Confocal Laser Endomicroscopy VERification

NCT ID: NCT06079970

Last Updated: 2025-04-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 208 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-18
• Study Completion Date: 2025-10-18

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).

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

nCLE arm

Diagnostic bronchoscopy is done according to institutional practice with the addition of nCLE

Group Type: EXPERIMENTAL

Neelde Based Confocal Laser Endomicroscopy

Intervention Type: DEVICE

Confocal microscopy through the TBNA needle before tissue sampling using the Cellvizio system and AQ flex probe (Mauna Kea Technologies)

Conventional diagnostic bronchoscopy

Intervention Type: PROCEDURE

Conventional diagnostic bronchoscopy with r-EBUS and optionally fluoroscopy AND/OR EMN AND/OR VB AND/OR ultrathin scope

Control arm

Diagnostic bronchoscopy is done according to institutional practice without the addition of nCLE

Group Type: ACTIVE_COMPARATOR

Conventional diagnostic bronchoscopy

Intervention Type: PROCEDURE

Conventional diagnostic bronchoscopy with r-EBUS and optionally fluoroscopy AND/OR EMN AND/OR VB AND/OR ultrathin scope

Interventions

Neelde Based Confocal Laser Endomicroscopy

Confocal microscopy through the TBNA needle before tissue sampling using the Cellvizio system and AQ flex probe (Mauna Kea Technologies)

Intervention Type: DEVICE

Conventional diagnostic bronchoscopy

Conventional diagnostic bronchoscopy with r-EBUS and optionally fluoroscopy AND/OR EMN AND/OR VB AND/OR ultrathin scope

Intervention Type: 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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mauna Kea Technologies

INDUSTRY

Sponsor Role: collaborator

Amsterdam University Medical Centers (UMC), Location Academic Medical Center (AMC)

OTHER

Sponsor Role: lead

Responsible Party

Prof. J.T. Annema, MD, PhD

Prof. dr. J.T. Annema

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jouke Annema, Prof. dr.

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC

Locations

Montefiore Medical Center

New York, New York, United States

Site Status: RECRUITING

Vienna General Hospital

Vienna, , Austria

Site Status: NOT_YET_RECRUITING

General University Hospital Prague

Prague, , Czechia

Site Status: RECRUITING

Sotiria Hospital

Athens, , Greece

Site Status: RECRUITING

Morgagni Pierantoni Hospital

Forlì, , Italy

Site Status: NOT_YET_RECRUITING

Amsterdam University Medical Centers

Amsterdam, , Netherlands

Site Status: RECRUITING

University Hospital basel

Basel, , Switzerland

Site Status: NOT_YET_RECRUITING

Countries

United States; Austria; Czechia; Greece; Italy; Netherlands; Switzerland

Central Contacts

Saskia van Heumen, MSc

Role: CONTACT

s.vanheumen@amsterdamumc.nl

+31(0)20 566 2694

Jouke Annema, Prof. dr.

Role: CONTACT

j.t.annema@amsterdamumc.nl

Facility Contacts

Ali Sadoughi, MD, DAABIP

Role: primary

Daniela Gompelmann, Prof.

Role: primary

Zuzana Šestáková

Role: primary

Grigoris Stratakos, MD, PhD

Role: primary

Venerino Poletti, Prof.

Role: primary

Claudia Ravaglia

Role: backup

Saskia van Heumen, MSc

Role: primary

Jouke Annema, Prof. dr.

Role: backup

Jürgen Hetzel, Prof.

Role: primary

References

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.

Reference Type: BACKGROUND

PMID: 31023849 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 37562791 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 36535801 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34172559 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34506792 (View on PubMed)

van Heumen S, Kramer T, Korevaar DA, Gompelmann D, Bal C, Hetzel J, Jahn K, Poletti V, Ravaglia C, Sadoughi A, Stratakos G, Bakiri K, Koukaki E, Anagnostopoulos N, Votruba J, Sestakova Z, Heuvelmans MA, Daniels JMA, de Bruin DM, Bonta PI, Annema JT. Bronchoscopy with and without needle-based confocal laser endomicroscopy for peripheral lung nodule diagnosis: protocol for a multicentre randomised controlled trial (CLEVER trial). BMJ Open. 2024 Jul 4;14(7):e081148. doi: 10.1136/bmjopen-2023-081148.

Reference Type: DERIVED

PMID: 38964802 (View on PubMed)

Other Identifiers

NL83267.018.22

Identifier Type: -

Identifier Source: org_study_id