Development of a Robust and Reliable Pulse Oximeter for Use by Frontline Healthcare Providers Caring for Children With Pneumonia in Low-income Countries
Phase: NA
Conditions: Pneumonia in Children, Measurement of Peripheral Oxygen Saturation
Sponsor: The Lifebox Foundation

Clinical Investigation Plan: Lifebox Project: [Version 1.6] 26th January 2017 
 
IRAS No: 211895 
 
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Full title of trial 
 
Development of a robust and reliable pulse oximeter 
for use by frontline healthcare providers caring for 
children with pneumonia in low-income countries: 
clinical usability testing in children aged 0-59 months 
at Great Ormond Street Hospital, London 
Short title 
 
Lifebox Project 
Version and date of protocol 
Version 1.6, 26th January 2017 
Sponsor: 
Lifebox Foundation 
Sponsor protocol number 
Version 1.6, 26th January 2017 
Funder (s)  
Bill and Melinda Gates Foundation 
Investigational Devices 
AH-MX handheld pulse oximeter and Lifebox A2 
oximeter probe prototype 
Sites(s) 
UK site: Great Ormond Street  Hospital  
 
 
Chief investigator: 
 
Dr. Isabeau Walker 
 
Great Ormond Street Hospital, 
Great Ormond Street,  
London, 
WC1N 3JH 
 
Tel: 02078298865  
Email: Isabeau.walker@gosh.nhs.uk 
 
 
Sponsor Representative: 
 
Kristine Stave 
 
The Lifebox Foundation, 
21 Portland Place, 
London, 
W1B 1PY 
 
Tel: 02076318881 
Email: Kristine@lifebox.org  

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Signatures 
The Chief Investigator and the Sponsor have discussed this protocol. The investigators agree to 
perform the investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP and 
UK Regulations for CTIMPs (SI 2004/1031; as amended), the UK Data Protection Act (1998), the Trust 
Information Governance Policy (or other local equivalent), the Research Governance Framework 
(2005’ 2nd Edition; as amended), the Sponsor’s SOPs, and other regulatory requirements as 
amended. 
 
Chief investigator 
Isabeau Walker 
26th January 2017 
 
Signature 
Date 
Sponsor Representative 
Kristine Stave 
 
26th January 2017 
 
Signature 
Date 
 
 
 
 
 

Clinical Investigation Plan: Lifebox Project: [Version 1.6] 26th January 2017 
 
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Contents 
1 
Trial personnel ............................................................................................................................... 6 
2 
Summary ........................................................................................................................................ 7 
3 
Introduction ................................................................................................................................... 9 
3.1 
Background ................................................................................................................. 9 
3.2 
Preclinical data ............................................................................................................ 9 
3.3 
Rationale ................................................................................................................... 10 
3.4 
Assessment and management of risk ....................................................................... 10 
4 
Objectives ..................................................................................................................................... 10 
5 
Study design ................................................................................................................................. 11 
6 
Selection of Subjects .................................................................................................................... 12 
6.1 
Inclusion criteria ........................................................................................................ 12 
6.2 
Exclusion criteria ....................................................................................................... 12 
7 
Recruitment ................................................................................................................................. 13 
8 
Study procedures and schedule of assessments.......................................................................... 13 
8.1 
Informed consent procedure .................................................................................... 13 
8.2 
Baseline assessments ................................................................................................ 13 
8.3 
Definition of end of study ......................................................................................... 14 
8.4 
Discontinuation/withdrawal of participants and ‘stopping rules’ ............................ 14 
9 
Name and description of Investigational Device ......................................................................... 14 
10 
Recording and reporting of adverse events and reactions .......................................................... 15 
10.1 
Definitions ................................................................................................................. 15 
10.2 
Recording adverse events ......................................................................................... 16 
10.2.1 
Severity ................................................................................................................. 16 
10.2.2 
Causality ................................................................................................................ 17 
10.2.3 
Expectedness ........................................................................................................ 17 
10.2.4 
Seriousness ........................................................................................................... 17 
10.3 
Procedures for recording and reporting Serious Adverse Events ............................. 18 
10.4 
Annual progress reports............................................................................................ 18 
10.5 
Reporting Urgent Safety Measures ........................................................................... 18 
10.6 
Notification of Serious Breaches to GCP ................................................................... 18 
11 
Data management and quality assurance .................................................................................... 18 
11.1 
Confidentiality ........................................................................................................... 18 
11.2 
Data collection tools ................................................................................................. 18 
11.3 
Data handling and analysis ....................................................................................... 19 
12 
Record keeping and archiving ...................................................................................................... 19 
13 
Statistical Considerations ............................................................................................................. 19 
13.1 
Outcomes .................................................................................................................. 19 
13.1.1 
Primary outcomes ................................................................................................. 19 
13.1.2 
Secondary outcomes ............................................................................................. 19 
13.2 
Sample size and recruitment .................................................................................... 20 
13.2.1 
Sample size calculation ......................................................................................... 20 
13.2.2 
Planned recruitment rate ...................................................................................... 21 
13.3 
Statistical analysis plan ............................................................................................. 21 
13.3.1 
Primary outcome analysis ..................................................................................... 21 
13.3.2 
Secondary outcome analysis ................................................................................. 21 
13.3.3 
Sensitivity and other planned analyses................................................................. 21 
13.4 
Name of Committees involved in trial ...................................................................... 21 
14 
Direct Access to Source Data/Documents ................................................................................... 22 
15 
Ethics and regulatory requirements............................................................................................. 22 
16 
Monitoring ................................................................................................................................... 22 
17 
Finance ......................................................................................................................................... 22 

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18 
Insurance ...................................................................................................................................... 22 
19 
Statement of compliance ............................................................................................................. 22 
 
