Confocal Laser Endomicroscopy VERification

Study Overview
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Brief Summary
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The goal of this multi-center randomized clinical trial is to evaluate the added value of needle based confocal laser endomicroscopy (nCLE)-imaging to regular diagnostic bronchoscopic peripheral lung lesion analysis on the diagnostic yield in patients with peripheral pulmonary nodules suspect for malignancy. The main question[s] it aims to answer are: To determine if the addition of nCLE-imaging to conventional diagnostic bronchoscopic peripheral lung lesion analysis results in an improved diagnostic yield (defined as the proportion of patients in whom the bronchoscopic procedure results in a definitive diagnosis out of the total number of patients that have received the diagnostic bronchoscopic procedure). Participants will undergo diagnostic bronchoscopy either with or without the addition of nCLE imaging before each TBNA. Based on the feedback of the CLE images on (in)correct placement of the needle, the needle might be repositioned before sampling. Comparison between the diagnostic yield of these groups will be done including subgroup analysis.

Detailed Description
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Rationale: Lung cancer screening and the increasing use of chest-computed tomography (CT) has led to an increase in the number of (incidental) found suspected malignant lung lesions. Since tissue acquisition for pathological analysis is prerequisite for diagnosis and optimal treatment, a drastic increase in the number of patients that need to undergo bronchoscopy is expected. Over 70% of the suspected lesions develop in the periphery of the lung and are therefore not visible during conventional bronchoscopy. Although several bronchoscopic navigational techniques demonstrated an improved navigation towards the target lesion, the diagnostic yield remains suboptimal due to a substantial near-miss rate. As a result, the need for complementary bronchoscopic guidance that provides real-time feedback on the correct positioning of the biopsy instruments is urgent. Needle-based Confocal laser endomicroscopy (nCLE) is a novel high-resolution imaging technique that uses an excitation laser light to create 'real-time' microscopic images of tissues. nCLE can be integrated into the biopsy needle, allowing real-time cancer detection at the tip of the biopsy needle during bronchoscopy. The confocal microscope captures autofluorescence of tissues or, combined with intravenously (IV) infused fluorophores (such as fluorescein) allows imaging of individual tumor cells. Recent studies on nCLE-imaging in lung tumors and metastatic lymph nodes have identified and validated nCLE criteria for malignancy (enlarged pleomorphic cells, dark clumps and directional streaming) and airway/lung parenchyma (alveoli, elastin fibres of the conducting airway, bronchial epithelium and still image) and granulomas. A recent study demonstrated that these nCLE-criteria can be used in real-time to fine-tune the needle positioning during ongoing bronchoscopy and thereby potentially improve the diagnostic yield. This randomized controlled trials aims to evaluate the added value of nCLE-imaging (smart needle) to the conventional used bronchoscopic approach for peripheral lung lesion analysis. Objective: This multicenter, randomized controlled trial, aims to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared to conventional bronchoscopy without nCLE in the diagnosis of peripheral lung nodules. Study design: Investigator-initiated, international, multi-center randomized controlled trial including university and general hospitals. Study population: Patients (>18 years old) with suspected malignant peripheral lung lesions with an indication for bronchoscopic analysis. Procedure: Bronchoscopy will be performed according to institutional practice, including radial endobronchial ultrasound (r-EBUS) and optionally fluoroscopy, electromagnetic navigation, virtual bronchoscopy and/or ultrathin bronchoscopy. This is followed by transbronchial needle aspiration (TBNA) and (cryo-)biopsies (control arm). In the study arm, nCLE-imaging will be added prior to TBNA tissue acquisition to fine-tune the sampling area. Cytology staining for rapid onsite evaluation (ROSE) and cellblock will be performed according to local practice. Primary objective: To determine if the addition of nCLE-imaging to conventional bronchoscopic peripheral lung lesion analysis results in an improved diagnostic yield. (defined as the proportion of patients in whom the bronchoscopic procedure results in a definitive diagnosis out of the total number of patients that have received the diagnostic bronchoscopic procedure).

Official Title
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nCLE-guided Bronchoscopy for Peripheral Lung Cancer Diagnosis; a Randomized Controlled Trial

Conditions
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Lung Cancer, Lung Neoplasm Malignant, Carcinoma, Non-Small-Cell Lung, Neoplasm of Lung

