A Multi-component Intervention for Controlling Hypertension in the Adult Rural Population of Pakistan: a Protocol for a Hybrid Type III Implementation-effectiveness Cluster Randomized Controlled Trial
Phase: NA
Conditions: Hypertension
Sponsor: Aga Khan University

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Cardiovascular Disease Risk Reduction: A comprehensive package 
for the reduction of risk in Sindh, Pakistan  
 
NCT Number: NCT06726057 
Document date: 27 April 2025 
 

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Cardiovascular Disease Risk Reduction: A comprehensive package for the reduction of risk in Sindh, 
Pakistan 
 
Contents 
Multicomponent hypertension intervention (MCHI)............................................................................ 3 
Introduction ............................................................................................................................................ 3 
Research questions ................................................................................................................................. 4 
Methods .................................................................................................................................................. 5 
Study design ........................................................................................................................................ 5 
Phase 1: Barriers and Facilitators to Scale Up & Implementation Strategies ..................................... 5 
Phase 2: Effectiveness and Cost-effectiveness of the Implementation Strategies. ............................ 6 
Study setting ....................................................................................................................................... 6 
Participants ..................................................................................................................................... 9 
Health Facility Assessment Survey ...................................................................................................... 9 
Interventions ................................................................................................................................. 10 
Phase 3: Barriers and Facilitators to Scale Up .................................................................................. 16 
Ethical Aspects .................................................................................................................................. 17 
Personal Data ................................................................................................................................ 17 
Data Information Flow ................................................................................................................... 18 
Ethical conduct ............................................................................................................................. 18 
Consent ......................................................................................................................................... 18 
Confidentiality ............................................................................................................................... 18 
Right to refuse or withdraw............................................................................................................ 18 
Specific cultural considerations .................................................................................................... 19 
References ............................................................................................................................................ 19 
 
 
 

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Multicomponent hypertension intervention (MCHI) 
Introduction 
Targeting the considerable burden of NCDs, affecting the poorest billion of the world, forms a 
key goal in global policies and plans.1 However, most LMICs lack the fiscal and human capacity 
to address NCD-associated health, economic, and social burdens, posing barriers to the 
achievement of Sustainable Development Goals (SDGs).2 In Afghanistan and Pakistan, the 
rapid increase in NCD-related morbidity and mortality represents a critical challenge (see 
figures below from the GBD visualization tool).3 In health systems and policies traditionally 
geared towards communicable diseases and maternal/neonatal disorders and heavily 
battered by the diversion of resources to manage regional conflicts; the enormous threat of 
NCDs, especially cardiovascular diseases (CVD), type-2 diabetes (diabetes), and common 
mental disorders (CMD) remains largely unaddressed.4 
According to the 2018 WHO progress report, an average person in Pakistan between the ages 
of 30-70 carries a 25-30% risk of premature death from NCDs. Yet, Pakistan has inadequate 
national system responses to NCDs. Locally relevant, high-quality data and empirical evidence 
on the effectiveness and cost-effectiveness of interventions addressing NCDs are scarce. The 
evidence gap exists both for population-level and individual-level interventions.  
A recent study estimated that among low and middle-income countries (LMICs), India and 
Pakistan are most likely to suffer from CVD deaths in the future.5 In addition to mortality, CVDs 
and NCDs also lead to a substantial increase in morbidity with a serious decrease in quality of 
life.6 The high mortality and morbidity rates associated with CVDs emphasise the urgent need 
for effective prevention and management strategies to improve public health outcomes. Most 
of this burden of deaths and morbidity can be prevented by controlling common risk-increasing 
factors, most importantly hypertension,7 as well as behavioural risk factors such as tobacco 
use, unhealthy diets, and lack of physical activity through adopting large-scale population-wide 
strategies. Control of obesity, hypertension, hyperglycaemia, and hyperlipidaemia along with 
low sodium intake, regular exercise and a healthy diet helps prevent the risk of CVDs.7 
Addressing the prevention and control of NCDs and CVD requires a multi-faceted approach 
that targets diverse populations across different settings. In some populations we have 
interventions that have been proven to be effective but have not been implemented for example 
in rural communities the COBRA-BPS trial has shown the effectiveness of a multi-component 
hypertension intervention (MCHI) in reducing blood pressure.8 However, the findings of this 
work have not translated to change in practice on the ground suggesting the need for 
implementation research to examine the best ways to implement this intervention in the real 
world.  
In other target populations such as school-going children where early interventions may stem 
the rise of NCDs and understanding the risk of other populations that may be high risk such as 
certain occupational groups, there is little evidence from Pakistan and formative research 

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needs to be done to be able to design potentially low cost and effective interventions. 
Therefore, in this work package, we propose three studies with the overarching long-term goal 
of CVD risk mitigation in our communities. These studies range from implementation studies to 
early formative research: implementation trial in the community, a workplace-based study, and 
a qualitative investigation focused on school-going children. In the following sections, we 
describe the different studies and approaches. Each study will be led by a senior and early 
career investigator from AKU, and input will be provided by our Centre Collaborators from 
Khyber Medical University (KMU) and the University of York. This overarching risk reduction 
package aims to explore and implement interventions across three distinct components 
comprehensively. By examining these different dimensions, we strive to improve 
cardiovascular health outcomes in various population groups. 
The first component of this study focuses on hypertension. High blood pressure is a major risk 
factor for CVDs and contributes to a significant burden of disease worldwide and there is a 
paucity of community-based behavioral interventions to address its burden in rural populations 
in developing countries. One such community-based intervention to address hypertension has 
been previously found to be effective in the Pakistani context in a cluster randomized controlled 
trial.8 However, the findings and the approach tested in this study have not been scaled-up in 
Pakistan. Hence, in the present work, we aim to assess the impact of this evidence-based 
intervention when implemented at scale in rural communities. 
An Implementation Science Cluster Randomised Controlled Trial of a 
Community-Based Intervention for Managing Hypertension 
Research questions 
1. What are the perceived barriers and drivers to scaling-up a community-based 
multicomponent hypertension intervention (MCHI) within a public health system for 
adults with hypertension living in rural Sindh, Pakistan? 
2. What strategies are needed for the adoption, implementation and maintenance of the 
MCHI when delivered at scale? 
3. Compared to scaling up MCHI on its own, what is the effectiveness and cost-
effectiveness of scaling up MCHI in combination with a set of implementation strategies 
in: 
a. Improving its adoption, implementation and maintenance? 
b. Lowering blood pressure in adults with hypertension? 
4. What are the barriers and drivers observed while scaling up MCHI (both, with and 
without implementation strategies), which could guide further adaptations and tailoring 
of its scale up? 
Hence the objectives of this study are: 
● To identify implementation strategies for scaling up a proven community based multi-
component hypertension intervention (MCHI) using implementation research frameworks 

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● To assess the effect of adding implementation strategies to community based MCHI in 
improving access to evidence-based hypertension care and on lowering blood pressure in 
adults with hypertension. 
● Assess the cost effectiveness of implementation strategies to community based MCHI in 
improving access to evidence-based hypertension care on lowering blood pressure in 
adults with hypertension. 
● To explore barriers and drivers observed while scaling-up MCHI to guide adaptation and 
tailoring of scale up 
Methods 
Study design 
This study follows the MRC framework for developing and evaluating complex interventions.9 
Specifically, the focus is on the implementation phase of the framework.10 This is because 
there is an intervention (MCHI) that has already been proven effective and cost-effective in a 
large, high-quality multicountry RCT.8 However, despite this trial being conducted and 
disseminated in Pakistan, this evidence-based intervention has not been scaled up. 
Moreover, there is equipoise regarding the effects of implementation strategies on the 
adoption and maintenance of the MCHI when delivered at scale. 
The study will have three phases: Phase 1 will address research questions 1 & 2, Phase 2 will 
address questions 3a and 3b, and Phase 3 will address question 4. 
Phase 1: Barriers and Facilitators to Scale Up & Implementation 
Strategies  
In this phase, we will identify potential barriers and drivers to scaling up MCHI in rural public 
health facilities in Sindh. Then, we will select implementation strategies to address these 
potential barriers and strengthen potential drivers.  
The updated Consolidated Framework for Implementation Research (CFIR)11,12 and the Expert 
Recommendations for Implementing Change compilation (ERIC) 13 (Appendix-1) will underpin 
our proposed work. The following activities will be conducted. 
To better understand the potential barriers and drivers for implementing MCHI at scale in public 
health facilities, we will be conducting a series of workshops. Two sets of workshops will be 
held in each district (4 in total). Primary health service providers, including district health 
officers, district NCD focal persons, district Lady Health Workers (LHW) programme 
coordinators, LHWs and general practitioners will be invited to attend. A researcher trained in 
implementation science will facilitate these workshops, with a focus on identifying potential 
barriers and facilitators to scale up first and then the implementation strategies. We 
understand the importance of power imbalances and will ensure expert facilitation to address 

