Tools for the Integrated Management of Childhood Illness: Evaluation of Pulse Oximetry & Clinical Decision Support Algorithms in Primary Care - Pragmatic Cluster Randomised Controlled Trial, With Embedded Mixed Methods, Cost & Cost-effectiveness Studies in India and Tanzania
Phase: NA
Conditions: Pneumonia, Primary Health Care, Child Health, Hypoxia, Referral and Consultation, Decision Support Systems, Clinical, Oxymetry
Sponsor: Swiss Tropical & Public Health Institute

Study Protocol
TIMCI: Tools for the Integrated Management of Childhood Illness
Evaluation of pulse oximetry and clinical decision support algorithms in
primary care
Pragmatic cluster randomised controlled trial, with embedded mixed
methods, cost and cost-effectiveness studies in India and Tanzania
NCT: NCT04910750
Date: 4th February 2023

Tools for the Integrated Management of Childhood Illness
Evaluation of pulse oximetry and clinical decision support algorithms in primary care
Pragmatic cluster randomised controlled trial, with embedded mixed methods, cost and cost-
effectiveness studies in India and Tanzania
Version / date
Description
Prepared by
India & Tanzania specific protocol
Versions 0.1.1 to 0.1.5
Draft versions (internal only)
Version 0.1.6, 2nd Apr 2020
Protocol shared with PATH for
independent Scientific Merit Review
submission
Version 0.1.8 20th May 2020
Protocol shared with PATH in response to
independent Scientific Merit Review
Version 0.1.9, 3rd June 2020
Protocol with track changes approved by
independent Scientific Merit Review
Version 0.2.0, 3rd June 2020
Protocol without track changes approved
by independent Scientific Merit Review
for submission to WHO ERC
Version 0.2.1, 6th August
Protocol shared with WHO ERC in
response to Secretariat Memorandum
Version 0.2.2, 19th     November
Protocol shared with WHO ERC in
2020
response to review letter
Version 0.2.3, 11th March 2022
Protocol shared with WHO ERC with
amendments for Tanzania
Version 0.2.4, 2nd February 2023     Protocol shared with WHO ERC with
amendments for Tanzania and India
Swiss
TPH,
PATH,
UoW, KGMU, IHI
Swiss TPH
Swiss
TPH,
PATH,
UoW, KGMU, IHI
Swiss TPH
Swiss TPH
Swiss TPH, PATH
Swiss
TPH,
PATH,
UoW, KGMU, IHI
Swiss TPH
Swiss TPH
The information contained in this document is confidential. It is intended solely for the Investigators,
potential Investigators, consultants, or applicable Independent Ethics Committees and Regulatory

Authorities. It is understood that this information will not be disclosed to others without prior written
authorization from the Sponsor, except where required by applicable local laws.
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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Contents
Abbreviations...................................................................................................................................................................................6
1       Summary .................................................................................................................................................................................8
Background / rationale...........................................................................................................................................................8
Study design...............................................................................................................................................................................8
Study setting...............................................................................................................................................................................8
Interventions...............................................................................................................................................................................9
Outcomes..................................................................................................................................................................................10
2       General information.........................................................................................................................................................12
2.1        Trial registration......................................................................................................................................................12
2.2        WHO Trial Registration Data Set......................................................................................................................12
2.3        Funding.......................................................................................................................................................................12
2.4        Roles & responsibilities........................................................................................................................................12
2.4.1     Protocol development.....................................................................................................................................14
2.4.2     Project governance...........................................................................................................................................16
3       Background & rationale.................................................................................................................................................19
3.1        Rationale for pulse oximetry..............................................................................................................................19
3.2        Rationale for clinical decision support algorithm......................................................................................21
3.3        The TIMCI project...................................................................................................................................................22
4       Goal & objectives..............................................................................................................................................................23
5       Study design.......................................................................................................................................................................24
5.1        Pilot phase.................................................................................................................................................................25
5.2        Pragmatic cluster randomised controlled trial............................................................................................26
5.3        Service provision assessment ............................................................................................................................27
5.4        Facility-based process mapping and time-flow study.............................................................................27
5.5        Healthcare providers’ acceptability and perceptions of the intervention........................................28
5.6        Caregiver perceptions of the intervention and health-seeking behaviour .....................................28
5.7        Stakeholder perceptions and project data review.....................................................................................29
5.8        Cost and cost-effectiveness study...................................................................................................................29
6       Participants, interventions, and outcomes..............................................................................................................31
6.1        Study setting ............................................................................................................................................................31
6.1.1     India........................................................................................................................................................................31
6.1.2     Tanzania ................................................................................................................................................................32
6.2        Eligibility criteria......................................................................................................................................................32
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6.2.1     Pragmatic cluster RCT (including pilot) ....................................................................................................32
6.2.2     Other mixed methods studies......................................................................................................................33
6.2.3     Cost and cost-effectiveness study..............................................................................................................34
6.3        Interventions.............................................................................................................................................................34
6.4        Outcomes ..................................................................................................................................................................39
6.4.1     Pilot phase............................................................................................................................................................39
6.4.2     Pragmatic cluster RCT......................................................................................................................................39
6.4.3     Other mixed methods studies......................................................................................................................41
6.4.4     Cost and cost-effectiveness study..............................................................................................................42
6.5        Participant timeline................................................................................................................................................42
6.5.1     Pragmatic cluster RCT......................................................................................................................................42
6.5.2     Other mixed methods studies......................................................................................................................48
6.5.3     Cost and cost-effectiveness study..............................................................................................................49
6.6        Sample size ...............................................................................................................................................................49
6.6.1     Pragmatic cluster RCT......................................................................................................................................49
6.6.2     Mixed methods studies...................................................................................................................................50
6.6.3     Cost and cost-effectiveness study..............................................................................................................52
6.7        Recruitment ..............................................................................................................................................................52
7       Assignment of intervention ..........................................................................................................................................55
7.1        Allocation...................................................................................................................................................................55
7.1.1     Sequence generation.......................................................................................................................................55
7.1.2     Allocation concealment mechanism..........................................................................................................55
7.1.3     Implementation..................................................................................................................................................55
7.2        Blinding.......................................................................................................................................................................55
8       Data collection, management and analysis............................................................................................................56
8.1        Data collection methods......................................................................................................................................57
8.1.1     Pragmatic cluster RCT......................................................................................................................................58
8.1.2     Routine data........................................................................................................................................................59
8.1.3     Other mixed methods studies......................................................................................................................60
8.1.4     Cost and cost-effectiveness study..............................................................................................................61
8.2        Data management .................................................................................................................................................64
8.2.1     Data flow, storage and transfer ...................................................................................................................65
8.2.2     Data entry, handling and validation...........................................................................................................67
8.2.3     Data privacy protection...................................................................................................................................68
8.2.4     Data quality assurance and control............................................................................................................69
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8.3        Statistical methods.................................................................................................................................................70
8.3.1     Pragmatic cluster RCT......................................................................................................................................71
8.3.2     Other mixed methods studies......................................................................................................................72
8.3.3     Cost and cost-effectiveness study..............................................................................................................74
9       Monitoring...........................................................................................................................................................................76
9.1        Harms..........................................................................................................................................................................76
9.2        Auditing......................................................................................................................................................................76
10     Ethics and dissemination ...............................................................................................................................................77
10.1      Research ethics approval.....................................................................................................................................77
10.2      Protocol amendments ..........................................................................................................................................78
10.3      Consent or assent...................................................................................................................................................78
10.3.1       Pragmatic cluster RCT.................................................................................................................................78
10.3.2       Other mixed methods studies.................................................................................................................78
10.3.3       Cost and cost-effectiveness study.........................................................................................................79
10.4      Confidentiality..........................................................................................................................................................79
10.4.1       Pragmatic cluster RCT.................................................................................................................................79
10.4.2       Other mixed methods studies.................................................................................................................79
10.4.3       Linking between pragmatic cluster RCT and mixed methods studies ....................................80
10.4.4       Cost and cost-effectiveness study.........................................................................................................80
10.5      Risk and benefits to participants......................................................................................................................81
10.6      Access to data..........................................................................................................................................................81
10.7      Dissemination policy .............................................................................................................................................81
11     References ...........................................................................................................................................................................84
12     Appendix..............................................................................................................................................................................91
12.1      Informed consent forms appended to the protocol ................................................................................91
12.2      Study instruments appended to the protocol ............................................................................................91
12.3      Budget and collaboration appended to the protocol..............................................................................92
12.4      TIMCI Preliminary Theory of Change..............................................................................................................93
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Abbreviations
(co)-PI
(e)CRF
ASHA
BI
CDSA
CE
CG
CHC
CS
CSO
DALY
DB
DHIS
DHS
DMC
DMP
EDC
ePOCT
ERC
FGD
GCP
GPS
HC
HCP
HMIS
HMSC
HP
HQ
IAG
ICC
ICD-10
(co)-Principal Investigator
(electronic) Case Report Form
Accredited Social Healthcare Activist
Burnet Institute
Clinical Decision Support Algorithm
Conformité Européenne
Caregiver
Community Health Center
Case Studies
Civil Society Organization
Disability-Adjusted Life Years
Database
District Health Information System
Demographic And Health Surveys
Data Monitoring Committee
Data Management Plan
Electronic Data Capture
electronic Point of Care Tool
Ethical Review Committee
Focus Group Discussion
Good Clinical Practice
Global Positioning System
Health Center
Health Care Provider
Health Management Information System
Health Ministry’s Screening Committee
Health Post
Headquarters
International Advisory Group
Intercluster Correlation Coefficient
International Statistical Classification of Diseases and Related Health Problems
ICH
International Council for Harmonisation (of Technical Requirements for
Pharmaceuticals for Human Use)
ICMR
Indian Council of Medical Research
ID
Identification
IDI
In-Depth Interview
IEC
Institutional Ethics Committee
IHI
Ifakara Health Institute
IMCI
IQR
IRB
KGMU
KII
LMIC
M&E
MedAL-C
MedAL-R
Integrated Management of Childhood Illnesses
Interquartile Range
Institutional Review Board
King George's Medical University
Key Informant Interview
Low- and middle-income countries
Monitoring and Evaluation
Medical Algorithm - Creator
Medical Algorithm - Reader
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MedDRA
MEP
MIS
MOH
NHM-UP
NIMR
NRRC
PHC
PII
QoC
RA
RCT
RHC
SAP
SNOMED CT
SOP
SPA
SRA
Swiss TPH
TIMCI
ToC
UCAD
UoN
US FDA
VPN
WHO
Medical Dictionary for Regulatory Activities
Monitoring and Evaluation Plan
Management Information System
Ministry Of Health
National Health Ministry – Uttar Pradesh
National Health Research Ethics Committee
National Research Registration Committee
Primary Healthcare Center
Personal Identifiable Information
Quality of Care
Research Assistant
Randomised controlled trial
Rural Health Center
Statistical Analysis Plan
Systemized Nomenclature of Medicine - Clinical Terms
Standard Operating Procedure
Service Provision Assessment
Stringent Regulatory Authority
Swiss Tropical and Public Health Institute
Tools for integrated managment of childhood illness
Theory of Change
Université Cheikh Anta Diop de Dakar
University of Nairobi
United States Food and Drug Administration
Virtual Private Network
World Health Organisation
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1 Summary
Background / rationale
Achieving global targets for child mortality reduction in low- and middle-income countries
(LMICs) requires significant improvements in the detection and management of severely ill
children. Existing guidelines are inconsistently implemented by healthcare providers and, as
they are based on clinical signs, are inadequate for the detection of hypoxaemia, a strong
predictor of mortality.
The overall goal of the Tools for the Management of Childhood Illness (TIMCI) project is to
reduce morbidity and mortality in sick children attending primary care facilities, while
supporting the rational and efficient use of diagnostics and medicines by healthcare providers.
The evaluation component of the project seeks to generate evidence on the health impact,
operational priorities, cost and cost-effectiveness of introducing pulse oximetry, alone or
embedded into a Clinical Decision Support Algorithm (CDSA), at primary care level in LMICs,
for children 0 – 59 months of age, to facilitate national and international decision-making on
scale-up.
Study design
Health and quality of care impact are evaluated through pragmatic, parallel group, cluster
randomised controlled superiority trials in India and Tanzania, and quasi-experimental pre-
post studies in Kenya and Senegal.
In the pragmatic cluster randomised controlled trial (RCT), primary care facilities (clusters) are
randomly allocated (1:1) to pulse oximetry or control in India, and (1:1:1) to pulse oximetry plus
CDSA, pulse oximetry, or control in Tanzania..
The intervention package will be piloted and refined over a 3-month period prior to the start
of the definitive pragmatic cluster RCT.
This will be complemented by embedded mixed methods sub-studies to evaluate key
components of quality of care and gain a deeper understanding of the implementation
processes, mechanisms and context following a realist approach. These studies include
modified Service Provision Assessments (SPAs), a facility-based process mapping and time-
flow study, qualitative studies with caregivers, healthcare providers and key stakeholders, a
survey sent to selected key stakeholders on a quarterly basis, a desk-based project document
and monitoring and evaluation (M&E) review, and a cost and modelled cost-effectiveness
study.
Study setting
The study setting encompasses facility-based primary care level in three districts of Uttar
Pradesh in India (Unnao, Sitapur, and Deoria) and in three councils in Tanzania (Mwanza, Tanga
and Tabora). Caregivers often attend different types of facilities to meet their primary care
needs; the study setting therefore includes a diverse range of facilities providing primary care
services, including outpatient settings within larger health centres in addition to the more
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traditionally-labelled primary care facilities. This includes primary healthcare centres (PHCs) and
community health centres (CHCs) in India and dispensaries and health centres (HCs) in
Tanzania.
Key Eligibility Criteria
Consenting government-designated healthcare facilities providing outpatient curative primary
care services for children 0 – 59 months of age will be included. Facilities will be excluded if
they use pulse oximetry as a routine part of outpatient consultations of children prior to the
start of the intervention.
Children 0 – 59 months, for whom caregivers provide consent, will be eligible if attending any study
facility with an illness, excluding those admitted as inpatients within the facility, or attending for a
consultation related to trauma only.
Caregivers of enrolled children, and healthcare providers at study sites involved in the care of children 0 –
59 months of age, and stakeholders involved in or affected by the intervention, will be eligible for
inclusion in the applicable studies.
Interventions
The TIMCI project will introduce pulse oximetry, alone or embedded into a CDSA, into primary
care facilities, supported by targeted training and embedded into monitoring, supportive
supervision and maintenance systems. Refresher training will be provided to healthcare
providers in the routine care arm.
The pulse oximeters provided in the study will be UNICEF-approved handheld pulse oximeters
with paediatric and neonatal probes. Healthcare providers will be provided with guidance
(paper-based, or within the CDSA) and trained on the following criteria for pulse oximetry use:

All children under 2 months of age

Children 2 – 59 months of age presenting with cough / difficulty breathing

Children 2 – 59 months of age with Integrated Management of Childhood Illness (IMCI)
signs of moderate / severe disease (IMCI ‘yellow’ or ‘red’ classification)
Healthcare providers will be advised to use a cut-off of SpO2 <90% for referral, unless specific
national guidance states otherwise. Different SpO2 cut-offs for referral for sites at high altitude
will be finalised with the International Advisory Group (IAG) and Ministries of Health (MoHs).
The tablet-based CDSA, provided to facilities in arm 1, guides healthcare providers through
medical consultations with an algorithm called electronic point-of-care tool (ePoct+). The
clinical algorithm will be adapted to reflect national guidelines for the management of children 0
– 59 months of age in primary care (based on IMCI and additional relevant case management
guidelines), and will be validated through consultation of international and national experts in
each country.
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Outcomes
Two primary outcomes will be assessed in order to improve the ability to detect a difference
between each of the intervention arms (pulse oximetry alone, or embedded into a CDSA) and
the control arm, given the relatively low occurrence of severe outcomes at primary care level:

Proportion of children with a severe complication (death or secondary hospitalisation)
by Day 7

Proportion of children admitted to hospital within 24 hours of the Day 0 primary care
consultation and as a result of a referral
Important secondary and other outcomes include:

Proportion of children with severe complication (death or secondary hospitalisation) by
Day 28

Proportion of children cured (defined as caregiver reported recovery from illness) at
Day 7 follow-up

Proportion of children referred by a primary care healthcare provider to a higher level of
care (either to a hospital or to an inpatient part of a larger primary healthcare facility) at
Day 0 consultation

Proportion of children who completed referral, as reported at day 7 follow-up

Proportion of children with hypoxaemia (according to differing cut-offs) with severe
complication

Proportion of children prescribed an appropriate antibiotic at Day 0 consultation
Sub-group analyses will include age (under 2 months, 2 – 12 months, 13 – 59 months), sex, and
clinical presentation (with cough / difficulty breathing, fever, other). Other exploratory analysis
will be conducted of individual and health system factors associated with health and patient-
centred outcomes.
Mixed methods sub-studies will mostly be exploratory, to evaluate quality of care outcomes
and explore perceptions, values, attitudes and beliefs. Process evaluation criteria will be
evaluated according to the Medical Research Council criteria.
Cost and modelled cost-effectiveness will assess:

Full implementation cost of the intervention per focal country (cost to health system as
well as direct costs paid by the household to the health system)

Cost per child assessed using pulse oximetry devices and CDSA per country; where
applicable, compared to cost per child in routine care

Modelled cost per DALY averted attributed to the introduction of pulse oximetry and
CDSAs
Sample size
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The sample size for the pragmatic cluster RCT is calculated separately for each country to
compare each of the intervention arms with the control arm. In order to detect a 30% reduction
in the severe complication primary outcome (from 1.1% to 0.77%) with 80% power, we estimate a
sample size in each country as follows:

India – Initial sample size calculation for the three arm trial was 0 facilities per arm,
recruiting an average of 510 children over the 12 month period, with an average of 110
per CHC per month and 20 children per PHC, and a facility ratio of CHC : PHC of 1:3,
equating to 20,400 children per arm over the study. Following the decision not to
introduce the CDSA plus pulse oximetry arm, a decision was made to reallocate facilities
to the remaining to arms up to 60 facilities per arm.

