Does Extra-Corporeal Membrane Oxygenation Alter Anti-infectives Therapy Pharmacokinetics in Adult Critically Ill Patients
Conditions: Critical Illness, Extracorporeal Membrane Oxygenation Complication, Infection
Sponsor: Royal Brompton & Harefield NHS Foundation Trust

 
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Does Extra-Corporeal Membrane Oxygenation alter 
Anti-infectives Therapy PharmacoKinetics in adult 
critically ill patients? 
 
 
Short Study Title/Acronym: EAT-PK  
IRAS number: 228196 
 
 
CHIEF INVESTIGATOR: 
 
Dr Anna Reed 
Consultant in Respiratory and Transplant Medicine 
Royal Brompton & Harefield NHS Foundation Trust 
Hill End Road, 
Harefield 
Middlesex 
UB9 6JH 
 
Phone: 01895 823737 ext 5087 
Email: a.reed@rbht.nhs.uk  
Fax: 01895 822870 
 
SPONSOR REPRESENTATIVE: 
 
Dr Jenny Rivers 
Royal Brompton and Harefield NHS Foundation Trust (RB&HFT) 
Royal Brompton Hospital (RBH) 
Research Office  
Chelsea Wing, Level 2 
Sydney Street 
London SW3 6NP 
 
Phone: 0207 352 8121 ext. 2610  
Email: j.rivers@rbht.nhs.uk  
Fax: 020 8725 0794 
 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the 
execution or the ethical review of the study, without written authorisation from RB&HFT Research Office. 
 
 
 

 
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Signature Page  
The Chief Investigator (CI) and the Research Office have discussed and agreed this study 
protocol. The investigators agree to perform the investigations outlined in this study protocol  
and to abide by this protocol except in the case of medical emergency that will be notified to 
the Research Office. 
 
The Investigator agrees to conduct the trial in compliance with the study protocol and/or 
any subsequent amendments approved by the main REC and the Research Office, the Data 
Protection Act (1998), the Trust Information Governance Policy (or other local equivalent), 
the Research Governance Framework for Health & Social Care, 2nd Edition (2005), the 
Sponsor’s SOPs, and any other applicable regulatory requirements. 
 
This protocol has been written in accordance with the Sponsor’s guidance for writing non-
CTIMP protocols.  
 
 
Chief Investigator (CI) 
 
 
Dr Anna Reed 
Consultant in Respiratory and 
Transplant Medicine 
Royal Brompton and Harefield NHS 
Foundation Trust (RB&HFT) 
Signature 
Date 
Sponsor Representative 
 
 
Dr Jenny Rivers 
Associate Director of Research  
Royal Brompton and Harefield NHS 
Foundation Trust (RB&HFT) 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of contents 
 
1. 
LIST OF ABBREVIATIONS 
5 
2. 
STUDY PERSONNEL AND FACILITIES 
6 
3. 
STUDY SYNOPSIS 
8 
4. 
INTRODUCTION 
9 
4.1 
BACKGROUND 
9 
4.2 
PRE-CLINICAL DATA/CLINICAL DATA 
10 
4.3 
STUDY RATIONALE AND RISK/BENEFIT ANALYSIS 
13 
4.4 
MANAGEMENT OF POTENTIAL STUDY RISKS 
13 
5. 
STUDY OBJECTIVES 
14 
5.1 
PRIMARY OBJECTIVE 
14 
5.2 
SECONDARY OBJECTIVES 
14 
6. 
TRIAL DESIGN 
14 
6.1 
OVERALL DESIGN 
14 
6.2 
TREATMENT AND RATIONALE 
15 
6.3 
SCHEMATIC OF TRIAL DESIGN 
15 
7. 
ELIGIBILITY CRITERIA 
17 
7.1 
INCLUSION CRITERIA 
17 
7.2 
EXCLUSION CRITERIA 
17 
7.3 
DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS AND STOPPING RULES 
17 
8. 
SUBJECT/PATIENT RECRUITMENT PROCESS 
17 
9. 
STUDY PROCEDURES 
17 
9.1 
INFORMED CONSENT 
17 
9.2 
RANDOMISATION PROCEDURE 
20 
9.3 
EMERGENCY UNBLINDING 
20 
10. 
STUDY ASSESSMENTS 
20 
10.1 
SCREENING ASSESSMENTS 
20 
10.2 
BASELINE ASSESSMENTS 
20 
10.3 
STUDY PROCEDURES 
20 
10.4 
SUBSEQUENT ASSESSMENTS 
21 
10.6 
SUMMARY CHART OF STUDY ASSESSMENTS 
21 
11. 
METHODS 
21 
11.1 
Laboratory Procedures 
21 
11.3 
DEFINITION OF THE END OF TRIAL 
22 
12. 
SAFETY REPORTING 
22 
12.1 
ANTICIPATED COMPLICATIONS 
22 
12.2 
RECORDING ADVERSE EVENTS (AES) 
23 

 
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12.3 
ASSESSMENT OF SAES 
23 
12.4 
REPORTING SAES 
23 
12.6 
ANNUAL PROGRESS REPORTS (APRS) 
24 
12.7 
REPORTING URGENT SAFETY MEASURES 
24 
13. 
DATA MANAGEMENT AND QUALITY ASSURANCE 
24 
13.1 
 CONFIDENTIALITY 
24 
13.2 
 DATA COLLECTION TOOL 
24 
13.3 
DATA HANDLING AND ANALYSIS 
25 
13.4 
ARCHIVING ARRANGEMENTS 
25 
14. 
STATISTICAL DESIGN 
25 
14.3 
STATISTICAL ANALYSIS PLAN 
26 
14.4 
RANDOMISATION 
ERROR! BOOKMARK NOT DEFINED. 
15. 
COMMITTEES IN INVOLVED IN THE STUDY 
26 
16. 
MONITORING AND AUDITING 
26 
16.1 DIRECT ACCESS TO SOURCE DATA 
27 
17. 
ETHICS AND REGULATORY REQUIREMENTS 
27 
18. 
FINANCE 
27 
19. 
INSURANCE AND INDEMNITY 
27 
20. 
PUBLICATION POLICY 
28 
21. 
STATEMENT OF COMPLIANCE 
28 
22. 
LIST OF PROTOCOL APPENDICES 
28 
23. 
REFERENCES 
29 
 
 
 
 
 
 
 
 
 

 
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1. LIST OF ABBREVIATIONS  
 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
ASR 
Annual Safety Report 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
EXACT 
Exacerbations of Chronic Pulmonary Disease Tool 
GAfREC 
Governance Arrangements for NHS Research Ethics 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
ICF 
Informed Consent Form 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised   
MUST 
Malnutrition Universal Screening Tool 
NHS R&D 
National Health Service Research & Development   
NIMP 
Non- Investigational Medicinal Product 
PerLR 
Personal Legal Representative 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Document Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2. STUDY PERSONNEL AND FACILITIES 
 
Principal Investigator (PI): Dr Anna Reed 
Royal Brompton and Harefield NHS Foundation Trust 
 
