Community-based, eHealth Supported Type 2 Diabetes Care by Lay Village Health Workers in Rural Lesotho Protocol for a Cluster-randomized Trial Within the ComBaCaL Cohort Study (ComBaCaL T2D TwiC)
Phase: NA
Conditions: Type 2 Diabetes Mellitus (T2D)
Sponsor: University Hospital, Basel, Switzerland

ComBaCaL T2D TwiC 
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Study Protocol 
 
 
Community-based, eHealth supported type 2 diabetes care by lay village 
health workers in rural Lesotho 
 
Protocol for a cluster-randomized trial within the ComBaCaL cohort study 
(ComBaCaL T2D TwiC) 
 
 
 
 
Type of Research 
Project 
Research project involving collection of health-related data from 
persons 
  
Study acronym/ID 
ComBaCaL T2D TwiC 
Protocol Version Nr 
1.2 
Date 
07.06.2025 
Project Leader / 
Responsible 
Prof. Dr. Niklaus Labhardt, MD, DTM&H, MIH 
Head Division of Clinical Epidemiology  
University Hospital Basel  
Totengaesslein 3, 4051 Basel, Switzerland 
+4179 870 18 59 
niklaus.labhardt@usb.ch 
 
Funding Agency 
Swiss Development Cooperation, World Diabetes Foundation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 GENERAL INFORMATION 
 
1.1 
List of Project Leaders and other key persons involved in the study 
 
 
Title 
Names 
Institution 
Position 
Function in study 
Prof. Dr. 
DTM&H, 
MIH 
Labhardt Niklaus 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Division Head 
Principal 
Investigator & 
Steering 
Committee 
Member 
MD/PhD 
Irene Ayakaka 
Solidarmed Lesotho 
Technical 
Director 
National Project 
Leader 
BSN 
Madavida 
Mphunyane 
NCD Program MoH 
Program 
Manager 
Steering 
Committee 
Member 
MD 
Litaba Malitaba 
NCD Program MoH 
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 
Ravi Gupta 
SolidarMed Lesotho 
Project 
Manager 
Project Manager, 
Study physician 
MIH 
Lejone Thabo 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
PhD Student 
Co-Investigator 
PhD 
Chammartin 
Frédérique 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Scientific 
Collaborator 
Statistician 
MD 
Gerber Felix 
University of Basel, 
University Hospital Basel 
PhD Student 
Investigator 
MD/PhD 
Amstutz Alain 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
Post-Doctoral 
Researcher 
Co-Investigator 
MSc 
Raeber Fabian 
University of Basel, 
University Hospital Basel 
MD PhD 
Student 
Co-Investigator 
MSc 
Mahlatsi Palesa 
University of Basel, 
University Hospital Basel 
PhD Student 
Co-Investigator 
MSc 
Saavedra Elis 
University of Basel, 
University Hospital Basel 
PhD Student 
Co-Investigator 
MBBS, 
FAMMED 
Mamakhala 
Chitja 
SolidarMed Lesotho 
NCD 
Technical 
Advisor 
Co-Investigator, 
study physician 
 
 
The project leader is qualified individuals by education and training and responsible for the whole 
project. All further key persons are also qualified by education and training to perform their 
assigned tasks and responsibilities. 

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1.2 
Signatures 
 
Study Title: “Community-based, eHealth supported  type 2 diabetes care by lay village health workers in 
rural Lesotho: Protocol for a cluster-randomized trial within the ComBaCaL cohort study (ComBaCaL T2D 
TwiC)” 
 
The following project leaders have approved the protocol, version 1.2, dated 07.06.2025, 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 Investigator: 
• 
I have read this protocol, version 1.2, dated 07.06.2025, 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 Investigators 
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, 4051 Basel 
Phone 
+41 79 870 18 59 
 
 
National Principal Investigator 
Signature 
 
 
 
 
Name  
Irene Ayakaka 
Date of Signature 
(DD.MM.YYYY) 
Title 
MD/PhD 
Institution 
Solidarmed Lesotho 
Address 
Premium House 224, Kingsway, Maseru West 
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, 4051 Basel 
Phone 
 
 
 
Investigator 
Signature 
 
 
 
 
Name  
Felix Gerber 
Date of Signature 
(DD.MM.YYYY) 
Title 
M Med 
Institution 
Division of Clinical Epidemiology, University Hospital Basel, University of Basel 
Address 
Totengaesslein 3, 4051 Basel 
Phone 
+41 78 704 08 85 
 
 

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Table of contents 
 
1 
General Information 
2 
1.1 
List of Project Leaders and other key persons involved in the study ........................................................................... 2 
1.2 
Signatures .............................................................................................................................................................. 4 
1.3 
Abbreviations / Glossary of terms ............................................................................................................................ 8 
2 
Synopsis 
9 
3 
Background information 
15 
3.1 
Burden of type 2 diabetes ...................................................................................................................................... 15 
3.2 
Decentralized healthcare delivery .......................................................................................................................... 15 
4 
Objectives and purpose 
17 
4.1 
Objectives ............................................................................................................................................................ 17 
4.1.1 
Primary objective 
17 
4.1.2 
Secondary objectives 
17 
4.1.3 
Exploratory and implementation objectives 
17 
4.2 
Scientific justification of study population ............................................................................................................... 18 
5 
Study design 
19 
5.1 
Primary hypothesis, primary estimand and analysis sets ......................................................................................... 19 
5.2 
Endpoints ............................................................................................................................................................. 19 
5.2.1 
Primary endpoint 
19 
5.2.2 
Secondary endpoints 
19 
5.2.3 
Exploratory endpoints and implementation indicators 
20 
5.3 
Randomization ...................................................................................................................................................... 21 
5.4 
Measures to minimize bias .................................................................................................................................... 21 
5.4.1 
Blinding 
21 
5.4.2 
Measurements 
21 
5.5 
Study duration and duration of participant’s participation ......................................................................................... 21 
5.6 
Amendments ........................................................................................................................................................ 21 
5.7 
Withdrawal and discontinuation ............................................................................................................................. 21 
5.7.1 
Individual level 
21 
5.7.2 
Study and cluster level 
22 
5.8 
End of trial ............................................................................................................................................................ 23 
6 
Selection of study participants 
24 
6.1 
Selection of villages .............................................................................................................................................. 24 
6.2 
Recruitment of participants .................................................................................................................................... 24 
6.2.1 
Inclusion criteria 
24 
6.2.2 
Exclusion criteria 
24 
7 
Study procedures 
25 
7.1 
General Setting..................................................................................................................................................... 25 
7.2 
Screening ............................................................................................................................................................. 25 
7.3 
Enrolment ............................................................................................................................................................. 25 
7.4 
Baseline ............................................................................................................................................................... 25 
7.5 
Intervention .......................................................................................................................................................... 26 
7.6 
Follow-up and endpoint assessment ...................................................................................................................... 27 
7.6.1 
Scheduled follow-up visits and endpoint assessments 
27 
7.6.2 
Clinical follow-up 
27 
7.7 
Schedule of events ............................................................................................................................................... 29 
8 
Safety considerations 
31 
8.1 
Definition and documentation of safety outcomes ................................................................................................... 31 
8.2 
Causality of SAEs and AESIs ................................................................................................................................ 32 
8.3 
Management of AEs .............................................................................................................................................. 32 
8.3.1 
Control villages 
32 
8.3.2 
Intervention villages 
32 
8.4 
Reporting ............................................................................................................................................................. 33 
9 
Statistics 
34 
9.1 
Determination of sample size ................................................................................................................................. 34 
9.2 
Description of statistical methods ........................................................................................................................... 34 
9.2.1 
Datasets to be analysed 
34 
9.2.2 
Primary analysis 
34 
9.2.3 
Secondary analysis 
34 
9.3 
Handling of missing data ....................................................................................................................................... 34 
10 
Description of data management 
35 
11 
Quality control and quality assurance 
35 
12 
Ethical considerations 
36 
12.1 Independent Ethics Committees (IECs) .................................................................................................................. 36 
12.2 Risk-benefit ratio................................................................................................................................................... 36 
12.3 Participant information and consent ....................................................................................................................... 36 
12.4 Withdrawal on household or individual level ........................................................................................................... 37 
12.5 Service delivery for people declining consent ......................................................................................................... 37 
12.6 Participant confidentiality....................................................................................................................................... 37 
12.7 Participants requiring particular protection .............................................................................................................. 37 
12.8 Participant compensation ...................................................................................................................................... 38 
13 
Funding 
39 
14 
Dissemination of results and publication policy 
39 
14.1 Dissemination to scientific community .................................................................................................................... 39 

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14.2 Information of community and policy makers .......................................................................................................... 39 
15 
Appendix 
40 
16 
References 
42 
 
 

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1.3 
Abbreviations / Glossary of terms 
 
AE 
Adverse event 
AESI 
Adverse event of special interest 
aHT 
Arterial hypertension 
BMI 
Body mass index 
BG 
Blood glucose 
BP 
Blood pressure 
CC-VHW 
Chronic care village health worker 
CC nurse 
Chronic care nurse 
ComBaCaL 
Community-Based Chronic Disease Care Lesotho 
CVD 
Cardiovascular disease 
CVDRF 
Cardiovascular disease risk factor 
DHMT 
District Health Management Team 
EKNZ 
Ethics Committee of Northern and Central Switzerland 
FBG 
Fasting blood glucose 
HbA1c 
Glycated haemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICHOM 
International Consortium for Health Outcomes Measurement 
IEC 
Independent Ethics Committee 
IT 
Information technology 
ITT 
Intention-to-treat 
LHW 
Lay healthcare worker 
LMICs 
Low- and middle-income countries 
MoH 
Ministry of Health 
NCD 
Non-communicable disease 
NHREC 
National Health Research Ethics Council 
PP 
Per protocol 
RBG 
Random blood glucose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
T2D 
Type 2 diabetes mellitus 
TwiC 
Trial within cohort 
VHW 
Village health worker 
WHO 
World Health Organization  

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2 SYNOPSIS 
 
Project 
Leaders 
Prof. Dr. Niklaus Labhardt 
Study Title 
Community-based, eHealth supported type 2 diabetes care by lay village health 
workers in rural Lesotho: Protocol for a cluster-randomized trial within the 
ComBaCaL cohort study 
Short 
Title/Study ID 
ComBaCaL T2D TwiC 
Protocol 
Version and 
Date 
Version 1.2, 07.06.2025 
Study 
Category with 
Rationale 
Implementation research trial 
Risk category A 
Background 
and Rationale 
Globally, 9.3% of the adult population or 436 million individuals were estimated to 
be living with diabetes in 2019. Until 2045 this number is expected to increase by 
more than 50% to over 700 million.1,2 Four out of five people affected by diabetes 
are currently living in low- and middle-income countries (LMICs).3  
Over 90% of all diabetes cases are due to type 2 diabetes (T2D) which is also the 
main driver of the projected increase in overall diabetes cases1. The increase in T2D 
prevalence is caused by ageing populations and changing lifestyles with decreasing 
levels of physical activity, higher caloric diets and associated obesity.4  
Currently, only half of the people living with diabetes are aware of their high blood 
sugar levels and the associated health risks.1,2 The risk for diabetes to remain 
undetected and untreated and therefore earlier complications is significantly higher 
in LMICs than in high-income countries.3,5 At the same time, the management of 
diabetes complications is costly and not accessible in most LMICs in sub-Saharan 
Africa and elsewhere, therefore prevention via risk factor control and adequate 
antidiabetic treatment before onset of complications is essential.6,7 Setting-specific, 
affordable and scalable solutions need to be developed as it is not possible to plainly 
reproduce strategies from high-income countries in resource-scarce settings7.  
Incorporating lay healthcare workers (LHWs) delivering education, screening and 
care-support at community-level is a promising approach to improve access to and 
outcomes of diabetes care in sub-Saharan Africa8–10. Many countries have 
established LHW systems, traditionally focusing on maternal and neonatal health 
and on communicable diseases, especially HIV/AIDS. In recent years however, 
increasing evidence has emerged showing a beneficial effect and high cost-
effectiveness of LHW-based models on diseases outside this traditional scope, 
especially for non-communicable diseases (NCDs) such as diabetes and arterial 
hypertension (aHT)9,11,12.  
However, while screening, education and self-management support interventions 
by LHWs in the community have been tested successfully, it remains unclear 
whether such interventions are sufficiently effective to sustainably close the current 
treatment gap.7 A study in South Africa exploring NCD screening by LHWs at 
community-level has shown a high proportion of newly detected T2D cases, who 
were referred to a health facility for follow-up care. However, only 29% of 
participants with elevated blood glucose (BG) during screening actually linked to 
facility-based care indicating limited effectiveness of community-based screening 
and linkage services.13  

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In this trial embedded in the ComBaCaL (Community-based chronic disease care 
Lesotho) cohort, using the Trials within Cohorts (TwiCs) approach, we want to 
explore whether an LHW-led model could be capacitated to safely and effectively 
provide first-line management (including oral antidiabetic, lipid-lowering treatment 
and lifestyle counselling) at community-level. This TwiC has been developed based 
on a local NCD prevalence survey and burden assessment (NH-REC 130-2021), a 
scoping literature review14, multiple workshops with different stakeholders in 
Lesotho and the ComBaCaL pilot cohort study (NH-REC 176-2021). In villages 
randomized to the intervention arm, lay Chronic Care Village Health Workers (CC-
VHWs) operating within the existing Ministry of Health (MoH) village health worker 
system will be capacitated to screen for and diagnose T2D, to provide lifestyle 
counselling, to prescribe and to monitor first-line antidiabetic and lipid-lowering 
treatment for uncomplicated T2D and to provide treatment support for complicated 
T2D, supported by a tailored clinical decision support application (ComBaCaL app) in 
their villages. In villages randomized to the control arm, CC-VHWs will only screen 
for and diagnose T2D with subsequent standardized counselling and referral to the 
closest health facility for further care, but no village-based prescriptions or 
treatment support.  
Objectives 
Primary objective 
• 
To assess the effect of community-based, CC-VHW-led, eHealth supported  T2D 
care in rural Lesotho on blood sugar control among adults with uncomplicated 
T2D and a fasting blood glucose (FBG) ≥7 mmol/l at baseline 
 
Secondary objectives 
• 
To assess the effect of community-based, CC-VHW-led, eHealth supported T2D 
care in rural Lesotho on blood sugar control in different secondary analysis 
populations (see definition in section “Analysis Sets”)  
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on 10-year CVD 
risk using the WHO CVD risk prediction tool15 
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on CVD risk 
factors including body-mass index (BMI), abdominal circumference, blood lipid 
status, tobacco use, physical activity and dietary habits 
• 
To assess the safety of CC-VHW led, eHealth supported T2D care 
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on linkage and 
engagement in care and on adherence to treatment 
• 
To assess the sustained safety and feasibility of CC-VHW led, eHealth supported 
T2D care  and sustained effect on reaching blood sugar control, 10-year CVD 
risk, CVD risk factors, linkage to care, engagement in care and adherence to 
treatment among adults with uncomplicated T2D and a FBG ≥7 mmol/l at 
baseline and in different secondary analysis populations (see definition in 
section “Analysis Sets”). 
Hypothesis 
and estimand 
Primary hypothesis: Community-based, CC-VHW-led, eHealth supported T2D care in 
rural Lesotho is safe and superior with regard to HbA1c levels twelve months after 
enrolment compared to facility-based T2D care among non-pregnant adults with 
uncomplicated uncontrolled T2D. 
Primary estimand: HbA1c reduction (mean difference) 12 months after enrolment 
between community-based, CC-VHW-led, eHealth supported T2D care versus facility-
based T2D care, in non-pregnant adults with uncomplicated (no insulin, not more than 
one oral antidiabetic, no direct referral required) uncontrolled (FBG ≥ 7 mmol/l) T2D 
who are still alive and did not move out of their village, irrespective of the uptake of the 
intervention, T2D treatment, T2D treatment adherence and adverse events. 

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Endpoints 
Primary endpoint  
• 
Mean HbA1c twelve months after enrolment 
Secondary endpoints 
• 
10-year CVD risk estimated using the WHO CVD risk prediction tool15,16 at six 
and twelve months, as well as at subsequent timepoints over a total follow-
up period of up to 48 months after enrolment 
• 
Mean HbA1c at six months, as well as at subsequent timepoints over a total 
follow-up period of up to 48 months after enrolment 
• 
Mean FBG at six and twelve months, as well as at subsequent timepoints 
over a total follow-up period of up to 48 months after enrolment 
• 
Proportion of participants with an HbA1c below 8% at six and twelve months, 
as well as at subsequent timepoints over a total follow-up period of up to 48 
months after enrolment 
• 
Proportion of participants with an FBG below 7 mmol/l at six and twelve 
months, as well as at subsequent timepoints over a total follow-up period of 
up to 48 months after enrolment 
• 
CVD risk factors, such as smoking status, BMI, abdominal circumference, 
blood lipid status, blood pressure, dietary habits and physical activity at six 
and twelve months, as well as at subsequent timepoints over a total follow-
up period of up to 48 months after enrolment 
• 
Linkage to care: proportion of participants not taking treatment at 
enrolment who have initiated pharmacological antidiabetic treatment at six 
and twelve months, as well as at subsequent timepoints over a total follow-
up period of up to 48 months after enrolment 
• 
Engagement in care: proportion of participants who are engaged in care, 
defined as reporting intake of antidiabetic medication as per prescription of 
a healthcare provider (CC-VHW or healthcare professional) at six and twelve 
months, as well as at subsequent timepoints over a total follow-up period of 
up to 48 months after enrolment or reaching treatment targets without 
intake of medication 
• 
Self-reported adherence to antidiabetic medication at six and twelve 
months, as well as at subsequent timepoints over a total follow-up period of 
up to 48 months after enrolment 
• 
Occurrence of Serious Adverse Events (SAEs) and Adverse Events of Special 
Interest (AESIs) within six and twelve months, as well as at within 
subsequent time intervals during a total follow-up period of up to 48 months 
after enrolment 
 
The primary and secondary endpoints will first be assessed in the primary analysis 
set (see definition below), following the primary hypothesis and primary estimand. 
Secondly, the primary and secondary endpoints will be assessed in the three 
secondary analyses sets (see definition below). 
Intervention 
CC-VHWs are providing a T2D care package consisting of screening, diagnosis and 
counselling services as well as first-line antidiabetic treatment (metformin) and 
lipid-lowering treatment (atorvastatin) for uncomplicated T2D patients and 
treatment support and regular check-ups for patients with complicated T2D at 
community-level. CC-VHWs are equipped with a tablet where a dedicated 
application, the ComBaCaL app, guides them to provide the above-mentioned 
services. Appropriately trained, supervised and mentored by chronic care nurses (CC 
nurses) and guided by the ComBaCaL app they will follow-up persons with  T2D to 
monitor adherence, life-style changes, treatment response and side-effects. 

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Control 
Control villages will follow the standard of care in the ComBaCaL cohort study. CC-
VHWs will also receive tablets with the ComBaCaL app installed. They are trained, 
supervised and equipped to screen and diagnose T2D with subsequent referral to 
facility-based follow-up and care. In control villages the ComBaCaL app supports 
clinical decision making and documentation for screening, diagnosis and referral, 
but not prescription/provision and monitoring of antidiabetic or lipid-lowering 
medication for uncomplicated T2D patients or treatment support for complicated 
T2D patients.  
Study Design 
We are conducting a cluster-randomized controlled trial nested within the 
ComBaCaL cohort study following a trial within cohort (TwiC) approach17,18. 50% of 
the villages being part of the overarching ComBaCaL cohort will be randomized 
stratified by district and access to health facility to receive the intervention as 
described above.  
Eligibility 
criteria 
 Inclusion criteria 
- 
Participant of the ComBaCaL cohort study (signed informed consent 
available) 
- 
Aged 18 years or above 
- 
Living with T2D, defined as reporting intake of antidiabetic medication or 
being newly diagnosed during screening via standard diagnostic algorithm 
Exclusion criteria  
- 
Known type 1 diabetes mellitus 
- 
Reported pregnancy 
Analysis sets 
Primary analysis set: All study participants with uncomplicated, uncontrolled T2D at 
baseline, defined as: 
- 
Uncomplicated:  
o No treatment or uncomplicated treatment defined as taking only one 
class of oral antidiabetic drugs (i.e. metformin) 
o Not meeting criteria for direct referral, which are defined as:  
▪ 
FBG > 14 mmol/l OR  
▪ 
RBG > 16.7 mmol/l OR  
▪ 
Having polyuria, polydipsia and weight loss 
- 
Uncontrolled:  FBG ≥7 mmol/l 
Secondary analyses sets:  
a) Only study participants with uncontrolled, uncomplicated T2D and a baseline 
HbA1c 6.5% and above 
b) Only study participants with a baseline HbA1c 6.5% and above 
c) All study participants 
Measurements 
and 
Procedures 
Screening, enrolment, baseline and endpoint assessments will be conducted by CC-
VHWs at community-level. We refer to the current version the “ComBaCaL cohort 
study protocol” for detailed information about the cohort set-up and procedures. In 
brief, CC-VHWs screen for and diagnose T2D via capillary blood glucose (BG) 
measurements, based on standardized algorithms encoded in the tablet-based 
ComBaCaL app. In villages not allocated to the TwiC intervention (control villages), 
participants diagnosed with T2D receive a standardized counselling by the CC-VHW 
and are referred to the closest health facility for initiation or continuation of 
antidiabetic treatment.  
In the randomly selected intervention villages, CC-VHWs will provide a T2D care 
package including life-style counselling and the offer of oral first-line antidiabetic 
(metformin) and lipid-lowering (statin) treatment for uncomplicated T2D and 

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treatment support and monitoring for complicated T2D guided by the ComBaCaL 
app. Participants are free to accept or refuse the services offered by the CC-VHW at 
any time.  
Prior to implementation, CC-VHWs in intervention villages will receive trainings on 
the basic mechanisms of action, contraindications and potential side effects of the 
antidiabetic and lipid-lowering treatment used as well as on adherence counselling 
techniques, on the interpretation of BG values and on basic clinical examination 
skills for the recognition of possible adverse events. Direct guidance for treatment 
initiation, drug prescription, counselling and monitoring will be provided via the 
ComBaCaL app. All activities conducted by CC-VHWs in the communities, including 
counselling and drug prescription, will also be captured in the ComBaCaL app. Health 
care professionals and supervising study staff will monitor all activities in a web 
version of the app and will be intervening in case of missing data, non-adherence to 
the clinical algorithms, or unclear clinical conditions. The CC-VHWs may always 
request support by supervising health care professionals.  In case of complicated 
disease, unclear diagnosis, or presence of clinical alarm signs or symptoms, 
participants will be referred immediately to the closest health facility for further 
investigation. 
Endpoint assessments after six and twelve months, as well as after subsequent 
timepoints over a total follow-up period of up to 48 months after enrolment, 
including HbA1c, blood lipid status and FBG measurements, capturing of possible 
SAEs and AESIs as well as administration of questionnaires on adherence and 
modifiable cardiovascular disease risk factors (CVDRFs) will be conducted by CC-
VHWs in an identical manner in intervention and control villages and captured in the 
ComBaCaL app. If resources allow, certain endpoints (i.e. HbA1c) will be assessed by 
study personnel not involved in the care at village-level.  
In addition, questionnaires about participants’ satisfaction and acceptability of the 
TwiC intervention will be administered and semi structured interviews with a 
selection of participants, CC-VHWs and involved health care professionals will be 
conducted to qualitatively explore perceived risks, benefits and problems of 
community-based T2D care.  
Number of 
Participants 
with Rationale 
and Power 
Analysis 
The ComBaCaL cohort will consist of inhabitants of around 100 (range 90-112) 
randomly selected villages in rural Lesotho. The estimated mean number of adult 
ComBaCaL participants per village is 100 resulting in an estimated 10’000 adult 
cohort participants.  
Sample size for the TwiC is calculated assuming an individual randomization inflated 
by a design effect that account for variation at cluster level, according to the code 
developed by Rotondi and Donner19. Based on preliminary results from an NCD 
prevalence survey in the region (NH-REC ID 139-2021), we expect the prevalence of 
T2D in the adult population in the rural setting in Lesotho to be around 4%, with 
about 60% of people living with T2D fulfilling the criteria for the primary analysis set 
(not pregnant, no type 1 diabetes mellitus, no complicated treatment, not meeting 
criteria for insulin treatment, FBG ≥7 mmol/l). Hence, considering an average cluster 
size of 100 adult inhabitants, the mean number of inhabitants eligible for the TwiC 
is 2.4 per village.  
We estimate an effect size of 0.6% HbA1c mean difference between the two groups 
after 12 months. Assuming an intra-cluster correlation of 0.015 and an attrition rate 
of 20%, we calculate that a sample size of 240 individuals (120 per arm, 50 clusters 
per arm) is required to detect superiority with a type I error of 0.05 and a statistical 
power of 80%.   

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Study 
Duration and 
Schedule 
The follow-up period for the TwiC is twelve months for the evaluation of the primary 
endpoint. We plan to enrol first participants in March 2023 and expect an enrolment 
period of around four months. To assess the sustained effect of the intervention, 
the overall follow-up period will last 48 months. Thus, the primary endpoint 
assessment for the last participants is planned end of 2027.  
Study 
Centre(s) 
Scientific project lead: Division of Clinical Epidemiology, University of Basel  
Implementation lead: SolidarMed Lesotho 
Study sites: 100 (90 to 112) villages in rural areas of Butha-Buthe and Mokhothlong 
districts in Lesotho 
Statistical 
Analysis  
Analyses will be performed following the principles for analysis of cluster-
randomized trials in health research as first enunciated by Donner and Klar 20. 
Villages are our unit of random selection and individuals the unit of analysis.  The 
primary analysis will be the comparison of mean HbA1c between the two study 
arms. Superiority will be assessed in an intention-to-treat (ITT) set, i.e. as 
randomized, using linear mixed-effect regression models, adjusted for clustering 
and stratification variables as well as baseline fasting blood glucose, irrespective of 
the uptake of and adherence to the intervention, excluding participants that died, 
became pregnant, confirmed to move out from the village, or withdrew consent. 
Baseline characteristics will be described by study arm with summary statistics such 
as median and interquartile range or number and percentage. 
Secondary endpoints will be reported using descriptive statistics such as mean and 
95% Wald confidence intervals, frequency and percentages. Further details will be 
outlined in the statistical analysis plan (SAP). 
Ethical 
consideration 
This project will be carried out in accordance with the research plan outlined in this 
protocol and with principles enunciated in the current version of the Declaration of 
Helsinki as well as all national legal requirements and guidelines as applicable.  
This protocol will be reviewed by the Ethikkommission Nordwest- und 
Zentralschweiz (EKNZ, Ethics Committee of Northern and Central Switzerland) and 
by the National Health Research Ethics Committee (NHREC) of Lesotho before 
starting the study. 
Participation in the ComBaCaL cohort study and the TwiC intervention are voluntary.  
Potential risks associated with study participation include inadequate management 
by lay CC-VHWs. We will minimize this risk by providing adequate training, 
continuous supervision by health care professionals, and close guidance through the 
ComBaCaL eHealth application. Community-based care delivery is widely 
implemented in HIV care in Lesotho providing substantial benefits compared to 
purely clinic-based care. The here-presented intervention has the potential to 
increase the quality of care for T2D by improving access to treatment, increasing 
adherence and providing closer monitoring.  
The evidence generated in this study aims at informing future national and 
international clinical guidelines to improve chronic disease care in low-resource 
settings. Additionally, the community-based activities of the ComBaCaL project 
provide the added benefit of building a healthy and friendly community 
environment through community advocacy and participation, and helping to raise 
awareness and knowledge of chronic diseases within villages in Lesotho.  
Thus, the intervention is likely to have a direct positive impact on health outcomes 
of participants as well as generating evidence to improve context-specific NCD care 
delivery on a longer perspective. 

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3 BACKGROUND INFORMATION  
3.1 
Burden of type 2 diabetes 
Globally, 9.3% of the adult population or 436 million individuals were estimated to be living with diabetes 
in 2019. Until 2045 this number is expected to increase by more than 50% to over 700 million.1,2 Four 
out of five people affected by diabetes are currently living in low- and middle-income countries (LMICs). 
The proportional burden of LMICs continues to rise as most of the projected global prevalence increase 
over the next decades is expected to occur in LMICs.3  
Over 90% of all diabetes cases are due to type 2 diabetes (T2D) which is also the main driver of the 
projected increase in overall diabetes cases1. The increase in T2D prevalence is caused by ageing 
populations and changing lifestyles with decreasing levels of physical activity and higher caloric diets 
and associated obesity.4  
Currently, only half of the people living with diabetes are aware of their high blood sugar levels and the 
associated health risks.1,2 The risk for diabetes to remain undetected and untreated and therefore lead 
to earlier complications is significantly higher in LMICs than in high-income countries.3,5 At the same 
time, the management of diabetes complications is costly and not accessible in most LMICs in sub-
Saharan Africa and elsewhere, therefore prevention via risk factor control and adequate antidiabetic 
treatment before onset of complications is essential.6,7 Setting-specific, affordable and scalable solutions 
need to be developed as it is not possible to directly reproduce strategies from high-income countries 
in resource-scarce settings7.  
 
Lesotho is a landlocked country within South Africa, a typical example of an African LMIC where NCDs 
are overtaking HIV and other infectious diseases as major cause of disability, morbidity and early death21. 
A recent population-based survey in the districts of Mokhotlong and Butha-Buthe has revealed an T2D 
prevalence of 4% in the adult population in urban and rural areas combined and a relatively high 
treatment control rate of 40% compared to other LMICs (NH-REC 130-2021).  
 
3.2 
Decentralized healthcare delivery 
Effective, affordable, scalable setting-specific strategies are required to reverse the trend of increasing 
NCD-related burden in LMICs. The task-shifting to lay healthcare workers (LHWs) at community-level has 
been identified as a promising and cost-effective solution to increase access to T2D treatment in LMIC-
settings7,9,12,13,22,23. Many LMICs have established LHW systems that may be capacitated to play a more 
active role in the management of NCDs10,24. Traditionally, most LHW systems focus on maternal and 
neonatal health and communicable diseases, especially HIV/AIDS25–27, however in recent years, 
increasing evidence has emerged showing a beneficial effect and high cost-effectiveness of LHW-based 
models on diseases outside this traditional scope, especially for NCDs, such as T2D or arterial 
hypertension (aHT)9,10,12. For T2D, most studies about LHW-led care models have focused on screening, 
counselling, educational, self-management and referral interventions, while knowledge about the effect 
of LHW-led prescription of antidiabetic medication is lacking.7–9,11–13,22,28 
Current knowledge gaps include the question of whether prescription of first-line antidiabetics 
(metformin) and first-line lipid-lowering treatment (statin) can be included safely and effectively in LHW-
led T2D care models at community-level complementing the screening, counselling and referral services 
for which benefit has been shown already.  
Building on the existing knowledge and addressing the mentioned gaps, we are planning to conduct a 
cluster-randomized intervention within the ComBaCaL (Community-Based Chronic disease care Lesotho) 
cohort study (EKNZ ID AO_2022-00058, clinicaltrials.gov ID NCT05596773), a platform for the 
investigation of chronic diseases and their management in rural Lesotho that is maintained by local lay 
chronic care village health workers (CC-VHWs). CC-VHWs are lay healthcare workers operating within 
the Lesotho Ministry of Health (MoH) Village Health Worker (VHW) program who receive a specific 
training to deliver chronic care services. As in many other sub-Saharan African 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 

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been adopted many years ago29. Despite a drastic health workers shortage in Lesotho (0.9 doctors and 
10.2 nurses per 10,000 inhabitants, particularly in the rural areas where the majority of the population 
lives (77.6%)30, and the second-highest adult HIV prevalence globally (21.1%)31, Lesotho has managed to 
reduce HIV transmission and AIDS-related deaths considerably. This success is based on decentralized 
HIV testing and care, involving lower cadre healthcare workers and lay VHWs to deliver accessible and 
equitable services for the urban and rural population alike. Currently the community-based health care 
delivery in Lesotho is focused on HIV, maternal and neonatal diseases, largely neglecting NCDs. Thus, 
NCD screening, diagnosis, management and prevention are located at the health facilities. However, due 
to high workload, staff shortages, lack of specific training, medication stock-outs and outdated 
guidelines, NCD services are often not delivered adequately at facility-level.  
The Ministry of Health (MoH) of Lesotho has proposed in its NCD strategic plan that lessons learnt from 
HIV program should be incorporated into the NCD care and that delivery platforms should provide 
integrated HIV/NCD services.32 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.27,33 To our knowledge, no studies have been conducted or 
policy documents developed on how to provide pragmatic and scalable prevention and treatment 
models for T2D or other NCDs in the context of a high communicable disease burden in Lesotho. 
With the ComBaCaL project, we plan to tackle the growing NCD pandemic through a multi-disciplinary 
research and implementation partnership. ComBaCaL aims at establishing and validating a community-
based care model focused on ehealth supported NCD service delivery by lay CC-VHWss. The ComBaCaL 
cohort study provides the platform for the scientific assessment of the community-based NCD care 
model proposed. 
In the here described trial within the cohort (TwiC), we are aiming to assess the effect of a community-
based T2D care package which includes provision of first-line antidiabetic (metformin) and lipid-lowering 
(statin) treatment for uncomplicated T2D and treatment support for complicated T2D provided by lay 
CC-VHWs. The TwiC intervention has been developed based on a local NCD prevalence survey and 
burden assessment (NH-REC 130-2021), a scoping literature review14, multiple workshops with different 
stakeholders in Lesotho and the ComBaCaL pilot cohort study (NH-REC 176-2021). In the intervention 
clusters, CC-VHWs operating within the existing healthcare system will be capacitated to screen for and 
diagnose T2D, to prescribe and monitor first-line antidiabetic and lipid-lowering treatment for 
uncomplicated T2D and to offer treatment support for complicated T2D supported by a tailored clinical 
decision support application (ComBaCaL app) in their villages. The control group consists of people 
diagnosed with T2D living in villages that are also part of the ComBaCaL cohort but not sampled for the 
intervention (control villages), where CC-VHWs will only screen for and diagnose T2D with subsequent 
standardized counselling and referral to the closest health facility if T2D is present, but no village-based 
prescriptions.  
 
 
 

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4 OBJECTIVES AND PURPOSE 
4.1 
Objectives 
The overall objective of the ComBaCaL cohort study and nested TwiCs is to assess the impact of eHealth-
supported, lay-led chronic disease control measures in rural Lesotho. 
In this T2D TwiC, we will assess the effect, safety and feasibility of a community-based T2D care package 
which includes the offer of first-line oral antidiabetic and lipid-lowering treatment for uncomplicated 
T2D by lay CC-VHWs in comparison to facility-based care after community-based screening and 
diagnosis.  
 
4.1.1 
Primary objective 
• 
To assess the effect of community-based, CC-VHW-led, eHealth supported T2D care in rural Lesotho 
on blood sugar control among non-pregnant adults with uncomplicated, uncontrolled (fasting blood 
glucose (FBG) ≥ 7mmol/l) T2D  
 
4.1.2 
Secondary objectives  
• 
To assess the effect of community-based, CC-VHW-led, eHealth supported T2D care in rural 
Lesotho on blood sugar control among non-pregnant adults with uncomplicated, uncontrolled 
T2D and a baseline HbA1C of ≥6.5% 
• 
To assess the effect of community-based, CC-VHW-led, eHealth supported T2D care in rural 
Lesotho on blood sugar control among non-pregnant adults with T2D and a baseline HbA1C of 
≥6.5% independent of complicated or uncomplicated T2D  
• 
To assess the effect of community-based, CC-VHW-led, eHealth supported T2D care in rural 
Lesotho on blood sugar control among non-pregnant adults with T2D independent of baseline 
HbA1C and FBG values and independent of complicated or uncomplicated T2D 
• 
To assess the sustained safety and feasibility of CC-VHW led, eHealth supported T2D care and 
sustained effect on reaching blood sugar control, 10-year CVD risk, CVD risk factors, linkage to 
care, engagement in care and adherence to treatment among adults with uncomplicated, 
uncontrolled T2D and a baseline HbA1C of ≥6.5% 
 
All following secondary and exploratory objectives will also be investigated in the different analysis 
populations as above.  
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on 10-year CVD risk using the WHO 
CVD risk prediction tool15 
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on CVD risk factors including body-
mass index (BMI), abdominal circumference, blood lipid status, tobacco use, physical activity and 
dietary habits 
• 
To assess the safety of CC-VHW led, eHealth supported T2D care 
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on linkage and engagement in care 
and on adherence to treatment  
• 
To assess the sustained safety and feasibility of CC-VHW led, eHealth supported T2D care and 
sustained effect on reaching blood sugar control, 10-year CVD risk, CVD risk factors, linkage to care, 
engagement in care and adherence to treatment  
4.1.3 
Exploratory and implementation objectives 
• 
To assess the effect of CC-CHW led T2D care on the number of eligible participants accessing lipid-
lowering treatment 
• 
To assess and describe implementation parameters, i.e. acceptance, uptake of and satisfaction with 
CC-VHW led T2D care among involved stakeholders 
• 
To estimate the costs of CC-VHW led T2D care 

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• 
To assess quality indicators of the services provided and the data collected by CC-VHWs, such as 
completeness of the data collected and adherence to clinical algorithms provided via the eHealth 
application 
• 
To assess the 10-year CVD risk using the Framingham Risk Score 34 and the Globorisk Score35,36 
• 
To assess the effect of CC-VHW led, eHealth supported T2D care on quality of life using the EQ-5D-
5L instrument37, on health beliefs using the Beliefs about Medicines Questionnaire (BMQ) adapted 
for people living with T2D38,39 and on diabetes distress using the five item version of the “Problem 
Areas in Diabetes” (PAID-5) scale 40,41 
• 
To assess the effect of CCH-VHW led T2D care on self-reported access to care  
 
4.2 
Scientific justification of study population 
The ComBaCaL cohort study will be located in rural villages of Butha-Buthe and Mokhothlong districts in 
Lesotho. Lesotho is a typical example of an African LMIC where a developing health system is facing the 
heavy double-burden of the still highly prevalent infectious diseases HIV/AIDS and TB in combination 
with a rapidly spreading NCD epidemic21.  
 
 
 
 
 
 
 
 
 
 
 
 
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 areas29. The Lesotho VHW program thus represents 
a meaningful starting point for implementation research on enhancing community-based intervention 
strategies and provides a setting that is representative for the health systems in many other LMICs, 
especially in sub-Saharan Africa, where lay worker led care has a similar standing.   
 
 

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5 STUDY DESIGN 
5.1 
Primary hypothesis, primary estimand and analysis sets 
Primary hypothesis: Community-based, CC-VHW-led, eHealth supported T2D care in rural Lesotho is safe 
and superior with regard to HbA1c levels twelve months after enrolment compared to facility-based T2D 
care among non-pregnant adults with uncomplicated uncontrolled T2D. 
Primary estimand: HbA1c reduction (mean difference) 12 months after enrolment between community-
based, CC-VHW-led, eHealth supported T2D care versus facility-based T2D care, in non-pregnant adults 
with uncomplicated uncontrolled T2D who were still alive and did not move out of their 
village, irrespective of the uptake of the intervention, T2D treatment, T2D treatment adherence and 
adverse events. 
Primary analysis set: All study participants with uncomplicated, uncontrolled T2D at baseline, defined as: 
o Uncomplicated: No or only Metformin treatment  
o Not meeting criteria for direct referral, which are defined as:  
▪ 
FBG > 14 mmol/l OR  
▪ 
RBG >  16.7 mmol/l OR  
▪ 
Having polyuria, polydipsia and weight loss 
- 
Uncontrolled:  FBG ≥7 mmol/l 
Secondary analyses sets: 
a) Only study participants with uncomplicated and uncontrolled diabetes and a baseline HbA1c ≥ 6.5%  
b) Only study participants with a baseline HbA1c ≥ 6.5% 
c) All study participants 
  
5.2 
Endpoints 
For the endpoint assessments at twelve months, a range of 300 to 420 days after enrolment applies. For 
the endpoint assessments at six months, a range of 150 to 210 days applies. For endpoint assessments 
after twelve months, endpoint windows of 180 days apply. 
The primary and secondary endpoints will first be assessed in the primary analysis set, following the 
primary hypothesis and primary estimand. Secondly, the primary and secondary endpoints will be 
assessed in the secondary analysis sets. The analyses in the secondary analysis set that includes all study 
participants will explore the effects of our intervention among the entire non-pregnant T2D population 
including those with more intensive treatment. 
 
5.2.1 
Primary endpoint 
• 
Mean HbA1c twelve months after enrolment 
 
5.2.2 
Secondary endpoints 
• 
10-year risk for a fatal or non-fatal CVD event estimated using the WHO CVD risk prediction 
tool15,16 at six and twelve months, as well as at subsequent timepoints over a total follow-up 
period of up to 48 months after enrolment 
• 
Mean HbA1c at six months after enrolment, as well as at subsequent timepoints over a total 
follow-up period of up to 48 months after enrolment 
• 
Mean FBG at six and twelve months, as well as at subsequent timepoints over a total follow-up 
period of up to 48 months after enrolment 
• 
Proportion of participants with an HbA1c < 8% at six and twelve months, as well as at subsequent 
timepoints over a total follow-up period of up to 48 months after enrolment 
• 
Proportion of participants with an FBG < 7 mmol/l at six and twelve months, as well as at 
subsequent timepoints over a total follow-up period of up to 48 months after enrolment 
• 
CVD risk factors, such as BMI, abdominal circumference, blood lipid status, physical activity using 
the validated International Physical Activity Questionnaire Short Form (IPAQ-SF)42 adapted to the 
local context and language according to the IPAQ recommendations43, dietary habits using a 
shortened unquantified food frequency questionnaire adapted from an assessment tool for 

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obesity used in South Africa44 and alcohol and tobacco use at six and twelve months, as well as 
at subsequent timepoints over a total follow-up period of up to 48 months after enrolment 
• 
Linkage to care: proportion of participants not taking treatment at enrolment who have initiated 
pharmacological antidiabetic treatment at six and twelve months, as well as at subsequent 
timepoints over a total follow-up period of up to 48 months after enrolment 
• 
Engagement in care: proportion of participants who are engaged in care, defined as reporting 
intake of antidiabetic medication as per prescription of a healthcare provider (CC-VHW or 
healthcare professional) within the two weeks prior to assessment at six and twelve months, as 
well as at subsequent timepoints over a total follow-up period of up to 48 months after 
enrolment or reaching treatment targets without intake of medication 
• 
Occurrence of Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) 
within six and twelve months, as well as within subsequent time intervals during a total follow-
up period of up to 48 months  after enrolment 
• 
Self-reported adherence to treatment at six and twelve months, as well as at subsequent 
timepoints over a total follow-up period of up to 48 months after enrolment 
 
5.2.3 
Exploratory endpoints and implementation indicators 
• 
Number of consultations at a health facility and with the CC-VHW within six and twelve months, 
as well as within subsequent time intervals during a total follow-up period of up to 48 months 
after diagnosis 
• 
Trajectory of participants between facility-based and community-based care in the intervention 
villages (i.e. number of participants accepting community-based care at baseline, number of 
people switching to facility-based care and back to community-based care during the study 
period) 
• 
Proportion of participants with T2D who stop drug treatment or interrupt drug treatment for 
more than three weeks or require a switch of drug treatment due to (perceived) adverse events 
(AEs) within six and twelve months, as well as within subsequent time intervals during a total 
follow-up period of up to 48 months after enrolment 
• 
Proportion of participants who are reaching treatment targets (FBG <7 mmol/l) and are reporting 
no intake of antidiabetic medication in the two weeks prior to assessment at six and twelve 
months, as well as at subsequent timepoints over a total follow-up period of up to 48 months 
after enrolment 
• 
Proportion of participants accessing lipid-lowering medication at six and twelve months, as well 
as at subsequent timepoints over a total follow-up period of up to 48 months after enrolment  
• 
Participants’, CC-VHWs’ and involved health care professionals’ perception of the risks, benefits 
and problems of community-based management of uncomplicated T2D by CC-VHWs 
• 
Quality indicators of the CC-VHW activities, such as completeness of the data collected and 
adherence to clinical algorithms provided via the eHealth application 
• 
Causes for the stop or interruption of treatment or switch to health facility-based treatment 
after initiation by CC-VHWs in the community 
• 
Health system costs and individual costs for participants for the management of their condition 
within the first six and twelve months, as well as within subsequent time intervals during a total 
follow-up period of up to 48 months follow-up period of up to 48 months after enrolment after 
diagnosis 
• 
10-year CVD risk estimated using the Globorisk score36 and Framingham Risk Score 34 six and 
twelve months, as well as at subsequent timepoints over a total follow-up period of up to 48 
months after enrolment 
• 
Quality of life using the EQ-5D-5L instrument37, health beliefs using the Beliefs about Medicines 
Questionnaire (BMQ) adapted for people living with T2D38,39 and diabetes distress using the five 
item version of the “Problem Areas in Diabetes” (PAID-5) scale40,41 after twelve months, as well 
as at subsequent timepoints over a total follow-up period of up to 48 months after enrolment 
• 
Self-reported access to care and access to medication 

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• 
Type and dosage of antidiabetic and lipid-lowering medications prescribed by CC-VHWs or 
healthcare professionals six and twelve months, as well as at subsequent timepoints over a total 
follow-up period of up to 48 months after enrolment 
 
5.3 
Randomization 
50% of villages out of the ComBaCaL cohort villages will be randomly allocated to the intervention group 
by a statistician not involved in the study. The random allocation will be stratified by district (Butha-
Buthe versus Mokhothlong) and access to health facility (easy versus difficult access, defined as needing 
to cross a mountain or river or travel >10 km to the nearest health facility).  
 
5.4 
Measures to minimize bias 
5.4.1 
Blinding 
Participants are not blinded to the intervention due to the nature of the intervention. However, due to 
the cluster level randomization and TwiCs approach participants are blinded to the allocation (i.e. 
participants in the control villages are not aware of the intervention being implemented in the 
intervention villages). 
The CC-VHWs who are enrolling participants, providing the intervention and collecting the date cannot 
be blinded to the intervention nor the allocation. However, the main outcome is a laboratory 
measurement and the safety endpoints are assessed by an independent study physician blinded to the 
allocation. 
The statistician and data managers cannot be blinded to the allocation.  
 
5.4.2 
Measurements 
Baseline and endpoint assessments will be conducted by CC-VHWs supported by the ComBaCaL app. If 
resources allow, certain endpoints (i.e. HbA1c) will be assessed by study staff not involved in the care 
delivery at village level. Protocols and instructions for correct measurements and sample collection as 
well as structured questionnaires for the assessment of lifestyle risk factors, health beliefs, diabetes 
distress and quality of life are provided in the ComBaCaL app. For the duration of the study there will be 
regular field visits by supervising CC nurses to ensure that procedures for data collection are correctly 
followed by all involved CC-VHWs.  
 
5.5 
Study duration and duration of participant’s participation 
The follow-up period for this TwiC is twelve months for the evaluation of the primary endpoint. We plan 
to enrol first participants in March 2023 and expect an enrolment period of around four months. To 
assess the sustained safety and effect of the intervention, the overall follow-up period will last for 48 
months. Thus, the endpoint assessment for the last participants is planned for end of 2027.  
 
5.6 
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. 
 
5.7 
Withdrawal and discontinuation 
5.7.1 
Individual level 
Participants in the intervention villages may reject the intervention any time. They will be asked about 
the reasons for the rejection of village-based care, but may refuse to provide a reason for the rejection. 
The rejection of the intervention will not influence their affiliation to the ComBaCaL cohort study and 
their data will be included in the intention-to-treat (ITT) analysis. Participants in the control villages who 
do not want their data to be included in the TwiC analysis need to withdraw the ComBaCaL cohort 
consent as agreeing to use of collected data as control data is an integral part of the ComBaCaL cohort 
consent. 

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As outlined in the “ComBaCaL cohort study protocol” all participants can withdraw cohort consent at 
any time. After withdrawal of cohort consent, the participant’s profile in the ComBaCaL application will 
be de-activated and no further data will be collected. The possibility to re-enter the cohort later through 
contacting the local CC-VHW will be offered. Anonymized data collected until the time of withdrawal will 
be included in the analysis. By withdrawing the ComBaCaL cohort consent, automatically the 
intervention consent will be withdrawn, too.  
The study team will not discontinue individual participants.   
 
5.7.2 
Study and cluster level 
In intervention villages, the village chief may reject the intervention at village-level. The study team 
would then get in contact with the village chief to inquire the reasons for the intended rejection. If 
needed a community gathering (“Pitso”) will be held. If after discussion between the village chief, the 
community and the study team, the request for rejection of the intervention persists, the intervention 
will be stopped in the village and all participants will be referred to the responsible health facility for 
continuation of treatment. ComBaCaL cohort activities without the intervention will continue in the 
village. Participants may be asked specifically about their perceptions of the rejection of the intervention 
at village-level.  
 
If in a village, the CC-VHW is not able or willing to continue his/her tasks for the ComBaCaL study (i.e. 
due to death, migration, personal reasons, rejection by village chief or village population), the CC-VHW 
will be replaced while the village will remain in the study.  
 
The Principal Investigator in consultation with Co-Investigators may choose to pause or discontinue the 
ComBaCaL cohort study in certain or all villages or to pause or discontinue the intervention in one or 
more intervention villages.   
We refer to the “ComBaCaL cohort study protocol” for details regarding the criteria for interruption or 
stop of the ComBaCaL cohort study. If the ComBaCaL cohort is being interrupted or stopped in one or 
more villages, automatically also the nested TwiCs are interrupted or stopped in the concerned villages, 
while the participants will remain in the TwiC analysis population as outlined in section 9.  
 
The reasons to pause or discontinue the TwiC intervention in all intervention villages 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 the TwiC intervention in individual villages include the following:  
• 
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 of the ComBaCaL 
cohort study or the TwiC intervention. If the Principal Investigator chooses to terminate or pause the 
ComBaCaL cohort study or the TwiC intervention for safety reasons, they will immediately notify all 
investigators and subsequently provide written instructions for study termination. Co-investigators may 
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without written notice in advance. If Co-Investigators wish to pause or discontinue the ComBaCaL cohort 
study or the TwiC intervention, they may address the request to pause or discontinue in written form to 
the Principal Investigator. Co-Investigators may not pause or discontinue the ComBaCaL cohort study or 
the TwiC intervention for other reasons than safety concerns without consulting the Principal 
Investigator. 
 
5.8 
End of trial 
At the conclusion of the trial or premature termination, all study data will be locked and archived. The 
electronic database will be locked and a complete study dataset will be transferred to the statistician 
and the Principal Investigator through a secure channel. The study data will be stored by the Department 
of Clinical Research of the University Hospital Basel on a secure server for a minimum of 10 years and 
be destroyed thereafter (see section 10).  
Participants in intervention and control villages will be informed about the results of the TwiCs through 
the CC-VHWs after the analysis is complete.  
 

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6 SELECTION OF STUDY PARTICIPANTS 
6.1 
Selection of villages 
We refer to the “ComBaCaL cohort study protocol” for detailed information about the selection of 
villages for the ComBaCaL cohort.  
Out of the ComBaCaL cohort villages, 50% will be randomly allocated to the intervention group. We refer 
to the paragraph Error! Reference source not found. “Randomization” for information about the random 
allocation.  
 
6.2 
Recruitment of participants 
We refer to the “ComBaCaL cohort study protocol” for details regarding the recruitment for the 
ComBaCaL cohort. For this TwiC, CC-VHWs will screen for eligible individuals among adult ComBaCaL 
cohort participants in their villages via home visits according to the following criteria. 
 
6.2.1 
Inclusion criteria 
• 
Participant of the ComBaCaL cohort study (signed informed consent available) 
• 
Aged 18 years or above 
• 
Living with T2D, defined as reporting intake of antidiabetic medication or being newly diagnosed 
during screening via standard diagnostic algorithm (see appendix of the “ComBaCaL cohort study 
protocol”) 
 
6.2.2 
Exclusion criteria 
• 
Known type 1 diabetes mellitus 
• 
Reported pregnancy  
 
Participants in the intervention villages will be offered the intervention T2D care package including first-
line antidiabetic treatment (metformin) for eligible participants, lifestyle counselling and lipid-lowering 
medication (statin) by the CC-VHW after the screening. Participants are free to accept or reject all or 
parts of the pharmacological and non-pharmacological treatment offered by the CC-VHW.  
Data of ComBaCaL cohort participants living in villages not selected for the intervention will be used as 
control arm. As per the ComBaCaL cohort study protocol and informed consent, no specific recruitment 
or participant information will be provided to the participants in control villages.  
 

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7 STUDY PROCEDURES 
7.1 
General Setting 
Screening and enrolment for this TwiC will be embedded into the regular ComBaCaL cohort activities 
conducted in the villages by CC-VHWs. We refer to the current version the “ComBaCaL cohort study 
protocol” for detailed information about the cohort set-up. At every participant encounter, the CC-VHW 
will screen for warning signs and symptoms (i.e. shortness of breath, severe headache, chest pain, new-
onset confusion, impaired consciousness, severely impaired general state of health) and refer 
participants to the closest health centre in case of presence of any alarm sign or symptom. 
 
7.2 
Screening 
Screening and diagnosis for T2D among the ComBaCaL cohort members will be conducted by CC-VHWs 
according to the algorithms provided in the appendix of the “ComBaCaL cohort study protocol”. These 
algorithms are being encoded into the ComBaCaL app, guiding the question logic for data collection and 
serving as clinical decision aid for the CC-VHWs. After diagnosis of T2D, CC-VHWs will screen for the 
other eligibility criteria and based on the screening information, the trial eligibility will be determined 
via the ComBaCaL app.  
 
7.3 
Enrolment 
ComBaCaL cohort participants meeting the eligibility criteria for the TwiC, will automatically be included 
in the TwiC population. We refer to the current version of the “ComBaCaL cohort study protocol” and to 
the section 12.3 of this document for details regarding the consent procedures. Participants in 
intervention villages may reject the intervention at any time during the study and request referral to a 
health facility for the continuation of their treatment. Participants consenting to participation but 
subsequently rejecting care offered by the CC-VHW might be approached for qualitative inquiry on the 
reasons for the refusal of community-based care.  
 
7.4 
Baseline  
Most baseline data to describe the TwiC participants will be collected as part of the ComBaCaL cohort 
assessments (see current version of the “ComBaCaL cohort study protocol” for details). In brief, the 
following data will be collected by the CC-VHW at cohort baseline using the ComBaCaL eHealth 
application: age, sex, height, weight, abdominal circumference, household position, socioeconomic 
indicators of the household, level of education, income-generating activity, targeted medical history 
including previous T2D diagnosis, intake of antidiabetic medication, HIV status and cardiovascular 
complications, physical activity using the validated International Physical Activity Questionnaire Short 
Form (IPAQ-SF)42 adapted to the local context and language according to the IPAQ recommendations 43, 
dietary habits using a shortened unquantified food frequency questionnaire adapted from an 
assessment tool for obesity used in South Africa44, self-reported alcohol and tobacco use.  Participants 
will also be screened for aHT.  
In addition to the data collected as part of regular ComBaCaL cohort activities, further baseline 
information will be collected for TwiC participants based on the International Consortium for Health 
Outcomes Measurements’ (ICHOM) data collection reference guide for sets for diabetes in adults45. Data 
collected at TwiC baseline include HbA1c, blood lipids, quality of life using the EQ-5D-5L instrument37, 
health beliefs using the Beliefs about Medicines Questionnaire (BMQ) adapted for people living with 
T2D38,39, self-reported access to care and diabetes distress using the five item version of the “Problem 
Areas in Diabetes” (PAID-5) scale40,41. 
 
 
 

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Figure 2 Flow of events. FBG: Fasting Blood Glucose, CVD: Cardiovascular Disease, SAE: Serious Adverse Event, AESI: Adverse 
Event of Special Interest, T2D: Type 2 Diabetes, T1D: Type 1 Diabetes 
 
7.5 
Intervention 
In the intervention villages, CC-VHWs will offer a T2D care package including lifestyle counselling, first-
line antidiabetic (metformin) and lipid-lowering (statin)  treatment for uncomplicated T2D and 
treatment support and regular check-ups for complicated T2D  at village-level according to clinical 
algorithms based on international guidelines for primary healthcare management of T2D46,47 and the 
updated Lesotho Standard Treatment Guidelines (under review at the time of writing this protocol). 

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Where feasible, CC-VHWs might also provide refill services for other chronic medication upon 
prescription of a nurse or doctor at the health center in charge. Patients with history of a cardiovascular 
event will be offered antiplatelet treatment (aspirin) in line with local guidelines.  
The CC-VHWs in the intervention villages will receive specific training focused on lifestyle counselling, 
drug prescription, screening for potential adverse events of drugs administered, and disease monitoring 
and dose adjustment after treatment initiation.  
Direct guidance for treatment initiation, drug prescription, counselling and monitoring will be provided 
via the ComBaCaL app. All activities conducted by CC-VHWs in the communities, including counselling 
and drug prescription, will be captured in the same application.  
Health care professionals and supervising study staff will monitor all activities in a web version of the 
app and will be intervening in case of missing data, non-adherence to the clinical algorithms, or unclear 
clinical conditions. The CC-VHWs may always request support by supervising health care professionals. 
In case of complicated disease (i.e. if treatment targets are not reached with metformin alone), unclear 
diagnosis, relevant comorbidities or presence of clinical alarm signs or symptoms, participants will be 
referred to the closest health facility for further management. Participants are free to accept or refuse 
the treatment offered by the CC-VHWs. Participants refusing the CC-CHW-led treatment will be asked 
about the reasons for the refusal and will be referred to the responsible health facility for further 
management.  
In control villages, CC-VHWs will refer participants to the responsible health facility for therapeutic 
management after enrolment and baseline assessment. 
 
7.6 
Follow-up and endpoint assessment 
7.6.1 
Scheduled follow-up visits and endpoint assessments 
Follow-up visits by CC-VHWs including endpoint assessments will be scheduled six months (range 150 to 
240 days) and twelve months (300 to 420 days), 18 months (450 to 630 days), 24 months (630 to 810 
days), 30 months (810 to 990 days), 36 months (990 to 1170 days), 42 months (1170 to 1350 days), and 
48 months (1350 to 1530 days) after TwiC enrolment. If resources allow, certain endpoints (i.e. HbA1c) 
will be assessed by study staff not involved in the care delivery at village level. 
During the follow-up visits, HbA1c measurements will be conducted together with the collection of 
secondary endpoint data such as blood glucose, CVDRFs (physical activity, diet, blood lipid status, 
tobacco and alcohol use using the same assessment tools as for the baseline, height, weight, BMI, 
abdominal circumference), engagement in and adherence to antidiabetic treatment, quality of life, 
health beliefs and diabetes distress. 
All mentioned endpoints will be collected at six and 12 months. For follow-up visits beyond 12 months 
not all endpoints will be collected at every visit to avoid overburdening of the CC-VHWs and the 
participants. Specifically, physical activity, diet, blood lipid status, quality of life and health beliefs will 
only be assessed if deemed feasible and relevant. 
During follow-up visits, CC-VHWs will inquire about relevant clinical events since the previous visit 
(including screening of the Bukana for documentation of respective events). These events will be 
documented in a dedicated electronic case report form within the ComBaCaL app. Safety outcomes of 
this TwiC (SAEs and AESIs, see section 8 for definitions) are a subset of the clinically relevant events that 
are captured as part of the ComBaCaL cohort study. Reports of SAEs and possible AESIs will be reviewed 
by the study physician for final assessment and classification.  
In addition, specific questionnaires about participants’ satisfaction and acceptability of the TwiC 
intervention will be administered and semi structured interviews conducted with a selection of 
participants, CC-VHWs and involved health care professionals will be conducted to qualitatively explore 
perceived risks, benefits and problems of community-based therapeutic management of uncomplicated 
T2D. We will evaluate the quality of services provided and the data collected in the villages by analysing 
aggregated data and metadata of the reports submitted by the CC-VHWs via the eHealth application. 
 
7.6.2 
Clinical follow-up 
In intervention villages, the CC-VHWs will conduct clinical follow-up visits according to the clinical 
algorithms provided in the appendix. During these clinical follow-up visits, CC-VHWs will check BG values, 

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monitor treatment adherence, check for treatment side effects, adjust treatment dose if required, 
provide lifestyle counselling and refer participants to the responsible health facility, if treatment targets 
are not met under metformin alone or in case of side effects, clinical alarms signs or symptoms or 
relevant comorbidities. The therapeutic management provided by the CC-VHWs under guidance of the 
ComBaCaL app is in line with international guidelines on the treatment of T2D at primary healthcare 
level46,47 and the then valid Lesotho Standard Treatment Guidelines.  
In intervention and control villages, CC-VHWs will document deaths, hospitalizations and other relevant 
clinical events at any time after becoming aware of the event independent of scheduled visits. Likewise, 
if participants are moving out of the village, the CC-VHWs will document this in a dedicated form in the 
ComBaCaL app. 

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7.7 
Schedule of events 
 
 
Cohort baseline 
TwiC screening & 
baseline 
Intervention follow-
ups1 
6-month follow-up 
12-month follow-up 
Beyond 12-
months and up to 
48 months follow-
up 
Time in days relative to TwiC enrolment 
-60 – 0 
0 
0 – 420  
150 – 240  
300 – 420 
450-1530 
ComBaCaL cohort informed consent 
x 
 
 
 
 
 
Date of birth  
x 
 
 
 
 
 
Height, weight, abdominal circumference 
x 
 
 
x 
x 
X 
Sociodemographics 
x 
 
 
 
 
 
Short medical history2 
x 
 
 
 
 
 
CVDRFs3 
x 
 
 
x 
x 
(x)10 
FBG 
x 
 
 
x 
x 
X 
HbA1c 
 
x 
 
x 
x 
x 
Diabetes distress4 
 
x 
x 
x 
x 
(x)10 
Health beliefs5 
 
x 
 
 
x 
(x)10 
Quality of life6 
 
x 
 
x 
x 
(x)10 
Blood lipid status (total cholesterol, LDL 
cholesterol, HDL cholesterol, triglycerides) 
 
x 
 
x 
x 
(x)10 
Adherence to antidiabetic medication 
 
x 
x 
x 
x 
X 
Acceptability & satisfaction with T2D care7 
 
 
 
x 
x 
(x)10 
Screening for relevant clinical events 
x 
x 
x 
x 
x 
X 
Screening for clinical alarm signs/symptoms 
x 
x 
x 
x 
x 
X 
TwiC Control 
 
 
 
 
 
 
Referral to health facility8 
 
x 
 
x 
x 
x 
TwiC Intervention 
 
 
 
 
 
X 
Offer metformin 
 
x 
x 
x 
x 
x 
Offer lipid-lowering treatment 
 
x 
x 
x 
x 
x 
Provide lifestyle counselling 
 
x 
x 
x 
x 
x 
Referral to health facility9 
 
(x) 
(x) 
(x) 
(x) 
(x) 
1) 
Only for TwiC participants in intervention villages 
2) 
Including personal and family history for T2D / DM and other relevant conditions 
3) 
Physical activity using IPAQ-SF42, dietary habits44, tobacco and alcohol use 
4) 
Using the 5-item Problem Areas in Diabetes (PAID-5) scale41 
5) 
Using the Beliefs about Medicines Questionnaire38,39 
6) 
Using the EQ-5D-5L instrument37 
7) 
Only for a subset of participants 
8) 
For initiation or continuation of T2D treatment and/or in case of clinical alarm signs or symptoms 
9) 
In case of clinical alarm signs or symptoms, participants refusing community-based T2D care, complicated disease, unclear diagnosis or relevant comorbidity 
10) Assessment will not be taken every 6 months after primary 12 months study follow-up. Frequency will depend on VHW workload and considerations on scientific value of reassessments. 

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8 SAFETY CONSIDERATIONS 
8.1 
Definition and documentation of safety outcomes 
Adverse event (AE) 
Any untoward medical occurrence in a study participant, including 
occurrences that are not necessarily caused by or related to the study  
procedures 
Adverse event of 
special interest (AESI) 
AE consistent with complication of T2D, such as: 
• 
Myocardial infarction  
• 
Stroke 
• 
Symptomatic heart failure  
• 
Chronic kidney disease 
• 
Blindness, severe vision impairment   
 
AE probably related to intake of antidiabetic medication, such as: 
• 
Intolerance reaction against antidiabetic medication leading to 
discontinuation of the medication concerned (including allergic 
reactions, drug interactions or rare severe side effects) 
Serious adverse event 
(SAE) 
Any AE that: 
• 
Results in death  
• 
Is life-threatening  
• 
Requires hospitalization or prolongation of existing 
hospitalization 
o Hospitalizations due to uncomplicated delivery are not 
considered as SAE 
• 
Results in persistent or significant disability or incapacity 
• 
Consists of a congenital anomaly or birth defect 
Serious adverse event 
of special interest 
(SAESI)  
SAE consistent with complication of T2D, such as:  
• 
Myocardial infarction  
• 
Stroke 
• 
Symptomatic heart failure  
• 
Chronic kidney disease 
• 
Blindness, severe vision impairment 
  
SAE probably related to intake of antidiabetic or antidiabetic medication, 
such as:  
• 
Intolerance reaction against antidiabetic medication leading to 
discontinuation of the medication concerned (including allergic 
reactions, drug interactions or rare severe side effects) 
 
CC-VHWs will be trained to screen for and to recognize clinical events of special interest (AESIs) and 
serious alinical events (SAEs) and to document them in the dedicated report form in the ComBaCaL app. 
AESIs and SAEs for this TwiC are a subset of the clinically relevant captured as part of routine ComBaCaL 
cohort activities. 
 
 
 
 

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CC-VHWs may solicit AESIs and SAEs as part of the ComBaCaL activities in the following ways:  
- 
Active reporting by participants or friends or relatives outside of scheduled CC-VHW visits 
(scheduled visits are defined as visits being triggered through the ComBaCaL app based on 
regular or clinical follow-up algorithms or visits being assigned by supervising healthcare 
professionals) 
- 
Passive reporting by participants or friends or relatives after inquiry by CC-VHWs during 
scheduled VHW visits 
- 
Clinical observation of CC-VHWs during or outside scheduled CC-VHW visit 
- 
Screening of participants’ Bukanas (personal health booklet) 
- 
Reporting by health centre nurses 
 
In intervention villages, additional visits are scheduled for the therapeutic management of T2D during 
which CC-VHWs will conduct additional AE screening including specific screening for AEs possibly related 
to the therapeutic intervention. The intervention-specific AE screening will be closely guided via the 
eHealth application (i.e. a list of symptoms to be inquired for each drug will be provided).  
 
The anonymized, AESI reports will be submitted to the study physician who will remain blinded to the 
allocation related to the report submission. The study physician will classify the AESI reports of TwiC 
participants as SAEs (including type and if possible cause of SAE), AESIs (including type and if possible 
cause of AESI) or none of the two if sufficient clinical information for classification is available. If the 
clinical information available is not sufficient for classification of the case, the study physician will 
request the study Data Manager to unblind the respective report and then contact the responsible CC 
nurse and/or CC-VHW and ask for collection of further data.  
 
8.2 
Causality of SAEs and AESIs 
A causality assessment of all SAEs and of AESIs possibly related to the therapeutic management of T2D 
will be performed by the study physician based on the reports submitted by the CC-VHWs. As a result of 
the causality assessment, the study physician will provide a statement whether the SAE/AESI is possibly, 
likely or definitely related or unrelated to the T2D care provided.  
 
8.3 
Management of AEs 
 
8.3.1 
Control villages 
In control villages the entire clinical management after screening and diagnosis will be provided by 
healthcare professionals at the responsible health center without direct influence by study staff. 
ComBaCaL study staff will provide capacity building in NCD management at all involved health centers 
and support in case of clinical questions. If CC-VHWs become aware of clinical events in their village 
during the follow-up period, they will refer the respective individual to the health center.  
 
8.3.2 
Intervention villages 
In intervention villages, mild, common side effects of the drugs administered, for which neither 
professional assessment nor other measures than observation or an interruption of the prescribed drug 
is required, will be managed by the CC-VHWs at community-level. For the assessment and management 
of these events, close guidance will be provided via the eHealth application. Additionally, CC-VHWs will 
have the possibility to seek clinical advice from the supervising health center nurses or the CC nurses, 
either via messages sent through the eHealth application or via phone calls or field visits.  
Any AEs going beyond mild, common side effects or any unclear clinical conditions will prompt referral 
to the responsible health facility for further assessment and professional management. The ComBaCaL 
study staff will not directly intervene in the management of such cases but provide clinical support to 
the health center staff if required. Besides clinical support for the management of complex cases, the 
ComBaCaL study team will provide NCD-focused training at the involved health facilities to ensure high-
quality care for participants referred to the responsible health facilities.   

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8.4 
Reporting  
CC-VHWs will document SAEs and AESIs in dedicated electronic case report forms (eCRFs) in the 
ComBaCaL app with subsequent assessment and classification by the study physician. All deaths and all 
other SAEs that are possibly, probably or definitely related to the study intervention, will be reported to 
the principal investigator within one month after the study physician has become aware of the event. 
All deaths and all other SAEs that are possibly, probably or definitely related to the study intervention 
will be reported to the NH-REC on a yearly basis.  
 

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9 STATISTICS 
9.1 
Determination of sample size  
The ComBaCaL cohort will consist of inhabitants of around 100 (range 90-112) randomly selected villages 
in rural Lesotho. The estimated mean number of adult ComBaCaL participants per village is 100 resulting 
in an estimated 10’000 adult cohort participants. Sample size for this TwiC is calculated assuming an 
individual randomization inflated by a design effect that account for variation at cluster level, according 
to the code developed by Rotondi and Donner19. Based on preliminary results from an NCD prevalence 
survey in the region (NH-REC ID 139-2021), we expect the prevalence of T2D in the adult population in 
the rural setting in Lesotho to be around 4%, with about 60% of people living with T2D fulfilling the 
criteria for the primary analysis set (not pregnant, no type 1 diabetes mellitus, uncomplicated and 
uncontrolled T2D). Hence, considering an average cluster size of 100 adult inhabitants, the mean number 
of inhabitants eligible for the TwiC is 2.4 per village. We estimate an effect size of 0.6% HbA1c mean 
difference between the two groups after 12 months. Assuming an intra-cluster correlation of 0.015 and 
an attrition rate of 20%, we calculate that a sample size of 240 individuals (120 per arm, 50 clusters per 
arm) is required to detect superiority with a type I error of 0.05 and a statistical power of 80%.   
 
9.2 
Description of statistical methods  
Analyses will be performed following the principles for analysis of cluster-randomized trials in health 
research as outlined by Donner and Klar20.  
All analyses will be done using Stata48 or R49. 
 
9.2.1 
Datasets to be analysed 
All analyses sets are defined above (Chapter 5.1). 
All analyses sets will be analyzed according to an intention-to-treat ITT analysis, i.e., all participants 
analyzed as randomized.  
 
9.2.2 
Primary analysis 
Primary endpoint assessment will be done in the ITT set as defined above.  
We will use a linear mixed-effect effect regression model with random intercept at the level of the 
clusters to assess the effect of the intervention, while accounting for variability across the clusters and 
after adjusting for potential socio-demographic confounders.  
Superiority will be assessed according to regression coefficient and statistical significance will be based 
in 2-sided tests at the alpha level of 0.05.  
No per protocol or as-treated analyses are planned since they are vulnerable to bias. However, we are 
considering a Complier Average Causal Effect (CACE) analysis to assess the impact of compliance with 
the intervention as this provides a more unbiased treatment effect than a per protocol or as-treated 
analysis and the underlying assumptions for such an instrumental variable approach are given. We will 
obtain the CACE estimator using a “two-stage least squares” (TSLS) approach, which jointly models the 
two processes of participation and outcome (i.e. regression model of participation, and regression model 
predicting the outcome, given participation). Such a TSLS approach yields more accurate estimates and 
confidence intervals, than simply dividing the mean effect estimate by the proportion of compliers50. 
 
9.2.3 
Secondary analysis  
Secondary endpoints will be reported using descriptive statistics such as mean and 95% Wald confidence 
intervals, frequency and percentages.  
Further details will be outlined in the SAP. 
 
9.3 
Handling of missing data 
Participants with missing covariates will be imputed using multiple imputation chained equation 
techniques. Further details of missing data will be outlined in the SAP. 
 
 

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10 DESCRIPTION OF DATA MANAGEMENT 
We refer to the current version of the “ComBaCaL cohort study protocol” for the description of data 
management. For this TwiC no other procedures than the ones outlined there apply.  
 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
We refer to the current version of the “ComBaCaL cohort study protocol” for the description of quality 
control and quality assurance. For this TwiC no other procedures than the ones outlined there apply.  

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12 ETHICAL CONSIDERATIONS 
12.1 Independent Ethics Committees (IECs) 
This protocol and any protocol amendments will be reviewed and approved by the National Health 
Research Ethics Council (NH-REC) of Lesotho and by the Ethics Committee of Northern and Central 
Switzerland (EKNZ) before implementation. 
 
12.2 Risk-benefit ratio 
There is no substantial health risk associated with participation in this study. The T2D screening, 
diagnosis and management offered will be conducted in line with national and international 
recommendations. All participants found to be at risk for a relevant medical condition will be referred 
to the responsible health facility for professional work-up and care. 
Data collection will entail questionnaires and capillary blood measurements for HbA1c, BG and blood 
lipids. These procedures do not have the potential to cause significant harm to participants.  
No personalized data of participants will be shared with people other than the directly involved study 
team members if not agreed upon by the participant.   
The access to guideline-conform active community-based NCD screening will likely increase early case 
detection and thus improve access to potentially life-saving treatment. Additionally, follow-up in the 
community by CC-VHWs with re-linking services is likely to improve T2D care for participants. 
Potential risks associated with the TwiC intervention include inadequate management by lay CC-VHWs. 
We will minimize this risk by assuring adequate training, continuous supervision by health care 
professionals, and close guidance through the ComBaCaL eHealth application. Community-based care 
delivery is widely implemented in HIV care in Lesotho providing substantial benefits compared to purely 
clinic-based care. 
The evidence generated in this study may inform future national and international clinical guidelines to 
improve NCD care in low-resource settings. Additionally, the community-based activities provide the 
added benefit of building a healthy and friendly community environment through community advocacy 
and participation, and may help to raise awareness and knowledge of NCDs within participating villages. 
Thus, the ComBaCaL project is likely to have a direct positive impact on health outcomes of participants 
as well as generating evidence to improve context-specific NCD care on a longer perspective.  
This project will be carried out in accordance with the research plan outlined in this protocol and with 
principles enunciated in the current version of the Declaration of Helsinki as well as all national legal 
requirements and guidelines as applicable.  
 
12.3 Participant information and consent 
The ComBaCaL cohort consent is based on the cmRCT17 approach, i.e. all cohort participants consent to 
being randomized as part of a TwiC. Participant information and consent seeking for the ComBaCaL 
cohort will be conducted by the local ComBaCaL VHW in a three-stepped approach, first orally on village 
level, secondly orally on household level, and thirdly in written electronic form on individual level. We 
refer to the “ComBaCaL cohort study protocol” for details.  
Participants that are being randomized to the control group, will not be bothered and data collected 
within the scope of the ComBaCaL cohort will be used for the TwiC analysis without further TwiC-specific 
information or consent. For villages randomized into the TwiC intervention group, an oral village consent 
from the village chief will be sought before the intervention will be offered to eligible individuals in the 
community. Participants may decline any of the offered services without implications on further cohort 
affiliation and their data will also be used for TwiC analyses. As the intervention does not entail any 
activities other than the task-shifting of standard-of-care T2D management components from primary 
healthcare professionals to CC-VHWs, oral intervention consent will be sought as outlined in the 
“ComBaCaL cohort study protocol”.  
 
Participants will be able to reject care by the CC-VHW in the village at any time during the study and 
request referral to a health facility. Participants consenting to participation but subsequently rejecting 

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care offered by the CC-VHW might be approached for qualitative inquiry on the reasons for the refusal 
of community-based care. 
 
 
Figure 3 Consent cascade in ComBaCaL cohort and TwiC. Yellow: Consent, Orange: Randomization, Blue: Training or field 
activity 
12.4 Withdrawal on household or individual level 
ComBaCaL cohort consent can be withdrawn any time on individual or household (by household head) 
level without justification. No specific consent for the TwiC intervention will be sought at household 
level. Anonymized data collected until the time of withdrawal will be retained in the database. 
 
12.5 Service delivery for people declining consent 
CC-VHWs will offer the same screening, diagnostic and referral services to participants declining the 
intervention in intervention villages as in control villages.   
 
12.6 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 7.3 (enrolment procedures) and section 10 
(data management). 
 
12.7 Participants requiring particular protection 
Pregnant women with T2D will not be included in the intervention but being referred to the responsible 
health facility for further assessment and management. The same applies to people with a severe 
comorbidity with an estimated life-expectancy of less than one year.  
This study has a strong service delivery aspect and often people with mental or physical conditions 
impairing capacity for informed consent are particularly vulnerable to NCDs such as T2D and its 

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complications. Therefore, we will offer the intervention also to eligible people with impaired judgement 
if an oral guardian consent for the intervention is provided.  
 
12.8 Participant compensation 
No compensation will be paid for participation in the study.  
 
 

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13 FUNDING 
This research project is funded by the Swiss Agency for Development and Cooperation (SDC) and by the 
World Diabetes Foundation (WDF), through grants issued to SolidarMed. A written agreement between 
SolidarMed and the Division of Clinical Epidemiology of the University Hospital Basel defines the terms 
for the collaboration on the research aspects of the project. The funding sources are not involved in the 
study design, data collection, data analysis, interpretation of the results, or writing the manuscript. The 
study will be embedded in the SolidarMed Lesotho programme and will thus benefit from logistics and 
human resources of this organisation. The listed co-investigators have no conflicts of interest. 
 
 
14 DISSEMINATION OF RESULTS AND PUBLICATION POLICY 
14.1 Dissemination to scientific community 
International scientific conferences and publications in scientific peer-reviewed journals will serve for 
wider dissemination of results. Preference will be given to journals with an open-access publication 
model. Further, anonymised datasets will be made available on open data repositories, such as 
www.zenondo.org. The study will be registered on ClinicalTrials.gov prior to the start of the trial and a 
summary of the study protocol will be published in a peer-reviewed journal. The current version of the 
International Committee of Medical Journal Editors (ICMJE) recommendations is applicable regarding 
authorship eligibility.51 The use of professional writers is not intended. 
 
14.2 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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15 APPENDIX 
 
 
 
 
Figure 4 Treatment algorithm for participants with T2D not meeting criteria for direct referral to facility in intervention villages.  
 
Participants with an FBG > 14 mmol/l or a RBG > 16.7 mmol/l or with polyuria, polydipsia and weight loss 
(independent of blood sugar levels) will be directly referred to a health facility for further check-up and 
initiation of insulin treatment.  
Participants who are receiving complicated treatment defined as either taking insulin or more than one 
oral antidiabetic will only be offered metformin treatment in the community after recommendation of 
a healthcare professional (nurse or doctor). The same accounts for participants reporting previous side 
effects possibly related to any of the treatment components offered.  
At every visit, participants will be screened for clinical alarm signs and symptoms as well as for potential 
complications of T2D. In case of an alarm sign or symptom, the participant will be directly referred to a 
health facility. The routine staff of the responsible health facility will remain in charge of the clinical care 
of participants. The CC nurses will be available to provide clinical support if requested by the healthcare 
staff in charge. For both clinical alarm signs and symptoms and potential complications of T2D, a CC 
nurse is prompted to follow-up the event and submit a report in the ComBaCaL app.  
Before prescribing any drug, participants are screened for potential contraindications, prior side effects 
to the respective drug and the pregnancy status for female participants under the age of 55 years. In 
case of possible contraindications, prior side effects to a treatment component or pregnancy, the 
participant is referred to a health facility for further management.  
At every visit, the current medication, possible side effects and treatment adherence will be 
documented.   
As recommended by the local guidelines, aspirin will be offered to participants with a history of stroke 
or myocardial infarction after evaluating contraindications against the medication. Further, atorvastatin 

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10mg will be offered to all participants in a fire-and-forget approach after evaluating contraindications 
against the medication.  
CC-VHWs will advise participants to fast at the day of blood sugar check-up. However, if a RBG is available 
only, treatment adjustments will be conducted according to the above shown algorithm.  
 
 
 
 
 

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