Tanzania – 22 facilities per arm, recruiting an average of 1680 children over the 12
month period, with an average of 350 per health centre per month and 70 per
dispensary per month, and an average ratio of health center : dispensary of 1:3,
equating to 36,960 children per arm over the study
Service provision assessments and process mapping will be conducted in 6 facilities per arm
per country, stratified by rural / urban location and facility type, at 5 time points (once per
quarter in each facility). At each facility at each time point, 10 – 30 children per facility will be
included, resulting in an estimated sample size of 600 clinical observations, time-flow
observations and exit interviews per arm in each country over the study period.
Final sample size for qualitative studies will be determined by reaching thematic saturation. Per
country, an estimated total of 70-90 in-depth interviews (IDIs), 6 – 8 walking interviews and 12
focus group discussions (FGDs) will be conducted with caregivers, spread across the study
period. Similarly, 70-90 IDIs and 12 FGDs will be conducted with healthcare providers, and
approximately 45-55 key informant interviews with stakeholders.
Ethics Review
Following independent scientific merit review, the protocol will be submitted to all relevant
research ethics committees / institutional review boards in each country and the WHO ethical
review committee.
Estimated study timeline
Pending all relevant ethical approvals, first enrolment is anticipated to be in January 2021,
with completion of data collection in March 2022.
Depending on the evolution of the Covid-19 pandemic, we will keep implementation,
research processes and timelines under review and inform the necessary bodies and
institutions accordingly of any possible adaptations.
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2 General information
2.1 Trial registration
The trial is registered on clinicaltrials.gov, with the main register ID: NCT04910750. The study is
also registered at Clinical Trial Registry of India (CTRI) with registration number
CTRI/2022/03/041325.
2.2 WHO Trial Registration Data Set
To be uploaded once approved
2.3 Funding
The TIMCI project and associated research described in this protocol are funded by UNITAID.
PATH (Seattle) is the primary recipient of the funds and manages the project, with distribution of
funds for project implementation to PATH Country offices. All research partners are sub-
contracted by and accountable to PATH. PATH is responsible for all procurement related to
implementation (including medical supplies and consumables). Pulse oximeters used within
the study will be procured through and delivered by UNICEF.
2.4 Roles & responsibilities
PATH headquarters (Seattle) lead the project, including strategic direction and decision-
making, project oversight and compliance, global communications, risk monitoring and
mitigation, quality/change management, as well as serving as liaison with UNITAID, the
International Advisory Group and other relevant global partners, such as WHO and UNICEF.
Additional details on project governance are described below. PATH retain overall
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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responsibility
for
the
project,
but
have
sub-contracted
(
Fig. 1): the Swiss Tropical and Public Health Institute (Swiss TPH) to coordinate research design
and analysis, which includes collaboration with UniSanté, who lead the design and
development of the clinical decision support algorithm (CDSA); University of Waterloo (UoW)
to conduct cost-effectiveness analysis; and the following research partners leading country
research activities: King George’s Medical University (KGMU, India); University of Nairobi (UoN,
Kenya); Université Cheikh Anta Diop de Dakar (UCAD, Senegal); and Ifakara Health Institute
(IHI, Tanzania). As this protocol relates only to research activities in India and Tanzania, other
country research leads will not be further detailed in this document.
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Fig. 1. TIMCI project partners
PATH is the Sponsor of the research but is delegating certain responsibilities to Swiss TPH and
country research partners, outlined in Tab. 1. Through that delegation Swiss TPH, in
collaboration with the research partners in each country, will be responsible for the initiation
and management of the research. Each of the study countries has a separate tri-partite
agreement between the country research partner, PATH and Swiss TPH. Within this agreement,
Swiss TPH has the lead in development and design of the research. The respective in-country
research partner will be responsible for the adaption of the design to the country specific
context, in close collaboration with Swiss TPH and PATH.
Tab. 1. TIMCI Sponsor responsibilities and delegation
PATH
Investigator selection
Lead
Medical expertise
Review
Trial design
Review
Submission to WHO ethical review
Lead
Submission to country ethical review
Review
Preparation of study sites
Review
Trial management
Research conduct
Data collection
Quality assurance & control
Review
Safety reporting
Data analysis (country specific)
Data analysis (cross-country)
Dissemination
Review
Swiss TPH
Lead
Lead
Review
Review
Participates
Lead
Participates
Participates
Lead
Lead
Participates
Lead
Lead
Research Partners
Participates
Participates
Review
Lead
Lead
Participates
Lead
Lead
Lead
Lead
Lead
Participates
Lead
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Swiss TPH
Compensation
Financing
Insurance
Review
Lead
Participates
Lead
Lead
2.4.1 Protocol development
Swiss TPH leads the study design and protocol development in close collaboration with all
other partners. The University of Waterloo leads the development and conduct of the cost-
effectiveness component of the research, in close collaboration with Swiss TPH, PATH and the
country research partners. The RCT will be conducted in two countries, India and Tanzania. In
each country, Swiss TPH and PATH collaborate with research institutions, both of which have
extensive experience in implementing and conducting large-scale projects in their respective
study settings. PATH central contributes to the protocol development, ensuring alignment of
the proposed research with the intervention and the training packages, which are led by PATH. In
both study countries, the local PATH office interlinks with the research partners. Tab. 2
outlines the investigators and contributors to the protocol.
Tab. 2. TIMCI investigators and contributors for India and Tanzania study
Name
Prof. Kaspar Wyss
Prof. Valérie
d’Acremont
Dr. Fenella Beynon
Dr. Hélène Langet
Dr. Leah F. Bohle
Dr. Fabian Schär
Dr. Tracy Glass
Silvia Cicconi
Dr. Gillian Levine
Dr. Kristina Keitel
Dr. Elisabeth Reus
Dr. Vânia Oliveira
Anja Orschulko
Dr. Gaurav Kumar
Role
Co-PI
Co-PI
Clinical Research
Scientist, Co-I
Data Manager, Co-I
Social Scientist, Co-I
Project Manager, Co-I
Biostatistician
Biostatistician
Clinical Researcher
Senior Clinical Scientist
Clinical Operations
Clinical Operations
Social Scientist
Country Coordinator
India
Input
Oversight & overall responsibility for
research design for Swiss TPH
Oversight & overall responsibility for
research design for Swiss TPH
Quantitative study design and analysis,
clinical input for algorithm
Study design, data management oversight,
technical input for algorithm, link CDSA
into research design
Lead on qualitative study design &
analysis
Study design, Ethics approval, timelines
and link with research partners
Input into study design, data management
and analysis
Input into study design, data management
and analysis
Development of clinical content for young
infants; input into study design; qualitative
study design and analysis for young
infants; data analysis
Input in development of clinical content
for algorithm, input on study design
Development of monitoring plan, ethics
input
Monitoring of study conduct
Qualitative study design & analysis
In-country link between Swiss TPH,
Research Partner and PATH
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IHI
Unisanté
UoW
KGMU
Dr. Lena Matata
Vincent Faivre
Alan Vonlanthen
Prof. Susan Horton
Dr. Nnachebe
Michael Onah
Prof. Shally Awasthi
Dr. Divas Kumar
Mansi Tyagi
Anmol Jacob
Dr. Gidhar Agarwal
Dr. Ved Prakash
Prof. Monika Agarwal
Dr. Honorati Masanja
Dr. Irene Masanja †
Dr. Grace Mhalu
Dr. Abdallah Mkopi
Samwel Lwambura
Mr Ibrahim Mtebene
Suzan Makawia
John Maiba
Charles Festo
Country Coordinator
Tanzania
Deputy head of IT
department
Project Manager
Cost-effectiveness PI
Cost-effectiveness Co-I
National PI
Country Research
Coordinator
Country Lead Social
Scientist
Country Data Manager
Senior Biostatistician
GM Child Health &
Immunization
Professor, Dept of
Community Medicine
National PI
Former Country
Coordinator/co-
investigator
Country
Coordinator/Social
Scientist
Senior Research
Scientist
Country Data Manager
IT/Software and
software developer
Research scientist /
Economist
Social Scientist
Research Scientist
In-country link between Swiss TPH,
Research Partner and PATH
Software development
UniSanté Project Management, IT
department
Oversight and analysis of cost-
effectiveness study
Design and conduct of cost-effectiveness
study in collaboration with country
research partners
Lead for research activities in India
Lead coordination of in country research
team
Lead qualitative study
implementation & analysis
Data Manager, Quantitative study
implementation & analysis
Statistical analysis
Programmatic support
Technical support
Oversight &and overall responsibility for
research design for Tanzania
Contributed to the development of the
protocol and led the IHI research team
Contribute to the implementation of the
protocol and coordinate the IHI research
team / Lead qualitative study
implementation & analysis
Data Manager, Quantitative study
implementation & analysis
Data Manager, Quantitative study
implementation & analysis
IT/Software development
Conduct of cost effectiveness study
Qualitative study implementation and
coordination
Assist in quantitative data management,
analysis and study coordination
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PATH
Mr Mike Ruffo
Ms Mira Emmanuel-
Fabula
Dr. Helen Storey
Dr. Manjari Quintanar
Solares
Ms Tara Herrick
Mr Zachary
Clemence
Ms Tanya Lalwani
Dr. Kovid Sharma
Dr. Kanishk Gupta
Dr. Amos Mugisha
Dr. Deusdedit
Mjungu
TIMCI project director
TIMCI Project Manager
Senior Research Officer
Senior Program Officer
Senior Market
Analytics Officer
Market dynamics
Senior Associate
Senior Monitoring
Evaluation and
Learning Officer
PATH-India
PATH-India
PATH-Tanzania
PATH-Tanzania
Oversight & overall responsibility for
TIMCI
Global Project Management
Lead research PATH on Output 2
Training Lead
Cost-Effectiveness Lead
Implementation development
Monitoring & Evaluation Lead
TIMCI Country Lead
TIMCI Program Officer
PATH-Tanzania Country Representative
TIMCI Country Lead
2.4.2 Project governance
The TIMCI project has several different working groups for governance of implementation and
research activities, described in Tab. 3 below. As shown in Fig. 2, the research governance for
the RCT is shared with the longitudinal observational study (conducted in Kenyaand Senegal)
through a Research Steering Committee (RSC). The RSC is chaired by an independent expert,
and will include two sub-groups, which act as management groups, one for the RCT and one for
the longitudinal observational study. The Management groups will facilitate the day-to-day
running of the RCT and escalate issues to the RSC. Thematic Working Groups will consist of
thematic experts from all study countries. An independent Data Monitoring Committee (DMC)
will be established for the RCT.
Tab. 3. TIMCI project and research governance
Project Governance
Group
International
Advisory Group
Country
Implementation
Working Groups
Global
Implementation
Team
Membership
Unitaid*, ALIMA, WHO, UNICEF, USAID,
experts in paediatrics and IMCI, CHAI
*Unitaid is an observer in this group
PATH in-country project lead, leaders of
Swiss TPH and research/implementation
partners for research activities, key
implementation and/or management staff,
MOH representatives
PATH country- and HQ-based leadership,
Swiss TPH, Country Implementation
Working Group leaders
Function
Strategy and guidance focused;
shared with ALIMA – recipient of
parallel UNITAID award
Project management focused at
country level; ensures close
country-level collaboration across
multiple organizations and
implementation partners;
important link to MOH.
Pan-country strategic and
management function; forum to
build relationships between
countries, share learnings, and
ensure alignment.
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Consortium Executive
PATH and Swiss TPH executive-level
Board
leaders, Program Director, Senior Project
Manager
Country-Level
Depends upon country; link with most
Technical Working
applicable existing group, such as a child
Groups
health TWGs. Key influencers with MOH,
policy, operations
Manufacturers
Influential organizations involved with
Advisory Group
product development for pulse oximetry,
multimodal devices, O2, and possibly
clinical or procurement functions
Research Governance
Research Steering
Independent external chair, with
Committee
representation from Swiss TPH, and
research parners
Subgroup one: RCT
Swiss TPH, KGMU, IHI
management group
Subgroup two: LS
Swiss TPH, UoN, UCAD
management group
Data Monitoring
Independent Chair, Clinician and
Committee
Biostatistician with relevant experience
Thematic Working
Thematic experts Swiss TPH, BI, UoN,
Groups
UCAD, and IHI, KGMU
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
Strategic advisory and dispute-
resolution committee for PATH and
Swiss TPH.
Existing working groups that will
provide essential review and
oversight in each country; builds
and maintains linkages with
country operators.
Inform development of TPP, design
manufacturer incentive programs,
and ensure alignment with market
forces.
Regular review of research
progress in all four countries with
particular focus on trial and
longitudinal study
Internal working group for
management of RCT study
activities
Internal working group for
management of LS study activities
Monitoring of the RCT conduct
Exchange on content-specific
topics across all research partners
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Fig. 2. TIMCI governance overview
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3 Background & rationale
Despite progress in reducing child mortality in the last few decades, an estimated 5.3 million
children under five years of age died of preventable causes in 2018.1 If we are to achieve the
Sustainable Development Goal 3.2 by 2030, all countries must reduce under-five mortality to at
least as low as 25 per 1,000 live births and neonatal mortality to at least as low as 12 per 1,000
live births.2 Strengthening systems to identify and appropriately treat sick children,
alongside health prevention and promotion activities, is critical to achieving this goal.
The Integrated Management of Childhood Illness (IMCI) guidelines, launched in 1995 and now
adopted by over 100 countries, responded to the need to systematise the implementation of
evidence-based health interventions for children under five in primary care and the
community.3 The case management component provides a simple, structured approach to
assessment, classification and treatment of the sick child, with a particular focus on severe
illness.4
Yet despite the intention of IMCI to have high sensitivity for detection of severe disease, many
studies have demonstrated poor identification and management of severely ill children due to
both non-adherence by health workers5–9 and intrinsic problems of guidelines based on clinical
signs alone10–14. The Tools for the Integrated Management of Childhood Illness (TIMCI) project
seeks to address these issues by introducing clinical decision support algorithms (CDSAs) and
pulse oximetry to strengthen guideline implementation and accuracy in order to improve
quality of care and reduce morbidity & mortality.
3.1 Rationale for pulse oximetry
Hypoxaemia, a reduction in blood oxygenation, has a myriad of causes in children – both
respiratory and non-respiratory, but regardless of the cause, is strongly associated with
mortality.15 A meta-analysis of 13 studies on 13,928 children found a 5.5 fold increased risk of
death among children with acute lower respiratory infection (ALRI) with oxygen saturation
(SpO2) below 90%.15 The association of hypoxaemia with mortality in non-respiratory
conditions is less extensively documented, but a recent large study in Nigeria found adjusted
odds of death in hypoxaemic children to be 7.1 in ALRI, and range from 5.9 to 6.6 in the next
most common causes of hypoxaemia (malaria, acute febrile encephalopathy, sepsis, seizures).16
The prevalence of hypoxaemia is estimated to be around 13% among children with WHO
defined suspected pneumonia.17 Prevalence is also high among sick neonates (18 – 23%),
malaria (3 – 17%), meningitis (3 – 15%) and malnutrition (2 – 8%).ibid Studies have further
demonstrated the importance of hypoxaemia in children with asthma, sepsis, malaria, sickle
cell disease, tetanus and a variety of neonatal illnesses.16,18–22 However, the relative contribution
of different diseases to the burden of hypoxaemia is highly variable in different settings17, and
likely to reflect the local burden of disease. For example, in the aforementioned study of 23,926
hospitalised children in Nigeria, among all children (28 days – 14 years) with hypoxaemia, 37%
had ALRI, 33% malaria, 32% acute febrile encephalopathy, 27% sepsis and 18% seizures. In
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countries facing a lower burden of malaria, such as India (2.2% of under 5 deaths are attributed to
malaria, compared to 13.2% in Nigeria), whilst systematic data on hypoxaemia burden is not
available, this distribution is likely to be different.23
Given the prevalence of hypoxaemia and its role in mortality, a number of studies have sought to
evaluate the predictive power of clinical signs to detect hypoxaemia and guide oxygen
therapy. But no single sign or combination of signs has reliably been found to detect
hypoxaemia with adequate sensitivity or specificity.24 Using clinical signs alone thus leads to a
failure to identify all children who need oxygen and unnecessary administration of oxygen
(which is often in scarce supply) for children who do not need it.24
Pulse oximeters provide a non-invasive, accurate and easy to use method of evaluating
hypoxaemia. A number of observational studies at hospital level have shown significant
reductions in child mortality, referrals and triage time following the introduction of pulse
oximetry and associated interventions.13,25,26 Furthermore, a recent modelling study estimated
that implementing pulse oximetry could avert up to 148,000 deaths per year of children under-5
in fifteen high-burden pneumonia countries, far more than the potential deaths averted by
IMCI alone.27 In addition to the potential impact on child morbidity and mortality, there are
potential resource savings through the reduction in unnecessary oxygen use – up to two thirds of
children eligible for oxygen based on WHO criteria are not hypoxic.14
Whilst most data and guidance relating to pulse oximetry pertains to hospital settings, there is
emerging evidence on the benefit in primary care. In Malawi, provision of pulse oximetry to
rural health centres and community health workers resulted in increased referral rates among
children with WHO-defined severe pneumonia. They also found that pulse oximetry enabled
the identification of hypoxaemic children who otherwise would have been categorised as
having non-severe pneumonia.13 Whilst their study was implemented before the 2014
modification to WHO IMCI guidelines, retrospectively applying the criteria to their dataset
revealed that 69% of hypoxaemic children would not have been categorised as requiring
referral. Pulse oximetry therefore provides the opportunity to improve the sensitivity of IMCI
guidelines for severe disease. Implementation of pulse oximetry could also be a strategy to
rule-out severe disease and therefore reduce unnecessary hospital referrals and admissions,
though the exact oxygen saturation cut-off requires further validation.28
This potential to improve the detection and referral of children with severe disease has led to
strengthened interest in the potential to rollout pulse oximetry to primary care. However,
before significant investment is made in this area, it is critical to understand what health impact
pulse oximetry has, for which children in which contexts, and with what consequences – such as
over-referral to already stretched hospital resources. Impact is likely to depend on a number of
factors, including burden of hypoxaemia in primary care, choice of criteria for pulse oximetry use
(to optimise detection of hypoxaemic children whilst avoiding false positives and over-
burdening clinic staff) and pre-existing quality of care.
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3.2 Rationale for clinical decision support algorithm
Whilst the introduction of pulse oximetry can improve the identification of sick children in
primary care, it does not provide a comprehensive approach to improve adherence to
evidence-based guidelines. Observational studies have indicated that IMCI-trained healthcare
providers only correctly classify children according to IMCI guidelines 33 – 87% of the time.5
This lack of correct classification likely stems from incomplete assessments. Pooled data from
the Service Provision Assessment surveys in Namibia, Kenya, Tanzania and Uganda found
health workers conducted a complete danger signs assessment in less than 33% of 6856
children assessed.6 In Malawi, fewer than 1% of children had an assessment including all 16
elements of the history and examination.9 In the same study, respiratory rate was only checked in
16% of children presenting with cough or difficulty breathing.
Failure to assess key signs can result in under-classification of severity and inadequate
management of children with severe disease, leading to a higher mortality risk. For example, in
the above study in Malawi, clinical officers did not refer 41% of children with severe / very
severe pneumonia, and requested oxygen for only 23% of those that met criteria.9 Similarly, in a
study in South Africa, only 47% of children with severe disease were correctly identified by a
health worker.7
Even when health workers do recognise severe disease, they do not necessarily treat and refer
according to guidelines. In a study in Tanzania, only 38% of children with severe disease were
referred by IMCI-trained health workers, despite 95% having been recognised as having severe
pneumonia, severe malaria or both.8 The authors surveyed health workers and found that 91%
believed that referral was not a necessary component of management for certain severe
conditions.
Electronic clinical decision support algorithms (CDSAs) provide an electronic step-by-step
guide through a clinical consultation for healthcare providers, supporting the integrated
disease management approach promoted by WHO. Recent studies of two such tools, based on
IMCI and national guidelines, have demonstrated potential for significant improvements in
health outcomes and large reductions in unnecessary antimicrobial prescribing.29,30 The use of
one such tool by healthcare providers in consultations for all acutely unwell children was found to
improve cure rate at day 7 (97% compared to 92% in routine care) whilst reducing antibiotic
prescriptions from 84% to 15%.29 Another tool, ePOCT, used for children with fever and
integrating point of care diagnostic tests, reduced clinical failure rate to 2% (compared to 5% in
routine care) and antibiotic prescriptions to 11% (from 95%).31
The mechanisms by which CDSAs impact health worker practice may stem from the fact that
the electronic algorithms, by design, provide support in decision making for any combination of
clinical findings, whereas paper-based IMCI or national guidelines are, by necessity,
reductionist.10 In a mixed-methods exploration of the reasons for non-adherence to IMCI
guidelines by health workers, Lange and colleagues described “cognitive overload” as a
contributory factor to non-adherence.32 In such circumstances, support to the complex clinical
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decision making process with CDSAs can facilitate health workers to provide higher quality
care. This is likely to be particularly true in the case of introducing novel technology such as
pulse oximetry, which adds an additional level of complexity to the integrated clinical
assessment of children.
Implementing pulse oximetry embedded into a CDSA has the potential to improve the
detection of children with severe disease and improve the adherence of healthcare providers to
evidence-based, integrated disease management guidelines. We hypothesise that these
interventions will result in a reduction in adverse health outcomes through better treatment
and referral decisions, and an improvement in quality of care through the rational use of
essential medicines and improvements in the health worker and caregiver experience.
3.3 The TIMCI project
The Tools for Integrated Management of Childhood Illness (TIMCI) project builds on this
hypothesis to form part of the response to the need for better mechanisms to detect and
manage children with severe illness in LMICs. It is a 4 year UNITAID-funded project, focused on
the interventions of pulse oximetry and CDSAs in primary care, organised into four main
outputs: (1) introduction of pulse oximetry and CDSAs in four countries (India, Kenya, Senegal
and Tanzania); (2) evidence generation for pulse oximetry and CDSA introduction; (3) market
strengthening for adapted multi-modal devices; and (4) creating conditions for national and
global scale-up and sustainable use of these tools.
This protocol focuses on the evidence generation component of the TIMCI project in India and
Tanzania (a separate protocol has been developed for Kenyaand Senegal to reflect a different
study design).
To our knowledge, no large scale studies have systematically evaluated the health impact, cost-
effectiveness and optimal implementation approaches of pulse oximetry, alone or embedded
into a CDSA, for children with a broad range of clinical diagnoses in primary care.
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4 Goal & objectives
The overall goal of the TIMCI project is to reduce morbidity and mortality in sick children
attending primary care facilities, while supporting the rational and efficient use of diagnostics
and medicines by healthcare providers. The evaluation component of the project seeks to
generate evidence on the health impact, operational priorities, cost and cost-effectiveness of
introducing pulse oximetry, alone or embedded into a CDSA, into primary care in LMICs, for
children 0 – 59 months of age, to facilitate national and international decision-making on scale-
up. Specific objectives, according to these themes, include:
Health and quality of care impact
To evaluate the impact on health and quality of care outcomes of sick children 0 – 59 months of
age of introducing pulse oximetry, alone or embedded into a CDSA, for facility-based
primary care, compared to routine care, including on:

Mortality and hospitalisations

Adherence by primary healthcare providers to key components of assessment,
classification and management guidelines, in particular on referral decision-making and
antimicrobial prescription
To assess severe, moderate and mild hypoxaemia prevalence among sick children attending
intervention primary care facilities, and understand the association of different hypoxaemia
cut-offs with adverse outcomes, according to sociodemographic and clinical features.
Implementation and process

To understand the facilitators and barriers to uptake, acceptability of the intervention
and behaviour change by health care providers, caregivers and their children, and a
variety of stakeholders at community, health facility, national and international levels

To evaluate characteristics of children, caregivers, healthcare providers and health
facilities associated with uptake and impact of the interventions

To understand how the interventions affect patient flow and patient-provider
interactions, including change in care processes, consultation time, and communication
between caregivers and healthcare providers
Cost and cost-effectiveness

To determine the cost and estimate any cost savings and/or additional costs of
introducing pulse oximetry with or without CDSAs into primary care in four countries

To estimate cost effectiveness of the interventions compared to routine care and other
interventions aimed at improving the management of severe illness in children 0 – 59
months of age
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5 Study design
Health and quality of care impact are evaluated through pragmatic, parallel group, cluster
randomised controlled superiority trials in India and Tanzania, and quasi-experimental pre-
post studies in Kenya and Senegal.
In the pragmatic cluster randomised controlled trial (RCT), primary care facilities (clusters) are
randomly allocated (1:1) to pulse oximetry or control in India, and (1:1:1) to pulse oximetry plus
CDSA, pulse oximetry, or control in Tanzania.This assessment of the health impact of the
intervention will be complemented by embedded mixed methods sub-studies in both
countries to evaluate other key components of quality of care33 and gain a deeper
understanding of the implementation mechanisms and context. These studies include modified
Service Provision Assessments (SPAs), a facility-based process mapping and time-flow study,
qualitative studies with caregivers, healthcare providers and key stakeholders, a regular survey
sent to selected key stakeholders, a desk-based project document and monitoring and
evaluation (M&E) review, and an economic evaluation (Fig. 3, Tab. 8). Data from the mixed-
method studies will be triangulated in order to generate in-depth insights into implementation.
Fig. 3: Timeline of pragmatic cluster randomised control trial with pilot phase and embedded mixed
methods studies. Pre-intervention facilities: trial dataset, SPA and process-mapping and time-flow
study collected as a baseline. Pilot Part I – 2 to 4 facilities per arm, over 4 to 6 weeks, to refine the
intervention. Trial dataset, SPA, process-mapping and time-flow, and caregiver IDIs and HCP IDIs
collected. Pilot Part II – roll-out of the intervention to all study facilities to allow stabilisation
(familiarisation with devices by HCPs) over 6 – 8 weeks prior to study start. Definitive trial – expected to
last 12 months to capture seasonal disease burden variation and changes in implementation / impact over
time. SPAs – cross-sectional quarterly assessments in 6 facilities per arm comprising of observations of
consultations of sick children, exit interviews with caregivers, interviews with HCPs and facility
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assessments. Process-mapping and time-flow study – during baseline, early and late implementation
(intervention arms only). Qualitative studies with caregivers and with HCPs – during pilot phase I (IDIs
only) and across the implementation period to understand change over time. In Tanzania, IDIs will also
take place in the pre-intervention phase, and in the control arm. Key stakeholders – KIIs during baseline /
pilot, early and late implementation; and quarterly surveys. Cost and cost-effectiveness: cost data will be
collected prior to intervention and on start-up costs, and again during implementation with final data
collection to capture any missing information. Abbreviations: SPA – service provision assessments; IDIs –
in-depth interviews; FGDs – focus group discussions; KIIs – key informant interviews; HCPs – healthcare
providers
This mixed methods design draws on principles of realist evaluation (focusing on processes,
and mechanisms in their respective contexts leading to outcomes)34, the MRC guidance on
Process Evaluation for Complex Interventions35, the Theoretical Framework of Acceptability of
Health Care Interventions36, and the COM-B model of behaviour change37. It is further informed
by the project’s Theory of Change (ToC, Appendix), developed in line with the approach taken by
de Silva and colleagues38 and the Centre for Theory of Change39. The ToC components will be
tested and revised to incorporate unanticipated pathways and assumptions and provide
feedback to strengthen the intervention.
5.1 Pilot phase
The pilot phase will occur over an estimated 3-month period prior to the start of the definitive
pragmatic cluster RCT. It will serve to ensure the intervention package is optimised (Part I)
before roll-out to all study facilities, allow for stabilisation of the intervention (Part II) and for
piloting of the research instruments and processes. It will also allow certain mixed methods
sub-studies to be conducted in the intervention arms prior to intervention start, to allow for
comparison within the same facilities over time.
The RCT dataset collected during this pilot phase will be used for exploratory analysis of early
implementation, but will not be included in the definitive RCT analysis. Mixed methods study
data collected during this phase will be incorporated into the overall analysis to facilitate the
understanding of the implementation processes, mechanisms and context in order to inform
the development of the package for scale.
Part I – refining the intervention and piloting research processes
We will select 2 – 4 facilities per trial arm to tailor the introduction of the intervention, based on
qualitative feedback from healthcare providers and caregivers (in-depth interviews, informal
discussions) and key stakeholders (key informant interviews), combined with observation of
the way in which pulse oximetry and CDSAs are used (from SPA observation and exit interviews,
process mapping and time-flow, and training assessments conducted by PATH). These studies,
further detailed in study-specific sections below, will aid understanding of implementation
processes with a focus on acceptability, and barriers and facilitators to implementation to
inform potential refinement of the approach to training, supervision, caregiver engagement
and guidance on where to use the devices within the care process.
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In addition, we will conduct a pre-intervention (baseline) assessment in a sample of study
facilities in each arm, in which we will collect the RCT dataset, SPA assessments and facility-
based process mapping and time-flow study to allow for comparison within the same facilities
over time.
Concurrently, we will pilot the research instruments and processes and refine if necessary,
including eligibility screening, participant information and consent, and data collection tools.
We estimate this phase will take 4 – 6 weeks, but will extend if more major adjustments are
necessary (to intervention package, or to the protocol).
Part II – rolling-out the intervention and refining participant recruitment and follow-up
procedures
Once the intervention package is refined and finalised, devices will be introduced into all the
intervention facilities to enable a period of stabilisation of the intervention prior to start of the
definitive trial (to allow healthcare providers to become familiarised with the intervention). The
same dataset will be collected during this period, but set aside for exploratory analysis rather
than included in the definitive trial analysis.
During this stabilisation phase, we will also assess rates across facilities for eligibility,
recruitment, loss to follow-up and healthcare provider capacity to use pulse oximetry and
CDSAs, to identify and mitigate any major challenges prior to the definitive trial start. We
estimate that this phase will take 6 – 8 weeks, but will extend if adjustments are needed in
order to reduce the risk of major challenges to efficiency or internal validity in the definitive
trial.
5.2 Pragmatic cluster randomised controlled trial
We will conduct a pragmatic, three-arm 1:1:1 parallel group, cluster randomised controlled
superiority trial in Tanzania over a 12-month period. Following the pilot in India, a decision
was taken to remove one of the intervention arms, and conduct a two-arm 1:1 parallel group,
cluster randomised trial in India. Cluster unit is the facility providing primary care services, with
randomisation to one of the following groups:

Pulse oximetry plus CDSA (Tanzania only)

Pulse oximetry with paper job aid based on IMCI (or national guidelines) incorporating
pulse oximetry

Control (routine care, with refresher training)
Sick children 0 – 59 months of age will be managed by healthcare providers according to which
intervention the facility they attend have been assigned (see 6.3 for further detail).
As the intervention targets healthcare provider practice, we have opted for a cluster design at
the facility level to: avoid contamination that would occur if randomisation occurred at the
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individual level; avoid introducing different processes within one facility; and enable evaluation
of effectiveness in real-world settings.
5.3 Service provision assessment
This periodic assessment of service delivery will follow the approach of the Demographic and
Health Surveys (DHS) Program Service Provision Assessment (SPA) (facility assessment,
healthcare provider interview, sick child observation protocol and caregiver interview),40–42
modified to focus on child health, pulse oximetry and CDSA use and incorporate additional
quantitative and qualitative questions covering factors associated with child mortality and
health-seeking behaviour, as well as patient-centred outcomes including experience of care.
We will conduct cross-sectional surveys at a stratified sample of facilities at baseline and
quarterly over the following year of implementation in order to assess differences over time
and with varying burden of disease in different seasons. We will also conduct the SPA at the
pilot phase part I facilities to inform intervention refinement. Stratification is based on study
arm, rural / urban location and facility type. On the days of the surveys, we will conduct an
abbreviated facility assessment, administer a questionnaire to all providers consulting children
under five, and the modified ‘sick child’ observation and exit interview on all eligible children
attending the facility.
5.4 Facility-based process mapping and time-flow study
Prior to intervention, we will develop a basic process map defining the common steps in the
care pathway of sick children in primary care facilities in each country (adapted to facility type).
The map will be reviewed and refined through informal discussions with staff and non-
participant observation at a sample of intervention arm facilities prior to intervention (including
discussion on whether specific processes have been introduced or changed as a result of
COVID-19). Time-flow data will be captured for discrete steps in the care process through
observation of a sample of children attending the facility, from arrival through to consultation
(including on use of the devices), to departure from the facility. Non-participant observation
will focus on understanding rationale for care processes and when and why deviation from the
standard pathway may occur.
This ‘pre-intervention’ map will then be adapted to incorporate pulse oximetry and CDSAs
through discussions with staff and observations in the pilot phase part I facilities to understand
the impact of the intervention on care processes (including on time) and on patient-provider
interactions, and inform refinement of the intervention strategy if necessary.
After roll-out of the intervention, this will be repeated both early and late in the intervention
(intervention and control arms) to understand changes in care processes and time with the
refined intervention package, and adaptations that may have occurred as a result of provider
preferences (or as a result of other changes to care processes external to the TIMCI project).
This will generate information on whether the intervention has been normalised into care
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processes over the longer-term in order to understand sustainability and inform the package
for scale. Time-flow data will also be used in the cost and modelled cost-effectiveness study.
5.5 Healthcare providers’ acceptability and perceptions of the
intervention
We will conduct semi-structured in-depth interviews (IDIs) and possibly focus group
discussions (FGDs) with a purposive sample of healthcare providers working in intervention
facilities. IDIs (and informal group discussions where required) will be conducted during the
pilot phase to inform intervention refinement. IDIs and possibly FGDs will be conducted over
the course of the intervention to understand changes in perception of the intervention over
time and reasons for early and late adoption. In Tanzania only, IDIs will also take place pre-
intervention, and during the late intervention period in the control arm for comparison. Focus
group discussions will be based around clinical vignettes to facilitate discussion of experiences
with the devices (including usability, practicality and design) and on quality of care and
acceptability of tools without causing unwanted disclosure, or bias due to self-stigmatization or
self-censorship. In-depth interviews, which may include vignettes, will focus particularly on the
individual experience with the introduction of the intervention and over time; the
acceptability of the intervention; mechanisms, processes and contexts leading to behaviour
change and identifying barriers and facilitators for intervention success.
5.6 Caregiver perceptions of the intervention and health-seeking
behaviour
Semi-structured in-depth interviews (IDIs), and possibly focus group discussions (FGDs) will be
conducted with a purposive sample of caregivers who have attended study facilities. IDIs and
possibly FGDs will be carried out at the household and respective community level.
IDIs (and informal group discussions where required) will be carried out during the pilot phase to
inform intervention refinement. IDIs, and possibly FGDs will be conducted with caregivers
attending intervention facilities over the course of the implementation period to understand
changes in perception of the intervention over time and behaviour change, as well as reasons
for loss to follow-up among caregivers who will miss their Day 7 follow-up (Tanzania only). IDIs
will also take place during early and the late intervention period and possibly in the control
arm for comparison during the late intervention. The IDIs and possibly FGDs will focus on
aspects of the quality of care and acceptability frameworks, as well as health-seeking behaviour
and decision making, incorporating a realist approach.
Participants with a particularly interesting or divergent view in focus group discussions with
health care providers or caregivers might be approached for follow-up IDIs.
Additionally, a rapid qualitative inquiry among caregivers lost to follow-up (LTFU) will be
conducted. This includes IDIs with a selected caregiver who could not be reached during Day
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7 follow-ups so as to understand reasons, caregivers’ perceptions and challenges associated
with loss to follow-up, allowing to develop context-specific solutions.
Qualitative data collection is exploratory in nature; time points in data collection are
preliminary. Final time points will depend on the preliminary analysis of qualitative data and
findings throughout the data collection. Therefore the studies planned may require a closer
follow-up or data collection at additional time points (e.g. mid phase of the intervention).
5.7 Stakeholder perceptions and project data review
This will incorporate key-informant interviews (KIIs) with selected stakeholders at global,
national, subnational and local level with perspectives on implementation, policy and research.
Stakeholders will include those internal (i.e. project stakeholders; e.g. PATH) and external (i.e.
non-project stakeholders, e.g. Ministry of Health, community, other organisations) to the
project, either directly involved in implementation or affected by implementation. This includes,
but may not be limited to: selected International Advisory Group members, Unitaid and WHO
representatives, PATH headquarters staff, national policy makers, members of district health
management teams, health facility managers, community leaders, national and local PATH
implementation staff, and research staff. The KIIs will be conducted during the pilot phase, to
understand the start of implementation, and during late intervention, to gain reflections into
implementation over time to inform a package for scale. In Tanzania only, KIIs will also be
conducted prior to intervention, and local key stakeholders may be included late in the control
arm for comparison.
These interviews will be complemented by quarterly electronic surveys of selected project
informants and a structured review of key documents including PATH project reports,
(including on changes as a result of COVID-19), minutes and M&E data (e.g. on training
evaluation or maintenance and replacement of devices) for each country. It will primarily focus
on the processes, mechanisms and context (i.e. MRC process evaluation criteria) of
implementation including adaptations made.
In each country, PATH project data, along with routine Health Management Information
Systems (HMIS) data will be assessed for all facilities and administrative regions where the
project is running to draw inferences on the impact of the intervention on indicators used for
routine monitoring by Ministries of Health, and their potential for longer term use.
5.8 Cost and cost-effectiveness study
The economic evaluation will involve a cost and cost-effectiveness analysis using direct health
system costs in which financial and economic costs will be assessed. The scope of the costing
will cover only intervention costs and not research-based costs, and will include costs incurred
by the health system as well as estimated direct costs paid out of pocket by the households to
the health system. It is important to note that this cost methodology is not comprehensive. It
does not include the indirect costs incurred by the consumer (patient) e.g. the caregiver’s time
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or transport costs. Rather, it focuses exclusively on the provider’s direct costs, whether borne
by the health system or paid out of pocket by the patient’s household.
The approach that has been taken in applying this methodology has been to capture what is
thought to be the “most likely” cost scenario, on average. In identifying this “most likely” cost
scenario, effort will be made to supplement the analysis with a discussion about factors that
influence the level of costs (e.g. the number of trainees per training, or the frequency of
supervision) so as to provide a type of sensitivity analysis of the robustness of the estimates.
Cost scenarios will also guide possible future programme scale up. The cost resources for each
cost centre might differ between India and Tanzania. For instance, at some facilities laboratory
tests or some treatments may not be available, and patients have to be referred elsewhere: we
will have to take account of these differences.
Research-based costs are excluded to enable the costing to provide guidance on future
replication and potential scale up of the intervention. Full and incremental costing involving an
activity-based and ingredient-based approach will be used. When available, effectiveness data
will be combined with the cost data and cost per DALY averted will be estimated as outlined in
8.3.3. The costing and cost-effectiveness will use a 12-month time frame and a 3% discount
rate. Where applicable, discount rates will be adjusted to prevailing rates at country-level.
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6 Participants, interventions, and outcomes
6.1 Study setting
Whilst the study is taking place in diverse health systems and communities in Africa and Asia,
the common feature is the focus on facility-based primary care. Caregivers often attend a
diverse range of facilities to meet their primary care needs. The study setting therefore includes
any facilities providing primary care services, including outpatient settings within larger health
centres
in
addition
to
the
more
traditionally-labelled
primary
care
facilities.
Fig. 4. Map overview of the countries involved in TIMCI. Countries conducting the pragmatic cluster RCT
(India and Tanzania) are displayed in red, while countries that are involved in the longitudinal
observational study (Kenyaand Senegal) are displayed in yellow.
6.1.1 India
Setting
Three districts of Uttar Pradesh (Unnao, Sitapur, and Deoria). Under-
5 mortality rate 46/1000 live births43
Facilities
Primary healthcare centres (PHCs) and community health centres
(CHCs)
Services
PHCs provide outpatient only consultations for 6 – 8 hours per day,
Monday to Friday.
CHCs provide outpatient consultations and have capacity to admit
children for observation and management in a separate part of the
facility. They are open from 8am to 2pm (including 2 Saturdays per
month). Emergency services are available 24 hours a day, 7 days a
week.
Staffing
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Both PHCs and CHCs are staffed with non-specialist doctors: PHCs
usually have one doctor, while CHCs have 4 – 10 doctors, and may
have MD doctors and/or a paediatrician.
Referral system
Both PHCs and CHCs have normally access to free ambulance
services for referral of children for a higher-level of care, but this is
subject to availability in the area.
O2 availability
All CHCs have cylinder-based oxygen. Oxygen is occasionally
available at the PHC level. The availability of a 24x7 functional oxygen
cylinder at a PHC will need to be confirmed after an initial
assessment. Most ambulances also have an oxygen cylinder on
board.
6.1.2 Tanzania
Setting
Three councils (Sengerema District Council in Mwanza region, Tanga
City Council in Tanga region and Kaliua in Tabora region)
Tanzania under-5 mortality rate: 53 / 1000 live births44
Facilities
Dispensaries and health centres (HCs)
Services
Dispensaries offer services such as immunization, family planning,
antenatal care, treatment of common diseases, treatment and
management of tuberculosis, and HIV/AIDS counselling among
curative and preventive services. Although they provide services to
outpatients, a few dispensaries may also have a ward for observation.
HCs offer similar services to dispensaries with the addition of 24-hour
maternity service, emergency care, and casualty admissions in some
centres.
Staffing
Both dispensaries and HCs are staffed with nurses and clinical
officers. HCs may also have medical doctors
Referral system
Phone numbers for key people involved in the referral processes are
registered and displayed in public places, but use varies by provider.
Identified transport providers, such as boda bodas (motorbikes) and
taxis, are a quick mode of transport to the referral hospital.
O2 availability
Only HCs have cylinder-based oxygen.
6.2 Eligibility criteria
6.2.1 Pragmatic cluster RCT (including pilot)
Facility inclusion:

Consenting government-designated healthcare facilities within the selected
geographical areas of each country
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
Providing curative primary care services for children 0 – 59 months of age

Oxygen available or referral mechanism in place with oxygen available at a higher level
facility

Electricity available (from any source with continuous or intermittent supply)
Facility exclusion:

Attending to fewer than 20 sick children per month (based on the prior 12 month
average)

Already using pulse oximetry as a routine part of outpatient-based consultations of
children 0 – 59 months

Selected to be part of a major child health programmatic or research intervention
during the study period likely to significantly affect the primary outcome

Inaccessible to the study team (e.g. due to weather conditions or security issues) for
significant parts of the year.
Individual child inclusion:

Children 0 – 59 months for whom caregivers provide consent

Consulting for an illness, or reported to be unwell when attending for a routine visit
(e.g. vaccination, growth or chronic disease monitoring)
Individual child exclusion:

Children in the immediate post-natal period or first day of life

Attending for a consultation related to trauma only (including new and follow-up
presentations for burns, injuries, wounds)

Admitted within an inpatient part of the facility (including neonates delivered at the
facility admitted with their mother)

