Acute Lung Injury Clinical Trial
Official title:
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
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) that detects activated
neutrophils and also the damaging enzyme, human neutrophil elastase (HNE). The investigators
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.
The investigators 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 pulmonary infiltrates and 6 patients known to have
bronchiectasis.
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.
In the bronchiectasis study, patients will be recruited from the respiratory service in NHS
Lothian.
If the study (which is supported by the Medical Research Council) demonstrates safety and
also the ability to image activated neutrophils, the investigators intention is to design
future studies in patients with ALI.
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. The
investigators 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 in any organ accessible to endoscopy.
The primary end-point will be a proof of concept demonstration that this technique can be
used to visualise activated neutrophils over background autofluorescence. Other end points
include safety. The investigators shall also assess alveolar (by bronchoscopy) neutrophil
activation and elastase activity in patients. Demonstration of activated neutrophils by pCLE
in ICU would be expected to lead directly to clinical trials in patients with ALI/ARDS.
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