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The purpose of the clinical study is to validate the performance characteristics of the miR Scientific Sentinel™ PCa Test and the miR Scientific Sentinel™ CS Test. This study is a prospective, observational and non-interventional study. The informed participants will provide two or more urine samples over the course of the study, and consent to share relevant anonymized clinical data with the study team.
Participants, between the age of 50 and 80 years with suspicion of prostate cancer for whom a core-needle biopsy is performed, and otherwise meeting the inclusion and exclusion criteria, will be enrolled and will provide urine samples for the miR Sentinel™ PCa/CS Tests.
The miR Sentinel™ PCa Test uses a Classification Algorithm to produce a Sentinel™ PCa score that is compared to a calculated cutoff that controls sensitivity for a future patient at a desired level (95%), to distinguish between cancer and no cancer. The algorithm has been trained on a dataset consisting of: (1) control subjects who presented in urology for conditions unrelated to prostate cancer; (2) subjects with suspicion of prostate cancer known to not have prostate cancer based on the biopsy results; and (3) patients diagnosed with prostate cancer and whose core needle biopsy histopathology was reported as Grade Groups 1 through 5 prostate cancer.
The miR Sentinel™ CS Test uses a similar Classification Algorithm to produce a Sentinel™ CS Score that is compared to a calculated cutoff that controls sensitivity for a future patient at a desired level (95%), to distinguish between Clinically Significant cancer if the Sentinel™ CS Score is greater than or equal to the cutoff, or Clinically Insignificant prostate cancer if the Sentinel™ CS Score is less than the cutoff. The algorithm is trained using only the subset of patients known to have prostate cancer in the dataset used to train the Sentinel™ PCa Test.
The "gold standard" assessment of cancer will be made from the results of core needle biopsies: participants with no positive cores will be designated "cancer-free"; participants with cancer in one or more cores will be designated as having "Clinically Insignificant" prostate cancer provided all cores with cancer have no greater than Grade Group 1 histopathology; participants will be designated as having "Clinically Significant" prostate cancer if any cores have Grade Groups 2-5.
Primary Objective(s) To validate the performance of the miR Sentinel™ (Prostate Cancer) PCa test for identifying patients with prostate cancer in men of age 50-80 years with suspicion of prostate cancer for whom a core-needle biopsy is performed; to validate the performance of the miR Sentinel™ (Clinical Significance) CS Test to distinguish men (50 - 80 years of age) with Clinically Significant prostate cancer (Grade Group 2 or above) from men with Clinically Insignificant prostate cancer (Grade Group 1). These classifications will be compared to the results of core needle biopsies, and of radical prostatectomy (where available). The sensitivity, specificity, positive and negative predictive values will be established.
Time Perspective: Prospective This is an observational, non-interventional validation study. Patients between the age of 50 and 80 years who have a prostate core needle biopsy will be enrolled provided that they have provided a urine sample immediately prior to biopsy. Using the Pathological Grade Group system, the results of each biopsy will be grouped as either no cancer, Grade Group 1 (GG1) cancer, and Grade Groups 2-5 (GG2-5) cancer. The performance of both the miR Sentinel™ PCa Test to classify the disease status of a future patient as either prostate cancer or no prostate cancer and the miR Sentinel™ CS Test to classify a future patient with prostate cancer as having Clinically Insignificant (GG1) or Clinically Significant (GG2-5) will be established; the sensitivity, specificity, positive and negative predictive values will be determined for each test in the context of classifying a future patient with unknown disease status.
To estimate the prevalence of no cancer, GG1 cancer and GG2-5 cancer in the target population of men, previously published data are referenced below. These published data use Prostate Specific Antigen (PSA) level as a group identifier, and it is used here for the sole purpose of the prevalence estimations below. Note that the proposed clinical study does not in any way use PSA testing or scores to define eligibility criteria.
Definitions. The general notation P (A | B) = P(A , B)/P(B) is the probability of the event A given that the event B occurred; this means the probability (prevalence) of the event A among the subgroup of patients in a population all of whom have the event B.
