Clinical trial NCT06079970: Confocal Laser Endomicroscopy VERification
Official title: Bronchoscopy With and Without Needle-based Confocal Laser Endomicroscopy for Peripheral Lung Nodule Diagnosis: Protocol for a Multicenter Randomized Controlled Trial (CLEVER Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Lung Cancer
Lung Neoplasm Malignant
Carcinoma, Non-Small-Cell Lung
Neoplasm of Lung
Keywords: Confocal Microscopy
Bronchoscopy
Confocal laser endomicroscopy
CLE
Fluoroscopy
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Mauna Kea Technologies
First posted: 2023-10-12
Enrollment: 208
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: 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: 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).

Eligibility criteria: Inclusion Criteria:

1. ≥18 years of age
2. Suspected malignant peripheral lung lesion with an indication for a bronchoscopic diagnostic work-up as determined by the attending physician or tumor board. Peripheral pulmonary lesions are defined as lesions located beyond the visible segmental bronchi, not detectable by regular flexible bronchoscopy
3. Bronchus sign on pre-procedural CT or estimated confidence for successful navigation to the nodule resulting in a r-EBUS signal
4. Solid part of the lesion must be ≧10 mm
5. Largest dimension of lesion size on CT ≦30 mm (long-axis)
6. Ability to understand and willingness to sign a written informed consent

Exclusion Criteria:

1. Inability or non-willingness to provide informed consent
2. Endobronchial visible malignancy on bronchoscopic inspection
3. Target lesion within reach of the linear EBUS scope
4. Failure to comply with the study protocol
5. Known allergy or risk factors for an allergic reaction to fluorescein
6. Pregnancy or breastfeeding
7. Hemodynamic instability
8. Refractory hypoxemia
9. Therapeutic anticoagulant use that cannot be withheld for an appropriate interval before the procedure
10. Unable to tolerate general anesthesia according to the anesthesiologist
11. Undergoing chemotherapy as several chemotherapies have fluorescent properties at the same wavelength (e.g., doxorubicin)

Primary outcomes:
measure: Diagnostic yield (intermediate definition)
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
Secondary outcomes:
measure: Diagnostic sensitivity
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
measure: Diagnostic yield (strict definition)
timeFrame: After all patients have been included (expected total time frame 2 years)
measure: Procedure duration
timeFrame: During procedure (bronchoscopy)
measure: Proportion needle repositionings and fine-tuning
timeFrame: During procedure (bronchoscopy)
measure: Fluoroscopy time/dose
timeFrame: During procedure (bronchoscopy)
measure: Yield ROSE
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
measure: ROSE tool-in-lesion
timeFrame: During procedure (bronchoscopy)
measure: Complication rate
timeFrame: Up to 1 week after bronchoscopy
measure: Additional diagnostics needed
timeFrame: Up to 6 months after index bronchoscopy
measure: Diagnostic yield subgroup analysis (stratified by lesion size in mm)
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
measure: Diagnostic yield subgroup analysis (stratified rEBUS visibility)
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
measure: Diagnostic yield subgroup analysis (stratified by location in the lung)
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
measure: Diagnostic yield subgroup analysis (stratified by Brock score)
timeFrame: After all patients have been included and followed up to 6 months after bronchoscopy (expected total time frame 2 years)
Other outcomes:
Locations:
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Vienna
country: Austria
facility: Vienna General Hospital
city: Prague
country: Czechia
facility: General University Hospital Prague
city: Athens
country: Greece
facility: Sotiria Hospital
city: Forlì
country: Italy
facility: Morgagni Pierantoni Hospital
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centers
city: Basel
country: Switzerland
facility: University Hospital basel
Study officials:
affiliation: Amsterdam UMC
name: Jouke Annema, Prof. dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wijmans L, Yared J, de Bruin DM, Meijer SL, Baas P, Bonta PI, Annema JT. Needle-based confocal laser endomicroscopy for real-time diagnosing and staging of lung cancer. Eur Respir J. 2019 Jun 20;53(6):1801520. doi: 10.1183/13993003.01520-2018. Print 2019 Jun.
citation: Kramer T, Wijmans L, van Heumen S, Bansal S, Jeannerat D, Manley C, de Bruin M, Bonta PI, Annema JT. Needle-based confocal laser endomicroscopy for real-time granuloma detection. Respirology. 2023 Oct;28(10):934-941. doi: 10.1111/resp.14542. Epub 2023 Aug 10.
citation: Manley CJ, Kramer T, Kumar R, Gong Y, Ehya H, Ross E, Bonta PI, Annema JT. Robotic bronchoscopic needle-based confocal laser endomicroscopy to diagnose peripheral lung nodules. Respirology. 2023 May;28(5):475-483. doi: 10.1111/resp.14438. Epub 2022 Dec 19.
citation: Kramer T, Wijmans L, de Bruin M, van Leeuwen T, Radonic T, Bonta P, Annema JT. Bronchoscopic needle-based confocal laser endomicroscopy (nCLE) as a real-time detection tool for peripheral lung cancer. Thorax. 2022 Apr;77(4):370-377. doi: 10.1136/thoraxjnl-2021-216885. Epub 2021 Jun 25.
citation: Vachani A, Maldonado F, Laxmanan B, Kalsekar I, Murgu S. The Impact of Alternative Approaches to Diagnostic Yield Calculation in Studies of Bronchoscopy. Chest. 2022 May;161(5):1426-1428. doi: 10.1016/j.chest.2021.08.074. Epub 2021 Sep 7. No abstract available.