Describing the Differences in Oxygen Profiles in Premature Infants of Less Than 29 Weeks Gestational Age When Targeted to an Oxygen Saturation Range 92 to 97%, Compared to 90 to 95%
Phase: NA
Conditions: Premature Infant, Hypoxia, Hyperoxia
Sponsor: University of Edinburgh

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Non-CTIMP Study Protocol 
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Sponsor 
The University of Edinburgh and Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Sponsor Representative 
Chris Coner  
Protocol authors 
Rod Kelly, Ben Stenson 
Funder 
 
Funding Reference Number 
 
Chief Investigator 
Rod Kelly 
Sponsor number 
AC17098 
REC Number 
 
Project registration 
 
Version Number and Date 
Version 3 – 27 Nov 2017  
 
 
 
 
 
 
 

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CONTENTS 
1 
INTRODUCTION .......................................................................................................... 7 
1.1 
BACKGROUND ................................................................................................... 7 
1.2 
RATIONALE FOR STUDY ................................................................................... 7 
2 
STUDY OBJECTIVES .................................................................................................. 8 
2.1 
OBJECTIVES ...................................................................................................... 8 
2.1.1 
Primary Objective .............................................................................................. 8 
2.1.2 
Secondary Objectives ....................................................................................... 8 
3 
STUDY DESIGN ........................................................................................................... 9 
4 
STUDY POPULATION ............................................................................................... 10 
4.1 
NUMBER OF PARTICIPANTS ........................................................................... 10 
4.2 
INCLUSION CRITERIA ...................................................................................... 10 
4.3 
EXCLUSION CRITERIA ..................................................................................... 10 
4.4 
CO-ENROLMENT .............................................................................................. 10 
5 
PARTICIPANT SELECTION AND ENROLMENT ...................................................... 11 
5.1 
IDENTIFYING PARTICIPANTS ......................................................................... 11 
5.2 
CONSENTING PARTICIPANTS ........................................................................ 11 
5.2.1 
Withdrawal of Study Participants ..................................................................... 11 
6 
STUDY ASSESSMENTS ........................................................................................... 11 
6.1 
STUDY ASSESSMENTS ................................................................................... 11 
7 
DATA COLLECTION ................................................................................................. 11 
8 
STATISTICS AND DATA ANALYSIS ........................................................................ 11 
8.1 
SAMPLE SIZE CALCULATION .......................................................................... 11 
8.2 
PROPOSED ANALYSES ................................................................................... 12 
9 
ADVERSE EVENTS ................................................................................................... 12 
9.1 
DEFINITIONS .................................................................................................... 12 
9.2 
IDENTIFYING AEs AND SAEs .......................................................................... 13 
9.3 
RECORDING AEs AND SAEs ........................................................................... 13 
9.4 
ASSESSMENT OF AEs AND SAEs ................................................................... 13 
9.4.1 
Assessment of Seriousness ............................................................................ 13 
9.4.2 
Assessment of Causality ................................................................................. 13 
9.4.3 
Assessment of Expectedness ......................................................................... 13 
9.4.4 
Assessment of Severity ................................................................................... 14 
9.5 
REPORTING OF SAEs/SARs/SUSARs ............................................................. 14 
9.6 
REGULATORY REPORTING REQUIREMENTS ............................................... 14 
9.7 
FOLLOW UP PROCEDURES ............................................................................ 14 
10 
OVERSIGHT ARRANGEMENTS ............................................................................... 15 
10.1 
INSPECTION OF RECORDS ............................................................................ 15 
10.2 
RISK ASSESSMENT ......................................................................................... 15 
10.3 
STUDY MONITORING AND AUDIT ................................................................... 15 
The ACCORD Sponsor Representative will assess the study to determine if 
an independent risk assessment is required.  If required, the 
independent risk assessment will be carried out by the ACCORD 

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Quality Assurance Group to determine if an audit should be performed 
before/during/after the study and, if so, at what frequency. ................................ 15 
11 
GOOD CLINICAL PRACTICE .................................................................................... 15 
11.1 
ETHICAL CONDUCT ......................................................................................... 15 
Before the study can commence, all required approvals will be obtained and 
any conditions of approvals will be met. ............................................................. 15 
11.2 
INVESTIGATOR RESPONSIBILITIES ............................................................... 15 
11.2.1 Informed Consent ........................................................................................... 15 
11.2.2 Study Site Staff ............................................................................................... 16 
11.2.3 Data Recording ............................................................................................... 16 
11.2.4 Investigator Documentation ............................................................................. 16 
11.2.5 GCP Training .................................................................................................. 16 
11.2.6 Confidentiality ................................................................................................. 16 
11.2.7 Data Protection ............................................................................................... 16 
12 
STUDY CONDUCT RESPONSIBILITIES ................................................................... 17 
12.1 
PROTOCOL AMENDMENTS ............................................................................. 17 
12.2 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ..................................... 17 
12.3 
SERIOUS BREACH REQUIREMENTS ............................................................. 17 
12.4 
STUDY RECORD RETENTION ......................................................................... 17 
12.5 
END OF STUDY ................................................................................................ 17 
12.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY .............................................................................................................. 18 
12.7 
INSURANCE AND INDEMNITY ......................................................................... 18 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ........................ 18 
13.1 
AUTHORSHIP POLICY ..................................................................................... 18 
14 
REFERENCES ........................................................................................................... 18 
 

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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - Joint office 
for The University of Edinburgh and Lothian Health Board 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
PI 
Principal Investigator 
QA 
Quality Assurance 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 

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1 
INTRODUCTION 
1.1 
BACKGROUND 
The aim of oxygen therapy is to deliver sufficient oxygen to tissues to maintain tissue function 
and avoid adverse consequences, whilst minimising oxidative stress and oxygen toxicity. It is 
unclear how best to achieve this balance in premature infants, who are at high risk of 
developing oxygen-related morbidities because of their relative lack of antioxidant protection. 
 
Oxygenation can be monitored by measurement of pulse oximeter oxygen saturation (SpO2), 
which estimates the percentage of haemoglobin (an oxygen carrying molecule in red blood 
cells) binding sites occupied by oxygen, using a transcutaneous monitor to measure 
transcutaneous partial pressure of oxygen (TcPO2) which is the amount of oxygen diffusing 
across the skin, or by measuring the partial pressure of oxygen (PaO2) dissolved in arterial 
blood.  
 
The gold-standard for assessing oxygen levels is accepted to be arterial oxygen tension 
(PaO2) but measuring this is invasive and it cannot be measured continuously. SpO2 
monitoring provides a continuous, non-invasive measure, but SpO2 and PaO2 are related in a 
complicated, non-linear way. TcPO2 and PaO2 levels correlate well and are related in a linear 
way. 
 
In the early 2000s a number of cohort studies gave conflicting results about the optimum 
oxygen range in preterm babies. Therefore consensus was achieved to conduct a prospective 
meta-analysis of oxygen targeting studies, of sufficient power to test the hypothesis that a 
strategy of maintaining a functional SpO2 level in a “lower” (85-89%) versus a “higher” (91-
95%) range early in the course of extremely low gestational age neonates reduces the 
incidence of severe ROP without increasing important adverse neonatal outcomes(1). The 
Neonatal Oxygenation Prospective Meta-analysis (NeOProM) involved data from the 
SUPPORT, BOOST II Australia, BOOST NZ, COT, and BOOST II UK trials and was powered 
to detect a small but important 4% increase in death or severe disability in survivors(2). 
 
Three recent systematic reviews and meta-analyses using data from the five studies that 
make up the NeOProM collaboration have all revealed a significant increase in the risk of 
death associated with targeting infants to the lower SpO2 range. Saugstad OD, Aune D(3) 
found relative risks (RR; 95% CIs) comparing a low versus a high oxygen saturation target 
were 1.41 (1.14-1.74) for mortality at discharge or at follow-up.  Manja and 
Lakshminrusimha(4) found a significant increase in mortality before hospital discharge in 
infants targeted to the lower SpO2 range (RR, 1.18 [95% CI, 1.03-1.36]). Askie et al.(5) found a 
lower SpO2 target range significantly increased the incidence of death at 18 to 24 months 
corrected age (typical RR 1.16, 95% CI 1.03 to 1.31; typical RD 0.03, 95% CI 0.01 to 0.05; 5 
trials, 4873 infants). 
 
