Conditions: Sepsis
Keywords: Sepsis Emergency Care Albumin Crystalloid Fluid Resuscitation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 300
Healthy volunteers: no

Brief summary:
The aim of this research study is to compare two different fluids (Human Albumin Solution (HAS) and Balanced Crystalloid that are given via a drip to patients with severe infection (sepsis). The investigators plan to see which fluid is better, and to see if they have a role in improving a patient's recovery time, reducing complications and the length of time they stay in hospital. This study plans to find out if there is evidence that one fluid is better overall to determine the need for a subsequent definitive trial.

Detailed description:
This trial will be an open label two-arm, multicentre, pragmatic, parallel group randomised trial of adult patients with community acquired sepsis recruited from the Emergency Department and Medical and Surgical Assessment Units across \~10 UK NHS Hospitals. The treatment phase will be the first 6 hours following randomisation. 30-day and 90-day follow up will be conducted using routine data only. The exception to this will be the first 50 patients enrolled in the study, Health Related Quality of Life (HRQoL) will be measured using the EQ-5D-5L at baseline, 7 days and at 180 days. At baseline, the participant or their relative will be asked to recall the quality of life 4 weeks prior to the index hospital admission. Questionnaires will be administered by direct patient completion or, postal or email survey with telephone follow up for non-responders after two mailings two weeks apart.

Arms:
arm 1: Participants allocated to the treatment arm will receive intravenous 5% Human Albumin Solution (HAS) administered as the sole intravenous fluid during the initial 6-hour resuscitation period. The clinician can deliver up to 10ml/kg in the first 3 hours using 250ml boluses of HAS based on clinical judgement, using clinical assessment supplemented by technology if that is their usual practice. This will be followed by repeat clinical assessment after each bolus (including vital signs; lactate testing). After 3 hours further HAS boluses up to 6 hours post-randomisation will be at clinical discretion and will be documented in the CRF. Patients in the albumin arm should not receive balanced crystalloid as a resuscitation fluid in the first 6 hours. arm 2: Participant allocated to the usual care arm will receive intravenous balanced crystalloid administered as the sole intravenous fluid during the initial 6 hour resuscitation period. The clinician can deliver up to 30ml/kg in the first 3 hours using 250ml boluses of balanced crystalloid based on clinical judgement, using clinical assessment supplemented by technology if that is their usual practice. This will be followed by repeat clinical assessment after each bolus (including vital signs; lactate testing). Thereafter, further crystalloid boluses up to 6 hours will be at the discretion of the clinical team and will be documented in the CRF. Patients in the balanced crystalloid arm should not receive albumin as a resuscitation fluid in the first 6 hours.

Interventions: intervention 1: Human albumin intervention 2: Balanced crystalloid solution
Intervention descriptions: intervention 1: Any preparation of 5% Human Albumin Solution which has marketing authorisation in the UK to be used for this indication and is stocked by local hospital pharmacies at the participating sites, may be prescribed in this study intervention 2: Any preparation of intravenous "balanced" crystalloid which has marketing authorisation in the UK to be used for this indication and is stocked by local hospital pharmacies at the participating sites, may be prescribed in this study.

Protocol document:
Prot_000.pdf: 
ABC Sepsis Protocol  
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Study Protocol 
 
Feasibility of 5% Albumin compared with Balanced Crystalloid, as intravenous 
fluid resuscitation in adult patients with sepsis, presenting as an emergency to 
hospital: ABC Sepsis trial 
 
Co-sponsors 
The University of Edinburgh & Lothian Health 
Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Funder 
The Jon Moulton Charity Trust 
Funding Reference Number 
CH605 
Chief Investigator 
Professor Alasdair Gray 
Sponsor Reference 
AC20043 
EudraCT Number 
2020-013520-18 
Clinicaltrials.gov Reference  
NCT04540094 
REC Number 
20/SS/0110 
Version Number and Date 
V4.0 02 Jul 2021  


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KEY TRIAL CONTACTS 
 
Lead Investigator
Prof Alasdair J Gray* 
Emergency Medicine Research Group 
(EMERGE) 
Department of Emergency Medicine 
Royal Infirmary of Edinburgh 
51 Little France Crescent 
Edinburgh, EH16 4SA  
Tel: 0131 242 1340 
Fax: 0131 242 1339  
Email: alasdair.gray@ed.ac.uk 
 
Co-sponsor Representative
Dr Fiach O’Mahony 
Clinical Research Facilitator 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Tel: 0131 242 9418 
Fax: 0131 242 9447 
Email: fiach.o’mahony@ed.ac.uk  
 
Trial Management
Ms Kat Oatey   
Trial Manager 
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh EH16 4UX  
 
Tel: 0131 651 9913                                   
Email: ABCSEPSIS.trial@ed.ac.uk 
  
Trial Statistician 
 
Prof John Norrie*  
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh EH16 4UX  
Tel: 0131 651 7895  
Email: john.norrie@ed.ac.uk 
 
CO-APPLICANTS 
Dr Alasdair Corfield * 
Emergency Department 
Royal Alexandra Hospital 
Corsebar Road 
Paisley 
PA2 9PN 
 
Tel: 0141 314 6601  
Email: Alasdair.Corfield@ggc.scot.nhs.uk 
 
Prof Tim Walsh  
Chair of Critical Care                          
Department, Anaesthesia, Critical Care 
& Pain Medicine                            
Royal Infirmary of Edinburgh  
51 Little France Crescent                    
Edinburgh                                            
EH16 4SA 
 
Tel: 0131 242 6395 
Email: timothy.walsh@ed.ac.uk 


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Dr Naz Lone 
Anaesthesia, Critical Care and Pain 
Medicine 
Edinburgh Royal Infirmary 
51 Little France Crescent 
Edinburgh 
EH16 4SA 
Tel: 0131 242 3134       
Email: nazir.lone@ed.ac.uk 
Dr Dan Horner  
Consultant in Emergency Medicine and 
Intensive Care 
Salford Royal NHS Foundation Trust 
Stott Lane 
Salford 
M6 8HD 
 
Tel: 0161 206 0496 
Email: danielhorner@nhs.net 
Dr Andy Appelboam 
Academic Department of Emergency 
Medicine 
Royal Devon & Exeter Hospital 
Barrack Road, 
Exeter, Devon. 
 
Tel: 01392 411611 
Email: andy.appelboam@nhs.net 
 
Dr Peter Hall 
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh EH16 4UX  
 
Tel: 0131 6518510 
Email: p.s.hall@ed.ac.uk 
Mr Richard Skipworth 
Clinical Surgery 
Edinburgh Royal Infirmary 
51 Little France Crescent 
Edinburgh 
EH16 4SA 
Tel: 0131 242 3176  
richard.skipworth@nhslothian.scot.nhs.uk 
Prof Derek Bell OBE 
 
Faculty of Medicine, School of Public 
Health 
Chelsea and Westminster Hospital  
369 Fulham Road 
Chelsea 
London SW10 9NH 
Tel: 020 3315 5845 
Email: d.bell@imperial.ac.uk 
 
Dr Kevin Rooney 
Consultant in Anaesthesia 
and Intensive Care Medicine 
Royal Alexandra Hospital  
Paisley 
PA2 9PN 
 
Tel 0141 314 6695 
Email: kevin.rooney2@ggc.scot.nhs.uk 
 
 
* Protocol Authors  
 
 
 
 
 


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PROTOCOL APPROVAL SIGNATURE PAGE 
Feasibility of 5% Albumin compared with Balanced Crystalloid, as intravenous 
fluid resuscitation in adult patients with sepsis, presenting as an emergency to 
hospital 
ABC Sepsis 
EudraCT: 2020-0013520-18 
 
The undersigned accept the content of this protocol in accordance with the appropriate 
regulations and agree to adhere to it throughout the execution of the study. 
 
Prof Alasdair Gray 
 
 
 
Chief Investigator
Signature
Date
Prof John Norrie 
 
  
Trial Statistician
Signature
Date
Dr Fiach O’Mahony 
 
 
 
Lead Co-Sponsor 
Representative 
Signature
Date
 
 
For multi-site trials, the Principal Investigator must sign below to document that the 
protocol has been read and understood.  
 
 
 
 
 
 
 
Principal Investigator
Signature
Site
Date
 
 
 
Alasdair Gray (Jul 27, 2021 10:14 GMT+1)
Alasdair Gray
Jul 27, 2021
Fiach O'Mahony (Aug 2, 2021 10:13 GMT+1)
Fiach O'Mahony
Aug 2, 2021
JD Norrie (Aug 2, 2021 10:23 GMT+1)
JD Norrie
Aug 2, 2021


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CONTENTS 
 
1. 
INTRODUCTION ...................................................................................... 13 
1.1 
BACKGROUND ............................................................................... 13 
1.2 
RATIONALE FOR STUDY ............................................................... 15 
2. 
STUDY OBJECTIVES .............................................................................. 17 
2.1 
OBJECTIVES .................................................................................. 17 
2.1.1 
Primary Objective .......................................................................... 17 
2.2 
ENDPOINTS .................................................................................... 17 
2.2.1 
Primary Endpoint .......................................................................... 17 
2.2.2 
Secondary Endpoints .................................................................... 17 
3. 
STUDY DESIGN ....................................................................................... 18 
3.1 
Study Flowchart ............................................................................... 19 
4. 
STUDY POPULATION ............................................................................. 19 
4.1 
NUMBER OF PARTICIPANTS ......................................................... 19 
4.2 
INCLUSION CRITERIA .................................................................... 20 
4.3 
EXCLUSION CRITERIA ................................................................... 20 
4.4 
CO-ENROLMENT ............................................................................ 20 
4.4.1 
Observational Studies ................................................................... 20 
4.4.2 
Interventional Phase CTIMP-CTIMP Co-enrolment ....................... 20 
4.4.3 
CTIMP-CTIMP Co-enrolment ........................................................ 20 
4.4.4 
CTIMP-Non-CTIMP Co-enrolment ................................................ 21 
4.4.5 
Accidental/Unintentional Co-Enrolment Identified Retrospectively . 21 
5. 
PARTICIPANT SELECTION AND ENROLMENT .................................... 21 
5.1 
IDENTIFYING PARTICIPANTS ....................................................... 21 
5.2 
CONSENTING PARTICIPANTS ...................................................... 22 
5.3 
SCREENING FOR ELIGIBILITY ......... Error! Bookmark not defined. 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS .................... 28 
5.5 
RANDOMISATION ........................................................................... 28 
5.5.1 
Randomisation Procedures ........................................................... 28 
5.5.2 
Treatment Allocation ..................................................................... 28 
5.5.3 
Emergency Unblinding Procedures ............................................... 28 
5.6 
WITHDRAWAL OF STUDY PARTICIPANTS ................................... 29 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT AND COMPARATOR ....... 29 
6.1 
STUDY DRUG ................................................................................. 29 
6.1.1 
Study Drug Identification ............................................................... 29 
6.1.2 
Study Drug Manufacturer .............................................................. 29 
6.1.3 
Marketing Authorisation Holder ..................................................... 29 
6.1.4 
Labelling and Packaging ............................................................... 29 
6.1.5 
Storage ......................................................................................... 29 
6.1.6 
Destruction of Trial Drug ............................................................... 29 
Not applicable as using hospital routine supplies. ..................................... 29 