Enrolled in the study within the preceding 28 days at any study facility
6.2.2 Other mixed methods studies
Facilities for the remaining studies will be sampled from the pragmatic cluster RCT (including
pilot and non-pilot) study facilities. A stratified sample of facilities will be selected for the SPA
and process mapping and time flow study, with stratification factors including study arm (all
arms for SPA, intervention arm and control arm only for process mapping and time-flow),
location (rural/urban in Tanzania, district in India) and type of health facility (if applicable,
regional differences may also be taken into account). Sub-samples for qualitative studies with
healthcare providers and caregivers will be sampled from SPA facilities in the intervention arms
to allow for triangulation of data between studies, but may also be sampled from non-SPA
facilities and control arm facilities to avoid research fatigue or amplification of the Hawthorne
effect.
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Individual children and caregivers will be eligible for inclusion in the SPA observed consultation
and exit interviews if they are eligible for the RCT and attend a study facility selected for the
SPA during a period when it is being conducted (5 time points, for 3 – 10 days as outlined in
6.6.2). Caregivers will be eligible for inclusion in IDIs and FGDs if their child has been enrolled in
the RCT. Individual healthcare providers will be eligible for the SPA interview if they are
present on the day(s) of assessment and are involved in the care of children 0 – 59 months at
that facility. Healthcare providers for IDIs and FGDs will be eligible if they provide care for
children 0 – 59 months at any study facility.
Individual stakeholder eligibility: policy, implementation or research stakeholders at a national
or international level with expertise in child health and / or the devices introduced; local and
sub-national stakeholders either internal or external to the project, directly involved in any
aspect of implementation or affected by the intervention.
6.2.3 Cost and cost-effectiveness study
Medical and non-medical personnel from study facilities and the government-designated
hospitals to which they refer will be approached for costing data as described in section 6.6.3.
6.3 Interventions
The interventions included in the TIMCI project will be implemented in facilities according to
allocation arm:

Pulse oximetry plus CDSA (Tanzania only)
o Pulse oximeters, with guidance (integrated into CDSA), training and mentorship
as detailed below
o Tablet-based CDSAs, with guidance, training and mentorship as detailed below
o Refresher training on latest national / IMCI guidelines integrated with pulse
oximetry and CDSA training

Pulse oximetry with paper job aid: training on pulse oximetry,
o Pulse oximeters, with guidance (pulse oximetry specific job-aid, plus adapted
IMCI chartbook), training and mentorship as detailed below
o Refresher training on latest national / IMCI guidelines integrated with pulse
oximetry training

Control (routine care)
o Refresher training on latest national / IMCI guidelines
Where possible, the interventions of both pulse oximetry (and CDSA in Tanzania) will be
embedded into existing monitoring, supportive supervision and device maintenance systems.
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Refresher training on IMCI / national guidelines, delivered by MOHs (supported by PATH if
required), is incorporated into each arm to address the issue that many practicing healthcare
providers will not have received recent training, particularly on recent guideline updates. This is
provided in the routine care arm to control for the effect of training as part of the
introduction of pulse oximetry, alone or embedded into a CDSA.
Community engagement, further described below, will complement the facility-based
intervention in all arms, to promote health-seeking behaviour and compliance with referral
advice.
Pulse oximetry
UNICEF-approved handheld pulse oximeters (Acare, AH-MX)45 will be provided, along with a
package of supplies that includes a carry case, spare set of rechargeable batteries, battery
charger, and six reusable probes (two each of adult, paediatric and neonatal sizes). Handheld
devices were selected as they are portable, and thus better suited for point-of-care use in PHC
settings, and more affordable than benchtop devices. Handheld devices are also more
appropriate for children and neonates than fingertip devices, which are typically not designed
for these populations.
The criteria for pulse oximetry use, agreed with the International Advisory Group and Ministries
of Health of Tanzania are:

All children under 2 months of age

Children 2 – 59 months of age presenting with cough / difficulty breathing

Children 2 – 59 months of age with IMCI signs of moderate / severe disease (IMCI
‘yellow’ or ‘red’ classification)
These criteria aim to identify children with the highest likelihood of having hypoxaemia whilst
avoid unnecessary referrals of children with a low likelihood of having hypoxaemia and a false
positive result, as well as avoiding over-burdening healthcare providers or contributing to clinic
delays.
Young infants represent a small proportion of all clinic attendees46, but with a relatively high
prevalence of hypoxaemia and risk of severe disease and mortality.1,7,16 Children with cough or
difficulty breathing represent around 40 – 70% of children attending primary care. Children
with WHO-defined suspected pneumonia (around 15 – 30% of clinic attendees)7,46,47 are more
likely to be hypoxaemic than those with cough / cold, but respiratory rate, one of the key
differentiating signs is often not measured.16,47,48 All children with cough / difficulty breathing
are therefore chosen to avoid missing children inappropriately classified as not having
suspected pneumonia.
Lastly, children presenting with signs of moderate or severe disease are included to ensure
detection of children with illnesses such as sepsis, meningitis, malaria, malnutrition, diarrhoea,
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anaemia that may also present with hypoxaemia.16,17 Children with mild disease – such as
diarrhoea with no evidence of dehydration, fever with no evidence of malaria, meningitis /
encephalitis, or complicated measles – are very unlikely to have hypoxaemia and pulse oximetry
use will therefore not be advised in this group.
In certain circumstances, there may be a deviation from these criteria for operational reasons.
Such circumstances will be agreed with local decision-makers, but, for example, may include
the use of pulse oximetry during a triage step in large, high volume facilities. In such
circumstances, preference may be given to using pulse oximetry on all sick children. In the
event that this occurs, children found to have low oxygen saturation will be triaged for
immediate assessment by a clinician, who may repeat the pulse oximetry measurement if
needed.
In India, the Ministry of Health and Family Welfare opted to recommend be used in the
assessment in all sick children under five years of age.
Healthcare providers will be advised to use a cut-off of SpO2 <90% for referral, in line with
WHO guidance. The message to refer children with other signs will be reinforced. Different
SpO2 cut-offs for referral for sites at high altitude will be finalised with the IAG and MoHs,
given that the normal range for SpO2 varies with altitude, but this is unlikely to affect cut-offs
below 2500m.49
Healthcare providers will be advised to only take one measurement for children with severe or
moderate disease and will be advised not to attempt to obtain a reading for more than 5
minutes (most readings are obtainable within this time).13,50,51 However, if a child with no other
sign of moderate or severe disease (i.e. IMCI ‘green’ category) is found to have SpO2 <90% (or
altitude-specific cut-off), healthcare providers will be advised to repeat the reading. In cases of
conflicting readings (i.e. one <90% and one ≥90%, or altitude-specific cut-off), a third reading
will be advised as confirmatory.
As the cluster unit is the facility, and more than one level of facility is included in both India
and Tanzania, there is a possibility that an intervention lower-level facility (dispensary or PHC)
would routinely refer to a non-intervention higher-level facility (health centre or CHC). In this
circumstance, a child could be assessed and found to be hypoxaemic with pulse oximetry in a
lower-level facility and then be referred to be seen in a facility where pulse oximetry is not
routinely being used. To navigate this issue, staff at all lower-level facilities who find a child to be
hypoxaemic will be advised that they should refer a child directly to hospital, and only refer to
the inpatient / emergency area of a higher-level primary care facility (rather than their
outpatient consultation area) if oxygen is available.
The above guidance will be incorporated into the CDSA (facilities in Arm 1) and a paper-based
job aid and updated IMCI chartbook (facilities in Arm 2).
Clinical Decision Support Algorithm
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In addition to pulse oximetry, healthcare providers in the pulse oximeter plus Clinical Decision
Support Algorithm (CDSA) will be guided throughout their medical consultations by an
algorithm called ePoct+ and developed by Swiss TPH in collaboration with Unisanté/Wavemind
(Lausanne, Switzerland).
Healthcare providers will used ePoct+ for the assessment, diagnosis and management of all
sick children 0 – 59 months of age (i.e. only excluding those coming for routine immunisation or
monitoring visits and not reported to be unwell). In case a child comes back to the facility
during the same disease episode, ePoct+ can be used to manage the child in the same way as
during the baseline visit, as the algorithm takes into account duration of symptoms and
previous treatments provided.
MedAL-R, the front-end application developed by Unisanté/Wavemind to implement ePoct+ is
available for Android tablet or PC. The application can be deployed in health facilities in a
standalone mode or a multi-device mode to facilitate the collaboration of several healthcare
providers and storage of information in the patient’s medical records. In the context of this
study, MedAL-R will be deployed on tablets. The choice of a standalone / multi-device setting
will depend on discussions with the country MoHs.
The clinical algorithm will be adapted to reflect national guidelines for the management of
children 0-59 months of age in primary care. An expert group will be established and consulted in
each country using a Delphi method approach and / or nominal group technique to validate the
clinical algorithm.
The adaptation of ePoct+ will be done using MedAL-C, the back-end software developed by
Unisanté/Wavemind to manage, reference, modify and deploy the different versions of the
clinical algorithm into MedAL-R. Recommendations on use of additional point of care
laboratory and diagnostic test use, such as malaria or haemoglobin, will be incorporated into
the algorithm if routinely available at the targeted health facilities. Before the start of the study,
ePoct+ will be reviewed and validated by national key experts in child health. MedAL-C allows
an interactive visualization of the clinical algorithm and therefore clinicians without any IT
programming skills can modify the decision trees to release a new version of the clinical
algorithm. However, the clinical algorithm will not be updated for the duration of the study,
except for technical reason (patches).
Training
PATH, with input from other collaborators, will develop the pulse oximetry and CDSA curricula,
adapting existing materials (such as Lifebox training materials) to IMCI context using WHO and
national guidelines, specifically including examples of pneumonia and possible serious
bacterial infection. Materials will be pilot tested at PATH HQ, and the next iteration will be
reviewed by the technical working group in each country. The feedback from countries will be
incorporated into the final English version of the pulse oximetry training materials and job aids.
Materials will then be translated into local languages as applicable and back translated to
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ensure accuracy. Training materials and job aids will be printed and distributed to all TIMCI
health facilities in draft form for the pilot phase and pending finalization after the pilot phase.
In collaboration with respective Ministries of Health (MOHs), PATH will conduct training of
healthcare providers in the use of pulse oximetry and use of CDSA. To avoid creating a parallel
program and improve sustainability, PATH will work with each MOH to integrate with existing
training programs. Both India and Tanzania have updated their IMCI guidelines recently to
include changes in pneumonia management and offering outpatient treatment of possible
serious bacterial infection in young infants when referral is not feasible. As of March 2020, the
MOH in both countries is planning, but has yet to conduct, trainings in these updates. Per WHO
curricula, the trainings for these updates include clinical sessions with visits to health facilities to
see real life patients, which is out of the scope of the TIMCI project. To expedite the updated IMCI
training process, PATH may provide financial support to ensure that these trainings are
conducted in TIMCI areas. Trainings will be conducted using a “train the trainers” approach,
leveraging the experience of MOH IMCI trainers. Moreover, supervisors will also be included in
training sessions to equip them for their supportive supervision role.
The pulse oximetry and CDSA training sessions will be interactive, in line with adult learning
principles, and with sessions that allow hands-on practice on the use of the devices. At the end of
the pulse oximetry training session, a post-training written test and one observation of the use
of the pulse oximetry per participant will be used to determine immediate acquisition of
knowledge and skill. If incorrect answers or limited skills were observed, the trainer will
reinforce the correct concepts and provide supportive guidance and encouragement to correct
use of the pulse oximeter. At the end of the CDSA training session, a post-training practical
test based on a set of pre-recorded cases will be used to determine immediate acquisition of
knowledge and skills. Competency evaluation will be extended post-course by asking trainees
to perform a certain number of consultations while using the CDSA and including a minimum
number of classical IMCI conditions.
In the case of staff turnover in TIMCI facilities detected during monitoring visits, PATH in
consultation with the MOH will elaborate a plan for training such new staff either at the facility or
a in a group session elsewhere, depending on circumstances at the time.
Mentorship
As per training, PATH will work with each MOH to integrate pulse oximetry and CDSA use into
existing supervision mechanisms where possible. Supportive supervision for CDSA may
additionally include personalized feedback directly informed by data recorded in the device.
Intensive mentoring / supervision will be conducted following training, and then will be
gradually tapered and fully transferred to government mechanisms.
Community and caregiver engagement
PATH will build on existing relationships with local civil society organisations (CSOs) and
networks active in the child health space, and relevant Ministry of Health community initiatives
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(such as community healthcare provider networks), establishing new collaborations as needed.
PATH will work closely with these CSOs and Ministries of Health to integrate information on
the intervention, and content aimed at encouraging care seeking and following referral
recommendations into their ongoing child health activities.
Additional information materials on pulse oximetry and CDSAs will be provided at intervention
facilities, including multi-media materials or public health nurse talks, depending on
preferences within each country.
6.4 Outcomes
6.4.1 Pilot phase
Progression to the definitive trial will be based on the following outcomes:

80% of healthcare providers adhering to critical steps of the pulse oximetry use
guidelines (combination of WHO and manufacturer guidelines provided as part of
intervention), assessed using the SPA observation in pilot facilities

80% of eligible children recruited

90% of caregivers reachable by phone on Day 7 for outcome assessment
If these outcomes are not met during the pilot phase, the research steering committee will
review and advise on adjustments and progress to the definitive trial.
Furthermore, the following outcomes will be assessed in order to verify sample size
assumptions:

Attendance rate of eligible children per month attending study

Primary outcome proportions in routine care
If a deviation from the original assumptions are substantial, sample size calculations and
recruitment strategies will be reviewed and modified if necessary.
6.4.2 Pragmatic cluster RCT
Two primary outcomes will be assessed in order to improve the ability to detect a difference
between intervention and control arms, given the relatively low occurrence of severe outcomes
at primary care level:

Proportion of children with a severe complication (death or secondary hospitalisation)
by Day 7
o Secondary hospitalisation refers to any delayed hospitalisation (occurring at any
point greater than 24 hours after Day 0 consultation) and any hospitalisation
occurring without referral. The denominator is all enrolled children
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
Proportion of children admitted to hospital within 24 hours of the Day 0 primary care
consultation and as a result of a referral
o This is used as a proxy for ‘appropriate referral’ of children, as those with severe
disease should generally be admitted to hospital. The denominator for this
outcomes is also all children enrolled in the study, rather than only referred
children. This is because the proportion of referred children that are admitted
may be high in routine care, in the context of an inappropriately low referral
rate. The aim of the intervention is therefore to increase the overall referral rate
of children with severe disease. Hospital admission is chosen as the proxy of
severe disease rather than using primary care classification of severe disease, as
there are inadequacies in the classification of severe disease in routine practice
The trial will be interpreted as positive if either primary outcome is positive with no indication of
harm from non-significant outcomes. This will be assessed separately in India and Tanzania and
will also be assessed across the two countries for the sub-group of children presenting with
cough or difficulty breathing.
We anticipate that we will see a greater effect on the ‘appropriate referral’ outcome, given that
increasing detection and referral of children with severe disease is the focus of the intervention,
and that morbidity and mortality among children with severe disease is highly contingent on
quality of care at hospital level, which is not the focus of the intervention. Whilst hospital
admission is still contingent on factors beyond the remit of the intervention (e.g. on caregiver
completion of referral and hospital bed availability), it is not dependent on quality of care
during hospital admission.
Secondary outcomes:

Proportion of children with severe complication (death or secondary hospitalisation) by
Day 28

Proportion of children cured (defined as caregiver reported recovery from illness) at
Day 7 follow-up

Proportion of children referred by a primary care healthcare provider to a higher level of
care (either to a hospital or to an inpatient part of a larger primary healthcare facility) at
Day 0 consultation
Proportion of children who completed referral, as reported at day 7 follow-upOther outcomes
of interest – hypoxaemia (in intervention arms only)

Proportion of children with severe (SpO2 <90%), moderate (SpO2 90 – 91%) and mild
hypoxaemia (SpO2 92 – 93%), adjusted for sites at high altitude

Proportion of children with hypoxaemia (according to differing cut-offs) with severe
complication

Proportion of children with severe hypoxaemia not meeting any other clinical criteria
for severe disease
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
Proportion of children referred with hypoxaemia who receive oxygen at hospital
Other outcomes of interest – referral and follow-up

Proportion of children with non-severe disease referred to a higher level of care on Day
0

Average length of stay (in days) of children admitted to hospital

Proportion of children attending scheduled follow-up at the same facility by Day 7

Proportion of children presenting for unscheduled follow-up to any health facility by
Day 7
Other outcomes of interest – antimicrobial prescription

Proportion of children prescribed an antibiotic at Day 0

Proportion of children prescribed a diagnosis-appropriate antibiotic

Proportion of febrile children tested for malaria at Day 0

Proportion of malaria positive children prescribed an antimalarial

Proportion of malaria negative children prescribed an antimalarial

Proportion of untested children prescribed an antimalarial
Sub-groups for analysis of primary and secondary outcomes:

Age (under 2 months, 2 – 12 months, 13 – 59 months)

Sex

Presentation with cough / difficulty breathing
Other factors for exploratory analyses

Additional sociodemographic characteristics urban / rural location, distance from
health facility, key household indicators such as maternal age and education

Main complaint / symptom categories (including cough / difficulty breathing, fever,
diarrhoea and other) and time since onset of symptoms

Alternative hypoxaemia cut-offs

Healthcare provider severity classification

Facility and health system factors – type of facility, healthcare provider qualification and
previous training
6.4.3 Other mixed methods studies
These studies will mostly be exploratory, particularly the qualitative studies which seek to
understand perceptions, values, attitudes, and beliefs. Process evaluation criteria will be
evaluated according to the MRC criteria.35
Service provision assessments, at baseline and each quarter during implementation, will assess:
adherence to IMCI (or national guidelines) and device guidelines (only in relevant arms),
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including proportion of: caregivers asked about all three danger signs; caregivers asked about
all main symptoms; children with cough or difficulty breathing in whom a respiratory rate is
counted for a minute and (where applicable) in whom a pulse oximetry reading is attempted,
conducted correctly, obtained at first attempt or at repeated attempts; and proportion of
children in whom CDSA is used and recommendations are adhered to. Furthermore,
correctness of classification and treatment (as far as is possible with available information), and
other indices of quality of care will be assessed. Facility and healthcare provider factors
associated with health and quality of care impact and intervention uptake will be assessed.
Facility-based process maps and associated non-participant observational data will be
described and compared between baseline and early and late intervention periods. Time (in
minutes) will be compared (pre, early and late intervention) for total in clinic; in consultation;
and on use of devices, and any other relevant single steps of the care process. Comparison will be
made using mean (if parametric) or median (if non-parametric).
Qualitative enquiry with healthcare providers and caregivers will primarily focus on service
provision, the participant response to the intervention and acceptability of devices, with
exploration of change in perceptions, attitudes and behaviour over time. With caregivers, we
will also explore experience of care and care-seeking behaviour through IDIs, as well as reasons
for lost to follow-up and related perceptions and challenges.
The sub-study of stakeholder perceptions, surveys and project data review will primarily focus
on the processes, mechanisms and context (i.e. process evaluation criteria with focus on fidelity,
dose, reach, context and adaptation) of implementation including adaptations made.
6.4.4 Cost and cost-effectiveness study

Full implementation cost of the intervention per focal country (cost to health system as
well as direct costs paid by the household to the health system)

Cost per child screened using pulse oximetry devices and CDSA where applicable,
compared to cost per child in routine care.

Cost per DALY averted attributed to the introduction of pulse oximetry both with and
without CDSAs modelled on proportions referred to hospital on day zero or by day 7
or requiring secondary hospitalization by day 28 in each arm and the predicted
outcomes in each case, using published literature supplemented where necessary by
expert opinion. We will utilize data on any other severe outcomes and also use
predictors of severity on children who are admitted to hospital.
6.5 Participant timeline
6.5.1 Pragmatic cluster RCT
The study flowchart is presented in Fig. 5. Research assistants will screen and recruit
participants in the waiting area prior to consultation as outlined in Section 10.3. Following
informed consent and enrolment, research assistants (RAs) will record participant name,
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address and contact details (including personal and alternate contacts) for Day 7 and Day 28
follow-up, basic sociodemographic details, reason for attendance and care-seeking. This will
be collected from the caregiver before consultation, except in critical / emergency cases who
will be seen immediately by the healthcare provider. The clinical consultation will be conducted
by healthcare providers who have been advised to use the devices as described above
according to the facility allocation.
After the consultation, the RA will use extract information from the clinical records from the
caregiver (child health card and / or referral note), and / or from clinic ledgers or medical
records. Information will be extracted and recorded on the final diagnosis, oxygen saturation
and results of laboratory investigations (if performed), prescribed medication with dosage,
referral or follow-up advice and the usage of the pulse oximeter device and/or CDSA (if
applicable). Research assistants will seek clarification from healthcare providers in cases where
the diagnosis is not clear from the records.
Caregivers will be offered several options for completing follow-ups at Day 7 and Day 28.
Follow-up will be conducted remotely when possible. For caregivers who can provide a phone
number at the day of enrolment, Day 7 and Day 28 follow-ups will be conducted by phone. If
the initial phone call fails and the phone number is valid, at least three attempts will be made on
subsequent three days at different times of the day to try to reach the caregiver. If the phone
number is not valid, no other call attempts will be made and alternative follow-up options
will be initiated if consented for. Except during the initial phone call, follow-up can be carried
out with a caregiver other than the one who gave consent at the day of enrolment if this
person is able to provide information about the child. For caregivers who cannot provide a
phone number at the day of enrolment, community mechanisms will be relied on to arrange a
call with the caregiver through a community focal person, e.g. a community health worker
(CHW) or a community leader. To this aim, CHWs and community leaders in the targeted study
areas will be asked for their consent to have their phone numbers shared with RAs in order to
contact caregivers without a phone for their Day 7 and Day 28 follow-ups. Independently on
whether they provided a phone number or not, caregivers will be given the alternative option to
consent for in-person Day 7 follow-up that will have to be conducted as soon as possible after
all remote attempts failed. In-person Day 7 follow-ups could be conducted either at the
caregiver’s household or another specified community location.. If Day 7 follow-up has been
unsuccessful, Day 28 follow-up will still be attempted. During both Day 7 and Day 28 follow-
ups, a structured questionnaire will be administered to assess the primary and secondary
outcomes, including details of any government or private hospital admission. In case of non-
recovery, if the child is still at home, the study team will advise the family to return to the PHC
clinic for a follow-up consultation.
Additionally, visit information from government-designated hospital records will be collected
retrospectively for children reported to have attended hospital by the caregiver at follow-up or
referred at day 0 and lost to follow-up including clinical assessment on arrival (vital signs,
admitting diagnosis), admission details (duration, if oxygen was administered, intensive care
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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admission) and admission outcome (final diagnosis, discharge against medical advice, death).
The same data will be collected for children who visit a non-hospital higher-level of care
(emergency or admission unit of a primary or secondary care facility).
It is expected that some participants may present at the same or another health facility enrolled in
the study during the follow-up period. These visits and the findings will be recorded on the
appropriate scheduled / unscheduled visit eCRFs.
Fig. 5. Flowchart of the pragmatic cluster randomised controlled trial. CDSA = Clinical Decision Support
Algorithm. CG = Caregiver. HCP = Healthcare provider. OPD = Out-patient department. Arm 1 not
applicable in India.
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visit
care
visi
Tab. 4. Schedule of the visits and associated CRFs for the pragmatic cluster RCT. Arm 1 not applicable in India. The different types of data collectors are represented by the
following icons:
Facility-based research
assistants
Research assistant rotating
Healthcare
between different referral                         providers
health facilities
Higher level
Health facility baseline
of 
t1,Err
o
r!
Bookmark not
defined.
Call centre-based research
assistant
Scheduled2 or unscheduled visit
at any study facility
Phone follow-up
Time point /
window
Data collection
method
Day 0
Prospective data
collection
Day 0-7
Review of
medical
records /
registries
Day 1 -28
Prospective data collection
Day 7
Phone
interviews
Day 28
[28 - 35]
Phone
interviews
Events
Informed consent
Screening
Full identification
Contact information
Randomization3
Arm I
Arm II
Arm III
Arm I
Arm II
Arm III
Forms
-
TIMCI-01
TIMCI-02a
TIMCI-02b
Identification &
contact information
Socio-demographics
Visit info
Identification and contact
information check
Referral facility
identification
Follow-up identification
check
Care seeking behaviour,
transport and costs for
visiting health facility
reported by caregiver
TIMCI-02c
TIMCI-02d
TIMCI-02e
TIMCI-03
TIMCI-04a
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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Clinical presentation
& medical history
Basic measurements
& physical exams
Respiratory rate &
pulse oximetry
Laboratory
investigations
Visit and admission info
recorded by referral
facility (medical records,
registries)Error! Bookmark not
defined.
Patient journey reported
by caregiver at follow-up
Clinical presentation and
medical history reported
by caregiver at baseline
Medical history recorded
in clinical notes and / or
facility registries
Chief complaints and
medical history recorded
in CDSA
Basic measurements and
physical exams recorded
in clinical notes and / or
facility registries
Basic measurements and
physical exams recorded
in CDSA
Respiratory rate and pulse
oximetry recorded in
clinical notes and/or
facility registriesError!
Bookmark not defined.
Respiratory rate and pulse
oximetry recorded in
CDSAError! Bookmark not defined.
Respiratory rate and
oxygen saturation
recorded at arrival by
referral facilityError! Bookmark
not defined.
Laboratory investigations
recorded in clinical notes
TIMCI-04b
TIMCI-04c
TIMCI-05a
TIMCI-05b
TIMCI-05c
TIMCI-06a
TIMCI-06b
TIMCI-07a
TIMCI-07b
TIMCI-07c
TIMCI-08a
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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Diagnosis & care
management
Follow-up at Day 7
Follow-up at Day 28
and / or facility registries
Error! Bookmark not defined.
Laboratory investigations
recorded in CDSAError!
Bookmark not defined.
Diagnosis and care
management in clinical
notes and / or facility
registries (medical
records, discharge
summaries)
Diagnosis and care
management recorded in
CDSA
Diagnosis and care
management recorded by
referral facility (medical
records, discharge
summaries)
TIMCI-08b
TIMCI-09a
TIMCI-09b
TIMCI-09c
TIMCI-10
TIMCI-11
1 Data will be collected retrospectively for visits at facilities offering a higher level of care, including district hospitals, any study facility receiving referrals or admitting patients. 2
If appropriate for clinical management.
3 Allocation at the level of the facility to intervention or control groups.
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6.5.2 Other mixed methods studies
An overview of the timeline for participants recruited to the mixed methods studies and how
they are embedded in the pragmatic cluster RCT is shown in Fig. 6. In the sub-sample of
children (and their caregivers) selected as part of the SPA, two additional time-points of data
collection will occur – during the consultation (observation), and after their clinical consultation
(exit interview).
IDIs and FGDs with caregivers, and FGDs will take place after the day 7 follow-up phone call.
Fig. 6. Overview of the mixed methods studies and how they are embedded within the pragmatic cluster
RCT. CG = Caregiver. HCP = Healthcare provider. Healthcare provider focus group discussions will group
healthcare providers from different facilities.
Healthcare providers for the SPA will be invited to participate in the interview and consultation
observations at the time of the first SPA assessment at that facility, after information has been
provided to and assent obtained from the facility in-charge. At subsequent assessment rounds,
the SPA team will meet with the in-charge and HCPs briefly, provide information on updates if
required and answer any questions. Prior to participation in the interview or observation,
continued consent will be checked verbally by a member of the SPA team. If the supervisor was
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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not involved in a previous round, they will be fully informed as per the first round, and similarly if
an HCP was not previously recruited, the full written informed consent process will be
adhered to.
Healthcare providers recruited for qualitative interviews or FGDs will be invited for an
interview/FGD from SPA and/or non-SPA facilities. Participants with particularly interesting or
divergent views might be approached from FGDs for follow-up IDIs. The final selection of
stakeholders (outlined in Section 5.7) will be determined during implementation and based on
implementation experience.
6.5.3 Cost and cost-effectiveness study
Facility-based medical and non-medical personnel who provide information for costing will be
approached at a time convenient for them so as not to interfere with clinical or health service
delivery. Information will be provided about the study and consent will be sought for personal
data as outlined in 10.3.3. These providers will be approached pre-intervention and then again
during intervention for data collection, though different providers may be approached in case of
staff rotation.
6.6 Sample size
The estimated sample sizes for each of the studies are described below, but may be revised
during the course of the study. In the case of the RCT, this is due to uncertainty of some of the
assumptions (such as eligibility rate and outcome proportions in routine care, for which data
reliability is a challenge). Final qualitative sample sizes will be determined based on reaching
thematic saturation, i.e. when no new concepts are emerging.
The remaining sample sizes, for SPA, process mapping and time-flow study, have been chosen
pragmatically and will vary according to country depending on the degree of difference in care
processes between facility types and location, whilst allowing for exploratory analysis into more
in-depth aspects of quality of care from baseline to intervention, between the arms, and over
time within the intervention period (both due to changes in implementation uptake and
seasonal variation in burden of disease).
The sample size for the pilot phase will also be pragmatically based on the degree of difference
between facility types and location (and thus the potential need to understand and refine the
intervention strategy according to context), but is likely to include between 2 and 4 facilities
per arm per country.
6.6.1 Pragmatic cluster RCT
The sample size for the pragmatic RCT is calculated separately for each country, based on the
following common assumptions:

power of 80%
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
alpha level of 0.05 per arm

intracluster correlation coefficient (ICC) of 0.00152

control arm severe complication of 1.1% (based on comparable data from a previous
study in Tanzania)30

control arm appropriate hospitalisation of 1.5% (based on estimates from facility staff)