 E-mail:  a.reed@rbht.nhs.uk 
 
 Phone:  01895 823737 
 
 
 Fax: 01895 822870 
 
Statistician:                         Mr Winston Banya 
Royal Brompton and Harefield NHS Foundation Trust    
 
 E-mail:  w.banya@rbht.nhs.uk 
 
 Phone:  0207-3528121 
 
 
  
Expert advisors:                  Prof Jason Roberts 
 
 E-mail:  j.roberts2@uq.edu.au 
 
 Phone:  +61409 769 397 
 
 
 Fax: +61 7 3646 3542 
 
Co-Investigators: 
 
Ms Haifa Lyster 
Consultant Pharmacist – Transplantation & VADs 
Royal Brompton & Harefield NHS Foundation Trust 
 
Dr Andre Simon 
Director of Cardiothoracic Transplantation,  
Royal Brompton and Harefield NHS Foundation Trust 
 
Dr Brijesh Patel 
Consultant Intensivist, Royal Brompton and Harefield NHS Foundation Trust 
 
Dr Alex Rosenburg 
Consultant Intensivist,  
Royal Brompton and Harefield NHS Foundation Trust 
 

 
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Dr Darius Armstrong-James 
Consultant Infectious Diseases Physician and Medical Mycologist,  
Royal Brompton and Harefield NHS Foundation Trust 
 
Prof David Brown 
Professor of Pharmacy Practice, School of Pharmacy and Biomedical Sciences 
University of Portsmouth 
 
Dr Jeremy Mills 
Senior lecturer, School of Pharmacy and Biomedical Sciences 
University of Portsmouth 
 
 
Study Coordinator  
 
Ms Haifa Lyster 
  
 
 
 
Royal Brompton & Harefield NHS Foundation Trust 
  
 
 
 
h.lyster@rbht.nhs.uk 
  
 
 
 
07964125247 
 
Key Contact 
 Ms Haifa Lyster 
  
 
 
 
h.lyster@rbht.nhs.uk 
  
 
 
 
07964125247 
 
Central Laboratory: 
Neil Leaver, IMS laboratory, RBHFT, Harefield 
E-mail:  n.leaver@rbht.nhs.uk  
Phone:  01895 828967  
 
Fax: 01895 828901 
 
Pharmacy: 
Steven Man 
E-mail:  pharmacytrials@rbht.nhs.uk  
Phone:  +44 (0)20 7352 8121  
 
 
 

 
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3. STUDY SYNOPSIS 
 
Full study title: 
Does Extra-Corporeal Membrane Oxygenation alter anti-infectives therapy 
pharmacokinetics in adult critically ill patients? 
Short study title:  
EAT-PK 
Study drug (s) (non-
IMPs): 
Anti-infectives – including voriconazole, posaconazole and caspofungin 
Chief Investigator: 
Dr Anna Reed 
Medical 
condition/disease 
under investigation: 
Extracorporeal Membrane Oxygentation (ECMO) 
Study duration: 
3 years 
Clinical phase:  
Observational study 
Primary Objective: 
To study whether ECMO alters the PK of anti-infectives including 
voriconazole, posaconazole and caspofungin in critically ill patients on 
ECMO 
Secondary  
Objectives:  
 
Develop Population PK models of anti-infectives, including 
voriconazole, posaconazole and caspofungin in critically ill 
patients on ECMO 
 
 
Develop Physiological-Based PK (PBPK) model of anti-infectives, 
including: voriconazole, posaconazole and caspofungin in critically 
ill patients on ECMO 
Study population:  
Critically ill patients on ECMO 
Methodology:  
Observational study to determine whether ECMO alters the PK of anti-
infectives, by developing PK models. 
Eligibility criteria: 
Inclusion criteria: 
1. Age >18 years and <90 years 
2. Currently undergoing ECMO for respiratory +/- cardiac 
dysfunction 
3. Clinical indication for the anti-infectives, including voriconazole, 
posaconazole and caspofungin 
Exclusion criteria: 
1. History of allergy to any of the study drug 
2. Pregnant women 
Study intervention: (i.e. dose and mode of the study drug administration if applicable): 
 This is a non-interventional descriptive study in that the anti-infective drug selection and dosing will 
be at the discretion of the clinician, based on the clinical context and unit guidelines. Doses will be 
reconstituted and administered as per local hospital protocols in line with patient’s routine care. 
Patients will be asked to provide additional blood samples over the course of the anti-infective dosing 
schedule, these samples will be taken from existing arterial lines to help guide treatment in future 
patients on ECMO receiving these anti-infectives. 
 
 

 
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4. INTRODUCTION 
4.1 BACKGROUND 
Extracorporeal membrane oxygenation (ECMO) is an advanced life support system which 
allows for prolonged cardiopulmonary support in patients with life-threatening respiratory or 
cardiac failure (1, 2). It can be used as a bridge to either lung or heart transplantation, or to 
a long-term ventricular assist device. There are 2 types of ECMO – Venoarterial (VA) or 
Venovenous (VV) as shown in figure 1(3); in both the blood is drained from the venous 
system and oxygenated outside the body. In VV ECMO the blood is returned to the venous 
system; this is driven by the patients’ own heart function, hence maintaining pulsatile blood 
flow, and provides respiratory support only. While in VA ECMO the blood is returned to the 
arterial system bypassing both the heart and the lungs so it can be used for supporting both 
respiratory and cardiac failure.  
 
Figure 1. Schematic representation of ECMO.  
 
In both modalities, blood is drained from the venous system (blue). In VA ECMO it is 
returned (red) to the arterial system, and in VVECMO it is returned to the venous system. 
The direction of blood flow in the ECMO circuit is indicated by arrows. (Submitted for 
publication Shekar et al). 
Critically ill patients will often have a number of organ dysfunctions requiring support 
including mechanical ventilation and renal replacement therapy. These therapies together 
with the patients’ underlying pathophysiological conditions are known to affect the 
pharmacokinetics (PK) of many drugs, such as the volume of distribution (Vd) and clearance 
(Cl) (3, 4). Where Vd refers to the volume of plasma in which the total amount of drug in 
the body would be required to be dissolved in order to reflect the drug concentration 
attained in the plasma; and Cl is the volume of plasma cleared of drug per unit time by the 
processes of metabolism and excretion. 
Essentially, ECMO may alter the PK in a number of ways which include sequestration of the 
drug by the ECMO circuit (5, 6), increasing the Vd, alteration in renal and liver blood flow, 
altered plasma protein binding and decreased drug elimination. The impact of these PK 
changes can lead to either therapeutic failure or toxicity. The physicochemical properties of 
the drug will determine to what extent its PK is altered; in that those lipophilic drugs are 

 
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significantly sequestered in the circuit while hydrophilic drugs are significantly affected by 
hemodilution. Hence, the ECMO system itself may induce PK changes in a critically ill patient 
who already exhibits altered PK; the independent effects of ECMO add to the complexities in 
this group and are difficult to quantify. 
Common mechanisms by which ECMO may alter PK include increased volume of distribution 
( Vd), drug adsorption in circuits and decreased drug elimination. Factors affecting PK on 
ECMO are summarised in Fig 2. Renal replacement whilst on ECMO adds increasing 
complexity to the PK of drugs because the presence of two extracorporeal circuits can make 
the estimation of PK parameters more difficult. 
 