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any issues that may arise. Additional support will also be provided to workshop participants as 
needed. 
During the first set of workshops, attendees will receive a list of short descriptions of potential 
barriers and drivers based on CFIR construct definitions.13 They'll then be requested to evaluate 
the probability of facing each barrier/driver and their possible effects. Through the modified 
Delphi technique, they'll converge to a final list of the most important barriers/drivers (highly 
probable with significant effect) after 2 to 3 iterations.  
Prior to the second set of workshops, CFIR-ERIC Mapping Tool13 will be utilized to generate a 
list of potential ERIC strategies that can be evaluated to address each CFIR barrier and 
strengthen each driver identified in the first set of workshops. During the second set of 
workshops, participants will be required to select and rank up to 7 strategies that would be 
most effective in addressing each CFIR barrier/driver. ERIC strategies will be chosen based on 
the relevance of the strategy to the CFIR barrier, perceived improvement opportunities, and 
feasibility. Only those strategies that receive an endorsement of level 1 (by 50% or more 
participants) or level 2 (by 20%-49.9% of participants) for at least one CFIR barrier/driver will 
be included in the final list. Subsequently, these strategies will be categorized into three levels 
based on their feasibility: Level 1 strategies that are easy to implement and only require a 
change in processes, Level 2 strategies that require changes in the infrastructure, and Level 3 
financial strategies. 
Phase 2: Effectiveness and Cost-effectiveness of the Implementation 
Strategies. 
To investigate the effectiveness and cost-effectiveness of MCHI when delivered at scale, we 
will conduct a Type III effectiveness-implementation hybrid trial (Flowchart 1).10 Given that 
MCHI targets its population through community health workers and health facilities, a cluster-
randomized controlled trial design is chosen. 
Study setting 
The trial will take place in Thatta and Matiari, two rural districts located in the province of 
Sindh, Pakistan. Thatta has a predominantly rural population of approximately 1 million 
people, with 82% residing in rural areas. This district is divided into four sub-districts, also 
known as talukas. Similarly, Matiari is a rural district with a population of 0.77 million people, 
of which 76.2% live in rural areas. It is administratively divided into three talukas. The public 
sector health infrastructure includes primary, secondary, and tertiary healthcare facilities, as 
well as a group of LHWs. These LHWs are associated with primary healthcare facilities such 
as Basic Health Units and Rural Health Centres. With each Basic Health Unit, there are 
usually 3-13 (an average of 5) LHW affiliated and they cover its entire catchment population, 
roughly 250 households/LHW.  
In this trial, a cluster equates to a Basic Health Unit (BHU) and its catchment population. Each 
cluster will have a group of LHWs, 5 on average, providing essential public health services to 
the entire population. These clusters are situated within Union Councils, which are 

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contiguous administrative units. Each Union Council will have at least one BHU. Initially, 30 
Union Councils will be purposively selected in the two chosen districts (40 BHUs exist in the 2 
districts), and the corresponding BHU (30) will be identified. An eligible cluster will then be 
identified within each Union Council, typically comprising of 2-5 adjacent villages in rural 
Sindh. The distance of each cluster from its corresponding BHU will be determined using a 
GPS device. 
These clusters will be stratified into two strata based on their distance from the respective 
BHU, which will be used in stratified randomization. The randomization will be stratified by 
districts as well as by the distance from the BHU, and the clusters will be randomly assigned 
in a 1:1 ratio to either MCHI + implementation strategies (the intervention arm) or MCHI alone 
(the control arm) using a computer-generated randomization programme at AKU. 
 
 
 
 
 
 

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Flowchart 1: The MCHI Implementation Science Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomized (n=30) 
Analyzed (n=  ) 
 
• Excluded from analysis (give reasons) (n=  ) 
Allocated to Control = MCHI alone (n=15) 
• Received intervention C (n=  ) 
• Didn’t receive intervention C (reasons) (n=  ) 
Enrollment 
Analysis 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention = MCHI + 
Implementation Strategies (n=15) 
• Received intervention A (n=  ) 
• Didn’t receive intervention A (reasons) (n=  ) 
Analyzed (n=  ) 
• Excluded from analysis (give reasons) (n=  ) 
Excluded (n=   ) 
• Not meeting inclusion criteria (n=  ) 
• Declined to participate (n=  ) 
• Other reasons (n=  ) 
Follow-up (6 monthly for 24 
months) 
Cluster = Basic Health Unit (n=30) and  
its catchment population (n= 3000) 