a recruitment period of 12 months
In India, Initial sample size calculation for the three arm trial was based on having the power to
detect a 30% or greater decrease in severe complication and 30% or greater increase in
appropriate hospitalisation for each arm compared to control with 40 cluster per arm. This
assumes average recruitment of 510 children per cluster over the 12 month period, based on
available DHIS2 data summaries and estimates from facility staff for 2019 indicating, with an
average of 110 per CHC per month and 20 children per PHC, assuming that we recruit facilities
with an average ratio CHC : PHC of 1:3. Following the decision, based on the pilot, not to
introduce the CDSA, facilities were reallocated to the remaining two arms up to 60 facilities per
arm.
In Tanzania, we would have the power to detect a 30% or greater decrease in severe
complication and a 30% or greater increase in appropriate hospitalisation for each arm
compared to control with 22 clusters per arm. This assumes average recruitment of 1680
children per cluster over the 12 month period, based on available DHIS2 data summaries and
estimates from facility staff, with an average of 350 children per health centre per month and 70
children per dispensary per month assuming that we recruit facilities with an average ratio of
health center : dispensary of 1:3.
Given the challenges in reliability of routine data in both countries for the assumptions on both
expected eligibility rate and outcome proportions in routine care, we will assess these during
the pilot phase and over the course of the study and make adjustments to the sample size
calculation and recruitment strategy as necessary.
6.6.2 Mixed methods studies
We will conduct the assessment in 6 facilities per arm, stratified by location (district in India,
urban/rural in Tanzania) and facility type, at 5 time points – pre-intervention (whist pilot phase I
is occurring in other facilities), and each quarter over the 12 months of the RCT to capture
seasonal variation in burden of disease and changes to implementation over time. We will also
conduct the SPA at the pilot phase part I facilities to inform intervention refinement.
At each facility at each time point, observation and exit interview assessments will be
conducted over 3 – 10 working days, in order to achieve a sample size of 10 – 30 children per
facility. In smaller facilities with only one provider, the target will be a minimum of 10
observations and exit interviews, whereas in larger facilities, the target will be a minimum of 20
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observations and exit interviews with at least 5 for any single provider. This would result in an
estimated sample size of 600 observations per arm over the study period. Interviews will be
conducted with all consenting healthcare providers responsible for the care of sick children at
the study facility during the first assessment. These will only be repeated if details have changed
(e.g. training updates), or for new staff not present at the first assessment. We estimate around
15 – 30 healthcare provider interviews per arm. The full facility assessment will be done at the
first visit, and only variables which change over time will be recollected at subsequent visits.
We will conduct facility-based process mapping and time-flow assessments in each of the SPA
facilities. One process map (and associated notes on the care process and its rationale or
deviations) each will be developed per SPA facility and control arm facilities, which will be
revisited and revised during early and late intervention phases to reflect changes over time,
resulting in 2 to 3 maps per facility). Process maps will also be developed in the pilot facilities to
inform intervention refinement. Each map will involve informal discussion with 2 – 4
healthcare providers in the facility, and non-participant observation over a period of one week,
during which time-flow data will also be collected (for an estimated 10 – 30 children depending
on facility size).
Final sample size for in-depth interviews (IDIs) with healthcare providers and caregivers will be
determined by reaching thematic saturation, i.e. when no new concepts are emerging, while
keeping the balance to document change over time; sample size estimates are provided below.
IDIs with caregivers: A purposive sample of caregivers will be selected for IDIs including those
who completed referral (and arrived in the hospital within 24 hours) as well as those that did
not adhere to the advice, and those that were not referred. Within these sub-categories,
participants will be purposively selected with varying sociodemographic characteristics such as
rural / urban location, age of caregiver/child, and education. An estimated total of 70-80 IDIs
with caregivers in the intervention arms in each country throughout the entire project are
expected. Approximately 10 – 12 in-depth interviews per intervention arm with caregivers will
be conducted across different time points (pilot, early, mid and late intervention) within one
geographical area of each country. However, if geographical variation in health-seeking
behaviour and outcomes is felt to be significant, fewer time points may be selected in favour of
greater geographical diversity. Caregivers from IDIs will be different from FGD participants. In
Tanzania only, 10 – 15 IDIs will also take place pre-intervention, and possible late intervention in
the control arm should significant changes have occurred in the health system or community
aside from the intervention, for comparison. Further approximately 12-15 IDIs (i.e. 4-6 IDIs with
caregivers defined as lost to follow-up (LTFU) in each geographical area (i.e. region)) will be
conducted as part of a rapid qualitative inquiry.
FGDs with caregivers: If FGDs are carried out, one geographical area will be selected per
country, in which a total of 12 FGDs (3 in urban and 3 in rural location and in each arm) will be
conducted, each with 8 – 12 participants. These will be divided between early and late
intervention. Caregivers for FGDs will be different from IDI participants. Where possible
participants will be divided by age groups and gender as well as number of children.
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IDIs with healthcare providers: An estimated total of approximately 70-80 IDIs in the
intervention arms per country are expected, allowing to document change over time. This will
include approximately 10 – 12 IDIs with healthcare providers per intervention arm at different
time points (pilot, early, mid, late intervention) and by age of children they have consulted
purposively selected from facilities (during later intervention also from facilities with divergent
implementation) and by age of children they have consulted. Where possible, some healthcare
providers will be interviewed repeatedly over time. In Tanzania only, 10 – 15 IDIs will also take
place pre-intervention, and possibly also late intervention in the control arm should significant
changes have occurred in the health system or community aside from the intervention, for
comparison.
A total of up to 12 FGDs with healthcare providers will be conducted per country, with 6 – 8
participants per group.
Healthcare providers at SPA and non-SPA-facilities may be invited for IDIs and/or FGDs, with
purposive sampling of early and late adopters at a later stage of data collection during the
intervention.
KIIs with stakeholders: A total of approximately 20 key-informant interviews may be carried
out, split between early and late stages of the project. This will include approximately 3-6 KIIs at
global and 10-12 KIIs at national level at different time points (between pilot, early and late
stages) of the project. In Tanzania only, 10 – 15 KIIs will also take place pre-intervention, and
possibly also late intervention in the control arm should significant changes have occurred in
the health system or community aside from the intervention, for comparison. The final selection
of type and number of different types of stakeholders (outlined in Section 5.7) will be
determined during implementation, based on implementation experience.
6.6.3 Cost and cost-effectiveness study
Cost data will be collected from eight facilities per country (4 urban and 4 rural; 4 dispensaries
and 4 health centres in Tanzania, and 4 PHCs and 4 CHCs in India). The senior administrative
staff member at the facility will be interviewed to obtain the majority of the unit cost data, and
the senior medical staff member to obtain information on time allocation of front-line staff
(time seeing patients, time in supervision etc).
6.7 Recruitment
To reach the required sample size, and to ensure data collection across different seasons, it is
estimated that recruitment for the definitive trial will take place over 12 months (with prior 3
month pilot phase). As we intend to validate eligibility and recruitment rate estimates in the
pilot phase, we will either recruit additional facilities or slightly increase the study duration if
necessary. If recruitment rates change over the study period, we will consider adding facilities if
extension of the study duration is not possible.
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Child and caregiver participants will be recruited for the SPA and time-flow observations on
the relevant study assessment days consecutively until the sample size requirements detailed
above have been met. Children and their caregivers will be enrolled to these studies at the
same time as they are enrolled to the RCT. Longer assessment periods will be required for low-
volume facilities. All healthcare providers providing care for children under 5 years of age and
present at facilities during SPA assessments will be invited to participate in the SPA interview.
Participants for qualitative studies will be recruited as follows:
Caregivers for IDIs and possibly FGDs will be selected based on pre-defined queries (e.g. based
on information from the RCT database) after Day 7 follow-up has occurred in order to identify
potential participants within a selected geographical area. During the call, caregivers will be
asked for their verbal assent to be contacted by a person responsible for the recruitment of
participants for qualitative studies. Of those caregivers, who agreed to be contacted, a list will be
generated for the recruiter with basic sociodemographic details (divided into referred and not
referred for IDIs) of double the number of participants required (to allow for unreachable
participants or refusals to participate) for the time point in question. The qualitative researcher
will then contact participants (i.e. by phone) to arrange interviews or focus groups. If
recruitment with this strategy proves challenging, individuals may be approached directly at
facilities to arrange a follow-up in the community after 7 days or at the community level (i.e. by
a community health worker).
A pool of caregivers defined as lost to follow-up (i.e. those not reached on Day 7 follow-up
call) from a pre-defined time period will be established based on pre-defined queries (e.g.
based on information from the RCT database). Caregivers will be stratified by pre-defined
criteria (e.g. no phone number; invalid phone number; not able to be reached etc.) and
purposively sampled. A list will be generated for the recruiter with basic socio-demographic
details of double the number of participants required (to allow for unreachable participants or
refusals to participate) for the time point in question. Community Health Workers (CHWs) or a
person responsible for the recruitment of participants for qualitative studies will approach
selected caregivers at the household level, provide a short explanation on the reason for their
visit and ask for their verbal consent to participate in an IDI. If caregivers agree, the qualitative
data collector or person responsible for recruitment of participants for qualitative studies will
be called and an appointment scheduled.
Healthcare providers from study facilities will be invited to participate in the studies by the
person responsible for the recruitment of participants for qualitative studies. A pool of
healthcare providers based on pre-defined queries (e.g. with information received from the
PATH training log, M&E data and through RAs at TIMCI facilities) will be established. Healthcare
providers will be stratified by pre-defined criteria (e.g. cadre, age, age of children consulted,
sex, years working in profession etc.) and a purposive sample of HCPs established of double
the number of participants required (to allow for unreachable participants or refusals to
participate) for the time point in question. The qualitative researcher will then contact
TIMCI RCT Protocol v0.2.4, 2nd Feb 2023
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participants (i.e. by phone) to arrange for an interview appointment or possibly focus group
discussion appointments.
Some of the same healthcare providers invited to participate in the FGDs and IDIs will be re-
invited over time. After initial implementation, a pre-defined list of variables (e.g. from the RCT
study) will be used to classify healthcare providers into early and late adopters of the
intervention; and change in uptake over time. This will help to inform the focus of the
qualitative inquiry over the implementation period. However if the recruitment process proves
challenging due to staff rotation, clinical commitments or research fatigue, a broader range of
healthcare providers will be approached from both SPA and non-SPA facilities.
Recruitment of healthcare providers in the pre-intervention / non- / pilot / early intervention
phase: Where only one healthcare provider is present at the facility s/he will be invited. If more
than one healthcare provider is working at the same facility a purposive selection will be made,
based on a variety of sociodemographic factors to ensure a diverse sample (as outlined above).
Recruitment of healthcare providers in the mid/late intervention: Healthcare providers may be
purposively selected from facilities with divergent implementation. Divergent implementation
will be identified as described above. Additionally, providers may be purposively selected based
on the age of children consulted.
Stakeholders will be purposively selected with a focus on a diverse sample presenting the
different levels of implementation (global, national, regional and local level) as well as their
level of direct involvement in the project. Stakeholder mapping will be conducted to identify
potential participants internal and external to the project. All pre-selected key stakeholders
will be invited by the research assistant to participate in the study. The same respondents will
be invited over time. If the recruitment process proves challenging (e.g. due to staff rotation)
the same principals as with healthcare providers apply. Further details are outlined in Section
5.7 of the protocols on the type of stakeholders that will be invited to participate.
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7 Assignment of intervention
7.1 Allocation
7.1.1 Sequence generation
The allocation sequence will be generated by a statistician, independent from the study, for all
eligible facilities per country, stratified by facility type and location (urban/rural location in
Tanzania, district in India). The target number of facilities will be randomly selected from all
eligible facilities and allocated to the trial arms. The remaining eligible facilities will be retained in
a back-up list for later allocation (using the same procedure) should the need arise (e.g. in case
of facility exclusion at study start, or in case of need to add additional clusters in the event of
recalculation of sample size).
7.1.2 Allocation concealment mechanism
Given the cluster design, concealment will occur only at the stage of allocation of facilities,
which will be conducted centrally and distributed to study sites.
7.1.3 Implementation
Participants will be allocated to the intervention based on the facility they attend.
7.2 Blinding
Data for outcome ascertainment will be collected by phone by a research assistant blinded to
the trial arm and the facility the child attended.
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8 Data collection, management and analysis
The data used within the TIMCI project are described in Tab. 5. Primary research data will be
generated in study and pilot facilities through case report forms, questionnaires, interviews,
focus group discussions and surveys. In addition, relevant routine data will be extracted for all
intervention facilities (i.e. including those in which primary research data will not be collected).
This will include individual consultation data recorded in the CDSA for clinical purposes and
aggregate facility data that are reported to the national HMIS.
Tab. 5. Summary of the data used within the TIMCI project. CDSA = Clinical Decision Support Algorithm.
MedAL-R is the front-end application developed by Unisanté/Wavemind (Lausanne, Switzerland) to
implement ePoct+, the clinical algorithm. EDC = Electronic Data Capture. FGD = Focus Group Discussion.
HMIS = Health Management Information System. IDI = In-Depth Interview. KII = Key Informant Interview.
RCT = Randomized Controlled Trial. SARA = Service Availability and Readiness Assessment.
Ref
1.1
1.2
2.1
2.2
2.3
Methodology
Routine data
Pragmatic
cluster RCT
Service
provision
assessment
Facility-based
process
mapping and
time-flow
study
Healthcare
providers’
acceptability
and
Data
collection
CDSA
individual
consultation
data
Aggregate
facility data
Pragmatic,
parallel group,
cluster
randomised
controlled
superiority
trial
Modified
demographic
and health
survey
Process map
Time-flow
study
Semi-
structured in-
depth
interviews
Tool
MedAL-R with
ePoct+
National HMIS
Electronic case
report forms
(EDC platform)
Facility
assessment
(modified
SARA
questionnaire)
Healthcare
provider
interview
Sick child
observation
protocol
Structured exit
interview
Process map
tool
Time-flow tool
IDI tool for
healthcare
providers
Data format
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Abstract
Textual,
numerical,
categorical
Audio,
Textual,
numerical,
categorical
Data
origin
Primary
Secondary
Primary
Primary
Primary
Primary
Primary
Primary
Primary
Primary
Data
classification
Sensitive
personal
Non-
personal
Sensitive
personal
Non-
personal
Sensitive
personal
Sensitive
personal
Sensitive
personal
Non-
personal
Sensitive
personal
Sensitive
personal
Data
reuse
1.2
2.5
1.2
2.1
2.5
2.1
2.2
2.3
2.4
2.5
2.5
2.5
2.5
2.5
2.5
2.5
3.1
2.5
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2.4
2.5
3.1
perceptions
of the
intervention
Caregivers’
perceptions
of the
intervention
and health-
seeking
behaviour
Stakeholder’s
perceptions
of the
intervention
and project
data review
Cost and
modelled
cost-
effectiveness
Focus group
discussions
Semi-
structured in-
depth
interviews
Focus group
discussions
Semi-
structured in-
depth
interviews for
rapid
qualitative
inquiry
Key informant
interviews
Survey for
stakeholders
Project data
review
Cost analysis
Modelled
cost-
effectiveness
FGD tool for
healthcare
providers
IDI tool for
caregivers
FGD tool for
caregivers
IDI tool for
caregivers
KII tool
Online survey
tool
Document
review matrix
Medical
personnel
questionnaire
Non-medical
personnel
questionnaire
Hospital costs
Audio
Textual,
numerical,
categorical
Multimedia
(audio,
drawings),
Textual
Numerical
Multimedia
(audio, video-
/photo-
documented),
Textual,
numerical,
categorical
Multimedia
(audio),
Textual,
Numerical
Audio
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Primary
Primary
Primary
Primary
Primary
Primary
Secondary
Primary
Primary
Primary
Secondary
Sensitive
personal
Sensitive
personal
Sensitive
personal
Sensitive
personal
Sensitive
personal
Sensitive
personal
Non-
personal
Sensitive
personal
Sensitive
personal
Non-
personal
Non-
personal
2.5
2.5
2.5
2.5
2.5
2.5
N/A
2.5
3.1
2.5
3.1
2.5
3.1
2.5
8.1 Data collection methods
Quantitative research data for the pragmatic cluster RCT and mixed-method studies will be
collected using a secure third-party cloud based electronic data capture (EDC) platform that
meets research / ethical standards. CDSA routine individual consultation data will be extracted
from MedAL-R, a software developed by Unisanté/Wavemind (Lausanne, Switzerland) to
implement the clinical algorithm (ePoct+), while HMIS aggregate facility data will be extracted
from the national HMIS, following MoH approval. Qualitative data will be collected using both
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EDC, audio recordings, photo documentation and video recordings (method acting), and hand-
written paper notes and drawings. GPS data will be collected using a mobile device.
8.1.1 Pragmatic cluster RCT
For each participant enrolled in the pragmatic cluster RCT, data will be captured in the different
study arms according to the different assessments and Case Report Forms (CRFs) described in
the visit schedule displayed in Tab. 4. A description of the variables collected in each CRF are
available in appendix.
Health facility visits
Quantitative research assistants will use an EDC mobile application to enter the research data of
enrolled participants. The quantitative research assistant will collect from the caregiver
screening information, information on care seeking behaviour, transport and costs, and clinical
presentation and medical history. A number of in-depth sociodemographic and household
variables will also be collected either as surrogate measures of household wealth, or known to
be associated with health-seeking behaviour and / or child mortality (including maternal
education). Household wealth indicators were selected from DHS and other surveys in the
study countries as those which best estimate wealth index that can be directly collected from
the mother / caregiver and with a reasonable time vs. reliability trade-off. Data on laboratory
investigations (if performed), final diagnosis, prescribed medication, referral or follow-up
advice will be extracted from clinical notes and / or facility registers and/or frompaper-based
clinical information forms designed for the TIMCI (only in India, where registry information is
often incomplete). Quantitative research assistants will seek clarification from healthcare
providers only in cases where these variables are not clear from the records. Personally
identifiable information (PII), including participant’s name and date of birth, as well as
caregiver’s phone number and physical address, will be collected for linking data and detecting
possible duplicates and carrying out the study follow-up.
In the two intervention arms, information on oxygen saturation will be collected as recorded in
clinical notes and / or facility registers. Pulse oximeter device savings will be cross-checked by
quantitative research assistants at the end of the consultation where possible. In the pulse
oximetry plus CDSA arm, the research data of participants enrolled in the study will be linked
with their CDSA consultation data.
Follow-up
Quantitative research assistants will conduct the phone follow-up interviews using an EDC
mobile application. Personally identifiable information (PII) will be used for contacting
caregivers. No time window applies to Day 7 follow-up. A window of +7 days applies to Day 28
phone call attempts (Day 28 to Day 35).
Data that will be collected at Day 7 follow-up will include cure status (recovery from illness as
reported by the caregiver), death and hospitalization information between Day 0 and Day 7 as
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reported by caregivers. The primary outcomes on the proportion of children with severe
complications by Day 7 and on the proportion of children admitted to hospital within 24 hours of
the Day 0 primary care consultation as a result of a referral will be assessed based on Day 7
follow-up. Hospital name, duration of hospitalization and reason for admission will be collected
for children reported to have been hospitalized to facilitate the retrospective data collection at
referral hospital level.
Data collected at Day 28 follow-up will include death and hospitalization information as
reported by the caregiver. The secondary outcome on the proportion of children with severe
complications at Day 28 will be assessed on the basis of this interview.
Higher level of care visit
Data collection will be conducted retrospectively at all government-designated and private
referral facilities within the study area, including hospitals or emergency / inpatient area of
larger primary or secondary care facilities (e.g., study facilities that can admit paediatric
patients). A quantitative research assistant using the EDC mobile application will collect data
from referral facility records, registries and discharge summaries to document hospitalization
for all children reported to have been hospitalized between Day 0 and Day 7. Personally
identifiable information will be collected to cross-check the identity of the patients. Arrival date
and time, basic clinical information on arrival and, if admitted, admission and discharge
diagnosis, and admission duration and outcome will be collected. If available, data on oxygen
saturation at admission, oxygen administration and intensive care unit (ICU) admission and
duration will also be recorded.
8.1.2 Routine data
CDSA individual consultation data
As part of the CDSA intervention, healthcare providers will be asked to use MedAL-R during
their consultations. When they do so, they will routinely enter all data necessary for the clinical
management of children 0 – 59 months of age into MedAL-R. Data used within TIMCI will cover
clinical presentation (including symptoms and dangers signs), medical history (including HIV
and TB status if known), all physical exams and measurements relevant for clinical assessment
(including pulse oximetry), and laboratory investigations. Automated recommendations from
CDSA on diagnosis and child management will also be collected, as well as healthcare
provider’s agreement or disagreement with these recommendations and possible additional
diagnoses and treatments, which will be manually entered. A description of the variables
extracted from CDSA is available with other individual data in the appendix.
HMIS aggregate facility data
HMIS data will include the total number of outpatient consultations – for all patients and for
children 0 – 59 months of age (disaggregated by new and follow-up visit if possible) –, disease
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burden, and any other relevant indicators if available (such as referral rate or mortality rate),
disaggregated by age and sex if routinely collected with this granularity.
8.1.3 Other mixed methods studies
Some data required for the SPA (observation and caregiver exit interview) are common with
the pragmatic cluster RCT data and will not be collected again. To reconstruct the full SPA
dataset, SPA observation and caregiver exit interviews will be linked with the pragmatic cluster
RCT as described in Section 10.4.3. The consultation observation will be conducted by a
standardised clinical observer who will record information asked or provided by the healthcare
provider and / or caregiver during the consultation on key aspects relating to adherence to
IMCI (or national guidelines) and the use of pulse oximetry and CDSA (in applicable arms). The
observer will not ask any questions directly of the caregiver, but at the end of the consultation
will ask a limited number of questions of the healthcare provider to record diagnosis and
management.
In line with the WHO guidance on Ethical Issues in Patient Safety Research, observers in
Tanzania (deemed to have sufficient experience and expertise) will be advised to intervene in
the consultation only in the event that they witness an error, or suspect an imminent error,
during the consultation that is “highly likely to result in direct, severe or irreversible harm” and
could be mitigated by their intervention. Should they intervene, the observer will record the
intervention in the sick child observation protocol instrument. No information on individual
performance will be shared with supervisors, or anyone else. However, in order to mitigate the
ethical issues of non-intervention when poor performance has been observed, observers in
Tanzania will provide a short supportive feedback to the individual providers if they agree to it at
the end of the period of observation. This will be structured in line with supervision
procedures of respective MOHs. Feedback provided will be recorded.
In India, observers will not intervene or provide feedback as they are deemed not to have
sufficient experience or expertise.
The exit interview will be performed after the consultation by a non-clinical research assistant
who will record responses to questions on additional sociodemographic and clinical details
and experience of care. The healthcare provider interviews will collect information from
healthcare providers involved in the care of children 0 – 59 months, on qualifications, in-service
training and experience related to child health and pulse oximetry and experience of the
working environment. The facility assessment will focus on the basic infrastructure, staffing,
services, diagnostics and medicines relevant to child health, with additional information
collected on pulse oximetry, records and reporting and management. At the end of the SPA
assessment at the facility, the clinical observer and research assistant will note down additional
(prompted) summary observations about the use of pulse oximeter and / or CDSA in the facility.
For the process mapping and time-flow study, pre-drawn, country-specific process maps will
be reviewed and modified by research assistants with informal input from facility staff and
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observation. Time data will be recorded using an individual follow-through (timing one child
from arrival to exit) and/or area-based (waiting area timing, consultation timing, further
diagnostic timing, etc.) approach. Notes based on non-participant observation will be taken by
research assistants on observations within the facility (e.g. if devices are not charged, waiting
rooms are crowded, the type of interactions between patients and providers, change in
provision of care (e.g. new triage system introduced)) and will not include any individual patient
data.
If FGDs are conducted, they will be facilitated by a moderator and have an assigned note taker (in
charge of documentation). Prior to moving to the main topics of discussion, ice-breaker
exercises will be used to establish trust with participants and to provide an overview of the
topic for discussion (pulse oximetry with or without CDSA). The FGDs with healthcare providers
(and possibly caregivers) will use clinical vignettes which will be presented and jointly
discussed.
Qualitative data from IDIs, and KIIs will be collected by trained qualitative research assistants
using a voice recorder, , in addition to paper-based notes and drawings. Interviews will be
conducted using a semi-structured guideline interview tool, with emphasis placed on building
trust and using open-ended questions with probes.
Key-informant interviews with stakeholders will either be conducted in-person or via
telephone/Skype/Zoom. Interviews will be scheduled and interview questions shared in
advance if wished. Surveys (using an online survey tool such as Survey Monkey) for selected
stakeholders will be sent out on a regular basis (quarterly) via email. Participants will be asked to
answer the questions and upload additional documents. A single reminder will be sent in case
no response was received. Documents will be requested from partners on a quarterly basis;
a desk-review will be conducted and data entered into a document matrix.
8.1.4 Cost and cost-effectiveness study
Cost data collection will occur in all arms as shown in Fig. 3.
Definition of costs using an activity-based approach
An activity-based approach will be explored using available cost data. Specific activities in the
intervention will be allocated to different cost centres. In order to provide cost estimates that
will be as managerially-, policy- and programmatically-relevant as possible, the cost analysis
will adopt this approach as this separate research costs from the main programme
implementation costs. The focus will be on those costs that are expected to change with the
introduction of pulse oximetry and CDSAs. Costs including utilities and large equipment costs
will remain the same with or without the introduction of pulse oximetry and CDSAs.
To apply the activity-based approach, we will identify specific activities that are to be costed.
These will be referred to as “cost centres” (See Tab. 6). Cost centres are a way in which the
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resources used to produce the intervention activities—and the costs of those resources—are
grouped. Cost centres are defined in such a way that:
     The sum of the cost centres is comprehensive—including all the resources used to
produce each and every activity of the program—and together, the entire program, and

They are mutually exclusive—thus avoiding double counting any of the resources used
to provide the program.
It is important to note that this cost methodology is not comprehensive. As described in 5.8, it
does not include the indirect costs incurred by the consumer (patient) e.g. the caregiver’s time or
transport costs. Rather, it focuses exclusively on the provider’s direct costs, whether borne by
the health system or paid out of pocket by the patient’s household. The cost resources for each
cost centre may differ between Tanzania and India according to availability of services.
Tab. 6. Activity-Based Cost Centres of the TIMCI programme.
1
Training cost for staff involved in delivering the programme:
-
Consumable costs (including where applicable stationery, and other consumables) -
Personnel costs
-
Overhead costs (including where applicable, rent for training venue, administrative
costs, per diems and transport costs, and other overheads)
2
Delivery of intervention
-
Annualized1 fixed/equipment costs (including pulse oximetry device and CDSA tablet
costs)
-
Consumable costs (including medicines, diagnostic tests, and other consumables) -
Personnel costs
5
Out of pocket costs
-
Any out of pocket costs paid by patients’ households to the health system to access
care and prescribed treatment will be collected, including resources purchased outside
the facility due to unavailability in the facility. However, care not prescribed by facility
healthcare professionals will not be included.
1. Since costing needs to account for both capital and recurrent costs, annualizing capital costs (i.e.
calculating the annual value of a capital item) is the easiest way of combining capital and recurrent
costs meaningfully. Annualizing capital cost is based on three pieces of important information: the
initial purchase price of the item, its expected useful life, and a discount rate
Sources of cost data
Personnel and procurement units of the organisations involved in the TIMCI intervention
especially through different local PATH offices and sampled facilities will be sourced for the
cost data. Centrally available databases will be used to estimate personnel and consumable
(including medicines and diagnostics) costs where available.
Start-up costs which will include training and community sensitisation costs will be collected
pre facility enrolment and intervention. After facility enrolment, cost data will be collected from
non-medical administrative personnel. All personnel costs for those involved in each arm of
the intervention will also be collected since time in supervision, time of administrative support
staff is as important as that of front-line staff seeing patients. Personnel time, and volumes of
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Recurrent
diagnostic tests and treatments prescribed, will be obtained from the time-flow and service
provision assessment studies. Data on time required for supervision and administrative tasks
such as taking patient notes will be obtained from the senior medical professional at the facility,
along with information on grades of personnel. Salaries of personnel according to grade will be
sourced from centrally available databases which would include government salary
publications for health facility workers (medical and non-medical) and complemented with
salary costs sourced from health facility administrative databases where needed. Costs of
consumables will also be sourced centrally where available and would for instance include cost of
items on the National Essential Medicine List. Referral and hospitalization costs will be
sourced from interviewing senior administrative personnel at referral health facilities.
Total programme cost and cost per child will be estimated. We will collect administrative data
from appropriate levels in each country depending on organization of the specific health
system, and will use time-flow data collected elsewhere in the project before and after the
intervention.
The table below lists the broad areas of cost data collection for each cost centre and the
respective data sources.
Tab. 7. Sources of cost data
Type of Cost
Personnel (staff)
Consumables
Equipment/
Capital
(incurred every
few years)
Out of pocket
costs
Identification
Categories
All staff involved
(field workers
and managers,
administrators,
support staff
(drivers), etc)
Disposable
items usedper
child per
intervention
Pulse oximetry
devices, tablets
etc
All out of pocket
costs paid by
patients’
households to
the health
system for fever
management
Measurement
Costing
method
Percentage of
time spent on
different
activities
within TIMCI;
grade of
personnel
Quantity of
consumables
used per child
Annualised
cost of items
Direct fees
and charges
paid by
households to
health
systems
Sources
of
data
Time data
collected by
operational
research
Medical
personnel at
health facility
Interview,
observations,
and timing
Cost borne by
households
Valuation
Valuation
methods
Gross
remuneration
package costs
Market prices
Replacement
prices
Financial cost
Sources
of
data
Centrally from
government
databases and
complemented
with provider’s
payroll
department
Centrally from
government
databases and
complemented
with provider’s
procurement
department
Provider’s
financial
syndicate
office
Cost data
collected form
health system
administrative
records;
information
from interview
of senior non-
medical
personnel
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Definitions of types of costs and data to be collected
Staff time: For each activity within TIMCI, the responsible staff member involved with the
activity will be identified. Secondly the time involved will be ascertained from the time-flow
study and quantified. Supervision costs will similarly be estimated.
Consumables: The type and quantity of medicines, diagnostic tests and consumables used for
each intervention arm will be identified. In addition, unit costs of each consumable item will be
obtained (for example the cost of a box of cotton wool balls) and the size of unit (the number of
cotton wool balls in each box).
Equipment: All equipment used for each activity will be identified and the price for which it
was purchased. For the equipment costing, the lifespan for the equipment (usually between 3 –
5 years for smaller items including electronic tablets and pulse oximetry devices) will be
obtained and annualized. Annualization will follow the cost recovery methodology where item
cost, life span, and a defined interest rate is used to estimate the annual cost of an item. For
equipment that is shared with other programmes, the time spent per consultation will be
obtained as a percentage of total time spent using each equipment and used to calculate the
cost associated with the intervention after annualization. For donated equipment, market price
information will be sought.
Equipment inventories and training records will be used to collect retrospective costs. Time
spent by staff on consultations with children 0 – 59 months of age will be collected from data
obtained in the time-flow study. Time costs will then be determined by combining staff annual
salaries obtained from government sources and/or payroll offices with time spent per
intervention. Where applicable, this personnel cost will be disclosed only to the principal
researcher without the identity of staff involved. Consumables used will be examined to
determine the unit cost of each consumable, while equipment will be annualized to determine
their unit costs.
All capital and start-up costs will be annualised using an appropriate length of life and discount
rate. Out of pocket payments to health systems borne by households will be estimated to
capture all health system costs. These costs might vary across different settings since there
might be flat rates in one setting and a varied fee schedule in another. Hence, the cost data
collection for out of pocket payments will be country specific. The cost of hospital referrals
where applicable, will also be estimated from interviews with senior healthcare professionals at
the hospital level.
8.2 Data management
All data management procedures will be further described in the Data Management Plan
(DMP).
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8.2.1 Data flow, storage and transfer
The data management system will process and combine two main data flows: the research data
flow, which will be managed by a secure third-party cloud based EDC platform, and the routine
consultation data flow, which will be managed by a customized Server (Unisanté/Wavemind,
Lausanne, Switzerland). As illustrated in Fig. 7, there will be separate secured databases with
restricted access rights for storing and processing CDSA consultation data that are necessary
for all research operations, and (possible) linking between the different databases.

Study databases – These databases will contain de-identified quantitative research
data collected in study facilities. Unless specified otherwise per country requirements
in the DMP, these databases will be hosted on a device owned and maintained by the
country research partner.

CDSA consultation database – This database will contain routine consultation data
extracted from CDSA in all intervention facilities. CDSA consultation data from study
facilities will be de-identified, i.e. a link will exist between these data, the pragmatic
cluster RCT database and the identification database. There will be no such link for
CDSA consultation data from non-study facilities, which will then be fully anonymised.
Unless specified otherwise per country requirements in the DMP, this database will be
hosted on a device owned and maintained by the country research partner.

Identification database – This database will contain PII collected in study facilities. It
will be kept under strict operating procedures, in particular it will not be shared or
accessible outside of the country. The database will be used for generating follow-up
call logs and random selection of a purposive sample of caregivers for qualitative
studies. It will also be used for flagging possible duplicates in children enrolled in the
pragmatic cluster RCT.

Mapping database – This database will be used for linking data from the study
databases and the identification database. Each table will be maintained confidential
under strict operating procedures for the duration of the study. The mapping between
databases will not be shared or accessible outside of the research institution. When all
data validation and regulatory requirements have been met, the mapping database will
be destroyed, so that all the study databases and CDSA consultation database are
ultimately fully anonymized and independent from each other.
In addition, qualitative study repositories with restricted access rights will store raw (audio-
recordings, notes, drawings, photos, videos, GPS coordinates and document review grids) and
processed (transcribed, translated and coded) labelled qualitative material. Unless specified
otherwise per country requirements in the DMP, these repositories will be hosted on a device
owned and maintained by the country research partner.
A data transfer agreement will be requested from the national competent authorities for
providing access to and sharing a full copy of the de-identified study databases, de-identified
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consultation database and de-identified qualitative material with the core team at Swiss TPH. A
subset of these database will be additionally shared with UoW as needed for the cost and cost-
effectiveness study. Following approval from the national competent authorities, the copies
will be stored on servers hosted in Switzerland / Canada. Data ownership will remain with the
country research partner. After study termination or premature termination of the study, the
de-identified databases and de-identified qualitative material will be archived by the country
research partner in accordance with national laws. The shared copies will be archived for 10
years by Swiss TPH and UoW, unless otherwise stipulated by the applicable legislation. Research
partners will archive study data according to the applicable national regulations. After the
mandatory retention period has ended, a periodic review will check if data storage is still
needed for research purposes. If not, the study data will then be deleted. All repositories,
databases and related software files will be backed up by the administrator in conjunction with
any updates or changes.
Fig. 7. Overview of the research data and consultation data flows and supporting IT architecture used
within the TIMCI project. MedAL-R can receive updates directly from MedAL-C to be able to deploy
patches as needed. The MedAL-C server is hosted in Switzerland and managed by the IT Unisanté team in
Lausanne. This server will receive connection logs from the tablets when a network access is available.
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8.2.2 Data entry, handling and validation
Quantitative research data
The EDC mobile application will perform offline validation (e.g., range and consistency) checks
that immediately detect and request the correction of erroneous data entry, and prevent
missing values upon compulsory data entry, guaranteeing completeness of the mandatory
datasets. Standardized dictionaries such as SNOMED CT and ICD-10 will be implemented
within the data collection tools (and hence available offline) in order to code clinical findings
and symptoms in a consistent way. To ensure the integrity of the study-related duties and any
data generated, each quantitative research assistant will log into the EDC mobile application
using their secure user name and password. All passwords will be strictly personal and
confidential. Electronically signed data from the mobile application will be regularly
synchronized with the central server.
Procedures for cleaning and coding quantitative data will be developed by the core data
manager at Swiss TPH to ensure consistency across countries. These procedures will be further
described in the Data Management Plan. Data cleaning and coding activities will be supervised
by the data manager in charge in each country, with possible country-specific additions. These
activities will include, but will not be limited to, data de-identification, duplicate management
and free text management. Data quality checks will be run on a daily basis. A follow-up log
based on baseline visits and referral facility log based on Day 7 phone follow-up outputs will be
generated daily. The server will certify the integrity of data by using in-built range and
consistency checks to prevent errors during data manipulation.
An audit trail will be maintained for the life of the study for all quantitative research data. If a
correction is required for an entry, the time and date stamps will track the person entering or
updating entry and creates an electronic audit trail. There will be access control on the audit
trails so that a user cannot view information about another user or site that they are not allowed
to see. A synthetic visualization of the audit trail will be readily accessible by the data manager in
charge in each country, so that they can check all modification to data and meta-data and who
made them, as well as all successful and attempted system logins. At critical junctures of the
pragmatic cluster RCT, the research database will be reviewed and cleaned per established
procedures, before being locked. Consistency between the data cleaning procedures in each
country will be regularly reviewed. In addition, a dashboard will be developed for facilitating
the review of key indicators to trigger in-depth data review.
CDSA individual consultation data
Each patient attending an intervention facility will be given a unique identifier in the CDSA used
by this facility. Each new visit at the same facility will create a new case for the patient. Similar to
EDC mobile application, MedAL-R will perform offline validation checks and relies on
standardized dictionaries code clinical findings and symptoms in a consistent way. MedAL-R
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will allow the modification of consultation data by different healthcare providers within the
health facility until the case has been closed to ensure the flexibility required by the clinical
workflow. Routine consultation data from MedAL-R will be regularly synchronized with the
CDSA server. Consultation data records will be electronically signed before being transferred to
the central research database. A timestamp (date, time, device identifier number) will
guarantee the integrity of the data associated with the electronic signature.
In non-study facilities, CDSA consultation data will be anonymised before transfer, so that no PII
will leave the facility and these data can never be re-associated with the underlying
individual.
Qualitative research data
Qualitative data will be voice recorded and complemented by written notes, drawings, photos
and videos by a dedicated qualitative researcher. Audio-recordings, notes, drawings, photos,
videos, and GPS coordinates and document review grids will be either written up in electronic
files and/or directly transferred to the qualitative researcher’s computer and uploaded to the
central server. Electronic files will be stored on two separate password-protected devices
according to country specific mechanisms (e.g. audio recording stored on a password
protected computer and on an external drive in a password protected folder in locations where
internet cannot be accessed; back-up on server as soon as internet is available and deleting
from external drive).
Qualitative research data will be backed up at the first possible opportunity. Where connectivity
to the central server is not possible, field teams will make a second back up on an encrypted
external hard drive. Transcription and translations from voice recordings and hand-written
notes will be entered into Word documents and translated into English and/or French. Hand-
drawn process maps and health care seeking pathways will be digitalized.
8.2.3 Data privacy protection
Personally identifiable information will be maintained confidentially under strict SOPs,
complying with all applicable international regulations. Study team members with access to PII
will sign a confidentiality agreement prior to collecting or accessing any of the data. Each
participant will be given a different unique alphanumeric identifier for each study in which
he/she is associated. Voice recording files and written notes that refer to the same participant
interview will be labelled using the same identifier. The IT infrastructure will provide password
protected devices, laptops with encrypted hard drives, fileserver with customizable access
rights, and documented and audited access right management. All transfer of data via the
internet will be done via secure, encrypted connections.
All quantitative data collection instruments will be stored in closed, locked file cabinets with
restricted access. The EDC platform will be encrypted and password protected. All study
databases will be safeguarded against unauthorized access by established security procedures. A
double coding procedure will ensure that participant re-identification is not feasible. The
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name of the facility of enrolment, geographic information and some elements of dates related to
facility visits will also be de-identified. To further prevent re-identification of individuals
(patients, caregivers and healthcare providers), where appropriate, data will be de-identified so
that their level of granularity that does not allow indirect identification of an individual. In
addition, the data imported from another study datasets will be processed (e.g., aggregated
data, categorization of numeric values) so that a unique combination of facility and individual
characteristics does not allow indirect identification of an individual.
Voice recordings, photos and videos, as well as GPS mapping, will be deleted from the devices
after transcription, translation and digitalization. Transcriptions and translations of audio data,
typed-up field notes will be stored on the central database in password protected folders
accessible only to authorized qualitative researchers. Hand-written notes and drawings will be
stored in locked filing cabinets in an area with restricted access. During the coding process
qualitative data uploaded into the coding software will be manually de-identified (i.e. replacing
names, locations, other personal identifiers) ensuring that only de-identified interview material is
stored in the programme.
8.2.4 Data quality assurance and control
Quality assurance activities across all studies will be more intense during study start-up to
ensure quality data practices are instituted from the start of the trial. Further details will be
given in the DMP and SOPs.
All research assistants will be trained to provide information and seek written consent using
the information and consent form. Separate trainings will cover all aspects of quantitative data
collection and all aspects of qualitative data collection. A competency assessment using
scenarios will be done before commencing field work.
Data reconciliation between the different visits of the same child will be one of the most crucial
data quality activity in the pragmatic cluster RCT. Specific procedures will be developed for this
purpose. To identify repeat visits of children that may re-attend the study facility where they
enrolled or any other study facility during the follow-up period, participants will be given a
study card (or sticker) with a unique ID number. Retrospective search for data at referral level
will be restricted to facilities within the geographical area where the study is running and will be
targeted to include only children reported to have attended hospital by the caregiver at
follow-up and referred children lost to follow-up. The name of the referral facility will be
requested during the follow-up call. If available, it should further restrict the scope of the search
and the probability of negative matches when cross-checking the participant identity. Children
who re-attend any study facility more than 28 days after their previous enrolment will be
enrolled for the new disease episode and given a new ID number. If available, the old ID number
will be recorded to facilitate linking of the different disease episodes. Data to be potentially
reconciled will be flagged by automated cross-check of a set of personal identifiers. Given that
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personal identifiers may not be identically recorded at each visit, fuzzy matching methods will
be used to calculate a score of similarity between records and likelihood that they relate to the
same child. Reconciliation of records with high similarity scores will be manually validated.
The validity of quantitative data will be ensured through data definitions and field restrictions in
the electronic systems. Acceptable error rates in critical quantitative data will be established
during the pilot phase and documented in the DMP. Pre-defined automated high-frequency
checks will be performed including checks of completeness and indicators of other
irregularities such as completion time. Reports will be shared with individual quantitative
research assistants and their supervisors. In addition to reviewing automatically generated
reports for their supervisees, supervisors will perform random accuracy checks of research data
compared to available source data. In the pragmatic cluster RCT, quantitative research
assistants responsible for the Day 7 call will be audited through random checks of phone logs
and repeat phone calls. After confirmation that the study databases contain all expected data,
an internal review will check their accuracy and quality. Once all the required data quality
assurance and control have been completed and passed, the study databases will be “locked”.
During the pilot phase, qualitative tools will be translated and back translated, and tested using
cognitive interviewing to ensure questions asked are understood as intended and felt to be
appropriate. Regular quality checks of transcriptions and translations will be conducted by the
qualitative researcher in each country.
8.3 Statistical methods
Statistical methods will be described in detail in the Statistical Analysis Plan (SAP).
An interim analysis is planned to be conducted three months after the start of the study to
assess recruitment rate, follow-up and sample size assumptions. The Data Monitoring
Committee will review the results and make recommendations to the research steering
committee as to whether:

the sample size calculation should be adjusted based on estimated values in the control
groups;

the primary outcome measures should be revised due to a high number of missing
values;