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6.1.7 
Summary of Product Characteristics (SPC) Booklet or Investigators 
Brochure ....................................................................................... 30 
6.2 
COMPARATOR DRUG .................................................................... 30 
6.2.1 
Labelling and Packaging ............................................................... 30 
6.2.2 
Storage ......................................................................................... 30 
6.3 
DOSING REGIME ............................................................................ 31 
6.4 
PARTICIPANT ADHERENCE .......................................................... 32 
6.5 
OVERDOSE .................................................................................... 32 
6.6 
OTHER MEDICATIONS ................................................................... 32 
6.6.1 
Non-Investigational Medicinal Products ......................................... 32 
6.6.2 
Permitted Medications ................................................................... 32 
6.6.3 
Prohibited Medications .................................................................. 32 
7. 
STUDY ASSESSMENTS ................................ Error! Bookmark not defined. 
7.1 
STUDY ASSESSMENTS .................... Error! Bookmark not defined. 
7.2 
LONG TERM FOLLOW UP ASSESSMENTS .... Error! Bookmark not 
defined. 
8. 
DATA COLLECTION ............................................................................... 34 
8.1 
TRIAL DATABASE .............................. Error! Bookmark not defined. 
9. 
DATA MANAGEMENT ............................................................................. 35 
9.1.1 
Data Information Flow ................................................................... 35 
9.1.2 
Transfer of Data ............................................................................ 36 
9.1.3 
Data Controller .............................................................................. 36 
9.1.4 
Data Breaches .............................................................................. 36 
10. 
STATISTICS AND DATA ANALYSIS ...................................................... 36 
10.1 
SAMPLE SIZE CALCULATION ........................................................ 36 
10.2 
PROPOSED ANALYSES ................................................................. 37 
11. 
PHARMACOVIGILANCE ......................................................................... 38 
11.1 
DEFINITIONS .................................................................................. 38 
11.2 
IDENTIFYING AEs AND SAEs ........................................................ 38 
11.3 
RECORDING AEs AND SAEs ......................................................... 39 
11.3.1 Pre-existing Medical Conditions .................................................... 39 
11.3.2 Worsening of the Underlying Condition during the Trial ................. 39 
11.4 
ASSESSMENT OF AEs AND SAEs ................................................. 39 
11.4.1 Assessment of Seriousness .......................................................... 39 
11.4.2 Assessment of Causality ............................................................... 39 
11.4.3 Assessment of Expectedness ....................................................... 40 
11.4.4 Assessment of Severity ................................................................. 40 
11.5 
RECORDING OF AEs...................................................................... 40 
11.6 
REPORTING OF SAEs/SARs/SUSARs ........................................... 40 
11.7 
REGULATORY REPORTING REQUIREMENTS ............................. 42 
11.8 
FOLLOW UP PROCEDURES .......................................................... 43 


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11.9 
PREGNANCY .................................................................................. 43 
12. 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS............... 43 
12.1 
TRIAL MANAGEMENT GROUP ...................................................... 43 
12.2 
TRIAL STEERING COMMITTEE ..................................................... 43 
12.3 
DATA MONITORING COMMITTEE ................................................. 43 
12.4 
INSPECTION OF RECORDS .......................................................... 44 
12.5 
RISK ASSESSMENT ....................................................................... 44 
12.6 
STUDY MONITORING AND AUDIT ................................................. 44 
13. 
GOOD CLINICAL PRACTICE .................................................................. 44 
13.1 
ETHICAL CONDUCT ....................................................................... 44 
13.2 
REGULATORY COMPLIANCE ........................................................ 44 
13.3 
INVESTIGATOR RESPONSIBILITIES ............................................. 44 
13.3.1 Informed Consent ......................................................................... 44 
13.3.2 Study Site Staff ............................................................................. 45 
13.3.3 Data Recording ............................................................................. 45 
13.3.4 Investigator Documentation ........................................................... 45 
13.3.5 GCP Training ................................................................................ 46 
13.3.6 Confidentiality ............................................................................... 46 
13.3.7 Data Protection ............................................................................. 46 
14. 
STUDY CONDUCT RESPONSIBILITIES ................................................. 46 
14.1 
PROTOCOL AMENDMENTS ........................................................... 46 
14.2 
PROTOCOL NON COMPLIANCE.................................................... 46 
14.2.1 Definitions ..................................................................................... 46 
14.2.2 Protocol Waivers ........................................................................... 46 
14.2.3 Management of Deviations and Violations .................................... 47 
14.3 
URGENT SAFETY MEASURES ...................................................... 47 
14.4 
SERIOUS BREACH REQUIREMENTS ........................................... 47 
14.5 
STUDY RECORD RETENTION ....................................................... 47 
14.6 
END OF STUDY .............................................................................. 47 
14.7 
INSURANCE AND INDEMNITY ....................................................... 48 
15. 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ...... 48 
15.1 
AUTHORSHIP POLICY ................................................................... 48 
15.2 
PUBLICATION ................................................................................. 49 
16. 
REFERENCES ......................................................................................... 49 
 
 
 


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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 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
ECTU 
Edinburgh Clinical Trials Unit 
EudraCT 
European Clinical Trials Database 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HAS 
5% Human Albumin Solution 
HRQol  
Health Related Quality of Life  
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials Number 
MHRA 
Medicines and Healthcare products Regulatory Agency 
PI 
Principal Investigator 
NIMP 
Non-Investigational Medicinal Product 
QA 
Quality Assurance 
REC 
Research Ethics Committee 


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SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 


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TRIAL SUMMARY 
 
Trial Title 
Feasibility of 5% Human Albumin Solution compared with 
Balanced Crystalloid, as intravenous fluid resuscitation in 
adult patients with sepsis, presenting as an emergency to 
hospital 
Study Acronym 
ABC Sepsis 
Clinical Phase 
Phase III 
Trial Design 
Open label two-arm, multicentre, pragmatic, parallel group 
randomised trial 
Trial Participants 
Adult patients with community acquired sepsis recruited 
from the Emergency Department and Medical and Surgical 
Assessment Units in ~ 15 UK NHS Hospitals. 
Planned Number of Participants 
300 
Planned Number of Sites 
~15 
Countries Anticipated to be Involved in 
Trial 
UK 
Treatment Duration 
6 hours 
Follow up Duration 
90 days; except first 50 patients (180 days) 
Total Planned Trial Duration 
24 months 
Primary Objective 
This trial aims to investigate: 
 
the feasibility of being able to recruit adults with 
community acquired sepsis and a National Early 
Warning 
Score 
(NEWS/NEWS2) 
of ≥5 
in the 
Emergency Department 
 
the comparative effectiveness, by determining 30-day 
mortality, of intravenous 5% Human Albumin compared 
with intravenous balanced crystalloid in the early 
resuscitation phase of management of adults with 
community acquired sepsis. 
Primary Endpoint 
 
Recruitment rate from screening logs  
 
30 day mortality  


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Secondary Objectives  
1. To assess the mortality rate during index hospitalisation, 
in-hospital and at 90  days; 
2. To assess the ability to deliver the trial including the  time 
to first dose, data completeness and participant 
withdrawal; 
3. To quantify the proportion of patients who receive any 
other fluid apart, from the one being studied, in the first 
6 hours after recruitment; 
4. To assess the total volume of intravenous fluid in each 
arm at 6 hours and 24 hours 
5. To assess the level of critical care interventions 
administered;  
6. To investigate the length of hospital stay including critical 
care (HDU/ICU) admission;  
7. To investigate the proportion of patients readmitted to 
hospital in first 90 days after discharge;  
8. Delineate the proportion of patients developing any 
complications including acute kidney injury, pulmonary 
oedema and allergy including severe allergic reactions; 
9. To assess patient quality of life measures using EQ-5D-
5L questionnaire;   
10. To assess secondary care costs at 30 days.  
 


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Secondary Endpoints 
1. In-hospital mortality and 90-day mortality;  
2. Time to start of IMP; 
3. Data completeness; 
4. Study withdrawal; 
5. Volume of randomised fluid delivered in each arm in the 
first 6hrs and 24hrs; 
6. Proportion of participants needing critical care 
intervention: Intravenous vasopressors, renal 
replacement therapy and invasive ventilation;  
7. Proportion of patients who receive any other fluid apart 
from intervention or control in first 6 hrs after 
recruitment; 
8. Proportion of patients admitted to critical care 
(HDU/ICU); length of stay in critical care (HDU/ICU); 
9. Length of hospital stay;  
10. Proportion of patients readmitted in first 90 days after 
discharge. 
11. Proportion of patients developing any of: acute kidney 
injury (Defined by NICE (https://cks.nice.org.uk/acute-
kidney-injury#!scenario); 
pulmonary 
oedema 
(Radiology diagnosis or requirement for rescue 
management (new diuretic use); and allergy or 
anaphylaxis (Requirement for rescue management 
(antihistamines, 
adrenaline, 
intravenous 
fluids, 
steroids)). 
12. Health Related Quality of life (EQ-5D-5L) at 7 and 180 
days for the first 50 patients.  
13. Secondary care costs at 30 days (calculated from 
readmissions and length of stay at ward level and in 
critical care (HDU/ICU). 
IMP(s) 
5% Human Albumin Solution 
IMP Route of Administration 
Intravenous, peripheral or central 
Lay Summary of Trial  
The aim of this research study is to compare two different 
fluids (Human Albumin Solution (HAS) and Balanced 
Crystalloid that are given via a drip to patients with severe
infection (sepsis). We plan to see which fluid is better, and 
to see if they have a role in improving a patient’s recovery 
time, reducing complications and the length of time they 
stay in hospital. This study plans to find out if there is 
evidence that one fluid is better overall to determine the 
need for a subsequent definitive trial. 
 
 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
This trial will investigate the feasibility of delivering an early intravenous fluid 
resuscitation trial comparing 5% human albumin solution (HAS), (current 
recommended second line fluid therapy in septic shock) as first line therapy  with a 
balanced crystalloid (routine care; currently recommended first line therapy in 
international sepsis guidelines) [1,2] in adults with sepsis.  Previous trials and meta-
analyses show that HAS has a potential benefit in patients with sepsis. 
The trial intervention will be delivered in the critical first hours of hospital treatment. 
Patients will be enrolled in Emergency departments (ED) and Medical and Surgical 
Assessment Units (AAU). We aim to recruit in all groups of sepsis patients who require 
intravenous fluid resuscitation, not the minority whose care is delivered or will 
ultimately be delivered in critical care. This maximises generalisability and relevance 
to the NHS and is very different from previous HAS or previous international sepsis 
resuscitation trials. Most sepsis in UK hospitals is not managed in critical care; critical 
care patients are estimated to comprise around only 5-10% of all patients with 
suspected sepsis [3,4]. We propose an efficient trial design to investigate feasibility 
and potential effect size for the proposed primary effectiveness outcome, 30-day 
mortality.  
 
HAS is a potentially ideal resuscitation fluid for sepsis, but this study is needed 
because: 1. Evidence for HAS is promising but inconclusive; 2. HAS is costly (x25-50 
greater than balanced crystalloid; £2-4; Albumin 5% group £106); 3. HAS has not been 
studied in large sepsis resuscitation trials outside the critical care setting or early during 
the resuscitation phase; 4. All previous data relates to critical care management, only 
5-10% of eligible patients receive critical care in the UK [3,4, unpublished data from 
Plymouth, Aberdeen]; 5. Based on a survey of pharmacists, HAS use is increasing in 
Critical Care in the UK and globally [5] but use is minimal in Emergency Care [6,7]; 6. 
The International Surviving Sepsis Campaign guidelines [1] advise initial intravenous 
fluid resuscitation with crystalloids: ‘using HAS in addition to crystalloids…in patients 
with sepsis and septic shock when patients require substantial amounts of crystalloids’ 
(low evidence). NICE guideline 51[2] states: ‘Consider HAS for fluid resuscitation only 
in patients with sepsis and shock’; and 7. It is considered an important question for 
treating clinicians with a clear willingness to participate in a trial if funded [31/31 
respondents in survey completed prior to grant application].  
 
Adult patients presenting to UK EDs and AAUs with community acquired infection and 
abnormal vital signs (NEWS/NEWS2 ≥5) are common. Multiple data sets suggest that 
this sepsis patient cohort constitute around 1-1.5% of all emergency attendances [3, 
4, unpublished data from Plymouth, Aberdeen]. This group has a mean age around 
70, with a median length of stay 10 days and have significant mortality during index 
hospitalisation, around 20%. Patients who are older and/or more severely unwell with 
shock have significantly higher mortality. Overall, data suggest that a patient dies from 
sepsis every 20 minutes in the UK. Survivors suffer step reductions in health status, 
with reduced quality of life and functional status [8]. Key issues include cognitive 
decline and psychological morbidity, and increased risk of subsequent cardiovascular 
events, renal failure, and infections. Early sepsis management is likely to contribute 


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causally to long-term outcomes, by reducing subsequent inflammation, immune 
suppression, and organ dysfunction [9]. Guidelines highlight the importance of early 
antibiotics and intravenous fluid resuscitation, but the delivery of early fluids is 
logistically challenging and its direct association with outcomes is uncertain [10]. The 
proposed primary/secondary clinical outcomes all directly reflect or impact on 
population health and wellbeing. Our focus is on early sepsis intervention, which has 
plausibility for modifying short and long-term outcomes. We chose not to study an 
exclusively ICU population, because, in this population, the intervention is later, 
selection bias is possible, and disease modification is less plausible. This trial will 
uniquely include all sepsis presenting to hospitals (>90% of sepsis patients in the NHS 
are managed in a general ward setting), for whom there is very limited research 
evidence around the timing and type or volume of intravenous fluid resuscitation. This 
initial study will establish whether a definitive study comparing 5% HAS with the current 
standard of balanced crystalloid fluid is feasible in this population and setting. If this 
study is feasible, it will inform the design and conduct of a larger definitive trial with 
results that will be generalisable to all patients with community acquired sepsis. The 
cost of sepsis is high, both during index admission and subsequent ‘survivorship’ [10]. 
The excess treatment costs for HAS are likely to be around £110/patient, substantially 
increasing current fluid costs, but HAS use has already increased 2-3 fold in many 
hospitals since 2012 consistent with data from outside the UK [6]. The potential 
economic gains (health/social) from effective early sepsis interventions are substantial 
and lifelong so our definitive study will include a health economic evaluation which will 
provide key information to guide HAS use in the NHS. For example, a reduction of 1 
patient day in ICU would save around £1500 (equivalent to 12-13 units of HAS). 
 
The main types of intravenous resuscitation fluid: The two classes of commonly 
used intravenous resuscitation fluids are crystalloids (“normal” saline and balanced 
crystalloid) and colloids (hydroxyethyl starch and albumin) [6,7]. Current UK and 
international guidelines recommend balanced crystalloids as the first line choice of 
intravenous fluid in the resuscitation of adult patients with sepsis [1,2]. Recent 
international and UK data suggest that the use of non-balanced crystalloid remains 
widespread especially in emergency care settings [6,7]. Starch based colloids are no 
longer recommended because they were associated with harm in large sepsis and 
critical care trials. 
 
Supporting randomised controlled trials, meta-analyses and current research: 
Three large trials include data directly comparing HAS with crystalloid, one included a 
heterogeneous critical care population using iso-oncotic 4% albumin [31,32] and two 
only recruited sepsis populations admitted to critical care with hyper-oncotic solution 
of 20% albumin [33,34]. The reduction in the risk of death from septic shock with 
albumin as compared to crystalloid fluid was consistent across all three trials and 
ranged between 2.3% to 6.4% at 28 and 90 days respectively. In the Saline vs. Albumin 
Fluid Evaluation (SAFE) trial [31], in a general ICU population, HAS had no overall 
effect but the sepsis sub-group suggested lower mortality. This subgroup 
demonstrated a 5.2% mortality difference when adjusted for relevant baseline 
characteristics (35.5% vs. 30.2%; OR 0.71, 95% CI 0.52–0.97, p = 0.03). [32]. 
However, this post hoc analysis was at best hypothesis generating. The ALBIOS trial 


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[33] studied ICU patients with severe sepsis (comparing 20% HAS infusion with 
crystalloid) and found no overall effect on mortality, but lower mortality with HAS in the 
sub-group with septic shock (RR 0.87; 95% CI 0.77 to 0.99), equating to an absolute 
risk reduction of 5.3%; HAS also improved cardiovascular stability although, 
importantly, the treatment goal in this study was serum albumin concentration, not 
haemodynamic or end organ perfusion markers. The EARSS study in France, recruited 
798 patients with septic shock of less than 6 hours duration, but only in ICUs. These 
patients were randomised to receive: 100 ml of 20% albumin or 1000 ml of 0.9% saline 
every 8 hours for 3 days. Almost all patients had severe hypoalbuminemia at study 
inclusion. There were no significant differences in 28 day mortality rates between the 
two groups (24.1 vs. 26.3%). This study has never been published in full [34]. 
 
Several meta-analyses (MA) analysed these data plus results from a number of smaller 
trials. A MA of 5,534 patients (5 trials) comparing HAS with crystalloids (3,658 severe 
sepsis; 2,180 septic shock) found HAS was associated with a non-significant difference 
in 90-day mortality in severe sepsis (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; p = 
0.08) and significantly reduced mortality in septic shock (OR 0.81; 95% CI, 0.67 to 
0.97; p = 0.03) [35]. A MA of 3878 patients (7 trials) found a non-significant difference 
in mortality with HAS (RR 0.93; 95% CI 0.86 to 1.01; p=0.07), with possibly greater 
effects in septic shock (RR 0.91; 0.82 to 1.01; p=0.06) [36]. Differences between the 
MAs are likely to relate to the differences in included trials and methodologies, and 
small total number of participants. 
Importantly, none of these trials compare HAS to balanced crystalloid as the early 
resuscitation fluid in a pre-ICU setting despite these data being extrapolated in 
guidelines to precisely this environment. A search of trial registries 12th June 2020) 
found no ongoing trials addressing this research question. These MA support the need 
for a trial of HAS in early sepsis, powered for a clinically plausible effect size. In this 
study we will investigate feasibility of delivering a pragmatic trial during the 
resuscitation phase of treatment of adults with sepsis and provide pilot data that will 
inform the size of treatment effect between HAS and balanced crystalloid for the 
planned primary outcome – 30-day mortality - enabling an accurate sample size to be 
calculated for a subsequent definitive trial. 
 
1.2 
RATIONALE FOR STUDY 
Rationale for balanced compared with non-balanced crystalloid as comparator: 
There has been increasing concern relating to the potential adverse effects of 
crystalloids such as 0.9% “normal” saline due to the harmful effects of the high chloride 
content being associated with hyperchloraemic metabolic acidosis [11] and resultant 
increased risk of acute kidney injury [12]. More recently, three large pragmatic trials 
have shown divergent results in relation to the potential harm associated with non-
balanced crystalloids. The SPLIT trial showed no difference in the rates of acute kidney 
injury in ICU patients [13], whereas the SALT-ED in Emergency Department [14] and 
SMART in ICU patients [15] showed a reduced risk of acute kidney injury and other 
important clinical outcomes with balanced crystalloids when compared with non-
balanced crystalloids. We chose to mandate balanced crystalloid based on these 
recent large trials, We consider this an important stipulation in this feasibility trial given 
heterogeneity of use of balanced crystalloid in ED. 


