Community-based, eHealth Supported Management of Cardiovascular Risk Factors by Lay Village Health Workers for People With Controlled and Uncontrolled Arterial Hypertension in Rural Lesotho: Joint Protocol for Two Cluster-randomized Trials Within the ComBaCaL Cohort Study (ComBaCaL aHT TwiC 1 & ComBaCaL aHT TwiC 2)
Phase: NA
Conditions: Arterial Hypertension
Sponsor: University Hospital, Basel, Switzerland

ComBaCaL aHT TwiC 1 & aHT TwiC 2 
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Study Protocol 
 
 
Community-based, eHealth supported management of cardio-vascular risk-
factors by lay village health workers for people with controlled and 
uncontrolled arterial hypertension in rural Lesotho 
 
Joint protocol for two cluster-randomized trials within the ComBaCaL 
cohort study (ComBaCaL aHT TwiC 1 & ComBaCaL aHT TwiC 2) 
 
 
 
Type of Research 
Project 
Research project involving collection of health-related data from 
persons 
  
Study acronym/ID 
ComBaCaL aHT TwiC 1 & aHT TwiC 2 
Protocol Version Nr 
1.1 
Date 
07.02.2023 
Project Leaders / 
Responsible 
Prof. Dr. Niklaus Labhardt, MD, DTM&H, MIH
Head Division of Clinical Epidemiology  
University Hospital Basel  
Totengaesslein 3, 4051 Basel, Switzerland 
+4179 870 18 59 
niklaus.labhardt@usb.ch 
 
Dr. Dr. Alain Amstutz MD, PhD 
Post-doctoral researcher 
University Hospital Basel  
Totengaesslein 3, 4051 Basel, Switzerland 
+4179 489 94 48 
alain.amstutz@unibas.ch 
Funding Agency 
Swiss Development Cooperation, World Diabetes Foundation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 GENERAL INFORMATION 
 
1.1 
List of Project Leaders and other key persons involved in the study 
 
 
Title 
Names 
Institution 
Position 
Function in study
Prof. Dr. 
DTM&H, 
MIH 
Labhardt Niklaus 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Division Head 
Co-Principal 
Investigator 
MD/PhD 
Amstutz Alain 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
Post-Doctoral 
Researcher 
Co-Principal 
Investigator 
MD/PhD 
Irene Ayakaka 
Solidarmed Lesotho 
Technical 
Director 
National Project 
Leader 
BSN 
Madavida 
Mphunyane 
NCD Program MoH 
Program 
Manager 
Steering 
Committee 
Member 
MBBS, MPH 
Ravi Gupta 
SolidarMed Lesotho 
Project 
Manager 
Project Manager, 
Study physician 
MIH 
Lejone Thabo 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
PhD Student 
Co-Investigator 
PhD 
Chammartin 
Frédérique 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Scientific 
Collaborator 
Statistician 
M Med 
Gerber Felix 
University of Basel, 
University Hospital Basel 
PhD Student 
Investigator 
MBBS, 
FAMMED 
Mamakhala 
Chitja 
SolidarMed Lesotho 
NCD 
Technical 
Advisor 
Co-Investigator, 
study physician 
 
 
The project leaders are qualified individuals by education and training and responsible for the 
whole project. All further key persons are also qualified by education and training to perform their 
assigned tasks and responsibilities. 
 
 
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1.2 
Signatures 
 
Study Title: “Community-based, eHealth supported management of cardiovascular risk factors by lay 
village health workers for people with controlled and uncontrolled arterial hypertension in rural Lesotho: 
Joint protocol for two cluster-randomized trials within the ComBaCaL cohort study (ComBaCaL aHT TwiC 
1 & ComBaCaL aHT TwiC 2)” 
 
The following project leaders have approved the protocol version 1.1, dated 07.02.2023, and confirm hereby to 
conduct the project according to the current version of the Declaration of Helsinki as well as all national 
legal requirements and guidelines as applicable.  
 
 
Principal Investigators: 
x 
I have read this protocol version 1.1, dated 07.02.2023, and agree that it contains all necessary 
details for carrying out this study. I will conduct the study as outlined herein and will complete 
the study within the time designated. 
x 
I will ensure that all individuals and parties contributing to this study are qualified and I will 
implement procedures to ensure integrity of study tasks and data. 
x 
I will provide copies of the protocol and all pertinent information to all individuals responsible 
to me who assist in the conduct of this study. I will discuss this material with them to ensure 
they are fully informed and trained regarding their activities within the study conduct. 
x 
I will use only approved informed consent forms and will fulfil all responsibilities for submitting 
pertinent information to the Independent Ethics Committees responsible for this study. 
x 
It is understood that this protocol will not be disclosed to others without prior written 
authorisation from the Project Leader or Sponsor, except where required by applicable local laws 
 
 
Principal Investigators 
Signature 
 
 
 
 
Name  
Niklaus Labhardt 
Date of Signature  
Title 
Prof. Dr. DTM&H, MIH 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel
Address 
Totengaesslein 3, 4051 Basel
Phone 
+41 79 870 18 59 
 
Signature 
 
 
 
 
Name  
Alain Amstutz 
Date of Signature  
Title 
MD/PhD 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel 
Address 
Totengaesslein 3, 4051 Basel 
Phone 
+41 79 489 94 48 
 
 
 
 
 
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National Principal Investigator 
Signature 
 
 
 
 
Name  
Irene Ayakaka 
Date of Signature 
Title 
MD/PhD 
Institution 
Solidarmed Lesotho 
Address 
Premium House 224, Kingsway, Maseru West
Phone 
+266 28325172 
 
 
Statistician 
Signature 
 
 
 
 
Name  
Frédérique Chammartin 
Date of Signature 
Title 
PhD 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel 
Address 
Totengaesslein 3, 4051 Basel
Phone 
 
 
 
Investigator 
Signature 
 
 
 
 
Name  
Felix Gerber 
Date of Signature  
Title 
M Med 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel 
Address 
Totengaesslein 3, 4051 Basel
Phone 
+41 78 704 08 85 
 
 
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Table of contents 
 
1 
General Information 
2 
1.1 
List of Project Leaders and other key persons involved in the study ........................................................................... 2 
1.2 
Signatures .............................................................................................................................................................. 3 
1.3 
Abbreviations / Glossary of terms ............................................................................................................................ 7 
2 
Synopsis 
8 
3 
Background information 
16 
3.1 
Burden of arterial hypertension .............................................................................................................................. 16 
3.2 
Decentralized healthcare delivery .......................................................................................................................... 16 
4 
Objectives and purpose 
18 
4.1 
Objectives ............................................................................................................................................................ 18 
4.1.1 
Primary objective TwiC 1 
18 
4.1.2 
Primary objective TwiC 2 
18 
4.1.3 
Secondary objectives TwiC 1 & TwiC 2 
18 
4.1.4 
Exploratory and implementation objectives TwiC 1 & TwiC 2 
18 
4.2 
Scientific justification of study population ............................................................................................................... 19 
5 
Hypothesis 
20 
5.1 
Primary hypothesis TwiC 1 and primary estimand ................................................................................................... 20 
5.2 
Primary hypothesis TwiC 2 and primary estimand ................................................................................................... 20 
6 
Study design 
21 
6.1 
Endpoints ............................................................................................................................................................. 21 
6.1.1 
Primary endpoint TwiC 1 & TwiC 2 
21 
6.1.2 
Secondary endpoints TwiC 1 & TwiC 2 
21 
6.1.3 
Exploratory endpoints and implementation indicators 
21 
6.2 
Measures to minimize bias .................................................................................................................................... 22 
6.2.1 
Blinding 
22 
6.2.2 
Measurements 
22 
6.2.3 
Randomization 
22 
6.3 
Study duration and duration of participant’s participation ......................................................................................... 22 
6.4 
Amendments ........................................................................................................................................................ 22 
6.5 
Withdrawal and discontinuation ............................................................................................................................. 22 
6.5.1 
Individual level 
22 
6.5.2 
Study and cluster level 
23 
6.6 
End of trial ............................................................................................................................................................ 24 
7 
Selection of study participants 
25 
7.1 
Selection of villages .............................................................................................................................................. 25 
7.2 
Recruitment of participants .................................................................................................................................... 25 
7.2.1 
Inclusion criteria ComBaCaL-TwiC 1 
25 
7.2.2 
Inclusion criteria ComBaCaL-TwiC 2 
25 
7.2.3 
Exclusion criteria for both ComBaCaL-TwiC 1&2 
25 
8 
Study procedures 
26 
8.1 
General Setting..................................................................................................................................................... 26 
8.2 
Screening ............................................................................................................................................................. 26 
8.3 
Enrolment ............................................................................................................................................................. 26 
8.4 
Baseline ............................................................................................................................................................... 26 
8.5 
Intervention .......................................................................................................................................................... 28 
8.6 
Follow-up and endpoint assessment ...................................................................................................................... 28 
8.6.1 
Scheduled follow-up visits and endpoint assessments 
28 
8.6.2 
Clinical follow-up 
28 
8.7 
Schedule of events ............................................................................................................................................... 30 
9 
Safety considerations 
31 
9.1 
Definition and documentation of safety outcomes ................................................................................................... 31 
9.2 
Causality of SAEs and AESIs ................................................................................................................................ 32 
9.3 
Management of AEs .............................................................................................................................................. 32 
9.3.1 
Control villages 
32 
9.3.2 
Intervention villages 
32 
9.4 
Reporting ............................................................................................................................................................. 32 
10 
Statistics 
34 
10.1 Hypothesis ........................................................................................................................................................... 34 
10.2 Determination of sample size ................................................................................................................................. 34 
10.2.1 
aHT TwiC 1 
34 
10.2.2 
aHT TwiC 2 
35 
10.3 Description of statistical methods ........................................................................................................................... 36 
10.3.1 
Datasets to be analysed, analysis populations 
36 
10.3.2 
Primary analysis 
37 
10.3.2.1 
aHT TwiC 1 
37 
10.3.2.2 
aHT TwiC 2 
37 
10.3.3 
Secondary analysis 
37 
10.4 Handling of missing data ....................................................................................................................................... 37 
11 
Description of data management 
38 
12 
Quality control and quality assurance 
38 
13 
Ethical considerations 
39 
13.1 Independent Ethics Committees (IECs) .................................................................................................................. 39 
13.2 Risk-benefit ratio................................................................................................................................................... 39 
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13.3 Participant information and consent ....................................................................................................................... 39 
13.4 Participant confidentiality....................................................................................................................................... 41 
13.5 Participants requiring particular protection .............................................................................................................. 41 
13.6 Participant compensation ...................................................................................................................................... 41 
14 
Funding 
42 
15 
Dissemination of results and publication policy 
42 
15.1 Dissemination to scientific community .................................................................................................................... 42 
15.2 Information of community and policy makers .......................................................................................................... 42 
16 
Appendix 
43 
17 
References 
44 
 
 
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1.3 
Abbreviations / Glossary of terms 
 
AE 
Adverse event 
AESI 
Adverse event of special interest 
aHT 
Arterial hypertension 
BMI 
Body mass index 
BG 
Blood glucose 
BP 
Blood pressure 
CC-VHW 
Chronic care village health worker 
CC nurse 
Chronic care nurse 
cmRCT 
Cohort multiple randomized controlled trials 
ComBaCaL 
Community-Based Chronic Disease Care Lesotho 
CVD 
Cardiovascular disease 
CVDRF 
Cardiovascular disease risk factor 
DHMT 
District Health Management Team 
eCRF 
Electronic case report form 
EKNZ 
Ethics Committee of Northern and Central Switzerland 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICHOM 
International Consortium for Health Outcomes Measurement 
IEC 
Independent Ethics Committee 
IT 
Information technology 
ITT 
Intention-to-treat 
LHW 
Lay healthcare worker 
LMICs 
Low- and middle-income countries 
MoH 
Ministry of Health 
NCD 
Non-communicable disease 
NHREC 
National Health Research Ethics Council 
PP 
Per protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SPC 
Single-pill combination 
T2D 
Type 2 diabetes mellitus 
TwiC 
Trial within cohort 
VHW 
Village health worker 
WHO 
World Health Organization  
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2 SYNOPSIS 
 
