Title: RaPIDE – RAman Probe for In-vivo Diagnostics (during oesophgeal) Endoscopy.
Funder: Department of Health and Social Care

Abstract: We have a probe design (patent submitted) that can be manufactured using rapid prototyping methods. We have demonstrated an assembly method that allows swift production. The study will be split into five work packages: WP1 Probe optimization M0-6 In collaboration with our ISO 13485 accredited manufacturer (ITL) we will optimise the probe design to suit their production facilities. We will transfer the knowledge of our existing assembly methods and modify the assembly process in the light of input from the manufacturer. We will agree testing and quality criteria to be fulfilled at each stage of component procurement and production. We will commence component procurement and make initial tests on those components. We will define the sterilisation process to be used and construct dummy probes for bioburden tests to validate that process. Furthermore, we will perform an endoscope usability test to ensure smooth ergonomic action of the probes in conjunction with endoscopic functionality. WP2 Preparatory Steps for In vivo study: Probe manufacture and testing M7-12 / Regulatory (MHRA) and ethical approvals M7-18 We will build and test our optimised probes, based on our existing manufacturing methods, to enable accurate, reproducible production of the confocal probes. If probes can be cheaply and reproducibly made then they would be effectively disposable which is preferred for infection control purposes (British Society of Gastroenterology 2014 Working Party Guidance). WP2 will include the manufacture and testing of 50 disposable endoscopic probes; testing quality of signals and their reproducibility; small ex vivo sampling tests ensuring signals are of similar quality to those obtained using our prototype design. We will work with our manufacturers and regulatory consultant to make submissions for MHRA and LREC approvals. Milestone1: Functioning reproducible probes (n=50) (M12) Milestone2: Regulatory and ethical approvals gained (M18) WP3 In vivo feasibility and safety evaluation (Months 19-21) We will test the technique for safety and practical implementation on volunteer patients (n=5). This will include basic safety for the patient and operator; logistics and ergonomics; tissue biochemical signal to noise versus time and location; basic signal reproducibility evaluation. Milestone3: Safe in vivo measurements (M21) WP4 In vivo observational study (Months 22-27) We will undertake an in vivo observational study (n=40 patients). This is in effect the qualification phase for our developmental pathway. During this work package we will undertake an in vivo observational study to collect paired biopsies and in vivo Raman spectra to ensure we are able to replicate the biochemical signals we have measured ex vivo, thus providing sufficient evidence (that the approach would provide in vivo real-time discrimination of disease) to lead us to undertake further in vivo clinical trials. Participants/Sampling: We will recruit 40 patients from routine upper-GI endoscopy lists at GHs following informed written consent. GHs is a tertiary referral centre for Barrett s dysplasia patients, 4-500 undergoing surveillance per annum. During endoscopy, the extent of disease will be assessed visually by the endoscopist. Then the Raman probe will be passed down the standard biopsy channel of an endoscope, Raman spectra will be measured at the tissue surface in 1-2 seconds and a biopsy taken of the same location to send for routine histopathology. Aim to compare the endoscopy-only dysplasia score versus Raman versus histopathology from the same points at quadrant biopsies throughout Barrett s region. Milestone4: In vivo evidence of disease specific biochemical signals (M30). WP5 Pathway to commercialisation (Months 18-30) In parallel with in vivo clinical studies, health economic and commercial viability evaluations will be undertaken. The in vivo work will demonstrate the performance levels and relative costs of the approaches to enable evidence of healthcare utility and impact to be established.

Lay abstract: Background Cancer of the Oesophagus is the 5th most common cancer [CRUK 2015] and is one of the most likely to cause death, with around 15% of patients surviving 5 years from their first diagnosis. It is often discovered so late that successful treatment is very distressing, dangerous and difficult. We have already shown that it is possible to tell the difference between healthy and diseased tissue in the laboratory by looking at the light emitted by tissue when we shine a low power laser on to it. We intend to use this technique, known as &ldquo;Raman Spectroscopy&rdquo; to tell if tissue in the oesophagus is cancerous, healthy or at some stage before full blown cancer, which we term pre-cancer. We have shown in the laboratory that this method will be at least as accurate as the conventional methods used now, but will provide the surgeon with instant results without the delay and cost of a laboratory analysis by pathologists. We have designed a miniature probe that slides through a channel in the endoscope (telescope) to the surface of the oesophagus to make near instant assessments of its condition without the need for expensive and distressing tissue removal (biopsies). In this project we plan to move this technique from the laboratory to the clinic by demonstrating that the method is safe and reliable for use in real patients. We hope that this approach will provide doctors with a new way of finding and diagnosing cancers and pre-cancers at the earliest possible time; when treatments are likely to be more successful and less radical. AIMs To demonstrate that we can measure early cancerous changes in the lining of the oesophagus using our novel device. To demonstrate that the approach is quick and safe. To develop an understanding of how the new technique will improve diagnosis and care over and above current methods. To evaluate the cost benefits to the NHS. DESIGN & METHODS Our project is split into 5 packages of work: 1) Optimisation of the probe design and manufacture to result in low cost, disposable devices. 2) Probe production and regulatory approval for safe use. 3) Undertake first-in-man studies. Establish the safety and ease of use of our probes during an endoscopy procedure. 4) In vivo observational study - Collect evidence of the accuracy - provide justification for further large-scale clinical trials. 5) Establish routes to commercialise device. PPI Involvement We plan to engage with local oesophageal patients to monitor project progress and to develop written material for this study. We will run public events to share the aims of the project towards the start of the project & results as the work progresses. Dissemination Plan We plan to publish the results of the study in peer reviewed clinical & scientific journals (once any intellectual property has been protected, allowing us to develop a commercial product). The work will be presented at international, national and local clinical and scientific meetings. As stated above, we will run various PPI communication events.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS