Phase 1 Exploratory Clinical Study of Microdosing NAP for Optical Molecular Imaging in Human Lungs in Healthy Volunteers and in Patients With Acute Lung Injury in Intensive Care
Phase: EARLY_PHASE1
Conditions: Acute Lung Injury
Sponsor: University of Edinburgh

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Study Protocol 
Exploratory Clinical Study of Microdosing NAP for Optical Molecular Imaging 
in Human Lungs 
NAP 
Co-sponsors 
University of Edinburgh & NHS Lothian 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Funder 
Medical Research Council 
Funding Reference Number 
MRC : MR/J010901/1 
Chief Investigator 
Dr Kev Dhaliwal 
EudraCT Number 
2011-006169-17 
REC Number 
12/SS/0004 
Version Number and Date 
Version 11.2, 27th July 2015 
 

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RESEARCH CENTRE 
Co-Sponsor Contacts 
 
Dr Raymond French 
Dr Doug Young 
University of Edinburgh 
NHS Lothian 
ACCORD 
ACCORD 
Queens Medical Research Institute 
Queens Medical Research Institute 
47 Little France Crescent 
47 Little France Crescent 
Edinburgh 
Edinburgh 
EH16 4TJ 
EH16 4TJ 
 
Tel: 0131 242 9262 
Tel: 0131 242 3337 
Fax: 0131 242 9447 
Fax: 0131 242 3343 
Email: Ray.French@ed.ac.uk 
Email: Douglas.Young@luht.scot.nhs.uk 
 
Chief Investigator 
Dr Kev Dhaliwal 
Senior Clinical Lecturer and Honorary Consultant in Respiratory Medicine 
Room C2.12 
MRC Centre for Inflammation Research 
Queen’s Medical Research Institute 
University of Edinburgh 
Edinburgh 
EH16 4TJ 
 
Tel: 0131 242 6551 
Fax: 0131 242 6578 
Email: kdhaliwa@staffmail.ed.ac.uk 
 
Principal Investigator 
 
Professor Dave Newby 
Consultant Cardiologist 
University of Edinburgh 
 
OTHER MEMBERS OF THE RESEARCH TEAM 
• 
Prof Chris Haslett, Consultant in Respiratory Medicine, University of Edinburgh 
• 
Prof Tim Walsh, Consultant in Intensive Care Medicine, University of Edinburgh 
• 
Dr Nik Hirani, Senior Clinical Lecturer in Respiratory Medicine, University of 
Edinburgh 
• 
Dr Kalliroi Kefala, Consultant in Intensive Care Medicine, Royal Infirmary of 
Edinburgh 
• 
Dr Ahsan Akram, Specialist Registrar in Respiratory Medicine, NHS Lothian 
• 
Dr James Dear, Consultant in Clinical Pharmacology, University of Edinburgh 
• 
Dr Tom Craven, Specialist Registrar in Intensive Care Medicine, NHS Lothian 
 
 

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CONTENTS 
1 
INTRODUCTION .......................................................................................12 
1.1 
BACKGROUND ................................................................................12 
1.2 
RATIONALE FOR STUDY ................................................................12 
2 
STUDY OBJECTIVES ...............................................................................13 
2.1 
OBJECTIVES ...................................................................................13 
2.1.1 
Primary Objective...........................................................................13 
2.1.2 
Secondary Objectives ....................................................................13 
2.2 
ENDPOINT MEASURES FOR EXPLORATORY CLINICAL STUDY .13 
2.2.1 
Primary Endpoint ...........................................................................13 
2.2.2 
Secondary Endpoints .....................................................................13 
3 
REGULATORY REQUIREMENTS ............................................................13 
4 
STUDY DESIGN .......................................................................................13 
4.1 
A) Delivery of NAP to healthy volunteers ..........................................14 
4.2 
B) Delivery of NAP to 3 patients in ICU with pulmonary infiltrates .....15 
5 
STUDY POPULATION ..............................................................................17 
5.1 
NUMBER OF PARTICIPANTS..........................................................18 
5.2 
INCLUSION CRITERIA FOR PART A...............................................18 
5.3 
INCLUSION CRITERIA FOR PART B...............................................18 
5.4 
EXCLUSION CRITERIA FOR PART A .............................................18 
5.5 
EXCLUSION CRITERIA FOR PART B .............................................18 
6 
PARTICIPANT SELECTION AND ENROLMENT .....................................19 
6.1 
APPROACHING AND IDENTIFYING POTENTIAL PARTICIPANTS 
FOR PART A ....................................................................................19 
6.2 
APPROACHING AND IDENTIFYING POTENTIAL PARTICIPANTS 
FOR PART B ....................................................................................19 
6.3 
SCREENING FOR ELIGIBILITY .......................................................19 
6.4 
CONSENTING PARTICIPANTS .......................................................19 
6.5 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS ....................20 
6.6 
WITHDRAWAL OF STUDY PARTICIPANTS ....................................20 
6.6.1 
Reasons for Discontinuing Participants ..........................................20 
6.6.2 
Discontinuation Procedures ...........................................................20 
7 
INVESTIGATIONAL MEDICINAL PRODUCT AND PLACEBO ................20 
7.1 
STUDY DRUG ..................................................................................20 
7.1.1 
Study Drug Identification ................................................................20 
7.1.2 
Study Drug Manufacturer ...............................................................20 
7.1.3 
Labelling and Packaging ................................................................21 
7.1.4 
Storage ..........................................................................................21 
8 
STUDY ASSESSMENTS ..........................................................................21 
8.1 
OUTCOME MEASURES...................................................................21 
8.1.1 
Primary Outcome Measures...........................................................21 
8.1.2 
Other Measured Variables .............................................................21 
8.1.3 
Processing and Analysis of Blood Samples ...................................21 
8.2 
SAFETY ASSESSMENTS ................................................................21 
8.2.1 
Clinical ...........................................................................................21 
8.2.2 
Blood Tests ....................................................................................21 

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9 
ADVERSE EVENTS ..................................................................................22 
9.1 
DEFINITIONS ...................................................................................22 
9.2 
IDENTIFYING AEs AND SAEs .........................................................22 
9.3 
RECORDING AEs AND SAEs ..........................................................23 
9.4 
ASSESSMENT OF AEs AND SAEs ..................................................23 
9.4.1 
Assessment of Seriousness ...........................................................23 
9.4.2 
Assessment of Causality ................................................................23 
9.4.3 
Assessment of Expectedness ........................................................23 
9.4.4 
Assessment of Severity..................................................................23 
9.5 
REPORTING OF SAEs/SARs/SUSARs ............................................24 
9.6 
REGULATORY REPORTING REQUIREMENTS ..............................24 
9.7 
FOLLOW UP PROCEDURES ...........................................................24 
10 
PREGNANCY ...........................................................................................24 
11 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS ...............25 
11.1 
TRIAL MANAGEMENT GROUP .......................................................25 
11.2 
DATA MONITORING AND SAFETY COMMITTEE ...........................25 
11.3 
INSPECTION OF RECORDS ...........................................................25 
11.4 
RISK ASSESSMENT ........................................................................25 
11.4.1 Potential Risks to Subjects and Measures in Place to Minimise Risk
 ......................................................................................................25 
11.5 
STUDY MONITORING AND AUDIT .................................................26 
12 
GOOD CLINICAL PRACTICE ...................................................................26 
12.1 
ETHICAL CONDUCT ........................................................................26 
12.2 
REGULATORY COMPLIANCE .........................................................26 
12.3 
INVESTIGATOR RESPONSIBILITIES ..............................................27 
12.3.1 Informed Consent ..........................................................................27 
12.3.2 Study Site Staff ..............................................................................27 
12.3.3 Data Recording ..............................................................................27 
12.3.4 Investigator Documentation ...........................................................27 
12.3.5 GCP Training .................................................................................27 
12.3.6 Confidentiality ................................................................................28 
12.3.7 Data Protection ..............................................................................28 
13 
STUDY CONDUCT RESPONSIBILITIES ..................................................28 
13.1 
PROTOCOL AMENDMENTS ...........................................................28 
13.2 
PROTOCOL VIOLATIONS AND DEVIATIONS .................................28 
13.3 
SERIOUS BREACH REQUIREMENTS ............................................29 
13.4 
STUDY RECORD RETENTION ........................................................29 
13.5 
END OF STUDY ...............................................................................29 
13.6 
CONTINUATION OF DRUG FOLLOWING THE END OF STUDY ....29 
13.7 
INSURANCE AND INDEMNITY ........................................................29 
14 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS .......30 
14.1 
AUTHORSHIP POLICY ....................................................................30 
14.2 
PUBLICATION ..................................................................................30 
14.3 
PEER REVIEW .................................................................................30 
15 
REFERENCES ..........................................................................................30 
 

