Community-Based Chronic Disease Care in Rural Lesotho: The ComBaCaL Cohort Study
Conditions: Non-communicable Diseases (NCDs)
Sponsor: University Hospital, Basel, Switzerland

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Study Protocol 
 
 
Community-Based chronic disease Care in rural Lesotho: The ComBaCaL 
cohort study 
 
 
Type of Research 
Project 
Research project involving collection of health-related data from 
persons  
 
Study acronym/ID 
ComBaCaL cohort study 
Protocol Version Nr 
2.0  
Date 22.12.2025  
 
Project Leaders / 
Responsible 
Prof. Dr. Niklaus Labhardt, MD, DTM&H, MIH 
Division Head 
Division of Clinical Epidemiology  
University Hospital Basel  
University of Basel 
Totengaesslein 3, 4001 Basel, Switzerland 
+4179 870 18 59 
niklaus.labhardt@usb.ch 
 
Funding Agency 
Swiss Development Cooperation, World Diabetes Foundation 
 
 
 
 
 
 
 
 

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1 GENERAL INFORMATION 
 
I. 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 
Principal Investigator 
& 
Steering Committee 
Member 
MD 
Ayakaka Irene  
SolidarMed Lesotho 
Technical 
Director 
National Project 
Leader 
BSc 
Madavida 
Mphunyane 
NCD Program, Ministry 
of Health Lesotho 
Program 
Manager 
Steering Committee 
Member 
MD 
Litaba Malitaba 
NCD Program, Ministry 
of Health Lesotho 
NCD Doctor 
Steering Committee 
Member 
MD 
Sao Lebohang 
District Health 
Management Team 
Butha-Buthe 
District 
Medical 
Officer 
Steering Committee 
Member 
MD 
Tlahali Mosa 
District Health 
Management Team 
Mokhotlong 
District 
Medical 
Officer 
Steering Committee 
Member 
MBBS, MPH 
Gupta Ravi  
SolidarMed Lesotho 
Project 
Manager 
Project Manager, 
Study physician 
PhD 
Chammartin 
Frédérique 
Division of Clinical 
Epidemiology, University 
Hospital Basel, 
University of Basel 
Scientific 
Collaborator 
Statistician 
MD/PhD 
Gerber Felix 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
Post-doctoral 
researcher  
Co-Investigator 
MD/PhD 
Amstutz Alain 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
Post-Doctoral 
Researcher 
Co-Investigator 
MSc 
Raeber Fabian 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
MD PhD 
Student 
Co-Investigator 
MSc 
Mahlatsi Palesa 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
PhD Student 
Co-Investigator 
MSc 
Saavedra Elis 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
PhD Student 
Co-Investigator 
MD 
Tarumbiswa 
Tapiwa 
HIV & AIDS Program, 
Ministry of Health 
Lesotho  
HIV & AIDS 
Program 
Manager 
 
Co-Investigator 
MSc 
Phate-Lesihla 
Rosina 
HIV & AIDS Program, 
Ministry of Health 
Lesotho  
 
Clinical 
Officer  
Co-Investigator 

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MD 
Nthuseng 
Bridgett Marake 
HIV & AIDS Program, 
Ministry of Health 
Lesotho 
 
HIV 
Treatment 
and Care 
Officer 
 
Co-Investigator 
MD 
Mamotena 
Sekhobe 
Family Health Division, 
Ministry of Health 
Lesotho 
 
Head of 
Family Health 
Division 
Co-investigator 
 
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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II. Signatures 
 
Study Title: “Community-Based chronic disease Care in rural Lesotho: The ComBaCaL cohort study” 
The following project leaders have approved the protocol version 2.0, dated 22.12.2025, 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: 
• 
I have read this protocol version 2.0, dated 22.12.2025, 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. 
• 
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. 
• 
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. 
• 
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. 
• 
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 Investigator 
Signature 
 
 
 
 
Name  
Niklaus Labhardt 
Date of Signature 
(DD.MM.YYYY) 
Title 
Prof. Dr. DTM&H, MIH 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel 
Address 
Totengaesslein 3, 4001 Basel 
Phone 
+41 79 870 18 59 
 
 
 
National Principal Investigator 
Signature 
 
 
 
 
Name  
Irene Ayakaka 
Date of Signature 
(DD.MM.YYYY) 
Title 
MD 
Institution 
SolidarMed Lesotho 
Address 
Happy Villa, House No. 3A 
Phone 
+266 28325172 
 
 

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Statistician 
Signature 
 
 
 
 
Name  
Frédérique Chammartin 
Date of Signature 
(DD.MM.YYYY) 
Title 
PhD 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel 
Address 
Totengaesslein 3, 4001 Basel 
Phone 
+41 79 269 19 18 
 
 
 
 
 
 
 
 
 
 

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Table of contents 
 
1 
General Information 
2 
I. 
List of Project Leaders and other key persons involved in the study 
2 
II. 
Signatures 
4 
III. 
Abbreviations / Glossary of terms 
9 
IV. 
Synopsis 
11 
2 
Background information 
18 
2.1 
NCD burden ........................................................................................................................................................... 18 
2.2 
Decentralized integrated chronic care and prevention .............................................................................................. 18 
3 
Objectives and purpose 
20 
3.1 
Objectives .............................................................................................................................................................. 20 
3.1.1 
Specific objectives 
20 
3.2 
Scientific justification of study population ................................................................................................................. 20 
4 
Study design 
22 
4.1 
Variables of interest ............................................................................................................................................... 22 
4.1.1 
Cohort variables 
22 
4.1.2 
Implementation outcomes 
25 
4.2 
Measures to minimize bias...................................................................................................................................... 25 
4.2.1 
Blinding 
25 
4.2.2 
Measurements 
26 
4.2.3 
Randomization 
26 
4.3 
Study duration and duration of participant’s participation .......................................................................................... 26 
4.4 
Amendments .......................................................................................................................................................... 26 
4.5 
Withdrawal and discontinuation ............................................................................................................................... 26 
4.5.1 
Individual level 
26 
4.5.2 
Study and village level 
26 
4.6 
End of project......................................................................................................................................................... 27 
5 
Selection of study participants 
28 
5.1 
Selection of villages ............................................................................................................................................... 28 
5.2 
Selection of VHWs ................................................................................................................................................. 28 
5.3 
Recruitment of participants ..................................................................................................................................... 29 
6 
Study procedures 
30 
6.1 
General Setting ...................................................................................................................................................... 30 
6.2 
Baseline................................................................................................................................................................. 30 
6.3 
Follow-up ............................................................................................................................................................... 30 
6.3.1 
Regular follow-up 
30 
6.3.2 
Clinical follow-up 
31 
6.4 
Implementation assessments .................................................................................................................................. 31 
7 
Safety considerations 
32 
7.1 
Definition and documentation of safety outcomes .................................................................................................... 32 
7.2 
Causality of SCE(SI)s and CESIs ............................................................................................................................ 33 
7.3 
Reporting of SCEs and CESIs ................................................................................................................................. 33 
8 
Statistics 
34 
8.1 
Determination of sample size .................................................................................................................................. 34 
8.2 
General cohort statistics ......................................................................................................................................... 34 
8.3 
Analysis of the ComBaCaL activities’ effects on chronic disease care cascades ........................................................ 34 
8.3.1 
Hypothesis 
34 
8.3.2 
Endpoints 
34 
8.3.3 
Statistical methods 
35 
8.4 
Handling of missing data ........................................................................................................................................ 35 
9 
Description of data management 
36 
9.1 
Specification of source documents .......................................................................................................................... 36 
9.2 
Data recording ....................................................................................................................................................... 36 
9.3 
Confidentiality and coding ....................................................................................................................................... 36 
9.4 
Data security, access, archiving and back up ........................................................................................................... 37 
9.5 
Data storage on public data repositories .................................................................................................................. 37 
10 
Quality control and quality assurance 
38 
10.1 Supervision ............................................................................................................................................................ 38 
10.1.1 
Local supervision and data quality checks 
38 
10.1.2 
Central data monitoring and quality checks 
38 
10.2 Translations - Reference language .......................................................................................................................... 38 
10.3 Monitoring and auditing .......................................................................................................................................... 38 
10.4 Storage of biological material and related health data .............................................................................................. 39 
11 
Ethical considerations 
40 
11.1 Independent Ethics Committees (IECs) ................................................................................................................... 40 
11.2 Risk-benefit ratio .................................................................................................................................................... 40 
11.3 Participant information and consent ........................................................................................................................ 40 
11.3.1 
Household consent 
40 
11.3.2 
Individual consent 
41 
11.3.3 
Withdrawal on household or individual level 
41 
11.3.4 
Service delivery for people declining consent 
41 
11.4 Participant confidentiality ........................................................................................................................................ 41 
11.5 Participants requiring particular protection ............................................................................................................... 42 

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11.6 Participant compensation........................................................................................................................................ 42 
12 
Funding 
43 
13 
Dissemination of results and publication policy 
43 
13.1 Dissemination to scientific community ..................................................................................................................... 43 
13.2 Information of community and policy makers ........................................................................................................... 43 
14 
Appendix 
44 
14.1 Screening and diagnosis of aHT.............................................................................................................................. 44 
14.2 Screening and diagnosis of (pre)DM........................................................................................................................ 45 
15 
References 
46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
III. Abbreviations / Glossary of terms 
 
aHT 
Arterial hypertension 
ANC 
Antenatal care 
BMI 
Body mass index 
BG 
Blood glucose 
BP 
Blood pressure 
CC Nurse 
Chronic Care Nurse 
CESI 
Clinical event of special interest 
CHT 
Community Health Toolkit  
cmRCT 
Cohort multiple randomized controlled trials 
ComBaCaL 
Community-Based Chronic Disease Care Lesotho 
CVDRF 
Cardiovascular disease risk factor 
DHMT 
District Health Management Team 
DKF 
Department for Clinical Research 
DM 
Diabetes mellitus 
EKNZ 
Ethics Committee of Northern and Central Switzerland 
ESC/ESH 
European Society of Cardiology/ European Society of Hypertension  
FBG 
Fasting blood glucose 
HbA1c 
Glycated haemoglobin 

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HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus  
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IT 
Information technology 
LMICs 
Low- and middle-income countries 
MoH 
Ministry of Health 
MTA 
Material transport agreement 
MUAC 
Mid-upper arm circumference 
NCD 
Non-communicable disease 
NH-REC 
National Health Research Ethics Council 
PLHIV 
People living with HIV  
PNC 
Postnatal care 
PrEP 
Pre-exposure prophylaxis  
RBG 
Random blood glucose 
SCE 
Serious clinical event 
SCESI 
Serious clinical event of special interest  
SDC 
Swiss Agency for Development and Cooperation 
SRHR  
Sexual and Reproductive Health and Rights  
TB 
Tuberculosis 
TwiC 
Trial within cohort 
UHC 
Universal Health Coverage 
UNAIDS 
Joint United Nations Programme on HIV/AIDS 
VHW 
Village health worker 
VL 
Viral load 
WDF 
World Diabetes Foundation  
WHO 
World Health Organization  
 
 
 

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IV. Synopsis 
 
Project Leaders 
Prof. Dr. Niklaus Labhardt  
 
Study Title 
Community-Based chronic disease Care in rural Lesotho: The ComBaCaL 
cohort study 
Short Title/Study ID 
ComBaCaL cohort study  
Protocol Version 
and Date 
Version 2.0, 22.12.2025 
 
The purpose of amended protocol version 2.0 is to expand the scope of 
the cohort study and to facilitate the preparation for nested trials within 
cohorts (TwiCs), aimed at generating evidence on integrated 
community-based prevention and care strategies to support Universal 
Health Coverage (UHC) in rural Lesotho. In addition to non-
communicable diseases (NCDs) and HIV-related conditions, data 
collection will be broadened to include other conditions and essential 
health service needs, such as those related to sexual and reproductive 
health and rights (SRHR) and child health – most of which are 
traditionally managed by Village Health Workers (VHWs) in Lesotho 
already. The variables of interest outlined in the original protocol 
(Version 1.0) mainly remain unchanged, as they were already collected. 
However, the follow-up period has been extended, and new windows for 
endpoint collection have been added. The newly included endpoints 
related to additional health needs and conditions will be monitored from 
the time of the update onward. 
Study Category 
with 
Rationale 
Cohort study 
Risk category A 
Background and 
Rationale 
Globally, non-communicable diseases (NCDs) are the leading cause of 
death and disability1 with a particularly high burden in LMICs, where 
more than 75% of all premature NCD deaths occur.2 In Southern Africa, 
the NCD burden 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, 
arterial 
hypertension (aHT), obesity, diabetes mellitus (DM), dyslipidemia, and 
air pollution.3–6 At the same time, infectious diseases and health 
challenges in sexual and reproductive health rights (SRHR) and child 
health continue to persist – contributing to a situation that presents an 
increasingly complex burden of diseases requiring novel integrated 
health service delivery approaches. 
 
Despite a drastic health worker shortage, particularly in the rural areas 
where the majority of the population lives, and the second-highest adult 
HIV prevalence globally (21.1%)8 Lesotho has managed to reduce HIV 
transmission and AIDS-related deaths considerably.9 This success is 
based on decentralized HIV testing and care, involving lay village health 
workers (VHWs) to deliver accessible and equitable services in urban and 
rural areas alike.10,11 It has been demonstrated that decentralization and 
task shifting of healthcare services to lay healthcare workers have the 
potential to bring services closer to the community and to reduce access 

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barriers such as transport costs, travel time and lacking awareness 
without compromising quality of care, therefore forming the basis for 
integrated, community-based health service delivery.12–14 However, 
current community-based care delivery services in Lesotho and other 
Southern African countries remain largely fragmented with separate 
structures for HIV, SRHR and child health and are often largely neglecting 
NCDs.15 NCD care is located at health facilities where due to high 
workload, shortage of staff, lack of specific training and outdated 
practices, essential services often cannot be delivered adequately.  
HIV and NCDs are chronic diseases and share several characteristics such 
as the asymptomatic initial phase, progression to complications with 
disability and early death, and need for life-long treatment. Integrated 
service delivery models have the potential to address these jointly, while 
not only promoting a more efficient and coordinated use of resources 
but also potentially improving coverage and outcomes of essential 
health services. Despite its potential, there is only limited evidence on 
the effectiveness and implementation of community-based integrated 
health service delivery models in the Southern African context.  
 
In the open, prospective ComBaCaL cohort study, we aim to 
longitudinally investigate the burden of conditions related to NCDs, HIV, 
SRHR and child health, gaps in essential health service needs, and 
associated factors in rural Lesotho. Additionally, we seek to generate 
evidence on community-based, integrated prevention and care 
approaches to advance UHC in rural Lesotho and similar settings through 
nested trials. The health service delivery includes (either partially or 
fully) screening, diagnosis, monitoring, treatment/prevention support, 
and management for a range of conditions related to NCDs, HIV, SRHR 
and child health - provided by VHWs in a rural Southern African setting. 
Objectives 
 
• 
To assess the prevalence, treatment rate, control rate and risk 
factors of conditions of interest and essential health service 
needs over time in the districts of Butha-Buthe and 
Mokhothlong, Lesotho 
• 
To assess and describe implementation outcomes of VHW-led, 
community-based data collection and service delivery, i.e. the 
feasibility, acceptability, appropriateness, resource use, costs, 
service coverage and quality of data collected and services 
provided 
• 
To assess the effect of the ComBaCaL activities on condition-
specific care cascade outcomes, such as screening coverage, 
disease awareness, and linkage to careTo provide a platform for 
nested pragmatic trials (Trials within a Cohort, TwiCs) for the 
assessment of community-based, integrated prevention and 
care interventions 
Cohort variables 
and 
implementation 
outcomes 
Cohort variables 
The variables below will be collected at baseline or at the time of a 
cohort update. Variables which may change over time will be reassessed 
during follow-up visits at flexible intervals depending on clinical need 
and requirements of nested trials. Data for these variables are either 

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self-reported or retrieved from the personal health booklet, health 
registries, or obtained through screening tests or follow-up testing.  
 
 
For this protocol version household level data are: 
o Number of household members. A household member is 
defined as recognized as such by the head of household 
or representative. 
o Geolocation (GPS coordinates) 
o Socioeconomic indicators (household wealth, food 
security and healthcare access) 
 
For this protocol version individual sociodemographic data are:  
o Date of birth 
o Sex  
o Level of education (>= 10 years)  
o Income generating activity (>= 18 years) 
 
For this protocol version conditions of interest are:  
o AHT (>= 18 years)  
o (pre)DM (>= 40 years or >= 18 years and BMI >= 25kg/m2) 
o HIV and HIV related conditions 
o Cervical cancer and pre-cancerous cervical lesions (>= 18 
years) 
o Tuberculosis (People living with HIV (PLHIV) 
o Pregnancy (females >= 12 years)  
o Malnutrition (=< 5 years)  
 
For this protocol version essential health services are:   
o Family planning services (>= 12 years)  
o Maternal health services (>= 12 years and pregnant or 
recently given birth)  
o Under-5 child health services (=< 5 years) 
o NCD prevention (>= 10 years) and care (>= 18 years) 
o HIV prevention (>= 12 years) and care  
o Tuberculosis prevention and care (PLHIV & >= 12 years) 
 
For this protocol version the following indicators will be assessed: 
• 
Individual sociodemographic indicators 
• 
Presence of conditions of interest 
o For aHT, DM and HIV: see diagnostic algorithm in 
the appendix 
o Health 
information 
and 
risk 
factors 
for 
conditions of interest  
o Height, weight and BMI  
o Abdominal circumference (>= 10 years) 
o Targeted medical history such as presence of 
chronic kidney disease, prior stroke, prior 
myocardial infarction, prior cervical cancer/pre-
cancerous cervical lesions, prior TB diagnosis, 
prior pregnancies and births 

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o Physical activity using the validated International 
Physical Activity Questionnaire Short Form 
(IPAQ-SF)36, which has been adapted to the local 
context and language according to the IPAQ 
recommendations37 (>= 10 years) 
o Diet; using a shortened unquantified food 
frequency questionnaire adapted from an 
assessment tool for obesity used in South 
Africa38(>= 10 years)     
o Alcohol, tobacco and other substance use using 
the 
Alcohol, 
Smoking 
and 
Substance 
Involvement Screening Test (ASSIST)39 and/or 
the AUDIT-C questionnaire for assessing alcohol 
consumption or validated questionnaires (>= 10 
years) 
o Blood pressure (BP) (>= 18 years) 
o Blood glucose (BG) (>= 40 years or >= 18 years 
and BMI >= 25kg/m2) 
o HbA1c (diagnosed with (pre)DM (depending on 
access to and availability of HbA1c)) 
o HIV risk behaviour assessment using an adapted 
version of the risk screening tool from Lesotho’s 
national guidelines on the use of antiretroviral 
therapy for HIV prevention and treatment (>= 12 
years) 
o Immunisation status: Assessment of complete or 
incomplete immunisation status as per Lesotho 
national immunisation schedule (=< 5 years; for 
HPV: =< 15 years and female) 
o Under-5 malnutrition screening and growth 
monitoring: Malnutrition screening and growth 
monitoring using mid-upper arm circumference 
(MUAC), weight-for-age growth charts and 
checking for the presence of pitting oedemas (=< 
5 years) 
• 
Prevention and care cascade indicators for the essential 
health service needs and conditions of interest: 
o Screening coverage: number of participants who 
have been screened (among those who are 
screening-eligible) for essential health service 
needs or conditions of interest  
o Condition and health service awareness: number 
of participants who are aware of their condition 
of interest or the health services respective to 
their need(s) 
o Linkage to prevention and care: number of 
participants linked to prevention and care 
o Engagement in prevention and care: number of 
participants reporting drug intake for their 
respective essential health service needs or 
conditions of interest 

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o Adherence: adherence level of participants being 
engaged in prevention and care for respective 
essential health services needs or conditions of 
interest 
o Met essential health service needs and control 
level for condition of interest: number of 
participants who have their essential health 
service needs met or with controlled conditions 
of interest (including BP <140/90 mmHg for aHT, 
FBG < 7mmol/l and/or HbA1C < 7.0% for DM and 
documented viral suppression for HIV in the last 
12 months) 
• 
Occurrence of clinically relevant events (see section 
7.1)  
 
Implementation outcomes 
• 
Feasibility, 
acceptability, 
satisfaction, 
perceived 
appropriateness and other implementation outcomes of 
ComBaCaL activities among participants, VHWs, involved 
healthcare professionals and further stakeholders using mixed-
methods assessments 
• 
Coverage indicators, such as number of households visited by 
VHW, number of individuals monitored by one VHW, number of 
forms submitted per individual and specific prevention and care 
service, and number of individuals newly diagnosed with a 
condition of interest, number of inhabitants refusing ComBaCaL 
services  
• 
Resource use and cost of the ComBaCaL activities, including 
assessment of time-and-motion data among VHWs 
• 
Quality indicators of the ComBaCaL activities, such as 
completeness of the data collected by VHWs and adherence to 
clinical algorithms provided via the eHealth application and 
through quarterly supervisory checks on a randomly selected set 
of participants to confirm the data accuracy 
 
Study Design 
ComBaCaL is designed as an open prospective cohort study enrolling 
inhabitants of randomly selected villages in the rural areas of Butha-
Buthe and Mokhothlong districts in Lesotho. Each cohort village will be 
managed by a VHW, who lives in the village and is being elected by the 
village population. VHWs will be supported by a specifically developed 
eHealth application built on the CHT core framework (referred to for the 
purpose of this protocol as ComBaCaL app) for data collection and 
clinical decision-making. 
The ComBaCaL VHWs in all villages will regularly assess chronic disease 
indicators and risk factors and offer linkage services if relevant 
conditions are detected.  
For an implementation assessment of the cohort activities, metadata 
analysis of reports submitted via the ComBaCaL app, time-and-motion 
data, costing data and mixed-methods acceptability, satisfaction and 

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perceived appropriateness assessments as well as other implementation 
outcomes among different stakeholders will be used. 
In addition to the cohort procedures described in this protocol, we plan 
to conduct community-based interventions within the ComBaCaL cohort 
villages in a cohort multiple randomized controlled trials (cmRCT) 
approach19 also known as TwiCs. Each TwiC will be submitted separately 
to the Independent Ethics Committees (IECs) with reference to this 
protocol.  
Inclusion/Exclusion 
Criteria 
Inclusion criteria village level: 
• 
Estimated village size of 40 to 100 households 
• 
Village consent by village chief 
• 
Possibility to recruit and train a VHW from the village population 
who fulfils the eligibility criteria (outlined in chapter 5.2) 
Inclusion criteria individual level:  
• 
Primary residency in the respective village 
• 
Verbal household consent and written individual consent (or 
guardian consent for children and adolescents below the age of 
18 years) 
Measurements and 
Procedures 
For the cohort recruitment, all households of selected villages will be 
contacted by the VHWs in door-to-door visits. Consent will be sought 
first orally at household level from the household head or his/her 
representative in case of absence and then in written, electronic form at 
individual level.  
At baseline, the variables of interest at household and individual level 
will be collected by the VHWs. All adult participants will be screened for 
aHT via standardized screening algorithms using automated BP 
measurements (see appendix). Adult participants, 40 years or older or 
having a BMI equal or above 25kg/m2 will be screened for (pre)DM 
according to standardized screening algorithms using capillary BG 
measurements (see appendix). HbA1c levels may be measured in 
participants diagnosed with (pre)DM (depending on access to and 
availability of HbA1c). Pregnancy screening will be done using a 
pregnancy screening checklist and urine pregnancy tests. Participants 12 
years or older will be offered an oral HIV screening test for which follow-
up testing will be provided by VHW supervisors in case of reactive 
results. For participants younger than 5 years the mid-upper arm 
circumference (MUAC) measurements are done using specific MUAC 
measurement tapes. Growth monitoring will be done using the weight-
for-age growth charts provided by the Ministry of Health (MoH). 
Presence of pitting oedemas will be checked when assessing for 
malnutrition.     
Participants with clinical alarm signs or symptoms or any medical 
condition requiring further diagnostic work-up or treatment will be 
referred to the closest health facility or the respective district hospital.  
Follow-up visits by the VHWs will be conducted based on the clinical 
need and on requirements of nested trials throughout the duration of 
the study.  
Clinically relevant events will be documented throughout the duration 
of the cohort follow-up by the VHWs in dedicated electronic report 
forms within the ComBaCaL app (see section 7 for definitions).   

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To document the process of implementing and maintaining the cohort, 
we will conduct mixed-methods assessments about the acceptability, 
satisfaction and perceived appropriateness of the community-based 
activities 
among participants, 
VHWs and involved healthcare 
professionals at different points in time. 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 VHWs via 
the ComBaCaL application.  
Number of 
Participants with 
Rationale 
In a first step, we aim to enrol inhabitants of around 100 (range 90-110) 
randomly selected villages in rural Lesotho. The estimated mean number 
of inhabitants per village is 200. All inhabitants will be approached for 
consent and all consenting individuals (assent plus guardian consent for 
adolescents (10-17 years), guardian consent for children <10 years) will 
be enrolled into the ComBaCaL cohort. Consent rate is expected to be 
high (ca. 80%). Thus, the number of cohort members is estimated to be 
around 16’000. 
The number of participants was chosen based on available resources and 
with the aim to allow for meaningful TwiCs for the assessment of 
community-based chronic disease care delivery strategies.  
Study Duration 
The cohort will be followed up for at least four years. Cohort follow-up 
might be prolonged if resources allow.   
Study Schedule 
First-Participant-In: January 2023 
Last-Participant-Out: Mid-year 2027, later if resources for further 
maintenance of the cohort become available 
Study Centre(s) 
Scientific lead: Division of Clinical Epidemiology, University of Basel 
Implementing partners: Ministry of Health Lesotho, SolidarMed Lesotho 
Study sites: Pre-selected villages in rural areas of Butha-Buthe and 
Mokhothlong districts in Lesotho 
Statistical Analysis 
incl. Power 
Analysis 
As an open prospective cohort, ComBaCaL aims to provide observational 
data on conditions and essential health service needs related to NCDs, 
HIV, SRHR and child health, as well as related risk factors at individual 
and household level in addition to operational indicators describing 
implementation aspects of the cohort.  
A description of the cohort at different time points will be presented 
using descriptive statistics. Ordinal and binary variables will be 
presented as counts and proportions with 95% confidence intervals. 
Continuous variables will be described as medians and inter-quartile 
ranges and means with 95% confidence intervals.  
Furthermore, the ComBaCaL cohort will serve as a platform for the 
implementation of pragmatic TwiCs. These TwiCs, including statistical 
analysis and sample size calculations will be detailed in separate 
protocols and submitted for ethics review with reference to this 
protocol.  
Ethical 
consideration 
This project will be carried out in accordance with this protocol and with 
principles enunciated in the current version of the Declaration of 
Helsinki20, as well as all applicable national legal requirements and 
guidelines.  
The protocol will be reviewed by the Ethikkommission Nordwest- und 
Zentralschweiz (EKNZ, Ethics Committee of Northern and Central 

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Switzerland) and by the National Health Research Ethics Committee (NH-
REC) of Lesotho. 
Participation is voluntary, risks are minimal and consent can be 
withdrawn at any time. The evidence generated in this study aims at 
informing future national and international clinical guidelines and 
policies to improve integrated community-based health service delivery 
in low-resource settings and advance toward UHC. Participants will 
benefit from improved services in their villages through presence of 
trained eHealth supported and supervised VHWs. Thus, the ComBaCaL 
study is likely to have a direct positive effect on health outcomes of 
participants while generating robust evidence to guide the improvement 
and scale-up of context-specific integrated care models. 

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2 BACKGROUND INFORMATION  
2.1 
NCD burden 
Globally, non-communicable diseases (NCDs) are the leading cause of death and disability with a 
particularly high burden in low- and middle-income countries (LMICs)1 where more than 75% of all 
premature NCD deaths occur and where about 80% of deaths are caused by NCDs, resulting in a 
disproportionate health and socio-economic burden21. Arterial hypertension (aHT) is associated with 
10.8 million annual deaths globally, mostly in LMICs’ rural areas, where treatment rates are below 30%3–
6,22. There is a lack of scientifically validated pragmatic and scalable prevention and care models in LMICs 
to make NCD screening and treatment equitably accessible18. In sub-Saharan Africa, the NCD burden has 
risen significantly over the past two decades, driven by the increasing prevalence of cardiovascular risk 
factors such as unhealthy diets, smoking, insufficient physical activity, aHT, obesity, diabetes mellitus 
(DM), dyslipidemia, and air pollution3,4. 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 20307.  
 
Lesotho is a landlocked country within South Africa, a typical example of an African LMIC where NCDs 
are overtaking HIV and other infectious diseases (especially TB) as major cause of disability, morbidity 
and early death7. Of the adult population, 22% are affected by aHT and 6% by DM.1,16 
 
2.2 
Decentralized integrated chronic care and prevention 
Extensive evidence shows that decentralization of healthcare services with task-shifting to community-
based lay cadres may (cost)-effectively increase access to care and improve health outcomes for a variety 
of diseases, especially in settings where professional healthcare workforce and financial health system 
resources are scarce.12,23–26 Based on these findings, the World Health Organization (WHO) is promoting 
the strategic integration of community-based healthcare services in existing health systems27 and the 
United Nations Programme on HIV/ AIDS (UNAIDS) has launched a plan to recruit 2 million community 
health workers in Africa to support such a strategy.28 
Community-based lay health workers are bringing services closer to the community and are reducing 
access barriers such as transport costs, travel time and lacking awareness. In the spirit of “leave no one 
behind”, community-based care offers more equitable and less stigmatized access to health services 
than facility-based care thereby advancing progress towards universal health coverage (UHC). In 
addition, it has the potential to strengthen civil society and create job opportunities in rural areas. 27 
 
As in many other sub-Saharan African 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 ago15. Despite a drastic health 
worker 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%)29, and the second-highest adult HIV prevalence 
globally (21.1%)8, 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 providers to deliver accessible and equitable services for the urban and rural 
population alike. The HIV programs in rural areas have demonstrated that in Lesotho, healthcare tasks 
can be successfully decentralized and shifted to lay village health workers (VHWs), who support and act 
as a link between the community and the clinics to decrease the burden on overwhelmed health 
facilities. Currently, the community-based healthcare delivery in Lesotho is focused on HIV and maternal 
and neonatal diseases, largely neglecting  other chronic conditions. Furthermore, facility-based services 
are strained by high workload, staff shortages, lack of specific training and medication stock-outs 
resulting in persistent prevention and care gaps.  

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Thus, extending community-based service delivery towards an integrated comprehensive package for 
conditions and essential health service needs related to HIV, SRHR and child health could present a 
promising approach to strengthen primary care in Lesotho.  
 