 
Figure 2. Impact of Critical illness, inflammation, ECMO on drug pharmacokinetics 
(submitted for publication Shekar et al). Vd volume of distribution), CL (clearance), SIRS 
(Systemic Inflammatory Response Syndrome). 
 
4.2 PRE-CLINICAL DATA/CLINICAL DATA 
 
There are a number of PK studies in patients with ECMO; the majority were performed in 
neonates and showed significant changes in the PK of antibiotic, sedative and analgesic 
drugs. These results cannot be extrapolated to adults as the physiologic processes that 
affect absorption, distribution, metabolism and excretion have not fully developed and are 
thus different to those in adults. 
While the use of diuretics, anticoagulation, sedative, inotrope and vasopressor agents can 
be titrated to a measurable pharmacodynamic (PD) end-point, the use of anti-infectives 
cannot. Hence the application of PK principles in both selecting the appropriate anti-infective 
and its dosage regimen is important in optimizing outcome. Changes in antibiotic PK can 
lead to either therapeutic failure or toxicity in the patient; however, the potential emergence 
of resistant bacteria or fungi has wider implications. 
There are a few case studies or small studies in adult patients with ECMO which have 
investigated vancomycin (7), oseltamivir (8-10), voriconazole (11, 12) and caspofungin(11, 
12); the conclusions are preliminary and in the case of vancomycin and caspofungin they 
conclude with a recommendation of tailored dosing using therapeutic drug monitoring. 
However, not all of these drugs have their blood levels routinely measured e.g. caspofungin. 
An ex-vivo study investigated the influence of plasma protein binding on sequestration in the 

 
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ECMO circuit and concluded that for drugs with similar lipophilicity, the extent of protein 
binding may determine the degree of circuit loss (13). It would be anticipated that both 
caspofungin and posaconazole would be prone to sequestration as they are both highly 
lipophilic and have a high degree of protein binding. 
Currently there are no guidelines for dosing of drugs in patients with ECMO. The use of 
standard dosing in these critically ill patients can be sub-optimal, and ideally dosing should 
be individualized through the use of therapeutic drug monitoring. 
There is a multi-centre, open label, descriptive PK study currently recruiting – ASAP ECMO: 
Antibiotic, Sedative and Analgesic Pharmacokinetics during Extracorporeal Membrane 
Oxygenation(14). This research will add to the evidence base for dosing in this group of 
patients. 
Anti-infectives are commonly administered to critically ill patients on the intensive care unit, 
including those with ECMO. The antifungals: voriconazole, posaconazole and caspofungin 
are within the first- and second-line treatment guidelines at the Royal Brompton & Harefield 
NHS Trust (RB&HFT). Hence these drugs will be studied to determine whether the ECMO 
treatment alters their PK, which could lead to robust dosing guidelines in this group of 
patients. 
 
Our proposed study will provide critical PK data to guide clinicians in 
administering “the right dose of the right drug, at the right time” during ECMO. 
 
HYPOTHESES TO BE INVESTIGATED 
 
ECMO significantly alters the PK of anti-infectives, which include posaconazole, voriconazole 
and caspofungin, thereby contributing to an elevated risk of therapeutic failure, drug toxicity 
and emergence of microbial resistance in critically ill adult patients on ECMO. 
 
4.2.1 Results from our departmental ex-vivo experiments: 
 
ECMO circuits were primed with whole human blood, sodium chloride 0.9% and Human 
Albumin Solution 20% with a final volume of approximately 700-750ml; then the 
investigated drug was added. In the case of caspofungin, 3.75mg was added to achieve 
5mg/L concentration; posaconazole 3mg was added to achieve a concentration of 
approximately 4mg/L and for voriconazole 4mg was added to achieve 6mg/L concentration. 
 
The ECMO circuits were maintained at a flow-rate of 4-5L/min, at physiological pH and 
temperature for 24 hours. Control samples (2ml) were withdrawn and stored in PET 
vacutainer tubes in a water bath at 370C. Serial samples (2ml) were collected at baseline, 
30, 60, 120 and 360mins and at 12 and 24 hours; the concentrations of voriconazole and 
posaconazole were quantified using HPLC-mass spectrometry and caspofungin using a HPLC 
assay with fluorescence detection. The experiments were repeated four times for each 
caspofungin and posaconazole and twice for voriconazole and mean drug concentration vs 
time graph plots were drawn (figs 5.1.2a and 5.1.2b) 
 
 

 
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Figure 3. shows that there is a mean loss of 63% in posaconazole concentration in the ex-
vivo ECMO model compared with 11% in the controlled samples over 24 hours (p<0.005). 
 
 
 
 
Figure 4. Mean voriconazole concentration vs time plot over 24 hours in blood-primed 
ECMO circuit showed a mean loss of 27% in the ex-vivo ECMO model compared with 19.2% 
in the controlled sample (p<0.05) 
 

 
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Figure 5. Mean caspofungin concentration vs time plot over 24 hours in blood-primed 
ECMO circuit shows a mean loss in concentration of 80% in the ex-vivo ECMO model 
compared with 61% in the controlled samples over 24 hours (p=ns). Mean AUC 40.9±11.9 in 
blood-primed ECMO circuit compared with 48.03±14.4 in the control (p=0.024) 
 
4.3 STUDY RATIONALE AND RISK/BENEFIT ANALYSIS 
 
This is a non-interventional descriptive study in that the anti-infective drug selection and 
dosing will be at the discretion of the clinician, based on the clinical context and unit 
guidelines. Doses will be reconstituted and administered as per local hospital protocols in 
line with patient’s routine care. Patients will be asked to provide additional blood samples 
over the course of the anti-infective dosing schedule, these samples will be taken from 
existing arterial lines. 
 
The main benefit of this study will be to help guide treatment in future patients on ECMO 
receiving these anti-infectives. 
 
4.4 MANAGEMENT OF POTENTIAL STUDY RISKS 
 
As this is an observational study, the burdens and risks to patients will be minimal. All 
samples will be collected from patients while they are recovering on a ventilator in the ICU. 
As such, it is routine clinical practice for most patients to remain sedated for a variable 
period of time.  
 
Nearly all blood samples on the ICU are taken from in-dwelling vascular cannula (such as 
central venous catheters or arterial lines), so patients will not experience any additional pain 
or discomfort during blood sampling. Bloods will be taken by experienced staff members, 
and will probably go unnoticed by the patient. Patients on the ICU will routinely have a 

 
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urinary catheter inserted to monitor urine output. Urine samples will be collected from a bag 
that drains the bladder via the urinary catheter. 
 
 
5. STUDY OBJECTIVES 
 
5.1 PRIMARY OBJECTIVE 
 
 
Do adult patients with extracorporeal membrane oxygenation (ECMO) have altered 
pharmacokinetic profiles to commonly used anti-infectives, including caspofungin, 
posaconazole and voriconazole? 
 
5.2 SECONDARY OBJECTIVES 
 
a) Develop a physiologic based pharmacokinetic (PBPK) model for adult patients with 
ECMO 
b) Develop a population PK model for voriconazole in adult patients with ECMO  
c) Develop a population PK model for posaconazole in adult patients with ECMO 
d) Develop a population PK model for caspofungin in adult patients with ECMO 
 
 
6. TRIAL DESIGN 
 
6.1 OVERALL DESIGN 
 
Anti-infective drug selection and dosing will be at the discretion of the clinician, based on 
the clinical context and unit guidelines. Doses will be reconstituted and administered as per 
local hospital protocols and based on routine standard care. 
 
Blood samples will be drawn from an existing arterial line and collected in 3 ml tubes with 
Lithium Heparin anticoagulant. 
 
All patients will be sampled over a single dosing period on the first or second day of ECMO 
treatment, or of an antibiotic course where antibiotics are commenced whilst the patient is 
on ECMO. Where possible, sampling during one extra dosing interval will occur 4-8 later 
while on ECMO treatment and/or prior to the next tubing change. Where two or more anti-
infectives of interest are prescribed for one patient, collect data on timing of administration 
for both drugs and sample according to the antibiotic with the longer dosing interval.  
 
Blood samples (2ml) will be collected from an existing arterial line at the following time 
points 0 (pre-starting infusion, pre-NG/PO dose), 1 (end of infusion or 1hour post NG/PO 
dose), 2, 3, 4, 8 and either 12 (for twice daily regimen) or 24 (for once daily regimen) hours 
over the dosage interval. 
 
Where a patient is receiving medications where a validated drug assay exists in addition to 
the study drug (such as other anti-infectives), analysis of the additional therapy will also be 
attempted where practical. 
 

 
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6.1.1 Data collection 
 
For each patient various de-identified clinical and demographic data will be collected using 
the study Case Report Form (CRF): 
 
 
Patient demographics- Age, gender, weight, height 
 
Clinical details - Admission diagnosis, allergies 
 
S.Bilurubin, S.creatinine on day of study 
 
Disease Severity Scores – Sequential Organ Failure Assessment (SOFA) score on 
days 1, 3 and 5 & Acute Physiology and Chronic Health Evaluation II (APACHE II) on 
admission will be recorded  
 
Average daily flows on ECMO 
 
Type of oxygenator and pump head 
 
Use of Renal replacement therapy  
 
Doses and route of administered anti-infective agent 
 
Fluid balance, blood product requirements will be recorded on a daily basis. 
 
6.1.2 Pharmacokinetic Sample Analysis 
 
Plasma samples will be analysed using validated methodology at the Royal Brompton & 
Harefield NHS Foundation Trust (RB&HFT), Harefield Hospital Immunology Laboratory. Both 
total and unbound antibiotic concentrations will be determined in plasma. Where a patient is 
receiving antibiotic or antifungal therapy additional to the study drug, analysis of the 
additional therapy will also be attempted where practical. 
 
6.1.3 Data analysis 
 
Population PK model: Sample analysis results will be interpreted with the 
pharmacokinetic computer software NONMEM to develop a population pharmacokinetic 
model. The model will aim to determine if correlations exist between clinical interventions 
(e.g. ECMO settings) demographic and clinical factors and drug pharmacokinetics. If one or 
more of the variables are found to have a significant effect on the pharmacokinetics of the 
drug, then it can be incorporated into the final pharmacokinetic model. The final model can 
then be used to undertake Monte Carlo simulations of different drug doses to determine 
optimal dosing regimens for critically ill patients receiving ECMO. 
 
PBPK model: Sample analysis results will be interpreted with the pharmacokinetic 
computer software SimCyp (or PK-Sim or Berkley Madonna) to develop a PBPK model. 
 
6.2 TREATMENT AND RATIONALE 
 
Patients will have a clinical indication for the anti-infectives: voriconazole, 
posaconazole and caspofungin. Anti-infective drug selection and dosing will be at the 
discretion of the clinician, based on clinical context and unit guidelines. 
 
Our objective is to define the interplay between critical illness and the extracorporeal 
circuits (ECMO) that result in altered drug PK during ECMO. 
 
6.3 SCHEMATIC OF TRIAL DESIGN 

 
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7. ELIGIBILITY CRITERIA 
 
7.1 INCLUSION CRITERIA 
 
 
Age >18 years and <90 years 
 
Currently undergoing ECMO for respiratory +/- cardiac dysfunction 
 
Clinical indication for the anti-infectives: voriconazole, posaconazole and caspofungin 
Anti-infective drug selection and dosing will be at the discretion of the clinician, 
based on clinical context and unit guidelines. 
 
7.2 EXCLUSION CRITERIA 
 
 
History of allergy to any of the study drug 
 
Patients under the age of 18 
 
Pregnant women 
 
7.3 DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS AND STOPPING RULES 
 
Should participants wish to withdraw from the trial, data collected to date will be kept and 
may be used for research purposes with the patient’s agreement. All reasons for voluntary 
withdrawal from the study will be documented.  
 
 
8. SUBJECT/PATIENT RECRUITMENT PROCESS 
 
Patient recruitment at a site will only commence once the trial team has ensured that the 
following approval/essential documents are in place:  
 
1. The main REC and the Health Research Authority (HRA) approval,  
2. Final sponsorship 
3. Confirmation of Capacity and Capability (C&C), 
4. Local Site Delegation of Duties and Signature Log and the Investigator 
Site File (ISF) are set up by the Research Team. 
 
All sites participating in the trial will also be asked to provide a copy of the following:  
1. Signed Clinical Trial Site Agreement (CTSA) (if applicable), 
2. Confirmation of Capacity and Capability.  
 
9. STUDY PROCEDURES  
 
9.1 INFORMED CONSENT 
 
Critically ill patients admitted to the Intensive Care Units (ICU) at The Royal Brompton & 
Harefield NHS Foundation Trust who have a clinical indication for ECMO will be eligible for 
enrolment. Patients of interest will be receiving a study anti-infective for a clinical indication. 
A total of 12-15 patients will be enrolled for each study drug for this descriptive study. 
 

 
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Informed consent will be obtained by the Chief Investigator (CI), Principal Investigator (PI) 
and/or a nominated deputy as recorded on Sponsor’s Delegation of Responsibilities Log. 
Only those members of the study team who have clinical responsibility for the care of 
patients under the care of the general medical service will be permitted to undertake 
informed consent. All individuals taking informed consent will have received training in Good 
Clinical Practice (GCP). 
 
Consent to enter this study will be obtained after a full account has been provided of its 
nature, purpose, risks, burdens and potential benefits, and the patient has had the 
opportunity to deliberate. The patient will be allowed to specify the time they wish to spend 
deliberating, usually up to 24 hours.  
 
Periods shorter than 24 hours will be permitted if the patient feels that further deliberation 
will not lead to a change in their decision, and provided the person seeking consent is 
satisfied that the patient has fully retained, understood and deliberated on the information 
given. This provision has been made with the support of our patient advisory group.  
Likewise, periods longer than 24 hours will be permitted should the patient request this. The 
Investigator or designee will explain that the patients are under no obligation to enter the 
trial and that they can withdraw at any time during the trial, without having to give a 
reason. 
 
A copy of the signed Informed Consent Form (ICF) along with a copy of the most recent 
approved Patient Information Sheet (PIS) will be given to the study participant. The original 
signed consent form will be retained at the study site (one filed in the medical notes and 
one field in the Investigator Site File (ISF). A copy of the consent form will also be given to 
the patient. 
 
If new safety information results in significant changes to the risk–benefit assessment, the 
consent form will be reviewed and updated if necessary. All subjects, including those already 
being treated, will be informed of the new information, given a copy of the revised consent 
form and asked to re-consent if they choose to continue in the study. 
 
Some patients will be sedated to facilitate mechanical ventilation and some patients will lack 
capacity due to the severity of their critical illness despite being awake on ECMO. It may not 
be possible to obtain prospective consent from the patient at the time of enrolment. As all 
the study drugs are already routinely used in the management of infection there is minimal 
extra risk from participation in this study. 
  
9.1.1 Personal Legal Representative Consent 
 
If the patient is unable to give consent, informed consent will be sought from the patient’s 
‘Personal Legal Representative’ (PerLR) who may be a relative, partner or close friend. The 
PerLR will be informed about the trial by the responsible clinician or a member of the 
research team and provided with a copy of the Personal Legal Representative Information 
Sheet and asked to give an opinion as to whether the patient would object to taking part in 
such medical research. The PerLR will be approached following 24 hours of screening, and 
will be given a further period of time to consider the patient’s participation in the study. If 

 
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the PerLR decides that the patient would have no objection to participating in the trial they 
will be asked to sign the PerLR Consent Form which will then be counter signed by the 
responsible member of the research team. The PerLR will retain a copy of the signed 
Consent Form. A second copy will be placed in the patients’ medical records whilst the 
original will be retained in the Investigator Site File (ISF).  
 
9.1.2 Professional Legal Representative Consent 
 
If the patient is unable to give informed consent, and attempts to meet and discuss with a 
PerLR have failed, then a doctor who is not connected with the conduct of the trial may act 
as a Professional Legal Representative (ProLR). The doctor will be informed about the trial 
by a member of the research team and given a copy of the Covering Statement for 
Professional Legal Representative. If the doctor decides that the patient is suitable for entry 
into the trial, then they will be asked to sign the ProLR Consent form. The ProLR will retain a 
copy of the signed Consent Form. A second copy will be placed in the patients’ medical 
records whilst the original will be retained in the Investigator Site File (ISF). 
 
Subsequently, if a relative, partner or close friend visits the patient before he or she has 
regained consciousness, then they should be informed about the patient’s participation and 
also informed about the retrospective consent process.  
  
9.1.3 Retrospective Patient Information 
 
If and when the patient recovers and they regain the capacity to understand the details of 
the trial, a member of the research team will inform them of their participation in the trial. 
The patient will be given a copy of the Patient Information Sheet (PIS) to keep. The patient 
will be asked for consent to continue participation in the trial and to sign the Retrospective 
Consent Form. The patient will retain one copy of the signed Consent Form. Another copy 
will be placed in the patient’s medical records whilst the original will be retained in the 
Investigator Site File. If the patient does not want to continue participation in the study they 
will be given the choice of having the already collected data and samples excluded from the 
final analysis. 
 
The right of the participant or their PerLR to refuse to participate without giving reasons 
must be respected. After the participant has entered the trial the clinician remains free to 
give alternative treatment to that specified in the protocol at any stage if he/she feels it is in 
the participant’s best interest, but the reasons for doing so should be recorded. In these 
cases the participants remain within the study for the purposes of follow-up and data 
analysis. All participants are free to withdraw at any time from the protocol treatment 
without giving reasons and without prejudicing further treatment. 
  
9.1.4 General Practitioner (GP) 
 
We will not be informing the patient’s GP of their involvement in the trial because their 
involvement does not have any impact on the treatment that they will have received within 
the ICU or their future continued routine clinical treatment when participation in the trial has 
ended.  

 
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9.2 RANDOMISATION PROCEDURE 
 
Not applicable 
 
9.3 EMERGENCY UNBLINDING 
 
Not applicable 
 
10. STUDY ASSESSMENTS 
 
10.1 SCREENING ASSESSMENTS 
 
Critically ill patients admitted to the Intensive Care Units (ICU) at The Royal Brompton & 
Harefield NHS Foundation Trust, Royal Brompton Hospital and Harefield Hospital (2 sites), 
who have a clinical indication for ECMO will be screened for eligibility for enrolment. Patients 
of interest for enrolment will be receiving a study anti-infective for a clinical indication.  
 
10.2 BASELINE ASSESSMENTS 
 
For each patient various de-identified clinical and demographic data will be collected: 
 
 
Patient demographics- Age, gender, weight, height 
 
Clinical details- Admission diagnosis, allergies 
 
Serum Bilurubin, Serum Creatinine on day of study 
 
Disease Severity Scores – Sequential Organ Failure Assessment (SOFA) score on 
days 1, 3 and 5 & Acute Physiology and Chronic Health Evaluation II (APACHE II) on 
admission will be recorded  
 
Average daily flows on ECMO 
 
Type of oxygenator and pump head 
 
Use of Renal replacement therapy  
 
Doses and route of administered anti-infective agent 
 
Fluid balance, blood product requirements will be recorded on a daily basis. 
 
10.3 STUDY PROCEDURES 
 
There are no study drug treatments to be used as the patients of interest will be receiving a 
study anti-infective for a clinical indication. 
 
Anti-infective drug selection and dosing will be at the discretion of the clinician, based on 
the clinical context and unit guidelines. Doses will be reconstituted and administered as per 
local hospital protocols and based on routine standard care. 
 
Blood samples will be drawn from an existing arterial line and collected in 3 ml tubes with 
Lithium Heparin anticoagulant. 
 

 
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All patients will be sampled over a single dosing period on the first or second day of ECMO 
treatment, or of an antibiotic course where antibiotics are commenced whilst the patient is 
on ECMO. Where possible, sampling during one extra dosing interval will occur 4-8 days 
later while on ECMO treatment and/or prior to the next tubing change. Where two or more 
anti-infectives of interest are prescribed for one patient, collect data on timing of 
administration for both drugs and sample according to the antibiotic with the longer dosing 
interval.  
 
Blood samples (2ml) will be collected from an existing arterial line at the following time 
points 0 (pre-starting infusion), 1 (end of infusion or 1 hour post-nasogastric 
administration), 2, 3, 4, 8 and either 12 (for twice daily regimen) or 24 (for once daily 
regimen) hours over the dosing interval. 
 
10.4 SUBSEQUENT ASSESSMENTS 
 
10.4.1 Pharmacokinetic Sample Analysis 
 
Plasma samples will be analysed using validated methodology at the Royal Brompton & 
Harefield NHS Foundation Trust Immunology laboratory. Both total and unbound antibiotic 
concentrations will be determined in plasma. Where a patient is receiving medications where 
a validated drug assay exists in addition to the study drug (such as other anti-infectives), 
analysis of the additional therapy will also be attempted where practical. 
 
10.6 SUMMARY CHART OF STUDY ASSESSMENTS 
 
Please see the schematic table in Appendix 1. 
 
11. METHODS 
 
 
11.1 LABORATORY PROCEDURES 
 
Blood will be taken for measurement of drug concentrations. The blood will be spun 
immediately and stored at -80°C for subsequent assays. 
 
All samples will be stored in a pseudonymous form at The Heart Sciences Centre, Harefield 
Hospital. Biological samples will be pseudo-anonymised to allow sample identification from 
the same patient and for patient group purposes. We may choose to collaborate with 
academic or industrial partners by sharing the samples so that additional analyses can be 
performed, in order to derive maximum scientific value from the experimental effort. In case 
of samples being shipped elsewhere from the trial site a Material Transfer Agreement (MTA) 
will be in place. These partners may be within or outside of the European Union and the PIS 
will be drafted so that the patient is aware that s/he is consenting to this process also.  
 
Drug concentrations will be measured using validated methodology using HLPC/MS. 
 
After the completion of the study, relevant material may be retained in a research tissue 
bank for use in future research in other ethically approved projects. The patient information 

 
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sheet and consent form will clearly describe the intention to retain relevant material beyond 
the duration of this study, and retention of any relevant material will be subject to individual 
patient consent.  
 
11.3 DEFINITION OF THE END OF TRIAL 
 
The study will be completed following the last patient last visit (LPLV).  
 
12. SAFETY REPORTING 
 
12.1 ANTICIPATED COMPLICATIONS 
 
As this is an observational study, the burdens and risks to patients will be minimal. All 
samples will be collected from patients while they are recovering on a ventilator in the ICU. 
As such, it is routine clinical practice for most patients to remain sedated for a variable 
period of time.  
Nearly all blood samples on the ICU are taken from in-dwelling vascular cannulae (such as 
central venous catheters or arterial lines), so patients will not experience any additional pain 
or discomfort during blood sampling. Bloods will be taken by experienced staff members, 
and will probably go unnoticed by the patient. Patients on the ICU will routinely have a 
urinary catheter inserted to monitor urine output. Urine samples will be collected from a bag 
that drains the bladder via the urinary catheter 
 
12.2 DEFINITIONS 
 
Adverse Event (AE) — any untoward medical occurrence in a patient or clinical trial 
subject who is administered a treatment and which does not necessarily have a causal 
relationship with this treatment (i.e. any unfavourable or unintended change in the structure 
(signs), function (symptoms), or chemistry (lab data) in a subject to whom a 
treatment/study procedure has been administered, including occurrences unrelated to that 
product/procedure/device). 
 
Serious Adverse Event (SAE) – is defined as an untoward occurrence that: 
 
Results in death; or  
 
Is life-threatening (places the subject, in the view of the Investigator, at 
immediate risk of death) 
 
Requires hospitalization or prolongation of existing hospitalization (hospitalisation 
is defined as an inpatient admission, regardless of length of stay; even if it is a 
precautionary measure for observation; including hospitalisation for an elective 
procedure, for a pre-existing condition) 
 
Results in persistent or significant disability or incapacity (substantial disruption of 
one’s ability to conduct normal life functions) 
 
Consists of a congenital anomaly or birth defect (in offspring of subjects or their 
parents taking the study drug regardless of time of diagnosis) 
 
Is otherwise considered medically significant by the investigator. 

 
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Important medical events that may not be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the outcomes listed in the definition of serious will also be considered serious. 
 
12.2 RECORDING ADVERSE EVENTS (AES) 
 
All Adverse Events will be recorded in the hospital notes and Case Report Form (CRF).   
 
If the Investigator suspects that the disease has progressed faster due to the administration 
of the study treatment/procedure, then he/she will report this as an unexpected adverse 
event to the Sponsor and the main REC as detailed in Section 12.4.  
 
12.3 ASSESSMENT OF SAES 
 
Principal Investigator (PI) at all sites must report all SAEs to the Chief Investigator (CI) or a 
delegated individual in the research team. The CI and his research team at RBH are 
responsible for reporting events to the Research Office immediately and/or within 24 hours 
of becoming aware of the event using the Sponsor’s SAE Reporting Form.   
 
Classification and causality of Adverse Events (AEs) will be conducted by local PIs and 
reviewed by CI. The CI cannot downgrade the site PI’s classification and if there is 
disagreement which cannot be resolved during formal discussion then the assessment of the 
site PI will be accepted. The CI, can however, upgrade the seriousness of an event without 
consultation with the site PI.  
 
12.4 REPORTING SAES 
 
All AEs that are to be reported to the Research Office must be recorded, signed and dated 
by the Investigator at site. Research Office accepts study specific SAE forms, HRA SAE Form 
or RB&HFT template SAE Reporting Form available here.  
 
Information can be submitted in electronic format: 
 
E-mail: research.reporting@rbht.nhs.uk  
 
Fax: 0207 351 8829. 
 
An SAE occurring to a research participant will be reported to the Research Ethics 
Committee (REC) that gave a favorable opinion of the study (the ‘main REC’), the study 
Sponsor (RB&HFT Research Office) and the local R&D Office where in the opinion of the 
CI/PI the event was:   
 
 
‘related’: that is, it resulted from administration of any of the research procedures; 
and  
 
‘Unexpected’: that is, the type of event is not listed in the protocol as an expected 
occurrence.  
 
Reports of related and unexpected SAEs will be submitted within 15 days of the CI/PI 
becoming aware of the event; using the SAE reporting form for non-CTIMPs published on 
the HRA website and entitled non-CTIMP safety report to REC. The form should be 

 
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completed in typescript and signed by the Chief Investigator (CI) prior to submission to the 
REC.  
 
The coordinator of the main REC will acknowledge receipt of safety reports within 30 days. 
It is the responsibility of the CI and his/her research team to send a copy of the SAE 
notification and acknowledgement receipt to the Research Office.   
  
The research team also has the responsibility to report SAEs occurring in a certain period 
(28 days) after a patient completes the study. Any SAEs reported to the Investigators during 
this phase must be documented in the patient’s medical notes and submitted via an SAE 
form 
 
12.6 ANNUAL PROGRESS REPORTS (APRS) 
 
The Chief Investigator (CI) will prepare the APR for the study. It will be reviewed by the RO 
and sent to the main REC by the CI within 30 days of the anniversary date on which the 
favourable opinion was given by the main REC, and annually until the trial is declared 
ended. 
 
12.7 REPORTING URGENT SAFETY MEASURES 
 
The Sponsor and/or the Investigator may take appropriate urgent safety measures in order 
to protect the subjects of a clinical study against any immediate hazard to their health or 
safety. If safety measures are taken, the main REC approval is not required before the 
measure is taken.  
 
The Investigator will immediately and in any event no later than 3 days from the date the 
measures are taken, give written notice to the main REC and the study Sponsor of the 
measures taken and the circumstances giving rise to those measures. 
 
In order to prevent any delays in the reporting timelines the Sponsor has delegated this 
responsibility to the CI/PI. Therefore the CI/PI must report any urgent safety measures to 
the main REC directly, and in parallel to the Sponsor. The REC coordinator will acknowledge 
receipt of urgent safety measures within 30 days.  
 
13. DATA MANAGEMENT AND QUALITY ASSURANCE 
 
13.1  CONFIDENTIALITY 
  
All data will be handled in accordance with the Data Protection Act 1998, NHS Caldecott 
Principles, The Research Governance Framework for Health and Social Care, 2nd Edition 
(2005), and the condition of the main REC approval. 
 
The Case Report Forms (CRFs) will not bear the subject’s name or other personal 
identifiable data. The subject’s initials, Date of Birth (DOB) and trial Identification Number 
(ID), will be used for identification. 
 
13.2  DATA COLLECTION TOOL  

 
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Case Report Forms (CRF) will be designed by the CI and the final version will be reviewed 
and discussed with the study Sponsor. All data will be entered legibly in black ink with a ball-
point pen.  If the Investigator makes an error, it will be crossed through with a single line in 
such a way to ensure that the original entry can still be read. The correct entry will then be 
clearly inserted. The amendment will be initialled and dated by the person making the 
correction immediately. Overwriting or use of correction fluid will not be permitted. 
 
It is the Investigator’s responsibility to ensure the accuracy of all data entered and recorded 
in the CRFs. The Delegation of Responsibilities Log will identify all trial personnel responsible 
for data collection, entry, handling and managing the database. 
 
13.3 DATA HANDLING AND ANALYSIS 
 
Patient participants will be allocated a study number. A database to collect the clinical data 
and drug concentrations will be designed. The database will be accessed via Trust 
computers with a log in for the research team. 
 
The research will be conducted to ensure the confidentiality of personal data and to meet 
the requirements of the Data Protection Act 1998. The study will be followed according to 
the NHS Code of Confidentiality. All identifiable data will be treated in accordance with the 
Caldicott Principles. 
 
We would also like to apply retrospectively to use any drug samples that we have collected 
from previous ECMO patients, as this will allow us to examine a larger cohort for improved 
statistical power. 
 
13.4 ARCHIVING ARRANGEMENTS 
 
The study documents (including the Trial Master File (TMF), Case Report Forms (CRFs), 
Informed Consent Forms along with the trial database) will be kept for a minimum of five 
years. They will be stored in locked offices within the Royal Brompton and Harefield NHS 
Foundation Trust (RB&HFT). The CI is responsible for the secure archiving of trial 
documents. The trial database will also be kept electronically on the RB&HFT computer 
network, for a minimum of five years.  
 
The approved repository for longer retention of local materials for studies that involve 
RB&HFT patients is Box-It Storage UK. The study documentation will be prepared for 
archiving by the research team in line with the Research Office Archiving SOP and the 
transfer will be arranged by the Research Office.  
 
14. STATISTICAL DESIGN 
 
It is estimated that a minimum of 12 patients for each study drug will be sufficient for 
population PK analysis and is feasible to enrol. Although insufficient prior data in patients 
receiving ECMO exists, the minimum of 12 patients per antibiotic is based on data from 
previous non-interventional PK studies in critically ill patients. The power calculations 
supporting this sample size are based on previous work by Tam et al which suggest that 12 

 
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patients per drug obtains robust population PK parameter predictions with ~30% bias (and 
~20% precision) which is considered acceptable given the high PK variability likely to exist in 
this patient population(15). 
 
A total of 12-15 patients will be enrolled for each study drug for this descriptive study, there 
will be no formal statistical analysis plan. 
 
The protocol has been reviewed and ongoing statistical support will be by the Trust’s 
statistician, Mr Winston Banya. 
 
The number of ECMO performed at any centre will vary, based on transplant activity from 
previous years; we would expect to recruit approximately 40 patients over the course of 24 
months. and it has been decided that a formal sample size calculation is not required, as this 
is an observational pilot study. The sample size reflects our ECMO activity in previous years 
and internal consensus within the study team. 
 
14.1 Statistical analysis plan 
 
There will be no formal statistical analysis plan for this descriptive study. 
 
Statistical support will be provided by the Trust statistician, Mr Winston Banya. 
 
14.2 Pharmacokinetic modelling plan 
Plots of drug doses over time for each patient will be used to visually identify trends and 
outliers. We will perform population PK modelling for each study drug of interest using a 
non-linear mixed effects modelling approach (NONMEM®) as previously described and also 
develop a Physiologically-based Pharmacokinetic (PBPK) model with the additional ECMO as 
a separate compartment.  
 
This approach will be useful for the data to be generated in this study as we will be able to 
adequately describe sparse data (if required) and we will be able to detect the covariates 
that are associated with variability over time of volume of distribution (Vd) and clearance 
(Cl), which we believe are commonplace in the presence of ECMO. After developing and 
testing these PK models, we hope to perform dosing simulations (Monte Carlo Simulations) 
which can then form the basis for dosing guidelines for antibiotics use in patients on ECMO. 
This would be a significant advance for all centres globally that use ECMO, as no guidelines 
currently exist. The protocol will also allow us to study the influence of renal replacement 
therapy on PK during ECMO.   
 
 
15. COMMITTEES IN INVOLVED IN THE STUDY 
 
Trial Management Group (TMG) - normally includes those individuals responsible for the 
day-to-day management of the trial, such as the CI, statistician, trial manager, research 
nurse, pharmacist, and data manager. The role of the group is to monitor all aspects of the 
conduct and progress of the trial, ensure that the protocol is adhered to and take 
appropriate action to safeguard participants and the quality of the trial itself. 
 
16. MONITORING AND AUDITING 
 

 
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The requirement for study monitoring or audit will be based on the internal Research Office 
risk assessment procedure and applicable Standard Operating Procedures (SOPs). It is the 
responsibility of the RO to determine the monitoring risk assessment and explain the 
rationale to the study research team. 
 
Study monitoring and/or audit will be discussed with the CI before arrangements are made 
to conduct the visit.  
 
16.1 DIRECT ACCESS TO SOURCE DATA 
 
The Investigator(s)/institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents. Trial participants 
are informed of this during the informed consent discussion. Participants will consent to 
provide access to their medical notes. 
 
17. ETHICS AND REGULATORY REQUIREMENTS 
 
The Sponsor will ensure that the trial protocol, Patient Information Sheet (PIS), Informed 
Consent Form (ICF), GP letter and submitted supporting documents have been approved by 
the main Research Ethics Committee (REC), prior to any patient recruitment taking place. 
The protocol and all agreed substantial protocol amendments, will be documented and 
submitted for ethical approval prior to implementation. 
 
Before site(s) can enrol patients into the trial, the PI must apply for Site Specific Assessment 
from the Trust Research & Development (R&D) and be granted written NHS R&D approval. 
It is the responsibility of the PI at each site to ensure that all subsequent amendments gain 
the necessary approval. This does not affect the individual clinician’s responsibility to take 
immediate action if thought necessary to protect the health and interest of individual 
patients. 
 
Within 90 days after the end of the trial, the CI and Sponsor will ensure that the main REC is 
notified that the trial has finished. If the trial is terminated prematurely, those reports will be 
made within 15 days after the end of the trial. 
 
The CI will supply a final summary report of the clinical trial to the main REC and the 
Sponsor in parallel within one year after the end of the trial.  
 
18. FINANCE 
 
Funding has been granted internally as a studentship for Haifa Lyster. 
 
19. INSURANCE AND INDEMNITY  
 
NHS bodies are liable for clinical negligence and other negligent harm to individuals covered 
by their duty of care. NHS Institutions employing researchers are liable for negligent harm 
caused by the design of studies they initiate. The provision of such indemnity for negligent 
harm should be stated to the participant.  
 

 
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20. PUBLICATION POLICY 
 
Data ownership rights will lie with the institution. 
 
21. STATEMENT OF COMPLIANCE 
 
The trial will be conducted in compliance with the protocol, Sponsor’s Standard Operating 
Procedures (SOPs), GCP and the applicable regulatory requirement(s). 
 
The study conduct shall comply with all relevant laws of the EU if directly applicable or of 
direct effect and all relevant laws and statutes of the UK country in which the study site is 
located including but not limited to, the Human Rights Act 1998, the Data Protection Act 
1998, the Medicines Act 1968, and with all relevant guidance relating to medicines and 
clinical studies from time to time in force including, but not limited to, the ICH GCP, the 
World Medical Association Declaration of Helsinki entitled 'Ethical Principles for Medical 
Research Involving Human Subjects' (2008 Version), the NHS Research Governance 
Framework for Health and Social Care (Version 2, April 2005).    
 
This study will be conducted in compliance with the protocol approved by the main REC and 
according to RGF standards. No deviation from the protocol will be implemented without the 
prior review and approval of the Sponsor and the main REC except where it may be 
necessary to eliminate an immediate hazard to a research subject. In such case, the 
deviation will be reported to the Sponsor and the main REC as soon as possible. 
22. 
LIST OF PROTOCOL APPENDICES 
Appendix 1 Summary Chart of Study Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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23. 
REFERENCES 
 
1. 
Bartlett RH. Extracorporeal life support: history and new directions. ASAIO J. 
2005;51(5):487-9. 
2. 
Bartlett RH, Gattinoni L. Current status of extracorporeal life support (ECMO) for 
cardiopulmonary failure. Minerva Anestesiol. 2010;76(7):534-40. 
3. 
Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients 
receiving extracorporeal membrane oxygenation. Journal of critical care. 2012;27(6):741.e9-
18. 
4. 
Mousavi S, Levcovich B, Mojtahedzadeh M. A systematic review on pharmacokinetic 
changes in critically ill patients: role of extracorporeal membrane oxygenation. Daru : journal 
of Faculty of Pharmacy, Tehran University of Medical Sciences. 2011;19(5):312-21. 
5. 
Shekar K, Roberts JA, McDonald CI, Fisquet S, Barnett AG, Mullany DV, et al. 
Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal 
membrane oxygenation. Crit Care. 2012;16(5):R194. 
6. 
Wildschut ED, Ahsman MJ, Allegaert K, Mathot RA, Tibboel D. Determinants of drug 
absorption in different ECMO circuits. Intensive Care Med. 2010;36(12):2109-16. 
7. 
Mulla H, Pooboni S. Population pharmacokinetics of vancomycin in patients receiving 
extracorporeal 
membrane 
oxygenation. 
British 
journal 
of 
clinical 
pharmacology. 
2005;60(3):265-75. 
8. 
Lemaitre F, Luyt CE, Roullet-Renoleau F, Nieszkowska A, Zahr N, Fernandez C, et 
al. Oseltamivir carboxylate accumulation in a patient treated by haemodiafiltration and 
extracorporeal membrane oxygenation. Intensive care medicine. 2010;36(7):1273-4. 
9. 
Lemaitre F, Luyt CE, Roullet-Renoleau F, Nieszkowska A, Zahr N, Corvol E, et al. 
Impact 
of 
extracorporeal 
membrane 
oxygenation 
and 
continuous 
venovenous 
hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients 
with pandemic (H1N1) influenza. Therapeutic drug monitoring. 2012;34(2):171-5. 
10. 
Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R. Oseltamivir 
pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation 
support. Anaesthesia and intensive care. 2013;41(1):66-73. 
11. 
Ruiz S, Papy E, Da Silva D, Nataf P, Massias L, Wolff M, et al. Potential voriconazole 
and caspofungin sequestration during extracorporeal membrane oxygenation. Intensive care 
medicine. 2009;35(1):183-4. 
12. 
Spriet I, Annaert P, Meersseman P, Hermans G, Meersseman W, Verbesselt R, et al. 
Pharmacokinetics of caspofungin and voriconazole in critically ill patients during 
extracorporeal membrane oxygenation. The Journal of antimicrobial chemotherapy. 
2009;63(4):767-70. 
13. 
Shekar K, Roberts JA, McDonald CI, Ghassabian S, Anstey C, Wallis SC, et al. 
Protein-bound drugs are prone to sequestration in the extracorporeal membrane 
oxygenation circuit: results from an ex vivo study. Critical care (London, England). 
2015;19:164. 
14. 
Shekar K, Roberts JA, Welch S, Buscher H, Rudham S, Burrows F, et al. ASAP 
ECMO: Antibiotic, Sedative and Analgesic Pharmacokinetics during Extracorporeal 
Membrane Oxygenation: a multi-centre study to optimise drug therapy during ECMO. BMC 
anesthesiology. 2012;12:29. 
15. 
Tam VH, Preston SL, Drusano GL. Optimal sampling schedule design for populations 
of patients. Antimicrobial agents and chemotherapy. 2003;47(9):2888-91. 
 
 
 

 
 
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Appendix 1  
 
 
 
 
 
 
Schedule of study assessments 
 
Study Procedures 
ECMO 
insertion 
Enrolment 
(commencement of 
antifungals) 
Sample timing 
T0 
(pre-dose) 
T1  
(end of infusion or 
1 hour post-ng 
dose) 
T-2 hours 
3 hours 
4 hours 
8 hours 
12 (BD dosing) 
or 24 hours 
(OD dosing) 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
Baseline 
Haematology 
 
X 
 
 
 
 
 
 
 
Baseline 
Biochemistry 
 
X 
 
 
 
 
 
 
 
Type of ECMO  
(VA / VV) 
Flow rate (L/min) 
 
X 
 
 
 
 
 
 
 
CVVH 
(Y /N) 
 
 
X 
 
 
 
 
 
 
 
APACHE II/III (on 
admission) 
 
 
X 
 
 
 
 
 
 
 
Blood sampling (Day 2) 
 
 
X 
X 
X 
X 
X 
X 
X 
Repeat blood sampling 
(Day day 4-6 AND/OR pre-
tube change) 
 
 
 
X 
X 
X 
X 
X 
X 
X