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PROTOCOL APPROVAL 
Exploratory clinical study of microdosing NAP for optical molecular imaging in human 
lungs 
EudraCT number 2011-006169-17 
Signatures 
 
 
 
 
 
Dr Kev Dhaliwal 
 
 
19/01/2015 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Ray French 
 
 
 
Sponsors representative 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Professor Tim Walsh 
 
 
05/02/2015 
Co- Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Professor Dave Newby 
 
 
05/02/2015 
Principal Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Professor Chris Haslett 
 
 
05/02/2015 
Co-Investigator 
Signature 
 
Date 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - 
Joint office for University of Edinburgh and NHS Lothian 
ABG 
Arterial Blood Gas 
AE 
Adverse Event 
ALI 
Acute Lung Injury 
ARDS 
Adult Respiratory Distress Syndrome 
AR 
Adverse Reaction 
CRF 
Case Report Form 
CRP 
C Reactive Protein 
CTA 
Clinical Trials Authorisation 
CXR 
Chest X-Ray 
DMSC 
Data Monitoring and Safety Committee 
DPFS 
Developmental Pathway Funding Scheme 
ECG 
Electrocardiogram 
ECRF 
Edinburgh Clinical Research Facility 
FBC 
Full Blood Count 
FC 
Functional Capacity 
FDG PET 
Fludeoxyglucose Positron Emission Tomography 
FEV1 
Forced Expiratory Volume (1 second) 
FiO2 
Inspired Oxygen Concentration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
HIV 
Human Immunodeficiency Virus 
HNE 
Human Neutrophil Elastase 
ICU 
Intensive Care Unit 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
LFTs 
Liver Function Tests 
MHRA 
Medicines Health Regulatory Authority 
MI 
Molecular Imaging 
MRC 
Medical Research Council 
NAP 
Neutrophil Activation Probe 
PaO2 
Partial Pressure of Arterial Oxygen 
PCLE 
Probe Based Confocal Endomicroscopy 
PEEP 
Positive End Expiratory Pressure 
PISRC 
Phase I/First-in-Human Study Review Committee 

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QP 
Qualified Person 
R&D 
Research and Development 
RIE 
Royal Infirmary of Edinburgh 
REC 
Research Ethics Committee 
RML 
Right Middle Lobe 
RLL 
Right Lower Lobe 
SAE 
Serious Adverse Event 
SpO2 
Oxygen Saturations of pulsatile blood 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
TOPS 
The Over Volunteering Prevention System 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TSE 
Transmissible Spongiform Encephalopathy 
UAR 
Unexpected Adverse Reaction 
U&Es 
Urea and Electrolytes 
VAP 
Ventilator Associated Pneumonia 
WGH 
Western General Hospital 

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INVESTIGATOR STATEMENT 
Exploratory clinical study of microdosing NAP for optical molecular imaging in human 
lungs 
 
I agree to conduct the study according to this protocol, the principles of Good Clinical Practice 
(GCP) and the applicable regulatory requirements.  Any changes in procedure will only be made 
if necessary to protect the safety, rights or welfare of the participants. 
 
I agree to take responsibility for the conduct of the study and to ensure that all other staff 
involved are adequately informed about the protocol and amendments, and their study-related 
duties and functions. 
Signature 
 
 
 
 
 
Dr Kev Dhaliwal 
 
 
27/07/2015 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 

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LAY SUMMARY 
Seriously ill patients may develop a complication called acute lung injury (ALI), a form of 
inflammation in which lung tissue is filled by fluid containing white blood cells called neutrophils. 
ALI is common and is often fatal (for example in the USA it is estimated that 190,000 patients 
develop ALI per annum, of whom 75,000 die). No pharmacological treatment has been shown 
to improve ALI.  
 
Data from animal models and patients strongly suggest that neutrophils are central to disease 
progression. However no bedside methods exist to rapidly and accurately determine in 
seriously ill patients if neutrophils are present and if they are releasing damaging enzymes such 
as elastase. As such, the investigating team have developed and synthesised, to clinical grade, 
an imaging agent called NAP (Neutrophil Activation Probe). This detects activated neutrophils 
and also the damaging enzyme, human neutrophil elastase (HNE). We have extensively tested 
NAP in animal models for efficacy and safety. It reliably detects activated neutrophils and is not 
toxic. 
 
NAP is a small molecule that is delivered in tiny doses (called microdoses) to areas of 
inflammation in human lungs through a bronchoscope. The activity of NAP is visualised by 
imaging though a tiny camera that is also introduced through the bronchoscope. This camera 
system is now widely used throughout the world in over 150 sites. 
 
We therefore aim to test the utility and safety of NAP in an exploratory clinical study. The study 
involves the delivery of NAP to 6 healthy volunteers followed by delivering NAP to 3 patients in 
ICU with suspected ALI.  
 
In the healthy volunteers study, healthy male volunteers recruited from the University of 
Edinburgh will be invited to participate.  
 
In the ICU study, patients will be recruited from the ICU in the Royal Infirmary of Edinburgh 
(RIE) and the Western General Hospital (WGH), Edinburgh. 
 
If the study (which is supported by the Medical Research Council) demonstrates safety 
and also the ability to image activated neutrophils, we have secured further follow on 
funding to perform a clinical validation study. 

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PROFESSIONAL SUMMARY 
Acute lung injury (ALI)/adult respiratory distress syndrome (ARDS) is clinically important (16% 
of mechanically ventilated patients acquire ALI, of whom one third die), yet no pharmacological 
therapy has been shown to impact significantly on outcome. This is in part due to inadequate 
stratification of patients with neutrophil predominant ALI/ARDS and the inability to determine 
disease activity and hence target therapy. 
 
Molecular Imaging (MI) offers a potential strategy to visualize neutrophil activity in vivo in situ. 
Indeed FDG PET has been used to image neutrophil activity but it is not a bedside modality, 
and moving critically ill patients to remote scanners is dangerous and expensive and there there 
are currently no bedside ‘smart’ MI solutions that can guide, at the cellular/functional level, the 
diagnostic or therapeutic pathway in patients with inflammatory lung disease. Indeed, in ICU, 
there is a specific need to rapidly diagnose patients with deteriorating gas exchange, particularly 
those with chest X-ray (CXR) shadowing. Such CXR infiltrates result from numerous causes 
including cardiac failure, fluid overload, secondary pneumonia and ALI/ARDS. All require 
different treatments but, at present, options to distinguish these conditions are severely limited, 
resulting in empirical ‘blunderbuss’ antimicrobial therapy and non-correction of the primary 
condition. There is now a pressing need to rapidly stratify such patients to inform focused 
implementation of specific targeted therapies.   
 
Activated neutrophils and their histotoxic products, particularly human neutrophil elastase 
(HNE), have been specifically implicated in the pathogenesis of ALI/ARDS, and there is 
considerable clinical interest in new drugs in this area. However, there is currently no way of 
rapidly determining whether new therapeutic candidates are exerting their predicted effects in 
situ in the human lung prior to embarking upon major clinical trials. Such a solution would 
inevitably accelerate the pathway of new drugs to clinical application.  
 
The Proposed Solution: probe-based confocal laser endomicroscopy (pCLE) combined with 
direct intra-pulmonary instillation of microdoses (pharmacologically-inactive and non-toxic) of a 
highly specific and sensitive ‘smartprobe’ (NAP) will detect neutrophil activity and the presence 
of active HNE in the lungs of ventilated ICU patients.  
 
pCLE itself safely provides high-resolution, real-time images of the human lung at cellular 
resolution in situ. Alone, however, it provides no functional or molecular information. We have 
therefore embarked on a discovery programme to synthesise highly sensitive smartprobes, 
detectable by pCLE and specifically directed against key inflammatory events. This provides a 
new dimension of clinical application for this cutting-edge technology. NAP, the prototype has 
now been validated in vitro and in vivo where it is effective at a dose of <10µg and generates a 
powerful fluorescent signal in <30 sec. Our pilot study aims are to apply the combined utility of 
pCLE and NAP in healthy volunteers and patients with inflammatory lung disease. The study 
will also provide a prototypic foundation that can be applied to future smartprobes, not only in 
the lung but also in any organ accessible to endoscopy. 
 
The primary end-point will be to visualise the delivery of a microdose of NAP in 6 healthy 
volunteers and 3 ICU patients. Demonstration of activated neutrophils by pCLE in ICU would 
be expected to lead directly to clinical validation trials in patients with ALI/ARDS.  

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1 
INTRODUCTION 
1.1 
BACKGROUND 
Critically ill patients commonly develop acute lung injury (ALI) characterised by accumulation 
of neutrophil polymorphs in the alveolar space with attendant fluid ‘leak’ across the alveolar-
capillary membrane.1 The complication develops secondary to a wide range of primary 
pathologies, broadly classifiable into ALI secondary to pulmonary disease (e.g. pneumonia or 
aspiration of gastric contents) or extra-pulmonary disease (e.g. major extrathoracic trauma or 
sepsis). An American European Consensus Conference provided a pragmatic clinical definition 
for ALI2 fulfilled by, 
• 
acute onset,  
• 
the development of bilateral infiltrates on a frontal chest x-ray, 
• 
impaired oxygenation (a PaO2:FiO2 ratio of ≤ 300mmHg) and  
• 
the absence of left atrial hypertension (either on clinical grounds or by a measured 
pulmonary arterial wedge pressure of ≤18 mmHg).  
A more severe form of ALI, adult respiratory distress syndrome (ARDS), fulfills the same criteria 
but requires a PaO2:FiO2 ratio of ≤ 200mmHg. ALI and ARDS therefore represent continua of 
the same clinical spectrum.2 
 
ALI is common and has a high mortality. For example, a comprehensive study in the USA 
estimated that 190,000 Americans develop ALI each year, approximately 74,000 of whom die.3 
High rates of ALI have also been described in intensive care units (ICUs) in Europe and the 
UK.4-6 To place the clinical significance of ALI in context, it has been estimated that the mortality 
due to ALI is similar to that attributable to conditions such as human immunodeficiency virus 
(HIV), breast cancer or asthma.7 It is increasingly recognised that ALI/ARDS not only causes 
high mortality but consigns a high proportion of survivors to chronic morbidity and ill health.8,9 
 
Despite significant research efforts using a wide and logical range of drugs, no pharmacological 
treatment has yet been shown to impact significantly upon mortality from ALI/ARDS.10 Indeed 
the only medical intervention yet shown to influence mortality has been a ‘protective’ 
mechanical ventilation strategy.11 ALI therefore remains common, with an unacceptable 
associated mortality and morbidity. The lack of effective treatment may reflect the crucial role 
played by the blood neutrophil in the pathogenesis of ALI. Neutrophils are white blood cells, 
which are rapidly recruited to sites of inflammation during infection where they ingest and clear 
bacteria. In ALI this reaction appears inappropriate or over-exuberant and the neutrophil 
releases toxins which directly injure the lung.12 Reduction in neutrophil accumulation remains 
difficult to achieve by pharmacological means. 
1.2 
RATIONALE FOR STUDY 
Our group has an interest in the factors regulating the recruitment of neutrophils to the inflamed 
lung.13-15 We have also had a long interest in imaging neutrophils 16-18. Recently a 
multidisciplinary collaboration has been formed with Professor Mark Bradley in the Department 
of Chemistry to develop novel methodologies to image neutrophil activation. Funded by a MRC 
DPFS award, we have generated a compound that is non-toxic and functional as an optical 
imaging agent to detect activated neutrophils. It is delivered as a microdose locally in the 
alveolar space and neutrophil activity imaged using pCLE 19-21. (A microdose 22 is so small that 
it is not intended to produce any pharmacologic effect when administered to humans and 
therefore is also unlikely to cause an adverse reaction. For practical purposes this dose is 
defined as 1/100th of that anticipated to produce a pharmacological effect, or 100 micrograms, 
whichever is the smaller) It is envisaged NAP will be widely used in the future to detect 
neutrophil activity within the human lung in ICU to direct diagnostic and therapeutic decisions.  
 
 
The tools and the expertise available locally, present a unique opportunity to assess the 
effectiveness and safety of delivering NAP to healthy volunteers and patients in ICU as a 
prelude to larger definitive clinical validation studies.  
 

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The study has 2 parts 
Part A will evaluate the imaging parameters and safety of delivering NAP to 6 healthy volunteers 
within the MHRA accredited phase I unit at the Edinburgh Clinical Research Facility (ECRF) 
 
In Part B we shall assess NAP delivery to 3 patients in ICU with suspected ALI/ARDS and 
pulmonary infiltrates at the RIE and WGH.  
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
The primary objective is to deliver NAP as a microdose to 6 healthy volunteers and 3 patients 
in ICU and to test if activated neutrophils within the alveolar space can be detected with 
NAP and pCLE over background autofluorescence  
2.1.2 Secondary Objectives 
The secondary objective is to deliver NAP and to observe if NAP is non-toxic.  
2.2 
ENDPOINT MEASURES FOR EXPLORATORY CLINICAL STUDY 
2.2.1 Primary Endpoint 
• 
Visualise the delivery of a microdose of NAP in healthy volunteers and ICU patients. 
• 
Delineate the presence of activated neutrophils within CXR infiltrates in ventilated 
patients with suspected ALI/VAP. 
2.2.2 Secondary Endpoints 
Safety and tolerability as assessed by occurrence of adverse events (AEs) and serious adverse 
events (SAEs). 
3 
REGULATORY REQUIREMENTS 
The protocol will be submitted to the REC for ethical approval. Local R&D Management and 
Edinburgh Clinical Research Facility (ECRF) phase I committee (PISRC) approval before the 
first participant is recruited. The study is ‘First in Man’ but the maximum dose level required is 
defined as a microdose within the relevant ICH M3(R2) guidelines. A CTA will be submitted to 
the MHRA. 
4 
STUDY DESIGN 
The study is designed in 2 parts; 
  
Part A) is a dose escalation in 6 healthy volunteers to deliver NAP and designed to assess the 
imaging parameters of NAP in the healthy lung and to monitor any unexpected serious adverse 
events (SAEs). No volunteer will be permitted to take part more than once.  
 
Only if part A is successfully completed and the data monitoring and safety committee (DMSC) 
permit, part B will be undertaken. The REC will be informed of the outcome of part A and the 
DMSC decision to proceed. 
 
Part B) is an exploratory clinical study in ICU to provide preliminary ‘proof of concept’ in 3 
patients with suspected inflammatory lung disease. 

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4.1 
A) Delivery of NAP to healthy volunteers 
Volunteers will return on a morning agreed after the screening medical described in Section 7.1 
below. A brief history (pertaining to upper and lower respiratory tract symptoms) and respiratory 
examination will be repeated. Spirometry will be performed before proceeding. 
 
For Volunteers, 1-4, they will be bronchoscoped and pCLE performed of the right middle lobe 
(RML). Immediately following this, NAP will be instilled via microcatheter into the RML and 
pCLE performed again of the RML. 
 
Bronchoscopy will be performed using a standardised protocol and procedure employed 
throughout our work thus far.14 Briefly, local anaesthesia will be applied topically to the throat. 
Sedation with intravenous midazolam will be optional. Electrocardiogram (ECG) trace and SpO2 
will be monitored continuously. A flexible fibreoptic bronchoscope will be passed per-orum or 
nasally and the bronchoscope wedged into the medial segment of the right middle lobe. The 
alveoflex will be passed down the working channel and alveoscopy performed with upto 4 
transbronchial passes. Following this, the alveoflex will be withdrawn and a microcatheter 
passed into the medial segment of the RML and NAP instilled. Immediately following this pCLE 
will be performed as described above.  
 
For volunteers, 5 and 6, they will be bronchoscoped and pCLE performed of the right lower lobe 
(RLL) and right middle lobe (RML). Immediately following this, NAP will be instilled via 
microcatheter into the RLL and RML and pCLE performed again of the RLL and RML. The dose 
of NAP will be divided between 2 segments in the RLL and one segment in the RML. The 
volunteer will receive a total of 80mcg (+/-20%) NAP. 
 
Bronchoscopy will be performed using a standardized protocol and procedure employed 
throughout our work thus far.14 Briefly, local anesthesia will be applied topically to the throat. 
Sedation with intravenous midazolam will be optional. Electrocardiogram (ECG) trace and SpO2 
will be monitored continuously. A flexible fibre-optic bronchoscope will be passed per-orum or 
nasally and the bronchoscope wedged into right lower and middle lobes. The alveoflex will be 
passed down the working channel and alveoscopy performed with upto 4 transbronchial passes 
per segment. Following this, the alveoflex will be withdrawn and a microcatheter passed into 
the RLL and RML and NAP instilled. Immediately following this pCLE will be performed as 
described above.  
 
 
The volunteer will return to the ECRF after the procedure and will be monitored for a further 2 
hours after which he can eat and drink. Volunteers will remain within the ECRF overnight. In 
the morning if, on assessment, volunteers observations are within acceptable parameters and 
they have a satisfactory cardio-respiratory examination, they will be discharged from the ECRF, 
with a number to contact should they feel unwell. The volunteers will be telephoned 3 days after 
dosing to enquire about any possible late unexpected adverse events. 
 
6 volunteers will receive a dose escalation of NAP (below) on 6 separate days (each at least 6 
days apart). After each episode, data will be submitted to the DMSC for approval to proceed to 
the next volunteer.  The DMSC opinion will be documented and available to the ECRF prior to 
subsequent dosing events. 
Table 1 
Volunteer number 
Dose of NAP (+/- 20%) 
(mcg) 
Volume 
of 
NAP 
(mls)(80mcg/5mls) 
1-2 
5 
0.312 
3-4 
10 
0.625 
5-6 
80 
5 
 
Blood will be drawn just before bronchoscopy and delivery of NAP (t=0) and at t= 4 hours 
(±30mins). For participants 5 and 6 an additional blood sample (less than 5 ml) will be collected 

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at t=1 hour (±30 mins) for analysis to demonstrate the systemic uptake, or lack thereof, of the 
IMP. For participants 5 and 6, the first and second urine voiding following dosing will be 
collected for the same purpose. Spirometry will then be repeated 4 hours (±30mins) after NAP 
delivery and the following morning. Bloods will be taken again in the morning. After each dosed 
volunteer has completed the 3-day follow up, clinical and laboratory data will be checked by the 
sponsor’s representative prior to submission to the DMSC by the investigatory team. All data 
will be recorded on paper case report forms (CRFs). A summary of assessments and events is 
shown in table 2 below. 
 
Table 2 
 
Day of 
screening 
Study 
day on 
arrival 
Following 
NAP 
delivery 
1 hour 
after 
NAP 
delivery 
(± 
30mins) 
4 hours 
after 
NAP 
delivery 
(±30 
mins) 
Overnight 24 
hours 
(±30 
mins) 
CXR 
✓ 
 
 
 
 
 
 
✓ 
 
Cardiorespiratory 
examination 
✓ 
 
✓ 
 
 
 
✓ 
 
 
✓ 
 
Bloods: FBC, 
U&Es, LFTs, 
CRP 
✓ 
 
✓ 
 
 
 
✓ 
 
 
✓ 
 
Additional blood 
test for IMP level 
(Volunteers 5 
and 6 only- non 
safety) 
 
 
 
✓ 
 
 
 
 
Spirometry 
✓ 
 
✓ 
 
 
 
✓ 
 
 
✓ 
 
Informed 
consent 
✓ 
 
 
 
 
 
 
 
Urine collection 
for IMP level 
(non safety) 
 
 
 
✓ 
 
 
 
 
 
Observations, 
pulse, 
temperature, 
oxygen 
saturation 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
 
4.2 
B) Delivery of NAP to 3 patients in ICU with pulmonary infiltrates 
ICU patients will be screened daily by ICU research nurses. If they fit the inclusion criteria 
described in Section 5.3, they or their personal/professional legal representative will be 
approached by a member of the research team to obtain consent. The attending consultant will 
also be approached and only after also gaining permission from the attending consultant will 
the patient be considered for inclusion into the study. 
 
The pulmonary infiltrates will be identified on a CXR, which has been performed as part of 
routine clinical care and bronchoscopy and pCLE performed as above. A CXR will be performed 
immediately before the procedure. pCLE will be performed on areas without infiltrates as well 
as the affected segment/s. Following this, NAP will be instilled into the affected segment/s and 
unaffected segment/s via a microcatheter . A total of 80 mcg (+/-20%) of NAP will be delivered 

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to the patient divided between the affected and unaffected segments. pCLE will be 
subsequently performed on the segments in which NAP has been delivered. We have 
performed bronchoscopy in over 70 patients in ICU over the last 5 years 14. The whole 
procedure including delivery of NAP will take approximately 30 minutes. The table below 
summarise the events and data to be collected before and after the procedure. 
 
In addition, we intend to collect an additional sample (less than 5 ml) at t= 7.5 mins (±2.5 mins) 
for analysis to demonstrate the systemic uptake, or lack thereof, of the IMP. For these 
participants, the urometer will be emptied at the time of bronchoscopy and then any urine 
passed over the next 2 hours will be collected to demonstrate the systemic uptake, or lack 
thereof, of the IMP. 
 
 

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Table 3 
Day of 
screening 
Immediately 
pre 
procedure 
(within  1 
hour) 
7.5 mins 
(+/- 
2.5mins) 
2 hours 
(+/- 30 
mins) 
6 hours 
(+/- 30 
mins) 
24 
hours 
(+/- 30 
mins) 
CXR 
✔ 
✔ 
✔ 
Cardiorespiratory 
examination 
✔ 
NAP  blood 
sampling (non-
safety) 
✔ 
Bloods: FBC, 
U&E’s, LFTs, 
CRP 
✔ 
✔ 
✔ 
✔ 
ABG 
✔ 
✔ 
✔ 
✔ 
Urine Collection 
for IMP (non-
safety) 
 
 
 
✓ 
 
✓ 
 
 
 
Attending ICU 
consultant 
permission 
✔ 
Informed consent 
✔ 
✔ 
✔ 
✔ 
Observations, 
pulse, 
temperature, 
oxygen 
saturation 
✔ 
✔ 
✔ 
✔ 
✔ 
All ventilator 
settings, PEEP, 
oxygenation, P:F 
ratio 
✔ 
✔ 
✔ 
✔ 
✔ 
 
5 
STUDY POPULATION 
Part A: The study population will be comprised exclusively of healthy male volunteers. 
(±30mins) 
(±30mins) 
(±30mins) 

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Part B: The study population will be comprised of male patients in ICU (RIE and WGH) with 
pulmonary infiltrates. 
5.1 
NUMBER OF PARTICIPANTS 
A total of 6 participants will be recruited for Part A.  
 
A total of 3 patients will be recruited for Part B. 
5.2 
INCLUSION CRITERIA FOR PART A 
For part A, healthy male volunteers aged between 18 and 40. 
5.3 
INCLUSION CRITERIA FOR PART B 
5.4 
Ventilated male patients over the age of 18 in the ICU. 
5.5 
EXCLUSION CRITERIA FOR PART A 
A patient will not be eligible for inclusion in the study if any of the following criteria apply at 
entry: 
 
1. Age < 18 or >40 years 
2. History of any chronic or ongoing acute illness (with particular reference to asthma, 
upper respiratory tract infection, lower respiratory tract infection, bronchiectasis, 
congenital heart disease, ischaemic heart disease, valvular heart disease, diabetes 
mellitus, chronic renal impairment, urinary tract infection) 
3. Any current medication 
4. Any history of previous reactions to flourescein or any other anaphylaxis 
5. Abnormal physical signs detected at cardiorespiratory examination 
6. Temperature >37.3 degrees Celsius 
7. Oxygen saturation <95% breathing room air 
8. Haemoglobin, white cell count or platelet count outside the normal laboratory reference 
range 
9. Blood sodium, potassium, urea, creatinine, bilirubin, alanine aminotransferase, random 
glucose or C-reactive protein outside the normal laboratory reference range 
10. Forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) <80% 
predicted 
11. FEV1:FVC ratio <70% 
12. Any significant cardiorespiratory abnormality detected on chest x-ray 
13. Peripheral venous access insufficient to support 14 gauge cannulae. 
14. General practitioner confirmation of eligibility as a healthy volunteer not received 
15. Failure to provide suitable identification (passport/driving licence) 
16. Refusal to consent to enter details in ‘The Over Volunteering Prevention System’ 
(TOPS) database 
17. Positive urine drug screen 
18. Participation in any other interventional study or less than three months since their last 
participation in an interventional study 
19. Female 
5.6 
EXCLUSION CRITERIA FOR PART B 
1. Age <18years 
2. Any contraindication for bronchoscopy 22,23 
3. Refusal for participation by attending consultant 
4. Fi02 >70% 
5. PEEP>10cm  
6. Recent pneumothorax (whilst on ventilator) 
7. Any history of previous reactions to flourescein or any other anaphylaxis 
8. Participation in any other interventional study or less than three months since their last 
participation in an interventional study 
9. Female 

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6 
PARTICIPANT SELECTION AND ENROLMENT 
6.1 
APPROACHING AND IDENTIFYING POTENTIAL PARTICIPANTS 
FOR PART A 
An advert will be placed on University of Edinburgh email lists and on University of Edinburgh 
notice boards. Potential participants will be asked to make contact with the research team only 
if they consider themselves to be healthy. Interested individuals will be invited to contact the 
research team who will send out information on the study (participant information sheets and 
consent forms). Participants sent such information will be invited to contact the research team 
to arrange a screening visit (section 6.3 below) or to decline participation. If no reply is received 
after 2 weeks, the research team will send a reminder. 
6.2 
APPROACHING AND IDENTIFYING POTENTIAL PARTICIPANTS 
FOR PART B 
After screening by members of the routine healthcare team in ICU, the patient or if 
incapacitated, their personal/professional legal representative will be approached by a member 
of the research team. A professional legal representative will be a clinician responsible for the 
medical treatment of the patient if they are independent of the study or a person nominated by 
the healthcare provider and will only be approached if a personal legal representative is not 
available. Direct face-to-face approach will be made. If the patient is conscious and the clinician 
in charge judges the patient to have capacity to provide informed consent then he will be 
approached directly. The first approach will always be by a member of the research team who 
is a qualified nurse or doctor. 
6.3 
SCREENING FOR ELIGIBILITY 
For part A: 
Volunteers who contact the research team will be invited to attend for a screening visit. This will 
take the form of; 
 
• 
a short history  
• 
cardiorespiratory examination  
• 
full blood count 
• 
urea & electrolytes, liver function tests, random blood glucose, C-reactive protein 
• 
CXR 
• 
spirometry 
• 
oxygen saturation 
• 
urine toxicology screen 
• 
consent for the study 
• 
consent for details to be submitted to the TOPS database 
• 
Volunteer’s GP being contacted regarding health status and suitability to participate 
 
These are performed with the sole intention of identifying potential exclusion criteria as listed in 
section 5.4. 
A medically qualified member of the research team will perform the history, examination and 
investigations. 
 
For part B 
ICU patients will be screened by the ICU research team for inclusion and exclusion criteria. 
6.4 
CONSENTING PARTICIPANTS 
For healthy volunteers, eligible subjects will be asked to consider giving written consent. This 
will be taken by a medically qualified member of the research team. 
In ICU, patients who are ventilated and are judged by the clinician in charge to be able to 
provide informed consent- they will be given a written information sheet fully explaining the 
procedure with expected benefits and potential outcomes and risks. Consent will be obtained 
by clinically qualified members of the team. For ventilated patients who are not able to consent, 

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their personal/professional legal representative will be approached by the research team in 
person-they will be given a written information sheet fully explaining the procedure with 
expected benefits and potential outcomes and risks. 
 
Consent will be obtained by clinically qualified members of the team. One original will be signed 
and 2 copies made. The original will be filed in the patient’s notes along with the Information 
sheet. One copy will be given to the patient/patients personal/professional legal representative 
and one stored in the trial master file (TMF). 
6.5 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS 
For ineligible patients and eligible volunteers who are not subsequently entered into the study, 
the reason for ineligibility or non-recruitment will be entered on the paper CRF.  Only 
anonymised data will be entered on to the paper CRF and this will include gender, age, 
“ineligible” or “non-recruitment” and the associated reason. 
6.6 
WITHDRAWAL OF STUDY PARTICIPANTS 
Participation in the study is voluntary. A participant has the right to discontinue or completely 
withdraw from the study at any time for any reason. The Investigator has the right to discontinue 
a participant from the study at any time if it is deemed to be in the volunteer’s or patient’s best 
interest. The reason and circumstances for premature discontinuation will be documented in 
the participant’s Case Report Form (CRF). 
6.6.1 Reasons for Discontinuing Participants 
Reasons for discontinuation of the study may include 
 
Bronchoscopy 
• 
intolerance of the scope (i.e. unable to intubate the trachea) 
• 
marked coughing 
6.6.2 Discontinuation Procedures 
If a participant chooses to withdraw completely from the study and all study assessments this 
will be recorded in the CRF. Any concerns expressed by the participant will be addressed by 
the research team. 
7 
INVESTIGATIONAL MEDICINAL PRODUCT AND 
PLACEBO 
7.1 
STUDY DRUG 
7.1.1 Study Drug Identification 
Neutrophil Activation Probe sterile solution (NAP) 
The final dosage form of the investigational medicinal product (IMP) consists of 80 µg (+/- 
20%) of the drug substance NAP dissolved in 5 mL of sterile Phosphate Buffered Saline 
(PBS) pH 7.4 solution, presented in sterile nitrogen filled glass vials. The solution is intended 
for direct instillation into the distal lung delivery via a microcatheter at microdose levels (<100 
µg). Upon contact with neutrophils and/or the enzyme elastase, NAP will give a specific 
fluorescent signal that will be detected by pCLE.  
7.1.2 Study Drug Manufacturer 
The synthesis of NAP is carried out using standard solid phase chemistry at a GLP compliant 
manufacturing site, Aptuit Laurus, India. No materials at risk of transmitting transmissible 
spongiform encephalopathy (TSE) are used in the manufacturing process. NAP manufacture 
and filling, under aseptic conditions, and QP release are performed by Pharmacy Production 
Unit, Western Infirmary, 100 University Place Glasgow, G12 8TA, and are carried out according 
to Good Manufacturing Practices. The quality of the product is controlled by ensuring 

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compliance to internal specifications set with due regard to European guidance on the control 
of IMPs.  
7.1.3 Labelling and Packaging 
NAP labelling and packaging is being carried out by Pharmacy Production Unit, Western 
Infirmary, Glasgow. 
7.1.4 Storage 
The IMP is to be stored at room temperature. Stability studies have been conducted to confirm 
the stability of NAP formulation over the proposed study duration. NAP will be stored in the 
pharmacy at the RIE. 
 
7.2 
OTHER MEDICATIONS 
7.2.1 Non-Investigational Medicinal Products 
Paracetamol (in the event of significant symptoms of fever) 
Salbutamol (in the event of bronchospasm) 
Oxygen (in the event of hypoxia) 
Adrenaline (in the event of anaphylaxis). 
 
8 
STUDY ASSESSMENTS 
8.1 
OUTCOME MEASURES 
8.1.1 Primary Outcome Measures 
This is an exploratory clinical study. The primary outcome measure is measurement of 
fluorescence and imaging parameters determined using pCLE and Cellvizio viewer software. 
8.1.2 Other Measured Variables 
Safety in part A and part B and initial proof of concept in ICU to detect neutrophil activation.  
8.1.3 Processing and Analysis of Blood Samples 
‘Screening visit’ and all other blood samples will be sent to the hospital laboratories for 
assessment of full blood count, urea and electrolytes, blood glucose, liver function tests and C-
reactive protein. 
8.2 
SAFETY ASSESSMENTS 
8.2.1 Clinical 
In part A, Clinical assessment will be on a rolling basis throughout the study days (table 2). 
‘Vital signs’ (pulse, blood pressure, temperature and oxygen saturation) will be measured on 
arrival and at least hourly (±10mins) over the course of the day. The only exceptions will be that 
monitoring will be suspended overnight if the volunteer is sleeping comfortably. In this 
exception, the volunteer can be observed directly and continuous heart rate monitoring will 
continue, and additional monitoring can be re-initiated immediately if there are any features of 
clinical distress. During bronchoscopy there is continuous monitoring of ECG trace and oxygen 
saturation. Spirometry in part A will be a primary safety assessment with a greater than 15% 
reduction from baseline defined as significant.  
 
In part B, patients will be within ICU and be continually monitored. 
8.2.2 Blood Tests  

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In part A, blood tests (FBC, LFTs, U&Es, CRP) are submitted as outlined in table 2. In part B, 
blood tests are submitted as outlined in table 3.   
9 
ADVERSE EVENTS 
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definitions detailed below.   
Full details of contraindications and side effects that have been reported following 
administration of the IMP can be found in the Investigator’s Brochure (IB). 
Participants will be instructed to contact their Investigator at any time after consenting to join 
the trial if any symptoms develop.  All adverse events (AE) that occur after joining the trial must 
be reported in detail in the Case Report Form (CRF) or AE form.  In the case of an AE, the 
Investigator should initiate the appropriate treatment according to their medical judgment.  
Participants with AEs present at the last visit must be followed up until resolution of the event. 
9.1 
DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant which 
does not necessarily have a causal relationship with an investigational medicinal product (IMP). 
An adverse reaction (AR) is any untoward and unintended response to an IMP which is related 
to any dose administered to that participant.  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR that at any 
dose: 
• 
results in death of the clinical trial participant; 
• 
is life threatening*; 
• 
requires in-patient hospitalisation^ or prolongation of existing hospitalisation; 
• 
results in persistent or significant disability or incapacity; 
• 
consists of a congenital anomaly or birth defect; 
• 
results in any other significant medical event not meeting the criteria above. 
 
*Life-threatening in the definition of an SAE or SAR refers to an event where the participant 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe. 
 
^Any hospitalisation that was planned prior to inclusion into the study will not meet SAE criteria. 
Any hospitalisation that is planned post inclusion into the study will meet the SAE criteria. 
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is classified as 
serious and is suspected to be caused by the IMP, that it is not consistent with the information 
about the IMP in the Summary of Product Characteristics (SmPC) or Investigators Brochure. 
9.2 
IDENTIFYING AEs AND SAEs 
In part A, all AEs and SAEs will be recorded from the time a participant signs the consent form 
to take part in the study until 3 days after the participant has been dosed. 
For part A, a member of the research team will ask about the occurrence of AEs/SAEs during 
and on a surveillance call 3 days after the participant is dosed. Open-ended and non-leading 
verbal questioning of the participant will be used to enquire about AE/SAE occurrence. 
Participants will also be asked if they have been admitted to hospital, had any accidents, used 
any new medicines or changed concomitant medication regimens.  If there is any doubt as to 
whether a clinical observation is an AE, the event will be recorded. If the healthy volunteer 
participant is unavailable by phone at this time, a reasonable number of attempts to contact 
the participant by telephone will be made to follow up on safety outcomes as described in the 
consent process. 
In part B, all AEs and SAEs will be recorded from the time the NAP is delivered and until 3 days 
after dosing. 

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AEs and SAEs may also be identified via information from support departments e.g. 
laboratories.  The laboratory may fax the results directly to ACCORD. Details of the fax number 
will be placed on the laboratory request form as well as the mobile phone number of the Chief 
Investigator. 
9.3 
RECORDING AEs AND SAEs 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g. hospital notes, laboratory and diagnostic reports) related to the event.  The Investigator 
will then record all relevant information in the CRF and on the SAE form (if the AE meets the 
criteria of serious). 
Information to be collected includes dose, type of event, onset date, Investigator assessment 
of severity and causality, date of resolution as well as treatment required, investigations needed 
and outcome.   
9.4 
ASSESSMENT OF AEs AND SAEs 
Seriousness, causality, severity and expectedness will be assessed by the Chief Investigator. 
The Investigator is responsible for assessing each AE.   
The Chief Investigator (CI) may not downgrade an event that has been assessed by an 
Investigator as an SAE or SUSAR, but can upgrade an AE to an SAE, SAR or SUSAR if 
appropriate. 
9.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 9.1. 
9.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be related to the 
IMP according to the definitions below.   
 
• 
Unrelated: where an event is not considered to be related to the IMP. 
 
• 
Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the AE has a 
causal relationship to the study drug. The assessment of causality will be made against 
the reference safety information found in the Investigators Brochure. 
Where non Investigational Medicinal Products (NIMPs) e.g. rescue/escape drugs are given:  if 
the AE is considered to be related to an interaction between the IMP and the NIMP, or where 
the AE might be linked to either the IMP or the NIMP but cannot be clearly attributed to either 
one of these, the event will be considered as an AR. Alternative causes such as natural history 
of the underlying disease, other risk factors and the temporal relationship of the event to the 
treatment should be considered and investigated.  
9.4.3 Assessment of Expectedness 
If an event is judged to be an AR, the evaluation of expectedness will be made based on 
knowledge of the reaction and the relevant product information documented in the IB. 
The event may be classed as either: 
Expected: the AR is consistent with the toxicity of the IMP listed in the IB. 
Unexpected: the AR is not consistent with the toxicity in the IB. 
9.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE and record this on the 
CRF or SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with every day activities. 

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Moderate: an event that is sufficiently discomforting to interfere with normal everyday activities. 
Severe: an event that prevents normal everyday activities. 
Note: the term ‘severe’, used to describe the intensity, should not be confused with ‘serious’ 
which is a regulatory definition based on participant/event outcome or action criteria.  For 
example, a headache may be severe but not serious, while a minor stroke is serious but may 
not be severe. 
9.5 
REPORTING OF SAEs/SARs/SUSARs 
Once the Investigator becomes aware that an SAE has occurred in a study participant, the 
information will be reported to the ACCORD Research Governance & QA Office immediately 
or within 24 hours. If the Investigator does not have all information regarding an SAE, they 
should not wait for this additional information before notifying ACCORD.  The SAE report form 
can be updated when the additional information is received. 
The SAE report will provide an assessment of causality and expectedness at the time of the 
initial report to ACCORD according to Sections 10.4.2, Assessment of Causality and 10.4.3, 
Assessment of Expectedness. 
The SAE form will be transmitted by fax to ACCORD on +44 (0)131 242 9447 or may be 
transmitted by hand to the office or submitted via email to Safety.Accord@ed.ac.uk. Only forms 
in a pdf format will be accepted by ACCORD via email. 
Where missing information has not been sent to ACCORD after an initial report, ACCORD will 
contact the investigator and request the missing information.  
All reports faxed to ACCORD and any follow up information will be retained by the Investigator 
in the Investigator Site File (ISF). 
9.6 
REGULATORY REPORTING REQUIREMENTS 
The ACCORD Research Governance & QA Office is responsible for pharmacovigilance 
reporting on behalf of the co-sponsors (Edinburgh University and NHS Lothian). 
The ACCORD Research Governance & QA Office has a legal responsibility to notify the 
regulatory competent authority and relevant ethics committee (Research Ethics Committee 
(REC) that approved the trial).  Fatal or life threatening SUSARs will be reported no later than 
7 calendar days and all other SUSARs will be reported no later than 15 calendar days after 
ACCORD is first aware of the reaction.   
ACCORD will inform Investigators at participating sites of all SUSARs and any other arising 
safety information. 
An Annual Safety Report/Development Safety Update Report will be submitted, by ACCORD, 
to the regulatory authorities and RECs listing all SARs and SUSARs. 
9.7 
FOLLOW UP PROCEDURES 
After initially recording an AE or recording and reporting an SAE, the Investigator will follow 
each participant until resolution or death of the participant.  Follow up information on an SAE 
will be reported to the ACCORD office. 
AEs still present in participants at the last study visit will be monitored until resolution of the 
event or until no longer medically indicated. 
10 
PREGNANCY 
Pregnancy is not considered an AE or SAE; however, the Investigator will collect pregnancy 
information for female partners of dosed male participants who become pregnant while 
participating in the study.  The Investigator will record the information on a Pregnancy 
Notification Form and submit this to the ACCORD office within 14 days of being made aware 
of the pregnancy. 

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Female partners of dosed male participants who become pregnant while participating in the 
study will be followed up until following the outcome of the pregnancy. 
11 
TRIAL MANAGEMENT AND OVERSIGHT 
ARRANGEMENTS 
11.1 TRIAL MANAGEMENT GROUP 
The study will be co-ordinated by a Project Management Group, consisting of Dr Kev Dhaliwal, 
Professor Tim Walsh and Professor Chris Haslett.  
A Delegation Log will be prepared for each site, detailing the responsibilities of each member 
of staff working on the trial.   
11.2 DATA MONITORING AND SAFETY COMMITTEE 
An independent DMSC will be established to oversee the safety of subjects in the study. They 
will be informed of every participant’s response to NAP. The DMSC will comprise local and 
external experts who will be contacted at the end of each participant’s involvement. A decision 
to proceed will be required after each dosed participant as detailed in a DMSC charter 
monitored by ACCORD. At the end of part A, a DMSC report will also be sent to the regional 
ethics panel for recording successful completion of part A. 
11.3 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and audits 
on behalf of the sponsor, REC review, and regulatory inspection(s).  In the event of an audit or 
monitoring, the Investigator agrees to allow the representatives of the sponsor direct access to 
all study records and source documentation. In the event of regulatory inspection, the 
Investigator agrees to allow inspectors direct access to all study records and source 
documentation. 
11.4 RISK ASSESSMENT 
A comprehensive review and risk assessment of the study will be performed by the PISRC prior 
to the approval of the study. A contingency plan will be agreed and this will be audited by the 
CRF QA Manager once the study is underway. An independent risk assessment will be 
performed by an ACCORD Clinical Trials Monitor to determine if monitoring is required and if 
so, at what level. An independent risk assessment will also be carried out by the ACCORD 
Quality Assurance Group to determine if an audit should be performed before/during/after the 
study and if so, at what locations and at what frequency. 
11.4.1 Potential Risks to Subjects and Measures in Place to Minimise Risk 
11.4.1.1 Blood sampling/venous access 
Venepuncture is associated with mild discomfort and bruising, and there is a small risk of 
vasovagal syncope. The number of venepuncture procedures to be performed will be minimised 
by drawing blood from venous cannulae wherever possible. Bruising will be minimised by 
ensuring that venepuncture is carried out by experienced personnel. Withdrawal of 
cannulae/needles will be accompanied by firm pressure on the puncture for at least one minute. 
The risk of syncope will be minimised by having subjects recumbent or semi-recumbent for all 
venepuncture. 
11.4.1.2 NAP delivery 
In part A, 5-80μg (+/- 20%) NAP will be delivered via a microcatheter instilled in the working 
channel of the bronchoscope. The exact time and dose delivered will be recorded. Delivery of 
fluorescein and other dyes have been reported with no recorded adverse effects. 
 
Participants will be observed after NAP delivery and medications required to treat any adverse 
effects will be readily available (e.g. paracetamol in the event of significant symptoms of fever, 
salbutamol in the event of bronchospasm, oxygen in the event of hypoxia, adrenaline in the 

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event of anaphylaxis). The bronchoscopy suite and the ECRF are within the RIE and all 
resuscitation equipment and cardiac arrest teams are immediately to hand. Hence all the 
necessary facilities to safely undertake this procedure are available. 
11.4.1.3 Bronchoscopy and pCLE 
Participants will be closely monitored during and after the bronchoscopy. Healthy volunteers in 
part A will receive topical anaesthesia to the oral cavity (to prevent discomfort). The subject will 
also be offered light sedation in the form of intravenous midazolam.  
 
Bronchoscopy can be associated with low oxygen levels (rarely). Prior to bronchoscopy 
subjects will be given supplemental oxygen. The test will be stopped if the oxygen levels fall 
significantly. Predefined stopping criteria are established and if oxygen levels as measured by 
pulse oximetry falls to <92% from baseline, bronchoscopy will be stopped.  
 
Other risks of bronchoscopy include aspiration (in the rare event of vomiting while there are 
significant gastric contents) and arrhythmia if too much local anaesthetic is used. We have 
minimised the risk of vomiting firstly by offering ‘non-sedated’ bronchoscopy (thereby 
eliminating midazolam, the principal cause of nausea), and secondly by ensuring at least 8 
hours between the patient’s breakfast and bronchoscopy. The risk of arrhythmia will be 
minimised by limiting airway anaesthesia to ≤10ml 2% lignocaine and by the fact that we study 
healthy volunteers (in whom arrhythmia is extremely rare).23 
 
For part A, bronchoscopy will be undertaken in a dedicated bronchoscopy suite. All the 
necessary facilities to safely undertake this procedure are available. For part B, bronchoscopy 
will be performed in ICU. 
 
Subjects can experience cough and fever within 24 hours following bronchoscopy. Subjects will 
be advised how to manage symptoms (paracetamol as anti-pyretic and analgesia) and given a 
telephone number to contact a member of the study team if any symptoms develop after leaving 
hospital. 
 
pCLE has been performed in over 500 patients worldwide with no recorded serious adverse 
events. It is now a routine procedure in many institutions. 19,20 We have performed it locally in 
ventilated animals and patients with no adverse events. 
11.5 STUDY MONITORING AND AUDIT 
An ACCORD Clinical Trials Monitor or an appointed monitor will visit the Investigator site prior 
to the start of the study and during the course of the study if required, in accordance with the 
monitoring plan. Risk assessment will determine if audit, by the ACCORD QA group, is required. 
Details will be captured in an audit plan. Audit of Investigator sites, study management activities 
and study collaborative units, facilities and 3rd parties may be performed.  The CRF QA manager 
will perform audits at key stages of the protocol to ensure compliance with the PISRC decisions. 
12 
GOOD CLINICAL PRACTICE 
12.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 
A favorable ethical opinion will be obtained from the appropriate REC and local R&D approval 
will be obtained prior to commencement of the study. 
12.2 REGULATORY COMPLIANCE 
The study will not commence until a Clinical Trial Authorisation (CTA) is obtained from the 
appropriate Regulatory Authority. The protocol and study conduct will comply with the 
Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. 

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12.3 INVESTIGATOR RESPONSIBILITIES 
The Chief Investigator is responsible for the overall conduct of the study at the site and 
compliance with the protocol and any protocol amendments.  In accordance with the principles 
of ICH GCP, the following areas listed in this section are also the responsibility of the 
Investigator.  Responsibilities may be delegated to an appropriate member of study site staff.   
Delegated tasks must be documented on a Delegation Log and signed by all those named on 
the list prior to undertaking applicable study-related procedures. 
12.3.1 Informed Consent 
The Chief Investigator is responsible for ensuring informed consent is obtained before any 
protocol specific procedures are carried out.  The decision of a participant to participate in 
clinical research is voluntary and should be based on a clear understanding of what is involved. 
Participants must receive adequate oral and written information – appropriate Participant 
Information and Informed Consent Forms will be provided.  The oral explanation to the 
participant will be performed by the Investigator or qualified delegated person, and must cover 
all the elements specified in the Participant Information Sheet and Consent Form. 
The participant must be given every opportunity to clarify any points they do not understand 
and, if necessary, ask for more information.  The participant must be given sufficient time to 
consider the information provided.  It should be emphasised that the participant may withdraw 
their consent to participate at any time without loss of benefits to which they otherwise would 
be entitled. 
The participant will be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor(s) but understand that their name will 
not be disclosed outside the hospital. 
The Investigator or delegated member of the trial team and the participant will sign and date 
the Informed Consent Form(s) to confirm that consent has been obtained.  The participant will 
receive a copy of this document and a copy filed in the Investigator Site File (ISF) and 
participant’s medical notes. 
12.3.2 Study Site Staff 
The Chief Investigator must be familiar with the IMP, protocol and the study requirements.  It is 
the Investigator’s responsibility to ensure that all staff assisting with the study are adequately 
informed about the IMP, protocol and their trial related duties. 
12.3.3 Data Recording 
The Chief Investigator is responsible for the quality of the data recorded in the CRF at each 
Investigator Site. The source data plan identifies which source data correspond to CRF data 
and states which data are recorded directly into the CRF. 
12.3.4 Investigator Documentation 
Prior to beginning the study, each Investigator will be asked to provide particular essential 
documents to the ACCORD Research Governance & QA Office, including but not limited to: 
• 
An original signed Investigator’s Declaration (as part of the Clinical Trial Agreement 
documents); 
• 
Curriculum vitae (CV) signed and dated by the Investigator indicating that it is 
accurate and current. 
• 
Evidence of GCP training within the past two years. 
The ACCORD Research Governance & QA Office will ensure all other documents required by 
ICH GCP are retained in a Trial Master File (TMF), where required, and that appropriate 
documentation is available in local ISFs. 
12.3.5 GCP Training 

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The Chief Investigator has completed GCP training. The clinical research fellows directly 
attached to the study will be required to complete GCP training before the first patient is 
enrolled.  
12.3.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant, except as necessary for monitoring and auditing by the Sponsor, 
its designee, Regulatory Authorities, or the REC. The Chief Investigator and study site staff 
involved with this study may not disclose or use for any purpose other than performance of the 
study, any data, record, or other unpublished, confidential information disclosed to those 
individuals for the purpose of the study. Prior written agreement from the Sponsor or its 
designee must be obtained for the disclosure of any said confidential information to other 
parties. 
12.3.7 Data Protection 
All Investigators and study site staff involved with this study will comply with the requirements 
of the Data Protection Act 1998 with regard to the collection, storage, processing and disclosure 
of personal information and will uphold the Act’s core principles. Access to collated participant 
data will be restricted to those clinicians treating the participants, representatives of the 
sponsor(s) and representatives of regulatory authorities. 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
Published results will not contain any personal data that could allow identification of individual 
participants. 
13 
STUDY CONDUCT RESPONSIBILITIES 
13.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of a urgent safety measure, must be reviewed and 
approved by the Chief Investigator.   
Substantial amendments to the protocol must be submitted in writing to the appropriate REC, 
Regulatory Authority and local R&D for approval prior to participants being enrolled into an 
amended protocol. 
 
Where amendments result in changes to participant information sheets and/or consent forms, 
participants who have already signed a consent form and are still taking part in the trial will be 
asked to review the updated participant information sheets with the research team. Participants 
will be given the opportunity to ask any questions regarding their ongoing participation and will 
be asked to sign an updated consent form if they decide to continue with the study.  
 
13.2 PROTOCOL VIOLATIONS AND DEVIATIONS 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors and 
therefore will not be implemented, except where necessary to eliminate an immediate hazard 
to study participants. If this necessitates a subsequent protocol amendment, this should be 
submitted to the REC, Regulatory Authority and local R&D for review and approval if 
appropriate. 

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Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to the 
sponsors every 3 months. Each protocol violation will be reported to the sponsor within 3 days 
of becoming aware of the violation. 
13.3 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (accord.seriousbreach@ed.ac.uk) must be notified within 24 hours.  
It is the responsibility of the co-sponsors to assess the impact of the breach on the scientific 
value of the trial, to determine whether the incident constitutes a serious breach and take the 
appropriate action. 
13.4 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 15 years from the protocol defined end 
of study point. When the minimum retention period has elapsed, study documentation will not 
be destroyed without permission from the sponsor. 
13.5 END OF STUDY 
In part A, the end of study is defined as 3 days after the last participant’s dosing or the resolution 
of any on going AEs from any participant, whichever is later.  
In part B, the end of the ICU study is defined as 3 days after the delivery of NAP in the last 
patient. 
The Investigators and/or the trial steering committee and/or the co-sponsor(s) have the right at 
any time to terminate the study for clinical or administrative reasons.  
The end of the study will be reported to the REC and Regulatory Authority within 90 days, or 
15 days if the study is terminated prematurely.  The Investigators will inform participants of the 
premature study closure and ensure that the appropriate follow up is arranged for all 
participants involved. 
A summary report of the study will be provided to the REC and Regulatory Authority within 
1 year of the end of the study. 
13.6 CONTINUATION OF DRUG FOLLOWING THE END OF STUDY 
NAP will only be administered once to each participant. 
13.7 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
• 
The Protocol has been designed by the Chief Investigator and researchers employed 
by the University and collaborators.  The University has insurance in place (which 
includes no-fault compensation) for negligent harm caused by poor protocol design 
by the Chief Investigator and researchers employed by the University. 
• 
Sites which are part of the United Kingdom's Nation Health Service will have the 
benefit of NHS Indemnity. 

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14 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
14.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.  On completion of 
the study, the study data will be analysed and tabulated, and a clinical study report will be 
prepared in accordance with ICH guidelines.  
14.2 PUBLICATION 
The clinical study report will be used for publication and presentation at scientific meetings. 
Investigators have the right to publish orally or in writing the results of the study. 
14.3 PEER REVIEW 
The results of the study will be disseminated by peer review publication and presentation at 
national and international meetings. 
15 
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APPENDIX 1: Data Monitoring and Safety Committee