse using a screening questionnaire and measurement of blood 
pressure. Eligible patients who agree to participate will then be asked to review and sign 
the informed consent form. The study nurse will answer any questions the patients may 
have about the study. Once informed consent is obtained, the study nurse will conduct 
the pregnancy test (if applicable) and a point-of-care creatinine test (Abbott/Piccolo 
Xpress) to complete the enrollment process. Patients who are not pregnant and have 
glomerular filtration rate greater than 60 ml/min/1.73 m2 will be enrolled in the study. 
Patients who are pregnant, have abnormal renal function, or are confirmed to have 
uncontrolled hypertension will be referred to clinic for additional care by the nurse and 
enrollment will not be completed.  
 

52 
 
 
E.  Informed Consent 
Informed consent procedures will be performed by research nurses who have been trained in 
the ethical conduct of human subject’s research and informed consent procedures. This 
procedure will be carried out in the participant’s in a private area of the home or clinic in either 
English or in isiZulu. Any eligible patients who previously participated in Aim 1 discussion 
groups and who are randomly selected for recruitment in the RCT, will be asked to sign the 
RCT informed consent form if they agree to participate.  
 
F.  Randomization 
Consenting participants will be randomized by the REDCap randomization module to the 
standard of care  (SOC), (CBPM) or (eCBPM+) study arms (Figure 1). Randomization will be 
stratified by clinic and active use of anti-hypertensive therapy. Randomization will be 
conducted in blocks of 9. In brief, after screening has been completed, eligibility confirmed, 
and informed consent forms signed, a study participant is given a unique consecutive 
identification number in REDCap. The randomization field is selected, and the research 
assistant is informed which arm the participant has been selected for by the application. 
Strategy allocation will be unblinded to participants or clinic staff. 
 
G. Aim 2 Study Procedures 
a. Blood Pressure Monitoring Procedures by Study Arm 
i. SOC: Baseline Visit for Clinic-Based Standard of Care Participants (Figure 2) 
All study participants, including in the SOC arm, will receive standardized educational 
materials for BP medication adherence support, nutritional guidelines,  lifestyle 
modification techniques for individuals with elevated blood pressure, and medications for 
individuals with elevated blood pressure. Participants in the SOC arm will be referred to 
their clinic for initiation (if newly diagnosed) or active care (if previously diagnosed) as 
per standard clinical protocols. All care will be provided at the clinic. Routine care 
consists of regular visits to the clinic until BP is under control (<140/90 mmHg) and then 
at 6 monthly intervals. BP measurements to guide management decisions will be made 
at the clinic using standard clinic equipment. Symptoms related to hypertension and/or 
medications will be assessed at each visit. Medications available will include medications 
on the South African Essential Drug list and which are available in the pharmacy (which 
include hydrochlorothiazide, enalapril, amlodipine and spironolactone). Prescriptions are 
picked up at the clinic pharmacy by patients as per routine protocol at the clinics. CBPMs 
may also conduct monitoring as guided by clinical guidelines and as advised by their 
clinical supervisors during the study period to assess for adherence and provide 
education. 
 
 
 
 
 
 
 
 
 
 
 
 

57 
 
 
data quality control, study scheduling, randomization, and real-time study monitoring. 
Questionnaires and clinical records will be completed in real-time and entered by study 
staff using encrypted study mobile tablets. The REDCap application allows for both 
online (real-time) data entry or, when internet service is not available, offline entry with 
syncing to the server when internet becomes available again. 
 
ii. 
Hypertension Management Application 
In both intervention arms, we will use a clinical decision support system (CDSS). The 
clinical decision support will receive blood pressure measurements information every 
two to four weeks (either manually by the CBPM/Nurse team in Intervention (CBPM) or 
via direct cellular data transfer in Intervention (eCBPM+)). The CDSS will be designed 
to make treatment recommendations based on the participants blood pressure 
measurements, prior drug reaction history if any, and current treatment status in 
accordance with the South African Hypertension guidelines in use in the PCCs in KZN. 
Additionally, if any laboratory tests are recommended based on the guidelines, the 
CDSS will also recommend these tests be done.  
 