The Ministry of Health (MoH) of Lesotho has, in its NCD strategic plan, already proposed that lessons 
learnt from the HIV program should be incorporated into the NCD care strategy and that delivery 
platforms should provide integrated HIV/NCD services.30 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 the best of our knowledge, no 
studies have been conducted or policy documents developed on how to provide pragmatic and scalable 
integrated prevention and treatment models that address NCDs, HIV, SRHR and child health within the 
community in Lesotho. 
 
We plan to address this gap 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, integrated health service delivery model involving eHealth-
supported lay healthcare workers. The ComBaCaL cohort study provides the platform for the scientific 
assessment of the proposed community-based chronic disease care model through nested trials within 
cohorts (TwiCs).  
 
 

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3 OBJECTIVES AND PURPOSE 
3.1 
Objectives 
The overall objective of the ComBaCaL cohort study and subsequent nested trials is to assess the impact 
of community-based, lay-led prevention and care interventions towards UHC in rural Lesotho.  
We aim to establish a prospective research and service delivery platform in rural Lesotho that is managed 
by eHealth-supported VHWs providing regular screening, monitoring and referral services for conditions 
and health needs related to NCDs, HIV, SRHR and child health. We want to assess implementation 
outcomes of the cohort as well as the effect of the cohort activities on condition-specific prevention and 
care cascades. Subsequently, we will develop nested trials to assess the effectiveness and 
implementation of specific community-based health service delivery interventions.  
 
3.1.1 
Specific objectives 
• 
To assess the care cascades – including prevalence, treatment rate, control rate – as well as risk 
factors of various health conditions and essential health service needs over time in the districts 
of Butha-Buthe and Mokhothlong, Lesotho.  
• 
To assess and describe implementation outcomes of the VHW-led, community-based data 
collection and service delivery, i.e. the feasibility, acceptability, appropriateness, service 
coverage, resource use (including time and motion), costs and quality of the data collected and 
the services provided. 
• 
To assess the effect of the ComBaCaL activities on condition specific care cascade outcomes, 
such as screening coverage, disease awareness, and linkage to care. 
• 
To provide a platform for nested pragmatic trials for the assessment of community-based, 
integrated prevention and care interventions.  
 
3.2 
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 epidemic7.  
 
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 areas15. The Lesotho VHW program thus represents 
a meaningful starting point for implementation research on enhancing community-based healthcare 
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. The lack of 

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evidence on integrated, community-based prevention and care strategies that work to support UHC in 
rural Lesotho is the gap that the ComBaCaL cohort study is aiming to fill and that is justifying the choice 
for the rural setting in Lesotho where the need for local NCD implementation research has remained 
unaddressed so far.  
4 STUDY DESIGN 
The ComBaCaL cohort is an open prospective cohort enrolling inhabitants of randomly pre-selected 
villages in the rural areas of Butha-Buthe and Mokhothlong districts in Lesotho. At cohort initiation, we 
will enrol inhabitants of around 100 (range 90-110) villages. Each cohort village will be managed by a 
VHW, who lives in the village and is being elected by the village population. VHWs will be supported by 
the specifically developed tablet-based ComBaCaL app for data collection and clinical decision support 
for screening and diagnosis of conditions related to NCDs, HIV, SRHR and child health. VHWs will be 
supervised by healthcare professionals of the respective catchment area’s health facility and Chronic 
Care nurses (CC nurses).  
The VHWs in all villages will regularly update the cohort census, assess for indicators of our conditions 
and essential health service needs of interest and their associated risk factors. If required, they will offer 
linkage and monitoring services for the respective conditions.  
For an implementation assessment of the cohort activities, metadata analysis of reports submitted via 
the eHealth application, mixed-methods acceptability, satisfaction and perceived appropriateness 
assessments as well as time and motion data and other implementation outcomes among different 
stakeholders will be used. 
In addition to the cohort activities described in this protocol, we plan to assess the effect of community-
based chronic disease prevention and care interventions within the ComBaCaL villages in a cohort 
multiple randomized controlled trials (cmRCT) approach19,34,35 also known as trials within a cohort 
(TwiCs). These TwiCs are not part of this protocol but will be submitted separately to the IECs with 
reference to this protocol.  
 
4.1 
Variables of interest 
4.1.1 
Cohort variables 
 
All cohort variables will be assessed at baseline or at the time of a cohort update. Variables which may 
change over time will be reassessed during follow-up visits at flexible intervals depending on clinical 
need and requirements of nested trials.    
 
For this protocol version household level data are: 
• 
Number of household members. A household member is defined as recognized as such by the 
head of household or representative. 
• 
Geolocation (GPS coordinates) 
• 
Socioeconomic indicators (household wealth, food security and healthcare access) 
 
For this protocol version individual sociodemographic data are:  
• 
Date of birth 
• 
Sex 
• 
Level of education (>= 10 years)  
• 
Income generating activity (>= 18 years)  
 
For this protocol version conditions of interest are:   
• 
AHT (>= 18 years) 
• 
(pre)DM (>= 40 years or >= 18 years and BMI >= 25kg/m2) 
• 
HIV and HIV related conditions (all; people living with HIV (PLHIV)) 
• 
Cervical cancer and pre-cancerous cervical lesions (>= 25 years) 

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• 
Tuberculosis (PLHIV) 
• 
Pregnancy (>= 12 years) 
• 
Malnutrition (=< 5 years) 
 
For this protocol version essential health services are:  
 
• 
Family planning services (>= 12 years); including education, pregnancy screening, and 
comprehensive engagement in contraceptive care. 
• 
Maternal health services (>= 12 years and pregnant or recently given birth); including education, 
comprehensive engagement in antenatal and postnatal care, timely immunizations, as well as 
access to and use of preventive deworming and supplements (e.g. iron folate). 
• 
Under-5 child health services (=< 5 years); including education of caregivers, malnutrition 
screening, growth monitoring, timely immunizations, as well as access to and use of age-
appropriate preventive deworming and supplements (e.g. Vitamin A and other micronutrients). 
• 
NCD prevention (>= 10 years) and care (>= 18 years); including education, counselling on CVD 
prevention, screening and management of NCDs such as aHT, (pre)DM and pre-cancerous 
cervical lesions/cervical cancer. Adequate prevention of cervical cancer further encompasses 
timely HPV vaccination for adolescent girls aged 9-15 years. 
• 
HIV prevention (>= 12 years) and care; including education, access to and use of preventive 
methods (e.g. risk behaviour counselling, condoms or biomedical HIV prevention) and HIV 
testing. In addition, comprehensive engagement in HIV care entails access to and use of 
antiretroviral treatment and adherence support, as well as regular screening for opportunistic 
infections and monitoring of viral load. 
• 
Tuberculosis prevention and care (PLHIV & >= 12 years); including education, access to 
tuberculosis testing and diagnosis and tuberculosis preventive treatment. Furthermore, 
engagement in comprehensive tuberculosis care. 
 
For this protocol version the following indicators will be assessed: 
• 
Individual sociodemographic indicators 
• 
Presence of conditions of interest 
o For aHT, DM and HIV: see diagnostic algorithm in the appendix 
• 
Health information and risk factors for conditions of interest  
o Height, weight and BMI  
o Abdominal circumference (>= 10 years) 
o Targeted medical history such as presence of chronic kidney disease, prior stroke, 
prior myocardial infarction, prior cervical cancer/pre-cancerous cervical lesions, 
prior TB diagnosis, prior pregnancies and births  
o Physical activity using the validated International Physical Activity Questionnaire 
Short Form (IPAQ-SF)36, which has been adapted to the local context and 
language according to the IPAQ recommendations37 (>= 10 years) 
o Diet; using a shortened unquantified food frequency questionnaire adapted from 
an assessment tool for obesity used in South Africa38(>= 10 years)     
o Alcohol, tobacco and other substance use using the Alcohol, Smoking and 
Substance Involvement Screening Test (ASSIST)39 and/or the AUDIT-C 
questionnaire for assessing alcohol consumption or validated questionnaires (>= 
10 years) 
o Blood pressure (BP) (>= 18 years) 
o Blood glucose (BG) (>= 40 years or >= 18 years and BMI >= 25kg/m2) 
o HbA1c (diagnosed with (pre)DM (depending on access to and availability of 
HbA1c)) 

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o HIV risk behaviour assessment using an adapted version of the risk screening tool 
from Lesotho’s national guidelines on the use of antiretroviral therapy for HIV 
prevention and treatment (>= 12 years) 
o Immunisation status: Assessment of complete or incomplete immunisation 
status as per Lesotho national immunisation schedule (=< 5 years; for HPV 
adolescent girls aged 9-15 years) 
o Under-5 malnutrition screening and growth monitoring: Malnutrition screening 
and growth monitoring using mid-upper arm circumference (MUAC), weight-for-
age growth charts and checking for the presence of pitting oedemas (=< 5 years) 
 
• 
Prevention and care cascade indicators for the essential health service needs and 
conditions of interest  
o Screening coverage: number of participants who have been screened (among 
those who are screening-eligible) for essential health service needs or conditions 
of interest  
o Condition and health service awareness: number of participants who are aware 
of their condition of interest or the health services respective to their need(s) 
o Linkage to prevention and care: number of participants linked to prevention and 
care 
o Engagement in prevention and care: number of participants reporting drug 
intake for their respective essential health service needs or conditions of interest 
o Adherence: adherence level of participants being engaged in prevention and care 
for respective essential health services needs or conditions of interest 
o Met essential health service needs and control level for condition of interest: 
number of participants who have their essential health service needs met or with 
controlled conditions of interest (including BP <140/90 mmHg for aHT, FBG < 
7mmol/l and/or HbA1C < 7.0% for DM and documented viral suppression for HIV 
in the last 12 months) 
 
• 
Occurrence of clinically relevant events (see section 7.1) 
 
 
 
4.1.2 
Implementation outcomes 
For an evaluation of the ComBaCaL cohort implementation, the following indicators will be assessed: 
• 
Feasibility, acceptability, satisfaction, perceived appropriateness and other implementation 
outcomes of ComBaCaL activities among participants, VHWs, involved healthcare professionals 
and further stakeholders using mixed-methods assessments 
• 
Coverage indicators, such as number of households visited by VHW, number of individuals 
monitored by one VHW, number of forms submitted per individual and specific prevention and 
care service, and number of individuals newly diagnosed with a condition of interest, number of 
inhabitants refusing ComBaCaL services  
• 
Resource use and cost of the ComBaCaL activities, including assessment of time-and-motion data 
among VHWs 
• 
Quality indicators of the ComBaCaL activities, such as completeness of the data collected by 
VHWs and adherence to clinical algorithms provided via the eHealth application and through 
quarterly supervisory checks on a randomly selected set of participants to confirm the data 
accuracy 
 

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4.2 
Measures to minimize bias 
4.2.1 
Blinding 
No blinding is foreseen for the cohort study.  
 