 
 

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List of abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
GCP 
Good Clinical Practice 
GOSH 
Great Ormond Street Hospital 
IB 
Investigator Brochure 
MHRA 
Medicines and Healthcare products Regulatory Agency 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
REC 
Research Ethics Committee 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 

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1 
Trial personnel 
Sponsor Representative: 
 
Kristine Stave 
 
 
e-mail: Kristine@lifebox.org 
 
Chief investigator: 
 
Dr. Isabeau Walker 
e-mail: Isabeau.walker@gosh.nhs.uk 
 
Research Consultant: 
 
 
 
Dr Iain Wilson 
 
 
 
 
 
 
e-mail: iainhwilson@me.com 
 
Lifebox clinical investigator: 
 
 
Dr Nicholas Boyd 
 
 
 
 
 
     
e-mail: nicholas.boyd@gosh.nhs.uk 
 
Research Associate: 
 
    
     
Dr Carina King 
 
 
 
 
 
 
e-mail: c.king@ucl.ac.uk 
 
Consultant Medical Device Development: 
Mr Michael Bernstein  
 
 
 
 
 
 
mike@physio-monitor.com 
 
Statistician: 
Dr. Tim Colbourn 
e-mail:  t.colbourn@ucl.ac.uk  
 
 
 

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2 
 Summary 
 
Objectives: 
The primary objective is to determine the proportion of oxygen 
saturation measurements obtained within 60 seconds when the 
oxygen saturation is measured by expert users and by trained 
healthcare workers using the redesigned Lifebox oximeter and 
probe for children aged 0-59 months  
The secondary objective is to provide further description of the 
‘usability’ of the redesigned oximeter and probe in children aged 
0-59 months by healthcare workers, to assess how well children 
tolerate the probe, and the difference in time to a stable 
oximetry reading for expert users and healthcare workers in 
different settings, or for different ages of children.  
Type of study: 
Mixed methods observational usability testing  
Study design and 
methods: 
This observational usability testing involves three types of data 
collection from three sites in the UK, Malawi and Bangladesh. 
This protocol relates specifically to the UK testing at Great 
Ormond Street Hospital.   
Expert usability testing:  the probe and oximeter will be used by 
an expert on 204 stable children (i.e. not physiologically unstable 
or admitted to a high-dependency or intensive care unit) of 
different ages and with varying illness states. Children will be 
purposefully recruited from inpatient wards to meet age criteria 
by a clinical researcher. Following consent, an oxygen saturation 
measurement will be done by the expert user. An independent 
observer will note the condition of the child, along with other key 
demographic, performance and clinical features and the time to 
successful measurement of oxygen saturation.  
Healthcare provider usability testing:  the probe and oximeter will 
be used by healthcare providers on healthy or mild systemically ill 
patients (i.e. with a normal oxygen saturation, i.e. >94%). 
Children will be purposefully recruited from inpatient wards to 
meet age requirements by a clinical researcher and pre-screened 
for their oxygen saturation. 17 healthcare workers will be 
assessed for their performance with the prototype probe. Each 
HCW will undertake an oxygen saturation measurement on 12 
children  (maximum 204 children at Great Ormond Street 
Hospital). An independent observer will note the condition of the 
child, along with other key demographic, performance and 
clinical features and time to successful measurement of oxygen 
saturation.  
Usability Questionnaire: HCW will be asked to complete a 
usability questionnaire to collect quantitative and qualitative 
feedback about the oximeter and probe usability. The 
questionnaire will be completed following the usability testing by 
all the healthcare providers.  

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Study duration per 
participant: 
Healthcare providers are the main study participants and will be 
involved in the study between 1 and 4 hours, with each 
healthcare provider taking 12 oxygen saturation measurements.  
Children will be involved in the study intermittently for up to 80 
minutes. Children will be assessed for recruitment and consented 
prior to each measurement.  
Estimated total study 
duration: 
4 weeks 
Planned study sites: 
Great Ormond Street Hospital [single-site]  
Total number of 
participants planned: 
17 healthcare providers, and up to 408 children aged 0-59 
months 
Main inclusion/exclusion 
criteria: 
The study will be conducted in the inpatient wards of Great 
Ormond Street Hospital, with recruited healthcare providers and 
children aged 0-59 months. 
Inclusion: 
- 
Children aged 0-59 months in an inpatient ward at Great 
Ormond Street Hospital 
- 
Healthcare provider working on an inpatient ward at 
Great Ormond Street Hospital 
Exclusions:  
- 
Children aged >59 months 
- 
Children in critical condition 
- 
Guardians lacking capacity to give informed consent for 
their child 
- 
Guardians unable to speak English 
Statistical methodology 
and analysis: 
We will calculate the proportion of readings that meet the target 
product profile requirement of 95% stable readings within 60 
seconds. We will describe the time to stable reading, looking at 
the median time and inter-quartile range. We will compare these 
descriptive statistics between patient age groups, expert and 
healthcare provider participants, and with measurements from 
sites in Malawi and Bangladesh. We will describe differences 
between these sub-groups using t-tests. Qualitative 
questionnaire data will be analysed using an inductive thematic 
approach. 
 
 
 
 
 
 

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3 
Introduction 
3.1 
Background 
Pneumonia is the leading infectious cause of death in children under five and causes an estimated 
935,000 deaths every year.  Most deaths occur in sub-Saharan Africa and Southeast Asia. The 
outcomes for children with pneumonia can be improved through appropriate treatment and better 
case management using the WHO Integrated Community Case Management guidelines (ICCM) and 
Integrated Management of Childhood Illness (IMCI) guidelines. 
Severe pneumonia is associated with hypoxemia, and peripheral oxygen saturation (SpO2) of less 
than 90% is associated with increased mortality. The WHO guidelines use this measure to 
differentiate pneumonia where the child needs referral for oxygen therapy and parenteral antibiotic 
treatment, from basic treatment which can be managed safely in the community with oral 
antibiotics. Hypoxemia can be detected non-invasively with a pulse oximeter. Routine screening for 
hypoxemia provides an opportunity for improved case management, referral and treatment decision 
making, and has been shown to improve outcomes in children with pneumonia in developing 
countries. Despite being in widespread use in high-income settings, the uptake of pulse oximeters in 
low-income countries has been limited due to cost, durability and lack of systems to support this 
essential technology.  
The Lifebox Foundation was formed in 2011 to improve access to pulse oximeters in developing 
countries following the inclusion of pulse oximetry in the 2009 WHO Guidelines for Safe Surgery. 
These oximeters, designed in collaboration and with end-users from developing countries in mind, 
have received good feedback from anaesthetists, paediatricians and healthcare workers in 
developing countries. However, there are some key areas for improvement that are required to 
make suitable for use in routine paediatric pneumonia care. This includes the need to improve the 
reusable oximeter probe for neonates and infants, to reduce the time taken to obtain a reading 
when the oximeter is used for repeated spot checks, and to improve the battery life and resilience to 
power fluctuations.  
The problem of probe design in children is common to all regions and all users, both expert and non-
expert. The solution in high-income settings is to use single-use disposable oximeter probes with an 
adhesive strip, costing $10-15 each, making this approach not sustainable in resource-poor settings. 
A re-designed oximeter and paediatric probes, optimised for use in routine care at all levels of the 
healthcare system, is an important step to improving pneumonia diagnostics and care.  
3.2 
Preclinical data 
In order to ensure that any re-designed oximeter and probe is fit for purpose, a process of Human-
Centred Design has been used for the re-design. Human Centred Design is an iterative creative 
process to problem solving where end-user engagement is embedded into all stages of the product 
design. Crucially this approach will help to ensure that the end-product will be context appropriate 
and reflect the specific requirements of healthcare workers who will be using the oximeter. To date 
we have conducted focus group discussions (FGDs) with healthcare providers in Malawi and 
Bangladesh, and elicited feedback from a group of international experts in pulse oximetry about the 
re-designed paediatric probe and oximeter. This feedback has led to changes and modifications in 
the design of the probe, with two rounds of prototypes developed prior to the one being taken 
forward to usability testing.  

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3.3 
Rationale 
This project aims to design an upgraded pulse oximeter and re-usable probes specifically for children 
aged 0-59 months, suitable for use in all healthcare settings. A target product profile (TPP) produced 
through expert consultation by the Bill and Melinda Gates Foundation forms the baseline for the re-
design. It specifies the required performance, functional, design and stakeholder needs, with a focus 
on the design of the interface between the probe and the patient (i.e. how the probe is attached to 
the child). In the formative work for this study, we have gone through a human centred iterative 
design process, engaging with end-users in developing countries and international experts, to 
produce a redesigned probe and oximeter. We are now undertaking final usability testing to ensure 
that the redesigned oximeter and probe meet the TPP in a range of children and in three different 
sites with different levels of training of healthcare workers (Great Ormond Street Hospital, district 
hospitals and community hospitals in Malawi and Bangladesh). This clinical investigation plan relates 
to the study proposed at Great Ormond Street Hospital only, but the results obtained will be pooled 
with results from other sites. 
Hypothesis: the redesigned probe and oximeter will perform according to the target product profile 
of achieving 95% of measurements within 60 seconds.  
Feedback from end-users to date has highlighted that measurements can take between 2-15 
minutes in some settings, such as with agitated children in rural community healthcare settings in 
low-income countries. Therefore, achieving 95% of measurements within 60 seconds would 
constitute a significant improvement in paediatric pulse oximetry for use in a wide range of settings.  
3.4 
Assessment and management of risk 
This study is categorised as: Type A = No higher than the risk of standard medical care. 
Pulse oximetry is a non-invasive measurement that is routinely done in Great Ormond Street 
Hospital, by all levels of healthcare providers. It poses no risk to the patient, and all measurements 
taken during the study will be done by either experts or healthcare providers with a minimum 
required training.   
4 
Objectives 
Primary:  
The primary objective is to determine the proportion of oxygen saturation measurements obtained 
within 60 seconds when the oxygen saturation is measured by expert users and by trained 
healthcare workers using the redesigned Lifebox oximeter and probe for children aged 0-59 months  
Secondary:  
The secondary objective is to provide further description of the usability of the redesigned oximeter 
and probe in children aged 0-59 months by expert users and healthcare workers:  
• 
Is this pulse oximeter probe easy to use by an expert and by healthcare providers?  
• 
Does this oximeter provide a reliable reading when used by an expert and by healthcare 
providers?  
• 
Is the probe well tolerated by the child? 
• 
Is there a difference in the time taken to obtain a stable oximetry reading by the expert user 
compared to healthcare providers in different settings, or for different ages of children? 

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5 
Study design 
This is an observational usability study. ‘Usability’ is a broad concept defined by the international 
standard ISO 9241-11 as: 
The extent to which a product can be used by specified users to achieve specified goals with 
effectiveness, efficiency and satisfaction in a specified context of use.  
There is no specific statistical test for usability. We have defined usability in this study as a measure 
that is clinically relevant, that is, the proportion of oxygen saturation measurements obtained within 
60 seconds by any level of healthcare worker. This measure is taken from the TPP and is the 
parameter by which the redesigned probe and oximeter will be deemed a success, that is, for a 
target of 95% of measurements to be obtained within 60 seconds.  
Time taken to obtain a reading is only one dimension of usability so we will also be using a mixed 
questionnaire with quantitative and qualitative data for feedback from end-users based on use 
failure modes effect analysis (U/FMEA) - this data will be important if we find a low proportion of 
measurements meet the TPP, to understand the barriers to effective use. These data will be 
interpreted together to give a broader conclusion of usability, alongside our primary end-point. We 
will collect additional observational data on the number of repositions of the oximeter probe, the 
quality of the waveform (used to judge whether a measurement is stable) and condition of the child. 
There will be two different types of usability clinical testing performed in this stage, assessing slightly 
different usability criteria, initially with expert users and then by healthcare providers with a range 
of training and experience.  The primary analysis for the timed outcome of usability will be a pooled 
analysis from all the participating sites, stratified by expert user and healthcare provider. As the 
oximeter and probe should be appropriate for different settings, albeit with different levels of staff 
training, this will provide us an overall measure of usability.  
Expert usability testing:  the probe and oximeter will be assessed on a range of children, including 
different ages and with varying illness states (excluding those who are critically ill). Children will be 
purposefully recruited from inpatient wards at GOSH to meet age criteria by a clinical researcher. 
The attending guardian will be given study information and asked for informed consent. Following 
consent, the expert user will take an oxygen saturation measurement. An independent observer will 
note the condition of the child, along with other key demographic, performance and clinical 
features, and the time to successful reading.  
The end point for a successful reading is defined as the time from when the probe is placed on the 
child to when the reading is stable (one full screen of a stable pulse waveform); the user says ‘STOP’ 
at this point. The time for the successful reading, and the total time taken to obtain a reading 
including the number of attempts to obtain the reading will be recorded.  
Healthcare provider usability testing:  the probe and oximeter will be assessed on healthy or mild 
systemically ill patients (with a normal oxygen saturation, i.e. >94%).  Children will be purposefully 
recruited from inpatient wards at GOSH to meet age requirements by a clinical researcher, who will 
pre-test children to ensure that their oxygen saturation is above 94% at the point of recruitment. 
Healthcare providers will be purposefully recruited in each site to have a range of pulse oximeter 

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experiences and qualifications. Healthcare providers and attending guardians will be given study 
information and asked for informed consent.  
Following consent, the healthcare provider will take an oxygen saturation measurement. An 
independent observer will note the condition of the child, along with other key demographic, 
performance and clinical features, and time to successful measurement.  
The end point for a successful reading is defined as the time from when the probe is placed on the 
child to when the reading is stable (one full screen of a stable pulse waveform); the user says ‘STOP’ 
at this point. The time for the successful reading, and the total time taken to obtain a reading 
including the number of attempts to obtain the reading will be recorded.  
Usability Questionnaire: A usability questionnaire, which will provide a subjective rating of a 
product’s usability, will be used to gather quantitative and qualitative measures of the new probes 
usability from the healthcare providers. The questionnaire will be conducted following the usability 
testing.  
6 
Selection of Subjects 
6.1 
Inclusion criteria 
Child participants: 
- 
Inpatients (or child awaiting surgery on pre-operative ward) in Great Ormond Street Hospital 
- 
Aged 0 - 59 months 
- 
Clinically stable (as judged by the ward sister and medical team) 
- 
Guardian (parent or adult with legal responsibility for the child) present  
- 
Written informed consent from the guardian 
 
Healthcare providers: 
- 
Healthcare provider employed at Great Ormond Street Hospital who are trained in the use 
of pulse oximetry 
- 
Written informed consent from the healthcare worker 
6.2 
Exclusion criteria 
Child participants: 
- 
Unstable or critically unwell patients (as judged by the ward sister and medical team) 
- 
Parents (or adult with parental responsibility) who are not able or willing to give informed 
consent 
- 
Parents (or adult with parental responsibility) unable to speak English well enough to 
understand study methods or consent form 
- 
For part (2) of the study (usability of the probe by healthcare workers), patients with oxygen 
saturation 95% or below will be excluded 
 
Healthcare providers: 
- 
Healthcare provider who are not trained to use a pulse oximeter 
- 
Healthcare provider who have not given written informed consent 

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7 
Recruitment 
Child participants: 
Recruitment of children will be purposeful; to ensure a range of ages (0-59 months old) are included 
in the study. Children will be recruited from inpatient wards at GOSH, by the clinical researcher with 
the assistance of the ward sister. We will ask the ward sister to identify patients in the four different 
age categories who are stable and whose parents (or adult with parental responsibility) are present 
on the ward. We will ask the ward sister to hand out patient information leaflets to the guardian, 
and the research team will only approach potential participants if they are happy to be approached. 
Basic patient demographic data will be collected from the electronic patient notes. Data from other 
sources will not be required.  
 
Healthcare providers: 
Recruitment of healthcare providers will be purposeful, to ensure a range of experiences with pulse 
oximetry are included in the study. Any nurse employed at Great Ormond Street Hospital who is 
trained to use pulse oximetry will be eligible to participate in the study. We will approach nurses on 
each ward in the hospital and hand out study healthcare worker information. Any nurse who is 
willing to participate will be asked for informed consent.  
8 
Study procedures and schedule of assessments 
8.1 
Informed consent procedure 
It is the responsibility of the clinical researcher to obtain written informed consent from each subject 
prior to participation in the study, following adequate explanation of the aims, methods, anticipated 
benefits and potential hazards of the study. No study procedure will be conducted prior to taking 
consent from the participant. Consent will not denote enrolment into the study.  The signed consent 
form will be retained at the study site and a copy placed in the medical notes. 
Child participants: 
A member of the research team will approach the responsible clinical team for potential 
participants. Having identified a potential patient, the nurse responsible for the patient will make 
the initial approach to the child and provide the guardian with an information sheet. Only after this 
point will a member of the research team then approach the parent to ask for informed consent, 
provided the parent is happy to be approached, making it clear that participation will have no impact 
on the child's ongoing care and is entirely voluntary. Guardians will have the opportunity to ask 
questions to the research team prior to consent being taken. Children will be given a picture to 
illustrate how a pulse oximeter is used to measure the oxygen saturation levels in the body. The 
picture has also been designed to provide a colouring-in activity for the child 
Healthcare providers: 
A member of the research team will approach the ward sister of each inpatient ward with written 
study information. We will ask for volunteer nurses to take part in the study and arrange in advance 
a suitable time for this to happen, at the convenience of the nurse and research team. Potential 
participant nurses will be given information sheets by the research team and have the opportunity 
to ask questions to the research team prior to consent being taken 
8.2 
Baseline assessments  
All children will be assessed for their age and clinical condition; children who are critically unwell will 
not be included in the study. Children with oxygen saturations of <95% will not be measured by the 
healthcare providers.  