b. Data Protection and Confidentiality 
Paper forms that include participant protected health information will be stored on the 
day of enrollment  in participant specific folders within locked file cabinets in locked 
research offices. Only study staff will have access to the file cabinets. All other study 
data will be free of identifying information. Data will be stored on an encrypted data 
servers hosted by the Africa Health Research Institute. Access to the study database 
both on site and remotely is restricted to study staff and password protected. All study 
mobile tablets will be password protected and encrypted prior to study initiation. Data 
collected on mobile tablets will be uploaded to the server in real-time during data entry 
or synced to the server as soon as data/Internet access becomes available if it is not 
during data entry, using the REDCap Offline Application. Data shared between tablets 
and the server will be encrypted during transmission. Any data shared with the clinical 
decision app that will be used to generate treatment recommendations for the nurse to 
use in managing hypertension will also be encrypted during transmission. No personally 
identifiable information will be shared with, or stored by, the clinical decision application, 
in compliance with the South African Protection of Personal Information Act (POPI) 
regulations. 
 
c. Data Sharing 
During study conduct, data access will be restricted to study. Upon completion of the 
study, in compliance with guidance by the study funders (U.S. National Institutes of 
Health), study data will be fully de-identified and posted to a public data repository 
where it may be shared with other scientists for secondary use. 
 
d. Specimen Collection and Testing 
A single blood specimen will be collected in this study at enrollment for renal function 
assessment to determine eligibility and help guide therapy. Participants will receive a 
point-of-care creatinine (Cr) using a lancet for finger-stick blood collection to evaluate 
renal function which can be used for study eligibility and initiation of certain therapies 
depending on normal renal function. No additional blood or specimens will be collected 
as part of the trial.  
 

58 
 
 
e. Data Monitoring and Quality Control 
Study data coordinators will perform routine reviews of data quality to identify unusual 
values and missing data entries. Initial analyses will include common exploratory data 
analyses, table construction, and scatterplots to assist in data quality control, 
randomization balance, and exploring for possible outliers. A data flow map will be 
developed to describe the process for data flow from the home to the nurses and the 
CDSS and back to the CBPMs and then back to the participant’s home in repeating 
cycles in Intervention (CBPM) and (eCBPM+). Additional checks will be in place for data 
coordinators to assess face validity of key indicators such as blood pressure 
measurements and medication prescriptions.  
 
I. Study Monitoring and Regulatory Oversight 
a. Staff Training 
i. Research Staff 
All research assistants will complete training through the CITI biomedical human 
subjects research course, a South Africa-based good clinical practice course, and/or a 
refresher course, as indicated. Only research staff fluent in the local languages (IsiZulu) 
will conduct informed consent and survey procedures. Study staff certified in 
phlebotomy will complete any blood collection procedures. Study staff will maintain 
active research ethics certification and attend any annual research ethics conferences 
as mandated by local policy at their institutions. 
 
ii. Provider Staff 
Prior to study initiation, nurses will complete a training to use the CDS and its treatment 
recommendations to manage hypertension using the current guidelines. CBPMs will be 
trained to understand hypertension as a condition, how to measure blood pressure 
using automated cuffs, retrieving recorded blood pressure measurements from the cuff 
memory, and educating patients about managing blood pressure symptoms and the 
importance of proper use of medication. The course will be designed and directed by 
study Co-Investigators Drs. Thomas Gaziano, Shafika Abrahams-Gessel and 
Nambulelo Magula and conducted at the study sites. 
 
 
b. Regulatory Oversight and Safety Monitoring 
Study protocols will be submitted for review to the University of KwaZulu-Natal 
Biomedical Research Ethics Committee and the Institutional Review Board of 
Massachusetts General Brigham. The protocol will also be submitted for registration at 
Clinicaltrials.gov. All protocol amendments, adverse events, unexpected events, and 
data monitoring review activities will also be submitted to each of these regulatory 
authorities per the guidelines. 
 
i. Safety Monitoring: 
The study co-principal investigators will be ultimately responsible for study conduct, 
safety, reporting, and interactions with regulatory authorities. Study PIs will ensure: 1) 
proper conduct of the informed consent process (e.g. that informed consent is obtained 
before proceeding with study procedures); 2) goal enrollment of study subjects; 3) 
adequate and high-quality collection and analysis of data; 4) the implementation of 
study procedures in accordance with study standard operating procedures in order to 
ensure monitoring of subjects for possible adverse events; 5) prompt review and 

59 
 
 
response to adverse and unexpected events, and reporting to IRBs; and 6) 
maintenance of the privacy and confidentiality of study subjects. The PIs will be in 
contact with the research team on a regular basis to review the progress of the study 
and address any human subject issues that occur. These discussions may involve 
adverse event prevention measures, recruiting of appropriate study subjects, research 
staff training on protection of human subjects, as well as occurrence of adverse events, 
unexpected incidents, or protocol problems.  
 