4.2.2 
Measurements 
Processes for measurements of clinical outcomes and for the diagnosis of conditions of interest will be 
standardized and closely supervised. The screening and diagnostic algorithms for conditions such as  aHT, 
DM and HIV (see appendix) will be coded into the ComBaCaL app ensuring that the same measurement 
procedures and diagnostic criteria will be applied for all participants. All VHWs will undergo a baseline 
as well as regular refresher trainings with emphasis on correct BP and BG and other measurements as 
well as interviewing techniques and data entry into the ComBaCaL app. For the provision of oral HIV 
screenings, the VHWs will receive a 5-day course run by the MoH. Further, they receive individual 
supervision and mentoring by the CC nurse. Health center nurses and CC nurses will undergo a training 
adapted to their supervisory tasks. For the duration of the study there will be regular field visits by 
supervising CC nurses that also include quality supervision reports assessed by the study team to ensure 
that procedures for data collection are correctly followed by all involved VHWs.  
 
4.2.3 
Randomization 
No randomization is planned as part of the cohort procedures described in this protocol.   
However, the selection of the ComBaCaL villages among all rural settlements in Butha-Buthe and 
Mokhothlong is done randomly to avoid selection bias. See section 5.1 for details.  
 
4.3 
Study duration and duration of participant’s participation 
The cohort will be followed up for at least four years (48 months). The cohort follow-up may be 
prolonged beyond the five-year horizon if resources would become available. We plan to enrol first 
participants in January 2023. 
 
4.4 
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. Protocols of TwiCs nested within the ComBaCaL cohort population will be submitted to 
both involved IECs with reference to this protocol.  
 
4.5 
Withdrawal and discontinuation 
4.5.1 
Individual level 
Participants can withdraw cohort consent at any time without being asked justification. The possibility 
to re-enter the cohort later through contacting the local VHW will be offered. Data collected until the 
time of withdrawal will be included in the analysis.  
The study team will not discontinue individual participants.  
Participants may refuse specific parts of the assessments/screenings at enrolment or follow-up but 
remain in the cohort study. For example, a participant may refuse blood glucose measurement but agree 
to the other assessments. 
 
4.5.2 
Study and village level 
The village chief may request withdrawal of a village via the local VHW. The study team will then get in 
contact with the village chief to inquire the reasons for the intended withdrawal. 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 withdrawal persists, the data collection for the ComBaCaL study will be 
stopped in the village while the VHW will continue with the routine activities as part of his/her task 
assigned by the MoH.  

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After withdrawal of village consent in one or more villages, the study team may replace withdrawing 
villages by other villages randomly selected from the list of rural villages not yet included in any other 
study in Mokhothlong and Butha-Buthe districts (see section 5.1).  
If in a village, the 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 VHW will be 
replaced while the village will remain in the study.  
The Principal Investigator in consultation with Co-Investigators may choose to pause or discontinue the 
entire study or certain villages.  
 
The reasons to pause or discontinue the entire study include the following: 
• 
Insufficient funding to continue the study 
• 
Significant opposition by local health authorities 
• 
Safety or other ethical concerns 
• 
Alteration in accepted clinical practice, national policy or scientific evidence that make the 
continuation of the study unwise 
• 
Insurmountable technical or organizational problems  
 
The reasons to pause or discontinue individual villages include the following:  
• 
Insufficient funding to continue the study in all villages 
• 
Significant opposition by local health authorities 
• 
Safety or other ethical concerns 
• 
Insurmountable organizational problems 
• 
Impossibility to recruit a VHW from the village population in case replacement of the initially 
recruited VHW is required 
 
The Principal Investigator would provide the project partners and the Co-Investigators written notice 
submitted at a reasonable time in advance of the intended discontinuation or pause. If the Principal 
Investigator chooses to terminate or pause the study for safety reasons, he will immediately notify all 
investigators and subsequently provide written instructions for study termination. Co-investigators may 
pause the study in certain villages in case of safety concerns without written notice in advance. If Co-
Investigators wish to pause or discontinue the study or certain villages, they may address the request to 
pause or discontinue in written form to the Principal Investigator. Co-Investigators may not pause or 
discontinue the study or certain villages for other reasons than safety concerns without consulting the 
Principal Investigator.  
 
4.6 
End of project 
At the closure of the study 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 (DKF) at the University Hospital Basel on a secure server for a minimum 
of 10 years and be destroyed thereafter (see section 9.4). 
 

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5 SELECTION OF STUDY PARTICIPANTS 
5.1 
Selection of villages 
Participants of the ComBaCaL cohort will be recruited in randomly selected rural villages in Mokhothlong 
and Butha-Buthe districts in Lesotho. Based on the 2016 Lesotho Population and Housing Census44, a 
total of 675 rural village-clusters have been identified in Mokhothlong (321) and Butha-Buthe (354) 
districts. Villages that were too small and remotely isolated, or were government settlements (e.g. 
informal mining village or other construction project) or belong to the area that will be flooded due to 
the construction of the Polihali dam were excluded. Out of the 675 rural villages, 70 (35 per district) 
were excluded because they were involved in other chronic disease related studies. In particular, 60 (30 
in each district) were part of a population-based NCD prevalence survey and burden assessment (NH-
REC ID 139-2021) and 10 (5 in each district) are part of the ComBaCaL pilot study (NH-REC ID 176-2021). 
Out of the 605 (319 in Butha-Buthe, 286 in Mokhothlong) remaining villages, 140 (70 per district) were 
randomly sampled, stratified by district 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), by a statistician 
not involved in the study. The 140 villages will be assessed for eligibility applying the following criteria:  
 
Inclusion criteria village level:  
• 
Village size of 40 to 100 households 
• 
Village consent obtained from village chief 
• 
Possibility to identify or recruit a VHW from the village population meeting the following 
requirements which are largely in line with the criteria of the Lesotho VHW Program Policy:  
o Criteria of the Lesotho Village Health Program Policy45: 
▪ 
Having primary residence in the village (according to village chief) 
▪ 
Having a proven record of trustworthiness in the resident village 
▪ 
Having proven ability to maintain confidentiality on public matters 
▪ 
Being aged between 20 and 50 years 
▪ 
Being able to provide written reports and being able to do basic mathematical 
calculations 
▪ 
Having at least educational level equivalent to high school leaving certificate 
(Junior Certificate) 
 
o Additional ComBaCaL criteria:  
▪ 
Having the ability and willingness to work with a tablet-based eHealth tool 
▪ 
Having good social and communication skills 
▪ 
Having the ability and willingness to interact with health professionals and the 
village population 
▪ 
Being able to speak, understand and write in English 
▪ 
Having successfully completed the ComBaCaL VHW training including final 
assessment 
 
5.2 
Selection of VHWs 
Prior to cohort recruitment, in each ComBaCaL cohort village, one VHW will be appointed. In villages 
where an existing VHW has the qualifications and capacity to fulfil the tasks associated with the 
ComBaCaL activities, he/she will be approached for collaboration in the project. In villages, where there 
is no VHW or where the existing VHW does not have the qualifications or capacity to fulfil the ComBaCaL 
tasks or where the existing VHW is declining the offer of collaboration, a new VHW will be selected 
through a participatory process involving the study team, the MoH district health management team 
(DHMT) and the village population: The study team together with the local DHMT will send a letter 
explaining the VHW criteria as outlined above to the village committee composed of the chief, the area 
councillor and existing VHWs if applicable. The village committee will select three candidates among the 

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village inhabitants meeting the criteria. Among these three candidates, one will be elected to become 
the VHW by the village population during a community gathering (“pitso”).  
The selected VHWs will undergo a targeted training covering basic pathophysiological concepts, 
screening, diagnosis and basic life-style counselling for chronic diseases, such as aHT and DM, as well as 
technical trainings on the devices and tools used, especially on correct BP and BG measurements and 
data entry into the tablet-based ComBaCaL eHealth application. 
Additionally, VHWs may undergo the standard six-week VHW training as per the Lesotho Village Health 
Program Policy.45 ComBaCaL specific activities may be started independent of whether the standard 
VHW training has been completed or not.  
 
5.3 
Recruitment of participants 
All households in selected villages will be visited by the local VHW in a door-to-door cohort recruitment 
campaign. All present household members will be asked for consent to participation in the ComBaCaL 
cohort study. Details regarding the two-stepped consent procedure are outlined in section 11.3. The 
number of absent household members will be registered and the VHW will return to all households with 
absent members within the following days to complete recruitment.   
The ComBaCaL cohort is an open cohort. Thus, at any follow-up visit, new inhabitants of the selected 
villages will be approached for consent and be enrolled into the cohort if consenting while inhabitants 
moving out of the village or deceased inhabitants will be removed from the active cohort population.  
 
Inclusion criteria individual level:  
• 
Having primary residence in the village (self-reported at time of enrolment) 
• 
Being able and willing to consent to participation or in case of individuals aged below 18 years, 
a caregiver who provides consent (with participant’s assent for adolescents) 
 
 

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6 STUDY PROCEDURES 
6.1 
General Setting 
Measurements and data entry will be conducted by VHWs. The VHWs will be equipped with the essential 
tools required for condition  monitoring in the community (i.e. BP machines, scales, measuring band, 
glucometers,  urine dipsticks, urine pregnancy tests and oral HIV screening tests). They will undergo a 
theoretical and practical training covering all aspects required for correct data collection and chronic 
disease screening, diagnosing, referral and counselling services. At every visit, the VHW will screen 
participants for warning signs and symptoms (such as shortness of breath, severe headache, chest pain, 
new-onset confusion, impaired consciousness, severely impaired general state of health, prolonged 
fever or seizures) and pregnant participants and children under five will be screened for age- or 
pregnancy-specific warning signs (such as vaginal bleeding for pregnant participants or not being able to 
be breastfed or skin and eyes appearing yellow for under five year old). In case of any danger-sign the 
participant is referred to the closest health centre. The VHWs will be continuously monitored and 
supervised by health centre nurses of the respective village’s catchment area, mainly through direct 
interaction during monthly VHW meetings and by CC nurses through field visits, remote interaction via 
phone calls or messages sent via the ComBaCaL app and through direct contact during the monthly VHW 
meetings at the health centre.  
The VHWs are embedded within the Lesotho MoH VHW program and may during the project period be 
trained and equipped to provide further routine services in their communities. The supervision of these 
routine tasks outside the ComBaCaL activities will be provided within the existing VHW framework by 
health centre nurses and will not be influenced by the ComBaCaL activities.  
 
6.2 
Baseline  
After recruitment, all variables of interest (see section 4.1.1) at household and individual person level 
will be collected.  
All adult participants will be screened for aHT applying a standardized, evidence-based screening 
algorithm using automated BP measurements (see appendix). Participants aged 40 years and above or 
participants aged 18 years and above and having a BMI of equal or above 25kg/m2, will be screened for 
(pre)DM applying a standardized, evidence-based screening algorithm using capillary BG measurements 
(see appendix). Participants not living with HIV and aged 12 years and above will be offered an oral HIV 
self-screening test; reactive test results will be followed up by the supervising CC nurses using HIV 
fingerprick blood tests. Female participants between 12 and 49 will be screened for pregnancy using a 
six-item pregnancy checklist (as described in the WHO family planning provider handbook) and if 
required receive a urine pregnancy test. Participants, for whom a relevant condition is detected will be 
referred to the closest health facility or the district hospital for further work-up and treatment.  
 
6.3 
Follow-up 
6.3.1 
Regular follow-up 
Follow-up visits will be conducted at flexible intervals. During the follow-up visits, the VHWs will update 
the variables of interest collected at baseline (see section 4.1.1). In addition, variables newly introduced 
as part of this amendment will also be collected. Alongside the updates of individual participant’s data, 
the cohort census will be updated through registration of new households or new members of previously 
registered households as well as removal of emigrated or deceased participants from the active cohort 
population. During the follow-up, VHWs will inquire about the occurrence of clinically relevant events 
(see section 7.1) since the previous visit (including screening of the personal health booklet (Bukana), 
for documentation of respective events). All clinically relevant events will be documented in a dedicated 
electronic case report form within the ComBaCaL app. All reports of clinically relevant events will be 
reviewed and validated by the supervising CC nurses and forwarded to the study physician. 
 

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6.3.2 
Clinical follow-up 
In addition to the regular follow-up visits, the VHWs will conduct follow-up visits for conditions and 
essential health service needs related to NCDs, HIV, SRHR and child health as well as associated 
conditions of interest according to the clinical algorithms provided in the appendix. These visits entail 
confirmatory BP and BG measurements for the diagnosis/exclusion of DM and aHT in case of elevated 
screening values detected at baseline or during regular follow-ups as well as monitoring of participants 
with established diagnosis of aHT or DM. For HIV, after a reactive oral HIV screening result, trained 
ComBaCaL study nurses will perform a follow-up finger prick HIV test. SRHR and child health follow-up 
visits will be conducted if needed.    
Furthermore, VHWs will document census updates and clinically relevant events any time during the 
cohort follow-up when being informed thereof independent of scheduled visits. 
 
6.4 
Implementation assessments 
For the assessment of satisfaction, acceptability, perceived appropriateness and other implementation 
outcomes, such as costing data for delivering services or time and motion data of the community-based 
activities among different stakeholders, questionnaires will be presented via the ComBaCaL application. 
The questionnaires may be self-reporting (for VHWs and involved healthcare professionals) or will be 
administered by VHWs or other study staff (i.e. for participants, VHWs or involved healthcare 
professionals). Additionally, qualitative research approaches, such as focus group discussion or semi-
structured interviews may be applied to gather information among participants, VHWs or involved 
healthcare professionals. 
 
 

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7 SAFETY CONSIDERATIONS 
7.1 
Definition and documentation of safety outcomes 
Clinical event of special 
interest (CESI) 
Clinical event that is consistent with chronic condition complications, 
such as 
• 
Myocardial infarction  
• 
Stroke 
• 
Symptomatic heart failure  
• 
Chronic kidney disease 
• 
Diabetic foot syndrome 
• 
Peripheral arterial disease 
• 
Hypertensive urgency or emergency 
• 
Hyperglycemic emergency 
• 
Visual impairment or blindness 
• 
Peripheral neuropathy 
• 
HIV/AIDS-related event  
• 
New TB diagnosis  
 
Clinically relevant event possibly related to chronic condition 
treatment, such as  
• 
Intolerance reaction against chronic disease medication 
leading to discontinuation of the medication concerned 
(including allergic reactions, drug interactions or rare severe 
side effects such as lactic acidosis)  
Serious clinical event (SCE) 
Clinical event that: 
• 
Results in death   
• 
Requires hospitalization  
o Hospitalizations due to uncomplicated delivery are 
not considered as SCE 
• 
Results in persistent or significant disability or incapacity 
• 
Consists of a congenital anomaly or birth defect 
Serious clinical event of 
special interest (SCESI)  
SCE consistent with chronic condition complications, such as 
• 
Myocardial infarction  
• 
Stroke 
• 
Symptomatic heart failure  
• 
Chronic kidney disease 
• 
Diabetic foot syndrome 
• 
Peripheral arterial disease 
• 
Hypertensive urgency or emergency 
• 
Hyperglycemic emergency 
• 
Visual impairment or blindness 
• 
Peripheral neuropathy 
• 
HIV/AIDS-related event  
• 
New TB diagnosis 
 
SCE possibly related to chronic condition treatment, such as 
• 
Intolerance reaction against chronic disease medication 
leading to discontinuation of the medication concerned 
(including allergic reactions, drug interactions or rare severe 
side effects such as lactic acidosis) 

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VHWs will be trained to screen for and to recognize SCE(SI)s and CESIs and to document them in a 
dedicated form in the ComBaCaL app.  
VHWs may solicit SCE(SI)s and possible CESIs in the following ways:  
- 
Reporting by participants or friends or relatives after inquiry by VHWs during scheduled VHW 
visits 
- 
Active reporting by participants or friends or relatives outside of scheduled 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 supervisors) 
- 
Clinical observation of VHW during or outside scheduled VHW visit 
- 
Screening of participants’ personal health booklets (Bukanas) 
- 
Reporting by staff from health care facilities or other VHWs 
 
Participants, friends, relatives and health centre nurses will be encouraged to notify the VHW about 
relevant medical events during the cohort follow-up. Many CESIs (i.e. chronic kidney diseases) cannot 
be recognized clinically without access to further diagnostic tools (i.e. laboratory). For these cases, the 
VHW will primarily document the results of investigations conducted and diagnosis made by healthcare 
professionals from entries in the personal health booklet or reports communicated by health centre 
nurses during the VHW meetings. If needed, the CC nurse may inquire further details at the facilities 
where the participant was treated for the SCE(SI). On the other hand, the VHW may through her/his 
continuous presence in the village capture events (i.e. death after stroke or myocardial infarction) that 
would otherwise remain undocumented.  
 
All SCE(SI)/CESI reports that are submitted by VHWs will be reviewed, validated and if required 
completed and/or corrected by the supervising CC nurse in the ComBaCaL app within 30 days after 
submission of the report. Deaths for which the cause cannot be identified by the CC nurse will follow up 
and gather any additional information that can be obtained.  
 
The SCE(SI)/CESI reports will subsequently be discussed on a weekly basis within the data monitoring 
team together with the CC nurse related to the report submission and then classified by a physician as 
SCE other than SCESI, SCESI, CESI or none of the three (if sufficient clinical information for classification 
is available). If the clinical information available is not sufficient for classification of the case, the 
responsible CC nurse and/or VHW are asked to collect further data.  
 
7.2 
Causality of SCE(SI)s and CESIs 
The ComBaCaL cohort study does not entail any intervention other than screening, diagnosing, 
counselling and referral of participants with relevant conditions as well as other routine VHW tasks. 
Therefore, a direct causation between the study activities and an SCE(SI) or CESI is highly unlikely. An 
indirect causation (for example a car accident on the way to the health centre or a drug reaction after 
prescription of chronic disease treatment after referral) is possible. No causality assessment will be 
performed for reported SCE(SI)s and CESIs. 
 
7.3 
Reporting of SCEs and CESIs 
A list of all SCE(SI)s and CESIs will be submitted to the Principal Investigators on a quarterly basis and to 
the NH-REC along with the yearly reports.   
 
 

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8 STATISTICS 
8.1 
Determination of sample size  
This is an open prospective cohort study and no sample size calculation is performed. In a first step, we 
aim to enrol inhabitants of around 100 villages. Assuming an average of 200 eligible inhabitants per 
village and a high participation around 80%, we estimate that we will reach a cohort population of 
around 16’000 participants. We have secured the funding to pursue a cohort of this size for at least four 
years.  
Sample size calculation for future projects nested in the cohort (e.g. TwiCs) will be detailed within the 
corresponding sub-protocols.  
 
8.2 
General cohort statistics 
The variables collected within the ComBaCaL cohort will be summarized using descriptive statistics such 
as counts, proportions with 95% confidence intervals, medians and interquartile ranges and means with 
95% confidence intervals at time point of collection as defined. To establish the prevention and care 
cascade, proportions will be derived by dividing the number of occurrence of events at a specific stage 
of the cascade by the population at risk at the corresponding stage. 
 
Statistical methods for future projects nested in the cohort will be part of the corresponding sub-
protocols and separate statistical analysis plans. 
 
8.3 
Analysis of the ComBaCaL activities’ effects on condition specific prevention and 
care cascades  
The ComBaCaL activities with NCD, HIV, HIV related, SRHR and child health related screening and referral 
services are likely to have an effect on prevention and care cascade outcomes compared to the current 
standard at community-level. We will conduct a pre-specified analysis to assess the effect of the 
ComBaCaL activities on condition specific prevention and care cascades.  
 
8.3.1 
Hypothesis 
VHW-led screening, monitoring and referral services improve care and prevention cascade outcomes for 
NCDs, HIV, SRHR and child health as well as other associated health conditions and essential health 
service needs will improve after introduction of the ComBaCaL activities in the respective villages 
compared to baseline.  
 
8.3.2 
Endpoints 
 
Data for all endpoints is either self-reported or retrieved from the personal health booklet, health 
registries at facilities or ComBaCaL app. 
 
