(90 days)
Not Found
No
The device is a chemiluminescent immunoassay for measuring procalcitonin levels. The analysis of the results involves calculating a change in PCT level over time and comparing it to thresholds, which is a standard statistical analysis, not AI/ML. The summary does not mention any AI/ML algorithms or models used in the device's operation or data interpretation.
No
This device is an in vitro diagnostic (IVD) assay designed to quantitatively determine procalcitonin (PCT) levels in human serum and plasma. It aids in risk assessment for sepsis, all-cause mortality, and decision-making on antibiotic therapy and discontinuation. It does not directly treat or prevent a disease, but rather provides information to guide clinical management.
Yes
This device is an in vitro diagnostic device used for the quantitative determination of procalcitonin (PCT) from patient samples, which assists in the risk assessment and management of antibiotic therapy for patients with specific conditions like severe sepsis, septic shock, and lower respiratory tract infections. The "Intended Use / Indications for Use" section explicitly states its purpose as an "Aid in the risk assessment" and "Aid in decision making" for clinical conditions. The final sentence of the "Intended Use / Indications for Use" section further clarifies, "For in vitro diagnostic use only."
No
The device description clearly states that the device includes physical components such as reagents, calibrators, and controls, which are used in a chemiluminescent microparticle immunoassay (CMIA) on the ARCHITECT iSystem. This indicates it is an in vitro diagnostic (IVD) device with hardware and chemical components, not a software-only device.
Yes, this device is an IVD (In Vitro Diagnostic).
The document explicitly states "For in vitro diagnostic use only" for both the calibrators and controls, which are integral components of the ARCHITECT B.R.A.H.M.S PCT assay. The intended use also describes the quantitative determination of procalcitonin in human serum and plasma, which are biological specimens used for diagnostic purposes outside of the body.
N/A
Intended Use / Indications for Use
The ARCHITECT B R A H M S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem.
Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT BR A-H-M-S PCT assay is intended for use as an:
- Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.
- Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
- Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
- Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The ARCHITECT B R A H M S PCT Calibrators are for the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.
The ARCHITECT B-R-A-H-M-S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.
Product codes (comma separated list FDA assigned to the subject device)
PRI, PMT, PTF, JIT, JJX
Device Description
The ARCHITECT B.R.A.H.M.S PCT assay reagents are available in 100 or 500 test kits.
Kit Components and Chemical Composition:
PCT Microparticles (1 bottle): Reactive Ingredients: Rat monoclonal anti-PCT (CALC 01R 03-1C2) coated microparticles. Materials: Bovine serum albumin, Rat IgG. Main Buffer Component: Tris based buffer, Preservatives: Sodium Azide .08% and ProClin 950.
PCT Conjugate (1 bottle): Reactive Ingredients: Mouse monoclonal anti-PCT (23-101) acridinium-labeled conjugate. Materials: Bovine serum albumin. Main Buffer Component: Sodium phosphate buffer, Preservatives: Sodium Azide .08% and ProClin 950.
Calibrators: The ARCHITECT B.R.A.H.M.S PCT Calibrators kit consists of 6 bottles (2.0 mL each). Calibrator A contains normal human plasma. Calibrators B-F contain different concentrations of recombinant human PCT in phosphate buffer with PCT concentrations that range from 0.10-100.00 ng/mL. All of the calibrators contain the preservatives ProClin 950 and sodium azide.
Controls: The ARCHITECT B.R.A.H.M.S PCT Controls kit consists of 2 x 3 bottles (3.0 mL each). The Low Control, Medium Control, and High Contain recombinant PCT prepared in phosphate buffer at 3 target concentrations: Low (0.20 ng/mL), Medium (2.00 ng/mL), and High (70.00 ng/mL). All of the controls contain the preservatives ProClin 950 and sodium azide. The control ranges are as follows: Low (0.14-0.26 ng/mL), Medium (1.38-2.62 ng/mL), and High (42.00-98.00 ng/mL).
Materials required but not provided:
- ARCHITECT B.R.A.H.M.S PCT Assay file obtained from the ARCHITECT iSystem e-Assay CD-ROM found on www.abbottdiagnostics.com
- ARCHITECT B.R.A.H.M.S PCT Calibrators
- ARCHITECT B.R.A.H.M.S PCT Controls or other control material
- ARCHITECT Pre-Trigger Solution
- ARCHITECT Trigger Solution
- ARCHITECT Wash Buffer
- ARCHITECT Reaction Vessels
- ARCHITECT Sample Cups
- ARCHITECT Septum
- ARCHITECT Replacement Caps
- Pipettes or pipette tips
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
The safety and performance of PCT-guided therapy for individuals younger than age 18 years was not formally analyzed in the supportive clinical trials.
Intended User / Care Setting
Used in conjunction with other laboratory findings and clinical assessments. Intensive Care Unit (ICU), emergency department or other medical wards for critically ill patients. Inpatient setting or emergency department for patients with suspected or confirmed lower respiratory tract infections.
Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
The ARCHITECT B.R.A.H.M.S PCT assay was evaluated for the prediction of cumulative 28-day all-cause mortality in a prospective clinical trial (MOSES study -Procalcitonin Monitoring Sepsis Study; ClinicalTrials.gov Identifier: NCT01523717) of 858 adult patients diagnosed with severe sepsis or septic shock admitted to ICU care. PCT levels were measured on Days 0, 1, and 4 across the 13 investigational sites in the United States. The analysis population (598 subjects) included 44% female and 56% male patients with a mean age of 64 years. About half of the patients had severe sepsis (51%) versus (vs.) septic shock (49%). Infections were mainly community acquired (91%). Testing was performed at 2 external sites and one internal site. Validation of the ARCHITECT B.R.A.H.M.S PCT assay as an aid in predicting mortality was performed in a study population with an overall 28-day mortality of 22%.
Clinical concordance analysis used human K2EDTA plasma specimens (n = 142) from various hospital departments in Switzerland. Each donor sample was thawed and run on both instruments on the same day.
Reference Range study used normal healthy donor K2EDTA plasma collected from n=446 individuals, males (n=217) and females (n=229).
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Analytical Performance
- Reproducibility/Precision:
- Internal Precision: Single site precision study using CLSI EP05-A3. Three PCT level controls (low, medium, high) and three PCT plasma panels (1, 3, 5) were evaluated in duplicate with two runs per day over 20 testing days (Total 320 replicates). Within-laboratory precision (total) was 2.5% to 2.8% for Low control, 2.1% to 2.5% for Medium control, 3.5% to 3.8% for High control, 2.5% for Panel 1, 2.1% for Panel 3, and 2.2% to 2.3% for Panel 5.
