Mechanistic Inflammatory Sub-study Embedded Within the Albumin vs Balanced Crystalloid Trial
Conditions: Sepsis
Sponsor: University of Edinburgh

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Study Protocol 
 
 
 
MIS-ABC Sepsis: Mechanistic Inflammatory Sub-study 
embedded in the Albumin versus Balanced Crystalloid 
in Sepsis trial – ABC Sepsis 
 
 
Sponsor 
The University of Edinburgh and Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Protocol authors 
Dr John (Jack) Cafferkey, Dr Andrew Ferguson 
Funder 
Royal College of Emergency Medicine 
Funding Reference Number 
G/2021/1 
Chief Investigator 
Dr John (Jack) Cafferkey 
Sponsor number 
AC21050 
REC Number 
21-SS-0052; 21/NW/0200 
Project registration 
NCT04963569 
Version Number and Date 
V1.0 09 June 2021 
Amended for upload 27 February 2023 
 
 

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CONTENTS 
1 
INTRODUCTION ...................................................................................................... 6 
1.1 
BACKGROUND .............................................................................................. 6 
1.2 
RATIONALE FOR STUDY .............................................................................. 7 
2 
STUDY OBJECTIVES .............................................................................................. 7 
2.1 
OBJECTIVES .................................................................................................. 8 
2.1.1 
Primary Objective ........................................................................................ 8 
2.1.2 
Secondary Objectives .................................................................................. 8 
2.2 
ENDPOINTS ................................................................................................... 8 
2.2.1 
Primary Endpoint ......................................... Error! Bookmark not defined. 
2.2.2 
Secondary Endpoints ................................... Error! Bookmark not defined. 
3 
STUDY DESIGN ....................................................................................................... 8 
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 ................................................. 10 
5.1 
IDENTIFYING PARTICIPANTS .................................................................... 10 
5.2 
CONSENTING PARTICIPANTS ................................................................... 11 
5.2.1 
Participant consent .................................................................................... 11 
5.2.2 
Personal/Professional Representative consent ......................................... 11 
5.2.3 
Consent via Telephone .............................................................................. 12 
5.2.4 
Deferred Consent ...................................................................................... 13 
5.2.5 
When the participant regains capacity ....................................................... 14 
5.3 
WITNESSED METHODS OF OBTAINING SIGNATURES .......................... 16 
5.4 
WITHDRAWAL OF STUDY PARTICIPANTS ............................................... 16 
6 
STUDY ASSESSMENTS ....................................................................................... 16 
6.1 
STUDY ASSESSMENTS .............................................................................. 16 
6.2 
BLOOD SAMPLING ...................................................................................... 17 
6.3 
LONG TERM FOLLOW UP ASSESSMENTS .............................................. 17 
6.4 
STORAGE AND ANALYSIS OF SAMPLES ................................................. 17 
7 
DATA COLLECTION ............................................................................................. 17 
7.1 
Source Data Documentation ........................... Error! Bookmark not defined. 
7.2 
CASE REPORT FORMS .............................................................................. 18 
7.3 
TRIAL DATABASE ........................................................................................ 19 
8 
DATA MANAGEMENT ........................................................................................... 19 
8.1 
PERSONAL DATA ........................................................................................ 19 
8.2 
DATA INFORMATION FLOW ....................................................................... 20 
8.3 
TRANSFER OF DATA .................................................................................. 20 
8.4 
DATA CONTROLLER ................................................................................... 20 
8.5 
DATA BREACHES ........................................................................................ 20 
9 
STATISTICS AND DATA ANALYSIS .................................................................... 20 
9.1 
SAMPLE SIZE CALCULATION .................................................................... 20 

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9.2 
PROPOSED ANALYSES .............................................................................. 21 
10 
ADVERSE EVENTS ..................................................... Error! Bookmark not defined. 
10.1 
AEs OF INTEREST ......................................... Error! Bookmark not defined. 
10.2 
EXPECTED EVENTS ..................................... Error! Bookmark not defined. 
10.3 
ASSESSMENT OF AEs AND SAEs ............... Error! Bookmark not defined. 
10.3.1 Assessment of seriousness ......................... Error! Bookmark not defined. 
10.3.2 Assessment of causality .............................. Error! Bookmark not defined. 
10.3.3 Assessment of severity ................................ Error! Bookmark not defined. 
10.4 
RECORDING OF AEs .................................... Error! Bookmark not defined. 
10.5 
REPORTING OF SAEs ................................... Error! Bookmark not defined. 
10.6 
FOLLOW UP PROCEDURES ........................ Error! Bookmark not defined. 
11 
OVERSIGHT ARRANGEMENTS ........................................................................... 21 
11.1 
INSPECTION OF RECORDS ....................................................................... 21 
11.2 
STUDY MONITORING AND AUDIT ............................................................. 21 
12 
GOOD CLINICAL PRACTICE ................................................................................ 22 
12.1 
ETHICAL CONDUCT .................................................................................... 22 
12.2 
KEY ETHICAL CONSIDERATIONS ............................................................. 22 
12.2.1 Consent process ........................................................................................ 22 
12.2.2 Burden on patients ..................................................................................... 22 
12.2.3 Genetic analysis ........................................................................................ 23 
12.2.4 Relationship with the main ABC Sepsis trial .............................................. 23 
12.3 
INVESTIGATOR RESPONSIBILITIES ......................................................... 23 
12.3.1 Informed Consent ...................................................................................... 23 
12.3.2 Study Site Staff .......................................................................................... 24 
12.3.3 Data Recording .......................................................................................... 24 
12.3.4 Investigator Documentation ....................................................................... 24 
12.3.5 GCP Training ............................................................................................. 24 
12.3.6 Confidentiality ............................................................................................ 24 
12.3.7 Data Protection .......................................................................................... 24 
13 
STUDY CONDUCT RESPONSIBILITIES .............................................................. 25 
13.1 
PROTOCOL AMENDMENTS ....................................................................... 25 
13.2 
MANAGEMENT OF PROTOCOL NON-COMPLIANCE ............................... 25 
13.3 
SERIOUS BREACH REQUIREMENTS ........................................................ 25 
13.4 
STUDY RECORD RETENTION ................................................................... 25 
13.5 
END OF STUDY ........................................................................................... 25 
13.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF STUDY ... 26 
13.7 
INSURANCE AND INDEMNITY ................................................................... 26 
14 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS .................. 26 
14.1 
AUTHORSHIP POLICY ................................................................................ 26 
14.2 
PUBLICATION .............................................................................................. 26 
14.3 
DISSEMINATION OF RESULTS .................................................................. 27 
15 
REFERENCES ....................................................................................................... 27 

