Exploratory Clinical Study of Neutrophil Activation Probe (NAP) for Optical Molecular Imaging in Human Lungs
Condition: Acute Lung Injury
MeSH terms: Lung Injury; Acute Lung Injury
Study type: Interventional
Phase: Early Phase 1

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) 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.
    

Detailed description: 
      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.
    

Intervention name(s): Microdose of NAP
Intervention type(s): Other
Intervention description(s): Delivery of NAP at microdose (<100mcg) by direct pulmonary administration followed by fibreoptic confocal microendoscopy
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Optical Imaging; Neutrophil; Elastase; Molecular Imaging; Acute Lung Injury; ARDS