1. Sensitivity = P (screening test + | truly disease).
2. Specificity = P (screening test - | truly no disease).
3. Positive Predictive Value (PPV) = P (truly disease | screening test +).
4. Negative Predictive Value (NPV) = P (truly no disease | screening test -).
Published data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate Cancer Prevention Trial (PCPT) are used below to estimate population prevalences. It is estimated that:
1. The sensitivity of the PSA≥ 3.0 ng/mL assay for positive biopsy is 44%
2. The specificity of the PSA≥ 3.0 ng/mL assay for positive biopsy is 68%
3. The PPV of serum PSA≥ 3.0 ng/mL for positive biopsy is 24%
4. The NPV of the serum PSA≥ 3.0 ng/mL assay for positive biopsy is 86%
Using the numbers above, the population proportion estimate of core needle biopsy positive is 0.14*(2/3) + 0.24*(1/3) = 0.18, and thus the population proportion with a negative core needle biopsy is 82%. Note that the ERSPC used sextant biopsies instead of 12-core and for this reason, it is considered that 18% to be a lower bound on the population prevalence of positive (12-core) biopsy.
Also, using data that 66% of patients with core needle biopsy positive are in GG1, it is estimated the population prevalence of GG1 and GG2-5 core needle biopsies to be (0.18)*(2/3) = 0.12 and 0.18*(1/3) = 0.06.
The following assumptions are used to estimate the misclassification rates of core-needle biopsy:
i) P(true GG1 | Biopsy - ) = 0.12 ii) P(true GG2-5 | Biopsy -) = 0.02 iii) P(true GG2-5 | Biopsy GG1) = 0.25 iv) P(true GG1 | Biopsy GG2-5) = 0.08
Therefore, at most 82% of participants that enter the study will have negative biopsy, at least 12% will have positive biopsy and GG1 cancer, and at least 6% will have positive biopsy and GG2-5 cancer. At most 10% of participants will actually be GG1 with a negative biopsy (false negative) and at most 2% will be GG2-5 with a negative biopsy (false negative).
Of the participants labeled with GG1 cancer from biopsy, at least 3% to be truly GG2-5. A very small proportion of participants are expected to be labeled as GG2-5 on biopsy but truly GG1.
Estimate of Sample Size. The proposed prospective study will serve to establish the performance of the miR Sentinel™ PCa Test on a representative sample of participants with any suspicion of prostate cancer for whom a core needle biopsy is ordered. The miR Sentinel™ PCa test is trained on retrospective data. The current proposed study is targeted to enroll 2000 participants between the age of 50 and 80 years who receive a core-needle biopsy and who provided a urine sample immediately prior to biopsy being performed. At least 6 % of participants entering the study will be biopsy-positive and GG2 or above (120/2000), at least 12% will be biopsy-positive and GG1 (240/2000) and at most 82% (1640/2000) will be biopsy negative.
Regarding false negative misclassifications, at most 200/2000 will be biopsy negative but truly GG1 and at most 40/2000 will be biopsy negative but truly GG2-5. On the other hand, at least 60/2000 participants to be labeled as GG1 on biopsy but truly GG2-5 and at least 10/2000 participants to be labeled GG2-5 on biopsy but truly GG1.
For a cutoff of the miR Sentinel™ PCa Score that results in an observed sensitivity estimate of 0.97 among the 360 participants expected to be enrolled in this prospective study with prostate cancer, the one-sided upper 95% confidence interval (CI) for the population sensitivity of the miR Sentinel™ PCa test that uses this cutoff, denoted P.SE, would be P.SE > 0.95, that is, at least 95% sensitivity in the population after considering sample variation by only using 360 participants.
For a cutoff of the miR Sentinel™ CS Test that results in an observed sensitivity estimate of 0.97 among the 110+60+40 = 210 participants enrolled in this prospective study with GG2-5 prostate cancer (taking into account the false-negative rate of biopsy), the one-sided upper 95% confidence interval (CI) for the population sensitivity of the miR Sentinel™ CS Test that uses this cutoff, denoted P.CS.SE, would be P.CS.SE > 0.95, that is, at least 95% sensitivity in the population after considering sample variation by only using 210 participants in GG2-5.
This prospective study will continue to enroll participants until a total of 2000 participants are enrolled.
