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Clinical Validation of ThyroidPrint: A Gene Expression Signature for Diagnosis of Indeterminate Thyroid Nodules

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ClinicalTrials.gov Identifier: NCT03309631
Recruitment Status : Unknown
Verified October 2017 by Hernán González, Pontificia Universidad Catolica de Chile.
Recruitment status was:  Recruiting
First Posted : October 13, 2017
Last Update Posted : October 26, 2017
Sponsor:
Collaborator:
Geneprodx
Information provided by (Responsible Party):
Hernán González, Pontificia Universidad Catolica de Chile

Brief Summary:
A clinical trial is proposed, to clinically validate, in a US population, the diagnostic performance of a new genetic test (ThyroidPrint). It will determine the nature of thyroid nodules that have been informed as indeterminate by cytology through a fine needle aspiration (FNA). The Genetic Classifier for Indeterminate Thyroid Nodules is a test that determines the expression of a panel of 10 biomarkers (CXCR3, CCR3, CXCl10, CK19, TIMP1, CLDN1, CAR, XB130, HO-1 and CCR7). Gene expression data is analyzed through an algorithm that generates a composite score that predicts the risk of malignancy. It´s intended use is for patients with thyroid cytology as indeterminate (Bethesda III and IV, according to The Bethesda System for Reporting Thyroid Cytopathology). This test uses a fine needle aspiration (FNA) sample.

Condition or disease Intervention/treatment
Indeterminate Thyroid Cytology Diagnostic Test: In vitro Diagnostic

Detailed Description:

Thyroid nodules are a very frequent condition reaching up to 30-40% of the adult population. Although most thyroid nodules have little clinical significance, in many cases a fine needle aspirate (FNA) biopsy will be performed to determine its nature. In 70% of cases, a FNA will be reported as benign and in 10% of cases as cancer. However, the remaining 20% of cases the thyroid nodule will be reported as indeterminate. The latter patients have a risk of malignancy ranging from 15 to 25%, and in most cases the patient will undergo thyroid lobectomy or total thyroidectomy to determine the final pathology, resulting in an unacceptable number of unnecessary surgeries. This has a major health impact, including surgical risks and permanent hormonal supplementation, as well as unwarranted health costs estimated at 1.6 billion USD. Therefore, there is a need for diagnostic tools in order to improve the diagnostic accuracy of the FNA and avoidance of the high rate of unnecessary surgeries.

GeneproDx has developed a gene expression signature to improve the diagnostic accuracy of FNA biopsy of thyroid nodules reported as indeterminate. The ThyroidPrint diagnostic measures the expression of 10 genes in a FNA sample. It combines the results of the 10 biomarkers using a proprietary algorithm to predict benign thyroid nodules. This assay is classified as multi-analyte algorithm assays (MAAA).

The biomarkers consist of multiplex TaqMan® gene expression assays run on Qiagen's Rotor-Gene Q MDx RT-PCR IVD Platform instrument, which is a FDA cleared instrument. The following 10 genes comprise the biomarker panel: CXCR3, CCR3, CXCL10, CK19, TIMP1, CLDN1, CAR, XB130, HO-1 and CCR7. Each gene run in a multiplex configuration with two reference genes. Each assay is performed with Research Use Only (RUO) kits and reagents on a FDA cleared instrument.