the study should be terminated prematurely due to inability to achieve its objectives.
As comparisons between arms and hypothesis testing will not be performed, no adjustements
to the final analysis are necessary.
We will conduct all analyses described below per country, in addition to a pooled cross-country
analysis. Quantitative analyses will be conducted using Stata (or alternative statistical analysis
software, depending on investigator for certain country-specific or sub-study specific analyses).
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8.3.1 Pragmatic cluster RCT
Analyses will follow CONSORT guidelines and intention-to-treat principles, including all
participants as randomized. A flowchart will describe the inclusion and follow-up of participants
by study arm.
Baseline characteristics will be described by study arm with summary statistics such as median
and interquartile range or number and percentage; no formal testing between arms will be
performed. Outcomes will be described by arm using summary statistics. The two primary
outcomes, the proportion of children with a severe complication and the proportion of children
appropriately hospitalized, will be assessed using a random effects logistic regression models
with the cluster included as a random effect. Results will be reported with odds ratios, risk
differences and 95% confidence intervals (CI). Binary secondary outcomes will be evaluated in
the same way. Continuous secondary outcomes will be assessed using random effects linear
regression models, reporting adjusted mean differences between arms with 95% CIs.
All models will be adjusted for randomization stratification factors and any baseline variables
found to be randomly imbalanced across arms. Assessment for imbalances between baseline
variables will be by visual inspection only; there will be no formal testing of baseline
characteristics across randomized groups.53,54
For the analysis of the primary endpoints, we will use a hierarchical fallback procedure, which is
a closed test procedure using a weighted Bonferroni.55,56 This method recycles unspent
significant levels to test subsequent hypotheses with a pre-specified hypothesis sequence.57
This uses alpha propagation making it more powerful that the Bonferroni method.
The primary outcomes will be evaluated according to hierarchy of importance as follows:
H1: There is no difference between the experimental arm and control arm with respect to severe
complications by day 7
H2: There is no difference between the experimental arm and control arm with respect to
hospital admissions within 1 day of the primary consultation
First, we would test the null hypothesis H12 which is that neither H1 nor H2 are significant. We
would reject the null hypothesis of H12 if either p1≤α1 or p2≤α2 where α is equally distributed
between the endpoints i.e. α1=0.025 and α2=0.025.
If we fail to reject the null hypothesis H12 then we will stop and this point and conclude that the
study is negative as neither of the co-primary outcomes were significant. If we reject the null
hypothesis H12 then we would go on to test H1 and H2. If p2≤α2 then we reject H2 and test H1 as
p1≤α. If p2>α2 then we do not reject H2 and test H1 as p1≤α1.
All outcomes will be evaluated regardless of the outcome of the first evaluation. For each
intervention arm, the overall trial will be interpreted as positive if either primary outcome is
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positive compared to control. This will be assessed separately in India and Tanzania and will
also be assessed across the two countries.
Missing data on key endpoints is to be expected due to the pragmatic nature of the study. If
substantial data are missing (e.g. >10%), a set of sensitivity analyses shall be carried out where
missing data are handled following different approaches such as, best/worst case scenario,
complete cases, simple imputation or multiple imputation with chained equations (71, 72). The
impact of each method on the primary outcomes results will be taken into account when
interpreting the final analysis results. Further information on missing data handling will be
detailed in the SAP.
We will conduct planned subgroup analysis of the primary outcomes to assess effect modifiers,
specifically age, sex, clinical presentation (particularly cough / difficulty breathing) and
diagnosis (particularly severity classification) and healthcare provider decision-making
(particularly referral and antimicrobial prescription). Effect modification will be assessed by
incorporating an interaction between trial arm and the variable in the model, acknowledging
that power will be low. Planned sensitivity analysis will be conducted including only the first
disease episode of each child during the study period (as some children may attend the facility
on more than one occasion over the 12-month period). Further exploratory analysis will be
detailed in the SAP.
8.3.2 Other mixed methods studies
Quantitative
Descriptive analysis will be conducted of the data obtained from the SPA studies by country,
facility type and location and child and healthcare provider characteristics. Indices of adherence
to key practices will be described and compared between arms and time points (pre-
intervention and the 4 post intervention time points). Time-flow data will also be compared
between pre-intervention and each of the post-intervention periods and between facilities of
different RCT arms. Effect modifiers will be explored.
Relevant aggregated data from routine HMIS will be used to monitor trends over time in all
facilities and administrative regions where the project is running. This will be compared with
routine CDSA data and study data to identify indicators for longer term monitoring of the
intervention.
Descriptive analysis will be conducted of the quantitative data (e.g. socio-demographic
questions) collected as part of the qualitative studies.
Machine learning methods will be used to identify prognostic features associated with
outcomes.
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Qualitative analyses
Quality assurance steps for transcription and translation will be built into the process.
Qualitative data will be transcribed verbatim using modified transcription rules by Kallmeyer
and Schütze58 verbatim and translated into English (and/or French. A random sample of
transcripts and translations will be quality checked by listening to audio-recordings and back
translations and measures taken accordingly. After familiarization with all interviews/FGDs, an
experienced qualitative researcher will code the transcripts using a qualitative coding software. A
random sample of a total of 10-15% of the qualitative interviews will be coded using the
framework analysis by Gale et al.59 following an inductive and deductive approach; in-vivo
codes will be created where applicable. The final draft code tree will be exported, codings
deleted and the same interviews coded by a second and independent qualitative researcher
for inter-rater reliability check. The Kappa-Cohen value will be calculated. Differences in coding
will be discussed and a joint solution developed. A Kappa-Cohen value above 80% will allow
using the code tree after minor adaptations based on joint agreements by the two coders and
for final coding. The finalized code tree will be used to code the entire material. Finally, each
code and each sub-code with its coded material will be exported into excel tables. A team of
qualitative researchers will review the tables and jointly analyse the data identifying patterns,
similarities, and differences as well as change over time. Secondary analysis of data from all
study countries may be conducted jointly and findings compared across countries.
Document review
The document review data will be entered into a grid with predefined categories in line with
process evaluation criteria. Data will be triangulated against qualitative and quantitative data
collected.
Process evaluation
The process evaluation will draw on data from the various sub-studies to describe the context,
implementation process and mechanisms of impact as outlined in Fig 8.
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Fig 8. Overview of MRC process evaluation of complex interventions (Image credit Moore et al)35
8.3.3 Cost and cost-effectiveness study
When all the cost components have been collected, the data will be aggregated or collated in
Excel. Once the summary is completed, a cost profile of the programme activities will be derived
and after the total costs of the programme have been calculated, the unit costs will then be
derived (i.e. total costs divided by the sample size). These profiles are useful in highlighting
major cost components (and thus identifying potential areas where improvements in efficiency
may have significant impact on costs). For this evaluation, analysis will focus on full costing and
incremental costing approach. Total, average and incremental costs per year will be estimated.
Costs associated with increasing the oxygen saturation referral threshold will be estimated
based on the additional proportion of children meeting referral criteria.
When available, effectiveness data will be combined with the cost data and cost per DALY
averted will be estimated. Effectiveness will be modelled using the information on severe
outcomes such as mortality, and secondary hospitalization, adjusting as far as possible the level
of severity of illness of the child at presentation.
At primary care facilities, these will include measurements (when taken by healthcare providers)
such as anthropometry, respiratory rate, temperature and routine investigations where
available (e.g. haemoglobin, CRP), and oxygen saturation (post-intervention/in intervention
arms). We will also use diagnosis and severity classification recorded by primary care providers.
At hospital level, we will also utilize the same measurement data, and other vital sign data (such
as a paediatric early warning score if recorded), decision to admit, intensive care and / or
ventilation, provisional and final diagnosis, admission outcome (discharge, death, left against
medical advice) and length of hospital stay. We will then use these indicators, along with
mortality from phone call follow-up data by Day 28, to predict probability of mortality based on
available literature. The DALY calculation will be based primarily on probability of mortality
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over a relatively short horizon (to be determined based on a review of literature, likely between
three and six months to reflect the time windows used in post hospital discharge mortality
studies). The types of illnesses considered do not typically lead to long-term disability, and the
duration of illness is too short to have a big impact on DALY calculations. We will not use age
weights: we will use GBD (2017) DALYs, 60 and we will not use country-specific disutility data,
both since we are unsure these exist for all the countries, and they render cross-country
comparisons more difficult.
Sensitivity analysis
As not all data will be available precisely, we will explore possible assumptions using sensitivity
analysis which will assess how the estimates would react to percentages changes in the value of
the assumptions. It can help the reviewer to determine which parameters are the key drivers of a
model’s results. Guidelines and standard textbook recommend that economic evaluations
should include sensitivity analysis.61 We will undertake one-way sensitivity analysis of key
parameters using the major outcome and cost parameters. Typically, such analyses are more
sensitive to the assumptions about outcomes, and for this we have to rely on the best
judgement of the epidemiologists.
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9 Monitoring
All studies will be conducted in accordance with the protocol and international and applicable
national regulatory requirements. The pragmatic cluster RCT will be monitored in accordance
with ICH Good Clinical Practice in addition to the aforementioned requirements. Independent
trial monitoring will be conducted by the Clinical Operations Unit within the Department of
Medicine at Swiss TPH (separate unit from lead investigators). The Clinical Operations Unit will
be responsible for setting up and carrying out the monitoring of trial conduct using a risk-
based approach, combining on-site, remote and centralised monitoring.
On-site monitoring will be done for a random selection of sites and can be triggered in addition
for sites appearing to be breaching. Screening data, consent, recruitment rates and missing
data on primary and important secondary endpoints will be reviewed remotely. Findings of
remote monitoring may influence on-site monitoring.
For the pragmatic cluster RCT, an independent data monitoring committee (DMC) will be
established, comprising of a Chair, Biostatistician and Clinician with relevant experience. The
DMC will meet after three months from the study start to review and evaluate the interim
analysis results. In addition, regular reviews will be conducted throughout the course of the
study as described and agreed in the DMC charter. The DMC will provide the research steering
committee with recommendations after blinded and unblinded reviews of relevant data on trial
progress and safety, and any issues identified by monitors.
9.1 Harms
We will collect data on death and secondary hospitalisations as part of the primary outcome.
Given the low-risk nature of the intervention, the pragmatic nature of the trial, and that deaths
and hospitalisations are, unfortunately, expected in this population, the DMC will review
summarised rates of adverse events will be summarized by intervention and control arms and
included in a report for the DMC to review. If a considerate difference (of >30%) is found, we
will conduct a more in-depth evaluation (through analysis of clinical data, and collection of
additional case note data from hospitals if required) of whether deaths or secondary
hospitalisations are attributable to the intervention will be conducted.
9.2 Auditing
Internal or external auditing will be triggered in case of concerns about trial conduct.
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10 Ethics and dissemination
10.1 Research ethics approval
Following two independent scientific merit reviews, the protocol will be submitted to all
relevant research ethics committees / institutional review boards in each country. Receipts of
submission to each local ethical review board will be submitted with the master protocols to
the WHO Research Ethics Review Committee (ERC).
For India, this includes a) the National Health Ministry, Uttar Pradesh (NHM-UP), b) the
Institutional Ethics Committee (IEC) of KGMU and c) the Health Ministry’s Screening Committee
(HMSC) of the Indian Council of Medical Research (ICMR)
For Tanzania, this includes a) the National Health Research Ethics Committee (NIMR), b) the
Ifakara Health Institute IRB (IHI-IRB) (c) the Medical Research Coordinating Committee (MRCC),
and (d) Commission of Science and Technology (COSTECH).
Regulatory status of the intervention
Pulse oximetry
The pulse oximetry device selected for the TIMCI project is the Acare AH-MX device. This was
selected as it is available through the UNICEF catalogue, which infers a level of quality and
device appropriateness. The competitive procurement process established by UNICEF
incorporates pulse oximetry specifications developed through a collaborative process involving
global and national level experts. Devices in the catalogue have regulatory approval from a
stringent regulatory authority (SRA) such as the United States Food and Drug Administration
(US FDA) or Conformité Européenne (CE) mark.
Country level regulatory approval will vary. It is possible that the devices will have approval in
some of the countries. If the device does not have pre-existing regulatory approval in a project
country, the project team will work with the MOH to receive a waiver to use the device for the
study purposes. If appropriate, the study team will continue to work with the manufacturer and
MOH in each country to receive a permanent regulatory approval to facilitate scale of that
device.
Clinical Decision Support Algorithm
The regulatory classification of clinical decision support software is currently subject to debate at
the US FDA, depending on how and in what context the software is used. In this study, the CDSA
is intended to provide decision support for the diagnosis and treatment of childhood illness.
It will collate and analyse patient-specific information to suggest possible diagnoses and
recommend treatment plans or diagnostic tests to healthcare providers (HCPs). These
suggestions and recommendations will be evidence-based and will support the decision-
making of the HCP when considering treatment options or diagnostic tests for a patient. The
HCP may then use this information to make a decision about the care of the patient, along with
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other information and factors of which he/she is aware. In addition, the CDSA presents a low
risk profile since it will supports the implementation of and strengthen the adherence to
standard clinical guidelines. These functions do not meet the definition of a medical device per
country regulatory authorities and the CDSA is therefore regarded as a non-regulated device.
10.2 Protocol amendments
Any important protocol modifications will be submitted to relevant research ethics committees,
trial registries and study sites including participants where appropriate.
10.3 Consent or assent
10.3.1Pragmatic cluster RCT
Information and consent procedures will be conducted in accordance with national regulatory
and ethical requirements (for example on the criteria applied to determine capacity of a
caregiver to provide consent). Prior to study start, information and consent mechanisms and
content will be reviewed and refined with community advisory boards and piloted with
participants and modified if necessary to ensure they are appropriate.
As the intervention is at the facility level, approvals from relevant authorities will be sought
before engaging with facility management and staff prior to study start.
Informed consent from caregivers will be sought for the collection of data and follow-up of
individual children in the pragmatic cluster randomised controlled trial. Information will be
provided in the waiting area of facilities in accordance with country-specific mechanisms, which
may include written, pictorial, video or spoken information. Potentially eligible children will be
identified at registration (based on age) during working hours and will be screened by a
research assistant in the waiting area for eligibility. Consecutive caregivers of eligible children
will be provided with more detailed information on the study and provided with an opportunity
to ask questions. Written informed consent will be obtained for those that agree to participate. In
the case of an illiterate caregiver, an impartial witness will be asked to sign on their behalf,
along with a thumbprint of the caregiver. Caregivers will be informed that they can withdraw at
any point up to study completion (and anonymization) and that non-participation or
withdrawal will not affect their care in any way. If the clinical condition of the child requires
immediate treatment, this will supersede the written consent process, which will be conducted
once the child is stabilized, and if this is still not possible, they will not be included in the study.
10.3.2Other mixed methods studies
Additional consent from caregivers, healthcare providers and stakeholders will be sought for
the embedded mixed methods studies. For the SPA, this will be conducted at the health facility as
per the pragmatic cluster RCT.
The person responsible for the recruitment for qualitative studies (possibly with the help of an
assistant such as a community health worker) will invite caregivers for participation providing
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verbal information and asking for verbal consent. Prior to the start of the IDI or FGD participants
will receive written information and asked to provide written consent. For method acting FGDs,
explicit consent will be sought for photo- and video-recording. Participants will have the option
to take part in the FGD but withhold consent for video-/photo-recording. In this instance, the
respective participants will be kept out of shot.
For healthcare providers written information will be provided and written consent sought. No
information on individual decisions to accept or decline participation will be shared, neither
with supervisors nor with health authorities. For key stakeholders, written information will be
provided and verbal consent sought prior to an interview via telephone; or written consent if an
interview is conducted person-by-person. Stakeholders participating in the online survey will
receive information on the survey in an email and need to provide consent by ticking a box in the
survey prior to proceeding with the questions.
10.3.3 Cost and cost-effectiveness study
We will obtain consent from healthcare providers (including medical and non-medical
personnel) participating in the costing study. An information sheet on the study will be
provided prior to data collection, discussed with target providers from sampled health facility
before written consent is obtained. Data relevant to the costing study collected as part of other
studies will be extracted and provided as anonymised, summary data for the purposes of the
costing study.
10.4 Confidentiality
Participant identifiable data will only be collected for the purpose of study conduct (participant
follow-up, duplicate checking, and qualitative analysis) and will be destroyed in accordance
with standard operating procedures.
10.4.1Pragmatic cluster RCT
Study and participant data will be handled confidentially and will only be accessible to
authorised personnel who require the data to fulfil their duties within the scope of the study. All
personnel who have access to data forms will be asked to sign confidentiality agreements. We
will make sure consent forms make provision for future sharing of data.
A unique identifier number will be assigned to each participant (including healthcare providers)
and facilities.
10.4.2Other mixed methods studies
Qualitative data will be audio recorded using an encrypted device after which it will be
transcribed and translated verbatim (personal identifiers not removed) in each country with
staff signing a confidentiality clause. During walking interviews audio-recordings will only be
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done during the bilateral interview between the caregiver and data collector (but e.g. switched
off when the caregiver has a conversation with a third person). Hand-written notes of relevant
conversations and observations will be taken in addition. Audio data will be fully de-identified
when uploaded to and read through in the qualitative coding programme and according to
SOPs including use of pseudonyms. Audio files will be destroyed after quality checking of
transcription and translation has been completed. GPS tracking data of the walking interviews,
as well as photos and videos of the method acting FGDs will be additionally analysed. Audio
tracks from videos will be removed after transcription has been conducted and replaced by
transcripts and/or sub-titles. Only the qualitative data collectors facilitating the FGD and the
authorised qualitative researchers (including qualitative researchers in country, in other TIMCI
countries, and the Swiss TPH lead social scientist) will view the non-de-identified acting method
videos/photos for the purpose of primary analysis, after signing a confidentiality agreement
and agreeing with the Code of Conduct. All raw qualitative material will be destroyed after
validation of the final database of consolidated qualitative material. Further information on
data management can be found in Section 8.2.
10.4.3Linking between pragmatic cluster RCT and mixed methods studies
Data collected during the mixed-method studies will be linked with a subset of data collected
during the pragmatic cluster RCT. The privacy protection of enrolled participants will be
ensured following a multiple coding procedure: each participant will be given a different
unique alphanumeric identifier for each study in which he/she is associated. These identifiers
will be linked with the RCT identifier by the clinical management system. This means that the
knowledge of both codes and their mutual link is needed to access the full dataset about a
participant. The link between two study identifiers will be maintained confidential information
under strict operating procedures (in a central, secured database with restricted access rights)
for the duration of the study. In particular, this information will not be shared or accessible
outside of the research institution. When all data validation and regulatory requirements have
been met, the link between study identifiers will be destroyed, so that all study databases are
ultimately fully independents.
10.4.4 Cost and cost-effectiveness study
Confidentiality of personnel cost of staff participating in the study will be ensured by protecting
the identity of staff whose grade level will be collected as part of the study. Information on
staff salaries collected will be stored in a restricted cabinet with only access to the principal
investigator. All data collected will be stored in a research server with other intervention data
with limited access. We will assign unique identifiers to health facilities and maintain a link
between facility name and identifier stored in the research server. However, for the analyses
which will be performed in Waterloo, Canada, only de-identified data will be used.
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10.5 Risk and benefits to participants
No major risks are foreseen given the low risk nature of the intervention. The only potential
risk envisaged is the time involved in participation in the study, which will be clearly outlined
during the informed consent process. The potential risk of delaying care of sick children as a
result of recruitment to the study will be mitigated by training of research assistants and
sensitization of healthcare providers to ensure that they are aware that no research activity
should take priority over clinical care. Scenarios in which they should not attempt to recruit
participants will be provided during training to ensure this is clearly understood.
No participants will receive incentives, but participants in qualitative mixed methods studies
may receive a small reimbursement (monetary/non-monetary) for their time (e.g. to
compensate for travel costs or lost time) and according to country specific standards.
In order to avoid the risk of diverting healthcare providers from clinical duties, all data
collection from healthcare providers will be scheduled at appropriate times. For the SPA
interviews, this will be at a less busy time of the day (e.g. towards the end of the day) or just
after the end of their shift. IDIs and FGDs will take place after hours or at weekends unless
express (generic, not participant-specific) permission is provided to conduct during working
times without clinical duties.
Whilst there are no direct benefits to participants, this study could benefit them and their
community in future as a result of the understanding generated by this study.
10.6 Access to data
Access to study data will be governed by a data sharing agreement between each country
research partner, Swiss TPH, UoW and PATH, in accordance with country-specific regulations.
The final, anonymised datasets will be made available on an open access data sharing platform
after the end of the study, in order to promote transparency and facilitate global cooperation in
child health research.
10.7 Dissemination policy
The protocol will be published after all ethical approvals have been received.
Findings from the study will be shared through community engagement mechanisms
described in Section 6.3. Findings will also be shared with the healthcare providers at facilities
involved in the study, and supervisors / other stakeholders within district health management
teams. Advocacy work through various mechanisms at national and international level based
on the findings of the study will be conducted as part of Output 4 of the TIMCI project.
Globally, the project is collaborating closely with technical partners, UN agencies, and the WHO
to refine research plans and ensure evidence generation is directly applicable to national and
global scale-up. A key output of the TIMCI project is focused on advocacy and policy adoption.
Policy and guideline landscapes have been conducted in each country and these are informing
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advocacy strategies that are under development. The goal of these advocacy strategies is to
work with the governments to incorporate learnings from these studies into routine practice.
Pulse oximeters are currently available at a wide range of prices and PATH is planning to
provide technical assistance to the governments to support procurement of appropriate
devices for scale-up. Other activities to support scale-up focus on clinical guidelines, HCW
training curricula, procurement guidance, financing plans, and annual budgets.
Results will be shared with the wider scientific community through presentations at national
and international conferences, and through open-access peer-reviewed journal publications.
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Impact of intervention on QoC
(health outcomes, key practices)
Evaluation of implementation (incorporating process
evaluation, acceptability framework, realist approach)
Tab. 8. Multi-method intervention evaluation overview
Sub-study title
Pragmatic cluster
randomised
controlled trial
(India & Tanzania)
Longitudinal
observational study
(Kenya, Senegal)
Service provision
assessments
Facility-based
process mapping and
time-flow study
Healthcare provider
perceptions of the
intervention
Caregiver
perceptions of the
intervention and
health-seeking
behaviour
Stakeholder
perceptions
Project data review
Objectives
Large-scale evaluation of impact of pulse oximetry and
CDSAs on health outcomes (death, hospitalisations, cure
rate) and healthcare provider practice (antimicrobial
prescriptions, referral decisions)
To evaluate impact of pulse oximetry / CDSAs on quality
of care (referral, antimicrobial prescriptions with
exploratory assessment of outcomes
To evaluate the effect of the intervention on adherence
to IMCI guidelines, including the correct classification
and management of children under five years & to
evaluate health system factors associated with impact
To understand change in care processes including time
taken for consultation and use of devices
To understand acceptability, usability of devices by HCPs
and gain insight on perceived facilitators and barriers to
successful implementation
To understand knowledge, attitudes and behaviour (i.e.
experience of care, care seeking pathways, perception of
devices, adherence to advice (in last consultation), child
health literacy) related to the health care received
To explore knowledge, attitudes, values, beliefs related
to the devices, experiences with clinical care with a focus
on aspects of quality of care (i.e. people-centred
outcomes, provision of care and experience of care).
To understand health care provision in the non-
intervention arm; and specifically intervention
mechanisms / decision-making, identification of
facilitators and barriers to implementation, best
practices, inform package for scale
Design
3-arm parallel cluster RCT comparing:

Pulse ox + CDSA (Tanzania only)

Pulse ox + paper job aid

Routine care (refresher training)
Quasi-experimental pre-post:

3 mo baseline

1 year intervention (early/late)

3 mo comparison Q1 and Q5
Periodic assessment (in each phase) using
Service Provision Assessment methodology –
i.e. collecting data at facilities for (1-5) days
per facility per quarter
Baseline and intervention process mapping
with group discussion at sample of facilities,
with observation and timing of key steps
Qualitative work with HCPs from a sample of
facilities in pilot, early and late intervention
Community follow-up of individual
caregivers, purposively selected (e.g. referred
/ unreferred, adverse / non-adverse
outcomes) during intervention period
FGD of purposively selected caregivers (urban
/ rural, type of facility, location) grouped by
age/sex; During pilot, early and late
intervention phases
Baseline & late intervention
Late intervention
Tools
D0 –
clinical/sociodemographic data
at facility
D7 – primary outcome
D28 – secondary outcome
D0 –
clinical/sociodemographic
data at facility
D7 - outcome / health-seeking
Facility assessment
HCP interview
Sick child observation
Exit interview
Process map
Time-flow study
IDIs
FGDs
IDIs, Case Studies
FGDs
KIIs with govt & project
stakeholders
Desk review incl. project data
e.g. on devices, training
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11 References
1. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels &
Trends in Child Mortality: Report 2019, Estimates developed by the United Nations Inter-
agency Group for Child Mortality Estimation. (2019).
2. UN General Assembly Resolution. Transforming our world: the 2030 Agenda for
Sustainable Development. A/RES/70/1.
3. Costello, A., Dalglish, S. & on behalf of the Strategic Review Study Team. Towards a
Grand Convergence for child survival and health: A strategic review of options for the
future building on lessons learnt from IMNCI. (2016).
4. World Health Organization (WHO). Integrated Management of Childhood Illness
Chartbook. (2014).
5. Nguyen, D. T. K., Leung, K. K., McIntyre, L., Ghali, W. A. & Sauve, R. Does Integrated
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12 Appendix
12.1 Informed consent forms appended to the protocol

01 TIMCI ICF RCT V0.3.3, 19Nov2020

02 TIMCI ICF RCT CG SPA V0.2.2 19Nov2020

03 TIMCI ICF RCT CG TF V0.2.2, 19Nov2020

04 TIMCI ICF RCT CG Walking Interview V0.2.3, 19Nov2020

05.1 TIMCI ICF CG IDI intervention V0.2.3 19Nov2020

05.2 TIMCI ICF CG IDI non-intervention V0.2.3 19Nov2020

06 TIMCI ICF CG FGD v0.2.2, 19Nov2020

07 TIMCI ICF CG method acting v0.2.2, 19Nov2020

08 TIMCI ICF RCT HCP SPA V0.2.2, 19Nov2020

09.1 TIMCI ICF RCT HCP IDI V0.2.3, 19Nov2020

09.2 TIMCI ICF RCT HCP IDI pre-intervention V0.2.3, 19Nov2020

10 TIMCI ICF RCT HCP FGD V0.2.3, 19Nov2020

11 TIMCI ICF SH KII V0.2.3, 19Nov2020
      12 TIMCI ICF SH survey V0.2.3, 19Nov2020
      13 TIMCI ICF RCT costing V0.3, 19Nov2020
12.2 Study instruments appended to the protocol

01-TIMCI RCT CRF description v1.5 clean, 29May20

02-TIMCI RCT SPA Exit Interview instrument v1.4 clean, 29May20

03-TIMCI RCT SPA Facility Assessment instrument v1.4 clean, 29May20

04-TIMCI RCT SPA HealthCare Provider Interview v1.4 clean, 29May20

05-TIMCI RCT SPA Sick Child Observation instrument v1.5 clean, 24Nov20

06-TIMCI RCT process map timeflow tool v3.0, 29May20

07-TIMCI caregiver walking interview v4.0

08-TIMCI caregiver FGD v5.0, 19Nov20

09.1-TIMCI stakeholder KII v5.0, 19Nov20

09.2-TIMCI stakeholder KII v3.0_TZ, 19Nov20

10-TIMCI document review matrix v3.0

11-TIMCI stakeholder survey v4.0

12.1-TIMCI HCP IDI v5.0, 19Nov20

12.2- TIMCI HCP IDI v3.0_TZ, 19Nov20

13-TIMCI HCP FGD v5.0

14.1-TIMCI caregiver IDI v5.0, 19Nov20

14.2 TIMCI caregiver IDI v3.0_TZ, 19Nov20

15-TIMCI non-medical personnel questionnaire 08.06.20

16-TIMCI medical personnel questionnaire 08.10.20

17-TIMCI hospital costs 09.06.20

18-Training Comm sensitization costs TIMCI 09.06.20
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12.3 Budget and collaboration appended to the protocol
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12.4 TIMCI Preliminary Theory of Change
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