Confocal Laser Endomicroscopy for Lung Cancer

(CLEVER Trial)

Recruiting at 7 trial locations

Overseen By Jouke Annema, Prof. dr.

Age: 18+

Sex: Any

Trial Phase: Academic

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

Must not be taking: Anticoagulants, Chemotherapy

Disqualifiers: Pregnancy, Breastfeeding, Hypoxemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

208 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that therapeutic anticoagulant use must be withheld for an appropriate interval before the procedure. If you are undergoing chemotherapy, you may not be eligible to participate.

What data supports the effectiveness of the treatment Confocal Laser Endomicroscopy for Lung Cancer?

The research suggests that needle-based confocal laser endomicroscopy, a new imaging technique, allows doctors to see individual cells in real-time, which can help diagnose small lung nodules more accurately when combined with robotic bronchoscopy. ^{1 2 3 4 5}

Is confocal laser endomicroscopy for lung cancer safe?

Flexible bronchoscopy, a related procedure, is generally considered safe, but complications can include bleeding, pneumothorax (collapsed lung), and fever. Most complications are rare and can be managed with proper medical care. ^{6 7 8 9 10}

How is confocal laser endomicroscopy different from other treatments for lung cancer?

Confocal laser endomicroscopy is unique because it allows doctors to see living cells in the lungs in real-time during a bronchoscopy, providing detailed images of cellular structures at the needle tip. This technique offers a high level of accuracy in diagnosing lung cancer by enabling virtual histology, which is not possible with traditional bronchoscopy methods. ^{3 11 12 13 14}

Research Team

Jouke Annema, Prof. dr.

Principal Investigator

Amsterdam UMC

Eligibility Criteria

This trial is for adults over 18 with suspected malignant lung lesions suitable for bronchoscopic diagnosis. The lesion must be solid, larger than 10mm but not exceeding 30mm, and accessible by conventional bronchoscopy as indicated by a CT scan. Participants must understand and consent to the study.

Inclusion Criteria

If the pre-procedural CT-scan does not reveal an airway leading to the target lesion, there is a low likelihood of successful access with a conventional bronchoscope and study participation would be declined.

I am 18 years old or older.

I am suspected to have lung cancer and need a lung biopsy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Procedure

Participants undergo diagnostic bronchoscopy with or without nCLE imaging

During procedure

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the bronchoscopy procedure

6 months

Treatment Details

Interventions

• Conventional diagnostic bronchoscopy
• Neelde Based Confocal Laser Endomicroscopy

Trial Overview The trial tests if adding needle-based confocal laser endomicroscopy (nCLE) to regular diagnostic bronchoscopy improves the chances of correctly diagnosing lung cancer in patients with peripheral pulmonary nodules.

Participant Groups

Group I: nCLE arm Experimental Treatment 2 Interventions

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

Group II: Control arm Active Control 1 Intervention

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

Conventional diagnostic bronchoscopy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Diagnostic Bronchoscopy for:

• Diagnosis of lung diseases
• Evaluation of lung lesions
• Sampling of lung tissue

Approved in United States as Diagnostic Bronchoscopy for:

• Diagnosis of lung diseases
• Evaluation of lung lesions
• Sampling of lung tissue

Approved in Canada as Diagnostic Bronchoscopy for:

• Diagnosis of lung diseases
• Evaluation of lung lesions
• Sampling of lung tissue

Approved in Japan as Diagnostic Bronchoscopy for:

• Diagnosis of lung diseases
• Evaluation of lung lesions
• Sampling of lung tissue

Approved in China as Diagnostic Bronchoscopy for:

• Diagnosis of lung diseases
• Evaluation of lung lesions
• Sampling of lung tissue

Approved in Switzerland as Diagnostic Bronchoscopy for:

• Diagnosis of lung diseases
• Evaluation of lung lesions
• Sampling of lung tissue

Who Is Running the Clinical Trial?

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

Lead Sponsor

Trials

17

Recruited

7,800+

Mauna Kea Technologies

Industry Sponsor

Trials

20

Recruited

1,800+

Findings from Research

In a study of 362 patients with visible endobronchial tumors, pre-biopsy bronchial brushing significantly improved the diagnostic yield for lung cancer compared to post-biopsy brushing, with yields of 49.2% versus 31.8% respectively.

The study found no significant difference in the occurrence of treated bleeding between pre- and post-biopsy brushing, indicating that the technique is safe while enhancing diagnostic effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The optimal sequence for bronchial brushing and forceps biopsy in lung cancer diagnosis: a random control study. Hou, G., Miao, Y., Hu, XJ., et al.[2020]

Surgical resection remains the only curative option for lung cancer, with the five-year survival rate significantly improving when tumors are detected early.

Bronchoscopy is crucial for both diagnosing and treating lung cancer, helping to identify tumors and manage symptoms like bleeding and difficulty breathing through various therapeutic techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung Cancer: A Bronchoscopic Approach. Strausz, J.[2019]

Robotic bronchoscopy has improved navigational success for diagnosing small lung nodules, but challenges remain due to the risk of missing the target nodule.

The introduction of needle-based confocal laser endomicroscopy allows for real-time visualization of cells during robotic bronchoscopy, potentially enhancing the accuracy of diagnosing small lung nodules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Robotic Navigational Bronchoscopy Combined with Needle-Based Confocal Laser Endomicroscopy: Case Report of a Novel Approach to Diagnose Small Lung Nodules. Manley, C., Kramer, T., Kumar, R., et al.[2022]

Flexible bronchoscopy has a high diagnostic yield of 88% for detecting endoscopically visible lung malignancies, significantly improved by using cytological techniques like bronchial washings and brushings in addition to biopsies.

Cytological sampling techniques increased the diagnostic yield from 77% with biopsies alone to 88% overall, and repeat bronchoscopies after non-diagnostic results were successful in 9 out of 11 cases, indicating their importance in diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bronchoscopic diagnosis of endoscopically visible lung malignancies: should cytological examinations be carried out routinely? Dobler, CC., Crawford, AB.[2010]

Recent advancements in bronchoscopy technology enhance the ability to perform minimally invasive evaluations and a variety of interventions in the tracheobronchial tree, improving diagnostic and therapeutic outcomes.

There is a critical need for well-designed studies to establish guidelines for the effective use of new bronchoscopic techniques in clinical practice, addressing their limitations and cost-effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flexible bronchoscopy and its role in the staging of non-small cell lung cancer. Herth, FJ., Eberhardt, R.[2010]

In a 15-month study of 697 patients undergoing advanced diagnostic bronchoscopy, severe complications were rare, occurring in only 2.4% of patients, but they had serious consequences, including unplanned hospital visits and deaths.

Many complications occurred days or weeks after the procedure, highlighting the need for proactive monitoring to identify and manage these delayed adverse events effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thirty-Day Complications, Unplanned Hospital Encounters, and Mortality after Endosonography and/or Guided Bronchoscopy: A Prospective Study. Magnini, D., Sotgiu, G., Bello, G., et al.[2023]

In a study of 1,100 interventional pulmonology procedures, trainee involvement was linked to longer procedure times (average of 50.81 minutes compared to 32.49 minutes) and increased sedation requirements, indicating a potential impact on efficiency.

The presence of trainees also correlated with a higher complication rate (4.5% with trainees vs. 1.2% without), suggesting that while training is essential, it may pose additional risks to patients during procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trainee impact on procedural complications: an analysis of 967 consecutive flexible bronchoscopy procedures in an interventional pulmonology practice. Stather, DR., MacEachern, P., Chee, A., et al.[2022]

Flexible bronchoscopy is a crucial diagnostic tool in respiratory medicine, but it carries a range of potential complications due to its invasive nature.

To minimize risks associated with flexible bronchoscopy, it is essential to have a skilled team, close monitoring, and immediate access to resuscitation facilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Successful risk management in flexible bronchoscopy]. Darwiche, K., Hecker, E., Volmerig, J., et al.[2009]

In a study of 259 lung transplant recipients undergoing flexible fiberoptic bronchoscopy, complications occurred in only 0.7% of procedures, indicating that bronchoscopy is generally safe for these patients.

The involvement of trainees in bronchoscopies did not significantly increase the rate of complications, suggesting that trainee participation is safe and does not adversely affect patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An analysis of potential risk factors for early complications from fiberoptic bronchoscopy in lung transplant recipients. Smith, L., Singer, JP., Hayes, M., et al.[2012]

In a study involving 159 asthmatic patients who underwent 273 bronchoscopies, the procedures were found to be generally safe, with adverse events occurring in only 34 instances, none of which followed allergen challenges.

Most complications were associated with the combination of endobronchial biopsy and bronchoalveolar lavage, indicating that bronchoalveolar lavage may be responsible for the majority of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of research bronchoscopy, biopsy and bronchoalveolar lavage in asthma. Elston, WJ., Whittaker, AJ., Khan, LN., et al.[2013]

Confocal laser endomicroscopy is a cutting-edge endoscopic technique that allows for real-time histological diagnosis of gastrointestinal diseases, enhancing the accuracy of detecting conditions like gastrointestinal neoplasia.

This technique is particularly valuable for screening and monitoring gastrointestinal neoplasia, potentially improving patient outcomes through earlier and more precise diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Confocal laser endomicroscopy of the upper digestive tract: history of development and screening]. Sukhikh, MV., Panchenkov, DN.[2020]

Confocal laser endomicroscopy is a feasible imaging technique for lepidic adenocarcinomas, which are a type of lung cancer.

This imaging method could potentially enhance the effectiveness of virtual electromagnetic navigation bronchoscopy for identifying ground-glass opacities in real-time, suggesting a promising direction for future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Confocal laser endomicroscopy to guide sampling of a pure ground-glass opacity. Viatgé, T., Villeneuve, T., D'Aure, D., et al.[2021]

Confocal laser endomicroscopy, using acriflavine hydrochloride, allows for high-quality imaging of living lung cells during bronchoscopy, with no reported side effects, making it a safe diagnostic tool.

This technique demonstrated high accuracy in detecting neoplastic changes, with a sensitivity of 96.0% and specificity of 87.1%, potentially enabling rapid diagnosis of lung cancer during the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Confocal laser endomicroscopy for diagnosing lung cancer in vivo. Fuchs, FS., Zirlik, S., Hildner, K., et al.[2013]

Needle-based confocal laser endomicroscopy (nCLE) is a safe and feasible method for real-time imaging of suspected peripheral lung cancer, with no adverse events reported in a study of 26 patients.

The nCLE imaging successfully detected malignancy in 22 out of 23 lung cancer cases, and blinded raters achieved 95% accuracy in distinguishing cancerous tissue from normal lung parenchyma, indicating its potential as a valuable tool for bronchoscopic guidance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bronchoscopic needle-based confocal laser endomicroscopy (nCLE) as a real-time detection tool for peripheral lung cancer. Kramer, T., Wijmans, L., de Bruin, M., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

The optimal sequence for bronchial brushing and forceps biopsy in lung cancer diagnosis: a random control study. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Lung Cancer: A Bronchoscopic Approach. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Robotic Navigational Bronchoscopy Combined with Needle-Based Confocal Laser Endomicroscopy: Case Report of a Novel Approach to Diagnose Small Lung Nodules. [2022]

4. Australia pubmed.ncbi.nlm.nih.gov

Bronchoscopic diagnosis of endoscopically visible lung malignancies: should cytological examinations be carried out routinely? [2010]

5. United States pubmed.ncbi.nlm.nih.gov

Flexible bronchoscopy and its role in the staging of non-small cell lung cancer. [2010]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Thirty-Day Complications, Unplanned Hospital Encounters, and Mortality after Endosonography and/or Guided Bronchoscopy: A Prospective Study. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Trainee impact on procedural complications: an analysis of 967 consecutive flexible bronchoscopy procedures in an interventional pulmonology practice. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

[Successful risk management in flexible bronchoscopy]. [2009]

9. Switzerland pubmed.ncbi.nlm.nih.gov

An analysis of potential risk factors for early complications from fiberoptic bronchoscopy in lung transplant recipients. [2012]

10. England pubmed.ncbi.nlm.nih.gov

Safety of research bronchoscopy, biopsy and bronchoalveolar lavage in asthma. [2013]

11. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Confocal laser endomicroscopy of the upper digestive tract: history of development and screening]. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Confocal laser endomicroscopy to guide sampling of a pure ground-glass opacity. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Confocal laser endomicroscopy for diagnosing lung cancer in vivo. [2013]

14. England pubmed.ncbi.nlm.nih.gov

Bronchoscopic needle-based confocal laser endomicroscopy (nCLE) as a real-time detection tool for peripheral lung cancer. [2022]