As described above, the search for the optimum oxygen level to target preterm infants to is 
still ongoing. Although there is very good evidence targeting infants to a lower oxygen level 
results in harm, it is not clear whether the higher target level used in the NeOProM studies 
achieves the optimum survival advantage. 
1.2 
RATIONALE FOR STUDY 
There is still considerable uncertainty about what oxygen levels premature babies should be 
targeted too. Although there is clear evidence that targeting babies to a lower oxygen 
saturation (SpO2) level is associated with harm, it is not clear whether we have found the 
optimum oxygen target level which maximises survival benefit. 
We believe the question of oxygen targeting is an important one in neonatology, and this 
proposal would be a safe and reliable way of characterising the actual oxygen levels achieved 
at a higher SpO2 target range. We hope the results of this study would inform a larger 
research study using higher SpO2 limits and powered to analyse clinical outcomes.  

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Because very high oxygen levels may cause 
harm (such as increasing the risk of retinopathy of prematurity - a condition that although 
treatable can affect vision), it is prudent to increase oxygen target limits by small increments, 
and for a short amount of time. This is why we are proposing a small increase in SpO2 target 
limits from 90-95% to 92-97%, for a short period (6 hours).  
Based on previous research it is very unlikely that these slightly higher ranges will be 
associated with hyperoxia (high levels of oxygen in the blood), but it is also sensible to 
monitor oxygen levels by more than just SpO2, as SpO2 is not the best way of measuring 
hyperoxia. This is why we are proposing to use transcutaneous oxygen monitoring (TcPO2) 
throughout the study, as previous research has demonstrated TcPO2 is better at detecting 
hyperoxia than SpO2.  
In order to minimise confounding factors, we propose that infants act as their own controls, 
being randomised either a higher or standard SpO2 target limit, and then crossing over to the 
other SpO2 target range after 6 hours.  
As described above, we feel that the research question is an important one, and our proposal 
will be able to answer it. We believe this proposal minimises risk to infants. Although previous 
research has suggested a very high levels of oxygen are associated with increased risk of 
ROP, there is good evidence to suggest that our proposed slightly higher SpO2 range will not 
be associated with hyperoxia, and the use of TcPO2 is an additional safety measure. We 
need to balance the risk of ROP with the very real risk that we are missing the opportunity to 
reduce mortality in premature babies by not using an SpO2 target range that is high enough 
to achieve maximum survival advantage.  
Written informed consent will be sought from the parents of eligible infants by research staff 
trained in GCP, and all information will be handled in accordance with Caldicott principles. 
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
To discover the percentage time spent above an SpO2 of 97% and below an SpO2 of 90% 
when infants are targeted to an SpO2 range of 92-97% compared to 90-95% 
2.1.2 Secondary Objectives 
To discover the percentage time spent above a TcPO2 of 80mmHg and below a TcPO2 of 
50mmHg when infants are targeted to an SpO2 range of 92-97% compared to 90-95% 
 
To discover the variability in SpO2 (measured by standard deviation) when infants are 
targeted to an SpO2 range of 92-97% compared to 90-95% 
 
To discover the variability in TcPO2 (measured by standard deviation) when infants are 
targeted to an SpO2 range of 92-97% compared to 90-95% 
 
In infants who are undergoing PaO2 measurement as part of their routine care describe the 
PO2 values observed in the two target ranges. 
 
To generate a pooled frequency histogram of percentage time at each SpO2 point between 80 
and 100% for infants targeted to an SpO2 range of 92-97% compared to 90-95% 
 
To generate a pooled frequency histogram of percentage time at a TcPO2 of below 30mmHg, 
30-39.9mmHg, 40-49.9mmHg, 50-59.9mmHg, 60-69.9mmHg, 70-79.9mmHg, and 80mmHg 
and above for infants targeted to an SpO2 range of 92-97% compared to 90-95% 

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3 
STUDY DESIGN 
Summary  
This study is a single centre randomised crossover study. Infants born at less than 29 weeks 
gestation, greater than 48 hours of age and receiving supplementary oxygen would be eligible 
for inclusion. The study is at the Royal Infirmary of Edinburgh. Total study time is 12 hours for 
each infant (6 hours at the standard 90-95% range used in our unit, and 6 hours at 92-97%). 
It is a crossover study with infants acting as their own controls.  
A complete list of all monitoring that will be carried out is shown below: 
1. SpO2 monitoring 
2. TcPO2 monitoring 
3. Heart rate monitoring (used to validate SpO2 readings as described below) 
4. Arterial gas sampling (only if conducted by the direct care team as part of the routine care 
of the infant will these be recored. No extra blood samples will be taken as part of the study) 
 