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LIST OF ABBREVIATIONS 
 
ABC Sepsis 
Albumin versus Balanced Crystalloid Feasibility Study (main randomised control trial) 
ACCORD 
Academic and Clinical Central Office for Research & Development - Joint Office for The 
University of Edinburgh and Lothian Health Board 
AE 
Adverse Event 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTIMP 
Clinical Trial of Investigatory Medical Product 
eCRF 
Electronic Case Report Form 
ECTU 
Edinburgh Clinical Trials Unit 
ED 
Emergency Department 
EDTA 
Ethylenediaminetetraacetic Acid 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HDU 
High Dependency Unit 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
ISF 
Investigator Site File 
MIS-ABC 
Sepsis 
Mechanistic Inflammatory Sub-study of ABC Sepsis (the sub-study considered in this 
protocol) 
NEWS(2) 
National Early Warning Score (2) 
NICE 
National Institute for Health and Care Excellence 
PI 
Principal Investigator 
PICC 
Peripherally Inserted Central Catheter 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
R&D 
Research and Development office 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
ST4 
Specialty Trainee in 4th year of training 

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Trial summary 
Trial Title 
MIS-ABC Sepsis: Mechanistic Inflammatory Sub-study embedded in the 
Albumin versus Balanced Crystalloid in Sepsis trial – ABC Sepsis 
Study Acronym 
MIS-ABC Sepsis 
Trial Design 
Prospective observational study 
Trial Participants 
Adult patients with community acquired sepsis recruited from the 
Emergency Department and Medical and Surgical Assessment Units in ~5 
UK NHS Hospitals, who are enrolled into the ABC Sepsis trial 
Planned Number of Participants 
At least 70 participants 
Planned Number of Sites 
7 
Countries Anticipated to be Involved in 
Trial 
UK 
Follow up Duration 
Sampling period: 24 hours 
Follow up: 90 days 
Total Planned Trial Duration 
12 months 
Primary Objective 
To investigate whether the inflammatory response to community acquired 
infection/sepsis is dependent on the type of intravenous fluid used during 
resuscitation. 
Primary Endpoint 
No primary endpoint: analysis will be exploratory. 
Secondary Objectives  
1. To understand the inflammatory response in patients with community 
acquired infection/sepsis by the analysis of a panel of cytokines. 
2. To evaluate whether the early inflammatory response to 
infection/sepsis at the time of presentation to secondary care predicts 
clinically important outcomes. 
3. To investigate whether transcriptomic analysis can provide an 
explanation for varying physiological response to fluid therapy and clinical 
outcomes in infection/sepsis. 
Secondary Endpoints 
No specific secondary endpoints: analysis will be exploratory. 
Lay Summary of Trial  
This is a sub-study looking to understand how the immune response in 
patients with infection changes during the early stages of the illness, as well 
as after intravenous fluid treatment.   Participants in the main trial will be 
given one of two types of fluid (Human Albumin Solution (HAS) and 
Balanced Crystalloid) via a drip when they present to the hospital with 
severe infection (sepsis). The main trial is assessing which fluid is better, 
and we are going to take three blood samples around the time people come 
to hospital to see what happens to their immune system as a result of the 
infection and fluid treatment. We hope our findings will explain why one fluid 
might be better than another. It may also give us an important information 
about whether we can predict which people might get sicker despite 
treatment. 
 
  
 
 

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1 
INTRODUCTION 
1.1 
BACKGROUND 
Systemic illness due to infection is a common reason for patients to present to an Emergency 
Department (ED) [1].  Up to half develop sepsis [2], defined as life-threatening organ 
dysfunction caused by a dysregulated host response to infection [3].  Sepsis is a major public 
health problem with overall mortality estimated at 22%, reflecting a global burden of more than 
11 million deaths annually and 52,000 in the UK alone [4,5].  In addition, sepsis is the leading 
cause of admission to Intensive Care Units (ICU) and the most common cause of ICU death 
[6], whilst sepsis survivors commonly experience significant morbidity and impaired quality of 
life [7]. Host response to infection is highly variable, influenced by factors including age, 
genetics, background physiological status and causative organism. Several distinct sepsis 
phenotypes have been identified, each with differing patterns of immune response, natural 
history and clinical outcomes [8].  The balance between the pro- and anti-inflammatory 
response to infection is crucial to determining clinical course [9].   
 
IV fluids in Sepsis  
Patients with sepsis often present with hypotension. This is multifactorial in aetiology but 
primarily owed to septic shock (due to the systemic effects of endothelial damage, endothelial 
dysfunction and increased capillary permeability) and hypovolaemia caused by reduced oral 
intake, increased losses or bleeding during the illness period [10].  
This hypotension is addressed, in part, by intravenous fluid therapy. All key national and 
international guidance advocates fluid resuscitation in septic patients who are hypotensive, 
although a significant degree of uncertainty exists in the best type of fluid to use, the volume of 
fluid that should be used and the stage at which fluid is no longer useful for these patients and 
vasoactive medications must be used. The ABC Sepsis pilot study aims to assess the feasibility 
of a pragmatic trial comparing two types of intravenous fluid: albumin solution versus balanced 
crystalloid.  
 
Types of IV fluid 
There are two types of commonly used IV fluid in the resuscitative management of patients with 
Sepsis. These are crystalloid (balanced and unbalance) and large molecule colloid fluids.  
Balanced crystalloids contain salts at physiological concentrations found in healthy humans, 
and are advocated as first line for sepsis by NICE and the surviving sepsis guidelines [11]. 
Resuscitation with crystalloid (either balanced or unbalanced) is the preferred treatment of 
choice for shocked septic patients according to an international survey [12].  
Albumin, used in this setting as 5% Human Albumin Solution (HAS), is a colloid fluid which 
NICE directs clinicians to consider for patients with sepsis and shock [13]. However its specific 
role in sepsis management is, undefined and is largely clinician dependent in the absence of 
definitive evidence for its use.  
 
The Evidence for Albumin 
Albumin is a protein produced by the liver which is responsible for 80% of the intravascular 
cellular oncotic pressure. Other functions include a pivotal role in acid-base homeostasis, 
transport of a number of key molecules including drugs, and scavenging of reactive oxygen 
species [14].  
Hypoalbuminaemia in sepsis is a poor prognostic factor for mortality, probably reflecting the 
severity of disease through endothelial dysfunction and decreased serum albumin half-life 
[15,16]. 
A small number of trials have examined the use of albumin in sepsis. The SAFE trial 
randomised ICU patients to 4% albumin or normal saline for intravascular fluid resuscitation for 
28 days, and found no difference between 28-day mortality, and although a pre-specified 

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subgroup analysis of patients with severe sepsis signalled a benefit for albumin, this too did not 
reach statistical significance [17].  The ALBIOS study randomised patients with severe sepsis 
to either 20% albumin and crystalloid fluid or crystalloid fluid alone, with the former arm targeting 
serum albumin levels of above 30g/L or more. Again, this study found no significant difference 
between 28 day mortality [18]. However, a subsequent secondary analysis in patients with 
severe shock and raised lactate identified a survival benefit in the albumin arm reaching 
statistical significance [19]. A 2014 meta-analysis which included these, amongst three other 
trials, found a significant improvement in mortality for patients with severe septic shock, and 
trends towards benefit for those with severe sepsis against crystalloid [20].  
These studies have demonstrated safety of albumin but are yet to demonstrate a significant 
survival benefit in ICU patients. Although undoubtedly these studies select for the sickest 
patients with sepsis, it is possible that studies in such environments miss a cohort of severely 
unwell patients who are not suitable for ICU but who may benefit in a similar way from the 
treatment. Intervention at admission to ICU may even be too late to interrupt the downward-
spiralling sequelae of septic shock like end organ failure in some patients.  
 
Immunology and Predicting Response to Treatment  
Whilst in broad terms, the rationale for these different intravenous therapies is underpinned by 
physiological factors, it is highly likely that an individual’s immunological response to sepsis and 
our treatments, will affect this physiology.  It may also predict whether and explain why one 
treatment option is better than another.  
The measurement of novel sepsis biomarkers has great potential to fulfil this knowledge gap. 
Several have already been shown to predict 30-day mortality.  However, their ability to predict 
deterioration when measured at time of hospital presentation is largely unknown. In addition, 
many promising biomarkers have not been directly evaluated in the relevant population, ED 
patients with suspected sepsis. We propose to measure pro and anti-inflammatory cytokines 
(GM-CSF; IFN gamma; IL-1 beta; IL-2; IL-4; IL-5; IL-6; IL-8 (CXCL8); IL-10 (CXCL10); IL-12p70; 
IL-13; IL-17A (CTLA-8); MCP-3 (CCL7); and TNF alpha). Our rationale is based on the premise 
that these cytokines are acutely altered in sepsis and may predict different risks (such as clinical 
severity or risk of deterioration).  
Accurate prediction of deterioration prior to the onset of critical illness is key to improving 
outcomes for patients with sepsis. This enables prompt delivery of treatment “bundles” and 
consideration of timely ICU admission, both associated with improved survival [21,22].  
Currently, patients in the ED with features of systemic infection are risk-stratified using clinical 
scores and lactate measurement. However, these methods demonstrate inadequate sensitivity 
and specificity when validated against 30-day clinical outcomes [23], and tell us little about the 
time-course of deterioration.  Consequently, their utility as tools to guide “shop-floor” decision 
making is questionable. Improved understating of inflammatory cytokine changes  during sepsis 
could aid development of a better tool to differentiate patients at high risk of deterioration. This 
would substantially inform clinical decisions around escalation of care and the initial level of 
monitoring required.  
 
We hypothesise that different types of intravenous fluids used in resuscitation (albumin versus 
balanced crystalloid) may mediate different pro and anti-inflammatory response as measured 
by these cytokines. We also hypothesise that plasma levels of these cytokines, measured at 
time of ED admission, will enable improved differentiation of patients with suspected sepsis 
who are at high risk of deterioration 
 
1.2 
RATIONALE FOR STUDY 
Currently, there is controversy about the optimal fluid choice in patients presenting to hospital 
with sepsis. Understanding how each fluid type affects the underlying inflammatory process 
may provide a mechanistic argument for clinician choice, future research and professional 
recommendations.  

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MIS-ABC Sepsis is a sub-study of the ABC-Sepsis trial, a pilot feasibility trial recruiting patients 
with community acquired infection/sepsis with a NEWS2 score of five or more and randomising 
the participants to receiving either balanced crystalloid or 5% HAS as the intravenous 
resuscitation fluid up to six hours after randomisation.  
 
MIS-ABC Sepsis will take serial blood samples from a small number of these participants, at 
hospital  presentation and  at two further points early during the patient’s admission, to allow 
analysis of how inflammation changes during their course of illness. Investigating temporal 
change and differences between treatment arms of the main study will allow a nuanced analysis 
of the interplay between severity of illness, physiological changes over time and any potential  
differences between fluid treatment arm. 
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 
Primary Objective 
To investigate whether the inflammatory response to infection/sepsis is dependent on the type 
of intravenous fluid used during resuscitation in the Emergency Department. 
2.1.2 
Secondary Objectives 
1. To understand the inflammatory response in patients with community acquired 
infection/sepsis by the analysis of a panel of cytokines. 
2. To evaluate whether the early inflammatory response to infection/sepsis at the time of 
presentation to secondary care predicts clinically important outcomes. 
3. To investigate whether transcriptomic analysis can provide an explanation for varying 
physiological response to fluid therapy and clinical outcomes in infection/sepsis. 
2.2 
ENDPOINTS 
This study is exploratory in nature and we have not set primary or secondary endpoints. 
However, prospective planning for analysis has been conducted and is detailed in Section 9.2 
Proposed Analysis. 
3 
STUDY DESIGN 
This is a prospective observational study enrolling patients randomised to the ABC Sepsis 
study. Centres for this trial will be selected from UK NHS hospitals who are recruiting to the 
main ABC Sepsis study. Participants will be recruited as soon as possible, and up to 12 hours 
after presentation to the Emergency Department, Surgical Assessment Unit or Medical 
Admissions Unit. 
 
The treatment phase of the main study spans 6 hours following randomisation, with the follow 
up period extending to 90 days. This sub-study requires three blood samples: immediately after 
enrolment, at approximately 12 and 24 hours thereafter. The follow up period similarly extends 
to 90 days, using routine data from the medical records for follow up. 
 

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Study diagram depicting MIS-ABC Sepsis trial in the context of the main ABC Sepsis 
feasibility trial.  