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8.3 
Definition of end of study 
The study will be completed at the end of recruitment. There will not be any follow-ups of the 
healthcare providers or children involved in the study.  We anticipate the recruitment to take a 
maximum of 4 weeks.  
8.4 
Discontinuation/withdrawal of participants and ‘stopping rules’ 
The study will stop recruitment if the first 25 readings obtained by the expert user are deemed 
unreliable according to clinical criteria (i.e. unable to obtain a stable oxygen saturation reading 
within 5 minutes of application of the probe in a cooperative child). In this situation the redesigned 
probe and oximeter will be considered ‘unusable’.  
9 
Name and description of Investigational Device 
The study involves the use of the AH-MX pulse oximeter manufactured by Acare Technology Co Ltd 
(Taiwan), and a new prototype pulse oximeter probe manufactured for use with the AH-MX pulse 
oximeter, the Lifebox A2 pulse oximeter probe (MHRA Class 11b device).  
Pulse oximeters are comprised of two parts: the oximeter monitor and the oximeter probe. There is 
no change in the intended use of the pulse oximeter.  
1. The AH-MX Pulse Handheld Pulse Oximeter monitor 
The existing Lifebox pulse oximeter is the AH-MX Handheld Pulse Oximeter manufactured by Acare 
Technology Co Ltd in Taiwan.  
The AH-MX handheld pulse oximeter is intended for continuously monitoring or spot checking 
peripheral oxygen saturation (SpO2) and pulse rate (PR) for adult, paediatric or neonatal patients. 
This device can be used in institutions or units with health care capability. This includes outpatient 
departments, emergency rooms and departments of internal medicine in hospitals, ordinary 
departments in clinics, nursing hospitals and community medical institutions. It may also be used in 
the home. 
The AH-MX pulse oximeter has been CE marked according to the following safety standards: 
Safety: IEC 60601-1:2012-Ed.3.1 (EN 60601-1:2006/A1:2013)    
EMC: IEC 60601-1-2:2007-Ed.3.0 (EN 60601-1-2:2007/AC:2010)  
Pulse Oximeter consensus standard: (EN)ISO 80601-2-61:2011  
 
Modifications to the AH-MX Pulse Oximeter  
The AH-MX pulse oximeter monitor has been modified for this project  (AH-MX v3) 
There have been no changes to the hardware of the oximeter. The oximeter will be powered by 3 
commercially available AA alkaline batteries for the study. There has been no change to the intended 
use of the oximeter 
 
The software in the AH-MX oximeter has been upgraded to allow the oximeter to respond more 
quickly and more reliably at low perfusion in children 0-59 months. No oxygen saturation readings 
will be taken for clinical care during the study and there are no safety hazards associated with the 
upgraded software in this device.  
 
2. Lifebox A2 Pulse oximeter probe 
 

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The project team has designed a new prototype pulse oximeter probe for children 0-59 months (the 
Lifebox A2 probe), intended for use with the AH-MX pulse oximeter. This probe is the focus of this 
usability testing study. The probe has been designed to fit on the foot of infants, and the finger of 
older children and adults.  
 
The Lifebox pulse oximeter prototype probes are manufactured with the intent to make them 
suitable for human use.  The materials chosen are all currently in use as part of FDA and ISO cleared 
devices.  The outer shell is of a polycarbonate / acrylonitrile butadiene styrene (ABS) blend and the 
pads are silicone.  These materials are identical to those used in the Nellcor DS100a which has been 
in use globally for 25 years. The cable jacket is made of a polyurethane that has been FDA cleared 
and met ISO requirements in the Envisen Bridge FQ series of sensors which are also sold under 
EnviteC and Bluepoint brands. 
  
While the prototypes as assembled have not yet been subjected to a biocompatibility test, historical 
experience is that if only known biocompatible materials are used, the device will meet the 
requirements. 
  
Electrical safety of the sensors in all pulse oximeters is provided in the monitor. For the purpose of 
the study at GOSH the oximeter will be powered by 3 commercially available AA alkaline batteries. 
10 
Recording and reporting of adverse events and reactions 
10.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
subject where the trial medical device is used and which does not 
necessarily have a causal relationship with this treatment. 
Adverse Reaction (AR) 
Any untoward and unintended response in a subject where the trial 
medical device is used, which is related to the medical device.  
This includes uses outside of protocol (including misuse and abuse 
of product) 
Serious adverse event 
(SAE), serious adverse 
reaction (SAR) or 
unexpected serious 
adverse reaction  
Any adverse event, adverse reaction or unexpected adverse 
reaction, respectively, that: 
• 
results in death 
• 
is life-threatening 
• 
requires hospitalisation or prolongation of existing 
hospitalisation 
• 
results in persistent or significant disability or 
incapacity 
• 
consists of a congenital anomaly or birth defect 
Important Medical Event 
These events may jeopardise the subject or may require an 
intervention to prevent one of the above 
characteristics/consequences. Such events should also be 
considered ‘serious’. 
Unexpected adverse 
reaction 
An adverse reaction the nature and severity of which is not 
consistent with the information about the device in question set 
out in the investigator's brochure relating to the trial in question. 

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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
10.2 
Recording adverse events 
All adverse events will be recorded in the child’s medical records following consent. If the clinical 
researcher suspects that the subjects’ clinical condition has been affected by the oxygen saturation 
measurement, then they will record and report this as an unexpected adverse event. All adverse 
events will be recorded with clinical symptoms and accompanied with a simple, brief description of 
the event.  All adverse events will be recorded until the oxygen saturation observation is completed.  
10.3 
Assessments of Adverse Events 
Each adverse event will be assessed for the following criteria: 
10.2.1 
Severity  
Category 
Definition 
Mild 
The adverse event does not interfere with the volunteer’s daily routine, and 
does not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the volunteer’s routine, or 
requires intervention, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
 

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10.2.2 
Causality 
The assessment of relationship of adverse events to the pulse oximetry measurement is a clinical 
decision based on all available information at the time of the completion of the measurement.  The 
following categories will be used to define the causality of the adverse event: 
Category 
Definition 
Definitely: 
There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the 
event occurred within a reasonable time after administration of the 
trial medication). However, the influence of other factors may have 
contributed to the event (e.g. the patient’s clinical condition, other 
concomitant events). 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. 
the event did not occur within a reasonable time after 
administration of the trial medication). There is another reasonable 
explanation for the event (e.g. the patient’s clinical condition, other 
concomitant treatments). 
Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 
 
10.2.3 Expectedness 
Category 
Definition 
Expected 
An adverse event that is classed in nature as serious and which is 
consistent with the information about the pulse oximeter and probe 
listed in the Investigator Brochure or clearly defined in this 
protocol. 
Unexpected 
An adverse event that is classed in nature as serious and which is not 
consistent with the information about the pulse oximeter and probe 
in the Investigator Brochure  
 
10.2.4 Seriousness 
Seriousness as defined for an SAE in section 10.1. Collection, recording and reporting of adverse 
events (including serious and non-serious events and reactions) to the sponsor will be completed 
according to the sponsor’s guidelines. 
 

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10.3 
Procedures for recording and reporting Serious Adverse Events 
All serious adverse events will be recorded in the medical notes. The CI will submit a serious adverse 
event notification and send this to the sponsor within one working day of becoming aware of the 
event. The CI will respond to any SAE queries raised by the sponsor as soon as possible.  
All SUSARs will be notified to the sponsor immediately (or at least within one working day). The 
sponsor will notify the REC and MHRA of all SUSARs.  SUSARs that are fatal or life-threatening will be 
notified to the MHRA and REC within 7 days after the sponsor has learned of them.  Other SUSARs 
must be reported to the REC and MHRA within 15 days after the sponsor has learned of them.   
10.4 
Annual progress reports 
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended. The CI will 
prepare the APR. 
10.5 
Reporting Urgent Safety Measures  
If any urgent safety measures are taken the CI and Sponsor shall immediately and in any event no 
later than 3 days from the date the measures are taken, give written notice to the MHRA and the 
relevant REC of the measures taken and the circumstances giving rise to those measures. 
10.6 
Notification of Serious Breaches to GCP  
 A “serious breach” is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the subjects of the study 
(b) the scientific value of the study 
The study sponsor will notify the licensing authority in writing of any serious breach of the 
conditions and principles of GCP in connection with the study or the protocol relating to the study, 
within 7 days of becoming aware of that breach. The sponsor will be notified immediately of any 
case where the above definition applies during the study.   
11 
Data management and quality assurance 
11.1 
Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. All data collected will 
not bear the subject’s name or other personal identifiable data.  A study assigned patient and 
healthcare provider ID will be used for identification. 
11.2 
Data collection tools  
Data collection will be done using Android tablets for the observational data and with paper forms 
for the usability questionnaire. These data collection tools have been developed for the purpose of 
this study, but are based on the Systems Usability Scale and tools developed by the Malaria 
Consortium for evaluating pulse oximeter performance. The tools have been piloted with the study 
team and will be piloted with end-users prior to implementation.  

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It will be the responsibility of the investigator to ensure the accuracy of all data entered in the 
electronic form.  
11.3 
Data handling and analysis 
All observational data will be collected using ODK Collect on an Android tablet. Validation rules will 
be in-built in the ODK Collect form on the tablet (i.e. not allowing input of invalid values). The tablet 
will be password protected and the data uploaded to a secure server, which only study personnel 
can access, with password and username protection. Data will be downloaded as a CSV file and 
converted to a Stata file. All electronic data will be stored on secure University servers, accessed on 
password protected computers.  
The usability questionnaire will be collected on paper. Quantitative answers will be entered into an 
Access database and exported into a Stata file. Qualitative data will be analysed directly from the 
paper forms, with specific quotes transcribed into Microsoft Word. All paper data will be stored in 
locked cabinets in the Lifebox office.  
12 
Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report. All 
paper data will be archived in a locked cabinet in the Lifebox offices, and all databases and electronic 
data will be stored on secure University and Lifebox servers.   
The CI is ultimately responsible for the secure archiving of essential trial documents and the study 
database. All essential documents will be archived for a minimum of 5 years after completion of the 
study. Destruction of essential documents will require authorisation from the Sponsor.   
13 
Statistical Considerations  
13.1 
Outcomes 
13.1.1 Primary outcomes 
The primary outcome in the study is the proportion of measurements in which a stable oxygen 
saturation reading was obtained within 60 seconds of placing the pulse oximetry probe by all 
healthcare providers. This will be measured in both expert users and healthcare providers and the 
results pooled 
13.1.2 Secondary outcomes 
Secondary study outcomes include: 
- 
The difference in the time to a stable oximetry reading for expert users compared to 
healthcare providers in different settings 
- 
The difference in the time to a stable oximetry reading for children of different age 
- 
Qualitative evaluation of the usability of the probe and oximeter 
- 
The fit of the probe on the child's hand or foot 
- 
The child’s tolerance for the probe  