Design 
Each infant will be monitored simultaneously with an SpO2 monitor and TcPo2 monitor, with 
data recording starting from the time the transcutaneous monitor finishes calibrating. SpO2 
readings will be downloaded directly from the multiparameter patient monitor. SpO2 will be 
measured using a Siemens Infinity SC7000 multiparameter monitor (Siemens Medical 
Systems, Danvers MA). This monitor uses Siemens’ Oxisure pulse oximetry technology and 
Nellcor Oximax (Nellcor Puritan Bennett, CA, USA) saturation probes and incorporates ECG 
to reduce motion artefact. To reduce the influence of artefact further, data from an infants 
chest leads (recording heart rate) will also be downloaded. If there is a greater than 10beats 
per minute difference between heart rate measured from the pulse oximeter and heart rate 
measured from the chest leads, SpO2 for that time point will be disregarded. 
TcPO2 will be measured using a SenTec Digital Monitoring System with OxiVent sensor 
(SenTec AG, Switzerland, European patent No. 1535055, CE 0120). TcPO2 is calculated by 
dynamic fluorescence quenching which measures oxygen molecules present in the vicinity of 
a fluorescent dye incorporated within the sensor surface. The sensor is operated at a 
constant temperature of 43 degrees Celsius. Control of sensor temperature and application 
duration are designed to meet all applicable standards and this monitoring device is used 
routinely in many neonatal units, with transcutaneous monitoring part of the monitoring 
equipment we use in selected infants in our unit and being transported by our local neonatal 
transport team. Temperature is supervised by two independent circuits, as well as by the 
monitor firmware.  
Transcutaneous data will be transferred contemporaneously to a bedside PC via the 
proprietary software V-STATS (with V-CareNeT) version 4.01 (SenTec AG, Ringstrasse 39, 
CH-4106 Therwill, Switzerland). We will ensure the time on the monitor is synchronised with 
the time displayed on the electronic patient record system recording SpO2 and heart rate. V-
STATS software can identify any spurious spikes in TcPO2 caused by air bubbles and these 
identified segments of data will be discarded. Artefact has not significantly affected readings 
during the routine use of this monitor previously on our neonatal unit and with our neonatal 
transport team. The site of the transcutaneous probe will be rotated on each infant every 2 
hours.  
SpO2, TcPO2 and heart rate data will be recorded every second. The time of any arterial 
oxygen samples taken routinely during the study will be recorded from the unit blood gas 
analyser (ABL800 FLEX, Radiometer, Denmark, 2005). 
 

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4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
A sample of 20 preterm babies born at the Royal Infirmary of Edinburgh meeting the inclusion 
criteria will be recruited. Because we are obtaining pilot data to inform the design of future 
studies we do not have a basis for a power calculation 
4.2 
INCLUSION CRITERIA 
Infants born at less than 29 weeks gestation 
Infants greater than 48 hours of age 
Infants who are receiving supplementary oxygen 
4.3 
EXCLUSION CRITERIA 
Congenital anomalies that would affect oxygenation (eg. cardiac defects, congenital 
diaphragmatic hernia) 
4.4 
CO-ENROLMENT 
The neonatal unit frequently conducts research projects - both single centre and multicentre 
projects. There is no contraindication to participating in this research if currently enrolled in 
another study. We have found that parents greatly appreciate being involved in studies, and 
are unlikely to be overwhelmed by being approached for multiple studies. Parents are made 
aware that they are free to decline to participate in any study without giving a reason. 

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5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
Potential participants would initially be identified by the direct care team. 
5.2 
CONSENTING PARTICIPANTS 
The parents of babies born at less than 29 weeks gestation will be approached by a member 
of the research team and given an information leaflet. If parents then would like to discuss the 
study further, a member of the research team (with appropriate GCP training) will discuss this 
with them at their convenience, and ask for consent if they are willing to participate. 
 
5.2.1 Withdrawal of Study Participants 
Parents will be free to withdraw their infant from study at any time without having to give a 
reason. As the study involves routinely used equipment and is of short duration it is not 
anticipated that this will happen. 
6 
STUDY ASSESSMENTS 
6.1 
STUDY ASSESSMENTS 
By targeting babies to higher oxygen saturation levels there is a possibility that they will be 
subjected to higher oxygen levels than previously recommended for short periods. Previous 
research and audit of our unit’s blood gas machine results suggests that at a SpO2 target 
range of 92 to 97% this is very unlikely, and is in fact more likely to keep babies’ within the 
previously suggested oxygen tension target range. In addition, the use of the transcutaneous 
monitor with upper limit alarms enabled, mitigates the risk of high PaO2 levels, and the very 
short study period means infants are only targeted to slightly higher oxygen levels for 6 hours. 
 
Transcutaneous oxygen monitoring is part of routine clinical practice. The use of 
transcutaneous probes have in the past been associated with transient skin redness in 
preterm babies’ skin (as the probe is heated). Modern devices use a lower temperature than 
those used in previous research, and probes have safety mechanisms whereby the probe is 
no longer heated if it is left in place for longer than the recommended time.  
7 
DATA COLLECTION 
The study diagram is section 3 details the timepoints and data collected during each study 
period. Collection of data is contemporaneous and checked for validity as described above. 
Valid and anonymised SpO2 and TcPO2 will then be used in the analysis.  
8 
STATISTICS AND DATA ANALYSIS 
8.1 
SAMPLE SIZE CALCULATION 
This is a pilot study to inform a larger study of SpO2 and possibly TcO2 ranges. 
Recruitment is planned to end when 20 babies have been recruited and randomised. Based 
on the frequency of delivery of preterm babies in our unit we estimate the study to last 1 year.  

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8.2 
PROPOSED ANALYSES 
For each group we will calculate the percentage of readings above an SpO2 of 97% and 
below an SpO2 of 92%. These percentages will then be compared between groups by using a 
Student’s T-test. 
The variability of SpO2 for each group will be expressed by calculating the standard deviation 
of all the valid SpO2 data points in each group. Comparison between variability between 
groups will be performed by Student’s T-test. 
Pooled SpO2 data from each infant randomised to the 90-95% SpO2 group will then be used 
to generate time at each SpO2 point for the group as a whole, expressed as a percentage of 
the total number of valid SpO2 readings. This process will then be repeated for the 92-97% 
SpO2 target range group.  
Pooled TcPO2 data from each infant randomised to the 90-95% SpO2 group will then be used 
to generate time within the following TcPO2 ranges for the group as a whole:  below 30mmHg, 
30-39.9mmHg, 40-49.9mmHg, 50-59.9mmHg, 60-69.9mmHg, 70-79.9mmHg, and 80mmHg 
and above. This will be expressed as a percentage of the total number of valid TcPO2 
readings. This process will then be repeated for the 92-97% SpO2 target range group.  
9 
ADVERSE EVENTS 
This study uses monitoring equipment that has been used routinely in neonatal units for many 
years, and therefore the risk of adverse events is small. By targeting babies to higher oxygen 
saturation levels there is a possibility that they will be subjected to higher oxygen levels than 
previously recommended for short periods. Previous research and audit of our unit’s blood 
gas machine results suggests that at a SpO2 target range of 92 to 97% this is very unlikely, 
and is in fact more likely to keep infants within the previously suggested oxygen tension target 
range. The risk of hyperoxia in infants is mitigated by the short study period and the use of 
transcutaneous monitoring which detects hyperoxia better than saturation monitoring.  
 
The researcher will be present throughout the short study period for each infant. If the direct 
care team feel that the additional monitoring equipment is interfering in any way with routine 
care of the infant, the study will be discontinued in that infant.  
9.1 
DEFINITIONS 
This study is not a drug study. The following concerns definitions and reporting of adverse 
events that may arise due to the study intervention (targeting infants briefly to a slightly higher 
oxygen saturation range). 
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant which 
does not necessarily have a causal relationship with the study intervention.  
An adverse reaction (AR) is any untoward and unintended response to the study 
intervention.  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR that: 
 
results in death of the clinical trial participant; 
 
is life threatening* 
 
requires in-patient hospitalisation^ or prolongation of existing hospitalisation; 
 
results in persistent or significant disability or incapacity; 
 
consists of a congenital anomaly or birth defect; 
 
results in any other significant medical event not meeting the criteria above. 
 

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*Life-threatening in the definition of an SAE or 
SAR refers to an event where the participant was at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it were more 
severe. 
 
