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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2012 by University of Edinburgh.
Recruitment status was  Not yet recruiting
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
University of Edinburgh
ClinicalTrials.gov Identifier:
NCT01532024
First received: January 12, 2012
Last updated: August 24, 2012
Last verified: January 2012
  Purpose

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 6 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.

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 Intervention Phase
Acute Lung Injury
Other: Microdose of NAP
Phase 0

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University of Edinburgh:

Primary Outcome Measures:
  • Image Neutrophil activity [ Time Frame: 15 minutes ] [ Designated as safety issue: No ]
    Fluorescent amplification of NAP upon exposure to activated neutrophils in lungs of patients with Acute Lung Injury


Secondary Outcome Measures:
  • Safety [ Time Frame: Within 24 hours of delivery of NAP ] [ Designated as safety issue: Yes ]
    Absence of any adverse events


Estimated Enrollment: 12
Study Start Date: August 2012
Estimated Study Completion Date: January 2013
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: Acute Lung Injury in ICU
Delivery of NAP (10mcgs) to ALI/ARDS
Other: Microdose of NAP
Delivery of NAP at microdose (<100mcg) by direct pulmonary administration followed by fibreoptic confocal microendoscopy

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 safety in a healthy volunteer study. The investigators shall also assess alveolar (by bronchoscopy) neutrophil activation and elastase activity in 6 ICU patients. Demonstration of activated neutrophils by pCLE in ICU would be expected to lead directly to clinical trials in patients with ALI/ARDS.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • PART A: healthy male volunteers aged between 18 and 40.
  • PART B: All male ventilated patients in ward 118 over the age of 18 with unilateral infiltrates on CXR

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01532024

Contacts
Contact: Kevin Dhaliwal, MD kdhaliwa@staffmail.ed.ac.uk

Locations
United Kingdom
Ward 118, Intensive Care, Royal Infirmary of Edinburgh Not yet recruiting
Edinburgh, Scotland, United Kingdom, EH16 4TJ
Principal Investigator: Timothy Walsh, MD         
Wellcome Trust Clinical Research Facility Not yet recruiting
Edinburgh, United Kingdom, EH16 4SA
Principal Investigator: Kev Dhaliwal, MD         
Principal Investigator: David Newby, MD         
Sponsors and Collaborators
University of Edinburgh
Medical Research Council
Investigators
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
  More Information

No publications provided

Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT01532024     History of Changes
Other Study ID Numbers: NAP-001, 2011-006169-17
Study First Received: January 12, 2012
Last Updated: August 24, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee
United Kingdom: National Health Service

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

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

ClinicalTrials.gov processed this record on September 18, 2014