PENK Methylation Test for Detecting Bladder Cancer

A Multicenter, Single-blind, Prospective Clinical Trial to Evaluate the Clinical Performance of EarlyTect® Bladder Cancer Test in the Urine DNA for Detecting Bladder Cancer Among Hematuria Patients

The primary objective of this clinical trial is to determine the sensitivity and specificity of the EarlyTect® Bladder Cancer test for bladder cancer among patients with hematuria by comparing it to the results of cystoscopy examinations.

The second objective is to compare the clinical performance of EarlyTect® Bladder Cancer test with a NMP22 test and urine cytology test with respect to bladder cancer. By histopathological examination, lesions identified during cystoscopy will be confirmed as malignant or non-malignant by histological examination.

Study Overview

• Status: Recruiting
• Conditions: Bladder Cancer; Hematuria; Benign
• Intervention / Treatment: Diagnostic test: EarlyTect® Bladder Cancer test

Detailed Description

Patients with hematuria who are scheduled for cystoscopy will be asked to collect a urine sample for EarlyTect® Bladder Cancer test and will undergo NMP22 and urine cytology tests. The participants will undergo a cystoscopy within 30 days of enrollment. For confirmation of the diagnosis and stage of the tumor, representative histopathology slides from TURBT (Transurethral Resection of Bladder Tumors) may be retrieved and examined by the central pathology laboratory.

• Study Type: Observational
• Enrollment (Estimated): 1549

Contacts and Locations

• Study Contact: Name: Cheol Kwak, MD PhD; Phone Number: 82-2-2072-0817; Email: mdrafael@snu.ac.kr
• Study Contact Backup: Name: In Gab Jeong, MD PhD; Phone Number: 82-2-3010-5892; Email: igjeong@amc.seoul.kr

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
    • Contact: In Gab Jeong, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with hematuria

Description

Inclusion Criteria:

• Individuals who agree to voluntarily sign an informed consent prior to the initiation of screening
• Adults aged ≥40
• Subjects who have had gross or microscopic hematuria within the 3 months
• Subjects who had no history of bladder cancer and upper tract urothelial cancer
• Subjects who will undergo cystoscopy, NMP22 test, and urine cytology within 1 month after consent

Exclusion Criteria:

• Individuals who do not agree to voluntarily sign an informed consent prior to the initiation of screening
• Subjects aged <40 years
• Subjects with a history of bladder cancer and upper tract urothelial cancer
• Female who are currently menstruating or who have had their last menstrual period within the last 3 days
• Subjects who have undergone invasive procedures in the urinary tract system within the last 3 months
• Subjects with suspected upper urothelial cancer lesions on ultrasound or CT scan
• Subjects who have previously received pelvic radiation therapy
• Subjects who have been diagnosed with other cancers and have received or are currently receiving chemotherapy or immunotherapy within 6 months
• Subjects who require treatment for an active urinary tract infection or vaginitis
• Subjects undergoing prostate cancer treatment or requiring a prostate biopsy
• Subject has any condition which, in the opinion of the investigator should preclude participation in the study

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Hematuria patients aged ≥40; Device: EarlyTect Bladder Cancer test, PENK methylation assay by LTE (Linear Target Enrichment)-qMSP (quantitative methylation-specific real time PCR)	Diagnostic test: EarlyTect® Bladder Cancer test; A highly accurate and sensitive real-time PCR employing Linear Target Enrichment and Quantitative Methylation-Specific PCR (LTE-qMSP) for measuring PENK methylation in urine DNA to detect bladder cancer in hematuria patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity and specificity of the EarlyTect® Bladder Cancer test	Sensitivity and specificity of the EarlyTect® Bladder Cancer test for detecting bladder cancer (Stages Ta high-grade and T1-T4) in patients with hematuria compared to the cystoscopy examination, both in terms of detecting bladder cancer. The reference method is the cystoscopic procedure, and lesions will be assessed histopathologically. EarlyTect® Bladder Cancer test includes a measurement of PENK methylation and COL2A1 as a DNA control. PENK methylation in urine DNA will be assessed quantitatively by Linear Target Enrichment-coupled Quantitative Methylation-Specific PCR (LTE-qMSP) using the Real-time PCR method. The results will be dichotomized by the CT (cycle threshold) cutoff value as either positive or negative. Sensitivity = 100*(positive PENK methylation test/positive cystoscopy), Specificity = 100*(negative PENK methylation test/negative cystoscopy).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The performance of the EarlyTect® Bladder Cancer test	The performance of the EarlyTect® Bladder Cancer test in detecting Bladder cancer in hematuria patients will be compared with those of the NMP22 and urine cytology tests.	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of clinical sensitivity and specificity to the NMP22 test	Comparison of clinical sensitivity and specificity to the NMP22 test	1 year
Comparison of clinical sensitivity and specificity to the urine cytology test	Comparison of clinical sensitivity and specificity to the urine cytology test	1 year
Sensitivity of EarlyTect® Bladder Cancer test for detecting bladder cancer with stages CIS and Ta low-grade	Sensitivity of EarlyTect® Bladder Cancer test for detecting bladder cancer with stages CIS and Ta low-grade	1 year
Positive predictive value (PPV) and Negative predictive value (NPV)	Positive predictive value and negative predictive value of EarlyTect® Bladder Cancer test for detecting bladder cancer	1 year
Evaluation of clinical sensitivity and specificity in the combination of EarlyTect® Bladder Cancer and NMP22 tests	Clinical sensitivity and specificity in the combination of EarlyTect® Bladder Cancer and NMP22 tests for detecting bladder cancer	1 year
Evaluation of clinical sensitivity and specificity in the combination of EarlyTect® Bladder Cancer and cytology tests	Clinical sensitivity and specificity in the combination of EarlyTect® Bladder Cancer and cytology tests for detecting bladder cancer	1 year
Evaluation of clinical sensitivity and specificity in the combination of EarlyTect® Bladder Cancer, NMP22, and cytology tests	Clinical sensitivity and specificity in the combination of EarlyTect® Bladder Cancer, NMP22, and cytology tests for detecting bladder cancer	1 year