• 
Screening and service coverages: number of participants who have been screened for the above-
mentioned essential health service needs or conditions of interest (see section 4.1.1) will be 
assessed at several timepoints; 0, 6 and 12 months after enrolment and the introduction of the 
respective service and at least annually thereafter. Screening coverages are defined as the 
proportion of screening-eligible participants that have been screened for the respective essential 
health service need or condition of interest out of the overall number of screening-eligible 
participants. Service coverages are defined as the proportion of service-eligible participants that 
have received the respective service.  Screenings for conditions of interest specifically also 
include those conducted at the facility in this timeframe. 
• 
Awareness of the above-mentioned essential health services or conditions of interest (see 
section 4.1.1) will be assessed at several timepoints; 0, 6 and 12 months after enrolment and the 
introduction of the respective service and at least annually thereafter. Awareness is defined as 

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the proportion of participants diagnosed with a condition of interest or eligible for an essential 
health service who report being aware of their condition or the respective service. 
• 
Linkage to care for the above-mentioned conditions of interest (see section 4.1.1) will be 
assessed at several timepoints; 0, 6 and 12 months after enrolment and the introduction of the 
respective service and at least annually thereafter. Linkage is defined as the number of 
participants with an above mentioned condition of interest who (re)started treatment for their 
respective condition since enrolment. 
• 
Engagement in care for the above mentioned conditions of interest will be assessed at several 
timepoints; 0, 6 and 12 months after enrolment and the introduction of the respective service 
and at least annually thereafter. Engagement is defined as the number of participants with an 
above-mentioned condition of interest who had a check-up measurement, are taking medication 
for their condition or reaching control status without intake of medication. 
• 
Level of adherence to drug treatment for the above mentioned conditions of interest will be 
assessed at several timepoints; 0, 6 and 12 months after enrolment and the introduction of the 
respective service and at least annually thereafter. Adherence is defined as the number of doses 
of medication taken within the specified timeframe, which may be the last 7 days, 28 days or 
more, depending on the appropriate timeframe for adherence evaluation specific to each 
medication. 
• 
Disease control level for above mentioned conditions of interest will be assessed at several 
timepoints; 0, 6 and 12 months after enrolment and the introduction of the respective service 
and at least annually thereafter.. Disease control level is defined as the number of participants 
with a condition of interest who are reaching condition-specific treatment targets (BP <140/90 
mmHg for aHT, FBG < 7mmol/l and/or HbA1C < 7.0% for DM, and viral load <50 copies/ml for 
HIV). 
 
8.3.3 
Statistical methods 
We will test for difference in proportion of the different elements of the cascades between the different 
time points (enrolment to 48 months at least once annually ) using chi-square tests or similar statistical 
methods for comparing proportions. For other analyses such as for nested trials (TwiCs) and analyses 
beyond the pre-post cascade evaluations, separate statistical analysis plans will be developed.  
 
8.4 
Handling of missing data 
Missing data might be populated by additional information coming from relevant external registries. 
Multiple imputations techniques might be used to impute missing adjusting factors in subsequent 
analyses and will be detailed, if applicable, in the corresponding sub-protocols. 
 
 

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9 DESCRIPTION OF DATA MANAGEMENT 
9.1 
Specification of source documents 
Data collected in the villages will be entered directly into the tablet-based ComBaCaL application by the 
local VHW. Thus, the electronic forms within the ComBaCaL application serve as source documents in 
most cases. If required, the VHW may extract clinical data from the patient’s personal health booklet or 
from clinical reports and registers at the health facilities. For participants living with HIV the personal 
ART number will be collected to retrieve VL results and other measurements from the viral load data 
base (NH-REC ID 134 2016). Similarly, data might be collected from the registries for NCDs, TB, cervical 
cancer, PrEP, ANC/PNC, under-five, or family planning. These sources may be important for 
documentation if participants are not able to provide the exact clinical information. The personal health 
booklet will always remain with the patient and paper-based or electronic routine clinical reports and 
registers will remain at the health centres.  
 
9.2 
Data recording 
All data collected in the villages will be directly entered using the tablet-based ComBaCaL application 
with regular synchronization to a secure server (hosted at University Hospital of Basel) by trained VHWs.  
The ComBaCaL app is based on the open source Community Health Toolkit (CHT) Core Framework, the 
most widely-used open source software toolkit designed specifically for community health systems. 47 
Within the CHT Core Framework, a user hierarchy reflecting relevant healthcare cadres and facilities can 
be configured as well as a variety of tools such as task scheduling, clinical decision support and messaging 
services. According to the configured user hierarchy, access levels are defined: a VHW will have access 
to the data collected in his/her village, a health centre nurse will have access to the data of the villages 
in her/his catchment area and a CC nurse will have access to the data collected by the VHWs she/he is 
supervising. Adapted to the realities of community-based healthcare delivery, CHT defines a household 
level between village and individual participants. All individual participants are allocated to a household 
for which a household head is defined.  
Follow-up visits will be prompted as tasks with a due date defined within the ComBaCaL app based on 
the algorithms encoded. This feature will minimize number of missing visits and enable efficient work 
planning for VHWs and uncomplicated supervision of pending and upcoming tasks.  
Besides the task scheduling, efficient remote supervision is facilitated within CHT through a report 
validation function and messaging services.  
 
9.3 
Confidentiality and coding 
The data collected by VHWs and documented in the ComBaCaL app will be used for clinical decision-
making, central supervision, programme monitoring and research at the same time. The data collected 
will be handled with uttermost discretion and only be accessible to authorized personnel who require 
the data to fulfil their clinical or research duties. Each VHW will have a single, password-protected tablet. 
Due to the use of the data collected for clinical decision support, contact and clinical data will both be 
collected in the ComBaCaL app. The app contains a specific contact form capturing personally identifying 
information such as name, date of birth and contact details for the purpose of identification by VHWs 
and nurses involved in clinical care. Identifiable data will only be accessible by the respective VHW, the 
supervising health centre and CC nurse and the study Data Manager overseeing the application’s 
database, and it will not be included in any exported clinical data or metadata. Study participants are 
automatically allocated a unique participant number, which will be used to identify participants in all 
data exports containing clinical information. The investigators will respect participants’ privacy 
according to all applicable privacy laws. Only anonymized study data will be published in scientific 
journals and presented at scientific meetings and conferences. All participants’ personal and medical 
information are confidential and disclosure to third parties is prohibited. Access to identifiable data for 
the purpose of data quality control may be granted upon request to the Principal Investigators and other 
members of the study team responsible for data quality control. 

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9.4 
Data security, access, archiving and back up 
The study data will be stored on secure servers during the duration of the study in access restricted 
folders. Participant data will only be accessible to authorized personnel defined by their role. After 
termination of the study, the database will be locked and the data will remain on secure severs at the 
University Hospital Basel, where they will be stored for a minimum of 10 years and be destroyed 
thereafter.  
 
9.5 
Data storage on public data repositories 
Following the FAIR principles48, anonymized datasets of cohort analyses will be deposited on an openly 
accessible data repository, such as zenodo.org49. 
 
 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Supervision  
10.1.1 Local supervision and data quality checks 
Data will be collected by the VHWs and documented directly in the tablet-based ComBaCaL app. Direct 
supervision of VHWs and data quality checks will be ensured by two complementary cadres. In the first 
cadre, routine health centre nurses will provide clinical supervision for the VHWs in their catchment area 
through a supervisor login of the ComBaCaL app, which will allow them to review data collected and to 
send messages for queries to individual VHWs. Furthermore, health centre nurses will provide 
mentoring, training and supervision in monthly meetings at the health centre where VHWs will 
participate together with other VHWs.  
In the second cadre, CC nurses will complement the supervision provided by routine health centre 
nurses. CC nurses are registered nurses who will be trained specifically on study procedures and on the 
management of DM, aHT, as well as HIV and HIV-related conditions. Each CC nurse will be responsible 
for the supervision of around 25 VHWs. The CC nurses will regularly review and authorize the reports 
uploaded by the VHWs in the ComBaCaL app. Additionally, they will conduct regular field visits in the 
villages for direct supervision and mentoring of the VHWs, submit supervision reports, and will also be 
regularly present at the monthly VHW meetings at the health centres where they will provide NCD-
specific training and mentoring for health centre nurses and VHWs.  
 
10.1.2 Central data monitoring and quality checks 
In addition to the local supervision and data quality checks, regular data quality checks will be run by 
the study Data Manager on the overall database and anonymized, aggregated data will be shared with 
the study team for discussion of data quality issues. Queries will be communicated to the respective 
VHWs either via messages sent within the ComBaCaL app or via the CC nurses.  
 
10.2 Translations - Reference language  
The reference language of the study documents is English. Official languages in Lesotho are English and 
Sesotho. No Sesotho translation will be provided for the study protocol, as all staff of responsible IECs 
and the study team including the VHWs are literate in English. The electronic patient information and 
ICFs as well as the paper-based patient information leaflets will be translated from an English master 
document into Sesotho and provided in both languages. The quality of translation will be ensured by 
quality and comprehension checks by bilingual individuals not involved in the translation. 
 
10.3 Monitoring and auditing 
Members of the Ministry of Health or the NH-REC may visit the research sites. To ensure appropriate 
organization of the visits, they may inform the principal investigators at least 14 days before the planned 
visit. Direct access to the source data and all project related files and documents will be granted on such 
occasions if feasible (access to participant-based personal health booklet might not always be possible).  
Principal investigators and co-investigators may conduct site-visits, i.e. visiting certain villages to 
monitor adherence to the study protocol, verify correct conduction of study procedures or clarify 
uncertainties regarding data quality. 
The data management team will conduct regular central monitoring at least on quarterly basis, 
monitoring data accuracy and completeness, progress in enrolment, adherence to clinical algorithms, 
occurrence of CESIs, and follow-up visits. 
Systematic site visits by external monitors are not foreseen as visiting all 100 villages by external 
monitors would be resource intensive and because given that all key data are directly collected in the 
ComBaCaL app source-verification can be done on distance through the central monitoring. However, in 
case central monitoring should raise concerns or red flags regarding protocol adherence or data quality 
in specific villages, the investigators may organize external monitoring site visits of these villages. 
 

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10.4 Storage of biological material and related health data 
Plasma or dried blood spot samples of cohort participants may be collected for storage and future 
analysis. Samples collected fall under the biobank agreement (“Biobanking regulations, v2.0”) approved 
by the ethics committees in Lesotho and Switzerland. Samples will be stored in biobanks in Butha-Buthe 
or Mokhothlong districts in Lesotho. Samples may only be exported for analysis after submission and 
approval of a material transport agreement (MTA) by the NH-REC. No human genome analysis will be 
conducted on the samples collected. Results of analysis that are relevant for the health of participants 
will be communicated to participants. Samples will be destroyed latest five years after termination of 
the study.  
 