Intervention / Treatment
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* Device: Neelde Based Confocal Laser Endomicroscopy
* Procedure: Conventional diagnostic bronchoscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Suspected malignant peripheral lung lesion with an indication for a bronchoscopic diagnostic work-up Solid part of the lesion must be >10 mm Largest dimension of lesion size on CT equal to or less than 30 mm Positive bronchus sign on pre-procedural CT-scan: in case no airway leads to the target lesion, our expectations are that the chance of reaching the lesion with a conventional bronchoscope are very low and therefore not suitable for study participation Ability to understand and willingness to sign a written informed consent Exclusion Criteria: Inability or non-willingness to provide informed consent Patients with an endobronchial visible lung tumor on bronchoscopic inspection Patients in which the target lesion is within reach of the linear EBUS scope Failure to comply with the study protocol Patients with known allergy for fluorescein or risk factors for an allergic reaction Pregnant or breastfeeding women Patients with hemodynamic instability Patients with refractory hypoxemia Patients with a therapeutic anticoagulant that cannot be held for an appropriate interval before the procedure Patients who are unable to tolerate anesthesia according to the anesthesiologist Patient undergoing chemotherapy as several chemotherapies have fluorescent properties at the same wavelength (e.g. doxorubicin)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nCLE arm<br>Diagnostic bronchoscopy is done according to institutional practice with the addition of nCLE | Device: Neelde Based Confocal Laser Endomicroscopy<br>* Confocal microscopy through the TBNA needle before tissue sampling using the Cellvizio system and AQ flex probe (Mauna Kea Technologies)<br>Procedure: Conventional diagnostic bronchoscopy<br>* Conventional diagnostic bronchoscopy with r-EBUS and optionally fluoroscopy AND/OR EMN AND/OR VB AND/OR ultrathin scope<br>|
| Active Comparator: Control arm<br>Diagnostic bronchoscopy is done according to institutional practice without the addition of nCLE | Procedure: Conventional diagnostic bronchoscopy<br>* Conventional diagnostic bronchoscopy with r-EBUS and optionally fluoroscopy AND/OR EMN AND/OR VB AND/OR ultrathin scope<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic yield (intermediate definition) | Diagnostic yield (defined as the proportion of patients in whom the bronchoscopic procedure results in a definitive diagnosis (either malignant, specific benign or non-specific benign confirmed as benign in follow-up), relative to the total number of patients that underwent the diagnostic bronchoscopic procedure). In case patients with multiple lesions are included, diagnostic yield will be computed both per nodule. | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic sensitivity | Diagnostic sensitivity for malignancy (defined as the proportion of patients in whom the bronchoscopic procedure diagnoses malignancy, relative to the total number of patients with a final diagnosis of malignancy as determined by the reference standard). | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 
| Procedure duration | Procedure duration (from bronchoscope insertion until removal) | During procedure (bronchoscopy) | 
| Proportion needle repositionings and fine-tuning | Percentage of patients in which the needle was fine-tuned (defined as moving the needle within the same distal airway) or repositioned (defined as the selection of a different distal airway for tissue sampling) based on nCLE feedback (defined as the number of patients the needle was fine-tuned/repositioned divided by the total number of patients in which nCLE imaging was used). | During procedure (bronchoscopy) | 
| Diagnostic yield subgroup analysis (stratified by lesion size in mm) | To assess the diagnostic yield (primary outcome) for two subgroups (<20 mm vs ≥20 mm) | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 
| Diagnostic yield subgroup analysis (stratified rEBUS visibility) | To assess the diagnostic yield (primary outcome) for three subgroups (eccentric vs concentric vs absent) | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 
| Diagnostic yield subgroup analysis (stratified by location in the lung) | To assess the diagnostic yield (primary outcome) for three subgroups (upper lobe (without lingual) vs middle lobe/lingual vs lower lobe) | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 
| Diagnostic yield subgroup analysis (stratified by Brock score) | To assess the diagnostic yield (primary outcome) for three subgroups (Brock score <10%, 10 - 35%, 36-70% and >70%) | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 
| Fluoroscopy time/dose | Fluoroscopy time/dose | During procedure (bronchoscopy) | 
| Yield ROSE | To assess the diagnostic yield of rapid on-site evaluation (ROSE) (defined as the proportion of patients in whom ROSE resulted in a classifying diagnosis (malignant or specific benign diagnosis), relative to the total number of patients). | After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years) | 
| ROSE tool-in-lesion | Proportion of patients in which ROSE provided tool-in-lesion confirmation, meaning that the acquired tissue shows signs of a malignant or non-malignant diagnosis and was not related to airway/lung parenchyma sampling such as bronchus epithelium/blood contamination, and tissue not suitable for a specific diagnosis such as atypical cells. | During procedure (bronchoscopy) | 
| Complication rate | Complication rate (defined as any complication occurring during or directly after the bronchoscopic procedure or any procedure-related complication in the follow-up period). | Up to 48 hours after bronchoscopy | 
| Additional diagnostics needed | Requirement of additional diagnostic procedures (CT-guided transthoracic biopsies, surgical diagnostics and/or additional bronchoscopy) during the 6-month follow-up period. | Up to 6 months after index bronchoscopy | 
| Diagnostic yield (strict definition) | Diagnostic yield according to the strict definition (defined as the proportion of patients in whom the bronchoscopic procedure results in a definitive diagnosis (either malignant or specific benign diagnosis), relative to the total number of patients that underwent the diagnostic bronchoscopic procedure). | After all patients have been included (expected total time frame 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluoroscopy, Confocal Microscopy, Bronchoscopy, Confocal laser endomicroscopy, CLE