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13.2 
Sample size and recruitment 
13.2.1 Sample size calculation 
To calculate 95% of measurements being stable within 60 seconds (as per the target product profile) 
with 2.5% precision and 95% confidence intervals requires 292 measurements. This is calculated 
using the standard formula to calculate a sample size for estimating a proportion:  
 
n>= (Z2 x p(1-p))/e2  
1  
(Z = confidence interval; p = expected true proportion; e = desired precision, half the desired CI 
width) 
 
n>= (0.952 x 0.95(1-0.95))/0.0252 
n>= 292 
 
The FDA HF/UE guidance and IEC 62366 state that at least 15 participants should be included from 
each identified user group interacting with the device. We intend to include 17 trained healthcare 
workers from a high-income setting, and 17 from each of two low-income settings where there is a 
high burden of disease in children, and where the Lifebox pulse oximeter is supplied. Each end-user 
will take 12 measurements (3 from each of four different age-group stratifications of children). This 
gives a total of 204 measurements from each user-type in each setting. In addition to our pooled 
primary analysis, this will give us enough power to conduct pooled stratified analyses by site and age 
group.   
The primary outcome will be a pooled analysis from all the participating sites, stratified by expert 
user and healthcare provider. Studying this number of healthcare workers will give the study 
sufficient power to undertake sub-group analysis by site and by age of the children assessed.  
A summary of the stratified analyses is presented in the table below: 
 
 
 
Primary Analysis 
GOSH 
Malawi 
Bangladesh Total (2 sites) 
Total (3 sites) 
Healthcare providers 
204 
204 
204 
408 
612 
Expert users 
204 
204 
204 
408 
612 
All measures 
408 
408 
408 
816 
1,224 
Sub-Analysis 
 
 
 
 
 
Neonates (HCW + expert) 
102 
102 
102 
204 
306 
Infants (HCW + expert) 
Toddler (HCW + expert) 
102 
102 
102 
102 
102 
102 
204 
204 
306 
306 
                                                          
1. For an online calculator: 
http://epitools.ausvet.com.au/content.php?page=1Proportion&Proportion=0.95&Conf=0.95&Precision=0.025&Po
pulation  

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Child (HCW + expert) 
102 
102 
102 
204 
306 
*shaded cell indicates sufficient power 
 
13.2.2 Planned recruitment rate 
We estimate that for 3 healthcare providers to take 12 oxygen saturation measurements will take up 
to one day. The expert will be taking oxygen saturation readings in parallel. Therefore, allowing for 
healthcare provider availability and patient turn-over on the inpatient wards, we anticipate 
recruitment to take a maximum of 3 weeks.  
13.3 
Statistical analysis plan 
13.3.1 Primary outcome analysis 
We will calculate the proportion of readings that meet the target product profile requirement of 
95% stable readings within 60 seconds. Differences in the proportion of successful readings will be 
compared between the expert and healthcare providers, between different age groups of children, 
and between the UK, Bangladesh and Malawi. This will be done using chi2 tests. All descriptive 
analyses will be done using Stata 14.  
13.3.2 Secondary outcome analysis 
We will describe the time to stable reading, looking at the median time and inter-quartile range. We 
will compare these descriptive statistics between patient age groups, expert and healthcare provider 
participants, and with measurements from Malawi and Bangladesh. We will look for statistical 
differences between these sub-groups using t-tests. Descriptive analysis of the observational data on 
usability, including correct positioning and number of re-positions of the probe, will be conducted. 
Qualitative questionnaire data will be analysed using an inductive thematic approach. 
13.3.3 Sensitivity and other planned analyses 
We will collect limited data on the number of children in whom we were unable to take 
measurements, recording their age and clinical condition to compare with those who we were able 
to take a measurement. We will compare the age distribution between the two groups, to give an 
indicator of age-bias in successful measurements.  
13.4 
Name of Committees involved in trial 
There will be structured oversight and reporting of the project. A Project Management Group (PMG), 
chaired by the CI will be overseeing the study. This committee will also serve the function of the 
Data Monitoring Committee, with expertise in observational studies and statistics.  
We have set up a project advisory group composed of international experts in pulse oximetry who 
have given input into the design and monitoring of the project and will be invited to provide 
feedback on the redesigned oximeter probe. They will be given regular updates on the progress of 
the study, and will act as an independent advisory committee.   
We have also involved the GOSH Patient and Public Involvement and Engagement (PPI/E) Team, for 
input into the study documents, and will feedback results from the study.  

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14 
Direct Access to Source Data/Documents 
The investigators will permit study-related monitoring, audits, REC review, and regulatory 
inspection, providing direct access to study documents.  Study participants will be informed of this 
during the informed consent discussion.   
15 
Ethics and regulatory requirements 
The sponsor will ensure that the study protocol, patient information sheet and consent form have 
been approved by the MHRA, HRA and research ethics committee, prior to any patient recruitment. 
The protocol and all agreed substantial protocol amendments, will be documented and submitted 
for ethical and regulatory approval prior to implementation. Within 90 days after the end of the 
study, the CI will ensure that the REC and MHRA are notified that the study has finished.  If the study 
is terminated prematurely, those reports will be made within 15 days after the end of the study. The 
CI will supply the Sponsor with a summary report of the study, which will then be submitted to the 
MHRA and REC within 1 year after the end of the trial.  
16 
Monitoring 
The sponsor will determine the appropriate level and nature of monitoring required for the trial.  
Risk will be assessed on an ongoing basis and adjustments made accordingly. The degree of 
monitoring will be proportionate to the risks associated with the trial. A trial specific oversight and 
monitoring plan will be established for studies. The trial will be monitored in accordance with the 
agreed plan. 
17 
Finance 
The study is funded by the Bill and Melinda Gates Foundation [grant code: OPP1133291]. The CI and 
all co-investigators declare no competing financial interests. 
18 
Insurance 
The Lifebox Foundation has purchased Clinical Trials Liability Insurance from CFC Underwriting. The 
sum insured is £5,000,000 for any one claim and in the aggregate. The basis is claims occurring 
during the period of the insurance. The period of insurance is for 5 years from the start of the trial.  
Great Ormond Street Hospital provides clinical negligence insurance cover for harm caused by GOSH 
employees under the NHS indemnity scheme. 
Participants may also be able to claim compensation for injury caused by participation in this clinical 
trial without the need to prove negligence on the part of University College London or another party.  
Participants who sustain injury and wish to make a claim for compensation should do so in writing in 
the first instance to the Chief Investigator, who will pass the claim to the Sponsor’s Insurers, via the 
Sponsor’s office. 
19 
Statement of compliance 
The trial will be conducted in compliance with the approved protocol, the UK Regulations, EU GCP 
and the applicable regulatory requirement(s). 
20 
References  

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Methodology: 
1. Field guide to Human Centered Design by IDEO.org (http://www.designkit.org) 
 
2. Description of usability testing from the British Standards Institute 
(http://www.bsigroup.com/LocalFiles/es-
ES/Medical%20devices/Papel_ingenieria_usabilidad_dispositivos_medicos_BSI.pdf) 
 
3. US Department for Health and Human Services, Food and Drug Administration. Applying human 
factors and usability engineering to medical devices. Guidance for Industry and Food and Drug 
Administration staff. February 2016. 
http://www.fda.gov/downloads/MedicalDevices/.../UCM259760.pdf 
 
Scientific Publications: 
1. Burn SL, Chilton PJ, Gawande AA, Lilford RJ. Peri-operative pulse oximetry in low-income 
countries: a cost-effectiveness analysis. Bull World Health Organ. 2014 Dec 
1;92(12):858-67. doi: 10.2471/BLT.14.137315. Epub 2014 Sep 24. Review. 
 
2. Finch LC, Kim RY, Ttendo S, Kiwanuka JK, Walker IA, Wilson IH, Weiser TG, Berry 
WR, Gawande AA. Evaluation of a large-scale donation of Lifebox pulse oximeters 
to non-physician anaesthetists in Uganda. Anaesthesia. 2014 May;69(5):445-51. 
doi: 10.1111/anae.12632. 
 
3. Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, Cousens S, Mathers C, Black 
RE. Global, regional, and national causes of child mortality in 2000-13, with 
projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 
2015 Jan 31;385(9966):430-40. doi: 10.1016/S0140-6736(14)61698-6. Epub 2014 
Sep 30. Erratum in: Lancet. 2015 Jan 31;385(9966):420. Lancet. 2016 Jun 
18;387(10037):2506. 
 
4. Duke T, Wandi F, Jonathan M, Matai S, Kaupa M, Saavu M, Subhi R, Peel D. 
Improved oxygen systems for childhood pneumonia: a multihospital effectiveness 
study in Papua New Guinea. Lancet. 2008 Oct 11;372(9646):1328-33. doi: 
10.1016/S0140-6736(08)61164-2. Epub 2008 Aug 15. 
 
5. Bhutta ZA, Das JK, Walker N, Rizvi A, Campbell H, Rudan I, Black RE; Lancet 
Diarrhoea and Pneumonia Interventions Study Group. Interventions to address 
deaths from childhood pneumonia and diarrhoea equitably: what works and at what 
cost? Lancet. 2013 Apr 20;381(9875):1417-29. doi: 10.1016/S0140-6736(13)60648- 
0. Epub 2013 Apr 12. 
6. Matai S, Peel D, Wandi F, Jonathan M, Subhi R, Duke T. Implementing an oxygen 
programme in hospitals in Papua New Guinea. Ann Trop Paediatr. 2008 
Mar;28(1):71-8. doi: 10.1179/146532808X270716. 
 
7. Soofi S, Ahmed S, Fox MP, MacLeod WB, Thea DM, Qazi SA, Bhutta ZA. 
Effectiveness of community case management of severe pneumonia with oral 
amoxicillin in children aged 2-59 months in Matiari district, rural Pakistan: a cluster randomised 
controlled trial. Lancet. 2012 Feb 25;379(9817):729-37. doi: 
10.1016/S0140-6736(11)61714-5. Epub 2012 Jan 27. 
 
8. Yeboah-Antwi K, Pilingana P, Macleod WB, Semrau K, Siazeele K, Kalesha P, 
Hamainza B, Seidenberg P, Mazimba A, Sabin L, Kamholz K, Thea DM, Hamer DH. 
Community case management of fever due to malaria and pneumonia in children 

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under five in Zambia: a cluster randomized controlled trial. PLoS Med. 2010 Sep 
21;7(9):e1000340. doi: 10.1371/journal.pmed.1000340. 
 
9. Faulkner L. Beyond the five-user assumption: benefits of increased sample sizes in 
usability testing. Behav Res Methods Instrum Comput. 2003 Aug;35(3):379-83.