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Participants 
Inclusion criteria 
1) Are of age ≥35 years 
2) Residents of the selected clusters 
3) Have hypertension defined as 
(a) either with persistently elevated BP (SBP ≥140 mm Hg or DBP ≥90 mm Hg) 
average of last two of three readings from two separate days, where BP 
measurements on the same day were measured at least one minute apart  
(b) or are on antihypertensive medications 
Exclusion criteria 
Pregnant women and persons with advanced illness (e.g., those receiving dialysis or with liver 
failure), cancer, or an inability to travel to the clinic or unwilling/unable to provide consent will 
be excluded. 
Identification, eligibility assessment, consent and enrollment  
Our first step will be to obtain a list of all adults living in households within the selected clusters 
from the District Health Office. Once we have received appropriate permissions from the 
community gatekeepers, such as councillors, LHWs and field research team will visit jointly to 
all targeted household and update Household list (Appendix: 2a English, 2b Sindhi). After 
obtaining written consent (Appendix: 7.2a English, and 7.2b Sindhi) the field team will then 
screen out all 35 years and above individuals in the target households for hypertension and 
other chronic diseases including ischemic heart disease, diabetes, kidney disease and the risk 
factors using a structured questionnaire (Appendix: 8c English, 8d Sindhi). LHWs will also 
chase the same participants for hypertension screening independently. (Appendix: 3a English, 
3b Sindhi). Blood pressure (BP) will be measured three times using a calibrated automated 
Blood Pressure Monitor with the individual in a sitting position. The readings will be taken one 
minute apart. Individuals with elevated BP (SBP ≥140 mm Hg or DBP ≥90 mm Hg) of the last 
two of three readings on the first visit will be revisited after 2 weeks for re-measurement of BP 
to confirm hypertension (Appendix: 4a English and 4b Sindhi). Those with persistently high 
blood pressure at the second screening visit will be invited for enrollment. Those who already 
on antihypertensive medications will be enrolled during the first visit. As part of the duty of care, 
all participants with elevated BP will be requested to see a trained general practitioner (GP) 
(Appendix: 5a English, 5b Sindhi). Those with very high BP (SBP ≥180 mm Hg or DBP ≥120 mm 
Hg) will be facilitated to receive an urgent hospital appointment.  
Health Facility Assessment Survey 
 
This observational Health Facility Assessment survey will be conducted in 30 selected health 
facilities (BHUs/RHCs) across District Thatta and Matiari to understand service availability in 
primary care settings.  

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Project Research Associates will receive training on the pre-designed data collection tool 
(Appendix-13) and will gather information using RedCap software. 
Interventions 
The MCHI will be scaled up in both trial arms; however, the implementation strategies will only 
be introduced in the intervention arm. 
Multicomponenet hypertension intervention 
The MCHI is a community-based intervention to reduce BP in people with hypertension and 
consists of the following components:  
1. BP monitoring and stepped-up referral to a trained GP using a checklist at 3-month 
intervals, every LHW will be provided with a digital BP apparatus and will monitor the 
BP of the study participants enrolled in the study. The LHW will also be completing a BP 
monitoring checklist following the recording of participants’ BP. Those participants with 
poorly controlled BP (Systolic Blood Pressure (SBP) ≥160 mm Hg or Diastolic Blood 
Pressure (DBP) ≥100 mm Hg) at any visit will be referred to a trained general practitioner 
(GP) for the management of hypertension. For each referral, LHW will be completing a 
GP referral checklist having patient details, his/her BP readings, and other relevant 
details.  
 
Home health education (HHE) delivered by LHWs: Training of LHWs will be 
conducted in conveying home health education (HHE) to the adult hypertensive 
population using a structured behavior change communication approach. The training 
will be for 5 days, followed by a refresher training in 3 months and then annually. The 
curriculum of HHE will be based on the manual developed as part of the MCHI trial. The 
health messages will largely be focused on hypertension and cardiovascular diseases 
(CVD) and will consist of the adverse effects of hypertension, the importance of 
adhering to a medication schedule, non-pharmacological approaches for controlling 
hypertension and preventing CVD, advice on weight loss strategies, low salt and 
saturated fat intake in the diet and high consumption of fruits and vegetables, promoting 
physical activity, and smoking cessation. These sessions will be delivered face-to-face 
by LHWs every three months. At the end of the HHE session, LHW will complete an 
HHE checklist with details on participants and put a checkmark against each of the 
areas listed above addressed during the HHE session, (Appendix: 6a English and 6b 
Sindhi). Our baseline team will visit to all known hypertensive individuals (known and 
newly diagnosed) and will obtain informed consent from each individual who wishes to 
participate in the study (Appendix 7a-English, 7b-Sindhi).  
2. Training of physicians in blood-pressure monitoring, management of hypertension, and 
use of the checklist (Appendix: 9). The physicians will be trained in using a hypertension 
management manual and an algorithm that was developed in the earlier COBRA study 