 

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11 ETHICAL CONSIDERATIONS 
11.1 Independent Ethics Committees (IECs) 
This protocol and any protocol amendments, the informed consent form (ICF), and all other forms of 
participant information related to the study and any other necessary documents 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. 
 
11.2 Risk-benefit ratio 
There is no substantial health risk associated with participation in the ComBaCaL cohort. The health 
condition  screening and diagnosis offered will be conducted in line with international 
recommendations. All participants found to be at risk for a relevant medical condition will be referred 
to local health facilities for professional work-up and care as per national standard of care. 
Data collection will entail questionnaires, automated BP measurements, capillary BG and HbA1C 
measurements, urine dip stick analysis, urine pregnancy tests and HIV screening tests if clinically 
indicated. None of the study components have the potential to cause significant harm to participants. 
The capillary blood collection might cause slight discomfort but no serious complications.  
No personalized data of participants will be shared with people other than directly involved study team 
members if not agreed upon by the participant.   
Access to guideline-conform active community-based screening for a range of conditions related to 
NCDs, HIV, SRHR and child health with linkage services will likely increase early case detection and thus 
improve access to potentially life-saving treatment. Additionally, regular follow-up with monitoring in 
the community by VHWs is likely to improve prevention and care for the respective condition for 
participants compared to standard clinic-based care.  
The evidence generated in this study may inform future national and international clinical guidelines to 
improve care for the previously mentioned conditions 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 the conditions 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 integrated prevention and care delivery on a longer perspective.  
 
11.3 Participant information and consent 
In a first step, before the recruitment of VHWs, the study team will obtain oral village consent from the 
village chief. Thereafter, participant information and consent seeking will be conducted by the local VHW 
in a two-stepped approach, first on household and then on individual level.  
 
11.3.1 Household consent 
When approaching a household, the VHW will first ask whether the household head or a representative 
is present. If neither the household head nor a representative is present, the VHW will register the 
household in the ComBaCaL app together with the name of the absent household head if this one is 
known.  
No further information about any household member will be collected on that day, but the VHW will 
return to the household within the next days to meet the household head to ask for household consent. 
If the household head or a representative is present, the VHW will inform her/him about the content, 
risks and aims of the study using digital patient information content on the tablet and ask for oral 
household consent. It will be mentioned specifically, that participation in the ComBaCaL cohort entails 
consenting to being randomized for future TwiCs and being included in the control population for 
analysis without further information or being approached for consent to participate in further 
community-based interventions. To illiterate household heads, texts will be read out or explained, 
ensuring that the complete information concerning participation is being transmitted. Ample time will 

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be given for consideration and all questions regarding participation will be answered by the VHW. The 
household consent will be documented in the ComBaCaL app by the VHW with a checkbox on the 
electronic household registration form.  
 
11.3.2 Individual consent 
If household consent is obtained, the VHW will inform all present household members about the 
content, risks and aims of the study using the same digital content as for the household head. To illiterate 
household members, the text will be read out or explained, ensuring that the complete information 
concerning participation is being transmitted. The ComBaCaL cohort consent is based on the cmRCT 
approach, i.e. all cohort participants consent to being randomized as part of a future TwiC. In case they 
are randomized to the control group, they will not be bothered and data collected as part of the cohort 
study will be used for the TwiC analysis. In case they are randomized to the intervention group, they will 
be offered the respective intervention, which they may then accept or refuse. Intervention consent will 
be asked orally, if the intervention is entailing no other than the task-shifting of procedures 
recommended by the local guidelines to VHWs (i.e. prescription of first-line aHT treatment by VHW). For 
all other interventions, written informed consent will be sought. Participants may decline any of the 
offered interventions without implications on further cohort affiliation. Data of participants declining 
the intervention, but not withdrawing the cohort consent will be included in TwiC analyses. In the 
participant information, it will be mentioned specifically, that participation in the ComBaCaL cohort 
includes consenting to being randomized as part of future TwiCs and to being approached for consent 
to specific interventions. Ample time for consideration will be given to all individuals. The VHW will make 
sure that all household members will have the opportunity to ask questions about participation in 
privacy if desired. Individual consent of household members will be documented with an electronic 
signature of the participant on the study tablet. Illiterate participants will confirm informed consent by 
drawing a cross in the electronic signature field, countersigned by an impartial witness (may or may not 
belong to the household).  
To children and adolescents under the age of 18 years, the same content will be explained in an age-
adapted manner. Written consent will be sought from a guardian aged 18 years or above together with 
written assent for adolescents aged 10 to 17 years. No written assent will be sought in addition to the 
guardian’s consent for children below 10 years.  
For every household at least one paper-based participant information leaflet will be provided containing 
all relevant information about study participation as well as contact details of the responsible study staff 
and representative of the NH-REC to be contacted in case of questions or concerns related to 
participation.   
 
11.3.3 Withdrawal on household or individual level 
Consent can be withdrawn any time on individual or household (by household head) level without 
justification. Anonymized data collected until the time of withdrawal will be retained in the database. 
 
11.3.4 Service delivery for people declining consent 
The VHW will offer the same chronic disease screening and linkage services applied within the study also 
to inhabitants of the village declining consent to be part of the ComBaCaL main cohort. The data of 
people not giving consent will not be entered in the ComBaCaL app, but only communicated orally to 
the individual and noted in the individual’s personal health booklet if desired. By not entering the data 
in the ComBaCaL app, the clinical decision support for diagnosis will not be available to people declining 
consent, which might limit the quality of services provided.   
 
11.4 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). 
 

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11.5 Participants requiring particular protection 
This study has a strong service delivery aspect as the data collected enables case finding and monitoring 
of the targeted diseases in the study population. Often people with mental or physical conditions 
impairing capacity for informed consent are particularly vulnerable to the targeted health issues and 
conditions. Therefore, we will offer participation to people with impaired judgement and include them 
in the ComBaCaL cohort if a guardian provides consent. The incapacity to give informed consent together 
with the reason will be documented in the electronic ICF together with the guardian’s electronic 
signature (or cross with signature of an impartial witness for illiterate guardians). The same services 
without the clinical decision support of the ComBaCaL app will be offered to people not capable of giving 
informed consent for whom no guardian consent is obtained.  
 
11.6 Participant compensation 
No compensation will be paid for participation in the study.  
 
 

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12 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 Division of Clinical Epidemiology of the University of 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. 
 
13 DISSEMINATION OF RESULTS AND PUBLICATION POLICY 
13.1 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 an open-access peer-reviewed journal. The current 
version of the International Committee of Medical Journal Editors (ICMJE) recommendations is 
applicable regarding authorship eligibility.50 The use of professional writers is not intended. 
 
13.2 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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14 APPENDIX 
14.1 Screening and diagnosis of aHT 
 
 
Figure 2 Screening and diagnosis algorithm for aHT 
For the determination of BP, standard operating procedure based on the European Society of 
Cardiology/European Society of Hypertension (ESC/ESH) guidelines 201851 and the 2020 Global 
Hypertension Practice Guidelines of the International Society of Hypertension 52 will be applied using 
automated BP machines (Omron M3 Comfort [HEM7131-E]53,54. BP measurements are taken after 
determination of the correct cuff size in a sitting position after 5 min of rest with feet on the floor, the 
arm supported without talking or moving during the measurement. At the first visit, the reference arm 
is determined by measuring BP on both arms. The arm with higher systolic BP is identified as reference 
arm and used for all subsequent BP measurements. The BP value used for the screening and diagnosis is 
calculated as the mean value of the last two out of three consecutive measurements at intervals of one 
minute. 
For diagnosis of aHT, two elevated measurements in the range of 140-179/90-109 mmHg on two 
different days are required or two measurements of 180/110 mmHg or higher on the same day, 30 
minutes apart. 
 

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14.2 Screening and diagnosis of (pre)DM  
 
Figure 3 Screening and diagnosis algorithm for (pre)DM. BG: Blood glucose, FBG: Fasting blood glucose, RBG: Random blood 
glucose.  
All adult individuals equal or above 40 years of age or with a BMI equal or above 25kg/m2 will be screened 
for (pre)DM using random (RBG) or fasting (FBG) capillary BG measurements. In patients with an FBG or 
RBG below 5.6 mmol/l, DM can be excluded and the next screening is recommended in three years. 
Patients with a BG level in the diabetic range (FBG ≥7 mmol/l or RBG ≥11.1 mmol/l) with at least one 
cardinal symptom of uncontrolled DM (polyuria, polydipsia or weight loss) fulfill the diagnostic criteria 
for DM. For patients with an elevated BG level, not fulfilling the diagnostic criteria for DM, a confirmatory 
measurement is required for diagnosis of DM or preDM. The diagnosis of DM is made if the confirmatory 
measurement is in the diabetic range. PreDM is diagnosed if the FBG is between 5.6 and 6.9 mmol/l.  
Patients with an FBG or an RBG value in the diabetic range presenting with all three cardinal symptoms 
of DM (polyuria, polydipsia or weight loss) will be assessed for ketonuria using urine dip sticks. In case 
of relevant ketonuria (defined as level 3 or more on a 5 level scale), patients will be immediately referred 
to a higher-level health facility as they may need admission, insulin treatment and close monitoring.  
 
 

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14.3 HIV Testing Algorithm  
 
 
 
Figure 4. Lesotho strategy for screening and test for triage (adapted from Lesotho National Guidelines)  
 
 
At the community level, VHWs will perform HIV screening (A0) using an oral HIV screening test 
(OraQuick®). Reactive screening results will be referred for follow-up and confirmatory testing, either 
conducted by trained ComBaCaL study nurses or trained ComBaCaL study nurse assistants at the 
community level using fingerprick blood tests (see Figure 5) or at the health facility or outreach services.  
 

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Figure 5. Lesotho national HIV diagnostic testing algorithm for individuals ≥18 months (source Health Research and Laboratory 
Services Lesotho) 
 
Diagnostic testing begins with Test 1 (Determine™). Individuals with a non-reactive result are reported 
as HIV negative. Those with a reactive Test 1 result undergo additional testing using Test 2 (Uni-Gold™). 
A second reactive result requires confirmatory fingerprick testing by second healthcare provider. 
If Test 1 and Test 2 results are discordant, both tests are repeated on the same specimen (or on different 
specimens if not feasible). Persistently discordant results require a third tie-breaker Test 3 (Bioline™). 
Individuals whose results remain inconclusive after three tests are classified as indeterminate and 
require HIV DNA/PCR testing or confirmatory fingerprick testing by a second healthcare provider. 
Individuals with non-reactive results after discordance resolution are reported HIV negative.  

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