(249 days)
Not Found
No.
The device performs a simple ratio calculation and compares it against pre-defined thresholds ("cutoffs") to classify results. There is no mention of AI, ML, or complex models being used for prediction or decision-making beyond these fixed rules. The ratio calculation is explicitly stated to be done manually by the operator, and the cutoffs were determined using traditional statistical methods on a training set, not through AI/ML model training.
No
The device is an in vitro diagnostic test intended to aid in identifying patients with amyloid pathology associated with Alzheimer's disease. It does not provide any treatment or therapy.
No
Explanation: The "Intended Use / Indications for Use" section explicitly states, "This test is not intended as a screening or stand-alone diagnostic test." Instead, it is intended "to aid healthcare providers to identify patients with amyloid pathology" and "results must be interpreted in conjunction with other patient clinical information."
No
The device is an in vitro diagnostic (IVD) test that relies on physical assays (Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma assays) performed on a hardware instrument (LUMIPULSE G1200 System) to generate concentration results. While a ratio is calculated from these results, the core technology involves wet-lab chemistry and instrumentation, not purely software. The summary explicitly states the LUMIPULSE G1200 performs the assays and that the ratio calculation must be done manually by the operator, further confirming it's not a software-only device.
Yes.
The device is an in vitro test that analyzes human plasma to aid in identifying patients with amyloid pathology associated with Alzheimer's disease.
N/A
# Intended Use / Indications for Use
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is an in vitro test using human plasma (K2EDTA) that combines the results of Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma assays into a ratio of pTau 217 to β-Amyloid 1-42 concentrations using the Lumipulse G1200 System.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is intended to aid healthcare providers to identify patients with amyloid pathology associated with Alzheimer's disease.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is indicated for adult patients, aged 50 years and older, presenting at a specialized care setting with signs and symptoms of cognitive decline.
A test result ≤ 0.00370 is a negative result which is consistent with patients who are unlikely to have amyloid pathology. These patients should be investigated for other causes of cognitive decline.
A test result ≥ 0.00738 is a positive result which is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of Alzheimer's disease or other cognitive disorders.
A test result between 0.00371 and 0.00737 is an indeterminate result which is consistent with patients who are uncertain to have amyloid pathology. These patients should be considered for further testing.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results must be interpreted in conjunction with other patient clinical information.
This test is not intended as a screening or stand-alone diagnostic test.
# Product codes (comma separated list FDA assigned to the subject device)
SET
# Device Description
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is a test that combines the test results of the Lumipulse G pTau 217 Plasma assay and Lumipulse G β-Amyloid 1-42-N Plasma assay from the same patient specimen (K2EDTA plasma sample) into a numerical ratio from 0.00000 – 1.00000. The numerical ratio will be compared to the established cutoffs.
Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio = Lumipulse G pTau 217 Plasma (results in pg/mL) / Lumipulse G β-Amyloid 1-42-N Plasma (results in pg/mL) = a numerical value targeted up to 1.00000
Components include:
1. Lumipulse G pTau 217 Plasma assay system: Uses chemiluminescent enzyme immunoassay (CLEIA) technology for quantitative measurement of pTau 217. Components include Antibody-Coated Particle Solution (0.025% anti-phosphorylated Tau (217) monoclonal antibody (mouse)-coated particles), Enzyme-Labeled Antibody Solution (0.50 µg/mL alkaline phosphatase (ALP)-labeled anti-Tau monoclonal antibodies (mouse) conjugate), and Assay Specific Solution.
2. Lumipulse G β-Amyloid 1-42-N Plasma assay system: Uses CLEIA technology for quantitative measurement of β-amyloid1-42. Components include Antibody-Coated Particle Solution (0.050% anti-Amyloid1-42 monoclonal antibody (mouse)-coated particles), Enzyme-Labeled Antibody Solution (0.50 µg/mL alkaline phosphatase (ALP)-labeled anti-β-amyloid monoclonal antibodies (mouse) conjugate), and Assay Specific Solution.
3. LUMIPULSE G1200: An instrument platform that performs automated chemiluminescence immunoassays, including dispensing, agitation, and photometric measurement.
The instrument reports the results of the individual pTau 217 and β-Amyloid 1-42-N plasma assays separately. The ratio is calculated manually by the operator.
# 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
Adult patients, aged 50 years and older.
# Intended User / Care Setting
Healthcare providers in a specialized care setting.
Clinical and Hospital laboratories.
# Description of the training set, sample size, data source, and annotation protocol
The assay cut-offs were determined using 208 banked K2EDTA plasma samples.
- Data sources:
- Patient samples from clinical phase III studies of elenbecestat (MissionAD, ClinicalTrials.gov Identifiers: NCT02956486 and NCT03036280).
- Plasma samples from BioFINDER-2 (ClinicalTrials.gov Identifier: NCT03174938).
- Plasma samples from BIOCARD (http://grantome.com/grant/NIH/U19-AG033655-06).
- Sample size: 208 samples.