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4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
We aim to recruit at least 70 patients from approximately 7 sites, ideally with at least 30 patients 
from each intervention arm of ABC Sepsis. The main study aims to recruit 300 patients from 
approximately 15 sites. Site selection for this sub-study will depend on whether that site has 
capacity to do so and will likely focus on sites who have demonstrated success with recruitment 
to the main study. Recruitment will take place over a period of around 6 months.  
4.2 
INCLUSION CRITERIA 
1. Able to obtain informed consent  
2. Eligible for and randomised into the ABC Sepsis trial 
 
4.3 
EXCLUSION CRITERIA 
There are no specific exclusion criteria for this sub-study, and therefore it will map directly onto 
those of the ABC Sepsis trial:  
1. Excluded from the ABC Sepsis trial 
 
4.4 
CO-ENROLMENT 
Co-enrolment is permitted between the ABC Sepsis study and this MIS-ABC Sepsis 
(observational) study.   
Other co-enrolment considerations will follow those of the main study and investigators should 
refer to the ABC Sepsis protocol before considering co-enrolment. In the case of co-enrolment 
apart from that of MIS-ABC Sepsis (this sub-study) and ABC Sepsis (main study), the ACCORD 
policy will be consulted (POL008 Co-enrolment Policy) and relevant forms completed.  
Accidental or unintentional co-enrolment will be avoided with thorough consultation of available 
medical records and routine participant questioning. Should co-enrolment occur accidentally or 
unintentionally, a protocol deviation will be reported to the Sponsor. 
 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
The research team, where it is locally agreed that they are part of the clinical care team, will 
identify patients using triage information and clinical or electronic records in the Emergency 
Department, Medical or Surgical Assessment Units or any other area used for acute 
assessment in the recruiting site. In this case, it is anticipated they would identify patients and 
make the first approach. Any member of the clinical team who has received general and trial 
specific training and is on the delegation log may also identify patients in this way. Where 
researchers are not considered to be part of the care team, the researcher will ask a member 
of the direct care team to identify suitable patients and ask permission from the patient to be 
approached by the researcher to discuss participation. Triage notes or documentation of 
presenting complaint will also be consulted to see whether approaching participants for the 
study is appropriate. Patients may be approached for up to 12 hours after presentation for the 
ABC Sepsis study, so the same timeframe will be applied to this sub study. It is aimed that 
participant identification, approach, consenting and enrolment will be done simultaneously with 

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the main trial. It will be made clear at all points that the sub-study is both a separate, but linked, 
project, and also entirely optional for those participating in ABC Sepsis. Patient information, 
both written and verbal, will be designed to be complementary to the ABC Sepsis trial, building 
on information already explained to the potential participant, with an aim to reduce burden.  
5.2 
CONSENTING PARTICIPANTS 
The consent pathway below will be followed to determine the appropriate mechanism of 
consent to use for an individual participant and details where consent to continue is needed. 
This mechanism will differ between sites recruiting in England and Scotland. 
5.2.1 
Participant consent 
Potentially eligible participants who are willing to take part in the study, and have capacity to do 
so, will be asked to provide written informed consent. Consent will be obtained by trained 
members of the clinical team or members of the research team who have been delegated this 
responsibility. The Investigator is responsible for the delivery of processes to ensure informed 
consent is obtained before any protocol specific procedures are carried out.  The decision of a 
patient to participate in clinical research is voluntary and should be based on a clear 
understanding of what is involved.   
 
The participant will be given a Patient Information Sheet (PIS), which will explain the aims of 
the trial and the potential risks and benefits of the study treatments.  The participant will be 
given enough time to consider the trial and ask questions regarding their participation in the 
trial. Due to the need to sample at or before the time of the ABC Sepsis treatment starting, there 
may not be long for the participant to consider the trial.  Ideally, a period of 30-40 minutes will 
be given but it may be only 10-15 minutes due to the need for fluid resuscitation to begin. The 
research teams are experienced at recruiting patients in the emergency environment and given 
the nature of the intervention and the burden of the trial we believe this to be reasonable.  
Potential participants will receive adequate oral and written information.  The oral explanation 
to the patient will be performed by a member of the research team or a trained and delegated 
member of the clinical team and must cover all the elements specified in the Participant 
Information Sheet and Consent Form. The patient must be given every opportunity to clarify 
any points they do not understand and, if necessary, ask for more information.  The patient 
must be given sufficient time to consider all the information provided.  It should be emphasised 
that the patient may withdraw their consent to participate at any time without loss of benefits to 
which they otherwise would be entitled. The participant will be informed and agree to their 
medical records being inspected by representatives of the sponsor(s). 
The Investigator or delegated member of the trial team and the participant will sign and date 
the Consent Form to confirm that consent has been obtained.  If the participant is unable to 
sign the consent form for themselves then the witnessed verbal consent form can be used.  
The original consent form will be filed in the Investigator Site File (ISF), the participant will 
receive a copy of this document and a copy filed in the participant’s medical notes. 
 
Capacity will be assessed by the Principal Investigator (PI) or a clinician responsible for the 
treatment of the participant as part of the ABC Sepsis trial. This assessment of capacity will be 
documented in the participant’s medical records. 
5.2.2 
Personal Representative consent  
If a patient is not considered to have capacity to consent, then a Personal Representative will 
be approached for consent. 
 
In Scotland this is defined as:  

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Personal legal representative i.e.  Adult's Welfare Guardian or Welfare Attorney, or if not 
appointed the adult's nearest relative. 
 
In England and Wales this is defined as:  
Personal legal representative i.e. a person not connected with the conduct of the trial who is 
suitable to act as the legal representative by virtue of their relationship with the adult and is 
available and willing to do so.  
 
If a Personal Representative is present, they will be given information about the trial in the 
Personal Representative Information Sheet.  The Personal Representative will be given enough 
time to consider the trial and ask questions regarding their relative’s participation in the trial. 
Ideally, a period of 30-40 minutes will be given but this may be only 10-15 minutes due to the 
need the main trial interventions to begin within one hour and the sampling to happen 
simultaneously.   
 
The Personal Representative will be told they are being asked to give consent on behalf of the 
incapacitated adult, that they are free to decide whether they wish to make this decision or not 
and that they are being asked to consider what the adult would want, and to set aside their own 
personal views when making this decision. They will be informed that their relative will be asked 
whether or not they wish to continue in the study once they have regained capacity to do so.   
If they indicate they have had time to consider the trial, the impact on their relative and have 
been provided with the answers to any trial related questions, they will be asked to provide 
written consent.  The Investigator or delegated member of the trial team and the Personal 
Representative will sign and date the Consent Form to confirm that consent has been obtained.  
The original consent form will be filed in the ISF, the participant will receive a copy of this 
document and a copy filed in the participant’s medical notes. 
5.2.3 
Consent via Telephone 
Every effort will be made to approach and consent the Personal Representative in person. If 
the Personal Representative is only contactable by telephone then the informed consent 
process is permitted via telephone or an appropriate video conferencing technology such as 
NHS near me, provided the following: 
 
• 
The Representative who is being contacted has previously had the opportunity to discuss 
the clinical aspects of the patient’s care with the clinical team; 
• 
A member of the clinical team has sought permission for the Personal Representative to 
be contacted by a member of the clinical or research team regarding potential 
involvement in the study; 
• 
The approach to discuss consent is clearly identified as separate to any discussions 
made between the representative and the clinical team. 
 
A member of the research team will contact the Personal Representative by 
telephone/videoconferencing technology to explain what the study entails and answer any 
questions they may have. The Personal Representative will be given time to read and consider 
the information sheet. In situations where the Personal Representative does not have a copy 
of the PIS this will be read to them.  Ideally, a period of 30-40 minutes will be given but this may 
be only 10-15 minutes due to the need for fluid resuscitation to begin within one hour. If the 
Personal Representative chooses to enrol the patient onto the study, verbal consent will be 
obtained by a member of the research team who conducted the interview and will sign the 
consent form. This will be witnessed by an independent member of staff. 
In this circumstance, the participant must also receive information, according to their capacity 
of understanding, about the trial and its risks and benefits.   

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A copy of the signed Personal Representative Witness consent form will be sent to the Personal 
Representative electronically or by post along with a Personal Representative PIS and Consent 
form for signature by the Personal Representative. All efforts will be made to obtain a signature 
on the Personal Representative Consent form either electronically or by post. However, in the 
absence of this signature, a consent form completed by a member of the research team and 
witnessed by an independent member of staff will be acceptable. 
 
If there is no response from the Personal Representative one further reminder can be send 
after one month. If the Personal Representative does not return the signed consent form but 
does not ask for the participant to be withdrawn from the trial, the Professional Representative 
consent will remain valid and the patient will remain in the trial. 
 
If a Personal Representative objects to the inclusion of the patient in the trial their views will be 
respected and the patient not enrolled into the study. 
 
In sites recruiting in Scotland: If the patient does not have capacity, and there is not a 
Personal Representative available, the patient will not be enrolled in the MIS-ABC Sepsis sub-
study. Notably, this differs from the consent process with the ABC Sepsis study where a 
Professional Representative may be sought, or deferred consent may be used. The difference 
between recruitment at sites in England and Scotland within this study, and between this study 
and ABC Sepsis, is a result of what is permitted for non-CTIMP trials by the Adults With 
Incapacity (Scotland) Act 2000.    
5.2.4 
Professional Representative consent (England only) 
In sites recruiting in England: If the patient does not have capacity, and there is not a 
Personal representative available, consent from a Professional Representative will be sought. 
The definition is as follows: 
Professional legal representative i.e. a doctor responsible for the medical treatment of the adult 
if they are independent of the study, or a person nominated by the healthcare provider 
 
If there is not a Personal Representative immediately available (within 30 minutes), a 
Professional Representative will be approached to determine if it is appropriate for the patient 
to be entered into the trial so that treatment could be commenced within one hour. A Personal 
Representative should be approached for consent to continue as soon as they are available, 
and it is feasible to do so.  If the Personal Representative is unable to visit the hospital in person, 
the consent form will be sent to them by email or post.  The Personal Representative will be 
asked to return the signed consent form if they wish to remain in the trial or contact the study 
team if they wish to be withdrawn. If the patient does not return the signed consent form but 
does not ask to be withdrawn from the trial, the Professional Representative consent will remain 
valid.  
5.2.5 
Deferred Consent (England only) 
Patients who have “life threatening features” and who lack temporary capacity due to their 
current illness can be recruited to the trial using deferred consent if there is no 
Personal/Professional Representative to give consent on their behalf within 30 minutes so that 
treatment can be commenced within one hour. The decision to defer consent should be made 
by a senior doctor, i.e. ST4 (or above) or consultant, who has appropriate trial training and this 
should be clearly documented.    
 
The patient would be enrolled into the trial and receive their allocated treatment.  Consent would 
be sought as soon as possible from a Personal Representative (or a Professional 
Representative if they are available sooner).   If a Personal/Professional Representative 

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declines to give consent for continuation at this stage, their wishes will be respected and the 
withdrawal process in section 5.4 will be followed.  
5.2.6 
When the participant regains capacity  
When the participant regains capacity to consent (as assessed by a clinician), they will be given 
a Recovered Capacity PIS which will explain what has happened to them so far and seek written 
consent for continued participation in the trial.  This will be done as soon as it is feasibly 
possible.  If the participant is happy to continue, they will be asked to provide written consent.  
The Investigator or delegated member of the trial team and the participant will sign and date 
the Consent Form to confirm that consent has been obtained.  The original consent form will 
be filed in the Investigator Site File (ISF), the participant will receive a copy of this document 
and a copy filed in the participant’s medical notes. 
 
In the event that a patient is not able to be approached for consent to remain in the trial prior to 
hospital discharge, the local research team will seek written consent by sending a PIS and 
consent form by post. The patient will be asked to return the signed consent form if they wish 
to remain in the trial or contact the study team if they wish to be withdrawn. If there is no 
response, one further reminder can be sent after one month by post. If the participant does not 
return the signed consent form but does not ask to be withdrawn from the trial, the Professional 
Representative consent will remain valid and the participant will remain in the trial.  
 
If the participant is not happy to continue, the withdrawal process in section 5.4 will be followed.   
 
For any participant who was included but does not regain full capacity, consent from the 
Personal Representative will stand, or from the Professional Representative where there is no 
Personal Representative. Where no consent is given by any legal representative, i.e. deferred 
consent is used and no subsequent consent obtained, or a participant dies before any consent 
obtained the patient data collected would be destroyed. Patients with permanent incapacity will 
not be recruited and this is an exclusion criterion. 
 

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5.3 
WITNESSED METHODS OF OBTAINING SIGNATURES  
Consent will normally be recorded in writing, dated and signed or otherwise marked by the 
participant or their legal representative. In most instances this will take the form of a face-to-
face consent process with a wet ink signature. 
If face-to-face consent is not possible or feasible, verbal consent over the phone or video-call 
will be utilised, this will be witnessed and recorded in writing. If a verbal witnessed consent 
procedure is utilised we will also attempt to obtain a written signature from the participant or 
their legal representative by posting the consent form to them for signature and return as 
described previously. 
5.4 
WITHDRAWAL OF STUDY PARTICIPANTS 
Participants are free to withdraw from the study at any point or a participant can be withdrawn 
by the Investigator, or their Personal/Professional Representative (where appropriate). If 
withdrawal occurs, the primary reason for withdrawal will be documented in the participant’s 
case report form, if possible. They will have the option of withdrawal from: 
i) 
Further blood sampling  but consent to continuation of data collection from routine 
medical records and use of sub-study data collected up to that point 
ii) 
 All aspects of the trial but continued use of sub-study data collected up to that 
point. 
 To safeguard rights, the minimum personal information possible will be collected.  
 
If a participant withdraws from the main study (ABC Sepsis) they will be asked whether or not 
they wish to be withdrawn from the sub-study.   
 
6 
STUDY ASSESSMENTS 
6.1 
STUDY ASSESSMENTS 
During this trial the following assessments will be completed: 
Assessment  
Screening  Baseline  
12 (±4) 
hours* 
24 (±6) hours* 30 
days  
90 
days  
Consent 
X 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
Demographics, 
Medical 
History 
 
X 
 
 
 
 
Blood samples  
(EDTA and PAXgene tubes)  
X 
X 
X 
 
 
Vital signs 
 
X 
X 
X 
 
 
Mortality# 
 
 
 
 
X 
X 
Length 
of 
stay, 
Ward/HDU/ICU stay#  
 
 
 
 
X 
X 
Adverse events# 
 
X 
X 
X 
 
 
*after enrolment. #This data will be collected on the ABC sepsis CRF and shared with the MIS-
ABC trial 

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6.2 
BLOOD SAMPLING 
Participants in the MIS-ABC trial will have samples taken at three points:  
• 
Baseline (0 hrs): this sample will be taken at the point of enrolment into the sub-study, 
with the aim of characterising the inflammatory response to sepsis before, or at, the 
point of administration of the trial intervention. 
• 
Second sample (12 ±4 hrs) after enrolment  
• 
Last sample (24 ± 6 hrs) after enrolment  
In each case, two samples will be taken sequentially, from the same point of access. In order 
to minimise burden to the participants, the study team will work with the clinical team to identify 
opportunities to take blood simultaneously with routine sampling, as well as identifying sampling 
options which use existing points of access. Examples of this include: 
• 
Taking research samples at the same time that venepuncture is being performed for 
routine clinical samples (e.g. taking the research samples with the routine samples 
from the same ‘butterfly needle’)  
• 
Taking research samples at the same time that a new, or re-sited, point of vascular 
access is inserted (e.g. taking the research samples when a new peripheral cannula 
is inserted) 
• 
Taking research samples from an existing port of vascular access which allows 
sampling (e.g. taking research samples from an arterial line, a central line or a PICC). 
6.3 
LONG TERM FOLLOW UP ASSESSMENTS 
There is no long term follow up for this study.  Participants will be followed up for the ABC sepsis 
study using routine clinical data at 30 days and 90 days from the medical notes and this data 
will be shared for the analysis of the MIS-ABC study.   
6.4 
STORAGE AND ANALYSIS OF SAMPLES 
At each sampling point during this study, two blood samples will be taken. The first is a 4mL 
EDTA tube, and the second is a 2.5mL PAXgene tube. From the EDTA tube of blood, we will 
aliquot one millilitre into cytodelics cell preservation medium for cellular phenotyping (referred 
to as “cells”) and the remaining blood in EDTA tube will be spun down to isolate), which will be 
stored in aliquots for measuring cytokines. 
They will be labelled using pseudonymous study identifiers and stored locally at -80ºC until 
recruitment ends, at which point samples will be shipped to the central laboratory (at the Royal 
Infirmary of Edinburgh) for analysis.  
Consent will be sought for long term storage at the University of Edinburgh for all samples (i.e. 
PAXgene, cells and plasma), anticipated to be a period of up to 5 years. In the case of the 
PAXgene tube, funding is not yet secured for the planned sequencing analysis and the samples 
will be stored until this is possible. Because these tests include genetic analysis, explicit consent 
will be sought from patients with this in mind. However, the nature of the analysis will be limited 
to the specific patient presentation and immune response during the time studied. 
 
7 
DATA COLLECTION 
Data specific to the sub-study will be collected from consent until 90 days at a number of key 
points by a member of the research team: 
• 
At informed consent, enrolment and baseline investigations 

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o 
Eligibility and consent 
o 
0hr blood sampling 
o 
0hr vital signs 
o 
Results of nearest serum lactate measurement (if taken as part of routine care) 
• 
At 12 (±4) hours sampling 
o 
12 hour blood sampling 
o 
Vital signs and (±30 minutes from time of sampling) 
o 
Results of nearest serum lactate measurement (if taken as part of routine care) 
• 
At 24 (±6) hours sampling 
o 
24 hour blood sampling  
o 
Vital signs (at  ±30 minutes from time of sampling) 
o 
Results of nearest serum lactate measurement (if taken as part of routine care) 
All relevant intervention, outcome and follow up data will be collected as part of the ABC-Sepsis 
trial and a data sharing agreement will allow us to make use of this data. 
 
 
 
7.1 
 SOURCE DATA DOCUMENTATION 
Data will be collected from consent until final follow up visit. 
Source data will either be study specific or routine clinical data. Study specific source data, 
including consent forms, eligibility criteria forms, and sampling details (e.g. timing of samples) 
will be recorded on the relevant pseudonymised source study data worksheets distributed to 
participating sites.  
Clinical data, including physiological observations and blood samples taken as part of routine 
care, will be recorded according to local practice and transcribed onto the study data 
worksheets as agreed by site-specific source document plans.  
7.2 
CASE REPORT FORMS 
Paper CRFs (study data worksheets) will be completed as the participant progresses through 
the study and then entered into a database on a trial database on a secure NHS computer. 
Scanned images of the worksheets may also be sent to the trial management team for quality 
assurance purposes.  

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Processing of samples will be recorded on ‘processing logs’, paper sheets which will record the 
time and date of processing, number of samples and person processing them. They will be 
shared with the trial management team in a similar manner to the study data worksheets.  
Clinical outcome data will be collected as part of the ABC Sepsis study from NHS records and 
will include comorbidities; vital signs, routine blood results including baseline kidney function, 
liver function and albumin; relevant investigations or interventions including surgery, 
vasopressor use, renal replacement therapy, invasive ventilation, chest x-rays, prescriptions; 
time of start of ABC Sepsis IMP; length of stay including critical care, repeat hospitalisations, 
adverse events and decisions regarding treatment escalation planning and resuscitation. Detail 
will also be collected on the trial intervention including timing and volume of fluids. Length of 
stay and repeat hospitalisation will be recorded as part of follow up. These data will be shared 
with this sub-study in line with the ABC Sepsis data management plan for sharing and reuse. 
7.3 
TRIAL DATABASE 
 
At regular intervals throughout the study, the site research teams will transcribe the paper 
worksheets into the trial database specifically developed for this purpose. This central database 
will be managed by the trial management team and kept on secure servers at the host insitution. 
Scanned copies of the relevant paper worksheets (i.e. containing pseudonymised study data) 
may be requested from site teams for quality assurance. 
Following data analysis, the database will be archived by the trial management team. This 
archived database will be stored indefinitely on secure host institution servers once user access 
has been disabled. Access to the archived database will be controlled by the Chief Investigator. 
8 
DATA MANAGEMENT 
This trial will be coordinated from the Royal Infirmary of Edinburgh. Data will be collected at 
each site by local investigators and uploaded to the database. If a participant or their 
representative withdraws a previously given informed consent or refuses to consent for 
continuation in the trial, or if the participant dies and no participant consent is available, the 
patient’s data will be handled as follows: Data collected up to the point of withdrawal will be 
used in an intention to treat analysis. 
 
8.1 
PERSONAL DATA 
Local sites will also maintain a secure document as reference linking a participant’s study ID 
with the personal information (including name, date of birth, hospital number, address, 
telephone number, sex at birth, GP information) of the participant. Where relevant, personal 
data of the personal representative will also be collected to obtain consent (including name, 
home address, telephone number).  
The name, address and GP details will only be collected for the purposes of sending a letter to 
the GP informing them their participant is taking part, to send consent forms (if required), and 
to disseminate result of the trial (if the patient opts for this). This personal data will be kept at 
the study site.  
Personal data will be stored by the study team on NHS computers (desktop and/or laptop). 
Computers will be password protected and kept in locked offices. All paper files containing 
personal data will be held in filing cabinets in NHS offices that will be locked when unattended. 
Access to the study documents will be by the study team only. Data will be entered by those 
staff delegated to do so on the delegation log held at site. Personal data will be stored for 5 
years. 

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8.2 
DATA INFORMATION FLOW 
 
8.3 
TRANSFER OF DATA 
Personal data will not be transferred to any external individuals or organisations outside of the 
Sponsoring organisation.  
Every effort will be made to make data available for legitimate re-use via existing University of 
Edinburgh systems, according to the FAIR principles [24]. Data stored on such repositories will 
only be those with which we can guarantee sufficient protection to participant confidentiality, as 
per University policies and governance systems.  
8.4 
DATA CONTROLLER 
The University of Edinburgh and NHS Lothian are joint data controllers along with any other 
entities involved in delivering the study that may be a data controller in accordance with 
applicable laws (e.g. the site). 
 
8.5 
DATA BREACHES 
Any data breaches will be reported to the University of Edinburgh and NHS Lothian Data 
Protection Officers who will onward report to the relevant authority according to the appropriate 
timelines if required. 
9 
STATISTICS AND DATA ANALYSIS 
9.1 
SAMPLE SIZE CALCULATION 
Whilst a sample size of 300 has been calculated for the main ABC Sepsis study, as this sub-
study is an exploratory analysis no sample size calculation has been conducted. The majority 
of existing work on cytokine and RNA response focuses on sampling dates in a different 
context: over the course of days to weeks in patients presenting to hospital with sepsis. Our 
work will provide a foundation upon which to build further larger studies. We aim to recruit a 
minimum of 70, which has been selected because it confers a greater than 90% likelihood of 
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randomisation to each arm. 30 is a consensus figure arrived at by expert co-authors of the study 
with experience in related work in critical care research [25]. We anticipate enrolment would not 
continue beyond 80 participants: at this sample size there is a 99% likelihood of including at 
least 30 participants in each arm.   
9.2 
PROPOSED ANALYSES 
This project is primarily an exploratory analysis. We will report results by group as defined by 
the treatment arm into which they are enrolled, as well as by key outcomes (e.g. mortality at 30 
days, admission to ICU).  No interim analyses will be conducted.  
Analysis will be conducted, across treatment arms, of individual biomarkers as part of our 
cytokine panel, whether at individual timepoints or in terms of the change, and rate of change, 
from baseline results. It will also incorporate analysis of grouped variables (e.g. ‘pro-
inflammatory cytokines’ versus ‘anti-inflammatory cytokines’, or those known to be 
representative of specific pathophysiological damage like endothelial damage), again at 
individual timepoints or in terms of the change, and rate of change, from baseline. Further 
grouping may be taken, depending on the spread of our physiological data, to determine 
differences between ‘responders’ to fluid challenge versus ‘non-responders’ in either treatment 
arm.  
Taken as a whole, we will assess the accuracy of these biomarkers as predictors of our key 
clinical endpoints, with consideration of sensitivity, specificity and positive or negative predictive 
values. Receiver operator characteristic analysis will be explored for biomarkers with significant 
biological plausibility or which show promise in the preceding analysis. Transcriptomic data 
from RNA-seq will be interrogated to determine changes in RNA abundance at the gene level 
between sample points and by treatment arm, as well as at the transcript isoform level. 
 
Using the inclusion criteria mentioned before, it is plausible that we will include patients who 
ultimately are diagnosed with a pathology other than sepsis as a reason for their presentation 
to hospital. The inclusion of the results of such patients in the described analyses will be 
decided on discussion with the broader study team in the context of the frequency of this 
occurrence as well as the potential bias this might incur with the specific analysis. 
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 STUDY MONITORING AND AUDIT 
There is no routine monitoring or audit planned for this study.  

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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 KEY ETHICAL CONSIDERATIONS 
We recognise that the emergency presentation of sepsis is a challenging situation in which to 
conduct clinical research and it is critical that studies in such a setting are planned with ethical 
considerations centrally in mind. We have consulted with local patient and public involvement 
to both ensure acceptability of this study and optimise study documents.  
11.2.1 Consent process 
Emergency presentations for conditions such as sepsis are scary, uncertain and unsettling 
times for patients. It is fundamental to the design and conduct of this study that patient safety 
and dignity are the primary concerns of clinical and research teams involved in the care of these 
patients.  
In the acute setting, where trial interventions are necessarily time dependent, participants and 
researchers do not have the same luxury as many outpatient or non-emergency studies. 
Information must be communicated, explained and considered in a shorter than usual 
timeframe to allow informed consent within the window where interventions relevant to this 
study may have greatest impact. It is a priority, and area of significant experience, of the 
emergency medicine research team to communicate all information participants require to 
make informed decisions about participation of care. The majority of the research teams 
involved in this work will have first-hand experience of working within emergency departments 
and acute admission units, as well as broad experience of recruiting and communicating in 
busy and challenging environments.  
 
Beyond clear explanation of the study processes and understandable communication of risk 
and any deviation from standard practice, specific approaches which will be employed include:  
tailoring of information as guided by the patient in front of the researcher, and emphasizing the 
ability to opt out, ask further questions later, and to retain documents for review in the future.  
A significant proportion of patients presenting with sepsis are so unwell that their capacity is 
temporarily impaired. Furthermore, a number of comorbidities increase the likelihood of 
impaired capacity due to acute illness: using consent procedures designed for the non-acute 
setting would see this population underserved by research conducted with such measures. 
ABC Sepsis is a pragmatic trial, inclusive of many degrees of comorbidity which are typically 
excluded from sepsis research. MIS-ABC Sepsis is similarly pragmatic, with the aim that the 
findings are as broadly generalizable as possible.  
We see the Personal/Professional Representative mechanism as key to increasing inclusion 
into this area of research. However, we understand and expect that participants, and their 
Personal/Professional Representatives, may at times disagree or change their mind, and the 
withdrawal procedures have been carefully drafted to make that a clear and definitive process. 
11.2.2 Burden on patients 
In any research study, participants incur a somewhat increased burden. Often this is of 
questioning, decision making and testing. In creating the protocol for this sub-study there has 
been a careful balance struck between obtaining scientifically important data and following, as 
close as possible, routine paths of care to limit the burden we place upon participants.  

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In routine clinical practice when caring for patients unwell with sepsis, blood tests, physiological 
observations and clinical questioning and examinations are done frequently. This is particularly 
true for those patients who have physiological disturbances (i.e. high NEWS scores) and who 
require intravenous fluid therapy. Specific measures as part of this protocol like the leeway 
afforded to sampling times and the ability to take research and routine samples on the same 
blood draw mean that patients incurring additional venepuncture solely for the sake of blood 
samples will be a last resort. The second important area of burden, which is the discussion and 
information processing around informed consent at the beginning of this study process, has 
been designed to follow logically and concisely from the information given as part of the ABC 
Sepsis main study.  
11.2.3 Genetic analysis 
Often participants across studies are concerned about privacy implications of genetic analysis 
performed in research trials. Popularly, concerns around unearthing diagnoses or increased 
risks of disease which participants would not want to know about are cited as key concerns. 
Genetic material in blood samples taken as part of this sub-study will be analysed in a manner 
which is specific to sepsis, and in all likelihood specific to that presentation and subsequent 
response to treatment for sepsis.  
Separately, because this genetic analysis would be conducted for the purposes of scientific 
research it does not need to be disclosed to an insurance company [26]. 
11.2.4 Relationship with the main ABC Sepsis trial 
This sub-study is designed to be conducted with and alongside the ABC Sepsis trial, which has 
already been reviewed by a REC (Number 20/SS/0110). The investigator and management 
team conducting this sub-study are all involved in the main trial, with the full support of the main 
trial. In sites where both the main study and sub-study will take place, there is expected to be 
almost complete overlap in terms of the site teams undertaking the research. Collaboration and 
sharing of resources on all levels is envisaged to avoid waste and to ensure a streamlined 
process for both the studies and the participants. 
An inherent risk with any feasibility clinical trial like ABC Sepsis is that the objectives are not 
met and funding is not secured for a sufficient trial to answer the research question. Careful 
planning and preparation have been done on the part of both study and sub-study to avoid this, 
however in the event that the main study objectives are not met, it is hoped that this sub-study 
will improve our mechanistic understanding of the proposed interventions. Even in the event 
that results from the sub-study do not provide clear mechanistic data for the interventions, they 
will provide important information about inflammatory processes in a population which is, as 
yet, incompletely understood.  
11.3 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.   
Delegated tasks must be documented on a Delegation Log and signed by all those named on 
the list prior to undertaking applicable study-related procedures. 
11.3.1 Informed Consent 
The Investigator is responsible for ensuring the agreed informed consent process is undertaken 
and consent obtained before any protocol specific procedures are carried out. The decision of 
a participant to participate in clinical research is voluntary and will be based on a clear 
understanding of what is involved. 
Participants will receive adequate oral and written information – appropriate Participant 
Information and Informed Consent Forms will be provided. The oral explanation to the 

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participant will be performed by the Investigator or qualified delegated person, and will cover 
all the elements specified in the Participant Information Sheet and Consent Form. 
The participant will be given every opportunity to clarify any points they do not understand and 
the opportunity to ask for more information.  It will be emphasised during this process that the 
participant may withdraw their consent to participate at any time without impacting their clinical 
care or loss of benefits to which they otherwise would be entitled. 
The participant will be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor(s). 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. The participant will receive a copy of this document 
and a copy filed in the ISF and participant’s medical notes.  
In the event of consent via Personal Representative, relevant equivalent oral and/or written 
information will be provided to relevant individuals in that process. In this circumstance, once 
the participant has regained capacity, relevant oral and written information will be provided to 
them. 
 
11.3.2 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. 
11.3.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the CRF at each 
Investigator Site.  
11.3.4  Investigator Documentation 
The Principal Investigator will ensure that the required documentation is available in local ISFs.  
11.3.5 GCP Training 
All researchers are encouraged to undertake GCP training in order to understand the principles 
of GCP. However, this is not a mandatory requirement as this is not a CTIMP study.  GCP 
training status for all investigators will be indicated in their respective curricula vitae.  
11.3.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be identified in a 
manner designed to maintain participant confidentiality.  All records must be kept in a secure 
storage area with limited access.  Clinical information will not be released without the written 
permission of the participant.  The Investigator and study site staff involved with this study may 
not disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished information, which is confidential or identifiable, and has been disclosed to 
those individuals for the purpose of the study. Prior written agreement from the sponsor or its 
designee must be obtained for the disclosure of any said confidential information to other 
parties. 
11.3.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the requirements 
of the appropriate data protection legislation (including the General Data Protection Regulation 
and Data Protection Act) with regard to the collection, storage, processing and disclosure of 
personal information.  
Computers used to collate the data will have limited access measures via usernames and 
passwords. 

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Published results will not contain any personal data and be of a form where individuals are not 
identified and re-identification is not likely to take place. Data stored on a repository for re-use 
will be handled as described in Section 8.3 Transfer of Data. 
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 5 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 90 day follow up.   
The Investigators or the co-sponsor(s) have the right at any time to terminate the study for 
clinical or administrative reasons.  

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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 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 
No treatment is being conducted in this sub-study.  
 
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. Once the study is 
completed, analysis performed and study shut down complete, a clinical study report will be 
prepared and submitted to the sponsor within 1 year of the end of the study. A published journal 
article may take the place of this clinical study report if agreed with the sponsor. 
13.2 PUBLICATION 
Investigators have the right to publish, orally or in writing, the results of the study under direction 
of the Chief Investigator. The results of the study, together with other mandated information, 
will be uploaded to the relevant clinical trial registration page (ClinicalTrials.gov) within 1 year 
of the end of the study. 

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13.3 DISSEMINATION OF RESULTS  
Where participants have requested to be updated about results of the study and have 
consented for such contact, a summary of the results will be provided after the end of the study. 
Summaries of results may also be made available to Investigators and participating sites 
through short reports or via social media. 
14 
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