Project 
Leaders 
Prof. Dr. Niklaus Labhardt
Dr. Dr. Alain Amstutz 
Study Title 
Community-based, eHealth supported management of cardiovascular risk 
factors by lay village health workers for people with controlled and 
uncontrolled arterial hypertension in rural Lesotho: Joint protocol for two 
cluster-randomized trials within the ComBaCaL cohort study (ComBaCaL aHT 
TwiC 1 & aHT TwiC 2) 
Short 
Title/Study ID 
ComBaCaL aHT TwiC 1 & aHT TwiC 2
Protocol 
Version and 
Date 
Version 1.1, 07.02.2023
Study 
Category with 
Rationale 
Implementation research trial
Risk category A 
Background 
and Rationale 
Globally, arterial hypertension (aHT) is the single most important risk factor 
for early mortality, accounting for 10.8 million or almost 20% of all deaths in 
20191. Low- and middle-income countries (LMICs) are bearing a 
disproportionally high, still increasing share of the aHT-related burden, while 
many high-income countries have managed to reduce aHT-related burden 
substantially over the past decades.1–4 Besides demographic changes and the 
increasing prevalence of lifestyle-related risk factors and resulting conditions, 
the inadequate health system response on preventive and therapeutic level 
is a major reason for the disproportionally high cardiovascular disease (CVD) 
burden in LMICs. In many LMICs health systems are poorly prepared to 
address the increasing burden caused by aHT and other non-communicable 
diseases (NCDs) resulting in massive treatment gaps, with only around 10% of 
people living with aHT in LMICs reaching treatment targets5. Effective, 
affordable, scalable setting-specific strategies are required for a reversal of 
this baleful trend.  Increasing the global coverage of antihypertensive 
medications alone has been estimated to delay around 40 million deaths over 
25 years6. 
The task-shifting from facility-based healthcare professionals to lay 
healthcare workers (LHWs) at community-level has been identified as a 
promising solution to increase access to aHT treatment in LMICs7. Many 
LMICs have established LHW systems focusing on maternal and neonatal 
health and on communicable diseases, especially HIV/AIDS.  However, in 
recent years, increasing evidence has emerged showing a beneficial effect 
and high cost-effectiveness of LHW-based models on diseases outside of this 
traditional scope, especially for NCDs, such as aHT or type 2 diabetes mellitus 
(T2D). For aHT, most studies about LHW-led care models have focused on 
screening, counselling and referral interventions.7–12   
Independent of LHW involvement, sound evidence supports the use of simple 
aHT treatment protocols across different provider levels that include the 
prescription of single-pill combinations (SPCs) to reduce pill burden for 
patients and thereby promote adherence.13 
Current knowledge gaps include the question of whether prescription of first-
line SPCs can be included safely and effectively in LHW-led aHT care models 
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at community-level complementing the screening, counselling and referral 
services for which benefit has been shown already. Furthermore, evidence of 
whether and how community-based aHT care models could be adapted and 
successfully implemented in sub-Saharan Africa is very limited14 as the recent 
landmark trials have been conducted in other parts of the world.8,11,15  
Building on this knowledge and addressing the mentioned gaps, we are 
planning to conduct a cluster-randomized intervention within the ComBaCaL 
(Community-Based Chronic disease care Lesotho) cohort study (EKNZ ID 
2022-00058, NH-REC ID 210-2022, clinicaltrials.gov ID NCT05596773), a 
platform for the investigation of chronic diseases and their management in 
rural Lesotho that is maintained by local chronic care village health workers 
(CC-VHWs). CC-VHWs are lay healthcare workers operating within the 
Lesotho Ministry of Health (MoH) Village Health Worker Program who receive 
a specific training to deliver chronic care services. The here-described 
intervention has been developed based on a local NCD prevalence survey and 
burden assessment (NH-REC ID 130-2021), a scoping literature review14, 
multiple workshops with different stakeholders in Lesotho and the ComBaCaL 
pilot cohort study (NH-REC ID 176-2021). In the intervention clusters, CC-
VHWs operating within the existing healthcare system will be capacitated to 
screen for and diagnose aHT, to prescribe first-line antihypertensive SPCs for 
eligible participants and to monitor antihypertensive treatment supported by 
a tailored clinical decision support application (ComBaCaL app) in their 
villages. The control group consists of people diagnosed with aHT living in 
villages that are also part of the ComBaCaL cohort but not sampled for the 
intervention (control villages), where CC-VHWs will only screen for and 
diagnose aHT with subsequent standardized counselling and referral to the 
closest health facility if aHT is present, but no village-based prescriptions or 
treatment monitoring and support. 
We are planning to assess the effectiveness of this intervention in two 
different trial populations: On the one hand in people with uncomplicated but 
aHT and BP values above treatment target (≥ 140/90 mmHg) at baseline (aHT 
TwiC 1), and on the other hand in people with uncomplicated aHT and BP 
values below treatment target at baseline (aHT TwiC 2). We hypothesize that 
the ComBaCaL model of care is superior in ComBaCaL TwiC 1 and non-inferior 
in ComBaCaL TwiC 2. Randomization for the two TwiCs will be done at cluster 
level, meaning that all people with aHT in one village will be offered the same 
care package from their local CC-VHW.  
Objectives 
Primary objective aHT TwiC 1
x 
To assess the effectiveness of offering community-based, CC-VHW-led, 
eHealth supported aHT care including the prescription of first-line 
antihypertensive SPCs for eligible participants in people with 
uncontrolled aHT (newly diagnosed or receiving treatment without 
reaching treatment targets (≥140/90 mmHg)) in rural Lesotho 
 
Primary objective aHT TwiC 2 
x 
To assess the effectiveness of offering community-based, CC-VHW-led, 
eHealth supported aHT care including the prescription of first-line 
antihypertensive SPCs for eligible participant in people with controlled 
aHT (receiving treatment at baseline and reaching treatment targets 
(<140/90 mmHg)) in rural Lesotho 
 
 
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Secondary objectives aHT TwiC 1 & aHT TwiC 2 
x 
Key secondary objective: To assess the effect of CC-VHW led, eHealth 
supported aHT care on 10-year CVD risk using the WHO CVD risk 
prediction tool16 
x 
To assess the effect of CC-VHW led, eHealth supported counselling on 
CVD risk factors including body-mass index (BMI), abdominal 
circumference, blood lipid status, tobacco use, physical activity and 
dietary habits 
x 
To assess the safety of CC-VHW led, eHealth supported prescription of 
first-line antihypertensive SPCs for people with controlled / uncontrolled 
aHT 
x 
To assess the effect of CC-VHW led, eHealth supported prescription of 
first-line antihypertensive SPCs for people with controlled / uncontrolled 
aHT on linkage and engagement in care and on adherence to treatment 
Hypotheses 
and estimands 
aHT TwiC 1 
x 
Primary hypothesis: Community-based, CC-VHW-led, eHealth supported 
aHT care including the prescription of first-line antihypertensive SPCs for 
eligible participants is safe and superior with regard to BP control rates 
after twelve months compared to facility-based aHT care  in people living 
with uncontrolled aHT in rural Lesotho 
x 
Primary estimand: Difference in the proportion of participants with a 
documented measurement of controlled aHT (BP <140/90 mmHg) in the 
primary endpoint window (12 months after enrolment) between 
community-based, CC-VHW-led, eHealth supported aHT care versus 
facility-based aHT care, in non-pregnant adults with uncontrolled aHT 
(BP ≥140/90 mmHg at baseline), who did not experience a traumatic 
death and did not move out of their village, irrespective of the uptake of 
the intervention, aHT treatment, aHT treatment adherence and adverse 
events. 
aHT TwiC 2 
x 
Primary hypothesis: Community-based, CC-VHW-led, eHealth supported 
aHT care including the prescription of first-line antihypertensive SPCs for 
eligible participants is safe and non-inferior with regard to BP control 
rates after twelve months compared to facility-based aHT care  in people 
living with controlled aHT in rural Lesotho 
x 
Primary estimand: Difference in the proportion of participants with a 
documented measurement of controlled aHT (BP <140/90 mmHg) in the 
primary endpoint window (12 months after enrolment) between 
community-based, CC-VHW-led, eHealth supported aHT care versus 
facility-based aHT care, in non-pregnant adults with controlled aHT (BP 
<140/90 mmHg at baseline), who did not experience a traumatic death 
and did not move out of their village, irrespective of the uptake of the 
intervention, aHT treatment, aHT treatment adherence and adverse 
events. 
Endpoints 
Primary endpoint aHT TwiC 1 & aHT TwiC 2
x 
Proportion of participants whose blood pressure (BP) is within target 
(<140/90 mmHg) twelve months after enrolment 
 
 
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Secondary endpoints aHT TwiC 1 & aHT TwiC 2
x 
Key secondary endpoint: 10-year CVD risk estimated using the WHO 
CVD risk prediction tool16,17 six and twelve months after enrolment 
x 
CVD risk factors, such as smoking status, BMI, abdominal 
circumference, blood lipid status, dietary habits and physical activity 
six and twelve months after enrolment 
x 
Proportion of participants whose BP is within target (<140/90mmHg) 
six months after enrolment 
x 
Mean systolic (SBP) and diastolic (DBP) BP six and twelve months after 
enrolment  
x 
Linkage to care: proportion of participants not taking treatment at 
enrolment who have initiated pharmacological antihypertensive 
treatment six and twelve months after enrolment 
x 
Engagement in care: proportion of participants who are engaged in 
care, defined as reporting intake of antihypertensive medication as 
per prescription of a healthcare provider (CC-VHW or healthcare 
professional) six and twelve months after enrolment or reaching 
treatment targets without intake of medication 
x 
Self-reported adherence to antihypertensive medication and lifestyle 
advices 
x 
Occurrence of Serious Adverse Events (SAEs) and Adverse Events of 
Special Interest (AESIs) within six and twelve months after enrolment
Intervention 
CC-VHWs are providing screening, diagnosis, first-line antihypertensive
treatment for eligible participants and treatment monitoring and support at 
community-level. CC-VHWs are equipped with a tablet where a dedicated 
application, the ComBaCaL app, guides them to provide first-line 
antihypertensive SPCs to eligible individuals and treatment monitoring and 
support to all individuals found to have aHT. In addition, the CC-VHW offers 
enhanced lifestyle counselling, lipid-lowering treatment (statin) to 
participants with a high CVD risk and antiplatelet treatment (aspirin) to 
participants with a history of stroke or myocardial infarction. Appropriately 
trained, supervised and mentored by chronic care nurses (CC nurses) and 
guided by the ComBaCaL app they will follow-up persons with aHT to monitor 
adherence, life-style changes, treatment response and side-effects. 
Control 
Control villages will follow the standard of care in the ComBaCaL cohort study. 
CC-VHWs will also receive tablets with the ComBaCaL app installed. They are 
trained, supervised and equipped to screen and diagnose aHT with 
subsequent referral to facility-based follow-up and care. In control villages 
the ComBaCaL app supports clinical decision making and documentation for 
screening, diagnosis and referral, but not prescription/provision of 
antihypertensive or lipid-lowering medication. 
Study Design 
ComBaCaL aHT TwiC 1 and aHT TwiC 2 are two cluster-randomized controlled 
trials that are identical in intervention, design and endpoints. They only differ 
in the trial population and trial hypothesis. TwiC 1 enrols individuals with 
uncomplicated aHT with baseline BP values above treatment targets and the 
hypothesis is that in intervention clusters where community-based treatment 
is offered, a higher proportion will have controlled aHT at twelve months’ 
follow-up as compared to control clusters where participants are referred to 
the facility for further care after diagnosis. TwiC 2 enrols individuals with 
uncomplicated pharmacologically controlled aHT with the hypothesis that the 
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offer of community-based antihypertensive treatment is non-inferior to 
facility-based care with regard to BP control rates at twelve months. The trials 
are nested within the ComBaCaL cohort study following a cohort multiple RCT 
(cmRCT) or trial within cohort (TwiC) approach18,19. 50% of the villages being 
part of the overarching ComBaCaL cohort will be randomly allocated to 
receive the TwiC intervention. The non-selected villages will serve as 
comparators and follow the regular ComBaCaL cohort activities conducted by 
CC-VHWs, including screening, diagnosis, standardized counselling and 
referral to a health facility for further therapeutic management. The TwiC 
intervention will be offered to all eligible people living with aHT in the 
sampled intervention villages. Individuals with uncomplicated uncontrolled 
and uncomplicated controlled aHT at baseline will be enrolled in aHT TwiC 1 
and aHT 2 respectively.  
Eligibility 
criteria 
The two trial populations are mutually exclusive and together constitute the 
overall intervention population, thus every intervention-eligible participant is 
either allocated to aHT TwiC 1 or 2. 
Inclusion criteria aHT TwiC 1 
- 
Participant of the ComBaCaL cohort study (signed informed consent 
available) 
- 
Aged 18 years or above 
- 
Living with aHT, defined as reporting intake of antihypertensive 
medication or being newly diagnosed during screening via 
standardized diagnostic algorithm (see appendix of the “ComBaCaL 
cohort study protocol”)  
- 
BP ≥140/90 mmHg at baseline 
 
Inclusion criteria aHT TwiC 2 
- 
Participant of the ComBaCaL cohort study (signed informed consent 
available) 
- 
Aged 18 years or above 
- 
Reporting intake of antihypertensive medication 
- 
BP<140/90 mmHg at baseline 
Exclusion criteria aHT TwiC 1&2 
- 
Reported pregnancy (at baseline or during follow-up)  
Measurements 
and 
Procedures 
For both TwiCs, screening, enrolment and baseline assessments will be 
conducted by CC-VHWs at community-level. We refer to the current version 
the “ComBaCaL cohort study protocol” for detailed information about the 
cohort set-up and procedures. In brief, CC-VHWs screen for and diagnose aHT 
using automated BP machines, based on standardized algorithms encoded in 
the tablet-based ComBaCaL app. In villages not allocated to the TwiC 
intervention (control villages), participants diagnosed with aHT receive a 
standardized counselling by the CC-VHW and are referred to the closest 
health facility for initiation or continuation of antihypertensive treatment.  
In the randomly selected intervention villages, eligible participants diagnosed 
with aHT will be offered pharmacological first-line treatment and all 
participants will be offered lifestyle counselling and treatment monitoring 
and support in the villages by CC-VHWs guided by the ComBaCaL app. 
Participants are free to accept or refuse the services offered by the CC-VHW 
at any time. In case of refusal of the aHT care at village-level, participants will 
be referred to the closest health facility for further care.  
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Prior to the implementation, CC-VHWs in intervention villages will receive
trainings on the basic mechanisms of action, cardiovascular risk reduction 
potential, contraindications and potential side effects of the antihypertensive 
SPC prescribed as well as on adherence counselling techniques, on the 
interpretation of BP values and on basic clinical examination skills for the 
recognition of possible adverse events. Direct guidance for treatment 
initiation, drug prescription, counselling and monitoring will be provided via 
the ComBaCaL app. All activities conducted by CC-VHWs in the communities, 
including counselling and drug prescription, will also be captured in the 
ComBaCaL app. Health care professionals and supervising study staff will 
monitor all activities in a web version of the app and will be intervening in 
case of missing data, non-adherence to the clinical algorithms, or unclear 
clinical conditions. The CC-VHWs may always request support by supervising 
health care professionals.  In case of complicated disease, unclear diagnosis, 
or presence of clinical alarm signs or symptoms, participants will be referred 
immediately to the closest health facility for further investigation. 
Endpoint assessments after six and twelve months including BP and blood 
lipid status measurements, capturing of possible SAEs and AESIs as well as 
administration of questionnaires on adherence and modifiable CVDRFs will 
be conducted by CC-VHWs in an identical manner in intervention and control 
villages and captured in the ComBaCaL app.  
In addition, questionnaires about participants’ satisfaction and acceptability 
of the TwiC intervention will be administered and semi structured interviews 
with a selection of participants, CC-VHWs and involved health care 
professionals will be conducted to qualitatively explore perceived risks, 
benefits and problems of community-based prescription of antihypertensive 
first-line SPCs. 
Number of 
Participants 
with Rationale 
and Power 
Analysis 
The ComBaCaL cohort will consist of inhabitants of around 100 (range 90-112) 
randomly selected villages in rural Lesotho. The estimated mean number of 
adult ComBaCaL participants per village is 100 resulting in an estimated 
10’000 adult cohort participants.  
Sample size is calculated assuming an individual randomization inflated by a 
design effect that account for variation at cluster level, according to the code 
developed by Rotondi and Donner20. Based on preliminary results from an 
NCD prevalence survey in the region (NH-REC ID 139-2021), we expect the 
prevalence of aHT in the adult population in the rural setting in Lesotho to be 
around 18% with a control rate of 55%. Hence, considering an average cluster 
size of 100 adult inhabitants, the mean number of inhabitants with aHT is 
estimated at 18 (10 being controlled and 8 uncontrolled) with a standard 
deviation of 5. 
 
aHT TwiC 1 superiority trial  
In the intervention group, we assume an uptake of the care offered by CC-
VHWs of 75% and a probability of success of 60% among individuals that 
accept community-based care and 30% among those that refuse community-
based care. Hence, we estimate an overall success rate in the intervention 
group of 52.5%. We further assume an intra-cluster correlation of 0.015, a 
mean cluster size of 8 (standard deviation=5) and a probability of success of 
35% in the control group. We calculate that a sample size of 304 (152 in each 
arm, 19 clusters per study arm) is required to detect superiority with a type I 
error of 0.025 and a statistical power of 80%. 
 
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aHT TwiC 2 non-inferiority trial 
We set the non-inferiority margin for the odds ratio (OR) of reaching the 
primary endpoint to 0.58. On an absolute scale, this margin corresponds to a 
higher probability of failing to reach the primary outcome of 10 % in the 
intervention compared to the control group, assuming that the probability of 
success for the participants enrolled in the control arm is 80%. We assume an 
intra-cluster correlation of 0.015, a mean cluster size of 10 (standard 
deviation=5) and a probability of success of 80% in both intervention and 
control groups. This implies a sample size of 780 across 78 clusters (390 in 
each arm, 39 clusters per study arm) to be able to detect non-inferiority with 
a type I error of 0.025 and a statistical power of 80%. 
We inflate the calculated maximal number of cluster among the two TwiCs by 
25% in order to account for uncertainties in the estimates of aHT prevalence, 
number of ComBaCaL village inhabitants and the consent rate. We finally aim 
to recruit 100 clusters (50 per study arm) for a total of 800 participants with 
uncontrolled aHT (TwiC 1) and 1000 participants with controlled aHT (TwiC2). 
Study 
Duration and 
Schedule 
The follow-up period for the TwiC is twelve months. We plan to enrol first 
participants in April 2023 and expect an enrolment period of around four 
months. Thus, the primary endpoint assessment for the last participants is 
planned for August 2024.  
Study 
Centre(s) 
Scientific project lead: Division of Clinical Epidemiology, University of Basel 
Implementation lead: SolidarMed Lesotho 
Study sites: 100 (90 to 112) villages in rural areas of Butha-Buthe and 
Mokhothlong districts in Lesotho 
Statistical 
Analysis  
Villages are our unit of random selection and individuals the unit of analysis. 
The primary analysis for both TwiCs will be the comparison of treatment 
control rates between the two study arms.  
Baseline characteristics will be described by study arm with summary 
statistics such as median and interquartile range or number and percentage. 
We will use a mixed effect logistic regression model with random intercept at 
the level of the clusters to assess the effect of the intervention. 
Primary analysis aHT TwiC 1 
Superiority will be assessed in an intention-to-treat (ITT) approach according 
to the 95% confidence interval of the odds ratio.  
Primary analysis aHT TwiC 2 
Non-inferiority will be assessed according to the 95% confidence interval of 
the odds ratio and the pre-defined non-inferiority margin in the ITT and the 
per-protocol (PP) set. Further details will be provided in the statistical analysis 
plan (SAP). 
Secondary analysis aHT TwiC 1&2 
Secondary endpoints will be reported using descriptive statistics such as 
mean and 95% Wald confidence intervals, frequency and percentages. 
Further details will be outlined in the SAP. 
Ethical 
consideration 
This project will be carried out in accordance with the research plan outlined 
in this protocol and with principles enunciated in the current version of the 
Declaration of Helsinki as well as all national legal requirements and 
guidelines as applicable.  
This protocol will be reviewed by the Ethikkommission Nordwest- und 
Zentralschweiz (EKNZ, Ethics Committee of Northern and Central Switzerland) 
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by the National Health Research Ethics Committee (NHREC) of Lesotho before 
starting the study. 
Participation in the ComBaCaL cohort study and the TwiC intervention are 
voluntary and consent for both or the TwiC intervention alone can be 
withdrawn at any time.  
Potential risks associated with study participation include inadequate 
management by lay CC-VHWs. We will minimize this risk by providing 
adequate training, continuous supervision by health care professionals, and 
close guidance through the ComBaCaL eHealth application. Community-
based care delivery is widely implemented in HIV care in Lesotho providing 
substantial benefits compared to purely clinic-based care. The here-
presented intervention has the potential to increase the quality of care for 
aHT by improving access to treatment, increasing adherence and providing 
closer monitoring.  
The evidence generated in this study aims at informing future national and 
international clinical guidelines to improve chronic disease care in low-
resource settings. Additionally, the community-based activities of the 
ComBaCaL project provide the added benefit of building a healthy and 
friendly community environment through community advocacy and 
participation, and helping to raise awareness and knowledge of chronic 
diseases within villages in Lesotho.  
Thus, the intervention is likely to have a direct positive impact on health 
outcomes of participants as well as generating evidence to improve context-
specific NCD care delivery on a longer perspective. 
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3 BACKGROUND INFORMATION  
3.1 
Burden of arterial hypertension 
Globally, arterial hypertension (aHT) is the single most important risk factor for early mortality, 
accounting for 10.8 million or almost 20% of all deaths in 20191. Low- and middle-income countries 
(LMICs) are bearing a disproportionally high, still increasing share of the aHT-related burden, while many 
high-income countries have managed to reduce aHT-related burden substantially over the past 
decades.1–4 In sub-Saharan Africa, the burden of non-communicable diseases (NCDs) has risen 
significantly over the past two decades, driven by the increasing prevalence of cardiovascular risk factors 
such as unhealthy diets, smoking, reduced physical activity, aHT, obesity, type 2 diabetes mellitus (T2D), 
dyslipidemia, and air pollution3,21. It is anticipated that NCDs will overtake communicable, maternal, 
neonatal, and nutritional diseases combined as the leading cause of mortality in sub-Saharan Africa by 
203022. Besides demographic changes and the increasing prevalence of lifestyle-related risk factors, the 
inadequate health system response on preventive and therapeutic level is a major reason for the 
disproportionally high cardiovascular disease (CVD) burden in LMICs. In many LMICs health systems are 
poorly prepared to address the increasingly prevalent NCDs including aHT, resulting in massive 
treatment gaps, with only around 10% of people living with aHT in LMICs having their condition well 
controlled5. Increasing the global coverage of antihypertensive medications alone has been estimated 
to delay around 40 million deaths over 25 years6. 
Lesotho is a landlocked country within South Africa, a typical example of an African LMIC where NCDs 
are overtaking HIV and other infectious diseases as major cause of disability, morbidity and early death22. 
A recent population-based survey in the districts of Mokhothlong and Butha-Buthe has revealed an aHT 
prevalence of 21% in the adult population in urban and rural areas combined and a relatively high 
treatment control rate of 40% compared to other LMICs (NH-REC 130-2021).  
 