In compliance with National Institutes of Health policies, we will establish a formal Data 
and Safety Monitoring Board (DSMB) for study safety monitoring. The DSMB will meet 
after completion of the 6-month visit of 50% of study participants to conduct an 
unblinded assessment of study safety outcomes by arm, including adverse events and 
severe adverse events and present a formal letter to the study investigative team on 
recommendations to continue the study. The DSMB will be comprised of three clinical 
experts in epidemiology and/or hypertension care and will be guided by a DSMB charter 
signed by all members. Study data will be summarized by the study statisticians who 
will join the DSMB meetings as non-voting members. 
 
Finally, the study statistician and co-investigators will meet annually to perform the 
following  activities: a) review the research protocol and plans for data and safety 
monitoring; b) review progress of the trial, including analysis of data quality and 
timeliness; subject recruitment, randomization and retention; subject risk versus benefit; 
and other factors that may affect outcome. c) review serious and unexpected adverse 
event reports, provide commentary, and provide oversight to ensure that reports are 
relayed to individual IRBs; d) review proposed modifications to the study prior to their 
implementation.  
 
ii. Adverse and Unexpected Event Reporting: 
To identify adverse events: (1) study staff will perform a clinical review at each study 
visit and (2) study staff will instruct participants to report any unexpected or severe 
adverse events to their assigned research assistant. Such a report will immediately be 
brought to the attention of study principal investigators. Any adverse events that are 
unanticipated (i.e., not related to standard HTN clinical care or thought to be directly 
related to study procedures) or severe (e.g. death) will be recorded on an adverse 
events log form and brought to the attention of the principal Investigator, as well as be 
reported to participating ethical review committees within 7 days. The relevant 
committee will determine whether it is appropriate to pause the study or alter the study 
protocol and will provide suggestions/modifications to the study procedures as 
necessary. Possible modifications include adding adverse events to the consent form 
and re-consenting all study participants. The site principal investigator will be 
responsible for monitoring participant safety at each site on a monthly basis at regularly 
scheduled research meetings. They will keep a written log of all events and ensure that 
the ethical review committee is contacted when necessary. They will also keep a log of 
the outcome of committee decisions regarding adverse events and apprise the research 
team of any changes that need to occur as a result of such decisions. 
 
J. Statistical Considerations and Analyses 
a. Sample Size 
Based on prior studies we anticipate a mean blood pressure of 150/95 mmHg among 

61 
 
 
L. Aim 2 Analysis Plan 
We will summarize participant sociodemographic and clinical characteristics at baseline in all 
three arms. We will use linear regression to estimate the difference between arms, and its 95% 
confidence interval (CI), in systolic blood pressure at 6 months, adjusted for baseline systolic 
BP.  We will use logistic regression to estimate odds ratios (OR) and 95% CIs for the impact of 
the intervention on the proportion of participants who achieve blood pressure control (<140/90) 
at 6 months.   
 
Characteristics of individuals who are lost to follow-up will be tabulated by study arm.  Since 
study nurses will visit all participants at home to measure blood pressure at 6 and 12 months, 
we do not expect there to be differential loss to follow-up between arms.  In the primary 
analyses, participants with missing data at 6 months will be excluded. In sensitivity analyses, 
those with missing measurements will be considered to have no change in systolic BP and 
uncontrolled BP.  Missing values may also be imputed using multiple imputation. 
 
In pre-planned secondary analyses, we will fit regression models stratified by sex (to assess 
for sex as a biologic variable), age strata, socioeconomic status and baseline co-morbidities 
(i.e. obesity and HIV) to determine sub-group effect sizes and test the significance of an 
interaction term between sub-groups and the intervention to assess for effect modification. 
 
A detailed statistical analysis plan will be prepared before the data are examined by treatment 
arm. 
 