^Any hospitalisation that was planned prior to randomisation will not meet SAE criteria. Any 
hospitalisation that is planned post randomisation will meet the SAE criteria. 
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is classified as 
serious and is suspected to be caused by the study intervention, that it is not consistent with 
previous research and hypotheses highlighted in the Study Protocol.  
9.2 
IDENTIFYING AEs AND SAEs 
All AEs and SAEs will be recorded from the time a baby commences the first study period 
until 1 week after the final participant has completed the study. Adverse incidents may include 
skin redness following the use of transcutaneous probes or periods of hyperoxia. 
9.3 
RECORDING AEs AND SAEs 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g. hospital notes, laboratory and diagnostic reports) related to the event.  The Investigator 
will then record all relevant information in the CRF and on the SAE form (if the AE meets the 
criteria of serious). 
Information to be collected includes type of event, onset date, Investigator assessment of 
severity and causality, date of resolution as well as treatment required, investigations needed 
and outcome.   
9.4 
ASSESSMENT OF AEs AND SAEs 
Seriousness, causality, severity and expectedness will be assessed by the Principal 
Investigator. The Investigator is responsible for assessing each AE.   
The Chief Investigator (CI) may not downgrade an event that has been assessed by an 
Investigator as an SAE or SUSAR, but can upgrade an AE to an SAE, SAR or SUSAR if 
appropriate. 
9.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 10.1. 
9.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be related to the 
study intervention according to the definitions below.   
 
 
Unrelated: where an event is not considered to be related to the study intervention. 
 
 
Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the AE has a 
causal relationship to the study intervention.   
9.4.3 Assessment of Expectedness 
If an event is judged to be an AR, the evaluation of expectedness will be made based on 
knowledge of the reaction and either the relevant information about the additional monitoring 
device, or previous research on oxygenation of preterm infants.  
The event may be classed as either: 
Expected: the AR is consistent with the previous experience of the additional monitoring 
device, or consistent with previous peer-reviewed oxygenation research.  

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Unexpected: the AR is not consistent with the 
above. 
9.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE and record this on the 
CRF or SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the infant, not thought to cause discomfort and not 
interfering with physiological parameters outwith the short study period. 
Moderate: an event that is sufficiently discomforting or requires short-term intervention or 
monitoring outwith the study period. 
Severe: an event that causes severe physiological disturbance, discomfort or that requires 
long-term follow-up.  
Note: the term ‘severe’, used to describe the intensity, should not be confused with ‘serious’ 
which is a regulatory definition based on participant/event outcome or action criteria.  For 
example, a headache may be severe but not serious, while a minor stroke is serious but may 
not be severe. 
9.5 
REPORTING OF SAEs/SARs/SUSARs 
Once the Investigator becomes aware that an SAE has occurred in a study participant, the 
information will be reported to the ACCORD Research Governance & QA Office immediately 
or within 24 hours. If the Investigator does not have all information regarding an SAE, they 
should not wait for this additional information before notifying ACCORD.  The SAE report form 
can be updated when the additional information is received. 
The SAE report will provide an assessment of causality and expectedness at the time of the 
initial report to ACCORD according to Sections 10.4.2, Assessment of Causality and 10.4.3, 
Assessment of Expectedness. 
The SAE form will be transmitted by fax to ACCORD on +44 (0)131 242 9447 or may be 
transmitted by hand to the office or submitted via email to Safety.Accord@ed.ac.uk. Only 
forms in a pdf format will be accepted by ACCORD via email. 
Where missing information has not been sent to ACCORD after an initial report, ACCORD will 
contact the investigator and request the missing information.  
All reports faxed to ACCORD and any follow up information will be retained by the 
Investigator in the Investigator Site File (ISF). 
9.6 
REGULATORY REPORTING REQUIREMENTS 
The ACCORD Research Governance & QA Office has a legal responsibility to notify the 
regulatory competent authority and relevant ethics committee (Research Ethics Committee 
(REC) that approved the trial).  Fatal or life threatening SUSARs will be reported no later than 
7 calendar days and all other SUSARs will be reported no later than 15 calendar days after 
ACCORD is first aware of the reaction.   
ACCORD will inform Investigators at participating sites of all SUSARs and any other arising 
safety information. 
An Annual Safety Report/Development Safety Update Report will be submitted, by ACCORD, 
to the regulatory authorities and RECs listing all SARs and SUSARs. 
9.7 
FOLLOW UP PROCEDURES 
After initially recording an AE or recording and reporting an SAE, the Investigator will follow 
each participant until resolution or death of the participant.  Follow up information on an SAE 
will be reported to the ACCORD office. 
AEs still present in participants at the last study visit will be monitored until resolution of the 
event or until no longer medically indicated. 