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Mechanism of action of Human Albumin Solution: It is widely believed that colloids 
exhibit properties that result in them being superior to crystalloids for expansion of the 
intravascular space, enhancing cardiac output and thus end organ oxygenation and 
perfusion. Additionally, due to their larger molecules, they do not leak through the 
endothelial layer into the interstitium resulting in less tissue oedema than with 
crystalloids [14-16]. These properties should lead to less fluid resuscitation volume 
requirement for a given physiological effect, often cited as a ratio of 3:1 [14]. Recent 
understanding of the pathophysiological effects of sepsis on the glycocalyx in the 
endothelial wall suggest HAS might have important protective effects that could 
translate into clinical benefit; however, this potential benefit is controversial and 
unsubstantiated in clinical trials [15]. Importantly, glycocalyx injury is exacerbated by 
rapid fluid expansion and hypervolaemia, both of which may occur during early fluid 
resuscitation. HAS has a number of additional biological properties that may benefit 
oxygen delivery and end organ perfusion over and above circulating volume expansion 
in patients with infection and sepsis. Albumin is a key antioxidant in plasma scavenging 
oxygen free radicals [17-23] and acts as a transport protein binding inflammatory 
mediators [24]. Moreover, in animal models albumin improves myocardial function and 
oxygenation [25]. Laboratory studies suggest it is an essential component of the 
endothelium and may affect vascular permeability and endothelial dysfunction in 
sepsis [26-29]. As noted above, laboratory evidence suggests it may reduce damage 
to the glycocalyx in patients with sepsis [30]. 
 
Relevance and importance for current UK clinical practice now: The vast majority 
of patients with community acquired sepsis are managed in general wards in the NHS. 
This group is extremely common and has long lengths of hospital stay. The mortality 
rate for this patient group remains stubbornly high and there is limited scope for 
evidence based practice to lower it further. One possible beneficial intervention is 
intravenous fluid resuscitation. There is a paucity of evidence around type, timing and 
volume of intravenous fluid and this trial directly addresses this area. If HAS was shown 
to be superior the impact for NHS practice would be substantial, would improve patient 
experience and relieve suffering and would radically change the current NICE and 
international guidelines [1,2]. Conversely, if HAS is shown not to be superior, then the 
non-evidence based current drift of clinicians to extrapolate use of HAS to all sepsis 
settings could be curtailed, which would ensure patients only receive necessary 
treatment and also have significant cost savings for UK and international healthcare. 
The importance of this subject area to clinicians is evident by the clear support for a 
trial in this area from a recent international survey [6] and a 31/31 respondent 
agreement to participate rate from our recent survey. 
 
 
 
 
 


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2. 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
This trial aims to investigate: 
 
the feasibility of being able to recruit adults with community acquired sepsis and a 
National Early Warning Score (NEWS or NEWS2) of ≥5 in the Emergency 
Department 
 
the comparative effectiveness, by determining 30-day mortality, of intravenous 5% 
Human Albumin compared with intravenous balanced crystalloid in the early 
resuscitation phase of management of adults with community acquired sepsis. 
 
2.1.2 Secondary Objectives  
1. 
To assess the mortality rate during index hospitalisation, in-hospital and at 90  
days; 
2. 
To assess the ability to deliver the trial including the  time to first dose, data 
completeness and participant withdrawal; 
3. 
To quantify the proportion of patients who receive any other fluid apart, from the 
one being studied, in the first 6 hours after recruitment; 
4. 
To assess the total volume of intravenous fluid in each arm at 6 hours and 24 
hours 
5. 
To assess the level of critical care interventions administered;  
6. 
To investigate the length of hospital stay including critical care (HDU/ICU) 
admission;  
7. 
To investigate the proportion of patients readmitted to hospital in first 90 days 
after discharge;  
8. 
Delineate the proportion of patients developing any complications including 
acute kidney injury, pulmonary oedema and allergy including severe allergic 
reactions;  
9. To assess patient quality of life measures using EQ-5D-5L questionnaire;   
10. To assess secondary care costs at 30 days.  
 
 
2.2 
ENDPOINTS 
2.2.1 Primary Endpoint 
1. Recruitment rate from screening logs 
2. 30-day mortality  
 
2.2.2 Secondary Endpoints 
1. In-hospital mortality and 90-day mortality;  
2. Time to start of IMP; 
3. Data completeness;  
4. Study withdrawal;  
5. Volume of randomised fluid delivered in each arm in the first 6hrs and 24hrs; 
6. Proportion of participants needing critical care intervention: Intravenous 
vasopressors, renal replacement therapy and invasive ventilation;  


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7. Proportion of patients who receive any other fluid apart from intervention or 
control in first 6 hrs after recruitment; 
8. Proportion of patients admitted to critical care (HDU/ICU); length of stay in 
critical care (HDU/ICU); 
9. Length of hospital stay;  
10. Proportion of patients readmitted in first 90 days after discharge; 
11. Proportion of patients developing any of: acute kidney injury (Defined by NICE 
(https://cks.nice.org.uk/acute-kidney-injury#!scenario); 
pulmonary 
oedema 
(Radiology diagnosis or requirement for rescue management (new diuretic 
use); and allergy or anaphylaxis (Requirement for rescue management 
(antihistamines, adrenaline, intravenous fluids, steroids));  
12. Health Related Quality of life (EQ-5D-5L) at 7 and 180 days for the first 50 
patients; 
13. Secondary care costs at 30 days (calculated from readmissions and length of 
stay at ward level and in critical care (HDU/ICU). 
 
3. 
STUDY DESIGN 
 
This trial will be an open label two-arm, multicentre, pragmatic, parallel group 
randomised trial of adult patients with community acquired sepsis recruited from the 
Emergency Department and Medical and Surgical Assessment Units across ~15 UK 
NHS Hospitals. The treatment phase will be the first 6 hours following randomisation. 
30-day and 90-day follow up will be conducted using routine data only. The exception 
to this will be the first 50 patients enrolled in the study, Health Related Quality of Life 
(HRQoL) will be measured using the EQ-5D-5L at baseline, 7 days  and at 180 days. 
At baseline, the participant or their relative will be asked to recall the quality of life 4 
weeks prior to the index hospital admission (modified EQ-5D-5L).  Questionnaires will 
be administered by direct participant/relative completion or postal survey with 
telephone follow up for non-responders after two mailings two weeks apart.  
 
 
 
 
 
 
 
 
 
 
 
 


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3.1 
Study Flowchart  
 
 
 
 
4. 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
 
We aim to recruit 300 participants, from adults presenting to an Emergency 
Department or Medical/Surgical Assessment Units with signs or symptoms of 
community acquired sepsis and a NEWS (or NEWS2 if adopted by recruiting site) 
score of ≥5.  Recruitment will take place over approximately 12 months.   
 
 
 


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4.2 
INCLUSION CRITERIA 
 
Adult patients (18 years or older) who present to UK NHS hospitals with community 
acquired sepsis meeting all of the 5 criteria:  
 
1. Clinically suspected or proven infection resulting in principal reason for acute illness;  
2. NEWS/NEWS2 score ≥5;  
3. Hospital presentation within last 12hrs;  
4. Clinician decision has been made that immediate (within 1 hour of assessment) 
intravenous fluid resuscitation is needed; and;  
5. Ability to obtain informed consent.  
 
4.3 
EXCLUSION CRITERIA 
1. >1 litre of intravenous crystalloid fluid or any intravenous HAS administered prior to 
eligibility assessment; 
2. Clinically judged to require immediate surgery (within one hour of eligibility 
assessment); 
3. Chronic renal replacement therapy; 
4. Known allergy/adverse reaction to HAS; 
5. Known contraindications to balanced crystalloid as per reference SmPC. 
6. Known adverse reaction to blood products;   
7. Palliation/end of life care (explicit decision by patient/family/carers in conjunction 
with clinical team that any active treatment beyond symptomatic relief is not 
appropriate); 
8. Religious beliefs precluding HAS administration; 
9. Previous recruitment in the trial; 
10. Known recent severe traumatic brain injury (within 3 months); 
11. Patients with permanent incapacity;  
12. Known to have participated in interventional phase of another CTIMP study within 
the last 30 days.  
 
4.4 
CO-ENROLMENT 
4.4.1 Observational Studies 
Co-enrolment in observational studies will be permitted. For example, with studies that 
involve only the collection of data (e.g. questionnaires) or tissue samples (e.g. blood). 
 
4.4.2 Interventional Phase CTIMP-CTIMP Co-enrolment 
Enrolling a participant in the interventional phase of more than one CTIMP (i.e. a 
participant receiving IMP(s) from more than one trial concurrently) is not permitted and 
participants will be excluded from the study if they have participated in another CTIMP 
within 30 days. This is to maintain participant safety, avoid drug interactions and to 
ensure there is appropriate levels of research burden. 
 
4.4.3 CTIMP-CTIMP Co-enrolment 
In cases where participants are in long term follow-up (e.g. where follow data only is 
being collected) co-enrolment may be permitted. In such instances, the CTIMP-CTIMP 
Co-enrolment Checklist (POL008-F01) must be completed by the Sponsor 


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Representative(s) in conjunction with the CI prior to the co-enrolment proceeding. 
Where necessary, the combined risk assessment may need to be appraised as per 
ACCORD SOP GS002 (Combined Risk Assessment) 
 
4.4.4 CTIMP-Non-CTIMP Co-enrolment 
Participants who are active in the interventional phase of a non-CTIMP can be co-
enrolled to a CTIMP provided the CTIMP-non-CTIMP Co-enrolment Checklist 
(POL008-F02) is be completed by the Sponsor Representative(s) in conjunction with 
the CI prior to the co-enrolment proceeding. In addition, when considering permitting 
co-enrolment, investigators should be mindful of the potential burden upon 
participants, their families and research staff. 
 
4.4.5 Accidental/Unintentional Co-Enrolment Identified Retrospectively 
Investigators should aim to prevent accidental/unintentional co-enrolment by ensuring 
electronic and paper medical notes are checked for documentation of trial participation 
and by routinely asking participants if they are enrolled in another study prior to 
recruitment. 
The 
Sponsor’s 
representatives 
require 
that 
incidents 
of 
accidental/unintentional co-enrolment be reported to the Sponsor as a protocol 
deviation/violation so they can determine the appropriate course of action. 
 
 
5. 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
There will be no trial specific screening tests performed. The patient will receive routine 
acute clinical assessment including severity of illness assessment (vital signs and 
blood lactate measurement - which is needed to complete the randomisation) and be 
treated in accordance to current UK guidelines (Sepsis 6) [2,37]. The results of these 
will inform trial eligibility and the patient may be approached as soon as these are 
available. Patients may be approached up to 12 hours after presentation if their clinical 
condition means that fluid resuscitation needs to commence. This time window has 
been chosen as it allows the longest reasonable period for recruitment from arrival 
where the patient could be deemed to be receiving acute assessment.  
Patient and clinician will be unaware of treatment allocation until after randomisation. 
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 
should 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. 
 
 


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5.1.2 Pregnant Participants  
Pregnancy is not an exclusion criteria as the interventions are thought to be safe for 
use during pregnancy according to their representative Summary of Product 
Characteristics (SPC).  The safety of Human Albumin Solution for use in human 
pregnancy has not been established in controlled clinical trials. However, clinical 
experience with albumin suggests that no harmful effects on the course of pregnancy, 
or on the foetus and the neonate are to be expected. Human Albumin is also a normal 
constituent of human blood.    Compound Sodium Lactate solution can be used safely 
during pregnancy and lactation as long as the electrolyte and fluid balance is 
controlled.  
 
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.   
 
5.2.1. Patient 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 patient 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. If necessary, a 
Summary PIS will be provided first to provide a brief outline of the study and allow 
potential participants to decide whether or not they wish to proceed and before the full 
Patient Information Sheet is provided.   
 
The patient will be given enough time to consider the trial and ask questions regarding 
their participation in the trial. Due to the need to start treatment within one hour, 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 


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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 and written consent does not need to be obtained in addition to this.  
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. This assessment of capacity will be documented in 
the participant’s medical records.   
 
5.2.2. Personal/Professional Representative consent  
If a patient is not considered to have capacity to consent, then a Personal 
Representative or Professional Representative will be approached for consent. 
 
In Scotland this is defined as:  
1. Personal legal representative i.e.  Adult's Welfare Guardian or Welfare Attorney, 
or if not appointed the adult's nearest relative. 
2. 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.  
 
In England and Wales this is defined as:  
1. 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.  
2. 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 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 for fluid resuscitation to begin within one hour.   
 
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 
provided with the opportunity to have any trial related questions they will be asked to 


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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 Investigator 
Site File (ISF), the participant will receive a copy of this document and a copy filed in 
the participant’s medical notes. 
 
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 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. 
 
A copy of the signed Personal Rep 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. 
 


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If a Personal Representative objects to the inclusion of the patient in the trial, their 
views will be respected. 
 
The participant must also receive information, according to their capacity of 
understanding, about the trial and its risks and benefits.   
 
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 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.   
 
5.2.3. Deferred Consent 
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 an 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 declines to give consent for continuation at this stage, their wishes will 
be respected and the withdrawal process in section 5.6 will be followed.  
 
5.2.4. When the participant regains capacity  
If and 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 send 
after one month by post. If the patient does not return the signed consent form but 


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does not ask to be withdrawn from the trial, the Professional Representative and/or 
Personal Representative consent will remain valid and the patient will remain in the 
trial.  
 
If the participant is not happy to continue, the withdrawal process in section 5.6 will 
be followed.   
 
For any patient 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 criteria. 
 
5.2.5. 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.3 
SCREENING FOR ELIGIBILITY 
Participant eligibility will be verified by a clinical trial physician. Confirmation of eligibility 
will be recorded on the eligibility form/eCRF and within the participants’ medical 
records. 
 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS 
Patients who are eligible for inclusion but are not recruited will be recorded on the 
screening log to provide data to comply with CONSORT reporting for randomised 
controlled trials. The Data Protection Act will be complied with at all times. 
 
5.5 
RANDOMISATION 
5.5.1 Randomisation Procedures 
After assessment for eligibility and consent, the researcher or a delegated member of 
the clinical team will collect the baseline data necessary to complete the pre-
randomisation information on the eCRF (a blood lactate measurement is required in 
order to complete the randomisation). Vital signs and blood lactate taken within the last 
hour can be used to make the assessment. Use of clinical care results taken prior to 
consent is permitted.  If greater than one hour ago, a further blood lactate should be 
measured prior to randomisation.  Randomisation will be carried out using a web-
based randomisation service (managed by the Edinburgh Clinical Trials Unit (ECTU)) 
that ensures allocation concealment. Randomisation will be carried out within 12 hours 
of arrival at the hospital and within one hour of the decision being made that fluid 
resuscitation should be commenced. Once a patient is randomised, they will remain in 
the study and have all outcomes recorded regardless of compliance with randomised 
pathway allocation, unless they specifically withdraw consent to have data stored.  
Consented patients will be randomised on a 1:1 basis to albumin or balanced 
crystalloid in addition to standard care and will be stratified by age(<70 and ≥70) and 
lactate (<2 and ≥2)  and study site. 
 
5.5.2 Treatment Allocation 
5% Human Albumin Solution will be compared to balanced crystalloid. This is an open 
label study. 
 
1. 5% Human Albumin Solution arm 
Participants will receive 5% albumin as their sole resuscitation fluid in the first six hours 
following recruitment to the study. See section 6.3 for dosing and 6.5 for overdose.  All 
other care will be as per local protocol. 
 
2. Balanced crystalloid arm 
Participants will receive balanced crystalloid as their sole resuscitation fluid in the first 
six hours following recruitment to the study. All other care will be as per local protocol. 
 
5.5.3 Emergency Unblinding Procedures 
The study will be not be blinded, treating clinicians will be aware of which treatment 
the participant is receiving. 
 


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5.6 
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. If 
withdrawal occurs, the primary reason for withdrawal will be documented in the 
participant’s eCRF, if possible. The participant/their Representative will have the option 
of withdrawal from:  
1. 
Study treatment with continuation of the collection of clinical and safety data; 
2. 
All aspects of the trial but continued use of data collected up to that point. To 
safeguard rights, the minimum personal information possible will be collected. 
 
Randomised patients who wish to be withdrawn from the study before they have 
undertaken any study related procedures will be withdrawn from the study and 
another participant will be recruited to replace them. Data on the original participant 
will be kept on the eCRF/database. 
We anticipate ~1% withdrawal as previously found in the 3CPO, RATPAC and 
RAPID-CTCA trials [38-40]. 
 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT AND COMPARATOR 
6.1 
STUDY DRUG 
6.1.1 Study Drug Identification 
5% Human Albumin Solution. 
  
6.1.2 Study Drug Manufacturer 
Not applicable. Any preparation of 5% Human Albumin Solution which has marketing 
authorisation in the UK to be used for this indication and is stocked by local hospital 
pharmacies at the participating sites, may be prescribed in this study. 
  
6.1.3 Marketing Authorisation Holder 
An example of a Human Albumin Solution MA Holder is Octapharma Limited and the 
MA number is PL 10673/0030. This is being listed for representative purposes only.  
   
6.1.4 Labelling and Packaging 
No specific arrangements are planned for labelling since we will use the licensed 
medicinal products that are currently available in the UK. 
 
6.1.5 Storage 
The 5% HAS will be supplied by the local hospital pharmacy department at each 
participating site. The interventions will be kept in a secure place at each hospital 
pharmacy under conditions specified in the local internal procedures.   
 
6.1.6 Destruction of Trial Drug 
Not applicable as using hospital routine supplies. 
 


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6.1.7 Summary of Product Characteristics (SPC) Booklet or Investigators 
Brochure 
The NHS does not have a preferred brand or generic HAS.  Each hospital pharmacy 
may stock several brands and these may change over the course of the study. The 
pharmacy can dispense any brand of HAS currently in stock. A representative 
Summary of Product Characteristics (SPC) (is provided in a separate document with a 
cover sheet and signature page (signed and verified by the CI and Sponsor) and is 
filed in the TMF. 
  
6.2 
COMPARATOR DRUG 
6.2.1 Study Drug Identification  
Intravenous “balanced” crystalloid. 
6.2.2 Study Drug Manufacturer 
Not applicable. Any preparation of intravenous “balanced” crystalloid which has 
marketing authorisation in the UK to be used for this indication and is stocked by local 
hospital pharmacies at the participating sites, may be prescribed in this study. 
6.2.3 Marketing Authorisation Holder 
An example of an Intravenous “balanced” crystalloid MA Holder is Baxter Healthcare 
Ltd and the MA number is PL 00116/0332. This is being listed for representative 
purposes only. 
 
6.2.4 Labelling and Packaging 
No specific arrangements are planned for labelling since we will use the licensed 
medicinal products that are currently available in the UK. 
 
6.2.5 Storage 
The balanced crystalloid will be supplied by the local hospital pharmacy department 
at each participating site. It will be kept in a secure place at each hospital pharmacy 
under conditions specified in the local internal procedures.   
 
6.2.6 Destruction of Trial Drug 
Not applicable as using hospital routine supplies. 
 
6.2.7 Summary of Product Characteristics (SPC) Booklet or Investigators 
Brochure 
The NHS does not have a preferred brand or generic intravenous “balanced” 
crystalloid.  Each hospital pharmacy may stock several brands and these may change 
over the course of the study. The pharmacy can dispense any brand of intravenous 
“balanced” crystalloid currently in stock. A representative Summary of Product 
Characteristics (SPC) is provided in a separate document with a cover sheet and 
signature page (signed and verified by the CI and Sponsor) and is filed in the TMF 
 


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6.3 
DOSING REGIME 
Participants allocated to the treatment arm will receive intravenous 5% Human Albumin 
Solution (HAS) administered as the sole intravenous resuscitation fluid during the initial 
6-hour resuscitation period. It is anticipated that most participants will receive 
approximately 10ml/kg in the first 3 hours using 250-500ml rapid infusion (bolus) of 
HAS for resuscitation based on clinical judgement, using clinical assessment 
supplemented by technology within the usual  scope of practice.  After 3 hours, further 
HAS boluses for resuscitation up to 6 hours post-randomisation will be at clinical 
discretion and will be documented in the eCRF. Both vital signs and lactate, if 
measured, prior to treatment starting and at 1,3,5,7 hours (+/-30mins) after 
randomisation, will be recorded in the eCRF as well as source data worksheets or 
medical notes. 
 
To avoid contamination, participants in the HAS arm should not receive balanced 
crystalloid or other fluid as a resuscitation fluid in the first 6 hours post randomisation. 
If the treating clinician believes resuscitation to euvolaemia has been completed within 
the 6hour period post randomisation and wishes to commence  slow maintenance fluid 
within this timeframe using balanced crystalloid, this should be at a rate of no more 
than 125ml/hour. The reason for the fluid should be clearly recorded in the eCRF i.e., 
maintenance rather than resuscitation. In the subsequent event of further clinical 
deterioration during the intervention timeframe requiring resuscitation fluid, further 
boluses of HAS should be administered and documented as further bolus fluid for 
resuscitation. 
 
 
Participants allocated to the usual care arm will receive intravenous balanced 
crystalloid administered as the sole intravenous fluid during the initial 6 hour 
resuscitation period post randomisation. It is anticipated that most participants will 
receive approximately 30ml/kg in the first 3 hours using 250-1000ml rapid infusion 
(bolus) of balanced crystalloid for fluid resuscitation based on clinical judgement, using 
clinical assessment supplemented by technology within the  usual scope of practice. 
Thereafter, further crystalloid boluses for resuscitation up to 6 hours will be at the 
discretion of the clinical team and will be documented in the eCRF. Both vital signs 
and lactate, if measured, prior to treatment starting and at 1,3,5,7 hours (+/-30mins), 
will be recorded in the eCRF as well as source data or medical notes. 
 
Participants in the balanced crystalloid arm should not receive HAS or any other fluid 
as a resuscitation fluid in the first 6 hours. If the treating clinician wishes to administer 
maintenance rather than resuscitation fluid this should only be done after resuscitation 
is complete and should be at a rate of no more than 125ml/hour. The reason for the 
fluid should be clearly recorded in the eCRF i.e., maintenance rather than 
resuscitation. In the subsequent event of further clinical deterioration during the 
intervention timeframe requiring resuscitation fluid, further boluses of balanced 
crystalloid should be administered and documented as further bolus fluid for 
resuscitation. 
 


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For any participants requiring operative intervention during the 6 hours post 
randomisation treatment allocation should be maintained where possible in theatre and 
in critical care after but allow for anaesthetic discretion/judgement around other fluid 
and blood product use. 
 
6.3.1 Difference between current/planned care pathways 
There will be no difference between treatment arms other than intravenous 
resuscitation fluid in the first 6 hours of care after recruitment. Other care will follow 
national sepsis guidelines. 
 
6.4 
PARTICIPANT ADHERENCE  
Adherence with fluid prescription will be a feasibility outcome and will be recorded as 
part of the eCRF. This does not need to be reported to the Sponsor as a 
deviation/violation.   
 
6.5 
CROSSOVER OF TREATMENT ARMS  
If a participant receives the intervention from the arm they were not allocated to within 
24hours of randomisation then this will be recorded as an outcome in the eCRF at 
discharge.  This does not need to be reported to the Sponsor as a deviation/violation.   
 
6.6 
OVERDOSE 
There are no specific overdose features expected, beyond those associated with 
excessive intravenous fluid administration. Excess fluid administration will be handled 
in line with standard practice. 
 
6.7 
OTHER MEDICATIONS 
6.7.1 Non-Investigational Medicinal Products 
There are no NIMPs for this study. 
   
6.7.2 Permitted Medications 
Not applicable. 
 
6.7.3 Prohibited Medications 
Not applicable. 
6.7.4 Concomitant Medications  
No concomitant medications will be recorded as part of the eCRF.  These will be 
documented in the medical records and will only be recorded where they are relevant 
to AE/SAE reporting.  
 
 
 
 
 
 


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7. 
STUDY ASSESSMENTS 
7.1 
STUDY ASSESSMENTS 
 
The following study assessments will be completed:  
 
* Daily (+/- 12 hours) for any routine bloods collected up to 7 days. If bloods (or individual 
parameters) are not requested by the clinical team, this will not be recorded as a deviation. 
**Both vital signs and lactate, if measured, will be recorded prior to treatment starting and at 
1,3,5 and  7 hours after randomisation (+/-30mins).   Lactates up to 24hours post-
randomisation, if measured, will be recorded at 9,11,13,15,17,19,21,23 hours (+/-30mins).     
***First 50 participants only.  
# As Day 30 and Day 90 follow up is collected from the medical records it can be reviewed 
and recorded in the eCRF up to 7 days after the time point so it captures all 
admissions/events up to and including Day 30 and 90.   
 
For the first 50 participants enrolled in the study, HRQoL will be measured using the 
EQ-5D-5L at baseline, 7 days and at 180 days. If questionnaires are not completed on 
the specified day or are not returned by the participant, this will not be reported as a 
deviation. Vital status will be checked either using local electronic medical records or 
contact with participant GP prior to contacting participant. Outcome measures will be 
obtained via the medical notes.  
 
Screening Baseline
(Day 0) 
 
Day 1-6
 Day 7 
Discharge
Day 30 # 
 
Day 90 #
 
Day 180 
Consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
Randomisation  
 
X 
 
 
 
 
 
 
Demographics/Medical 
History/estimated weight  
 
X 
 
 
 
 
 
 
Routine blood results*  
 
X 
X 
X 
 
 
 
 
Routine urine and other 
culture results  
 
X 
 
 
 
 
 
 
Vital Signs/lactate** 
 
X 
 
 
 
 
 
 
IMP 
administration/adherence 
 
X 
 
 
 
 
 
 
Interventions  
 
X 
 
 
 
 
 
 
Mortality 
 
 
 
 
X 
X 
X 
 
Length of stay/ 
Ward/HDU/ICU stay 
 
 
 
 
X 
 
X 
 
Readmissions  
 
 
 
 
 
 
X 
 
Acute kidney injury/ 
Pulmonary oedema/  
Allergy/anaphylaxis  
 
 
 
 
X 
 
 
 
Adverse Events  
 
X 
X 
X 
 
 
 
 
EQ-5D-5L*** 
 
X 
 
X 
 
 
 
X 


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7.2 
LONG TERM FOLLOW UP ASSESSMENTS 
There is no long term follow up for this study – most participants will be followed up for 
90 days only, with the first 50 participants being followed up for 180 days.   
 
8. 
DATA COLLECTION 
Data will be collected from consent until final follow up visit.  Site-specific source data 
plans will be created to indicate where protocol required information will be originally 
documented. Source data worksheets created by the Edinburgh Clinical Trials Unit 
(ECTU) will be made available, but their use is optional. The eCRF can be used as 
source data for some data points (this should be noted on the source data plan by the 
site).  
Study data will be entered onto an eCRF (case report form) developed by ECTU.  
8.1 
CASE REPORT FORMS  
 
Patients will have data collected during index hospitalisation, comprising of age, sex 
at birth, past medical history.  Data will be collected from NHS records and will include: 
eligibility criteria, consent and baseline demographics; estimated weight, co-
morbidities; 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 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.  
 
Study Data Collected on eCRF 
Primary Outcome 
30-day mortality 
Recruitment rate from screening logs  
Secondary Outcomes  
 In-hospital mortality and 90-day mortality
Time to start of IMP
Data completeness
Study withdrawal
Volume of randomised fluid delivered in each arm in the first 6hrs and 24hrs
Proportion of participants needing critical care intervention: Intravenous 
vasopressors, renal replacement therapy and invasive ventilation 
Proportion of patients who receive any other fluid apart from intervention or control 
in first 6 hrs after recruitment 
Proportion of patients admitted to critical care (HDU/ICU); length of stay in critical 
care (HDU/ICU) 
Length of hospital stay
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Proportion of patients developing any of: acute kidney injury (Defined by NICE 
(https://cks.nice.org.uk/acute-kidney-injury#!scenario); pulmonary oedema 
(Radiology diagnosis or requirement for rescue management (new diuretic use); 
and allergy or anaphylaxis (Requirement for rescue management (antihistamines, 
adrenaline, intravenous fluids, steroids)). 
Health Related Quality of life (EQ-5D-5L) at 7 and 180 days for the first 50 patients.
Secondary care costs at 30 days (calculated from readmissions and length of stay 
at ward level and in critical care (HDU/ICU) 
8.2 
TRIAL DATABASE 
Data collected about the participants will be entered into a specially designed 
password protected online accessed secure database (REDCAP; http://www.project-
redcap.org) the server of which is held within the University of Edinburgh. Data can be 
entered directly to the database using is as an eCRF if the research team prefer. 
Following data analysis, the database will be archived by programmers in ECTU. This 
archived eCRF/database will be stored indefinitely on University of Edinburgh servers 
once user access has been disabled. Access to the archived database will be 
controlled by the Chief Investigator. 
 
9. 
DATA MANAGEMENT 
This trial will be coordinated from ECTU. Data will be collected at each site by local 
investigators and uploaded to the eCRF/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. All data on adverse events, 
including those routinely collected as outcomes, will be collected and reported as 
required by the relevant authorities. 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.    
 
9.1.1 Data Information Flow 
The following personal data will be collected as part of the study: Name; Initials; Home 
Address; Sex at birth; Date of birth and Health Information. The Name; Home Address 
and Phone Number of the personal representative will be collected if required to obtain 
consent.     
 
The name and address will only be collected for the purposes of sending a letter to the 
GP informing them their participant is taking part, to send the study questionnaires to 
the first 50 participants and to send consent forms (if required). This personal data will 
be kept at the study site. 
 
Personal data will be stored by the study team on NHS computers (desktop and 
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. 


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Personal data will also be stored on University computers hosting the study database.  
Edinburgh Clinical Trials Unit will provide and maintain a secure web based bespoke 
database compliant with the relevant regulations and Sponsor SOPs. Data will be 
entered by those staff delegated to do so on the delegation log held at site. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2 Transfer of Data 
Data collected or generated by the study (including personal data) will not be 
transferred to any external individuals or organisations outside of the Sponsoring 
organisation(s). 
 
9.1.3 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). 
 
9.1.4 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. 
 
10. STATISTICS AND DATA ANALYSIS 
10.1 SAMPLE SIZE CALCULATION 
A pragmatic sample size of 300 was based on projected recruitment over 12 months 
study period in around 15 centres. It is anticipated that this will provide sufficient data 
to demonstrate feasibility and inform design of a fully powered study  
As a pilot feasibility study, no formal sample size calculation is appropriate. However, 
indicatively on the first primary outcome of recruitment feasibility, an acceptance rate 
of 50% would be estimated with a 95% confidence interval of 44% to 56% if 300 from 
600 of those eligible agreed to be randomised. For the second primary outcome of 
death at 30 days, indicatively if the standard of care had a 30-day mortality of 35%, 


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with 300 randomised the study would have 90% power at a 5% level of significance to 
detect an approximate 50% relative reduction of 17%, to 18%.  
 