M. Risks, Protection from Risks and Benefits to Study Participation in Aim 2 
a. Risks and Protections 
One risk to participation is breach of confidentiality. Study staff will be trained in 
confidentiality and all staff members will be required to sign confidentiality agreements. 
Assurance of privacy in testing and communication of results will be done. Quality 
assurance processes will include regular support/supervision visits in the field and self-
evaluations in this study. To ensure confidentiality of participants, all data will be coded by 
subject number. Data recorded on paper will be kept in locked cabinets with access only 
by members of the research team. There will be strict limited access to electronically 
stored data as well, using password protection. Research records will be kept confidential 
following national regulations. The subject’s name or other personal identifiers will not be 
included with specimens sent to the laboratory, which will be identified only by a code 
number. Interviewers and support staff will be trained on procedures for maintaining 
confidentiality. 
We will conduct a single specimen collection during this study to conduct point of care 
creatinine testing that will be administered by trained study staff. A trained nurse will 
collect blood from a pin prick using standard precautions requiring a few drops of blood (< 
1ml) to be drawn.  
Study participants in both the SOC and intervention arms with uncontrolled hypertension 
will receive one of four blood pressure medications on the South African Essential 
Medication list according to the local guidelines including: hydrochlorothiazide, enalapril 
or other angiotensin converting enzyme inhibitor, amlodipine, or a beta-blocker. No 
experimental medications will be used. Participants will be followed for side-effects in 
accordance with the South African hypertension guidelines by the nurses and the 
CBPMs. All participants who experience any adverse event will receive follow-up until 
adverse event is resolved by the local study staff. Severe and serious adverse events will 

62 
 
 
be documented and reported to the involved regulatory bodies per their regulations. 
A secondary risk of participation in this Aim is loss of time from participation in interviews 
and/or discomfort with the questions asked or nature of the conversations. All 
participation will be voluntary and participants will be free to pause, interrupt, or not 
respond to any questions or content areas that make them uncomfortable. 
Participants in the CBPM and eCBPM+ arms of the study have a risk of receiving less 
than the standard of care by not attending the clinic, particularly if data from the home 
blood pressure cuffs are not being transmitted manually or automatically to the clinical 
decision support system. Protections will be in place such that the nurses who remain the 
backbone of hypertension care in all intervention and control clinics will have the ability to 
communicate with the CBPM to ensure a) blood pressure data is transmitted properly or 
faulty equipment is repaired or replaced, b) prescriptions are available for patients or 
delivered as allowed, or c) communicate through the CBPMs so that the participant can 
come in for a visit or make a home visit to ensure that care consistent with guidelines is 
available to all participants.  
b. Benefits 
Participants may lead to a reduction in their blood press level and overall improved blood 
pressure control. Participants in the intervention arm may develop proficiency in 
managing their own blood pressure and learning about the operation of a home blood 
pressure device.  
Participants may gain a better understanding of their cardiovascular risk profile. Any 
identified with having advanced renal disease may be referred for additional care and 
therapy. 
Some participants might gain a personal sense of pride from knowing they are 
contributing to development of a system that intends to improve hypertension care in their 
community, or for the opportunity to contribute to its design. 
If one of the interventions is ultimately successful, this study might provide a benefit to the 
community by helping to guide development of an improvement system of hypertension 
care. 
A financial incentive of R450 will be paid to participants for participation in the clinical trial. 
An incentive of R150 will be given after each study visit at baseline, month 6 and month 
12. These incentives are consistent with current SAHPRA recommendations.  
 
 
 

63 
 
 
VI. AIM 3 
Determine the fidelity, sustainability, acceptability, and cost-effectiveness of community-based, 
technology-supported hypertension interventions to reduce blood pressure in rural KwaZulu-
Natal.   
 
Aim 3 will have two primary components:  
(3a) Building on the qualitative research conducted before and early in the trial, we will conduct 
additional qualitative research to assess the acceptability of the interventions and quantitative 
monitoring of implementation throughout the trial to assess fidelity and sustainability. 
 
(3b) We will record the costs of care and of the interventions and determine the cost-
effectiveness of the intervention with microsimulation model (CVD PREDICT) that uses 
individual-level risk factor data and health cost inputs. 
 
A. Methods 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
The use of the CMIR and TFA (Aim 1) will be extended to evaluate the overall acceptability, 
fidelity, and sustainability of the intervention.  
 