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(Appendix: 10). The target blood pressure was a systolic blood pressure of less than 
140 mm Hg and a diastolic blood pressure of less than 90 mm Hg. Physicians will 
receive refresher training in 3 months and annually thereafter. 
3. Designated hypertension triage counter and hypertension care coordinators in Basic 
Health Units. A functional hypertension triage counter will be established at the Basic 
Health Units enrolled in the study. This will facilitate the care of hypertensive individuals 
who present to the clinic with a GP referral checklist (Appendix: 5a English, 5b Sindhi). 
The counter will be equipped with a digital BP device for standardized measurement of 
BP by a trained clinic nurse/assistant before evaluation by a trained physician. 
Additionally, a hypertension care coordinator will be appointed at each government 
clinic to facilitate tracking referrals by the LHWs of individuals with poorly controlled 
BP. 
Implementation Strategies 
In addition to MCHI, the intervention arm will also receive implementation strategies. While the 
specific implementation strategies will only be defined at the end of Phase 1, we envisage that 
these will be grouped as follows: 
1. Level 1 Strategies: Soon after receiving training on MCHI, the staff and facilities 
allocated to the intervention arm will be offered the first set of strategies. While 
important, these would be relatively easy to implement and may require a change in 
processes. These may include audits and feedback, the use of digital technology to set 
reminders and assist healthcare providers and identifying and supporting local 
champions.  
2. Level 2 Strategies: These strategies would typically require changes in the 
infrastructure. For example, these may include offering medications, changing 
recording and reporting systems and providing clinical supervision. Due to the nature of 
changes required to implement these strategies, these are more likely to be less 
feasible but still important.  
3. Level 3 Strategies: These would typically include financial strategies. For example, 
these may require financial restructuring to reward performance, financial incentives 
for additional services or finding new ways to finance the intervention. Such strategies 
tend to be most challenging to implement but likely to be effective.  
We will start with Level 1 strategies. Following interim analyses after the first and 
second follow-ups, respectively, the investigators will decide to either upgrade to the 
next level strategies or to continue at the current level using a set of pre-defined 
UPGRADE criteria, as follows: 
Criteria 
Indicator 
Source of data 

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Adoption 
At least 80% of all 
participants in the 
intervention arm, received 
a home visit by LHW for 
HHE and BP monitoring  
LHW checklist validated 
by the participant follow-
up questionnaire 
Implementation 
At least 80% of all 
participants received 
advice either from the 
trained physicians at 
Basic Health Units or 
practicing in the 
community after being 
identified as having 
uncontrolled BP (systolic 
blood pressure ≥140 mm 
Hg and/or diastolic blood 
pressure ≥90 mm Hg) by 
LHW at the first home visit  
LHW and physicians’ 
checklists validated by 
participant follow-up 
questionnaire 
 
If all of the above criteria are met, the current level of implementation strategies will continue. 
However, even if one of the criteria is not met, the implementation strategies will be upgraded 
to the next level.  
Outcomes and Data Collection 
Primary outcome 
Primary outcome will be the change in number of BP-lowering medications per participant. 
After estimating the proportional change in the number between the baseline and the 24-
month follow-up, the mean difference between the intervention and control arms will be 
estimated. A mean difference of 0.1 would be considered clinically significant.  
Implementation outcomes 
In addition, based on the RE-AIM Framework [21, 22], we will gather data on implementation 
outcomes for both the intervention and control arms (table 1). 
Table 1. implementation outcomes based on RE-AIM framework 
RE-AIM domain 
Outcome measure 
Data source 
Adoption 
1a. The proportion LHWs from 30 study 
clusters conducting HHE sessions, monitoring 
blood pressure and doing referrals of 
-LHW HHE & referral 
checklist 

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Effectiveness outcome: 
• The proportion of participants with controlled blood-pressure (SBP <140 mmHg and DBP 
<90 mmHg) 
hypertensive patients to health facilities 
during first 12 months 
 
2a. The proportion of Physicians from 30 
study clusters diagnosing and providing 
hypertension management to hypertensive 
patients at BHU/RHC referred by LHW during 
first 12 months 
-Baseline/follow up 
survey 
 
-GP checklists 
-Baseline/follow up 
survey 
Implementation 
1b. The mean number of the planned home 
visits/participant over 24 months (a maximum 
of eight visits, one every 3 months, are 
planned per participant) by LHW for HHE and 
BP monitoring 
-LHW HHE & referral 
checklist 
-Baseline/follow up 
survey 
 
2b. The mean number of healthcare contacts 
with Physicians at the Basic Health Unit per 
participant over 24 months among those 
identified as having uncontrolled BP 
(SBP≥140 mm Hg &/or DBP≥90 mm Hg) by 
LHW at one or more than one occasion during 
the trial 
-LHW HHE & referral 
checklist 
-Baseline/follow up 
survey 
Maintenance  
3a. The proportion of participants receiving 
visit by LHW for HHE and BP monitoring at 6, 
12, 18 and 24 months. 
-LHW HHE & referral 
checklist 
-Baseline/follow up 
survey 
 
3b. The proportion of participants that 
received advice and/or treatment from the 
GPs at the Basic Health Unit after being 
identified as having uncontrolled BP 
(SBP≥140 mm Hg &/or DBP≥90 mm Hg) by 
LHW at 6, 12, and 24months. 
-GP checklists 
-Baseline/follow up 
survey 

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• The participant reported health status according to the mean score on the visual-analogue 
scale of the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L; range, 0 to 100, with 
higher scores indicating better health). The HRQoL score based on responses to the EQ-
5D-5L and public preferences will also be used. 
Data collection: baseline and follow-up surveys 
Data from the recruited study participants will be collected at baseline and then every month 
via follow-up surveys over a period of two years. Each survey duration will be of 6 months. The 
data collection instrument i.e., questionnaire will be transformed into an android mobile 
application and data will be collected digitally. All the field staff will be provided training for 
data collection and the use of android version of the questionnaire. Data will be collected on 
the variables including socio-demographics, medical and family history dietary patterns, 
tobacco consumption (smoking and smokeless tobacco), second hand smoke exposure, 
alcohol consumption, physical activity levels, sleep, quality of life (using EQ-5D-5L), and 
health expenditure on CVD related medical conditions. In addition to blood pressure 
measurements, height, weight and waist circumference will also be measured. Biological 
measurements will be done at baseline  and include fasting blood sugar, serum LDL, HDL, 
total cholesterol,  and serum creatinine and 24 hrs urinary sodium excretion.  
In addition to the above, data on the risk factors and high-risk behaviors for cardiovascular 
disease (CVD), quality of life and CVD treatment-related expenses will be collected through a 
structured questionnaire (Appendix: 8a English, and 8b Sindhi. The variables will cover the 
following domains: 
● Socio-demographics 
● Dietary patterns/habits 
● Tobacco consumption (smoke and smokeless tobacco) 
● Secondhand smoke exposure 
● Alcohol consumption 
● Physical activity levels 
● Sleep 
● Out-of-pocket healthcare expenses for CVD 
The data collection instrument i.e., questionnaire will be turned into a digital format using Epi 
collect software. Epi collect is free and open-source software that enables the creation of a 
digital format of research questionnaires. The questionnaire can then be opened on Android 
phones and used to collect data in the field. All the field staff will be provided training for data 
collection. They will be given password-protected access to Epi collect version of 
questionnaires for baseline and follow-ups. Project team members will have password-
protected access to the data which can be accessed and exported from Epi collect into Excel 
format. 
In addition to the questionnaire, the following measurements will be carried out: 

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● Blood pressure  
● Height, weight, and waist circumference 
● Fasting sugar 
●  LDL, HDL, and total cholesterol 
●  Serum creatinine and 24 hrs urinary sodium excretion 
 
The biological samples will be collected early morning in a state of fasting. For this, members 
of the data collection team will visit study participants in the early morning, collect samples 
and transport these to the nearest AKU laboratory in the district. 
A similar pattern will be followed for follow-up surveys. In case a participant is not available at 
the time of the visit, their availability will be sought on the telephone before paying them a 
second visit. Follow-up surveys will be conducted every 6 months to determine the frequency 
of risk factors over two years. Laboratory tests will be conducted twice during the project 
duration i.e., at baseline only. 
Process Evaluation 
The fidelity of the implementation will be evaluated, and reasons for any differences between 
the observed and expected outcomes will be investigated. Process measures for the 
implementation strategies will be defined and included in the trial at the time of 
randomization. Additionally, the following process measures will be included:  
The percentage of scheduled HHE sessions conducted at the household level (based on the 
HHE session checklist collected from LHWs).  
The percentage of individuals with hypertension referred to a trained physician by LHWs 
(according to the physician referral checklist collected from hypertensive individuals). 
● The percentage of individuals with hypertension assessed by a trained physician (as per 
the physician management checklists collected from the district health office). 
 
 
Sample size 
Each cluster is served by 1 BHU and 5 LHW on average. Each LHW serves a minimum of 100 
households or 500 people (an average of 5 per household). Therefore, each cluster would have 
at least 2,500 people. Out of these, 625, would be above the age of 35 and of these 156 will 
have hypertension (25% prevalence of hypertension). If 20% refuse to participate, 
approximately 125 people will be eligible and ready for participation in each cluster.  
We propose to assess, between the two arms, a mean difference of 0.15 in the change in the 
number of BP-lowering medications/participants between the baseline to the final follow-up. 
If the implementation strategies are effective, over and above MCHI, those with a higher score 
at baseline are expected to show a bigger difference than those with a low score. Assuming a 

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mean difference of 0.15, a standard deviation of 0.83 (from the pooled data for Bangladesh and 
Pakistan, Jafar et al, 2020), 90% power, 5% alpha, correlation=0.5, ICC=0.02 (Jafar et al, 2020 
- sample size) and average cluster size of 100, then we would need to randomize 30 clusters 
(3,000 participants). 
Phase 3: Barriers and Facilitators to Scale Up 
Once intervention delivery is complete, the healthcare staff delivering MCHI including LHW and 
physicians will be asked to take part in Focus Group Discussions (FGD). There will be 4 Focus 
Groups (6-8 participants per FGD). Two will include LHWs from the intervention and control 
site respectively while the other two will include physicians from the two arms. In addition, we 
will also conduct in-depth qualitative interventions with managers including LHW district 
coordinators, and district health officers. Healthcare staff and service managers will be 
provided with information and asked to consent to participation (Appendix: 11). Each will focus 
on their experience of delivering and implementing the MCHI. In these FGDs and interviews, we 
will ask them about the CFIR barriers/drivers identified pre-intervention that were predicted to 
have the most potential to impact positively/negatively on intervention implementation (i.e., 
were these barriers/drivers evident in practice, were there other unanticipated barriers/drivers, 
and how supportive or not were the ERIC strategies.  
All interviews and FGDs will be conducted in the local language, face-to-face using topic guides 
(Appendix: 12) and digitally audio-recorded after obtaining written consent from the 
participants. A hermeneutics approach, which encourages participants to discuss features of 
the intervention to elicit data on their experience and evaluation of its delivery/receipt will be 
used.15  
Interviews and FGDs will be transcribed verbatim and translated into English and analyzed 
using the Framework Approach16 which is particularly useful for understanding and improving 
programmes/policies and when multiple researchers are working with the data.17 Excel 
software will aid in data handling. Integration of qualitative and quantitative findings will be done 
using a ‘triangulation protocol.’18 
Two post-implementation workshops, one in each district, will help us use the actual barriers 
and drivers identified during the delivery of MCHI to refine implementation strategies. We will 
invite the same groups of stakeholders as in the pre-implementation workshops. Participants 
will be presented with the findings of the FGDs describing the actual barriers/drivers to 
delivering MCHI contrasting it with those considered as potential barriers/drivers during Phase 
1. Participants will also learn about the extent to which the healthcare staff/service managers 
believe the respective implementation strategies succeeded in their execution. They will be 
allowed to re-endorse the list of the implementation strategies populated by using the CFIR-
ERIC Mapping Tool,13 before the workshop. They will be asked to select and rank up to 7 
strategies that would best address each CFIR barrier/driver. As before, only those strategies 
will be selected for the final list which would be either at level 1 or level 2 for at least one CFIR 
barrier/driver. At the end of these workshops, we will have a list of barriers/drivers (CFIR 

17 
 
constructs) to implementation and corresponding (ERIC) strategies to best support any future 
scale-up in the country. 
Statistical Analysis 
Analyses will be described in detail in a Statistical Analysis Plan drafted by the trial statisticians, 
agreed with the trial independent groups. Analyses will be conducted in accordance with the 
AKU’s SOPs and will be undertaken in Stata v17 or later (to be confirmed in the final report). 
Significance tests will be two-sided at the 5% significance levels under the principles of 
intention-to-treat. Reporting will be in accordance with CONSORT guidelines for cluster RCTs. 
The flow of clusters and participants through the trial will be presented in a CONSORT diagram. 
All baseline data will be summarized descriptively by treatment group. The primary analysis will 
compare the change in the number of medications/participant from the baseline to the last 
follow-up between groups. The primary outcome will be analyzed using a linear mixed model 
with fixed effects for baseline value of the outcome, district, distance of the cluster from the 
clinic, age, sex, time and interaction of time with a randomized group and random effects for 
the clusters and to account for the repeated measures by participants over time. The treatment 
effect at all time points will be extracted in the form of an adjusted mean difference, 95% 
confidence interval and p-value (with the primary being at 6 months). Continuous secondary 
outcomes will be similarly analyzed and other outcomes by appropriate regression techniques 
for the type of data. 
Economic Analysis 
A detailed Health Economic Analysis Plan will be developed by the study health economists. 
The cost-effectiveness of the implementation strategies will be assessed in terms of: i) their 
impact on improving its adoption, implementation and maintenance, and ii) their impact on 
patient health outcomes.  
Costs will be assessed from a healthcare perspective, reflecting the costs of the 
implementation strategies, the intervention, wider healthcare resource use related to CVD and 
out-of-pocket payments. For their impact on adoption, implementation and maintenance, 
outcomes will include. Cost-effectiveness will be expressed as an incremental cost per unit of 
effect. For their impact on health, outcomes will include life years, quality-adjusted life years 
(QALYs) and disability-adjusted life years (DALYs). Cost-effectiveness will be expressed as an 
incremental cost per unit of health outcome and incremental net health and monetary benefits 
based on accepted cost-effectiveness thresholds. 
Ethical Aspects 
Personal Data 
The following personal data will be collected as part of the research: 
 

18 
 
Name, contact details, village name, participant/household address, household roster, marital 
status, ethnicity, gender, age, date of birth, ethnicity, educational level, and occupation. 
Personal data will be stored by the research team in a password-protected format. Only the 
project team will have access to the data. Personal data will be stored in digital format and 
retained for 7 years as per institutional policy. However, it will be anonymized, and no personal 
identifiers will be attached to it whenever referred to in a publication or a presentation. 
Data Information Flow 
The data will be collected in a digital format using a questionnaire designed in Epi collect 
application. Data will be exported as an Excel spreadsheet from Epi collect application. 
Personal data will be stored along with research-related data in a password-protected file. 
Personal data may be retained along with other research data indefinitely but will be referred to 
without personal identifiers. 
Ethical conduct 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonization Tripartite Guideline for Good Clinical Practice (ICH GCP) in addition to the 
principles of the ethics committee(s)/Institutional Review Boards (IRBs) who have reviewed 
and approved this study. Before the study can commence, all required approvals will be 
obtained, and any conditions of approvals will be met. 
Consent 
A member of the research team or project field team will approach the participants. 
Participants will be explained the purpose of the study and any queries raised will be satisfied. 
A separate place will be arranged for conducting interviews to maintain privacy and 
confidentiality. 
Confidentiality 
The identity of participants in this study will be treated as confidential. The results of the study 
may be published for scientific purposes but will not give their name or include any identifiable 
reference. The data will be anonymized by assigning codes and personal identifiers will be 
removed. However, any records or data obtained as a result of participation in this study may 
be inspected by the sponsor or by AKU ERC members. 
Right to refuse or withdraw 
Participants will be informed and explained that they are free to choose whether to participate 
in this study. There will be no penalty or loss of benefits to which they may be entitled otherwise 
if they choose not to participate. They’ll be provided with any significant new findings developed 
during this study that may relate to or influence their willingness to continue participation. For 
participants who cannot read, a witness will be identified who will additionally ensure that the 
research that research participant has understood the consent. Such participants will be asked 

19 
 
to provide a thumb impression on the consent form whereas the witness will sign on the 
consent form. 
 
Participants can also be withdrawn by the primary investigator. If withdrawal occurs, the 
primary reason for withdrawal will be documented in the participant’s case report form, if 
possible. The participant will have the option of withdrawal from: 
● All aspects of the study but continued use of data (and samples) collected up to that 
point.  
● All aspects of the study with deletion of all previously collected data (and samples).  
 
Specific cultural considerations 
The field team responsible for data collection will comprise of male and female members. 
Given the cultural context, it will be appropriate will appropriate to have a female team member 
interview the female participants wherever appropriate. In certain villages, the field team may 
require permission from the village elders before starting data collection. In that case, a meeting 
with village elders will be organized wherever appropriate to apprise them of study objectives 
and seek their permission. 
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