10.2 PROPOSED ANALYSES 
All statistical analyses will be governed by a comprehensive Statistical Analysis Plan 
authored by the study statistician and agreed by the independent Trial Steering 
Committee. As a feasibility pilot trial, all analyses will be exploratory and mainly 
descriptive. The primary outcome of recruitment feasibility will be assessed as the 
proportions who visited the ED that were (a) eligible, and then (b) of those who were 
eligible that were approached and then (c) of those eligible and approached the 
proportion that consented to be randomised. The clinical primary outcome of all causes 
mortality at 30 days will be summarised by randomised treatment group and then 
analysed using a mixed effects logistic regression adjusting for site and adjusting for 
pre-specified baseline covariates known to be strong predictors of 30-day mortality. 
The range of possible treatment effects indicated by the 95% confidence interval 
around the estimate of difference in 30-day mortality, and that around the 30-day 
mortality rate in the standard of care group will be used to inform the design of a 
definitive trial. We plan a number of important predefined exploratory sub-group 
analyses on the primary outcome including severity of illness at recruitment 
(NEWS/NEWS2, qSOFA, lactate), age, pre-existing known heart failure, pre-existent 
chronic kidney disease, baseline albumin. We will also undertake a subgroup analysis 
of primary outcome for all patients not admitted to a critical bed (HDU or ICU) If the 
data permits, we will consider additional analyses exploring compliance (what 
cumulative dose of novel intervention or standard care was received) using causal 
models with an instrumental variable approach. Secondary outcomes (e.g. volume of 
intravenous fluid, length of stay) will be analysed using mixed effects linear models, 
while the secondary outcomes involving proportions (e.g. proportion receiving renal 
replacement therapy, vasopressor infusion, invasive ventilation, readmissions within 
90 days) will be analysed as per the primary outcome (with a mixed effects logistic 
regression). The proportions admitted to critical care (HDU or ICU) will be analysed 
using a proportional odds logistic regression. The safety outcomes will be analysed in 
a similar way according to their distribution. The quality of life data (at 180 days) will 
be analysed likewise with a model appropriate to the distribution. We will be interested 
in understanding the observed patterns of any missing data. 
No formal cost-effectiveness analysis in planned, however, if data quality allows, an 
exploratory estimate of the incremental Quality Adjusted Life Years (QALYs) (at 180 
days) and secondary care costs (at 30 days) will be made using the EQ-5D-5L. QALYs 
will be calculated by estimating a combined survival function and HRQoL function 
using the EQ-5D. Costs will be estimated by assigning national standard unit costs to 
inpatient stays (critical care and general ward level), readmissions and additional high 
costs activities observed in the study. Baseline (pre-admission) HQoL will be estimated 
using age/sex matched population reference data. In sensitivity analysis, surviving 
patients or proxies will be asked to provide a retrospective estimate of 1 month pre-
admission modified EQ-5D-5L responses. 
 


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11. PHARMACOVIGILANCE 
The Investigator is responsible for the detection and documentation of events meeting 
the criteria and definitions detailed below.   
 
5% Human Albumin Solution has a well-documented safety profile. Although the 
Summary of Product Characteristics suggests that rare cases of anaphylactic events 
might be associated with albumin administration, there is no evidence that the albumin 
treatment regime used in this trial is associated with an increased risk of anaphylaxis. 
Nevertheless, data on anaphylaxis events will be collected as secondary outcomes 
and will be presented to the independent Data Monitoring Committee (DMC) for 
unblinded review. 
Full details of contraindications and side effects that have been reported following 
administration of the IMP can be found in the relevant Summary of Product 
Characteristics (SPC) Booklet. 
 
11.1 DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant 
which does not necessarily have a causal relationship with an investigational medicinal 
product (IMP). 
An adverse reaction (AR) is any untoward and unintended response to an IMP which 
is related to any dose administered to that participant.  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR that 
at any dose: 
 
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. 
 
*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 enrolment will not meet SAE criteria. Any 
hospitalisation that is planned post enrolment 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 related to the IMP, that it is not consistent 
with the information about the IMP in the Summary of Product Characteristics (SPC) 
booklet or Investigators Brochure. 
 
11.2 IDENTIFYING AEs AND SAEs 
Participants will be asked about the occurrence of AEs/SAEs during the study and the 
medical records will be reviewed to identify these. AEs and SAEs will only be recorded 
and reported from consent until 7 days after randomisation due to the well-known 
safety profiles of the interventions. Open-ended and non-leading verbal questioning of 


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the participant will be used to enquire about AE/SAE occurrence.  Participants will also 
be asked if they have been admitted to hospital, had any accidents, used any new 
medicines or changed concomitant medication regimens.  If there is any doubt as to 
whether a clinical observation is an AE, the event will be recorded. 
AEs and SAEs may also be identified via information from support departments e.g. 
laboratories. 
 
11.3 RECORDING AEs AND SAEs 
When an AE/SAE occurs, it is the responsibility of the Investigator, or another suitably 
qualified physician in the research team who is delegated to record and report 
AEs/SAEs, 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 eCRF/AE log and on the SAE form (if the AE meets the criteria of serious). 
Information to be collected includes dose, type of event, onset date, Investigator 
assessment of severity and causality, date of resolution as well as treatment required, 
investigations needed and outcome. 
   
11.3.1 Pre-existing Medical Conditions 
Pre-existing medical conditions (i.e. existed prior to informed consent) should be 
recorded as medical history and only recorded as adverse events if medically judged 
to have worsened during the study.  
 
11.3.2 Worsening of the Underlying Condition during the Trial 
Medical occurrences or symptoms of deterioration that are expected due to the 
participant’s underlying condition should be recorded in the patient’s medical notes and 
only be recorded as AEs on the AE log if medically judged to have unexpectedly 
worsened during the study. Events that are consistent with the expected progression 
of the underlying disease should not be recorded as AEs.  
 
11.4 ASSESSMENT OF AEs AND SAEs 
Each AE must be assessed for seriousness, causality, severity and ARs must be 
assessed for expectedness by the Principal Investigator or another suitably qualified 
physician in the research team who has been delegated this role.  For randomised 
double blind studies, AEs will be assessed as though the participant is taking active 
IMP. SUSARs will be unblinded by ACCORD before they are reported to REC and CA 
(by ACCORD). 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. 
 
11.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 11.1. 
 
11.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be related 
to the IMP according to the definitions below. 
   
Unrelated: where an event is not considered to be related to the IMP. 


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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 drug.  Where non Investigational Medicinal Products 
(NIMPs) e.g. rescue/escape drugs are given:  if the AE is considered to be related to 
an interaction between the IMP and the NIMP, or where the AE might be linked to 
either the IMP or the NIMP but cannot be clearly attributed to either one of these, the 
event will be considered as an AR. Alternative causes such as natural history of the 
underlying disease, other risk factors and the temporal relationship of the event to the 
treatment should be considered and investigated. The blind should not be broken for 
the purpose of making this assessment. 
 
11.4.3 Assessment of Expectedness 
If the event is an AR the evaluation of expectedness will be made based on knowledge 
of the reaction and the relevant product information documented in the SPC Booklet 
 
The event may be classed as either: 
Expected: the AR is consistent with the toxicity of the IMP listed in the SPC Booklet. 
Unexpected: the AR is not consistent with the toxicity in the SPC Booklet. 
Fatal and life threatening SARs should usually be considered unexpected.  Fatal SARs 
can only be expected for IMPs with an MA in the EU, when it is clearly stated in the list 
of ARs of the SPC (Section 4.8) that the IMP causes fatal SARs. 
 
11.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE/SAR/SUSAR 
and record this on the eCRF/AE log or SAE form according to one of the following 
categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with every day activities. 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities. 
Severe: an event that prevents normal everyday activities. 
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. 
 
11.5 RECORDING OF AEs  
All adverse events identified between consent and 7 days after randomisation for each 
participant will be recorded in the medical notes for each participant. Only those events 
which would meet the criteria of seriousness and also qualify for reporting to the 
sponsor (see section 11.6.2) will be recorded on AE logs/ SAE forms and will be 
assigned the appropriate MedDRA Systems Organ Class (SOC) code.    
 
11.6 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 within 
24 hours. If the Investigator does not have all information regarding an SAE, they 


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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 via email to safety@accord.scot. 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. The Investigator must respond to these requests in a 
timely manner.   
All reports sent to ACCORD and any follow up information will be retained by the 
Investigator in the Investigator Site File (ISF). 
 
11.6.2 Reporting of SAEs/SARs/SUSARs and exemptions   
All SAEs that meet the definition given in section 11.1 and occur between consent and 
7 days afterwards should be reported to the Sponsor unless they meet the exemption 
criteria below.  These are outcome events are anticipated to occur in this participant 
group and will be exempt from reporting to the Sponsor:  
Death related to infection (including multi-organ failure) 
Critical care (HDU/ICU) admission  
Acute kidney injury  
Pulmonary oedema,  
Allergy or anaphylaxis 
 
Events That Are Common in the Trial Population: 
The primary event of infection is classified as a pre-existing condition. As such, the 
occurrence or expected progression of infection or sepsis-related events including 
death will occur. In addition, participants are likely to have many minor adverse events 
during the course of the trial. These events will be recorded in the medical records and 
assessed in the same way as AE/SAEs. However, they are not usually recorded as 
AEs/SAEs, unless they are thought to be related to participant involvement in the trial. 
 