Approximately 12 months after the start of the trial we will conduct key informants 
interviews and individual interviews with health workers and trial participants. Where 
appropriate we will include the same individuals sampled for Aim 1, to compare their 
experiences during the trial with their initial expectations and preferences. Qualitative data 
collection and analysis will be similar to Aim 1 methods, adapted as necessary to 
accommodate unforeseen issues that arise during the trial.  
 
Study documentation (e.g. coordination meeting minutes, supervision visit reports) will be 
reviewed to extract any relevant information contributing to document adaptations to 
implementation, and thereby fidelity, decision-making process and thereby acceptability 
(and feasibility), and short-term sustainability. 
 
These qualitative data will be complemented by collection of quantitative indicators of 
fidelity and sustainability of implementation. An assessment of the intervention’s fidelity will 
be performed 6 and 12 months after study enrollment (based on monthly data collection), 
while sustainability will be measured at the 12-month, 18-month, and 24-month visits. Data 
will be collected through repeated completion of intervention fidelity clinic checklists to 
estimate adherence, exposure, and quality of the intervention.  
 
b. (Aim 3b) Cost-effectiveness 
Cost-effectiveness of the intervention compared to standard of care in blood pressure 
management, will be calculated as incremental costs for absolute changes in blood 
pressure (costs/mmHg) and incremental costs per extra participant with controlled blood 
pressure. The Harvard CVD PREDICT microsimulation model for cost-effectiveness and 
changes in CVD-related health outcomes will be used to conduct this analysis. The cost-
effectiveness will be calculated across the entire intervention, as well as separately by each 
of the study arms.  
 
 

64 
 
 
B. Study Outcomes 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
Study outcomes measuring acceptability, fidelity, and sustainability of the intervention 
are summarized below in Table 4.  
c. (Aim 3b) Cost-effectiveness 
• Costs to participants of health care including (where applicable) the interventions 
• SBP reduction and blood pressure control resulting from the interventions 
• Quality adjusted life years (QALYs) 
• Incremental cost-effectiveness ratios (ICERs), that is, incremental cost per mmHg 
SBP reduction, per extra participant with controlled blood pressure, and per QALY 
gained as effects of the interventions 
 
 
 
 
 
 

 
66 
 
 
C. Data Sources  
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
Both the fidelity and the sustainability of the intervention will be assessed using data 
obtained through review of study check lists, the participant study records (including 
prescriptions), CDS records, CBPM study records, outreach team leader supervision 
records, and coordination meeting minutes.  
Key informant and individual interviews will assess overall acceptability and experience of 
the intervention.  
 
b. (Aim 3b) Cost-effectiveness 
Cost data will be obtained from trial participant interviews, KZN DoH unit prices, and 
analysis of intervention delivery.  
 
The trial will provide individual level outcome data on SBP and blood pressure control 6 
and 12 months. The PREDICT model will use these data to predict long term effects of the 
interventions on quality adjusted life years (QALYs) 
 
D. Recruitment 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
As appropriate, for key informants and individual interviews, we will try to recruit from the 
same sample used in Aim 1 in order obtain maximal information about changes in 
expectations and experiences before and after the trial. Key informants will be identified 
and contacted by study investigators at AHRI from current and prior collaborators working 
on improving health care in this rural population. Health care workers will be identified from 
personnel records at the study clinics and be invited to participate in interviews by study 
investigators. Participants will be identified from clinic registers for hypertensive patients.  
 
b. (Aim 3b) Cost-effectiveness 
Participants will not be enrolled for this part of Aim 3 and cost data will be obtained as 
described in Section C(b) above.  
 
E. Enrollment  
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
i. Inclusion Criteria for Key Informants  
• age 18 and over.  
• representative of the KZN DoH for involved in management of primary care 
delivery programs. 
 
ii. Inclusion Criteria for Health Care Workers  
• age 18 and over.  
• currently employed as a health care worker (physician, nurse, CHW, pharmacist, 
clinic administrator/operational manager) at one of the study clinics. 
 
iii. Inclusion Criteria for Participants  
• age 18 and over.  
• diagnosed with uncontrolled hypertension. 
• selection based on pre-defined criteria such as age, gender, trial arm, patients 
accepting/refusing the intervention. 