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10 
OVERSIGHT ARRANGEMENTS 
10.1 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and 
audits on behalf of the sponsor, REC review, and regulatory inspection(s).  In the event of 
audit or monitoring, the Investigator agrees to allow the representatives of the sponsor direct 
access to all study records and source documentation. In the event of regulatory inspection, 
the Investigator agrees to allow inspectors direct access to all study records and source 
documentation. 
10.2 RISK ASSESSMENT 
A study specific risk assessment will be performed by representatives of the co-sponsors, 
ACCORD monitors and the QA group, in accordance with ACCORD governance and 
sponsorship SOPs. Input will be sought from the Chief Investigator or designee. The 
outcomes of the risk assessment will form the basis of the monitoring plans and audit plans. 
The risk assessment outcomes will also indicate which risk adaptions (delete if no adaptations 
were possible) could be incorporated into to trial design. 
10.3 STUDY MONITORING AND AUDIT 
The ACCORD Sponsor Representative will assess the study to determine if an independent 
risk assessment is required.  If required, the independent risk assessment will be carried out 
by the ACCORD Quality Assurance Group to determine if an audit should be performed 
before/during/after the study and, if so, at what frequency. 
 
Risk assessment, if required, will determine if audit by the ACCORD QA group is required. 
Should audit be required, details will be captured in an audit plan. Audit of Investigator sites, 
study management activities and study collaborative units, facilities and 3rd parties may be 
performed. 
11 
GOOD CLINICAL PRACTICE 
11.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 
Before the study can commence, all required approvals will be obtained and any conditions of 
approvals will be met. 
11.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments.  In accordance with the principles of ICH 
GCP, the following areas listed in this section are also the responsibility of the Investigator.  
Responsibilities may be delegated to an appropriate member of study site staff.   
11.2.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out. The decision of a parent to enroll their infant in the study 
is voluntary and should be based on a clear understanding of what is involved. 

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Parents will receive written adequate oral and 
written information about the study - appropriate Participant Information and Informed 
Consent Forms will be provided. The oral explanation to the parents will be performed by the 
researcher who is GCP trained and will cover all the elements specified in the Participant 
Information Sheet and Consent Form. 
Parents must be given every opportunity to clarify any points they do not understand and, if 
necessary, ask for more information. Parents will be given sufficient time to consider the 
information provided (5 days).  It will be emphasized that parents may withdraw their consent 
to participate at any time without loss of benefits to which they otherwise would be entitled. 
The Investigator or delegated member of the trial team and the participant will sign and date 
the Informed Consent Form(s) to confirm that consent has been obtained. Parents will receive 
a copy of this document and a copy filed in the Investigator Site File (ISF). 
11.2.2 Study Site Staff 
The Investigator must be familiar with the protocol and the study requirements.  It is the 
Investigator’s responsibility to ensure that all staff assisting with the study are adequately 
informed about the protocol and their trial related duties. 
11.2.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the CRF at 
each Investigator Site.  
11.2.4  Investigator Documentation 
 
The Principal Investigator will ensure that the required documentation is available in 
local Investigator Site files ISFs.  
11.2.5 GCP Training 
The researcher is GCP trained, as indicated in his CV.  
11.2.6 Confidentiality 
Data will be anonymised and stored on an encrypted computer within a locked room. The 
anonymisation key and consent forms will be stored in a separate keypad accessed room in a 
locked cabinet. Data will be handled according to Caldicott principles and stored according to 
Accord SOPs.  
11.2.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the 
requirements of the Data Protection Act 1998 with regard to the collection, storage, 
processing and disclosure of personal information and will uphold the Act’s core principles. 
Access to collated participant data will be restricted to individuals from the research team 
treating the participants, representatives of the sponsor(s) and representatives of regulatory 
authorities. 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
Published results will not contain any personal data that could allow identification of individual 
participants. 