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Collaborators: National Cancer Center, Korea; Samsung Medical Center; Pusan National University Hospital; Chonnam National University Hospital; Seoul National University Hospital; Ulsan University Hospital; Korea University Anam Hospital; Seoul National University Bundang Hospital; Ajou University School of Medicine; Seoul Clinical Laboratories
• Investigators: Principal Investigator: Cheol Kwak, MD PhD, Seoul National University Hospital

Publications and helpful links

General Publications

• 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. 2. Charpentier M, Gutierrez C, Guillaudeux T, Verhoest G, Pedeux R. Noninvasive urine-based tests to diagnose or detect recurrence of bladder cancer. Cancers. 2021;13:1650. 3. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA 2011; 306: 737-745. 4. Kitamura H, Kakehi Y. Treatment and management of high-grade T1 bladder cancer: what should we do after second TUR? Japanese Journal of Clinical Oncology. 2015;45(4):315-322. 5. Sievert KD, Amend B, Nagele U, Schilling D, Bedke J, Horstmann M et al. Economic aspects of bladder cancer: what are the benefits and costs? World J Urol. 2009;27(3):295-300. 6. Nepple KG, O'Donnell MA. The optimal management of T1 high-grade bladder cancer. Can Urol Assoc. 2009,3(suppl4):S188-92. 7. Wakui M, Shiigai T: Urinary tract cancer screening through analysis of urinary red blood cell volume distribution. Int J Urol. 2000,7(7):248-253. 8. Yafi FA, Aprikian AG, Tanguay S, Kassouf W. Patients with microscopic and gross hematuria: practice and referral patterns among primary care physicians in a universal health care system. Con Urol Assoc J. 2011;5(2):97-101. 9. Beukers W, Kandimalla R, van Houwelingen D, Kovacic H, Chin JF, Lingsma HF et al. The use of molecular analyses in voided urine for the assessment of patients with hematuria. PLOS One. 2013;8(10):e77657. 10. Chung W, Bondaruk J, Jelinek J, Lotan Y, Liang S, Czerniak B et al: Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidemiol Biomarkers Prev. 2011,20(7):1483-91. 11. Oeyen E, Hoekx L, Wachter SD, Baldewijins M, Ameye F, Mertens I. Bladder cancer diagnosis and follow-up: The current status and possible role of extracellular vesicels. Mol. Sci. 2019;20(4),821 12. Sullivan PS, Chan JB, Levin MR, Rao J. Urine cytology and adjunct markers for detection and surveillance of bladder cancer. Am J Transl Res. 2010;2(4):412-40. 13. Soria, F, Droller MJ, Lotan Y, Gontero P, D'Andrea D, Gust KM et al. An up-to-date catalog of available urinary biomarkers for the surveillance of non-muscle invasive bladder cancer. World J Urol. 2018;36:1981-95. 14. Hajdijak T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol 2008;26(6):646-51. 15. Mbeutcha A, Lucca I, Mathieu R, Lotan Y, Shariat SF. Current status of urinary biomarkers for detection and surveillance of bladder cancer. Urol Clin N AM 2016;43:47-62 16. Chung W, Bondaruk J, Jelinek J, Lotan Y, Liang S, Czerniak B, Lssa JPJ. Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidermiol Biomarkers Prev. 2011;20(7):1483-91

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2022
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): January 31, 2024

Study Registration Dates

• First Submitted: January 7, 2022
• First Submitted That Met QC Criteria: January 21, 2022
• First Posted (Actual): February 2, 2022

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 1, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Bladder cancer; Urine; Hematuria; Methylation biomarker; EarlyTect® Bladder Cancer test; Real-time PCR (LTE-qMSP)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Hemorrhage; Urination Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Hematuria
• Other Study ID Numbers: 2021-1626

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No