 
67 
 
 
 
b. (Aim 3b) Cost-effectiveness 
Not applicable  
 
F. Sample Size  
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
• Key informants interviews: minimum 5 
• Interviews with professional health care workers: minimum 15 (3 per facility), 
• including chronic nurse, OM, nurse “supervising” CHW, doctors (supervisory role) 
• Interviews with CHW (minimum 3 per clinic) 
• Interviews with patients: minimum 15 
 
b. (Aim 3b) Cost-effectiveness 
All trial participants will be included in analysis of costs and cost effectiveness.  
 
G. Informed Consent 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
As in Aim 1, key informant discussants will be invited to participate in discussions about 
the planned study and their participation in meetings will be taken as consent to 
participate.  
Study research assistants will recruit participants enrolled in the study and health care 
workers to participate in the focus groups.  
 
Persons who participated in Aim 1 activities and who will participate in Aim 3 activities, 
will be reconsented regardless of whether they provided verbal or written consent in Aim 
1. Consenting procedures for Aim 3 will be identical to those described in Aim 1.  
 
b. (Aim 3b) Cost-effectiveness 
This will be included in the consent to participate in the trial.  
 
H. Data Collection 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
Data on fidelity outcomes will be obtained from study checklists and data collected with 
the electronic hypertension management tool in the intervention arms at 6,12, 18 and 24 
months. Sustainability measures, including changes in systolic blood pressure, will be 
collected using the same sources at 12 months in the intervention arms. In the standard 
of care arm changes in systolic blood pressure at 12 months and medication use will be 
obtained through participant chart reviews. All data will be combined into a database for 
analyses and all personal identifiers will be removed prior to analysis. Interviewers will 
use guides with open-ended questions to collect qualitative data on the overall 
acceptability of the intervention. 
 
b. (Aim 3b) Cost-effectiveness 
Resource allocation assessments in all three study arms will be conducted at 6 and 12 
months after the start of the trial using a time and motion study over five clinic days, along 
with medical records reviews and participant exit interviews. Using these measurements, 
the public-sector unit costs for managing hypertension will be calculated, including human 
resources, diagnostics and supplies, therapeutics, and home blood pressure monitors. 
Costs will be collected from relevant sources, including clinic sites, the South African 

 
68 
 
 
Department of Health, and published reports. A societal perspective will be applied to 
data collection and analysis. 
 
I. Analysis 
a. (Aim 3a) Fidelity, Sustainability, and Acceptability 
Quantitative data will be analyzed using Stata Statistical Software (Release 17. College 
Station, TX) and statistics for fidelity and sustainability outcomes will be generated.  
Qualitative data analysis will be performed using similar methods as in Aim 1. The key 
informants and individual interviews will be collected in isiZulu, then transcribed, and 
translated in English by a team of social science research assistants. A data-led coding 
framework will be developed, based on themes, which emerge from the data. The 
research assistants involved in collecting the data will work with other social science team 
members to agree on the coding framework and performing coding of the data. Thematic 
summaries will be prepared using the data and a process of building consensus among 
the whole study team. These summaries will form the building blocks for reporting the 
findings.  Organization of data on the acceptability of the intervention will again be 
organized into component constructs using the Theoretical Framework for Acceptability, 
as described in Aim 1.  
 
b. (3b) Cost and Cost-effectiveness 
Cost-effectiveness of the intervention compared to standard of care in blood pressure 
management, will be calculated as incremental costs for absolute differences in blood 
pressure (costs/mmHg) and incremental costs per extra participant with controlled blood 
pressure. This analysis will be performed using the Harvard CVD PREDICT model [15] for 
cost-effectiveness and changes in CVD-related health outcomes. The model will be used 
to assess the cost-effectiveness of the intervention and to model the impact on the 
observed change in systolic blood pressure on future CVD events. We will also use the 
model to translate the intervention effectiveness established during the trial into quality 
adjusted life years (QALY) and applying assumptions about effects of SBP reductions on 
survival, quality of life, and complications, based on the extant literature and confirmed 
locally as part of this trial.  
 
The cost-effectiveness will be calculated across the entire intervention, as well as 
separately by each of the study arms and expressed in incremental cost-effectiveness 
ratios (ICERs) and quality adjusted life years (QALYs).  
 
