Clinical trial NCT03847610
Conditions: Healthy Volunteers
Keywords: Pharmacokinetics Penicillin V Penicillins Proof of Concept Study Clinical Trial, Phase I Microneedle array
Sponsor: Imperial College London
Start date: 2018-04-12; Completion date: 2018-08-10
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is an in-house feasibility study of a microneedle biosensor developed within Imperial College London.

Detailed description:
Outline of the study:

This study will comprise the recruitment of 10-15 healthy volunteers. They will be recruited to test the microneedle biosensors and undergo rich plasma sampling with or without tissue microdialysis to calibrate the microneedle biosensor and evaluate its accuracy against current gold standards (i.e. plasma drug concentration and tissue microdialysis). This study will take place at the Imperial Clinical Research Facility (CRF).

Patient identification:

Healthy volunteers will be recruited from a healthy volunteer database held within Imperial College London and via identification of participants within the College. An initial advertisement e-mail will be sent and individuals responding will then followed up by telephone and invited to attend a screening visit at the Imperial CRF. They will be sent the participant information leaflet in advance of this meeting to give them time to consider the information. At this visit a member of the research team will go through the study procedure and answer any questions that the participant has.

Consent procedure:

Healthy volunteers who wish to participate in the study after considering the participant information leaflet will be consented by a trained researcher who will complete the eligibility screening for inclusion into the study.

Study Methodology:

10-15 healthy volunteers will be invited to participate in an exploratory study of the sensor device. On their screening visit routine blood tests will be performed to ensure that the participant is not anaemic and has no evidence of current infection. Before the study day the participant will be required to take 5 doses of oral penicillin to ensure that they are at steady state and to allow for stabilization of tissue distribution. Four of these doses will be taken at 6-hour intervals on the day before they attend the Imperial CRF. The final dose will be taken on the morning that they attend.

On arrival at the study centre the participant will have a microneedle biosensor sited for up to 12 hours whilst receiving antimicrobial therapy. The sensor will be sited peripherally (on an arm or leg). In a small number of cases the sensor may be sited centrally on the torso. These sensors are connected to potentiostat devices that records data, which can then be downloaded onto a computer for analysis.

Following arrival on the study day and placing of the sensor devices, a cannula will be sited for phlebotomy and a baseline beta-lactam antibiotic concentration will be taken. A microdialysis fibre will also be inserted peripherally into tissue close to the microneedle device to allow gold standard analysis of tissue antibiotic concentration. The participant will then undergo rich plasma drug sampling with up to 15 blood tests taken over a 6-12 hour period.

Each blood test will involve the collection of 3mL extra blood (\<1 teaspoons) via a cannula which will be cited on commencement of the study. Microdialysis may be performed in all participants who consent to this as a gold standard for determining tissue drug concentrations. If they do not consent for this, the study will be able to continue without microdialysis being performed. Participants will also be required to complete a visual analogue scale every hour testing their level of discomfort due to the microneedle sensor device and a member of the research team will document any redness or skin changes around the site of the device. A further dose of penicillin will be given approximately 6 hours into the study.

Time points for the blood sampling are planned to initially be taken at (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 360, 480, 600, 720 minutes). However, following initial pharmacokinetic (PK) analysis a D-optimal design will be employed using Pmetrics and BestDose PK software to determine the optimal time points for blood PK analysis. This will be performed by a trained member of the research team.

Clinically relevant data including demographic, co-morbidity, and medication data will be collected by members of the research team from the participant.

Arms: arm 1: None
Interventions: intervention 1: Phenoxymethyl Penicillin intervention 2: Microneedle array
Intervention descriptions: intervention 1: Phenoxymethylpenicillin tablets, 500mg every six hours for six doses, starting the day before study intervention 2: The microneedle biosensor will be sited peripherally (on the non-dominant arm) for the duration of the study. It will then be removed.

Protocol documents:
Prot_000.pdf: 
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Study protocol 
 
 
 
Minimally invasive sensing of beta-lactam antibiotics 
 
V 4.0  06/12/2017 
 
 
SPONSOR: Imperial College London 
    Joint Research Compliance Office,  
    Room 215, Level 2, Medial School Building, Norfolk Place,  
    W12  1PG 
   T: 0207 594 1872  
 
DOCUMAS Ref: 17IC4051 
 
    FUNDER: Imperial College Biomedical Research Centre (BRC), EPSRC EMBRACE pump priming award, 
     and Institut Merieux Research Grant 
   STUDY COORDINATION CENTRE: National Institute for Health Research Health Protection Research  
   Unit in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London. 
   NRES REF:  
   IRAS No: 236047 
 
Protocol authorised by: 
Name & Role 
Date 
Signature 
(Chief Investigator) 
 
 
(Sponsor) 
 
 
 
 
 
 
 
 
Chief Investigator:  
Prof Alison Holmes 


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Co-investigators:  
Prof Tony Cass 
Dr Pantelis Georgiou  
Dr Danny O’Hare 
Dr Timothy Rawson 
Dr Pau Herrero  
Dr Sanjiv Sharma 
Dr Sally Gowers 
Dr Michelle Rogers 
Mr Mark Gilchrist 
 
 
Study Management:  
National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infection and 
Antimicrobial Resistance, Imperial College London (Hammersmith Campus), Du Cane Road. London. W12 0NN. 
Study Coordination Centre  
For general queries, supply of study documentation, and collection of data, please contact: 
 
National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infection and 
Antimicrobial Resistance, Imperial College London (Hammersmith Campus), Du Cane Road. London. W12 0NN
 
 
 
 
 
 
 
Tel: 020 33132732  
 
 
 
 
 
 
 
Fax:  020 8383 3394 
 
Email: head.ops@imperial.ac.uk 
 
 
 
 
 
 
Clinical Queries 
Clinical queries should be directed to Dr Timothy Rawson (tmr07@imperial.ac.uk; 02033132732) who will 
direct the query to the appropriate person 
 


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Sponsor 
Imperial College London is the main research Sponsor for this study.  For further information regarding the 
sponsorship conditions, please contact the Head of Regulatory Compliance at:  
Joint Research Compliance Office, Imperial College London, Room 215, Level 2, Medical School Building, 
Norfolk Place, W12 1PG 
Tel: 0207 594 1872 
Funder 
Imperial Biomedical Research Centre, Institu Merieux Research Grants, EPSRC EMBRACE pump priming award. 
 
This protocol describes the IC REACT study and provides information about procedures for entering 
participants.  Every care was taken in its drafting, but corrections or amendments may be necessary. These will 
be circulated to investigators in the study. Problems relating to this study should be referred, in the first 
instance, to the Chief Investigator. This study will adhere to the principles outlined in the NHS Research 
Governance Framework for Health and Social Care (2nd edition). It will be conducted in compliance with the 
protocol, the Data Protection Act and other regulatory requirements as appropriate.  


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CONTENTS 
1. 
INTRODUCTION 
7 
1.1 
BACKGROUND 
7 
1.2 
RATIONALE FOR CURRENT STUDY 
8 
2.  STUDY OBJECTIVES 
10 
3.  STUDY DESIGN 
11 
3.1 Outline of the study: 
Error! Bookmark not defined. 
3.2 Patient identification: 
Error! Bookmark not defined. 
3.3 Consent procedure: 
Error! Bookmark not defined. 
3.4 Study Methodology: 
Error! Bookmark not defined. 
4. 
PARTICIPANT ENTRY 
14 
4.1 
Recruitment 
14 
4.2 
Inclusion Criteria 
14 
4.3 
EXCLUSION CRITERIA 
14 
4.4 
WithdrawAl criteria 
14 
5. 
ADVERSE EVENTS 
15 
5.1 
Definitions 
15 
5.2 
Reporting Procedures 
15 
6. 
ASSESSMENT AND FOLLOW-UP 
17 
7. 
STATISTICS AND DATA ANALYSIS 
17 
8. 
REGULATORY ISSUES 
18 
8.1 
Ethics approval 
18 
8.2 
Consent 
18 
8.3 
Confidentiality 
18 
8.4 
Indemnity 
18 
8.5 
Sponsor 
18 
8.6 
Funding 
18 
8.7 
Audits 
18 
9. 
STUDY MANAGEMENT 
20 
10. 
PUBLICATION POLICY 
20 
11. 
REFERENCES 
21 
 


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GLOSSARY OF ABBREVIATIONS 
POC 
Point of care 
DSS 
Decision support system 
AMR 
Antimicrobial resistance 
AMS 
Antimicrobial stewardship 
PCA 
Principle component analysis 
PPI 
Patient and public involvement 
AE 
Adverse event 
SAE 
Serious adverse event 
PIL 
Participant involvement leaflet 
 
 
 
 
 
 
 
 
KEYWORDS 
Antimicrobial resistance 
Closed-loop control 
Microneedle array 
Pharmacometrics 


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STUDY SUMMARY 
 
TITLE 
Minimally Invasive Sensing of Beta-Lactam Antibiotics 
DESIGN 
Evaluation of a microneedle array device for the monitoring of beta-
lactam antibitocs 
AIMS 
Evaluate the effectiveness of a minimally invasive microneedle 
biosensor for monitoring antibiotic concentrations in humans.  
OUTCOME MEASURES 
1) To investigate whether a microneedle biosensor can be used to 
monitor beat-lactam antibiotic concentrations in humans 
POPULATION 
(i) Healthy volunteers 
DURATION 
2 years 
 
 


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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
Antimicrobial chemotherapeutic agents are drugs which kill or inhibit the growth of micro-organisms. Whilst 
essential to modern medicine, the exposure of micro-organisms to antimicrobial agents also drives generation 
of resistant strains, termed antimicrobial resistance (AMR). This, combined with a paucity of new antimicrobial 
drug development, has led to AMR becoming a global threat to modern medicine and a leading patient safety 
issue 1.  
To address the challenge of AMR, it is imperative that the current finite pool of antimicrobial agents is 
optimised, maximising therapeutic success whilst minimising emergence of resistance  2. One avenue to 
optimise the use of antimicrobials is to ensure correct dosing strategies. Population pharmacokinetic (PK) 
modelling was developed from the simple concept of dose-response relationships in the 1960’s 3. More 
recently the idea of individualised dosing, which accounts for intra- and inter-individual variability in PK 
parameters, has gained popularity and has been demonstrated to improve patient outcomes in secondary care 
settings (J. A. Roberts et al., 2014). In tandem to optimisation of therapy through individualising dosing, 
population PK modelling also allows for the consideration of individualised therapeutic drug monitoring (TDM) 
protocols to help provide robust and accurate data to drive individualised dosing regimens.  
Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide antimicrobial agents, 
given fears over the narrow therapeutic window of these agents and the serious adverse events associated 
with toxicity. However, in critical care the role of TDM for optimisation of therapy has been demonstrated to 
help optimise dosing of patients who tend to have variable pharmacokinetic parameters (J. A. Roberts et al,). 
This is of growing importance given that low concentrations of antimicrobial agents, below a micro-organisms 
minimum inhibitory concentration (MIC) is believed to be a major driver of AMR.  
 
 
 
Figure. Concepts of therapeutic 
drug 
monitoring 
between 
different antimicrobial agents 
 
From: J. A. Roberts et al 2010 


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Moreover, in individuals managed with enhanced TDM protocols and individualised dosing protocols  there is 
evidence that this enhances patient outcomes and reduces the cost of care for these patients, reducing 
hospital stay and lengths of therapy 5. Whilst, most evidence in this field currently focuses primarily on critical 
care setting, there is evidence to suggest that optimisation of therapy in secondary care can impact 
significantly on AMR in crititical care. However, this must go beyond simply selecting the optimal antibiotic for 
the organism in question. We must also ensure that the optimal dose is selected to maximise micro-organism 
killing, whilst minimising the risk of toxicity or development of AMR. The observation of wide variability in 
therapeutic levels of antimicrobials being delivered to patients across a number of settings (e.g. ICU, obese, 
paediatric) has promoted the idea of individualised dosing that accounts for intra- and inter-individual 
variability in PK parameters. This has been demonstrated to improve target attainment and outcomes in 
secondary care (J. A. Roberts et al., 2014). To address the challenges of AMR and rapidly improve the use of 
antimicrobials in clinical practice, urgent validation of novel methods for precision prescribing and delivery of 
antimicrobial agents is required.  
 
1.2 
RATIONALE FOR CURRENT STUDY 
Bacteria and other microorganisms can cause infections in people outside of hospitals and also among patients 
admitted to hospital. The antimicrobials (drugs that kill or stop the growth of microorganisms including 
bacteria, thereby treating infections) commonly used to treat infections are becoming less effective over time 
as bacteria develop resistance to them. Antimicrobial usageage itself can leads to development and spread of 
antimicrobial resistance.  
Antimicrobial resistance is now a major threat to patient safety - increasingly we are seeing patients infected 
with bacteria for which there are very few antimicrobials that remain effective. If untreated, these infections 
can be fatal in some patients. To conserve the effectiveness of antimicrobials we need to develop ways to use 
them more effectively. One way to do this is ensure that we are providing the best dose (amount of drug) of an 
antimicrobial to kill the organism causing infection, whilst also ensuring that we don’t cause toxic side effects 
or promote the growth or antimicrobial resistance through giving too much or too little of a treatment.  
Currently we give most antibiotics in a (almost) one-size-fits-all way. However, everyone is different. This 
includes how our bodies process and excrete antibiotics. This can even change for the individual depending on 
how unwell you they are. There is evidence that shows that our current approach to giving antibiotics means 
that some people are not treated effectively, potentially leading to development of antimicrobial resistance, 
side effects, or even failure or treatment.  
We aim to investigate a small sensor that sits just beneath the skin to detect the amount of antimicrobial 
within a patient’s body. By linking this to a computer dosing algorithm we can adjust the amount dose of 
antimicrobial given to a patient ensuring that we give the optimal amount to kill bacteria, whilst preventing 
any of the harmful consequences that may occur due to inappropriate therapy.  
Microneedle technology was developed in the 1980's. Since then it has been applied to a number of different 
fields, including for the sensing of glucose levels in patients with diabetes as well as a mechanism for drug and 
vaccine delivery.  
Despite this, its role for the monitoring of antibiotic concentrations in patients has never been explored. Below 
the initial layer of the skin is an area called the dermal interstitial compartment. This compartment does not 
have blood vessels or nerves, but does contain interstitial fluid. This interstitial fluid is in equilibrium with 
capillary blood, meaning that it contains metabolites, proteins and drugs within the patients system. This 
includes antibiotics. This offers an opportunity to be able to detect the concentration of antibiotic within the 
interstitial fluid without having to take blood samples from the patient. Evidence provided by Roberts and 


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colleagues already supports the mirrored PK profiles observed between free antibiotic levels in both the 
plasma and extra-cellular compartment (evaluated using microdialysis). 
At Imperial College, we have developed a number of microneedle biosensors based on enzyme and aptamer 
based technology, that are able to detect changes in antibiotic concentrations at the levels expected in the 
interstitial fluid. This has been validated in the laboratory and is now ready for testing in human participants. 
The specific microneedle structure has been tested in healthy volunteers and type 1 diabetics as part of a 
separate study monitoring  glucose. It has been demonstrated to be safe and effective.  
This study aims to test the ability of a sensor that can monitor beta-lactam antibiotic concentrations in 
participants who will be given a beta-lactam antbiotic as a proof-of-concept and to allow further refinement of 
the sensor before progressing to test it on patients. commercial antimicrobial assays; and limited clinical data 
to support dose changes based on certain targets for therapy (such as trough levels or pharmacokinetic - 
pharmacodynamic indices).  
To address these problems a potential solution is to explore the use of minimally invasive biosensors linked to 
closed loop control systems, which will be addressed during this research study. This follows evidence 
supporting the equilibrium on free antimicrobial drug PK between the plasma and interstitial fluid, which may 
allow for tracking plasma PK.  
This study aims to translate an antibiotic biosensor, mounted on a microneedle device that has been 
demonstrated as safe and effective in previous human studies in diabetes. Demonstration of efficacy will allow 
this to be linked to a closed loop control system in the future. This has already been demonstrated to be 
effective in delivery of insulin for the management of diabetes and for delivery of intravenous and inhaled 
anaesthetic agents. 
 
 
 
 


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2.  STUDY OBJECTIVES 
 
The principle objectives of this study are:  
1) To investigate whether a microneedle biosensor can be used to monitor beat-lactam 
antibiotic concentrations in humans 
The secondary objectives are:  
(i) To determine the accuracy of an antibiotic microneedle biosensor compared to gold standard plasma drug 
concentration sampling. 


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3.  STUDY DESIGN 
This study is an in-house feasibility study of a microneedle biosensor and closed loop control algorithm 
developed within Imperial College London.  
OUTLINE OF THE STUDY:  
This study will comprise the recruitment of 10-15 healthy volunteers. They will be recruited to test the 
microneedle biosensors and undergo rich plasma sampling with or without tissue microdialysis to calibrate the 
microneedle biosensor and evaluate its accuracy against current gold standards (i.e. plasma drug 
concentration and tissue microdialysis).  
This study will take place at Imperial College Clinical Research Facility  
 
PATIENT IDENTIFICATION: 
   Healthy volunteers will be recruited from a healthy volunteer database held within Imperial College London 
and via identification of participants within the College. An initial advertisement email will be sent and 
individuals responding will then followed up by telephone and invited to attend a screening visit at the 
Imperial CRF. They will be sent the participant information leaflet in advance of this meeting to give them time 
to consider the information. At this visit a member of the research team will go through the study procedure 
and answer any questions that the participant has.  
 
CONSENT PROCEDURE:  
For healthy volunteers who wish to participate in the study after considering the participant information 
leaflet, a trained researcher will complete the eligibility screening and gain consent for the participant to be 
enrolled in phase I of the clinical study.    
 
STUDY METHODOLOGY:  
10-15 healthy volunteers will be invited to participate in an exploratory study of the sensor device. On their 
screening visit the patients full blood count, renal function, liver function, and C-reactive protein will be 
performed to ensure that the participant is not anaemic and has no evidence of current infection. Before the 
study day the participant will be required to take 5 doses of oral penicillin to ensure that they are at steady 
state and to allow for stabilization of tissue distribution.  
On arrival at the study centre the participant will have a microneedle biosensor sited for upto 12 hours.  
The sensor will be sited peripherally (on an arm or leg). In a small number of cases the sensor may be sited 
centrally on the torso. These sensors are connected to potentiostat devices that record data, which can then 
be downloaded onto a computer for analysis. 
 
Following arrival on the study day and placing of the sensor devices, a cannula will be sited for phlebotomy 
and a baseline beta-lactam antibiotic concentration will be taken.  


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A microdialysis fibre will also be inserted  peripherally into tissue close to the microneedle device.   
Once baseline samples have been collected the participant will receive a final dose of penicillin.  
The participant will then undergo rich plasma drug concentration sampling with up to 15 further blood tests 
taken over a 6-12 hour period. Each blood test will involve the collection of 3ml extra blood (1 teaspoons) via a 
cannula which will be cited on commencement of the study. Microdialysis may be performed in a number of 
cases as a gold standard for determining tissue drug concentrations. Participants will also be required to 
complete a visual analogue scale every hour testing their level of discomfort due to the microneedle sensor 
device.  
Time points for the blood sampling are planned to initially be taken at (0, 15, 45, 30, 60, 90, 120, 150, 180, 210, 
240, 360, 480, 600, 720 minutes). However, following initial PK analysis a D-optimal design will be employed 
using pmetrics and bestdose pharmacokinetic software to determine the optimal time points for blood PK 
analysis.  
Clinically relevant data including demographic, co-morbidity, and medication data will be collected by 
members of the research team from the participant.   
 
SAMPLE ANALYSIS: 
 
All blood samples will be put straight on ice following draw and aimed to be spun down and frozen within 2-3 
hours of collection. Samples should be allowed to clot for 15-20 minutes and then centrifuged at 2,400rpm for 
10 minutes. Serum from each sample will be separated into two to three vials and stored at -800C. These will 
be stored on the 8th floor of the Commonwealth Building at Hammersmith Hospital Campus. 
 
Beta-lactam concentrations will be measured using validated high-performance liquid chromatography 
methods.  
 
Consent will be gained for samples to be used for calibration of electrochemical sensors in ex-vivo studies. 
Ideally primary analysis for the study should be completed within 90 days of collection. 
 
 
PENICILLIN PRESCRIBING 
Upon prescription of penicillin for the study, this will be provided by the pharmacy department at Imperial 
College Healthcare NHS Trust. In advance of the study, the finalized ethics and study protocol will be provided 
to the pharmacy department for approval.  
Upon enrollment of participants into the study a prescription will be written for penicillin by a physician within 
the research team, who has assessed the patient for inclusion in the study and obtained consent. This will then 
be dispensed by the pharmacy department.  


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Summary of study participation 
 
 
Pre-study: 
Response to advertisement email received by researcher 
 
Screening visit: 
Meet with member of the research team 
• 
Discuss PIL and study 
• 
Blood test taken 
• 
Clinical review by researcher 
• 
Consent obtained 
• 
Time organised for study visit to CRF 
• 
Penicillin & dosing schedule provided 
Study Day 1: 
Participant to commence penicillin in the morning 
Study Day 2: 
Attends Imperial Clinical Research Facility in the morning for 6-12 hour 
study in the department 
 
• 
Sensor placement on arm 
• 
Blood test taken (15 times through a cannula) 
• 
Microdialysis performed 
• 
One further dose of penicillin given 


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4. 
PARTICIPANT ENTRY  
4.1 
RECRUITMENT 
Healthy volunteer identification:  
An email will be sent advertising the project to a healthy volunteer database kept within Imperial College. 
Furthermore, this email will be circulated internally within the college. If volunteers express an interest they 
will then be contacted by a member of the research team by phone to arrange a screening meeting. At the 
same time a copy of the patient information leaflet will be emailed to the volunteer to allow them time to 
consider the information prior to the screening visit.  
 
4.2 
INCLUSION CRITERIA 
HEALTHY VOLUNTEER INCLUSION CRITERIA 
• 
Adult >18 years old  
• 
Healthy adults, with no evidence of active infection 
• 
Previously received penicillin with no adverse effects 
 
4.3 
EXCLUSION CRITERIA  
HEALTHY VOLUNTEER EXCLUSION CRITERIA 
• 
High risk of skin soft tissue infection or local skin and soft tissue infection near sensor site  
• 
Previous history of allergies to adhesive strips or active dermatitis  
• 
Penicillin allergy or previous adverse event whilst receiving penicillin  
• 
Anaemia defined as <13 g/dL in males and <12 g/dL in females 
 
4.4 
WITHDRAWAL CRITERIA 
Patients can withdraw at any point during the study without being required to provide reason for this.  


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5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect that: 
Results in death 
Is life-threatening – refers to an event in which the subject 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 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
Results in persistent or significant disability or incapacity 
Is a congenital anomaly or birth defect 
Medical judgement should be exercised in deciding whether an AE is serious in other situations.  Important AEs 
that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed in the definition above, 
should also be considered serious. 
 
5.2 
REPORTING PROCEDURES 
All adverse events should be reported. Depending on the nature of the event the reporting 
procedures below should be followed. Any questions concerning adverse event reporting should be 
directed to the Chief Investigator in the first instance.   
 
5.2.1 NON SERIOUS AES 
All such events, whether expected or not, should be recorded.   
 
5.2.2 SERIOUS AES 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  However, 
relapse and death due to pre-existing conditions and hospitalisations for elective treatment of a pre-
existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the London-Harrow Regional Ethics Committee where in the opinion 
of the Chief Investigator, the event was: 
• 
‘related’, ie resulted from the administration of any of the research procedures; and 
• 
‘unexpected’, ie an event that is not listed in the protocol as an expected occurrence 


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Reports of related and unexpected SAEs should be submitted within 15 days of the Chief Investigator 
becoming aware of the event, using the NRES SAE form for non-IMP studies.  The Chief Investigator 
must also notify the Sponsor of all SAEs within 24 hours of becoming aware of these.  
Contact details for reporting SAEs 
Fax: 0208383394,  
Urgent attention Prof A Holmes 
Tel: 02033132732 (Mon to Fri 09.00 – 17.00) 
 
Sponsor office: attn Gary Roper 
Email: JRCO @imperial.ac.uk 


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6. 
ASSESSMENT AND FOLLOW-UP  
Patients will not be followed up beyond the five day study period described. 
  
7. 
STATISTICS AND DATA ANALYSIS 
 
For quantitative evaluation: The sensor calibration will be undertaken by members of Imperial Biomedical 
Engineering department who have extensive experience of biosensor development and calibration. 
Pharmacokinetic analysis will be undertaken by Dr Rawson using pmetrics, within R.   
 
Storage: Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, including the follow-up period. Participant consent forms will be kept in a locked 
cabinet within a locked room on the 7th floor of the commonwealth building. Only researchers and those with 
clearance to perform regulatory audits of research procedures will have access to this  
Anonymised data will be stored on an Imperial College networked computer within the firewall. This will be 
accessible to researchers only. 
 


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8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
The Chief Investigator is obtaining approval from the Research Ethics Committee and HRA.  The study will be 
conducted in accordance with the recommendations for physicians involved in research on human subjects 
adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions. 
 
8.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation has been given, 
an information leaflet offered and at least 24 hours has been allowed to decide upon participation. Signed 
participant consent will be obtained.  The right of the participant to refuse to participate without giving 
reasons will be respected.  After the participant has entered the study 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. 
 
8.3 
CONFIDENTIALITY 
Patient Identifiable Data from clinical and laboratory databases will only be accessed within the host NHS Trust 
firewall after the clinical team user has passed their Lightweight Directory Access Protocol (LDAP) 
authentication. Anonymised data will be analysed on an Imperial College London networked computer. Any 
data used for analysis outside of the firewall will be fully anonymised by recording it against the participants 
unique participation number.  
8.4 
INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance policies which apply to this 
study. 
8.5 
SPONSOR 
Imperial College London will act as the main Sponsor for this study.  Delegated responsibilities will be 
assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
Imperial College Biomedical Research Centre (BRC) (£260,000) and Institu Merieux Research Grants (Euro 
100,000) have funded this research project.  
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College London under their remit as sponsor and 
other regulatory bodies to ensure adherence to GCP and the NHS Research Governance Framework for Health 
and Social Care (2nd edition).  


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9. 
STUDY MANAGEMENT 
 
The Chief Investigator will be responsible for overall study oversight. They will chair a formal project oversight 
meeting once a quarter. The meeting will act to iteratively monitor project progress against the key 
deliverables and outcome measures, plan all future steps and identify any potential issues including the 
creation of intellectual property and the best methods for dissemination and communication of research and 
product outcomes.  
On a day to day basis the project will benefit from management by the Head of Operations within HPRU who is 
experienced in integrating the workflows of the multi-professional teams from the collaborating Centres.  
The study PI (AH) has an established collaboration with parallel managed teams in the fields of healthcare and 
bio-technology. The project will be subject to the usual management practices within the groups, meaning that 
updates of progress will be required at work-stream meetings within HPRU and wider work-inprogress 
meetings at Imperial College London.  
 
10. 
PUBLICATION POLICY 
 
The methods and results from the evaluation of the closed loop system will be presented at national and 
international conferences to both infection and patient safety specialists who are researchers and decision 
makers. Targeting of these specific groups in disseminating the research findings will allow not only engaged 
and productive feedback, but is also likely to generate further questions and raise awareness of the product as 
a resource for wider adoption. A key emphasis will be placed on highlighting both the barriers and the 
facilitators towards project completion, and on the impact of the product on antimicrobial prescribing, patient 
outcomes and antimicrobial resistance. The impact on patient outcomes will focus on both individual level 
outcomes, but also look at the wider perspective of the impact of the product on the patient pathway. 
 
High impact peer reviewed publications will arise from this research evaluation, enabling wider engagement of 
researchers and decision makers. Open-access fees have been included in the research costs requested, 
against four high impact journals to enable the widest possible dissemination of the findings. 
 


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11. 
REFERENCES 
1 
Holmes AH, Moore LSP, Sundsfjord A, et al. Understanding the mechanisms and 
drivers of antimicrobial resistance. Lancet 2015; 6736. DOI:10.1016/S0140-
6736(15)00473-0. 
2 
Mouton JW, Ambrose PG, Canton R, et al. Conserving antibiotics for the future: New 
ways to use old and new drugs from a pharmacokinetic and pharmacodynamic 
perspective. Drug Resist Updat 2011; 14: 107–17. 
3 
Csajka C, Verotta D. Pharmacokinetic–Pharmacodynamic Modelling: History and 
Perspectives. J Pharmacokinet Pharmacodyn 2006; 33: 227–79. 
4 
Roberts J a., Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for 
patients who are critically ill: Challenges and potential solutions. Lancet Infect Dis 
2014; 14: 498–509. 
5 
van Lent-Evers NA, Mathôt RA, Geus WP, van Hout BA, Vinks AA. Impact of goal-
oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on 
clinical outcome: a cost-effectiveness analysis. Ther Drug Monit 1999; 21: 63–73.