3.2 
Decentralized healthcare delivery 
Effective, affordable, scalable setting-specific strategies are required to reverse the trend of increasing 
NCD related burden in LMICs. The task-shifting to lay healthcare workers (LHWs) at community-level has 
been identified as a promising and cost-effective solution to increase access to aHT treatment in LMIC-
settings7–11,15. Many LMICs have established LHW systems that may be capacitated to play a more active 
role in the management of NCDs14. Traditionally, most LHW systems focus on maternal and neonatal 
health and communicable diseases, especially HIV/AIDS23–25, however in recent years, increasing 
evidence has emerged showing a beneficial effect and high cost-effectiveness of LHW-based models on 
diseases outside this traditional scope, especially for NCDs, such as aHT or T2D. For aHT, most studies 
about LHW-led care models have focused on screening, counselling and referral interventions, while 
knowledge about the effect of LHW-led prescription of antihypertensive medication is lacking.7–12 
Independent of LHW involvement, sound evidence supports the use of simple treatment protocols across 
different provider levels that include the prescription of single-pill combinations (SPCs) to reduce pill 
burden for patients and thereby promote adherence.13 
Current knowledge gaps include the question of whether prescription of first-line SPCs can be included 
safely and effectively in LHW-led aHT care models at community-level complementing the screening, 
counselling and referral services for which benefit has been shown already. Furthermore, evidence of 
whether and how community-based aHT care models could be adapted and successfully implemented 
in sub-Saharan Africa is very limited14 as the recent landmark trials have been conducted in other parts 
of the world.8,11,15  
Building on the existing knowledge and addressing the mentioned gaps, we are planning to conduct a 
cluster-randomized intervention within the ComBaCaL (Community-Based Chronic disease care Lesotho) 
cohort study (EKNZ ID AO_2022-00058, NH-REC ID 210-2022, clinicaltrials.gov ID NCT05596773), a 
platform for the investigation of chronic diseases and their management in rural Lesotho that is 
maintained by local lay chronic care village health workers (CC-VHWs). CC-VHWs are lay healthcare 
workers operating within the Lesotho Ministry of Health (MoH) Village Health Worker (VHW) program 
who receive a specific training to deliver chronic care services. As in many other sub-Saharan African 
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countries, the health system in Lesotho is facing the challenges of lacking human and financial resources. 
As a countermeasure, the integration of lay healthcare workers into the existing health system structures 
has been adopted many years ago26. Despite a drastic health workers shortage in Lesotho (0.9 doctors 
and 10.2 nurses per 10,000 inhabitants, particularly in the rural areas where the majority of the 
population lives (77.6%)27, and the second-highest adult HIV prevalence globally (21.1%)28, Lesotho has 
managed to reduce HIV transmission and AIDS-related deaths considerably. This success is based on 
decentralized HIV testing and care, involving lower cadre healthcare workers and lay VHWs to deliver 
accessible and equitable services for the urban and rural population alike. Currently the community-
based health care delivery in Lesotho is focused on HIV and maternal and neonatal diseases, largely 
neglecting NCDs. Thus, NCD screening, diagnosis, management and prevention are located at the health 
facilities. However, due to high workload, staff shortages, lack of specific training, medication stock-outs 
and outdated guidelines, NCD services are often not delivered adequately at facility-level.  
The Ministry of Health (MoH) of Lesotho has proposed in its NCD strategic plan that lessons learnt from 
HIV program should be incorporated into the NCD care and that delivery platforms should provide 
integrated HIV/NCD services.29 Although various modelling studies from the region suggest that 
integrated service delivery can be cost-effective, robust evidence around community HIV/NCD delivery 
platforms and their key enablers is missing.29, 30 To our knowledge, no studies have been conducted or 
policy documents developed on how to provide pragmatic and scalable prevention and treatment 
models for aHT or other NCDs in the context of a high communicable disease burden in Lesotho. 
We plan to tackle the growing NCD pandemic through a multi-disciplinary research and implementation 
partnership, the Community-Based chronic disease Care Lesotho (ComBaCaL) program. ComBaCaL aims 
at establishing and validating a community-based care model focused on eHealth supported NCD service 
delivery by lay healthcare workers. The ComBaCaL cohort study provides the platform for the scientific 
assessment of the community-based NCD care model proposed. 
In the here described trials within the cohort (TwiCs), we are aiming to specifically assess the effect of 
community-based aHT care including therapeutic management of uncomplicated aHT by lay CC-VHWs. 
The TwiC intervention has been developed based on a local NCD prevalence survey and burden 
assessment (NH-REC ID 130-2021), a scoping literature review14, multiple workshops with different 
stakeholders in Lesotho and the ComBaCaL pilot cohort study (NH-REC ID 176-2021). In the intervention 
clusters, CC-VHWs operating within the existing healthcare system will be capacitated to screen for and 
diagnose aHT, to prescribe first-line antihypertensive SPCs to eligible participants and to monitor and 
support antihypertensive treatment supported by a tailored clinical decision support application 
(ComBaCaL app) in their villages. The control group consists of people diagnosed with aHT living in 
villages that are also part of the ComBaCaL cohort but not sampled for the intervention (control villages), 
where CC-VHWs will only screen for and diagnose aHT with subsequent standardized counselling and 
referral to the closest health facility if aHT is present, but no village-based prescriptions. We are planning 
to assess the effectiveness of this intervention in two different trial populations: On the one hand in 
people with uncontrolled aHT at baseline (aHT TwiC 1), and on the other hand in people with controlled 
aHT at baseline (aHT TwiC 2). We hypothesize that the intervention is superior in ComBaCaL TwiC 1 and 
non-inferior in ComBaCaL TwiC 2. Randomization for the two TwiCs will be done at cluster level, meaning 
that all people with aHT in one village will be offered the same care package from their local CC-VHW. 
 
 
 
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4 OBJECTIVES AND PURPOSE 
4.1 
Objectives 
The overall objective of the ComBaCaL cohort study and nested TwiCs is to assess the impact of eHealth-
supported, lay-led chronic disease control measures in rural Lesotho. 
In the two aHT TwiCs, we will specifically assess the effect, safety and feasibility of community-based 
aHT care including therapeutic management of uncomplicated aHT by lay CC-VHWs in comparison to 
facility-based care after community-based screening and diagnosis.  
 
4.1.1 
Primary objective TwiC 1 
x 
To assess the effectiveness of offering community-based, CC-VHW-led, eHealth supported aHT care 
including the prescription of first-line antihypertensive SPCs for eligible participants in people with 
uncontrolled aHT (newly diagnosed or receiving treatment without reaching treatment targets 
(≥140/90 mmHg)) in rural Lesotho 
4.1.2 
Primary objective TwiC 2 
x 
To assess the effectiveness of offering community-based, CC-VHW-led, eHealth supported aHT care 
including the prescription of first-line antihypertensive SPCs for eligible participants in people with 
controlled aHT (receiving treatment at baseline and reaching treatment targets (<140/90 mmHg)) in 
rural Lesotho 
4.1.3 
Secondary objectives TwiC 1 & TwiC 2 
x 
Key secondary objective: To assess the effect of CC-VHW led, eHealth supported aHT care on 10-year 
CVD risk using the WHO CVD risk assessment tool16,17 
x 
To assess the effect of CC-VHW led, eHealth supported counselling on CVD risk factors including BMI, 
abdominal circumference, blood lipid status, tobacco use, physical activity and dietary habits 
x 
To assess the safety of CC-VHW led, eHealth supported prescription of first-line antihypertensive 
SPCs for people with controlled / uncontrolled aHT 
x 
To assess the effect of CC-VHW led, eHealth supported prescription of first-line antihypertensive SPCs 
for people with controlled / uncontrolled aHT on linkage and engagement in care and on adherence 
to treatment  
4.1.4 
Exploratory and implementation objectives TwiC 1 & TwiC 2 
x 
To assess the effect of CC-CHW led aHT care on the number of eligible participants accessing lipid-
lowering treatment 
x 
To assess and describe implementation parameters, i.e. acceptance, uptake of and satisfaction with 
CC-VHW led, eHealth supported prescription of first-line antihypertensive SPCs for people with 
controlled/uncontrolled aHT among involved stakeholders 
x 
To estimate the costs of CC-VHW led, eHealth supported prescription of first-line antihypertensive 
SPCs for people with controlled/uncontrolled aHT 
x 
To assess quality indicators of the services provided and the data collected by CC-VHWs, such as 
completeness of the data collected and adherence to clinical algorithms provided via the eHealth 
application 
x 
To assess the 10-year CVD risk using different risk assessment tools, such as the Framingham31 and 
the Globorisk Score32,33 
x 
To assess the effect of CC-VHW led, eHealth supported aHT care on  quality of life using the EQ-5D-
5L instrument34 and on health beliefs using the Beliefs about Medicines Questionnaire (BMQ) 
adapted for people living with aHT35,36 
x 
To assess the effect of CC-VHW led aHT care on the prevalence of BP values in the hypertensive 
urgency range (≥180/110mmHg) 
x 
To assess the effect of CC-VHW led aHT care on self-reported access to care  
 
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4.2 
Scientific justification of study population 
The ComBaCaL cohort study will be located in rural villages of Butha-Buthe and Mokhothlong districts in 
Lesotho. Lesotho is a typical example of an African LMIC where a developing health system is facing the 
heavy double-burden of the still highly prevalent infectious diseases HIV/AIDS and TB in combination 
with a rapidly spreading NCD epidemic22.  
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 Map of Lesotho with the two districts Butha-Buthe and Mokhothlong 
In the Lesotho health system, the VHW program plays a crucial role and has proven highly effective for 
the control of HIV/AIDS, especially for remote rural areas26. The Lesotho VHW program thus represents 
a meaningful starting point for implementation research on enhancing community-based intervention 
strategies and provides a setting that is representative for the health systems in many other LMICs, 
especially in sub-Saharan Africa, where lay worker led care has a similar standing.   
 
 
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5 HYPOTHESIS 
5.1 
Primary hypothesis TwiC 1 and primary estimand 
Primary hypothesis: Community-based, CC-VHW-led, eHealth supported aHT care including the 
prescription of first-line antihypertensive SPCs for eligible participants is safe and superior with regard 
to BP control rates after twelve months compared to facility-based aHT care in people living with 
uncontrolled aHT in rural Lesotho.  
Primary estimand: Difference in the proportion of participants with a documented measurement of 
controlled aHT (BP <140/90 mmHg) in the primary endpoint window (12 months after enrolment) between 
community-based, CC-VHW-led, eHealth supported aHT care versus facility-based aHT care, in non-pregnant 
adults with uncontrolled aHT (BP ≥140/90 mmHg at baseline), who did not experience a traumatic death and 
did not move out of their village, irrespective of the uptake of the intervention, aHT treatment, aHT treatment 
adherence and adverse events. 
 
 
5.2 
Primary hypothesis TwiC 2 and primary estimand 
Primary hypothesis: Community-based, CC-VHW-led, eHealth supported aHT care including the 
prescription of first-line antihypertensive SPCs for eligible participants is safe and non-inferior with 
regard to BP control rates after twelve months compared to facility-based care in people living with 
controlled aHT in rural Lesotho. 
Primary estimand: Difference in the proportion of participants with a documented measurement of 
controlled aHT (BP <140/90 mmHg) in the primary endpoint window (12 months after enrolment) 
between community-based, CC-VHW-led, eHealth supported aHT care versus facility-based aHT care, in 
non-pregnant adults with controlled aHT (BP <140/90 mmHg at baseline), who did not experience a 
traumatic death and did not move out of their village, irrespective of the uptake of the intervention, aHT 
treatment, aHT treatment adherence and adverse events. 
 
 
 
 
 
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6 STUDY DESIGN 
6.1 
Endpoints 
For the endpoint assessments at twelve months, a range of 300 to 420 days after enrolment applies. For 
the endpoint assessments at six months, a range of 150 to 210 days applies.  
 
6.1.1 
Primary endpoint TwiC 1 & TwiC 2 
x 
Proportion of participants whose blood pressure (BP) is within target (<140/90 mmHg) twelve 
months after enrolment 
 
6.1.2 
Secondary endpoints TwiC 1 & TwiC 2  
x 
Key secondary endpoint: 10-year risk for a fatal or non-fatal CVD event estimated using the WHO 
CVD risk prediction tool16,17 six and twelve months after enrolment 
x 
CVD risk factors, such as BMI, abdominal circumference, blood lipid status, physical activity using 
the validated International Physical Activity Questionnaire Short Form (IPAQ-SF)37 adapted to the 
local context and language according to the IPAQ recommendations38, dietary habits using a 
shortened unquantified food frequency questionnaire adapted from an assessment tool for 
obesity used in South Africa39 and alcohol and tobacco use six and twelve months after 
enrolment 
x 
Proportion of participants whose BP is within target (<140/90mmHg) six months after enrolment 
x 
Mean systolic (SBP) and diastolic (DBP) BP six and twelve months after enrolment  
x 
Occurrence of Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) 
within six and twelve months after enrolment 
x 
Linkage to care: proportion of participants not taking treatment at enrolment who have initiated 
pharmacological antihypertensive treatment six and twelve months after enrolment 
x 
Engagement in care: proportion of participants who are engaged in care, defined as reporting 
intake of antihypertensive medication as per prescription of a healthcare provider (CC-VHW or 
healthcare professional) within the two weeks prior to assessment six and twelve months after 
enrolment or reaching treatment targets without intake of medication 
x 
Self-reported adherence to treatment six and twelve months after enrolment 
 
6.1.3 
Exploratory endpoints and implementation indicators 
x 
Number of consultations at a health facility and with the CC-VHW within six and twelve months 
after diagnosis 
x 
Proportion of participants in the intervention clusters not taking up community-based drug 
treatment by CC-VHWs at baseline and proportion switching to facility-based care within six and 
twelve months Proportion of participants with aHT who stop drug treatment or interrupt drug 
treatment for more than three weeks or require a switch of drug treatment due to (perceived) 
adverse events (AEs) within six and twelve months after enrolment 
x 
Proportion of participants who are reaching treatment targets (<140/90 mmHg) and are 
reporting no intake of antihypertensive medication in the two weeks prior to assessment after 
six and twelve months  
x 
Proportion of high CVD risk participants eligible for lipid-lowering treatment who are accessing 
lipid-lowering medication six and twelve months after enrolment  
x 
Participants’, CC-VHWs’ and involved health care professionals’ perception of the risks, benefits 
and problems of community-based management of uncomplicated aHT by CC-VHWs 
x 
Quality indicators of the CC-VHW activities, such as completeness of the data collected and 
adherence to clinical algorithms provided via the eHealth application 
x 
Causes for the stop or interruption of treatment or switch to health facility-based treatment 
after initiation by CC-VHWs in the community 
x 
Health system costs and individual costs for participants for the management of their condition 
within the first six and twelve months after diagnosis 
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x 
10-year CVD risk estimated using the Framingham31 and Globorisk40 scores33 six and twelve 
months after enrolment 
x 
Quality of life using the EQ-5D-5L instrument34and health beliefs using the Beliefs about 
Medicines Questionnaire (BMQ) adapted for people living with aHT35,36 after twelve months 
x 
Access to care and access to medication using the questions as proposed by the International 
Consortium for Health Outcomes Measurement’s (ICHOM) core outcome sets for aHT trials in 
LMICs12 six and twelve months after enrolment 
x 
Type and dosage of antihypertensive medications prescribed by CC-VHWs or healthcare 
professionals six and twelve months after enrolment 
x 
Number of participants with BP in the hypertensive urgency range (180/110 mmHg) six and 
twelve months after enrolment 
 
6.2 
Measures to minimize bias 
 
6.2.1 
Blinding 
Endpoint assessments will be conducted by the CC-VHWs; thus no blinding is possible. 
 
6.2.2 
Measurements 
Baseline and endpoint assessments will be conducted by CC-VHWs supported by the ComBaCaL app. 
Protocols and instructions for correct BP measurements and sample collection as well as structured 
questionnaires for the assessment of lifestyle risk factors are provided in the ComBaCaL app. Details 
regarding the protocol for BP measurements can be found in the appendix of the current version of the 
“ComBaCaL cohort study protocol”. All CC-VHWs will undergo a training with emphasis on correct BP 
measurements as well as interviewing techniques and data entry into the ComBaCaL app. For the 
duration of the study there will be regular field visits by supervising CC nurses to ensure that procedures 
for data collection are correctly followed by all involved CC-VHWs.  
 
6.2.3 
Randomization 
50% of villages out of the ComBaCaL cohort villages will be randomly allocated to the intervention group 
by a statistician not involved in the study. The random allocation will be stratified by district (Butha-
Buthe versus Mokhothlong) and access to health facility (easy versus difficult access, defined as needing 
to cross a mountain or river or travel >10 km to the nearest health facility).  
 
6.3 
Study duration and duration of participant’s participation 
The follow-up period for both TwiCs is twelve months. We plan to enrol first participants in April 2023 
and expect an enrolment period of around four months. Thus, the endpoint assessment for the last 
participants is planned for August 2024.  
 
6.4 
Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents will be submitted 
to NH-REC and EKNZ for approval before implementation while minor amendments will be submitted to 
NH-REC only. 
 
6.5 
Withdrawal and discontinuation 
 
6.5.1 
Individual level 
Participants in the intervention villages may reject the intervention any time. They will be asked about 
the reasons for the rejection of village-based care, but may refuse to provide a reason for the rejection. 
The rejection of the intervention will not influence their affiliation to the ComBaCaL cohort study and 
their data will be included in the ITT analysis. Participants in the control villages who do not want their 
data to be included in the TwiC analysis need to withdraw the ComBaCaL cohort consent as agreeing to 
use of collected data as control data is an integral part of the ComBaCaL cohort consent. 
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As outlined in the “ComBaCaL cohort study protocol” all participants can withdraw cohort consent at 
any time. After withdrawal of cohort consent, the participant’s profile in the ComBaCaL application will 
be de-activated and no further data will be collected. The possibility to re-enter the cohort later through 
contacting the local CC-VHW will be offered. Data collected until the time of withdrawal will be included 
in the analysis. By withdrawing the ComBaCaL cohort consent, automatically the intervention consent 
will be withdrawn, too.  
The study team will not discontinue individual participants.   
 
6.5.2 
Study and cluster level 
In intervention villages, the village chief may reject the intervention at village-level. The study team 
would then get in contact with the village chief to inquire the reasons for the intended rejection. If 
needed a community gathering (“Pitso”) will be held. If after discussion between the village chief, the 
community and the study team, the request for rejection of the intervention persists, the intervention 
will be stopped in the village and all participants will be referred to the responsible health facility for 
continuation of treatment. ComBaCaL cohort activities without the intervention will continue in the 
village. Participants may be asked specifically about their perceptions of the rejection of the intervention 
at village-level.  
 
If in a village, the CC-VHW is not able or willing to continue his/her tasks for the ComBaCaL study (i.e. 
due to death, migration, personal reasons, rejection by village chief or village population), the CC-VHW 
will be replaced while the village will remain in the study.  
 
The Principal Investigators in consultation with Co-Investigators may choose to pause or discontinue the 
ComBaCaL cohort study in certain or all villages or to pause or discontinue the intervention in one or 
more intervention villages.   
We refer to the “ComBaCaL cohort study protocol” for details regarding the criteria for interruption or 
stop of the ComBaCaL cohort study. If the ComBaCaL cohort is being interrupted or stopped in one or 
more villages, automatically also the nested TwiCs are interrupted or stopped in the concerned villages, 
while the participants will remain in the TwiC analysis population as outlined in section 10.  
 
The reasons to pause or discontinue the TwiC intervention in all intervention villages include the 
following: 
x 
Insufficient funding to continue the study 
x 
Significant opposition by local health authorities 
x 
Safety or other ethical concerns 
x 
Alteration in accepted clinical practice, national policy or scientific evidence that make the 
continuation of the study unwise 
x 
Insurmountable technical or organizational problems  
 
The reasons to pause or discontinue the TwiC intervention in individual villages include the following:  
x 
Significant opposition by local health authorities 
x 
Safety or other ethical concerns 
x 
Insurmountable organizational problems 
x 
Impossibility to recruit a VHW from the village population in case replacement of the initially 
recruited VHW is required 
 
The Principal Investigators would provide the project partners and the Co-Investigators written notice 
submitted at a reasonable time in advance of the intended discontinuation or pause of the ComBaCaL 
cohort study or the TwiC intervention. If the Principal Investigators choose to terminate or pause the 
ComBaCaL cohort study or the TwiC intervention for safety reasons, they will immediately notify all 
investigators and subsequently provide written instructions for study termination. Co-investigators may 
pause the ComBaCaL cohort study or the TwiC intervention in certain villages in case of safety concerns 
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without written notice in advance. If Co-Investigators wish to pause or discontinue the ComBaCaL cohort 
study or the TwiC intervention, they may address the request to pause or discontinue in written form to 
the Principal Investigators. Co-Investigators may not pause or discontinue the ComBaCaL cohort study 
or the TwiC intervention for other reasons than safety concerns without consulting the Principal 
Investigators. 
 
6.6 
End of trial 
At the conclusion of the trial or premature termination, all study data will be locked and archived. The 
electronic database will be locked and a complete study dataset will be transferred to the statistician 
and the Principal Investigators through a secure channel. The study data will be stored by the 
Department of Clinical Research of the University Hospital Basel on a secure server for a minimum of 10 
years and be destroyed thereafter (see section 11).  
Participants in intervention and control villages will be informed about the results of the TwiCs through 
the CC-VHWs after the analysis is complete.  
 
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7 SELECTION OF STUDY PARTICIPANTS 
7.1 
Selection of villages 
We refer to the “ComBaCaL cohort study protocol” for detailed information about the selection of 
villages for the ComBaCaL cohort.  
Out of the ComBaCaL cohort villages, 50% will be randomly allocated to the intervention group. We refer 
to the paragraph 6.2.3 “Randomization” for information about the random allocation.  
 
7.2 
Recruitment of participants 
We refer to the “ComBaCaL cohort study protocol” for details regarding the recruitment for the 
ComBaCaL cohort. For these TwiCs, CC-VHWs will screen for eligible individuals among adult ComBaCaL 
cohort participants in their villages via home visits.  
The populations for the two TwiCs described in this protocol are mutually exclusive and together 
constitute the overall intervention-eligible population, thus every intervention-eligible participant is 
either allocated to ComBaCaL TwiC 1 or 2. 
 
7.2.1 
Inclusion criteria ComBaCaL-TwiC 1 
x 
Participant of the ComBaCaL cohort study (signed informed consent available) 
x 
Aged 18 years or above 
x 
Living with aHT, defined as reporting intake of antihypertensive medication or being newly 
diagnosed during screening via standard diagnostic algorithm (see appendix of the “ComBaCaL 
cohort study protocol”) 
x 
BP ≥140/90 mmHg at baseline 
 
7.2.2 
Inclusion criteria ComBaCaL-TwiC 2 
x 
Participant of the ComBaCaL cohort study (signed informed consent available) 
x 
Aged 18 years or above 
x 
Reporting intake of antihypertensive medication 
x 
BP<140/90 mmHg at baseline 
 
7.2.3 
Exclusion criteria for both ComBaCaL-TwiC 1&2 
x 
Reported pregnancy (at baseline or during follow-up)  
 
Eligible participants in the intervention villages will be offered the intervention consisting of the 
prescription of first-line antihypertensive SPC for eligible participants, treatment monitoring and 
support, lifestyle counselling, lipid-lowering medication in case of high CVD risk and antiplatelet 
treatment for participants with a history of stroke or myocardial infarction by the CC-VHW after 
diagnosing aHT. Participants are free to accept or reject all or parts of the pharmacological and non-
pharmacological care offered by the CC-VHW.  
Data of ComBaCaL cohort participants living in villages not selected for the intervention will be used as 
“control arm”. As per the ComBaCaL cohort study protocol and informed consent, no specific 
recruitment or participant information will be provided to the participants in control villages. 
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8 STUDY PROCEDURES 
8.1 
General Setting 
Screening and enrolment for these TwiCs will be embedded into the regular ComBaCaL cohort activities 
conducted in the villages by CC-VHWs. We refer to the current version the “ComBaCaL cohort study 
protocol” for detailed information about the cohort set-up. At every participant encounter, the CC-VHW 
will screen for warning signs and symptoms (i.e. shortness of breath, severe headache, chest pain, new-
onset confusion, impaired consciousness, severely impaired general state of health) and refer 
participants to the closest health centre in case of presence of any alarm sign or symptom. 
 
8.2 
Screening 
Screening and diagnosis for aHT among the ComBaCaL cohort members will be conducted by CC-VHWs 
according to the algorithms provided in the appendix of the “ComBaCaL cohort study protocol”. These 
algorithms are being encoded into the ComBaCaL app, guiding the question logic for data collection and 
serving as clinical decision aid for the CC-VHWs. After diagnosis of aHT, CC-VHWs will screen for the 
other eligibility criteria and based on the screening information, the trial eligibility will be determined 
via the ComBaCaL app.  
 
8.3 
Enrolment 
ComBaCaL cohort participants meeting the eligibility criteria for one of the two TwiCs, will automatically 
be included in the respective TwiC population. We refer to the current version of the “ComBaCaL cohort 
study protocol” and to the section 13.3 of this document for details regarding the consent procedures. 
Participants in intervention villages may reject any component of the care offered any time during the 
study and request referral to a health facility for the continuation of their treatment. Participants 
consenting to participation but subsequently rejecting care offered by the CC-VHW might be approached 
for qualitative inquiry on the reasons for the refusal of community-based care.  
 
8.4 
Baseline  
Most baseline data to describe the TwiC participants will be collected as part of the ComBaCaL cohort 
assessments (see current version of the “ComBaCaL cohort study protocol” for details). In brief, the 
following data will be collected by the CC-VHW at cohort baseline using the ComBaCaL eHealth 
application: age, sex, height, weight, abdominal circumference, household position, socioeconomic 
indicators of the household, level of education, income-generating activity, targeted medical history 
including previous aHT diagnosis, intake of antihypertensive medication, HIV status and cardiovascular 
complications, physical activity using the validated International Physical Activity Questionnaire Short 
Form (IPAQ-SF)37 adapted to the local context and language according to the IPAQ recommendations38, 
dietary habits using a shortened unquantified food frequency questionnaire adapted from an 
assessment tool for obesity used in South Africa39, self-reported alcohol and tobacco use,  Participants 
aged 40 years or more or having a BMI above 25kg/m2 will be screened for T2D using capillary blood 
glucose measurements. 
In addition to the data collected as part of regular ComBaCaL cohort activities, further baseline 
information will be collected for TwiC participants based on the International Consortium for Health 
Outcomes Measurements’ (ICHOM) outcome sets for aHT trials in LMICs12. Data collected at TwiC 
baseline include blood lipid status, quality of life using the EQ-5D-5L instrument34 and health beliefs 
using the Beliefs about Medicines Questionnaire (BMQ) adapted for people living with aHT will be 
assessed35,36.  
 
 
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Figure 2 Flow of events. BP: blood pressure, aHT: arterial hypertension, TwiC: trial within cohort, SAE: serious adverse event, 
AESI: adverse event of special interest, CVDRFs: cardiovascular disease risk factors, BMI: body-mass index. 
 
 
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8.5 
Intervention 
In the intervention villages, CC-VHWs will offer a community-based aHT care package including 
pharmacological and non-pharmacological treatment and monitoring  according to clinical algorithms 
based on international guidelines for primary healthcare level management of aHT41,42 and the then 
effective Lesotho Standard Treatment Guidelines (under review at the time of submission of this 
protocol). Eligible participants will be offered antihypertensive first-line SPC and regular lifestyle 
counselling focussed on smoking cessation, healthy diet and regular physical activity. Participants with 
a high CVD risk and no contraindications will be offered lipid-lowering treatment. High CVD risk among 
the participants who all have aHT is defined as additionally having a history of stroke or myocardial 
infarction, having DM or chronic kidney disease (CKD) or being 50 years or older and having one or both 
of the following risk factors: BMI ≥ 30 kg/m2, current smoking. Participants with a history of stroke or 
myocardial infarction and no contraindication will be offered antiplatelet treatment.   
The CC-VHWs in the intervention villages will receive specific training focused on lifestyle counselling, 
drug prescription, screening for potential adverse events of drugs administered, and disease monitoring 
and dose adjustment after treatment initiation.  
Direct guidance for treatment initiation, drug prescription, counselling and monitoring will be provided 
via the ComBaCaL app. All activities conducted by CC-VHWs in the communities, including counselling 
and drug prescription, will be captured in the application.  
Health care professionals and supervising study staff will monitor all activities in a web version of the 
app and will be intervening in case of missing data, non-adherence to the clinical algorithms, or unclear 
clinical conditions. The CC-VHWs may always request support by supervising health care professionals. 
In case of complicated disease (i.e. if treatment targets are not reached under first-line SPC), unclear 
diagnosis, relevant comorbidities or presence of clinical alarm signs or symptoms, participants will be 
referred to the closest health facility for further investigation. Participants are free to accept or refuse 
the treatment offered by the CC-VHWs. Participants refusing the CC-CHW-led treatment will be asked 
about the reasons for the refusal and will be referred to the responsible health facility for further 
management.  
In control villages, CC-VHWs will refer participants to the responsible health facility for therapeutic 
management after enrolment and baseline assessment. 
 
8.6 
Follow-up and endpoint assessment 
8.6.1 
Scheduled follow-up visits and endpoint assessments 
Follow-up visits by CC-VHWs including endpoint assessments will be scheduled six months (range 150 to 
240 days) and twelve months (300 to 420 days) after TwiC enrolment.  
During the follow-up visits, BP measurements will be conducted together with the collection of 
secondary endpoint data such as CVDRFs (physical activity, diet, blood lipid status, tobacco and alcohol 
use using the same assessment tools as for the baseline, height, weight, BMI, abdominal circumference), 
engagement in and adherence to antihypertensive treatment, quality of life and health beliefs.  
During follow-up visits, CC-VHWs will inquire about relevant clinical events since the previous visit 
(including screening of the Bukana for documentation of respective events). These events will be 
documented in a dedicated electronic case report form within the ComBaCaL app. Safety outcomes of 
this TwiC (SAEs and AESIs, see section 9 for definitions) are a subset of the clinically relevant events that 
are captured as part of the ComBaCaL cohort study. All reports of SAEs and possible AESIs will be 
reviewed by the study physician for final assessment and classification.  
In addition, specific questionnaires about participants’ satisfaction and acceptability of the TwiC 
intervention will be administered and semi structured interviews with a selection of participants, CC-
VHWs and involved health care professionals will be conducted to qualitatively explore perceived risks, 
benefits and problems of community-based therapeutic management of uncomplicated aHT. We will 
evaluate the quality of services provided and the data collected in the villages by analysing aggregated 
data and metadata of the reports submitted by the CC-VHWs via the eHealth application. 
 
8.6.2 
Clinical follow-up 
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In intervention villages, the CC-VHWs will conduct clinical follow-up visits according to the clinical 
algorithms provided via the ComBaCaL app. During these clinical follow-up visits, CC-VHWs will check BP 
values, monitor treatment adherence, check for treatment side effects, adjust treatment dose if 
required, provide lifestyle counselling and refer participants to the responsible health facility, if BP 
treatment targets are not met under high-dose first-line SPC or in case of side effects, clinical alarms 
signs or symptoms or relevant comorbidities. The therapeutic management provided by the CC-VHWs 
under guidance of the ComBaCaL app is in line with international guidelines on the treatment of aHT at 
primary healthcare level.41,42 
In intervention and control villages, CC-VHWs will document deaths, hospitalizations and other relevant 
clinical events at any time after becoming aware of the event independent of scheduled visits. Likewise, 
if participants are moving out of the village, the CC-VHWs will document this in a dedicated form in the 
ComBaCaL app. 
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8.7 
Schedule of events 
 
 
Cohort baseline 
TwiC screening & baseline
Intervention follow-ups1 
6-month follow-up 
12-month follow-up 
Time in days relative to TwiC enrolment 
-60 – 0 
0 
0 – 400  
150 – 240  
300 – 420 
ComBaCaL cohort informed consent 
x 
 
 
 
 
Date of birth  
x 
 
 
 
 
Height, weight, abdominal circumference 
x 
 
 
x 
x 
Sociodemographic data 
x 
 
 
 
 
Short medical history2 
x 
 
 
 
 
CVDRFs3 
x 
 
 
x 
x 
BG measurement 
x 
 
 
x 
x 
BP measurement 
 
x 
x 
x 
x 
Health beliefs4 
 
x 
 
x 
x 
Quality of life5 
 
x 
 
x 
x 
Blood lipid status (total cholesterol, LDL 
cholesterol, HDL cholesterol, triglycerides) 
 
x 
 
x 
x 
aHT specific medical history 
 
x 
 
x 
x 
Linkage to & engagement in care 
 
 
 
x 
x 
Adherence to antihypertensive medication 
 
x 
x 
x 
x 
Acceptability & satisfaction with aHT care6 
 
 
 
x 
x 
Screening for relevant clinical events 
x 
x 
x 
x 
x 
Screening for clinical alarm signs/symptoms 
x 
x 
x 
x 
x 
TwiC Control 
 
 
 
 
 
Referral to health facility7 
 
x 
 
x 
x 
TwiC Intervention 
 
 
 
 
 
Offer SPC and treatment monitoring 
 
x 
x 
x 
x 
Offer lipid-lowering treatment8 
 
x 
x 
x 
x 
Lifestyle counselling 
 
x 
x 
x 
x 
Referral to health facility9 
 
(x) 
(x) 
(x) 
(x) 
1) 
Only for TwiC participants in intervention villages 
2) 
Including personal and family history for aHT / DM and other relevant conditions 
3) 
Physical activity using IPAQ-SF37, dietary habits39, tobacco and alcohol use 
4) 
Using the Beliefs about Medicines Questionnaire35,36 
5) 
Using the EQ-5D-5L instrument34 
6) 
Only for a subset of participants 
7) 
For initiation or continuation of aHT treatment and/or in case of clinical alarm signs or symptoms 
8) 
Only to participants with high CVD risk 
9) 
Only in case of clinical alarm signs or symptoms, participants refusing community-based aHT care, complicated disease, unclear diagnosis or relevant comorbidity
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9 SAFETY CONSIDERATIONS 
9.1 
Definition and documentation of safety outcomes 
Adverse event (AE) 
Any untoward medical occurrence in a study participant, including 
occurrences that are not necessarily caused by or related to the study  
procedures 
Adverse event of 
special interest (AESI) 
AE consistent with complication of aHT, such as:
x 
Myocardial infarction  
x 
Stroke 
x 
Symptomatic heart failure  
x 
Chronic kidney disease  
 
AE probably related to intake of antihypertensive medication, such as: 
x 
Intolerance reaction against antihypertensive medication leading 
to discontinuation of the medication concerned (including allergic 
reactions, drug interactions or rare severe side effects) 
Serious adverse event 
(SAE) 
Any AE that: 
x 
Results in death  
x 
Is life-threatening  
x 
Requires hospitalization or prolongation of existing 
hospitalization 
o Hospitalizations due to uncomplicated delivery are not 
considered as SAE 
x 
Results in persistent or significant disability or incapacity 
x 
Consists of a congenital anomaly or birth defect 
Serious adverse event 
of special interest 
(SAESI)  
SAE consistent with complication of aHT, such as: 
x 
Myocardial infarction  
x 
Stroke 
x 
Symptomatic heart failure  
x 
Chronic kidney disease 
  
SAE probably related to intake of antihypertensive or antidiabetic 
medication, such as:  
x 
Intolerance reaction against antihypertensive medication leading 
to discontinuation of the medication concerned (including allergic 
reactions, drug interactions or rare severe side effects) 
 
CC-VHWs will be trained to screen for and to recognize adverse events of special interest (AESIs) and 
serious adverse events (SAEs) and to document them in the dedicated report form in the ComBaCaL app. 
AESIs and SAEs for this TwiC are a subset of the clinically relevant captured as part of routine ComBaCaL 
cohort activities 
 
CC-VHWs may solicit AESIs and SAEs as part of the ComBaCaL activities in the following ways:  
- 
Active reporting by participants or friends or relatives outside of scheduled CC-VHW visits 
(scheduled visits are defined as visits being triggered through the ComBaCaL app based on 
regular or clinical follow-up algorithms or visits being assigned by supervising healthcare 
professionals) 
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- 
Passive reporting by participants or friends or relatives after inquiry by CC-VHWs during 
scheduled VHW visits 
- 
Clinical observation of CC-VHWs during or outside scheduled CC-VHW visit 
- 
Screening of participants’ Bukanas (personal health booklet) 
- 
Reporting by health centre nurses 
 
In intervention villages, additional visits are scheduled for the therapeutic management of aHT during 
which CC-VHWs will conduct additional AE screening including specific screening for AEs possibly related 
to the therapeutic intervention. The intervention-specific AE screening will be closely guided via the 
eHealth application (i.e. a list of symptoms to be inquired for each drug will be provided).  
 
The anonymized, AESI reports will be submitted on a monthly basis to the study physician who will 
remain blinded to the village, CC-VHW or CC nurse related to the report submission. The study physician 
will classify the AESI reports of TwiC participants as SAEs (including type and if possible cause of SAE), 
AESIs (including type and if possible cause of AESI) or none of the two if sufficient clinical information 
for classification is available. If the clinical information available is not sufficient for classification of the 
case, the study physician will request the study Data Manager to unblind the respective report and then 
contact the responsible CC nurse and/or CC-VHW and ask for collection of further data.  
 
9.2 
Causality of SAEs and AESIs 
A causality assessment of all SAEs and of AESIs possibly related to the therapeutic management of aHT 
will be performed by the study physician based on the reports submitted by the CC-VHWs. As a result of 
the causality assessment, the study physician will provide a statement whether the SAE/AESI is possibly, 
likely or definitely related or unrelated to the aHT care provided.  
 
9.3 
Management of AEs 
 
9.3.1 
Control villages 
In control villages the entire clinical management after screening and diagnosis will be provided by 
healthcare professionals at the responsible health centre without direct influence by study staff. 
ComBaCaL study staff will provide capacity building in NCD management at all involved health centres 
and support in case of clinical questions. If CC-VHWs become aware of clinical events in their village 
during the follow-up period, they will refer the respective individual to the health centre.  
 
9.3.2 
Intervention villages 
In intervention villages, mild, common side effects of the drugs administered, for which neither 
professional assessment nor other measures than observation or an interruption of the prescribed drug 
is required, will be managed by the CC-VHWs at community-level. For the assessment and management 
of these events, close guidance will be provided via the eHealth application. Additionally, CC-VHWs will 
have the possibility to seek clinical advice from the supervising health centre nurses or the CC nurses, 
either via messages sent through the eHealth application or via phone calls or field visits.  
Any AEs going beyond mild, common side effects or any unclear clinical conditions will prompt referral 
to the responsible health facility for further assessment and professional management. The ComBaCaL 
study staff will not directly intervene in the management of such cases but provide clinical support to 
the health centre staff if required. Besides clinical support for the management of complex cases, the 
ComBaCaL study team will provide NCD-focused training at the involved health facilities to ensure high-
quality care for participants referred to the responsible health facilities.   
 
9.4 
Reporting  
CC-VHWs will document SAEs and AESIs in dedicated electronic case report forms (eCRFs) with 
subsequent assessment and classification by the study physician. All deaths and all other SAEs that are 
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possibly, probably or definitely related to the study intervention will be reported to at least one of the 
two principal investigators within one month after the study physician has become aware of the event. 
All deaths and all other SAEs that are possibly, probably or definitely related to the study intervention 
will be reported to the NHREC on a yearly basis.  
 
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10 STATISTICS 
10.1 Hypothesis 
aHT TwiC 1 
Community-based, CC-VHW-led, eHealth supported aHT care including the prescription of first-line 
antihypertensive SPCs for eligible participants is safe and superior with regard to BP control rates after twelve 
months compared to facility-based prescription in people living with uncontrolled aHT in rural Lesotho.  
 
aHT TwiC 2 
Community-based, CC-VHW-led, eHealth supported aHT care including the prescription of first-line 
antihypertensive SPCs for eligible participants is safe and non-inferior with regard to BP control rates 
after twelve months compared to facility-based prescription in people living with controlled aHT in rural 
Lesotho 
 
10.2 Determination of sample size  
The ComBaCaL cohort will consist of inhabitants of around 100 (range 90-112) randomly selected villages 
in rural Lesotho. The estimated mean number of adult ComBaCaL participants per village is 100 resulting 
in an estimated 10’000 adult cohort participants.  
Sample size is calculated assuming an individual randomization inflated by a design effect that account 
for variation at cluster level, according to the code developed by Rotondi and Donner20. Based on 
preliminary results from an NCD prevalence survey in the region (NH-REC ID 139-2021), we expect the 
prevalence of aHT in the adult population in the rural setting in Lesotho to be around 18% with a control 
rate of 55%. Hence, considering an average cluster size of 100 adult inhabitants, the mean number of 
inhabitants with aHT is estimated to 18 (10 being controlled and 8 uncontrolled) with a standard 
deviation of 5. The sample size for both TwiCs was calculated separately with the higher of the two 
defining the overall intervention sample size.  
 
10.2.1 aHT TwiC 1 
In the intervention group, we assume a study consent rate of 75%, a probability of success of 60% among 
individuals that consent and 30% among those that do not consent. Hence, we estimate an overall 
success rate in the intervention group of 52.5%. We further assume an intra-cluster correlation of 0.015, 
a mean cluster size of 8 (standard deviation=5) and a probability of success of 35% in the control group. 
We calculate that a sample size of 304 (152 in each arm, 19 clusters per study arm) is required to detect 
superiority with a type I error of 0.025 and a statistical power of 80%. 
 
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Figure 3 Individual sample size calculation for different power and type I error levels for aHT TwiC 1 
 
Figure 4 Cluster sample size calculation for different power and type I error levels for aHT TwiC 1 
 
10.2.2 aHT TwiC 2 
We set the non-inferiority margin for the odds ratio (OR) of reaching the primary endpoint to 0.58. On 
an absolute scale, this margin corresponds to a higher probability of failing to reach the primary outcome 
of 10 % in the intervention compared to the control group, assuming that the probability of success for 
the participants enrolled in the control arm is 80%. We assume an intra-cluster correlation of 0.015, a 
mean cluster size of 10 (standard deviation=5) and a probability of success of 80% in both intervention 
and control groups. This implies a sample size of 780 across 78 clusters (390 in each arm, 39 clusters per 
study arm) to be able to detect non-inferiority with a type I error of 0.025 and a statistical power of 80%. 
We inflate the calculated maximal number of cluster among the two TwiCs by 25% in order to account 
for uncertainties in the estimates of aHT prevalence, number of ComBaCaL village inhabitants and the 
consent rate. We finally aim to recruit 100 clusters (50 per study arm) for a total of 800 participants with 
uncontrolled aHT (TwiC 1) and 1000 participants with controlled aHT (TwiC2). 
 
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Figure 5 Individual sample size calculation for different power and type I error levels for aHT TwiC 2 
 
 
 
Figure 6 Cluster sample size calculation for different power and type I error levels for aHT TwiC 2 
 
10.3 Description of statistical methods  
Analyses will be performed following the principles for analysis of cluster-randomized trials in health 
research as outlined by Donner and Klar43.  
All analyses will be done using Stata44 or R45. 
 
10.3.1 Datasets to be analysed, analysis populations 
For both TwiCs, the intention-to-treat (ITT) set includes all participants as allocated per random selection 
of villages except those with reported pregnancy, a documented move out of the village, or traumatic 
death during the follow-up period who will be excluded. Participants with missing values (excluding 
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those moved out and those with traumatic death and those pregnant) will be considered as not having 
reached the endpoint of BP < 140/90 mmHg.  
For both TwiCs the per-protocol (PP) set includes all participants who linked to care according to the 
group specific procedure (i.e. all participants in intervention villages with at least one clinical visit in 
relation to aHT management by a CC-VHW and in the control villages, participants with at least one 
clinical visit in relation to aHT management at a health centre). Participants with missing values 
(excluding those moved out or those becoming pregnant and those with traumatic death during follow-
up) will be considered as not having reached the endpoint of BP < 140/90 mmHg. 
For both TwiCs, the complete case ITT set includes the same population as the ITT set. However, 
participants with missing endpoint data will be excluded instead of being considered as not having 
reached the endpoint of BP <140/90 mmHg.  
For both TwiCs, the complete case PP set includes the same population as the PP set. However, 
participants with missing endpoint data will be excluded instead of being considered as not having 
reached the endpoint of <140/90mmHg. 
For TwiC 1, we are considering a Complier Average Causal Effect (CACE) analysis to assess the impact of 
compliance with the intervention as this provides a more unbiased treatment effect than a per protocol 
or as-treated analysis and the underlying assumptions for such an instrumental variable approach are 
given. We will obtain the CACE estimator using a “two-stage least squares” (TSLS) approach, which jointly 
models the two processes of participation and outcome (i.e. regression model of participation, and 
regression model predicting the outcome, given participation). Such a TSLS approach yields more 
accurate estimates and confidence intervals, than simply dividing the mean effect estimate by the 
proportion of compliers.46 
10.3.2 Primary analysis 
We will use a mixed effect logistic regression model with random intercept at the level of the clusters to 
assess the effect of the intervention.  
 
10.3.2.1 aHT TwiC 1 
Superiority will be assessed according to the 95% confidence interval of the odds ratio of the 
intervention of the ITT analysis. 
 
10.3.2.2 aHT TwiC 2 
Non-inferiority will be assessed according to the 95% confidence interval of the odds ratio of the 
intervention of the ITT and the PP analysis and the pre-defined non-inferiority margin. Further details 
will be provided in the statistical analysis plan (SAP). 
 
10.3.3 Secondary analysis  
Secondary endpoints will be reported using descriptive statistics such as mean and 95% Wald confidence 
intervals, frequency and percentages.  
Further details will be outlined in the SAP. 
 
10.4 Handling of missing data 
Participants with missing outcomes due to traumatic death, pregnancy or after documented moving out 
of the village, will be excluded from the analyses.  
Missing outcomes due to atraumatic death or without any documentation will be regarded as a negative 
outcome (i.e. as not meeting the target of 140/90mmHg) in both the ITT and the PP populations.  
In the complete case analyses, only participants with observed outcomes will be considered. Further 
details of missing data will be outlined in the statistical analysis plan (SAP). 
 
 
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11 DESCRIPTION OF DATA MANAGEMENT 
We refer to the current version of the “ComBaCaL cohort study protocol” for the description of data 
management. For this TwiC no other procedures than the ones outlined there apply.  
 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
We refer to the current version of the “ComBaCaL cohort study protocol” for the description of quality 
control and quality assurance. For this TwiC no other procedures than the ones outlined there apply. 
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13 ETHICAL CONSIDERATIONS 
13.1 Independent Ethics Committees (IECs) 
This protocol and any protocol amendments will be reviewed and approved by the National Health 
Research Ethics Council (NH-REC) of Lesotho and by the Ethics Committee of Northern and Central 
Switzerland (EKNZ) before implementation. 
 
13.2 Risk-benefit ratio 
There is no substantial health risk associated with participation in this study. The aHT screening, 
diagnosis and management offered will conducted in line with national and international 
recommendations. All participants found to be at risk for a relevant medical condition will be referred 
to the responsible health facility for professional work-up and care. 
Data collection will entail questionnaires, automated BP measurements, capillary blood measurements 
for lipid status. These procedures do not have the potential to cause significant harm to participants.  
No personalized data of participants will be shared with people other than the directly involved study 
team members if not agreed upon by the participant.   
The access to guideline-conform active community-based NCD screening will likely increase early case 
detection and thus improve access to potentially life-saving treatment. Additionally, follow-up in the 
community by CC-VHWs with re-linking services is likely to improve aHT care for participants. 
Potential risks associated with the TwiC intervention include inadequate management by lay CC-VHWs. 
We will minimize this risk by assuring adequate training, continuous supervision by health care 
professionals, and close guidance through the ComBaCaL eHealth application. Community-based care 
delivery is widely implemented in HIV care in Lesotho providing substantial benefits compared to purely 
clinic-based care. 
The evidence generated in this study may inform future national and international clinical guidelines to 
improve NCD care in low-resource settings. Additionally, the community-based activities provide the 
added benefit of building a healthy and friendly community environment through community advocacy 
and participation, and may help to raise awareness and knowledge of NCDs within participating villages. 
Thus, the ComBaCaL project is likely to have a direct positive impact on health outcomes of participants 
as well as generating evidence to improve context-specific NCD care on a longer perspective.  
This project will be carried out in accordance with the research plan outlined in this protocol and with 
principles enunciated in the current version of the Declaration of Helsinki as well as all national legal 
requirements and guidelines as applicable.  
 
13.3 Participant information and consent 
The ComBaCaL cohort consent is based on the cmRCT18 approach, i.e. all cohort participants consent to 
being randomized as part of a TwiC. Participant information and consent seeking for the ComBaCaL 
cohort will be conducted by the local ComBaCaL VHW in a three-stepped approach, first orally on village 
level, secondly orally on household level, and thirdly in written electronic form on individual level. We 
refer to the “ComBaCaL cohort study protocol” for details.  
Participants that are being randomized to the control group, will not be bothered and data collected 
within the scope of the ComBaCaL cohort will be used for the TwiC analysis, too without further TwiC-
specific information or consent. For villages randomized into the TwiC intervention group, an oral village 
consent from the village chief will be sought before the intervention will be offered to eligible individuals 
in the community. Participants may decline any of the offered services without implications on further 
cohort affiliation and their data will also be used for TwiC analyses. As the intervention does not entail 
any activities other than the task-shifting of standard-of-care aHT management components from 
primary healthcare professionals to CC-VHWs, oral intervention consent will be sought as outlined in the 
“ComBaCaL cohort study protocol”. Before the delivery of services (i.e. the prescription of medications), 
the CC-VHWs will provide the participants with information about the risks and benefits of the respective 
care component. The completeness of information provided will be documented with a checkbox in the 
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ComBaCaL app. In addition, the participants will be asked whether they are willing and ready to accept 
the care component offered. The participants may freely accept or refuse any care component offered 
or ask for more time for consideration until a follow-up visit a few days later. Only after documentation 
of the participants’ readiness in the ComBaCaL app by the CC-VHWs the prescription of medications will 
be possible.  
 
Participants will be able to reject care by the CC-VHW in the village at any time during the study and 
request referral to a health facility. Participants consenting to participation but subsequently rejecting 
care offered by the CC-VHW might be approached for qualitative inquiry on the reasons for the refusal 
of community-based care. 
 
 
Figure 7 Consent cascade in ComBaCaL cohort and TwiC. Yellow: Consent, Orange: Randomization, Blue: Training or field 
activity 
 
 
Withdrawal on household or individual level 
ComBaCaL cohort consent can be withdrawn any time on individual or household (by household head) 
level without justification. No specific consent for the TwiC intervention will be sought at household 
level. Data collected until the time of withdrawal will be retained in the database. 
 
Service delivery for people declining consent 
CC-VHWs will offer the same screening, diagnostic and referral services to participants declining the 
intervention in intervention villages as in control villages.   
 
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13.4 Participant confidentiality 
The investigators will ensure that the participants’ confidentiality will be maintained at all times during 
and after the study, following procedures outlined in section 6.1 (enrolment procedures) and section 8 
(data management). 
 
13.5 Participants requiring particular protection 
Pregnant women with aHT will not be included in the intervention but being referred to the responsible 
health facility for further assessment and management. The same applies to people with a severe 
comorbidity with an estimated life-expectancy of less than one year.  
This study has a strong service delivery aspect and often people with mental or physical conditions 
impairing capacity for informed consent are particularly vulnerable to NCDs such as aHT and its 
complications. Therefore, we will offer the intervention also to eligible people with impaired judgement 
if an oral guardian consent for the intervention is provided.  
 
13.6 Participant compensation 
No compensation will be paid for participation in the study.  
 
 
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14 FUNDING 
This research project is funded by the Swiss Agency for Development and Cooperation (SDC) and by the 
World Diabetes Foundation (WDF), through grants issued to SolidarMed. A written agreement between 
SolidarMed and the Division of Clinical Epidemiology of the University Hospital Basel defines the terms 
for the collaboration on the research aspects of the project. The funding sources are not involved in the 
study design, data collection, data analysis, interpretation of the results, or writing the manuscript. The 
study will be embedded in the SolidarMed Lesotho programme and will thus benefit from logistics and 
human resources of this organisation. The listed co-investigators have no conflicts of interest. 
 
 
15 DISSEMINATION OF RESULTS AND PUBLICATION POLICY 
15.1 Dissemination to scientific community 
International scientific conferences and publications in scientific peer-reviewed journals will serve for 
wider dissemination of results. Preference will be given to journals with an open-access publication 
model. Further, anonymised datasets will be made available on open data repositories, such as 
www.zenondo.org. The study will be registered on ClinicalTrials.gov prior to the start of the trial and a 
summary of the study protocol will be published in a peer-reviewed journal. The current version of the 
International Committee of Medical Journal Editors (ICMJE) recommendations is applicable regarding 
authorship eligibility.47 The use of professional writers is not intended. 
 
15.2 Information of community and policy makers 
Results of this study will be shared with stakeholders at district and national level. In Lesotho, health 
care workers and stakeholders will be informed about the findings during district meetings headed by 
the District Health Management Team (DHMT) and at national level, the national research symposium 
of the MoH and the NCD Technical Working Group will serve as platforms to share the results and discuss 
their implications among the policy makers.  
 
 
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16 APPENDIX 
 
Figure 8 Treatment algorithm for uncomplicated hypertension. BP: Blood pressure, SPC: Single-pill combination, SBP: Systolic 
blood pressure, CVD: Cardiovascular disease 
In ComBaCaL intervention villages, participants diagnosed with aHT without contraindications will be 
offered antihypertensive pharmacotherapy according to the algorithm above.  
The molecules included in the antihypertensive SPC will be in line with the then valid Lesotho Standard 
Treatment Guidelines and with the selection of drugs that is available locally in routine primary 
healthcare. At the time of writing of this protocol, the Standard Treatment Guidelines of Lesotho were 
still at a draft stage and the Ministry of Health (MoH) of Lesotho was still in discussions about which SPC 
to procure, hence we are not specifying it here. According to the current draft version of the Lesotho 
Standard Treatment Guidelines, a combination of a calcium channel blocker (amlodipine) and a thiazide-
like diuretic (hydrochlorothiazide or indapamide) will be used.  
For the BP check-ups, the participant will be advised to rest and sit with the back supported. The average 
of the last two of three measurements will be considered (see current version of the ComBaCaL cohort 
protocol for details regarding BP measurements and the diagnostic algorithms applied).  
Participants with high CVD risk, and no contraindications will be offered a lipid-lowering treatment using 
a statin in a fire-and-forget approach. High CVD risk among the participants diagnosed with aHT is 
defined as additionally having a history of stroke or myocardial infarction, having DM or chronic kidney 
disease (CKD) or being 50 years or older and having one or both of the following risk factors: BMI ≥ 30 
kg/m2, currently smoking. The molecule used will be in line with the Lesotho Standard Treatment 
Guidelines and with what is locally available in routine primary healthcare.  
Participants with a history of myocardial infarction or stroke will be offered antiplatelet treatment using 
aspirin in line with the Lesotho Standard Treatment Guidelines.  
At every visit, the CC-VHW will ask the participant about the current medication, adherence, potential 
side effects and contraindications against the treatment offered. This data will be documented in the 
ComBaCaL app.  
Participants will be referred to a health facility for further care in case of complicated disease, unclear 
conditions, side effects against the antihypertensive treatment provided or if participants are not 
reaching treatment targets under the provided first-line treatment.  
 
 
 
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