If there is a significant reduction in SBP, we will measure the long term expected 
reductions in major cardiovascular events and mortality in the population beyond the 
study period, and for a nationally scaled population. For these predictive cost-
effectiveness analyses, we will assess the costs and cost-effectiveness of the 
intervention modeling the impact on the change in SBP on future CVD events. 
 
Health-related quality of life is measured using the time trade off approach for a reference 
population in sub-Saharan Africa as adopted in similar cost-effectiveness analyses. We 
will  conduct probabilistic sensitivity analysis by defining probability distributions of 
variables in the model used to calculate the costs and effectiveness. 
 
We will develop the cost-utility model using best practices outlined by the ISPOR Good 
Research Practice Task Force [16-19] and guidelines set out by the US Second Panel on 

 
69 
 
 
Cost-Effectiveness in Health and Medicine. 
 
J. Risks, Protection from Risks and Benefits to Study Participation in Aim 3a and 3b 
a. Risks and Protections 
i. The primary risk to participation is breach of confidentiality. We will not record names of 
any individuals taking part in interviews, now will we report them in findings to be 
disseminated as part of this project. Given the low number of people in the study and the 
identification of participants (e.g., stakeholders in the Department of Health) it is possible 
that their identities could be inferred and we will make this risk clear during the consenting 
process. 
ii. A secondary risk of participation in in this aim is loss of time from participation in 
interviews and/or discomfort with the questions asked or nature of the conversations. All 
participation will be voluntary and participants will be free to pause, interrupt, or not 
respond to any questions or content areas that make them uncomfortable. 
b. Benefits 
i. Most study participants in Aim 3 will derive no direct benefit from participation in the 
study. 
ii. Some participants might gain a personal sense of pride from knowing they are 
contributing to development of a system that intends to improve hypertension care in 
their community, or for the opportunity to contribute to its design. 
iii. If one of the interventions is ultimately successful, this study might provide a benefit to 
the community by helping to guide development of an improvement system of 
hypertension care. 
iv. The cost-effectiveness analysis will provide insight for policy makers into whether the 
proposed interventions is a good use of health care resources for reducing the disease 
burden of uncontrolled hypertension substantially in the new community based primary 
care model.  
v. A financial incentive of R50 of airtime (telephonic), R50 in cash (in-person), or a R50 
food voucher will be provided to participants for their participation in discussion groups 
and interviews, subject to COVID-19 restrictions in place.  
 
 

 
 
70 
 
 
VIII. 
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72 
 
Summary of Research Protocol Changes 
 
Initial Protocol Date: November 1, 2021 
Final Protocol Date: February 15, 2024 
 
Pre-trial protocol changes 
• June 25, 2022: Inclusion criteria expanded to restrict enrollment to residents 
living in an area served by a community health worker. 
• June 25, 2022: Screening procedures updated to ensure persons who declined 
a pregnancy test or point-of-care creatinine test would not be enrolled. 
• June 25, 2022: Clarified that individuals who completed Aim 1 patient focus 
groups would be allowed enrolled me if they met criteria for the clinical trial 
• June 25, 2022: Financial incentives updated to be R150 per specified study 
follow-up home visits (R450 for completion of all three study visits) to align with 
South Africa Health Products Regulatory Authority 
• August 15, 2022: The trial was registered on ClinicalTrials.gov, as required by 
the NIH (NCT05492955). 
• November 13, 2022: The trial was registered in the South African National 
Clinical Trial Registry, as required by the National Department of Health (DOH-
27-112022-4895). 
 
Intra- and post-trial protocol changes 
• January 18, 2023: At the request of the funder, the protocol was updated to add 
a data safety and monitoring board (DSMB) to the previously planned data 
safety and monitoring plan, to conduct an independent safety review after 50% 
of enrollment was complete. 
• January 18, 2023: The term community health worker (CHW) was replaced with 
community blood pressure monitor (CBPM) in the protocol and in the 
participant informed consent form for the clinical trial (Aim 2), as recommended 
by the local department of health. 
• January 18, 2023: The participant informed consent forms were updated to 
reflect South African requirements around protection of personal information 
(South African POPI Act). 
• May 29, 2024: After consultation with the Department of Health, a prolonged 
extension stage was offered to participants in the intervention arms after the 
12-month study completion visit. This allowed them to consent to continue in 
the hypertension control program until study completion in June 2025. 
Individuals who declined continuation were referred back to primary care clinics 
for routine care.