Abdominal pain, nonspecific or related to a pre-existing condition 
Accidents (domestic, traffic, occupational) including falls 
Agitation or Anxiety 
Atrial fibrillation or another cardiac dysrhythmia 
Bleeding 
Blood result abnormality (outside lab reported normal range) requiring no clinical 
intervention 
Breathlessness related to a pre-existing condition e.g. COPD 
Chest pain, non-specific or related to a pre-existing condition 
Confusion or delirium 


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Constipation 
Deep vein thrombosis/venous thromboembolism 
Diarrhoea and/or vomiting 
Dizziness or light headedness including vertigo 
Dysphagia 
Embolism 
Fatigue, tiredness or sleepiness (somnolence) 
Gastrointestinal disturbance, non-specific 
Headache 
Hypotension (if related to infection) 
Hypoxia (if related to infection)  
Incontinence, urinary or faecal 
Malignancy, new diagnosis or new treatment for existing diagnosis 
Mild ankle swelling not requiring treatment 
Mood disorders 
Muscle twitching 
Any musculoskeletal condition e.g. arthritis or mechanical back pain 
Peripheral vascular disease 
Pneumothorax 
Pressure sores or skin ulceration 
Procedures occurring as part of the management of infection e.g. urinary catheter, 
central venous line, arterial line, intubation 
Seizure 
Sinus tachycardia (if related to infection) 
Visual Loss e.g. cataract or macular degeneration or retinal detachment 
Weight loss 
Any other known complications of, or symptoms related to infection or sepsis 
 
 
11.7 REGULATORY REPORTING REQUIREMENTS 
ACCORD is responsible for pharmacovigilance reporting on behalf of the co-sponsors 
(The University of Edinburgh and NHS Lothian). 
ACCORD 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 (or delegate) will inform Investigators at participating sites of all SUSARs 
and any other arising safety information. 
ACCORD will be responsible for providing safety line listings and assistance; however, 
it is the responsibility of the Investigator to prepare the Development Safety Update 


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Report. This annual report lists all SARs and SUSARs reported during that time period. 
The responsibility of submitting the Development Safety Update Report to the 
regulatory authority and RECs, lies with ACCORD.  
 
11.8 FOLLOW UP PROCEDURES 
After initially recording an AE or recording and reporting an SAE, the Investigator 
should make every effort to follow each event until a final outcome can be recorded or 
reported as necessary. Follow up information on an SAE will be reported to the 
ACCORD office. 
If, after follow up, resolution of an event cannot be established, an explanation should 
be recorded on the eCRF or AE log or additional information section of SAE form. 
 
11.9 PREGNANCY 
Although pregnancy is not considered an AE or SAE; as a matter of safety, the 
Investigator will be required to record any female participant’s pregnancy identified 
from consent until 7 days afterwards. The Investigator will need to record the 
information on a Pregnancy Notification Form and submit this to the ACCORD office 
within 14 days of being made aware of the pregnancy. 
All pregnant female participants will be followed up until the outcome of the pregnancy. 
 
12. TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
12.1 TRIAL MANAGEMENT GROUP 
The trial will be coordinated by a Trial Management Group, consisting of the grant 
holders (Chief Investigator and Principal Investigator in Edinburgh), A Trial Manager 
and coordinating nurse. 
The Trial Manager will oversee the study and will be accountable to the Chief 
Investigator.  The Trial Manager will be responsible for checking the eCRF/database 
for completeness, plausibility and consistency.  Any queries will be resolved by the 
Investigator or delegated member of the trial team.  
A Delegation Log will be prepared for each site, detailing the responsibilities of each 
member of staff working on the trial.   
 
12.2 TRIAL STEERING COMMITTEE 
A Trial Steering Committee (TSC) will be established to oversee the conduct and 
progress of the trial.  The terms of reference of the Trial Steering Committee, the draft 
template for reporting and the names and contact details are detailed in CR015 DMC 
& TSC Charters. 
 
12.3 DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (DMC) will be established to oversee the 
safety of participants in the trial.  The terms of reference of the Data Monitoring 
Committee and the names and contact details are detailed in CR0015 DMC & TSC 
Charters. The DMC Charter will be signed by the appropriate individuals prior to the 
trial commencing.   
 


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12.4 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 an 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. 
 
12.5 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 could be incorporated into to trial design. 
 
12.6 STUDY MONITORING AND AUDIT 
ACCORD clinical trial monitors, or designees, will perform monitoring activities in 
accordance with the study monitoring plan. This will involve on-site visits and remote 
monitoring activities as necessary. ACCORD QA personnel, or designees, will perform 
study audits in accordance with the study audit plan. This will involve investigator site 
audits, study management audits and facility (including 3rd parties) audits as 
necessary.  
 
13. GOOD CLINICAL PRACTICE 
13.1 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.  
 
13.2 REGULATORY COMPLIANCE 
The study will not commence until a Clinical Trial Authorisation (CTA) is obtained from 
the appropriate Regulatory Authority. The protocol and study conduct will comply with 
the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. 
 
13.3 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.    
 
13.3.1 Informed Consent 


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The Investigator is responsible for ensuring informed consent is obtained before any 
study specific procedures are carried out. The decision of a participant to participate in 
clinical research is voluntary and should be based on a clear understanding of what is 
involved. 
Participants must receive adequate oral and written information – appropriate 
Participant Information and Informed Consent Forms will be provided. The oral 
explanation to the participant will be performed by the Investigator or qualified 
delegated person, and must cover all the elements specified in the Participant 
Information Sheet and Consent Form. The participant must be given every opportunity 
to clarify any points they do not understand and, if necessary, ask for more information.  
 
The participant must be given sufficient time to consider the information provided.  It 
should be emphasised that the participant 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 
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 
original will be signed in the Investigator Site File (ISF). The participant will receive a 
copy of the signed consent form and a copy will be filed in the participant’s medical 
notes. 
 
13.3.2 Study Site Staff 
The Investigator must be familiar with the IMP, 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 IMP, protocol and their trial related duties. 
 
13.3.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the 
eCRF at each Investigator Site.  
 
13.3.4  Investigator Documentation 
Prior to beginning the study, each Investigator will be asked to provide particular 
essential documents to the ACCORD Research Governance & QA Office, including 
but not limited to: 
 
An original signed Investigator’s Declaration (as part of the Clinical Trial 
Agreement documents); 
 
Curriculum vitae (CV) signed and dated by the Investigator indicating that it is 
accurate and current. 
 
ACCORD will ensure all other documents required by ICH GCP are retained 
in a Trial Master File (TMF) or Sponsor File, where required.  The Principal 
Investigator will ensure that the required documentation is available in local 
Investigator Site files ISFs. Under certain circumstances the TMF 
responsibilities may be delegated to the research team by ACCORD. 
 


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13.3.5 GCP Training 
All study staff must hold evidence of appropriate GCP training.  
 
13.3.6 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, confidential 
information 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. 
 
13.3.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the 
requirements of the appropriate data protection legislation (including where applicable 
the General Data Protection Regulation with regard to the collection, storage, 
processing and disclosure of personal information. Access to personal information 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. 
 
14.  STUDY CONDUCT RESPONSIBILITIES 
14.1 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.   
Proposed amendments will be submitted to the Sponsor for classification and 
authorisation. 
Amendments to the protocol must be submitted in writing to the appropriate REC, 
Regulatory Authority and local R&D for approval prior to implementation. 
 
14.2 PROTOCOL NON COMPLIANCE 
14.2.1 Definitions 
Deviation - Any change, divergence, or departure from the study design, procedures 
defined in the protocol or GCP that does not significantly affect a subjects rights, 
safety, or well-being, or study outcomes. 
Violation - A deviation that may potentially significantly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. 
 
14.2.2 Protocol Waivers 
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 


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an immediate hazard to study participants. If this necessitates a subsequent protocol 
amendment, this should be submitted to the REC, Regulatory Authority and local R&D 
for review and approval if appropriate. 
 
14.2.3 Management of Deviations and Violations 
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.Deviation logs / violation 
forms will be transmitted via email to QA@accord.scot. 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. The Investigator must respond to these requests in a timely 
manner.  
  
14.3 URGENT SAFETY MEASURES 
The Investigator may implement a deviation from or change to the protocol to eliminate 
an immediate hazard to trial participants without prior approval from the REC and the 
MHRA. This is defined as an urgent safety measure and the investigator must contact 
the Clinical Trial Unit at the MHRA and discuss the issue with a medical assessor 
immediately (+44 (0) 20 3080 6456).  
The Investigator will then notify the MHRA (clintrialhelpline@mhra.gsi.gov.uk), the 
REC and ACCORD, in writing of the measures taken and the reason for the measures 
within 3 days by submitting a substantial amendment. 
 
14.4 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 (QA@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 regulatory authorities and research ethics committees as 
necessary.  
 
14.5 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. 
 
14.6 END OF STUDY 
The end of study is defined as the last patient’s last 90 day follow up.  
The Investigators and/or the trial steering committee and/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, Regulatory Authority, 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 


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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. 
In accordance with ACCORD SOP CR011, a Clinical Study Report (CSR) will be 
provided to the Sponsor (QA@accord.scot) and REC within 1 year of the end of the 
study. 
Upon completion of the study, the Investigator will upload clinical trial results onto the 
EudraCT database on behalf of the Sponsor.  
The Investigator will submit a short confirmatory e-mail to the MHRA 
(CT.Submission@mhra.gsi.gov.uk) once the result-related information has been 
uploaded to EudraCT, with ‘End of trial: result-related information: EudraCT XXXX-
XXXXXX-XX’ as the subject line. The Sponsor(s) will be copied in this e-mail 
(QA@accord.scot).  It should be noted that you will not get an acknowledgment e-mail 
or letter from the MHRA. 
 
14.7 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 authored 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 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. 
 
The manufacturer supplying IMP has accepted limited liability related to the 
manufacturing and original packaging of the study drug and to the losses, 
damages, claims or liabilities incurred by study participants based on known 
or unknown Adverse Events which arise out of the manufacturing and original 
packaging of the study drug, but not where there is any modification to the 
study drug (including without limitation re-packaging and blinding). 
 
15. REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS 
15.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.  On 
completion of the study, the study data will be analysed and tabulated, and a clinical 
study report will be prepared in accordance with ICH guidelines.  
 


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15.2 PUBLICATION 
The Clinical Study Report (CSR) will be submitted to the Sponsor and REC within 1 
year of the end of the study. Where acceptable, a published journal article may be 
submitted as the CSR. The Chief Investigator will provide the CSR to ACCORD, for 
review, prior to finalization. The clinical study report may be used for publication and 
presentation at scientific meetings. Investigators have the right to publish orally or in 
writing the results of the study. The results of the study, together with other mandated 
information, will be uploaded to the European clinical trials database within 1 year of 
the end of the study. 
Summaries of results will also be made available to Investigators for dissemination 
within their clinics (where appropriate and according to their discretion). 
 
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