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12 
STUDY CONDUCT RESPONSIBILITIES 
12.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of an urgent safety measure, must be reviewed and 
approved by the Chief Investigator.   
Amendments will be submitted to a sponsor representative for review and authorisation 
before being submitted in writing to the appropriate REC, and local R&D for approval prior to 
participants being enrolled into an amended protocol. 
12.2 MANAGEMENT OF PROTOCOL NON COMPLIANCE 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors 
and therefore will not be implemented, except where necessary to eliminate an immediate 
hazard to study participants. If this necessitates a subsequent protocol amendment, this 
should be submitted to the REC, and local R&D for review and approval if appropriate. 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to 
the sponsors every 3 months. Each protocol violation will be reported to the sponsor within 3 
days of becoming aware of the violation.  All protocol deviation logs and violation forms 
should be emailed to QA@accord.scot 
Deviations and violations are non-compliance events discovered after the event has occurred.  
Deviation logs will be maintained for each site in multi-centre studies.  An alternative 
frequency of deviation log submission to the sponsors may be agreed in writing with the 
sponsors. 
 
12.3 SERIOUS BREACH REQUIREMENTS 
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 participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (seriousbreach@accord.scot) must be notified within 24 hours.  It 
is the responsibility of the co-sponsors to assess the impact of the breach on the scientific 
value of the trial, to determine whether the incident constitutes a serious breach and report to 
research ethics committees as necessary.  
12.4 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 3 years from the protocol defined end of 
study point. When the minimum retention period has elapsed, study documentation will not be 
destroyed without permission from the sponsor. 
12.5 END OF STUDY 
The end of study is defined as the last participant’s last visit.   
The Investigators or the co-sponsor(s) have the right at any time to terminate the study for 
clinical or administrative reasons.  
The end of the study will be reported to the REC, and R+D Office(s) and co-sponsors within 
90 days, or 15 days if the study is terminated prematurely. The Investigators will inform 
participants of the premature study closure and ensure that the appropriate follow up is 

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arranged for all participants involved. End of 
study notification will be reported to the co-sponsors via email to resgov@accord.scot.  
A summary report of the study will be provided to the REC within 1 year of the end of the 
study. 
 
12.6 CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY 
The monitoring used in the study is routine within neonatal units and will continue after the 
end of the study. A decision to change oxygen saturation target limits would only be made 
after careful consideration of all available peer-reviewed literature.  
 
12.7 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance 
or indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
 
The Protocol has been designed by the Chief Investigator and researchers 
employed by the University and collaborators.  The University has insurance in 
place (which includes no-fault compensation) for negligent harm caused by poor 
protocol design by the Chief Investigator and researchers employed by the 
University. 
 
Sites participating in the study will be liable for clinical negligence and other 
negligent harm to individuals taking part in the study and covered by the duty of care 
owed to them by the sites concerned.  The co-sponsors require individual sites 
participating in the study to arrange for their own insurance or indemnity in respect 
of these liabilities. 
 
Sites which are part of the United Kingdom's National Health Service will have the 
benefit of NHS Indemnity. 
 
Sites out with the United Kingdom will be responsible for arranging their own 
indemnity or insurance for their participation in the study, as well as for compliance 
with local law applicable to their participation in the study. 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
13.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.   
14 
REFERENCES 
 
1. Cole CH et al. Pulse oximetry saturation tiral for prevention of retinopathy of 
prematurity planning study group: resolving our uncertainty about oxygen therapy 
Pediatrics 2003 112:1415-1419 
2. Askie et al. NeOProM: Neonatal Oxygenation Prospective Meta-analysis 
Collaboration study protocol. BMC Pediatrics 2011 11:6 

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3. Saugstad OD, Aune D. Optimal 
oxygenation of extremely low birth weight infants: a meta-analysis and systematic 
review of the oxygen saturation target studies Neonatology. 2014;105(1):55-63 
4. Manja V, Lakshminrusimha S, Cook DJ. Oxygen saturation target range for extremely 
preterm infants: a systematic review and meta-analysis JAMA Pediatr. 2015 
Apr;169(4):332-40 
5. Askie LM, Darlow BA, Davis PG, Finer N, Stenson B, Vento M, Whyte R. Effects of 
targeting lower versus higher arterial oxygen saturations on death or disability in 
preterm infants Cochrane Database Syst Rev. 2017 Apr 11;4:CD011190