Exploratory Clinical Study of Neutrophil Activation Probe (NAP) for Optical Molecular Imaging in Human Lungs (NAP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01532024
Recruitment Status : Unknown
Verified January 2016 by University of Edinburgh.
Recruitment status was:  Recruiting
First Posted : February 13, 2012
Last Update Posted : January 20, 2016
Medical Research Council
Information provided by (Responsible Party):
University of Edinburgh

Brief 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.

Condition or disease Intervention/treatment Phase
Acute Lung Injury Other: Microdose of NAP Early Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
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
Study Start Date : October 2014
Estimated Primary Completion Date : May 2016

Arm Intervention/treatment
Experimental: Healthy Volunteers
Delivery of intrapulmonary NAP Dose escalation from 5 mcgs to 80mcgs
Other: Microdose of NAP
Delivery of NAP at microdose (<100mcg) by direct pulmonary administration followed by fibreoptic confocal microendoscopy
Experimental: Pulmonary Infiltrate in ICU
Delivery of NAP (80mcgs) to ventilated patients with pulmonary infiltrates
Other: Microdose of NAP
Delivery of NAP at microdose (<100mcg) by direct pulmonary administration followed by fibreoptic confocal microendoscopy
Experimental: Patients with Bronchiectasis
Delivery of NAP (80mcgs) to patients with bronchiectasis
Other: Microdose of NAP
Delivery of NAP at microdose (<100mcg) by direct pulmonary administration followed by fibreoptic confocal microendoscopy

Primary Outcome Measures :
  1. Image Neutrophil activity [ Time Frame: 15 minutes ]
    Fluorescent amplification of NAP upon exposure to activated neutrophils in lungs of patients with Acute Lung Injury

Secondary Outcome Measures :
  1. Safety [ Time Frame: Within 24 hours of delivery of NAP ]
    Absence of any adverse events

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • PART A: healthy male volunteers aged between 18 and 40.
  • PART B: Ventilated patients over the age of 18 in on ITU with pulmonary infiltrate
  • PART C: Male patients diagnosed with bronchiectasis over the age of 18

Exclusion criteria for part A:

  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:VC 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

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

Exclusion criteria for Part C

  1. Age <18years
  2. Any contraindication with bronchoscopy
  3. Refusal for aprticipation by attending consultant
  4. Recent pneumothorax (last 4 weeks)
  5. Myocardial infarction within preceding 4 weeks
  6. Any history of previous reactions to fluorescein or any other anaphylaxis
  7. Participation in any other interventional study or less than three months since their last participation in an interventional study.
  8. Female

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01532024

Contact: Kevin Dhaliwal, MD

United Kingdom
Ward 118, Intensive Care, Royal Infirmary of Edinburgh Recruiting
Edinburgh, Scotland, United Kingdom, EH16 4TJ
Principal Investigator: Timothy Walsh, MD         
Wellcome Trust Clinical Research Facility Completed
Edinburgh, United Kingdom, EH16 4SA
Royal Infirmary of Edinbrugh Recruiting
Edinburgh, United Kingdom
Contact: Kev Dhaliwal, PhD         
Sponsors and Collaborators
University of Edinburgh
Medical Research Council
Study Director: Kev Dhaliwal, MD University of Edinburgh
Principal Investigator: David Newby, MD University of Edinburgh
Study Chair: Chris Haslett, MD University of Edinburgh
Principal Investigator: Tim Walsh, MD University of Edinburgh

Responsible Party: University of Edinburgh Identifier: NCT01532024     History of Changes
Other Study ID Numbers: NAP
2011-006169-17 ( EudraCT Number )
First Posted: February 13, 2012    Key Record Dates
Last Update Posted: January 20, 2016
Last Verified: January 2016

Keywords provided by University of Edinburgh:
Optical Imaging
Molecular Imaging
Acute Lung Injury

Additional relevant MeSH terms:
Lung Injury
Acute Lung Injury
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiratory Tract Diseases
Thoracic Injuries
Wounds and Injuries
Respiration Disorders