ThyroidPrint has been developed using two different cohorts of samples, a training set and a testing set. Using linear discriminant analysis, the training set identified the final biomarker panel including; CXCR3, CCR3, CXCL10, CK19, TIMP1, CLDN1, CAR, XB130, HO-1 and CCR7. In brief, the biomarkers have the following significance. CCR3 and CCR7 are chemokine receptors that are highly expressed in papillary thyroid cancer tumor cells. CXCR3 is also a chemokine receptor and along with its receptor, CXCL10, are detected in thyroid autoimmune disease. CAR is a G-couple receptor and has been shown to be involved in cancer and has decreased expression in parathyroid adenoma. CK19 is a keratin and has been used in thyroid tumors to recognize papillary carcinomas. CLDN1 is a structural protein and has been shown to be differentially expressed in tumors compared to normal tissue and has increased mRNA levels in papillary thyroid carcinoma. XB130 is also a structural protein and its expression has been demonstrated in papillary thyroid carcinoma. TIMP1 is a protease inhibitor with mRNA levels increased in advanced stages of thyroid carcinoma. HO- 1 is an oxygenase and its expression has correlates with tumor aggressiveness in thyroid cancer. In the final classifier, the expression of each gene was ̈weighted ̈ based on its individual relative classifying ability. The cutoff score was chosen in the ROC curve generated in the training set based on a minimum Sensitivity of 92% to guarantee a high Negative Predictive Value (>95%). This cutoff score offered a Specificity of 83%.An independent testing set of samples reproduced the diagnostic performance observed in the training set and showed consistent results in FNA samples. The assay has proven to accurately predict benign nodules in thyroid FNA samples with a Negative Predictive Value of 96% and Specificity of 83% in both cohorts. The definitive validation of an MAAA requires a final validation set, which analyzes samples that will be used in the routine clinical setting; in this case indeterminate thyroid nodules samples. In addition, in order to show clinical validity, the validation set must be performed, as a statistically powered multi-institutional trial to assure that the data is applicable to a broad population spectrum and has appropriate confidence intervals. A first, statistically powered, multi-institutional trial is currently underway in Chile to prove Clinical Validity. This trial includes 8 sites and will recruit approximately 3000 FNA to be completed by December 2017.


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Study Type : Observational
Estimated Enrollment : 1500 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Clinical Validation of ThyroidPrint: A Gene Expression Signature for Diagnosis of Indeterminate Thyroid Nodules
Actual Study Start Date : March 1, 2016
Estimated Primary Completion Date : March 30, 2018
Estimated Study Completion Date : June 30, 2018

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. Ability to predict Benign thyroid nodules. [ Time Frame: 24 months ]
    This will be determined by the Negative Predictive Value

  2. Ability to predict Malignant thyroid nodules. [ Time Frame: 24 months ]
    This will be determined by the Positive Predictive Value

  3. Sensitivity of the test [ Time Frame: 24 months ]
    Number of true positives cases

  4. Specificity of the test [ Time Frame: 24 months ]
    Number of true negative cases


Biospecimen Retention:   Samples Without DNA
Fine needle Aspiration of a thyroid nodule


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with a thyroid nodule recommended to undergo a fine needle aspiration (FNA) cytology evaluation by there attending physician are invited to participate in the trial. At the time of the FNA an additional sample will be collected for molecular testing. Only patients with an indeterminate result (Bethesda III and IV) will continue in the trial.
Criteria

Inclusion Criteria:

  1. Patients undergoing FNA of a thyroid nodule.
  2. Thyroid nodule greater 1cm
  3. Age greater 18 years old.

Exclusion Criteria:

  1. Thyroid nodule greater 1cm
  2. Patients less than 18 years old,
  3. Previous history of coagulation disorders and patients.
  4. Ultrasound evidence of malignant cervical adenopathy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03309631


Contacts
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Contact: Hernan E Gonzalez, MD, PhD +56999734312 hgonzale@med.puc.cl
Contact: Natalia Mena, PhD 56966770494 natalia.paz.mensj@gmail.com

Locations
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United States, Alabama
Avantt Research Recruiting
Guntersville, Alabama, United States, 35976
Contact: Dr. Nixon, MD         
United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94305
Contact: Chris Holsinger, MD         
United States, Florida
Lee Moffit Cancer Center Recruiting
Tampa, Florida, United States
Contact: Bryan McIver, MD, PhD         
United States, Louisiana
Tulane University Recruiting
New Orleans, Louisiana, United States
Contact: Emad Kandil, MD         
United States, Ohio
Universidad de Cincinnati Recruiting
Cincinnati, Ohio, United States, 45220
Contact: Davis Stewart, MD         
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Mark Zafareo, MD         
Sponsors and Collaborators
Pontificia Universidad Catolica de Chile
Geneprodx
Investigators
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Principal Investigator: Mark Zafareo, MD M.D. Anderson Cancer Center

Publications:
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Responsible Party: Hernán González, Associate Professor, Pontificia Universidad Catolica de Chile
ClinicalTrials.gov Identifier: NCT03309631     History of Changes
Other Study ID Numbers: GPDX-001
First Posted: October 13, 2017    Key Record Dates
Last Update Posted: October 26, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Hernán González, Pontificia Universidad Catolica de Chile:
Gene classifier
Additional relevant MeSH terms:
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Thyroid Nodule
Thyroid Diseases
Endocrine System Diseases
Thyroid Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms