Developmental Clinical Studies-validation of the utility of a novel smartprobe detecting neutrophil activation/elastase activity in acute lung injury

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Inflammation Research

Abstract

40% of all patients in the intensive care unit (ICU) need a ventilator to support their lungs, with many associated complications. Currently the main indication of clinical deterioration is the presence/spreading of shadowing on the chest x- ray. This has many different causes (all requiring different treatments). There is a pressing need for rapid bedside tests to provide definitive diagnostic information about what is happening in the lungs themselves. Many studies have used blood markers, but in patients with multi-system disease these are not specific for the lung and the results are too slow to be useful in the rapidly-changing ICU setting.
We will employ cutting-edge technology to pass a tiny optical fibre deep into the lungs of ventilated patients and spray a 'microdose' of an imaging agent that will tell us the reasons for the lung deterioration. This approach has the potential to rapidly determine, at the bedside, if the lung shadowing is due to inflammation. Such an approach could revolutionise the way we deal with the critically ill patient and provide rapid, point of care diagnostics that would help tailor the patient's management.

Technical Summary

a) Healthcare need addressed:
To allow clinicians in intensive care units (ICU) to rapidly and accurately determine the aetiology of deteriorating respiratory function or clinical status suggested, for example, by new infiltrates on the chest x-ray (CXR).
b) The technology/solution:
We will employ a combined approach utilising recent advances in bronchoscopic confocal imaging for bedside-based, in situ real-time imaging together with the local, microdosed, instillation of next-generation 'smart' molecular probes targeting neutrophil activation (NAP). This will allow patient delineation for specific drug targeting and stratify/inform clinicians immediately for prognosis: specifically the presence and activity of neutrophils.
c)Methodology:
The study will be conducted in two phases. The first involves administering NAP to healthy volunteers with experimental lung inflammation. The second phase moves to a 100-patient clinical study in ICU. NAP will be delivered directly into inflamed lungs and 'heat maps' of pulmonary neutrophil dependent lung injury will be generated by pCLE.
d) Impact on healthcare:
Accurate, dynamic cellular/molecular diagnosis would lead to stratification of patient care and tailored prescribing patterns, including the use/non-use of expensive and potentially toxic anti-bacterials and ultimately reduced ventilator dependency and reduced mortality and morbidity in critically ill patients. This approach is applicable to disease detection/stratification/therapeutic intervention in other organs accessible by fibreoscopy.

Planned Impact

Impacts on Patients, Patient Pathways: Rapid and accurate bedside testing for pulmonary inflammation is a "holy grail" for modern critical care. Currently clinicians are faced with significant uncertainty in relation to triggers to commence treatment, the choice of agents, and especially the clinical confidence to de-escalate therapy. These issues are barriers to effective antibiotic stewardship, because of the proven association between delayed and inadequate antibiotic therapy and adverse clinical outcomes. Direct, bedside pulmonary molecular imaging provides the potential to break this cycle of uncertainty at an early stage, resulting in more appropriate antibiotic use, improved clinical outcomes, and reduced financial burden to healthcare organisations.

Greater characterisation of pulmonary inflammation in real-time provides the potential to target existing and novel therapies and detect early predictors of clinical response. For example, despite negative clinical trials, steroids are widely used in ALI. Smartprobes offer the potential to improve the risk/benefit profile of steroid therapy and other existing and new therapies by enabling cell-specific effects to be measured in the individual patient. Similar approaches have been proposed for sepsis therapies based on point-of-care blood tests, but these have flaws (outlined above) and our proposed technology is a novel approach to directly characterise disease and its response to therapy deep in the human lung; the organ failing most frequently during critical illness.

A quantitative estimate of the scale of potential benefits at a population level is difficult to assess but given that 40% of all ventilated patients have a diagnosis of ALI/ARDS and there are no current strategies for monitoring therapeutic efficacy of interventions or stratifying patients, this technology offers a unique opportunity to ICU, and the potential healthcare benefits are likely to be considerable. Given the unmet need in ICU, we foresee no major barriers to the translation of this technology in multi-centre trials and subsequent widespread clinical application. The equipment is truly 'bedside' and the proposed programme of research will generate sufficient quantities of each probe to study up to 10,000 patients.

Pharma are actively interested in screening drugs in in vivo, hence a major impact will be on the provision of cutting-edge assays to assess drug response in situ in patients with lung disease.

Regarding wealth formation for the public, there is a direct opportunity to take the products of this research into a new small business enterprise and create jobs to develop similar molecular optical imaging probes using the same development pathway. This technological approach to apply cutting-edge chemistry with state of the art physics to detect optical molecular signatures deep within human tissue in critically ill patients is internationally unique and brings significant scientific impact and prestige to the multidisciplinary UK team and health service framework prosecuting the work.

Publications

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Barr LC (2013) A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation. in American journal of respiratory and critical care medicine

 
Description IRC award (Bradley/Dhaliwal/Haslett)
Amount £11,600,000 (GBP)
Funding ID EP/K03197x/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2018
 
Description Cleveland Clinic 
Organisation Cleveland Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution Developing a collaborative partnership to expedite the implementation of optical molecular imaging in the USA and in particular in respiratory medicine. Exchanging ideas, projects and clinical protocols for the Cleveland Clinic to begin initiating an optical imaging programme in Respiratory Medicine using imaging agents developed in Edinburgh
Collaborator Contribution Access to patients and clinical network input to initiate clinical trials.
Impact The Cleveland Clinic has successfully received an eIND from the FDA to perform clinical studies using imaging agents that have been developed by the team at Edinburgh.
Start Year 2015
 
Description Guys 
Organisation Guy's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Developing a sterile fill collaboration with the Guys NIHR facility
Collaborator Contribution Providing academic rates for sterile fill GMP production so that we can complete clinical studies
Impact Successful GMP manufacture of optical imaging agents for clinical trials
Start Year 2014
 
Description Mauna Kea Technologies 
Organisation Mauna Kea Technologies
Country France 
Sector Private 
PI Contribution Developing a delivery catheter to deliver optical imaging agents to the distal lung. We tested prototypes, contributed to the risk assessment and also are performing the initial clinical trials of the catheter
Collaborator Contribution Manufacture, quality management systems , sterility validation
Impact Development and delivery of 40 clinical catheters to our group.
Start Year 2013
 
Description UMCG- Netherlands 
Organisation University Medical Center Gronigen
Country Netherlands 
Sector Hospitals 
PI Contribution Access to our imaging reagents developed in Edinburgh to the critical care team in Groningen.
Collaborator Contribution Clinical network and also help in clinical protocol development.
Impact No outputs yet, as collaboration just initiated
Start Year 2015
 
Title Optical imaging probes 
Description The present invention relates to methods of visualising cells especially although not exclusively in vivo using a dye, such as a dendrimer-dye molecule or polybranched-dye molecule which is internalised by the cells and thus permits subsequent visualisation by confocal fluorescence endomicroscopy or other optical detectors. There is also provided internally quenched probes for use in visualising cells especially although not exclusively in vivo by confocal fluorescence endomicroscopy and the use of internally quenched probes in combination with confocal fluorescence endomicroscopy, for visualising cells by virtue of internalisation and dequenching of a probe by the cells. In a particular embodiment the cells are activated neutrophils, such as within the lung of a subject. 
IP Reference WO2012136958 
Protection Patent granted
Year Protection Granted 2011
Licensed No
Impact 1) LICENSING Advanced discussions have taken place with a licensing agreement drafted and under review by Edinburgh Molecular Imaging (www.edinimage.com). The University of Edinburgh has agreed a heads of terms for the licensing deal. 2) CLINICAL STUDIES As well as the current ICU study, there are two other clinical studies with NAP A) In Lung Cancer to identify tumour associated neutrophils in Edinburgh B) In the Cleveland Clinic in USA. A FDA IND has been filed in the USA from the Cleveland Clinic for the use of NAP in the ICU 3) COLLABORATIONS 1) GSK have sponsored 2 PhD students to develop NAP imaging for inflammatory
 
Title NAP 
Description Currently undergoing phase 2 evaluation in the ICU. Ethics and sponsor risk assessments approved for a repeat dose delivery to ventilated incapacitated patients in the ICU A repeat dose GLP toxicology assessment has been completed with no toxicology concerns. NAP was delivered to rats at 700X human dose for 7 consecutive days intratracheally with no toxicology findings Stability of the drug product now shows it has a 2 year shelf life at room temperature. Successful GMP manufacture of the drug product by the Guys NIHR Sterile fill unit. Principal source of development is the MRC award. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact International patent protection in all territories being pursued Spin out of Edinburgh Molecular Imaging 
URL https://clinicaltrials.gov/show/NCT01532024
 
Title SNAP-IT 
Description Critically ill patients often succumb to acute respiratory disease. The lungs are the commonest organ to fail and require support in the ICU environment. However, no accurate bedside methodologies exist that permit the delineation of potential causes of respiratory deterioration in patients. One example of severe acute respiratory disease is a condition known as acute respiratory distress syndrome (ARDS). It can occur as a result of numerous different causes, confers a high risk of death and resists the majority of pharmacological therapies tested so far. We know that current methods of accurately diagnosing and stratifying ARDS in patients may erroneously include patients that don't have the condition and miss some that do, as well as not reflecting severity accurately enough. By using the field of optical molecular imaging and employing novel techniques and technologies, we hope to demonstrate here that a bespoke chemical probe administered in very small doses directly into the distal lung can rapidly and accurately detect activated neutrophils in the distal lung, cells of the immune system that are implicated in the development of this severe condition and so work towards a bedside test which could be used to diagnose, monitor and stratify patients who are critically ill in the future. A larger Phase III regulated clinical study will follow this exploratory study in order to determine if NAP can diagnose ARDS and inform clinical decisions. This Phase II Clinical Trial of Investigational Medicinal Product is designed to investigate the characteristics and performance of a new test (NAP/FE) in ventilated patients in order to justify and design any future work. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status On hold
Clinical Trial? Yes
Impact The SNAP-IT Phase II study described in this protocol aims to further test the clinical application of this tool primarily through demonstrating the reliability of the technique but also importantly in terms of its ability to predict and stratify the severity and outcome from critical respiratory illness. Whilst the technique cannot currently be used to inform clinical decisions, we hope, with the results of this study, to move to trials where it does inform clinical decision and so move forward towards personalised medicine, where a biological picture of a particular patient can be built up and therapy can be tailored to their individual needs. Recruitment to this Phase II study will not proceed until the completion of the first-in-human study. 
URL https://clinicaltrials.gov/show/NCT02804854
 
Title Triple Lumen Bronchoscopic Delivery Device 
Description This device was developed with Mauna Kea Technologies as part of a MICA award from the DCS award. The catheter has gone through extensive testing and has now been delivered to Edinburgh for clinical testing. It is a unique triple lumen catheter that is less than 1.7 mm in diameter and can access the working channel of the bronchoscope. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact New collaboration with the University of Utah - Professor Bob Hitchcock. Dept of Engineering. Novel applications have led to GSK being interested in using the device for pulmonary drug deposition studies and a GSK investigator led study is now being planned. 
 
Company Name Edinburgh Molecular Imaging 
Description SME that is focussing on Optical Molecular Imaging and the rapid commercialisation of in vivo optical imaging agents for human disease 
Year Established 2014 
Impact Raised £4M Series A. Awarded Innovate UK award.
Website http://www.edinimage.com