- Multi-Site Precision: Performed at two external CLIA certified laboratories and one internal laboratory according to CLSI EP15-A3. One reagent lot, one calibrator lot, one control lot, and one ARCHITECT i2000sr instrument per site over 5 days. Five replicates per sample with one run per day for 25 replicates per sample per site. Within-laboratory %CVs ranged from 1.5% to 4.0% for each site for concentrations > 0.1 ng/mL (SD 0.1 ng/mL (SD 80% or 80%) patient subgroups ranged from 1.49 to 3.38.
- Cox proportional hazards regression analysis for ΔPCT from Day 0 to Day 4 ( 80%): Hazard Ratio (HR) of 1.99 (95% CI: 1.28–3.09, p-value = 0.0021). Relative risk of cumulative 28-day mortality approx. 2-fold higher.
- Univariate hazard ratios for other clinical factors were also assessed, e.g., ICU Care on Day 4: HR 3.45 (95% CI: 2.24-5.31, p 80%) ranged from 1.55 to 1.96 depending on the model.
- Clinical concordance analysis: > 96% total agreement between ARCHITECT B.R.A.H.M.S PCT and B.R.A.H.M.S PCT sensitive Kryptor at medical decision points 0.5 µg/L and 2.0 µg/L.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
- 28-Day Mortality Prognostic Accuracy (Sensitivity/Specificity for ΔPCT > 80% vs. ≤ 80%):
- Day 0 to Day 4 (ICU): Sensitivity 73.4% (95% CI: 63.2-83.7), Specificity 38.0% (95% CI: 31.0-45.0)
- Day 0 to Day 4 (Non-ICU): Sensitivity 68.8% (95% CI: 51.8-85.7), Specificity 49.1% (95% CI: 43.1-55.1)
- Day 1 to Day 4 (ICU): Sensitivity 72.6% (95% CI: 62.0-83.1), Specificity 40.4% (95% CI: 33.3-47.5)
- Day 1 to Day 4 (Non-ICU): Sensitivity 71.9% (95% CI: 55.3-88.5), Specificity 47.6% (95% CI: 41.5-53.7)
- Hazard Ratios for 28-Day Cumulative Mortality (ΔPCT ≤ 80% vs. > 80%):
- ΔPCT (Day 0 to Day 4): 1.99 (95% CI: 1.28-3.09, p-Value 0.002)
- ΔPCT (Day 1 to Day 4): 2.03 (95% CI: 1.30-3.18, p-Value 0.002)
- Clinical Concordance: > 96% total agreement between subject device and predicate at 0.5 µg/L and 2.0 µg/L decision points.
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.
(a)
Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.
(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.
(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.
(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.
(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.
(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.
(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (
e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.
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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized image of three human profiles facing to the right, with a flowing ribbon-like element beneath them.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
June 1, 2017
FISHER DIAGNOSTICS c/o KENNON DANIELS, PH.D. SENIOR CONSULTANT, IVD REGULATORY AFFAIRS 2 BETHESDA METRO CENTER, SUITE 850 BETHESDA MD 20814
Re: K170652
Trade/Device Name: ARCHITECT B.R.A.H.M.S PCT, ARCHITECT B.R.A.H.M.S PCT Calibrators, ARCHITECT B.R.A.H.M.S PCT Controls Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis Regulatory Class: II Product Code: PRI, PMT, PTF, JIT, JJX Dated: March 1, 2017 Received: March 3, 2017
Dear Dr. Daniels:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the
1
electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
Kristian M. Roth-S
For: Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known) K170652
Device Name
ARCHITECT B·R·A·H·M·S PCT ARCHITECT B·R·A·H·M·S PCT Calibrators ARCHITECT B·R·A·H·M·S PCT Controls
Indications for Use (Describe)
The ARCHITECT B R A H M S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem.
Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT BR A-H-M-S PCT assay is intended for use as an:
· Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.
· Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
· Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
· Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The ARCHITECT B R A H M S PCT Calibrators are for the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.
The ARCHITECT B-R-A-H-M-S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.
Type of Use (Select one or both, as applicable)
| Prescription Use (Part 21 CFR 801 Subpart D) | |
|---|---|
| Over-The-Counter Use (21 CFR 801 Subpart C) |
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510K SUMMARY
A. GENERAL INFORMATION
| Submission Date: | March 1, 2017 |
|---|---|
| ------------------ | --------------- |
Submitter Information:
| Submitted By: | Fisher Diagnostics
A Div. of Fisher Scientific Company, LLC
A Part of Thermo Fisher Scientific, Inc.
8365 Valley Pike
Middletown, VA 22645 |
|-----------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact Person: | Connie Yang, MSPH
Regulatory Affairs Specialist
Clinical Diagnostics OEM & Contract Manufacturing
Thermo Fisher Scientific
Tel: (540) 868-3603
Fax: (540) 869-8117
Email: connie.yang@thermofisher.com |
B. PURPOSE FOR SUBMISSION
To obtain a substantial equivalence determination for the ARCHITECT B.R.A.H.M.S PCT, ARCHITECT B.R.A.H.M.S PCT Calibrators, and ARCHITECT B.R.A.H.M.S PCT Controls.
C. MEASURAND
Procalcitonin
D. TYPE OF TEST
Quantitative, chemiluminescent microparticle immunoassay (CMIA)
E. APPLICANT
Fisher Diagnostics
F. PROPRIETARY AND ESTABLISHED NAMES
ARCHITECT B.R.A.H.M.S PCT ARCHITECT B.R.A.H.M.S PCT Calibrators ARCHITECT B.R.A.H.M.S PCT Controls
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G. REGULATORY INFORMATION
| Assay | |
|---|---|
| Trade Name: | ARCHITECT B.R.A.H.M.S PCT |
| Classification: | Class II |
| Regulation: | 21 CFR 866.3215 |
| Regulation Name: | Device to detect and measure non-microbial analyte(s) in |
| human clinical specimens to aid in assessment of patients | |
| with suspected sepsis | |
| Product Code: | PRI, PMT, PTF |
| Panel: | 83 - (Microbiology) |
| Calibrators | |
| Trade Name: | ARCHITECT B.R.A.H.M.S PCT Calibrators |
| Classification: | Class II |
| Regulation: | 21 CFR 862.1150 |
| Classification Name: | Calibrator, Secondary |
| Product Code: | JIT |
| Controls | |
| Trade Name: | ARCHITECT B.R.A.H.M.S PCT Controls |
| Classification: | Class I |
| Regulation: | 21 CFR 862.1660 |
Regulation: Classification Name: Product Code:
21 CFR 862.1660 Quality Control Material (assayed and unassayed) JJX
H. INTENDED USE / INDICATIONS FOR USE
1. Intended Use
The ARCHITECT B.R.A.H.M.S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem.
Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT B.R.A.H.M.S PCT assay is intended for use as an:
- Aid in the risk assessment of critically ill patients on their first day of intensive care . unit (ICU) admission for progression to severe sepsis and septic shock.
- Aid in assessing the cumulative 28-day risk of all-cause mortality for patients . diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
- . Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
5
- . Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The ARCHITECT B.R.A.H.M.S PCT Calibrators are for the calibration of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.
The ARCHITECT B.R.A.H.M.S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.
-
- Special conditions for use statement(s):
For prescription use only
- Special conditions for use statement(s):
Warnings and Precautions for the Assay:
- The ARCHITECT B.R.A.H.M.S PCT assay is not indicated to be used as a stand-. alone diagnostic assay and should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence.
- Decisions regarding antibiotic therapy should NOT be based solely on PCT . concentrations.
- . PCT results should always be interpreted in the context of the clinical status of the patient and other laboratory results. Changes in PCT levels for the prediction of mortality, and overall mortality, are strongly dependent on many factors, including pre-existing patient risk factors and clinical course.
- . The need to continue ICU care at Day 4 and other covariates (e.g., age and SOFA score) are also significant predictors of 28-day cumulative mortality risk.
- . Certain patient characteristics, such as severity of renal failure or insufficiency, may influence PCT values and should be considered as potentially confounding clinical factors when interpreting PCT values.
- PCT levels may not be elevated in patients infected by certain atypical pathogens, . such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.
- . Low PCT levels do not always indicate absence of bacterial infection. Falsely low PCT levels in the presence of bacterial infection may occur during the early course of infections, in localized infections, and in subacute infectious endocarditis.
- . Increased PCT levels may not always be related to systemic bacterial infection. There are a few situations where PCT levels may be elevated by non-bacterial causes. These include, but are not limited to, the following:
- Neonates at 0.1 ng/mL and with a SD of ≤ 0.005 ng/mL where sample concentrations ≤ 0.1 ng/mL.
| Sample | Low
Control | Medium
Control | High
Control | Panel 1 | Panel 3 | Panel 5 |
|---------------------|----------------|-------------------|-----------------|----------------|---------|---------|
| 3 Sites | | | | | | |
| Between-Site %CV | 2.8% | 0.0% | 0.4% | 5.5% | 2.1% | 1.2% |
| Between-Day %CV | 1.4% | 2.0% | 2.0% | 0.0% | 0.9% | 0.0% |
| Between-Rep %CV | 2.6% | 2.0% | 2.7% | 5.4% | 1.9% | 2.0% |
| Total Precision %CV | 4.0% | 2.7% | 3.4% | 7.7% | 3.0% | 2.3% |
| Total Precision SD | N/A | N/A | N/A | 0.005
ng/mL | N/A | N/A |
| Site 1 | | | | | | |
| Between-Day %CV | 0.0% | 0.0% | 1.9% | 0.0% | 1.1% | 0.0% |
| Between-Rep %CV | 2.0% | 1.5% | 2.8% | 8.1% | 2.4% | 2.1% |
| Within-Lab %CV | 2.0% | 1.5% | 3.4% | 8.1% | 2.6% | 2.1% |
| Within-Lab SD | N/A | N/A | N/A | 0.005
ng/mL | N/A | N/A |
| Site 2 | | | | | | |
| Between-Day %CV | 1.2% | 1.4% | 1.8% | 0.0% | 1.0% | 0.8% |
| Between-Rep %CV | 2.1% | 1.6% | 2.2% | 2.8% | 1.4% | 1.5% |
| Within-Lab %CV | 2.4% | 2.6% | 2.9% | 2.8% | 1.8% | 1.7% |
| Within-Lab SD | N/A | N/A | N/A | 0.002
ng/mL | N/A | N/A |
| Site 3 | | | | | | |
| Between-Day %CV | 2.2% | 2.3% | 2.2% | 1.6% | 0.2% | 0.0% |
| Between-Rep %CV | 3.3% | 2.6% | 3.1% | 4.6% | 1.9% | 2.3% |
| Within-Lab %CV | 4.0% | 4.0% | 3.8% | 4.9% | 2.0% | 2.3% |
| Within-Lab SD | N/A | N/A | N/A | 0.003
ng/mL | N/A | N/A |
Summary of Multi-Site Precision Data
b. Linearity/Assay Reportable Range
Linearity
Assay linearity studies were performed at the Thermo Fisher internal laboratory according to CLSI Guideline EP06-A. Evaluation of the Linearity of Quantitative Measurement Procedures. The linearity data was obtained in two independent studies. For both studies, three unique EDTA plasma High pools were produced by pooling multiple clinical samples from multiple donors. From each "High" pool, ten sample levels in addition to the High sample were created by diluting each High pool gravimetrically with Calibrator Diluent. The targeted concentration range for the eleven sample levels was 0.01 ng/mL to ~110.00 ng/mL for each of the clinical sample sets. The PCT concentration of each clinical sample pool was unknown prior to executing
13
the study. The data from the studies demonstrate that the assay is linear in the range of 0.01 to 106.80 ng/mL.
Dilution Tests
The auto-dilution study was conducted at the Thermo Fisher internal laboratory using one lot of ARCHITECT B.R.A.H.M.S PCT assay reagents, calibrators, and controls on one ARCHITECT i2000sr instrument. The study utilized disease state plasma panels (≥0.5 ng/mL) spiked with recombinant PCT to the desired levels. The panels were evaluated using the 1:10 auto-dilution protocol, neat without dilution, and by manual dilution. Five specimens between Cal E and Cal F (>20.50 to ≤100.00 ng/mL) were evaluated by three methods (neat, manual dilution, and auto-dilution) in replicates of five. In addition, five specimens between Cal F and the auto-dilution limit of 1000.00 ng/mL were evaluated by manual dilution and auto-dilution in replicates of five. The study was completed on one day within two runs. The study demonstrates that the 1:10 auto-dilution protocol meets the 10% bias acceptance criteria from 20.5 ng/mL to the auto-dilution limit of 1000 ng/mL.
The studies support an analytical measuring range of 0.02 to 100.00 ng/mL and an extended measuring range with automatic dilution up to 1000.00 ng/mL.
c. Traceability, Stability, Expected Values (controls, calibrators, or methods) Reagent Stability
The reagent stability data was obtained in two independent studies with three lots of the ARCHITECT B.R.A.H.M.S PCT assay reagents per study for a total of six reagent lots. Both studies were run on one ARCHITECT i2000sr instrument at Thermo Fisher Scientific. Testing data support a shelf life of 9 months for Intended Storage in refrigerated conditions at 2-8°C. The Transport Stability data indicated the reagents can be shipped at ambient or refrigerated conditions.
Calibrator Stability
The calibrator shelf life data was obtained in two independent studies with three lots of the ARCHITECT B.R.A.H.M.S PCT Calibrators per study for a total of six calibrator lots. Both studies were run on one ARCHITECT i2000sR instrument at Thermo Fisher Scientific. Testing data for Intended Storage and In Use/Freeze/Thaw including 3 freeze/thaw cycles support stability at frozen conditions (-10°C or colder) for 9 months.
Controls Stability
The controls shelf life data was obtained in two independent studies with three lots of the ARCHITECT B.R.A.H.M.S PCT Controls per study for a total of six control lots. Both studies were run on one ARCHITECT i2000sr instrument at Thermo Fisher Scientific. Three ARCHITECT B.R.A.H.M.S PCT Controls were tested at each time point: low, medium and high. The ARCHITECT B.R.A.H.M.S PCT Controls were stable at the Intended Storage under frozen conditions (-10°C or colder) for 9 months. In addition, testing data to date support In Use Storage of 30 days post-thaw at 2-8°C for Controls aged for 6 months at the intended storage conditions (-10°C or colder).
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Expected Values
The ARCHITECT B.R.A.H.M.S PCT Calibrators contain six levels with one bottle per level. Calibrator A contains normal human plasma with native PCT removed (0.00 ng/mL). Calibrators B (0.10 ng/mL), C (0.50 ng/mL), D (12.10 ng/mL), E (20.50 ng/mL), and F (100.00 ng/mL) contain recombinant human PCT in phosphate buffer with protein (bovine) stabilizer.
The ARCHITECT B.R.A.H.M.S PCT Controls contain three levels including Low (0.20 ng/mL), Medium (2.00 ng/mL), and High (70.00 ng/mL) with two bottles per level. All controls comprise recombinant human PCT in phosphate buffer with protein (bovine) stabilizer.
d. Detection Limit
Per the CLSI Guideline EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures, the following studies were conducted at the Thermo Fisher internal laboratory to evaluate the detection limits of the ARCHITECT B.R.A.H.M.S PCT assay.
LoB:
The Limit of Blank (LoB) Study used four blank plasma lots run in replicates of six on each of the two i2000sr instruments and two reagent lots per instrument with one run per day for three days using three reagent lots and two calibrator lots. A total of 288 replicates were tested (n=72 replicates per reagent lot per instrument).
LoD:
The Limit of Detection (LoD) used one blank plasma lot spiked to four levels (~0.004, 0.005, 0.006, and 0.007 ng/mL, respectively). Each level was run in replicates of five with one run per day for five days on each of the two i2000sr instruments with three reagent lots and two calibrator lots. A total of 400 replicates were tested (n=100 replicates per reagent lot per instrument).
LoQ:
The Limit of Quantitation (LoQ) study was conducted with two blank plasma lots, and each lot was spiked to five levels spanning a concentration range of 0.0016 ng/mL to 0.0500 ng/mL (estimated to include a concentration with 20% CV). The ten spiked panels were run in replicates of five with one run per day for five days on each of the two i2000sr instruments with three reagent lots and two calibrator lots. A total of 1000 replicates were tested (n=250 replicates per reagent lot per instrument).
The LoB, LoD, LoQ of the method are 0.0004 ng/mL, 0.0018 ng/mL, and 0.0077 ng/mL, respectively.
e. Analytical Specificity/Cross Reactivity
The cross reactivity study followed the guidance of CLSI Guideline EP7-A2, Interference Testing in Clinical Chemistry. Four potential cross-reactants were evaluated in PCT-free plasma and 2 medically relevant levels of PCT (0.5 and 2.0
15
ng/mL). For each PCT level, two samples (a Test Sample and a Reference Sample) were tested in replicates of seven in a single run using one ARCHITECT i2000sR instrument and one reagent lot.
No interference was seen with up to 10 ng/mL Human Katacalcin, 2 ng/mL Human Calcitonin, 10 µg/mL Human a-CGRP, or 10 µg/mL Human ß-CGRP.
f. Interfering Substances
Endogenous
The endogenous interference study followed the guidance of CLSI Guideline EP7-A2, Interference Testing in Clinical Chemistry. Five potential endogenous interfering substances (Hemoglobin, conjugated Bilirubin, unconjugated Bilirubin, Total Protein and Triglycerides) were evaluated for their effect on the quantitation of PCT.
Three plasma-based panels (PCT-free, medium and high) were used for endogenous interference testing. For each interferent, a "reference sample" (endogenous level of interferent) and a "test sample" (elevated level of interferent) were tested in replicates of eight across three runs. The potentially interfering endogenous substances are listed below and were found not to affect the test performance up to the listed concentrations.
| Endogenous Interferents | Interferent Level | % Interference |
|---|---|---|
| Hemoglobin | ≤ 500 mg/dL | 1.9% |
| Triglycerides | ≤ 3000 mg/dL | 0.9% |
| Unconjugated Bilirubin | ≤ 20 mg/dL | 2.8% |
| Conjugated Bilirubin | ≤ 30 mg/dL | 3.9% |
| Total Protein | ≤ 12 g/dL | 4.8% |
Exogenous
The exogenous interference study followed the guidance CLSI Guideline EP7-A2: Interference Testing in Clinical Chemistry.
Drug Interferents
Stock drug solutions were prepared and spiked into plasma to form test samples at the approximate concentrations listed for the 8 potential drug interferents: Imipenem (1.18 mg/mL); Cefotaxime (90 mg/dL); Vancomycin (2.6 mg/mL); Dopamine (13 mg/dL); Noradrenaline (2 ug/mL): Dobutamine (11.2 ug/mL): Heparin (8000 U/L): Furosemide (2 mg/dL). Each drug was spiked into the three human PCT plasma panels (PCT-free plasma, medium and high) with varying amounts of PCT to form the Test Samples. Reference samples were also prepared in plasma by adding the same volume of solvent to the same volume of plasma for each of the samples. Test and reference samples were run in replicates of eight as a sample set in the same run. No interference was seen with up to the listed concentrations.
HAMA Effect
Human anti-mouse antibody (HAMA) stock solutions were spiked into the three PCT plasma panels (PCT-free plasma, medium, and high) at nominal concentrations of 4000, 6000, and 8000 ng/mL. Reference samples were prepared by performing the
16
same percent dilution with blank diluent instead of HAMA stock solution. Test and reference samples were run in replicates of eight as a sample set in the same run. No interference was seen with up to 3600 ng/mL.
RF Effect
A Rheumatoid Factor (RF) stock solution of 47,287 IU/mL was spiked into the three PCT plasma panels (PCT-free plasma, medium, and high) at nominal concentrations of 2,000 IU/mL, 1,000 IU/mL, and 500 IU/mL which created nine Test Samples. Reference samples were produced for each of the nine samples by spiking blank diluent (saline) into the three plasma samples. Each RF Test sample and its respective reference sample were run as a sample set in the same run in replicates of eight. No interference was seen with up to 2000 IU/mL.
g. High Dose Hook Effect
The Prozone or Hook Effect was evaluated at the Thermo Fisher internal laboratory on EDTA disease state plasma samples spiked with recombinant PCT. The EDTA plasma pools were prepared within 10% of CAL F at approximately 90, 95, and 99 ng/mL and at extremely high concentrations far above CAL F at 500, 1,000, 5,000, and 10,000 ng/mL. The seven spiked samples and CAL F were tested in one run with 18 replicates per sample. The study shows that assay is free of hook effects up to 10,000 ng/mL PCT.
h. Assay Cut-off
28-Day Mortality:
ΔPCT ≤ 80%
A decrease in the PCT levels below or equal to 80% defines a positive APCT test result representing a higher risk for 28-day all-cause mortality of patients diagnosed with severe sepsis or septic shock.
ΔPCT > 80%
A decrease in the PCT levels of more than 80% defines a negative ΔPCT result representing a lower risk for 28-day all-cause mortality of patients diagnosed with severe sepsis or septic shock.
Progression Risk:
PCT > 2 ng/mL
A PCT level above 2.0 ng/mL on the first day of ICU admission is associated with a high risk for progression to severe sepsis and/or septic shock.
PCT 0.50 ng/mL Antibiotic therapy strongly encouraged.
Sepsis Antibiotic Discontinuation: ΔPCT > 80% Antibiotic therapy may be discontinued.
PCT ≤ 0.50 ng/mL
Antibiotic therapy may be discontinued.
i. Specimen Stability
The Specimen Stability Study was carried out using fresh samples collected from 53 patients across the range of 0.02 to 62.28 ng/mL in four tube types from subjects located in various hospital departments (e.g., Emergency Department, Critical Care Unit, or In-Patient Unit) from two hospital sites in Switzerland. However, not all donors entered into each storage condition. The study used plasma and serum collected in four tube types:
-
- K2EDTA Plasma
-
- Serum
-
- Lithium Heparin Plasma
-
- Serum Separator Tube
All samples were tested in duplicate at one clinical laboratory on one ARCHITECT i2000SR instrument. The following storage conditions were tested in the study (all storage conditions were off the cells or clot unless otherwise noted) and the results are as follows.
On Board Stability:
Plasma and serum specimens are stable when left on-board the instrument for up to 3 hours.
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Room Temperature:
Specimens are stable at room temperature (15-30°C) for up to 24 hours for plasma or serum harvested from all four tube types. Further, the study verifies specimen stability at room temperature (15-30°C) for plasma left on the cells and for serum left on the clot or separator for:
- ≤ 8 hours on the clot, red blood cells, or separator gel; and .
- ≤ 24 hours off the clot, red blood cells, or separator gel. .
Refrigerated:
Specimens are stable for up to 48 hours when stored refrigerated (2-8°C) for plasma and serum harvested from all four tube types (off the clot, red blood cells, or separator gel).
Freeze-Thaw Cycles:
The study verifies specimen stability for up to 3 freeze/thaw cycles for plasma harvested from an EDTA tube and for serum harvested from a no-additive serum tube or from a serum separator tube. In addition, specimens are stable for 1 freeze/thaw cycle for plasma harvested from a lithium heparin plasma draw tube.
Frozen Short Term:
The study verifies short term frozen (-10°C or colder) specimen stability for up to 15 days for all four tube types (off the clot, red blood cells, or separator gel).
Frozen Long Term:
Sample stability studies that support 18-month stability at -70°C were performed on the MOSES clinical samples in DEN150009. In addition, long-term frozen stability was evaluated with MOSES samples on the ARCHITECT assay (see summary in Section 2 below).
i. Matrix Comparison
The Anticoagulant Matrix Comparison Study followed the guidance of the CLSI Guideline EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples. Matched set specimens were prospectively collected from donors located in various departments (e.g., Emergency Department, Critical Care Unit, or In-Patient Unit) at two hospitals sites in Switzerland. Four tube types were collected from each donor:
-
- K2 EDTA Plasma
-
- Serum
-
- Lithium Heparin Plasma
-
- Serum Separator Tube (SST)
For each patient, each sample was tested in duplicate per sample matrix. Results from serum and lithium heparin plasma were compared to the K2EDTA base tube. The data verify that the bias for Lithium heparin plasma, Serum, and SST with respect to the K2EDTA draw tube is +2%, -4%, and -6%, respectively. Therefore, these four tube types are considered equivalent.
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k. Method Comparison
The Method Comparison Study followed the guidance of CLSI Document EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples. A correlation study using human K2EDTA plasma specimens (n = 142) was performed. The specimens were tested with the ARCHITECT B.R.A.H.M.S PCT assay and compared to values obtained with the B.R.A.H.M.S PCT sensitive KRYPTOR assay. Each donor sample was thawed and run on both instruments on the same day. The results were evaluated using a weighted Deming regression method. The data demonstrates that the comparison of the ARCHITECT B.R.A.H.M.S PCT results to the predicate B.R.A.H.M.S PCT sensitive KRYPTOR® results yielded a slope of 1.00, and a correlation coefficient of 0.99. The data are summarized in the following table and figure.
| Concentration Range (ng/mL) | ||||
|---|---|---|---|---|
| ARCHITECT | ||||
| B.R.A.H.M.S PCT assay | B.R.A.H.M.S PCT sensitive | |||
| KRYPTOR assay | Correlation | |||
| Coefficient | Slope | Intercept | ||
| 0.01 - 91.03 | 0.03 - 82.39 | 0.99 | 1.00 | -0.02 |
Image /page/19/Figure/3 description: This image is a scatter plot that compares the ARCHITECT Mean to the Kryptor Mean, both measured in ng/mL. The plot includes a best fit line, represented by the equation ARCHITECT Mean = -0.02 + 1.00 * Kryptor Mean. The correlation coefficient (r) is 0.99, based on a sample size of n = 142, indicating a strong positive correlation between the two variables. The plot also displays the 95% confidence interval of the fit.
2. Clinical Studies
The ARCHITECT B.R.A.H.M.S PCT assay was evaluated for the prediction of cumulative 28-day all-cause mortality in a prospective clinical trial (MOSES study -Procalcitonin Monitoring Sepsis Study; ClinicalTrials.gov Identifier: NCT01523717) of 858 adult patients diagnosed with severe sepsis or septic shock admitted to ICU care. PCT levels were measured on Days 0, 1, and 4 across the 13 investigational sites in the
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United States. The analysis population (598 subjects) included 44% female and 56% male patients with a mean age of 64 years. About half of the patients had severe sepsis (51%) versus (vs.) septic shock (49%). Infections were mainly community acquired (91%). Testing was performed at 2 external sites and one internal site. Validation of the ARCHITECT B.R.A.H.M.S PCT assay as an aid in predicting mortality was performed in a study population with an overall 28-day mortality of 22%.
The binary test result (ΔPCT > 80% or ≤ 80%) was significantly associated with 28-day cumulative mortality (i.e., vital status on Day 28). The 2-sided Fisher's exact test p-value was 0.001. Adjusted for ICU vs. non-ICU patient subgroups (based on patient location at Day 4 after initial diagnosis), the association remained significant (Cochran-Mantel-Haenszel test p-value = 0.017). In each binary ΔPCT subgroup, the 28-day cumulative mortality rate was stratified by need to continue ICU care on Day 4 and the selection of Day 0 vs. Day 1 as the baseline measurement day for the ΔPCT calculation:
| 28-Day Mortality Risk Stratified by Patient Location on Day 4:
| ΔΡCT > 80% = Test Negative; ΔΡCT ≤ 80% = Test Positive | |||||
|---|---|---|---|---|---|
| Mortality (%) | Prognostic Accuracya | ||||
| APCT Interval | Day 4 Patient | ||||
| Location | ΔPCT > 80% | ||||
| (95% CI) | ΔPCT ≤ 80% | ||||
| (95% CI) | Sensitivity (%) | ||||
| (95% CI) | Specificity (%) | ||||
| (95% CI) | |||||
| Day 0 to Day 4 | ICU | 20.7 | |||
| (12.4-29.0) | 30.6 | ||||
| (23.7-37.5) | 73.4 | ||||
| (63.2-83.7) | 38.0 | ||||
| (31.0-45.0) | |||||
| Non-ICU | 5.7 | ||||
| (2.1-9.4) | 11.4 | ||||
| (6.7-16.2) | 68.8 | ||||
| (51.8-85.7) | 49.1 | ||||
| (43.1-55.1) | |||||
| Day 1 to Day 4 | ICU | 20.2 | |||
| (12.1-28.3) | 31.2 | ||||
| (24.2-38.3) | 72.6 | ||||
| (62.0-83.1) | 40.4 | ||||
| (33.3-47.5) | |||||
| Non-ICU | 5.3 | ||||
| (1.7-8.9) | 11.6 | ||||
| (6.9-16.3) | 71.9 | ||||
| (55.3-88.5) | 47.6 | ||||
| (41.5-53.7) |
a Prognostic accuracy refers to how accurate the ΔPCT (> 80% vs. ≤ 80%) can predict mortality risk.
Additional stratification of patients based on absolute initial PCT concentrations (> 2.0 ng/mL or 2.0 ng/mL at Day 0 (or Day 1) receiving ICU care on Day 4
- 2. Patients with PCT 2.0 ng/mL at Day 0 (or Day 1) without ICU care on Day 4
-
- Patients with PCT ≤ 2.0 ng/mL at Day 0 (or Day 1) without ICU care on Day 4
| 28-Day Mortality Risk Stratified by Patient Location on Day 4:
| ΔPCT > 80% = Test Negative; ΔPCT ≤ 80% = Test Positive | ||||||
|---|---|---|---|---|---|---|
| ΔPCT | ||||||
| Interval | Day 4 Patient | |||||
| Location | Initial PCT | |||||
| Concentration | ||||||
| (Day 0 or Day 1) | Mortality (%) | Prognostic Accuracya | ||||
| ΔPCT > 80% | ||||||
| (95% CI) | ΔPCT ≤ 80% | |||||
| (95% CI) | Sensitivity (%) | |||||
| (95% CI) | Specificity (%) | |||||
| (95% CI) |
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| 28-Day Mortality Risk Stratified by Patient Location on Day 4:
| ΔΡСТ > 80% = Test Negative; ΔΡCT ≤ 80% = Test Positive | ||||||
|---|---|---|---|---|---|---|
| Initial PCT | ||||||
| Concentration | ||||||
| (Day 0 or Day 1) | Mortality (%) | Prognostic Accuracya | ||||
| APCT | ||||||
| Interval | Day 4 Patient | |||||
| Location | ΔΡCT > 80% | |||||
| (95% CI) | ΔΡCT ≤ 80% | |||||
| (95% CI) | Sensitivity (%) Specificity (%) | |||||
| (95% CI) | (95% CI) | |||||
| Day 0 to | ||||||
| Day 4 | ICU | ≤ 2.0 ng/mL | 7.3 | |||
| (0.0-21.1) | 24.7 | |||||
| (14.5-34.9) | 94.1 | |||||
| (82.8-100.0) | 20.7 | |||||
| (10.6-30.8) | ||||||
| > 2.0 ng/mL | 23.2 | |||||
| (13.8-32.6) | 34.5 | |||||
| (25.4-43.7) | 66.5 | |||||
| (53.9-79.2) | 46.8 | |||||
| (38.0-55.6) | ||||||
| Non-ICU | ≤ 2.0 ng/mL | 3.3 | ||||
| (0.0-9.8) | 8.6 | |||||
| (3.5-13.7) | 90.9 | |||||
| (73.9-100.0) | 21.6 | |||||
| (14.0-29.1) | ||||||
| > 2.0 ng/mL | 6.3 | |||||
| (2.1-10.5) | 17.0 | |||||
| (7.2-26.7) | 55.2 | |||||
| (32.1-78.3) | 71.1 | |||||
| (63.7-78.6) | ||||||
| Day 1 to | ||||||
| Day 4 | ICU | ≤ 2.0 ng/mL | 12.4 | |||
| (0.0-32.3) | 25.7 | |||||
| (15.1-36.2) | 91.7 | |||||
| (77.7-100.0) | 17.9 | |||||
| (8.0-27.7) | ||||||
| > 2.0 ng/mL | 21.3 | |||||
| (12.5-30.1) | 35.0 | |||||
| (25.6-44.5) | 65.7 | |||||
| (52.8-78.7) | 50.9 | |||||
| (42.2-59.7) | ||||||
| Non-ICU | ≤ 2.0 ng/mL | 0.0 | ||||
| (0.0-12.3)b | 8.5 | |||||
| (3.5-13.5) | 100.0 | |||||
| (69.2-100.0)b | 19.8 | |||||
| (12.5-27.1) | ||||||
| > 2.0 ng/mL | 6.5 | |||||
| (2.1-10.9) | 18.2 | |||||
| (7.9-28.5) | 56.1 | |||||
| (33.1-79.0) | 71.4 | |||||
| (63.7-79.1) |
a Prognostic accuracy refers to how accurate the ΔPCT (> 80% vs.≤ 80%) can predict mortality risk. b Normality approximation of within-imputation variance not valid, therefore the estimate corresponds to withinimputation variation based on exact confidence intervals.
The relative mortality ratios for ΔPCT positive ( 80%) patient subgroups were:
- 1.49 for patients with PCT > 2.0 ng/mL at Day 0 receiving ICU care on Day 4 .
- 3.38 for patients with PCT ≤ 2.0 ng/mL at Day 0 receiving ICU care on Day 4 .
- 2.70 for patients with PCT > 2.0 ng/mL at Day 0 without ICU care on Day 4 .
- 2.61 for patients with PCT 80% decreases in each subgroup.
Time-to-event analyses, illustrated by the Kaplan-Meier curves below, demonstrate that patients had a lower survival probability (higher cumulative mortality risk) from Day 4 until the end of follow-up time (Day 28) when the APCT test result was positive compared to when the ΔPCT result was negative in all patient subgroups according to patient location on Day 4 and initial PCT concentration.
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Image /page/22/Figure/0 description: This image is a survival curve comparing two groups of patients. The x-axis represents time in days, ranging from 0 to 28, and the y-axis represents the proportion of patients surviving, ranging from 0% to 100%. The dashed line represents patients with negative delta PCT (n=78, deaths=18), while the solid line represents patients with positive delta PCT (n=104, deaths=36). The survival rate is higher for patients with negative delta PCT compared to those with positive delta PCT.
Survival until Day 28, PCT > 2.0 ng/mL at Day 0, ICU Day 4 (n=182)
Survival until Day 28, PCT > 2.0 ng/mL at Day 0, Non-ICU Day 4 (n=187)
Image /page/22/Figure/3 description: This image is a survival analysis plot comparing two groups of patients based on their delta procalcitonin (ΔPCT) levels. The x-axis represents time in days, ranging from 0 to 28, while the y-axis represents the proportion of patients surviving, ranging from 0% to 100%. The dashed line represents patients with negative ΔPCT (n=128, deaths=8), and the solid line represents patients with positive ΔPCT (n=59, deaths=10). The survival rate is higher for patients with negative ΔPCT compared to those with positive ΔPCT over the 28-day period.
23
Image /page/23/Figure/0 description: This image is a survival plot comparing two groups of patients, one with negative ΔPCT and the other with positive ΔPCT. The x-axis represents time in days, ranging from 0 to 28, while the y-axis represents the proportion of patients surviving. The plot shows that patients with negative ΔPCT have a higher survival rate compared to those with positive ΔPCT. Specifically, the negative ΔPCT group had 14 patients with 1 death, while the positive ΔPCT group had 69 patients with 17 deaths.
Survival until Day 28, PCT ≤ 2.0 ng/mL at Day 0, ICU Day 4 (n=84)
Survival until Day 28, PCT ≤ 2.0 ng/mL at Day 0, Non-ICU Day 4 (n=147)
Image /page/23/Figure/3 description: The image is a survival plot showing the proportion of patients surviving over time in days. The x-axis represents time in days from 0 to 28, and the y-axis represents the proportion of patients surviving from 0% to 100%. There are two survival curves, one for patients with negative delta PCT (n=30, deaths=1) and one for patients with positive delta PCT (n=116, deaths=10). The survival rate is higher for patients with negative delta PCT compared to those with positive delta PCT.
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For the prediction of absolute mortality risks, patient location on Day 4 and initial PCT concentration should be considered:
- An initial PCT concentration ≤ 2.0 ng/mL on Day 0 followed by a PCT concentration . decrease of more than 80% by Day 4 indicates approximately a one-third lower cumulative 28-day mortality risk (7.3%) for patients with severe sepsis or septic shock who are still in the ICU by Day 4 compared to those patients with an initial PCT concentration > 2.0 ng/mL (23.2%). Regardless of the initial PCT concentration, patients in the ICU on Day 4 that do not have a PCT concentration decrease of more than 80% in PCT plasma concentration from Day 0 to Day 4 have even higher mortality risks of 24.7% and 34.5%.
- An initial PCT concentration > 2.0 ng/mL that does not decrease by more than 80% ● by Day 4 signals that such patients remain at high mortality risk (17.0%) even when they are no longer receiving ICU care on Day 4. Mortality was otherwise observed between 3.3% to 8.6% for patients discharged from the ICU by Day 4. ΔPCT from Day 0 to Day 4 (≤ 80% vs. > 80%) as a prognostic for 28-day cumulative risk of mortality was quantified by Cox proportional hazards regression analysis with a hazard ratio of 1.99 (95% CI of 1.28–3.09, p-value = 0.0021). The relative risk of cumulative 28-day mortality is about 2-fold higher if an individual tests positive for ΔPCT (≤ 80%) than if an individual tests negative (> 80%).
| Predictors | Comparison | Hazard Ratio | 95% CI | p-Value |
|---|---|---|---|---|
| ΔPCT (Day 0 to Day |
-
| ≤ 80% vs. > 80% | 1.99 | 1.28-3.09 | 0.002 |
| ΔPCT (Day 1 to Day
4) | ≤ 80% vs. > 80% | 2.03 | 1.30-3.18 | 0.002 |
| APACHEa | Difference of 5 Units | 1.36 | 1.22-1.53 | 2 ng/mL vs. ≤ 2
ng/mL | 1.59 | 1.04-2.45 | 0.034 |
| Age | Difference of 5 Years | 1.16 | 1.08-1.24 | 80%) | Day 4 Patient
Location (ICU
vs. Non-ICU) | APACHE
(1 SD = 8.13) | Maximum
SOFA
(1 SD = 3.98) | Age
(1 SD = 16.18) |
| Day 0 to Day 4 | APACHE | 1.89
(1.14-3.14) | 2.59
(1.61-4.15) | 1.22
(0.98-1.53) | N/A | 1.60
(1.28-2.00) |
| | Maximum
SOFA | 1.55
(0.94-2.57) | 1.70
(1.03-2.80) | N/A | 1.93
(1.49-2.49) | 1.69
(1.35-2.11) |
| Day 1 to Day 4 | APACHE | 1.96
(1.20-3.22) | 2.61
(1.63-4.18) | 1.26
(1.01-1.58) | N/A | 1.56
(1.24-1.95) |
| | Maximum
SOFA | 1.74
(1.06-2.86) | 1.72
(1.05-2.83) | N/A | 1.94
(1.51-2.50) | 1.65
(1.32-2.06) |
a The models also included the following predictors (hazard ratio results not shown): antibiotic adequacy, sepsis severity, biological infection type, clinical infection type, positive blood culture, PCT concentration on Day 0, and gender.
The change of PCT over time can also be described by the ratio of PCT concentrations from Day 4 and Day 0 (or Day 1):
$$\mathsf{PCT}{\mathsf{ratio}} = \frac{\mathsf{PCT}{\mathsf{Day},4}}{\mathsf{PCT}_{\mathsf{Day}} \bullet (\mathsf{or} \ \mathsf{copy} \ t)}$$
A decline of ΔPCT = 80% translates into a PCT ratio of 0.2. The PCT ratio has values larger than 0.2 when the ΔPCT decrease is less than 80%, which is associated with a higher risk for cumulative 28-day all-cause mortality in patients diagnosed with severe sepsis or septic shock. Likewise, a PCT ratio below 0.2 indicates a lower risk for mortality within 28 days. On a continuous scale, the relative mortality risk for such
26
patients is higher the larger the PCT ratio. The following table lists the hazard ratios for an increase by the factor 2 in PCT ratio (i.e., the relative increase in mortality risk for a patient with any given PCT ratio compared to a patient with a 2-fold lower PCT ratio). For comparison, selected predictors are indicated with corresponding equivalents in standard deviation (0.53 SD for Day 0 until Day 4 and 0.72 SD for Day 1 until Day 4). For the patient location at Day 4, the risk estimate compares the hazards for patients with vs. without ICU care on Day 4.
| Hazard Ratio (95% CI) | ||||||
|---|---|---|---|---|---|---|
| Model | Continuous Predictors | |||||
| (HR per 2-fold increase in PCT ratio or per equivalent in SD) | Binary | |||||
| Predictor | ||||||
| ΔPCT | ||||||
| Interval | Score + | |||||
| Covariatesa | PCT Ratio (2- | |||||
| Fold Increase) | APACHE (SD | |||||
| Equivalent)b | Maximum | |||||
| SOFA (SD | ||||||
| Equivalent)b | Age (SD | |||||
| Equivalent)b | Day 4 Patient | |||||
| Location | ||||||
| ICU vs. | ||||||
| Non-ICU | ||||||
| Day 0 to | ||||||
| Day 4 | APACHE | 1.28 | ||||
| (1.14-1.44) | 1.07 | |||||
| (0.95-1.21) | N/A | 1.29 | ||||
| (1.15-1.45) | 2.50 | |||||
| (1.55-4.02) | ||||||
| Maximum | ||||||
| SOFA | 1.21 | |||||
| (1.07-1.36) | N/A | 1.36 | ||||
| (1.19-1.55) | 1.32 | |||||
| (1.18-1.48) | 1.69 | |||||
| (1.02-2.78) | ||||||
| Day 1 to | ||||||
| Day 4 | APACHE | 1.35 | ||||
| (1.17-1.57) | 1.18 | |||||
| (1.01-1.38) | N/A | 1.38 | ||||
| (1.18-1.61) | 2.54 | |||||
| (1.58-4.06) | ||||||
| Maximum | ||||||
| SOFA | 1.29 | |||||
| (1.10-1.50) | N/A | 1.55 | ||||
| (1.31-1.84) | 1.44 | |||||
| (1.23-1.67) | 1.74 | |||||
| (1.06-2.86) |
a The models also included the following predictors (hazard ratio results not shown): antibiotic adequacy, sepsis severity, biological infection type, clinical infection type, positive blood culture, PCT concentration on Day 0, and gender. b A unit change of ΔPCT on log-2-scale corresponded to 0.52 SD of ΔPCT from Day 0 until Day 4 (0.69 SD for ΔPCT from Day 1 until Day 4). Accordingly, the reported APCT hazard ratios refer to an increase of ΔPCT by a factor of 2. For comparability, hazard ratios of the other continuous predictors were estimated for the same fractional SD (i.e., 0.52 or 0.69, respectively).
Cumulative 28-day all-cause mortality did not differ significantly for male vs. female patients ($\chi^{2}$ p-value = 0.84). Demographics with outcome information are presented below:
| Variable | Class | All Patients
(n = 598) | Dead (n) | Alive (n) | Mortality (%) |
|-------------|------------------|---------------------------|----------|-----------|---------------|
| Gender | Female | 264 | 46 | 218 | 17.4% |
| | Male | 334 | 55 | 279 | 16.5% |
| Age (Years) | ≤ 30 | 39 | 1 | 38 | 2.6% |
| | > 30 to 45 | 45 | 4 | 41 | 8.9% |
| | > 45 to 55 | 74 | 8 | 66 | 10.8% |
| | > 55 to 65 | 149 | 26 | 123 | 17.4% |
| | > 65 to 75 | 125 | 21 | 104 | 16.8% |
| | > 75 | 166 | 41 | 125 | 24.7% |
| Ethnicity | African-American | 202 | 32 | 170 | 15.8% |
| | Asian | 7 | 0 | 7 | 0.0% |
| | Caucasian | 362 | 64 | 298 | 17.7% |
27
| Variable | Class | All Patients
(n = 598) | Dead (n) | Alive (n) | Mortality (%) |
|-------------------------|------------|---------------------------|----------|-----------|---------------|
| | Hispanic | 23 | 5 | 18 | 21.7% |
| | Other | 4 | 0 | 4 | 0.0% |
| PCT on Day 0
(ng/mL) | 2.0 | 360 | 72 | 288 | 20.0% |
| | Missing | 15 | 0 | 15 | 0.0% |
The clinical concordance analysis of the ARCHITECT B.R.A.H.M.S PCT clinical performance study showed more than 96% total agreement between the ARCHITECT B.R.A.H.M.S PCT and the B.R.A.H.M.S PCT sensitive Kryptor® (predicate device) at the medical decision points 0.5 µg/L and 2.0 µg/L.
3. Clinical Cut-Off
See Section N.1.h., Assay Cut-Off.
4. Expected Values/Reference Range
The Reference Range study was performed using the ARCHITECT B.R.A.H.M.S PCT Assay on normal healthy donor K2EDTA plasma collected from n=446 individuals, males (n=217) and females (n=229). The reference limits at the 2.5" and 97.5" percentiles were determined to be 0.006 ng/mL and 0.065 ng/mL, respectively.
| AGE | N | Ethnicity | ||||
|---|---|---|---|---|---|---|
| African American | Asian | Caucasian | Hispanic | Other | ||