Statistical Methodology. As outlined below, this clinical study will enroll participants between the ages of 50 and 80 years that are scheduled for a core needle biopsy based on any suspicion of prostate cancer. The study will evaluate the properties of the miR Sentinel™ PCa Test and the miR Sentinel™ CS Test that is based on use of a proprietary Classification Algorithm to identify future patients with prostate cancer and to classify prostate cancer as clinically significant or clinically insignificant.
The proprietary Classification Algorithm employed functions by controlling sensitivity at, or above, a pre-specified level, denoted 1-α; for example, the value that has been assumed in this design is α=0.05 so that sensitivity is at least 95% in the population. Note that the value of α represents the false-negative rate of the test, that is, the test is (incorrectly) negative for a patient who is truly positive.
To describe how the cutoff for the miR Sentinel™ PCa Score is calculated to control sensitivity, for each participant in the training dataset, the miR Sentinel™ PCa Score will be calculated using the remaining members of the training dataset and only his small non-coding RNA (sncRNA) sequence; that is, the true disease status of each patient in the training dataset will be blinded, thereby mimicking the setting for classification of a future patient. The cutoff used in the miR Sentinel™ PCa Test is then calculated so that the empirical sensitivity over patients in the training dataset with prostate cancer corresponds to the value that provides an upper one-sided 95% confidence interval for population sensitivity for a future patient of at least 1-α.
With this cutoff for the miR Sentinel™ PCa Score determined from the training dataset a priori, the corresponding values of sensitivity, specificity, positive and negative predictive values will be calculated, along with a corresponding upper 95% confidence intervals, on the prospective participants data accrued in this proposed study, with each biopsy result blinded, that is using only the participant's sncRNA sequence. Note that these error rates refer to the classification of a future patient with unknown disease status.
The statistical analysis of the prospective data accrued that blinds the group label from biopsy will provide an estimate of the proportion of participants that are mis-labeled by biopsy in the prospective dataset. For example, a participant labeled as having no prostate cancer by biopsy and whose blinded miR Sentinel™ PCa Score indicates prostate cancer may be a participant that was potentially a false negative by core-needle biopsy (biopsy label negative) but a miR Sentinel™ PCa Test suggesting the presence of prostate cancer. The validation of this discordance will be addressed in the follow-up data analysis.
The analysis for the miR Sentinel™ CS Test will employ a similar approach to that described above on the subset of the training dataset and the prospective data corresponding to participants labeled with GG1 and GG2-5 prostate cancer. Note that in the prospective data, all those participants determined to have cancer from the Sentinel™ PCa Test will be included in the analysis of the Sentinel™ CS Test. We will determine the performance of the proprietary Classification Algorithm for classifying a future patient as GG1 versus Grade Group 2 or above prostate cancer on the basis of the same 280 sncRNA sequences used in the miR Sentinel™ PCa Test. The corresponding sensitivity, specificity, positive and negative predictive values with 95% confidence intervals will be calculated over the prospective dataset using the cutoff for the miR Sentinel™ CS Score that was determined using the training dataset.
The blinded Sentinel™ CS Score, calculated for each participant in the prospective dataset using only his sncRNA sequence and the training dataset, will enable estimation of the proportion who were labeled as GG1 by biopsy, but actually have a Sentinel™ CS Score indicating GG2-5, the grade groups that are typically considered high risk and in need of treatment. Similarly, when a participant is labeled as GG2-5 but who has a favorable Sentinel™ CS Score (GG1), may imply the presence of stable/indolent disease.
Each study participant enrolled will be followed for one year. Participants will provide urine samples during each visit, and all relevant clinical data, including re-biopsies, PSA results and pathology report from radical prostatectomy (if administered as part of clinical care) will be obtained. The follow-up results, if available will be used for outcome analysis. For each urine sample provided, the miR Sentinel™ PCa and CS tests will be determined and compared with the available 1 year follow up outcome data to inform the sensitivity, specificity, positive and negative predictive values of the tests.
Urology of Greater Atlanta
Not yet recruiting
miR Scientific LLC
Published on BioPortfolio: 2019-09-27T06:30:41-0400
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