- Annotation protocol: Subjects' clinical data included signs and symptoms of cognitive decline, amyloid PET with FDA-cleared tracer and/or FDA-cleared amyloid CSF ratio information. These subjects are distinct from the subjects evaluated in the pivotal clinical validation study. The 208 patients are comprised of 12 patients with AD dementia, 150 with mild cognitive impairment (MCI), 7 with subjective cognitive decline (SCD) and 39 with other causes of cognitive decline. Amyloid positivity was derived from either a positive amyloid PET and/or a positive amyloid CSF ratio. The procedures of plasma collection, processing and handling were conducted according to the tube manufacturer's instructions. The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio assay cutoffs were calculated based on agreement with amyloid status.
# Description of the test set, sample size, data source, and annotation protocol
A clinical study of 499 patients was conducted to evaluate the performance of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio.
- Sample Size: 499 patients.
- Data Source:
- Polaris-AD (AriBio) patient samples from the screening period of the clinical phase III study of AR1001.
- Skåne University Hospital Memory Clinic, Malmö, Sweden plasma samples from subjects enrolled in BioFINDER-2.
- Bio-Hermes-001 samples obtained from Global Alzheimer's Platform Foundation.
- University of Wisconsin Plasma samples from subjects enrolled in Wisconsin Registry for Alzheimer's Prevention (WRAP).
- Annotation protocol: Amyloid positivity confirmed by historic amyloid PET with an FDA-cleared tracer or FDA-cleared amyloid CSF ratio. The patients were categorized into four diagnostic groups: 1.2% (6/499) other cognitive diagnoses, 9.8% (49/499) subjective cognitive decline (SCD), 30.9% (154/499) MCI, and 58.1% (290/499) AD patients. No other neurological diseases were included in this cohort.
# Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
**Analytical Performance**
1. **Reproducibility/Precision**:
* **Lumipulse G pTau 217 Plasma**: Precision ≤ 10.3% (total %CV). Study conducted per CLSI EP05-A3. Five human K2EDTA plasma panels assayed in replicates of two, twice a day for 20 days (N=80 for each panel) on one LUMIPULSE G1200 System.
* **Lumipulse G β-Amyloid 1-42-N Plasma**: Precision ≤ 3.8% (total %CV). Study conducted per CLSI EP05-A3. Five human K2EDTA plasma panels assayed in replicates of two, twice a day for 20 days (N=80 for each panel) on one LUMIPULSE G1200 System.
* **Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio**: Precision ≤ 10.2 % (total %CV). Study conducted per CLSI EP05-A3. Five human K2EDTA plasma panels assayed in replicates of two, twice a day for 20 days (N=80 for each panel) on one LUMIPULSE G1200 System. Qualitative agreement percentage of positive and negative results also reported for each panel.
2. **Linearity**:
* **Lumipulse G pTau 217 Plasma**: Linear across 0.037 pg/mL to 11.326 pg/mL. Correlated with expected concentrations per y = -0.001293 + 0.9849x; R²: 0.9993.
* **Lumipulse G β-Amyloid 1-42-N Plasma**: Linear across 0.8 pg/mL to 1012.0 pg/mL. Correlated with expected concentrations per y = 0.02084 + 1.01x; R²: 0.9997.
3. **Analytical Specificity/Interference**:
* **Interference**: Demonstrated interference of less than ± 10% for tested endogenous (Bilirubin, Hemoglobin, Total Protein, Triglycerides, Biotin, HAMA IgG, Rheumatoid Factor, Immunoglobulin G, Immunoglobulin M, Immunoglobulin A) and exogenous (various common medications/substances like Acetaminophen, Aducanumab, Aspirin, Caffeine, Donanemab, Donepezil, Heparin, Ibuprofen, Lecanemab, Memantine, etc.) interfering substances.
* **Cross-reactivity**: Highest observed cross-reactivity values were low (e.g., pTau 181: 0.050%, β-Amyloid 1-43: 0.200%).
4. **Assay Reportable Range**:
* **Lumipulse G pTau217 Plasma**: Analytical Measuring Interval (AMI) 0.047 pg/mL to 10.000 pg/mL; Reportable Range 0.041 pg/mL to 10.000 pg/mL.
* **Lumipulse G β-Amyloid 1-42-N Plasma**: AMI 0.8 pg/mL to 500.0 pg/mL; Reportable Range 0.2 pg/mL to 500.0 pg/mL.
5. **Detection Limit**:
* **Lumipulse G pTau 217 Plasma**: LoB at 0.025 pg/mL, LoD at 0.0407 pg/mL, LoQ at 0.0472 pg/mL.
* **Lumipulse G β-Amyloid 1-42-N Plasma**: LoB at 0.128 pg/mL, LoD at 0.2074 pg/mL, LoQ at 0.8 pg/mL.
6. **High Dose Hook Effect**: Not observed for Lumipulse G pTau 217 Plasma (up to 610 pg/mL) and Lumipulse G β-Amyloid 1-42-N Plasma (up to 2,200 pg/mL).
7. **Assay Cut-off**: Determined by analyzing 208 banked K2EDTA plasma samples from clinical studies and biobanks. Cut-offs: ≤ 0.00370 (Negative), ≥ 0.00738 (Positive), 0.00371 - 0.00737 (Indeterminate).
**Clinical Studies**
- **Evaluation of Patients Presenting with Cognitive Decline**:
* **Study Type**: Clinical performance evaluation compared to amyloid PET or CSF results.
* **Sample Size**: 499 patients.
* **Key Results**:
* **Predictive Value (PV) for Positive Result**: 91.8% (95% CI: 87.8%, 94.6%)
* **Likelihood Ratio for Positive Result**: 10.68 (95% CI: 6.90, 16.79)
* **PV for Indeterminate Result**: 50.0% (95% CI: 41.3%, 58.8%)
* **Likelihood Ratio for Indeterminate Result**: 0.96 (95% CI: 0.67, 1.36)
* **PV for Negative Result**: 2.7% (95% CI: 1.2%, 6.1%)
* **Likelihood Ratio for Negative Result**: 0.03 (95% CI: 0.01, 0.06)
**Reference Interval/Expected Values**
- **Cognitively Normal Individuals**: Study of 240 evaluable human plasma samples (115 males, 125 females, aged 51-84 years). Showed increasing percentage of positive results with age (from 2.2% in 51-65 age group to 60.0% in 81-84 age group).
- **Non-AD and other neurological conditions**: Study of 296 evaluable human plasma samples. Showed varying percentages of positive results across different conditions (e.g., 84.6% for Lewy Body Dementia, 15.4% for Multiple Sclerosis).
# Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
**Clinical Study (Evaluation of Patients Presenting with Cognitive Decline)**
- **Positive Predictive Value (PV)**: 91.8% (87.8%, 94.6%) for Positive Ratio (≥ 0.00738)
- **Predictive Value (PV)**: 50.0% (41.3%, 58.8%) for Indeterminate Ratio (0.00371 ≤ Ratio ≤ 0.00737)
- **Predictive Value (PV)**: 2.7% (1.2%, 6.1%) for Negative Ratio (≤ 0.00370)
- **Likelihood Ratio for Positive Result**: 10.68 (6.90, 16.79)
- **Likelihood Ratio for Indeterminate Result**: 0.96 (0.67, 1.36)
- **Likelihood Ratio for Negative Result**: 0.03 (0.01, 0.06)
- **Prevalence of Amyloid Status in the Study**: 51.1% (Positive).
**Assay Cut-off Determination Study**
- **Positive Predictive Value (PV)**: 94.6% (88.7%, 97.6%) for Positive Ratio (≥ 0.00738)
- **Predictive Value (PV)**: 47.6% (34.7%, 60.9%) for Indeterminate Ratio (0.00371 ≤ Ratio ≤ 0.00737)
- **Predictive Value (PV)**: 4.3% (3.9%, 16.0%) for Negative Ratio (≤ 0.00370)
- **Likelihood Ratio for Positive Result**: 14.51 (6.49, 33.90)
- **Likelihood Ratio for Indeterminate Result**: 0.75 (0.44, 1.28)
- **Likelihood Ratio for Negative Result**: 0.07 (0.03, 0.15)
- **Prevalence of Amyloid Status in the Study**: 54.8% (Positive).
# 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.
[DEN200072](https://510k.innolitics.com/search/DEN200072)
# 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
N/A
FDA 510(k) Clearance Letter - Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio
Page 1
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
www.fda.gov
Doc ID # 04017.07.05
May 16, 2025
Fujirebio Diagnostics, Inc.
Stacey Dolan
Senior Manager, Regulatory Affairs
201 Great Valley Parkway
Malvern, Pennsylvania 19475
Re: K242706
Trade/Device Name: Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio
Regulation Number: 21 CFR 866.5840
Regulation Name: Alzheimer's Disease Pathology Assessment Test
Regulatory Class: Class II
Product Code: SET
Dated: April 17, 2025
Received: April 17, 2025
Dear Stacey Dolan:
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 (the 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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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.
Page 2
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 Part 801 and Part 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/unique-device-identification-system-udi-system.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-devices/medical-device-safety/medical-device-reporting-mdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-
Page 3
assistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Ying Mao -S
Ying Mao, Ph.D.
Branch Chief
Division of Immunology and Hematology Devices
OHT7: Office of In Vitro Diagnostics
Office of Product Evaluation and Quality
Center for Devices and Radiological Health
Enclosure
Page 4
Food and Drug Administration
Indications for Use
Form Approved: OMB No. 0910-0120
Expiration Date: 07/31/2026
See PRA Statement below.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Submission Number (if known): K242706
Device Name: Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio
Indications for Use (Describe)
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is an in vitro test using human plasma (K2EDTA) that combines the results of Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma assays into a ratio of pTau 217 to β-Amyloid 1-42 concentrations using the Lumipulse G1200 System.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is intended to aid healthcare providers to identify patients with amyloid pathology associated with Alzheimer's disease.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is indicated for adult patients, aged 50 years and older, presenting at a specialized care setting with signs and symptoms of cognitive decline.
A test result ≤ 0.00370 is a negative result which is consistent with patients who are unlikely to have amyloid pathology. These patients should be investigated for other causes of cognitive decline.
A test result ≥ 0.00738 is a positive result which is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of Alzheimer's disease or other cognitive disorders.
A test result between 0.00371 and 0.00737 is an indeterminate result which is consistent with patients who are uncertain to have amyloid pathology. These patients should be considered for further testing.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results must be interpreted in conjunction with other patient clinical information.
This test is not intended as a screening or stand-alone diagnostic test.
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)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
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"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
Page 5
Premarket Notification Lumipulse® G pTau 217/β-Amyloid 1-42 Plasma Ratio
510(k) Decision Summary
I. BACKGROUND INFORMATION
A. 510(k) Number
B. Applicant
Fujirebio Diagnostics, Inc
C. Proprietary and Established Names
Lumipulse G p Tau 217/β-Amyloid 1-42 Plasma Ratio
D. Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
|---|---|---|---|
| SET | Class II | 21 CFR 866.5840 – Alzheimer's Disease Pathology Assessment Test | IM - Immunology |
II. SUBMISSION/DEVICE OVERVIEW:
A. Purpose for Submission:
New Device
B. Measurand:
Ratio of two analytes: pTau217 and β-Amyloid 1-42
C. Type of Test:
Fully automated, chemiluminescent enzyme immunoassays (CLEIA)
III. INTENDED USE/INDICATIONS FOR USE:
A. Intended Use(s):
Page 6
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is an in vitro test using human plasma (K2EDTA) that combines the results of Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma assays into a ratio of pTau 217 to β-Amyloid 1-42 concentrations using the LUMIPULSE G1200 System.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is intended to aid healthcare providers to identify patients with amyloid pathology associated with Alzheimer's disease.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is indicated for adult patients, aged 50 years and older, presenting at a specialized care setting with signs and symptoms of cognitive decline.
A test result ≤ 0.00370 is a negative result which is consistent with patients who are unlikely to have amyloid pathology. These patients should be investigated for other causes of cognitive decline.
A test result ≥ 0.00738 is a positive result which is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of Alzheimer's disease or other cognitive disorders.
A test result between 0.00371 and 0.00737 is an intermediate result which is consistent with patients who are uncertain to have amyloid pathology. These patients should be considered for further testing.
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results must be interpreted in conjunction with other patient clinical information.
This test is not intended as a screening or stand-alone diagnostic test.
B. Indication for Use(s):
Same as Intended Use
C. Special Conditions for Use Statement(s):
For in vitro diagnostics use only.
D. Special instrument requirements:
LUMIPULSE G1200 System (cleared under K142895)
Page 7
IV. DEVICE/SYSTEM CHARACTERISTICS:
A. Device Description:
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is a test that combines the test results of the Lumipulse G pTau 217 Plasma assay and Lumipulse G β-Amyloid 1-42-N Plasma assay from the same patient specimen (K2EDTA plasma sample) into a numerical ratio from 0.00000 – 1.00000. The numerical ratio will be compared to the established cutoffs.
Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio = Lumipulse G pTau 217 Plasma (results in pg/mL) / Lumipulse G β-Amyloid 1-42-N Plasma (results in pg/mL) = a numerical value targeted up to 1.00000
1. Lumipulse G p Tau217 Plasma
Lumipulse G pTau 217 Plasma is an assay system including a set of immunoassay reagents, for the quantitative measurement of pTau 217 in K2EDTA plasma specimens based on chemiluminescent enzyme immunoassay (CLEIA) technology by a specific two-step immunoassay method on the LUMIPULSE G System. The components of the Lumipulse G pTau 217 Plasma are as follows:
Lumipulse G pTau217 Plasma
| Component | Volume | Contents |
|---|---|---|
| Antibody-Coated Particle Solution | Liquid 150µL/Immunoreaction Cartridge | 0.025% anti-phosphorylated Tau (217) monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine) in 50 mM Tris buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: 0.1% ProClin 300. |
| Enzyme-Labeled Antibody Solution | Liquid 220µL/Immunoreaction Cartridge | 0.50 µg/mL alkaline phosphatase (ALP)-labeled anti-Tau monoclonal antibodies (mouse) conjugate, protein (bovine) and chemical stabilizers in 50 mM MOPS buffer. Preservative: 0.1% ProClin 300 |
| Assay Specific Solution | Liquid 80µL/Immunoreaction Cartridge | 3.45% chemical stabilizers in 50mM Tris buffer. Preservative: 0.1% ProClin 300 |
Additional materials required but sold separately:
- Lumipulse G pTau 217 Plasma Calibrators: Five (5) Lumiuplse G pTau 217 Calibrators with concentrations of 0, 0.250, 1.000, 5.000 and 10.000 pg/mL.
- Lumipulse pTau 217 Plasma Controls: Two (2) levels of Lumipulse pTau 217 Plasma Controls, liquid (frozen)
Page 8
2. Lumipulse G β-Amyloid 1-42-N Plasma
Lumipulse G β-Amyloid 1-42-N Plasma is an assay system including a set of immunoassay reagents, for the quantitative measurement of β-amyloid1-42 in K2EDTA plasma specimens based on CLEIA technology by a two-step immunoassay method on the LUMIPULSE G System. The components of the Lumipulse G β-Amyloid 1-42-N Plasma are as follows:
Lumipulse G β-Amyloid 1-42-N Plasma
| Component | Volume | Contents |
|---|---|---|
| Antibody-Coated Particle Solution | Liquid 150µL/Immunoreaction Cartridge | 0.050% anti-Amyloid1-42 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine) in 50 mM MES buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: 0.1% Proclin 300. |
| Enzyme-Labeled Antibody Solution | Liquid 250µL/Immunoreaction Cartridge | 0.50 µg/mL alkaline phosphatase (ALP)-labeled anti-β-amyloid monoclonal antibodies (mouse) conjugate, protein (bovine) and chemical stabilizers in 50 mM MES buffer. Preservative: 0.1% ProClin 300 |
| Assay Specific Solution | Liquid 120µL/Immunoreaction Cartridge | 2.05% detergents in 50 mM MES buffer. Preservative: 0.1% ProClin 300 |
Additional materials required but sold separately:
- Lumipulse G β-Amyloid 1-42-N Plasma Calibrators: Four (4) Lumiuplse G β-Amyloid 1-42 Plasma Calibrators with concentrations of 0, 30, 100, and 1000 pg/mL.
- Lumipulse β-Amyloid Plasma Controls: Two (2) levels of Lumipulse β-Amyloid Plasma Controls, liquid (frozen)
3. LUMIPULSE G1200
LUMIPULSE G1200 is an instrument platform that can perform automated chemiluminescence immunoassays of specimens using LUMIPULSE G reagents, conducting various processes such as dispensing, agitation and photometric measurement.
B. PRINCIPLE OF OPERATION
1. Specimen Collection
Refer to the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio package insert.
2. Specimen Storage
Specimens may be stored at the following conditions:
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| Temperature (°C) | On Board | 2 to 8 | -30 to -10 | -60 |
|---|---|---|---|---|
| Stability | 3 hours | 1 day | 1 month | 1 month |
NOTE: Specimens used in the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio degrade rapidly at room temperature. Avoid storage and shipment at room temperature (23-28 °C).
3. Lumipulse G pTau 217 Plasma
Lumipulse G pTau 217 Plasma is an assay system including a set of immunoassay reagents, for the quantitative measurement of pTau 217 in K2EDTA plasma specimens based on chemiluminescent enzyme immunoassay (CLEIA) technology by a specific two-step immunoassay method on the LUMIPULSE G System as follows:
- First reaction step: pTau 217 calibrator or specimen are added to particle solution.
- pTau 217 in specimens or calibrators specifically binds to anti- phosphorylated Tau (217) monoclonal antibody (mouse) on the particles, and antigen-antibody immunocomplexes are formed.
- Washing step: The particles are washed and rinsed to remove unbound materials.
- Second reaction step: Alkaline phosphatase (ALP)-labeled anti-Tau monoclonal antibodies (mouse) are added and specifically bind to the prior formed immunocomplexes on the particles, and additional immunocomplexes are formed.
- Washing step: The particles are washed and rinsed to remove unbound materials.
- Enzyme reaction step: Substrate Solution is added and mixed with the particles. AMPPD* contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles.
- Luminescence measurement step: Luminescence (at a maximum wavelength of 477 nm) is generated by the cleavage reaction of dephosphorylated AMPPD*. The luminescent signal reflects the amount of pTau 217 present in the sample.
*AMPPD: 3-(2'-spiroadamantane)-4-methoxy-4-(3"-phosphoryloxy) phenyl-1, 2-dioxetane disodium salt
4. Lumipulse G β-Amyloid 1-42-N Plasma
Lumipulse G β-Amyloid 1-42-N Plasma is an assay system including a set of immunoassay reagents, for the quantitative measurement of β-amyloid1-42 in K2EDTA plasma specimens based on CLEIA technology by a two-step immunoassay method on the LUMIPULSE G System as follows:
- Sampling: β-Amyloid 1-42 Plasma calibrator or specimen are added to the particle solution.
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- First reaction step: β-amyloid1-42 in specimens or calibrators specifically binds to the anti-β-amyloid1-42 monoclonal antibody (mouse) on the particles, and antigen-antibody immunocomplexes are formed.
- Washing: The particles are washed and rinsed to remove unbound materials.
- Second reaction: Alkaline phosphatase (ALP)-labeled anti- β-amyloid monoclonal antibodies (mouse) are added and specifically bind to the prior formed immunocomplexes on the particles, and additional immunocomplexes are formed.
- Washing: The particles are washed and rinsed to remove unbound materials.
- Enzyme reaction: Substrate Solution is added and mixed with the particles. AMPPD* contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles.
- Luminescence measurement: Luminescence (at a maximum wavelength of 477 nm) is generated by the cleavage reaction of dephosphorylated AMPPD*. The luminescent signal reflects the amount of β-amyloid1-42 present in the sample.
*AMPPD: 3-(2'-spiroadamantane)-4-methoxy-4-(3"-phosphoryloxy) phenyl-1, 2-dioxetane disodium salt
5. Interpretation of Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio Results
The LUMIPULSE G1200 reports the results of the Lumipulse G pTau 217 Plasma and the Lumipulse G β-Amyloid 1-42-N Plasma separately. The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio must be manually calculated because the instrument does not report the final result. The final result (positive, indeterminate, and negative) must be interpreted according to the table below:
| pTau 217/β-Amyloid 1-42 Plasma Ratio | Test Result | Interpretation |
|---|---|---|
| Result ≤ 0.00370 | Negative | A negative result is consistent with patients who are unlikely to have amyloid pathology. These patients should be investigated for other causes of cognitive decline. |
| Result ≥ 0.00738 | Positive | A positive result is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of AD or other cognitive disorders. |
| 0.00371 ≤ Result ≤ 0.00737 | Indeterminate | An indeterminate result is consistent with patients who are uncertain to have amyloid |
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pathology. These patients should be considered for further testing.
Note: The ratio must be rounded up to 5 decimal places before comparing against the interpretation of results. If the concentration of the analytes is outside the measuring interval, the following rules apply:
- If the Lumipulse G pTau 217 Plasma assay result is 10.000 pg/mL, then the assay result used to calculate the ratio should be 10.000.
- If the Lumipulse G β-Amyloid 1-42-N Plasma assay result is ≥ 500.0 and the Lumipulse G pTau 217 Plasma assay result is ≤ 1.85 pg/mL, then the Lumipulse G β-Amyloid 1-42-N Plasma assay result used to calculate the ratio should be 500.0.
- If the Lumipulse G β-Amyloid 1-42-N Plasma assay result is ≥ 500.0 and the Lumipulse G pTau 217 Plasma assay result is > 1.85 pg/mL, then the ratio cannot be calculated.
- If the ratio cannot be calculated, then sample should be re-tested. If upon re-test, one or both of the individual assay results remain outside the AMI the ratio cannot be determined. A repeat blood draw is not recommended.
V. SUBSTANTIAL EQUIVALENCE INFORMATION:
A. Predicate Device Name(s):
Lumipulse G β-Amyloid Ratio (1-42/1-40)
B. Predicate 510(k) Number(s):
C. Comparison with Predicate(s):
Similarities and Differences
| Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio (Proposed Device) | Lumipulse G β-Amyloid Ratio (1-42/1-40) (Predicate Device) DEN200072 | |
|---|---|---|
| Device Type | In vitro diagnostic | Same |
| Classification | Class II | Same |
| Product Code | SET | QSE |
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| Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio (Proposed Device) | Lumipulse G β-Amyloid Ratio (1-42/1-40) (Predicate Device) DEN200072 | |
|---|---|---|
| Analyte | pTau 217 and β-Amyloid 1-42 | β-Amyloid 1-42 and β-Amyloid 1-40 |
| Regulation Number | 21CFR § 866.5840 | Same |
| Product Usage | Clinical and Hospital laboratories | Same |
| Principle of Operation | Automated Chemiluminscent Enzyme Immunoassay (CLEIA) | Same |
| Specimen Collection Method | Routine Phlebotomy Techniques | Lumbar Puncture |
| Intended Use | The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is an in vitro test using human plasma (K2EDTA) that combines the results of Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma assays into a ratio of pTau 217 to β-Amyloid 1-42 concentrations using the LUMIPULSE G1200 System. The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is intended to aid healthcare providers to identify patients with amyloid pathology associated with Alzheimer's disease. The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is indicated for adult patients, aged 50 years and older, presenting at a specialized care setting with signs and symptoms of cognitive decline. A test result ≤ 0.00370 is a negative result which is consistent with patients who are unlikely to have amyloid pathology. These patients | The Lumipulse G β-Amyloid Ratio (1-42/1-40) is an in vitro cerebral spinal fluid (CSF) test that combines the results of Lumipulse G β-Amyloid 1-42 and Lumipulse G β-Amyloid 1-40 assays into a ratio of β-amyloid 1-42 to β-amyloid 1-40 concentrations using the LUMIPULSE G 1200 System. The Lumipulse G β-Amyloid Ratio (1-42/1-40) is intended to be used in adult patients, aged 55 years and older, presenting with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. A test result ≥ 0.073 is a negative result which is consistent with a negative amyloid positron emission tomography (PET) scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD. A test result ≤ 0.058 is a positive result which is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder. |
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| Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio (Proposed Device) | Lumipulse G β-Amyloid Ratio (1-42/1-40) (Predicate Device) DEN200072 | |
|---|---|---|
| should be investigated for other causes of cognitive decline. A test result ≥ 0.00738 is a positive result which is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of Alzheimer's disease or other cognitive disorders. A test result between 0.00371 and 0.00737 is an intermediate result which is consistent with patients who are uncertain to have amyloid pathology. These patients should be considered for further testing. The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results must be interpreted in conjunction with other patient clinical information. This test is not intended as a screening or stand-alone diagnostic test. | A test result between 0.059 and 0.072 is considered as a likely positive result as it is more likely consistent with a positive amyloid PET scan result. A likely positive result does not establish a diagnosis of AD or other cognitive disorders and has increased uncertainty in regard to amyloid PET positivity. The Lumipulse G β-Amyloid Ratio (1-42/ 1-40) results must be interpreted in conjunction with other patient clinical information. This test is not intended as a screening or stand-alone diagnostic test. | |
| Instrument System | LUMIPULSE G1200 System | Same |
| Assay Type | Two-step sandwich immunoassays based on chemiluminescent technology | Same |
| Assay Antibodies | pTau 217: anti-phosphorylated Tau (217) monoclonal antibody (mouse)-coated particles and alkaline phosphatase (ALP)-labeled anti-Tau monoclonal antibodies (mouse) | β-Amyloid 1-42: anti-β-amyloid1-42 monoclonal antibody (mouse)-coated particles and biotinylated anti-β-amyloid antibody (mouse) β-Amyloid 1-40: anti-β-amyloid1-40 monoclonal antibody (mouse)-coated |
Page 14
| Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio (Proposed Device) | Lumipulse G β-Amyloid Ratio (1-42/1-40) (Predicate Device) DEN200072 | |
|---|---|---|
| β-Amyloid 1-42 Plasma: anti-β-amyloid1-42 monoclonal antibody (mouse)-coated particles and alkaline-phosphatase (ALP)-labeled anti-β-amyloid1-42 monoclonal antibodies (mouse) conjugate | particles and alkaline-phosphatase (ALP)-labeled anti-β-amyloid antibody (mouse) conjugate | |
| Type of Specimen | Plasma - Dipotassium ethylenediaminetetraacetic acid (K2EDTA) | Cerebrospinal fluid (CSF) |
| Ratio Range | 0.00000 to 1.00000 | 0.001 to 1.000 |
| Measuring Range | pTau 217: 0.047 to 10.000 pg/mL β-Amyloid 1-42 Plasma: 0.8 to 500.0 pg/mL | β-Amyloid 1-42: 38 to 2203.5 pg/mL β-Amyloid 1-40: 156.3 to 28450.3 pg/mL |
| Ratio Calculation | Operator calculates the ratio of pTau 217 to Aβ1-42. | A web-based calculator tool calculates the ratio of Aβ1-42 to Aβ1-40. |
VI. STANDARDS/GUIDANCE DOCUMENTS REFERENCED
- CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
- CLSI EP06, 2nd ed: Evaluation of the Linearity of Quantitative Measurement Procedures – Second Edition
- CLSI EP07, 3rd ed: Interference Testing in Clinical Chemistry; Approved Guideline – Third Edition
- CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline Second Edition
- CLSI EP37: Supplemental Tables for Interference Testing in Clinical Chemistry: Approved Guideline; First Edition
- CLSI EP34: Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking; Approved Guideline; First Edition
- CLSI EP28-A3c: Defining, Establishing and Verifying Reference Intervals in the Clinical Laoratory; Approved Guideline – Third Edition
- CLSI EP35: Assessment of Equivalence or Suitability of Specimen Types for Medical Laboratory Measurement Procedures; Approved Guideline – First Edition
- CLSI EP39: A Hierarchical Approach to Selecting Surrogate Samples for the Evaluation of In Vitro Medical Laboratory Tests; Approved Guideline – First Edition
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VII. PERFORMANCE CHARACTERISTICS
A. Analytical Performance
1. Reproducibility/Precision
Lumipulse G pTau 217 Plasma
Lumipulse G pTau 217 Plasma demonstrated precision ≤ 10.3% (total %CV) in a study run per Clinical & Laboratory Standards Institute (CLSI) EP05-A3. Five human K2EDTA plasma panels were assayed in replicates of two at two separate times of the day for 20 days (N=80 for each panel) using one LUMIPULSE G1200 System. Within-Laboratory (Total) precision combines Within-run, Between-run and Between-day precision data. Data from this study are presented below.
| Panel | Mean (pg/mL) | Within-Run (Repeatability) | Between Run | Between-Day | Within-Laboratory (Total) | ||||
|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| 1 | 0.083 | 0.008 | 10.1 | 0.002 | 1.9 | 0.000 | 0.0 | 0.009 | 10.3 |
| 2 | 0.210 | 0.006 | 3.0 | 0.006 | 3.1 | 0.003 | 1.6 | 0.010 | 4.6 |
| 3 | 0.100 | 0.006 | 6.5 | 0.000 | 0.0 | 0.003 | 2.7 | 0.007 | 7.0 |
| 4 | 4.492 | 0.075 | 1.7 | 0.044 | 1.0 | 0.053 | 1.2 | 0.102 | 2.3 |
| 5 | 8.606 | 0.147 | 1.7 | 0.090 | 1.0 | 0.082 | 0.9 | 0.190 | 2.2 |
Lumipulse G β-Amyloid 1-42-N Plasma
Lumipulse G β-Amyloid 1-42-N Plasma demonstrated precision ≤ 3.8% (total %CV) in a study run per CLSI EP05-A3. Five human K2EDTA plasma panels were assayed in replicates of two at two separate times of the day for 20 days (N=80 for each panel) using one LUMIPULSE G1200 System. Within-Laboratory (Total) precision combines Within-run, Between-run and Between-day precision data. Data from this study are presented below.
Page 16
| Panel | Mean (pg/mL) | Within-Run (Repeatability) | Between Run | Between-Day | Within-Laboratory (Total) | ||||
|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| 1 | 22.4 | 0.5 | 2.2 | 0.3 | 1.3 | 0.1 | 0.7 | 0.6 | 2.6 |
| 2 | 38.8 | 1.3 | 3.4 | 0.7 | 1.8 | 0.1 | 0.3 | 1.5 | 3.8 |
| 3 | 19.4 | 0.5 | 2.6 | 0.2 | 0.9 | 0.2 | 1.1 | 0.6 | 2.9 |
| 4 | 195.5 | 2.1 | 1.1 | 5.1 | 2.6 | 1.0 | 0.5 | 5.6 | 2.9 |
| 5 | 451.1 | 4.6 | 1.0 | 8.9 | 2.0 | 5.1 | 1.1 | 11.3 | 2.5 |
Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio
Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio demonstrated precision ≤10.2 % (total %CV) in a study run per CLSI EP05-A3. Five human K2EDTA plasma panels were assayed in replicates of two at two separate times of the day for 20 days (N=80 for each panel) using one LUMIPULSE G1200 System. Within-Laboratory (Total) precision combines Within-run, Between-run and Between-day precision data. Data from this study are presented below.
| Panel | Mean Ratio | Within-Run (Repeatability) | Between Run | Between-Day | Within-Laboratory (Total) | ||||
|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| 1 | 0.00372 | 0.00036 | 9.8 | 0.00011 | 2.9 | 0.00000 | 0.0 | 0.00038 | 10.2 |
| 2 | 0.00542 | 0.00021 | 3.8 | 0.00021 | 3.9 | 0.00008 | 1.5 | 0.00031 | 5.7 |
| 3 | 0.00514 | 0.00037 | 7.2 | 0.00000 | 0.0 | 0.00014 | 2.8 | 0.00040 | 7.7 |
| 4 | 0.02298 | 0.00050 | 2.2 | 0.00053 | 2.3 | 0.00000 | 0.0 | 0.00073 | 3.2 |
| 5 | 0.01909 | 0.00040 | 2.1 | 0.00027 | 1.4 | 0.00034 | 1.8 | 0.00059 | 3.1 |
The result of Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio for each panel member (N=80) were further analyzed to evaluate qualitative agreement. The % of ratio
Page 17
positive results was calculated for each panel member based on the number of positive Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results. The % of ratio negative results was calculated for each panel member based on the number of negative Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results. Results are summarized in the tables below:
Qualitative agreement
| Panel member | Mean Ratio | Total Replicates (N) | Number of positive Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results at ≥ 0.00738 | % Ratio Positive Results |
|---|---|---|---|---|
| 1 | 0.00372 | 80 | 0 | 0.0% |
| 2 | 0.00542 | 80 | 0 | 0.0% |
| 3 | 0.00514 | 80 | 0 | 0.0% |
| 4 | 0.02298 | 80 | 80 | 100.0% |
| 5 | 0.01909 | 80 | 80 | 100.0% |
Qualitative agreement
| Panel member | Mean Ratio | Total Replicates (N) | Number of negative Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results at ≤ 0.00370 | % Ratio Negative Results |
|---|---|---|---|---|
| 1 | 0.00372 | 80 | 38 | 47.5% |
| 2 | 0.00542 | 80 | 0 | 0.0% |
| 3 | 0.00514 | 80 | 0 | 0.0% |
| 4 | 0.02298 | 80 | 0 | 0.0% |
| 5 | 0.01909 | 80 | 0 | 0.0% |
2. Linearity
Lumipulse G pTau 217 Plasma
Lumipulse G pTau 217 Plasma on the LUMIPULSE G1200 System demonstrated linearity in a study consistent with the guidelines in CLSI EP06-Ed2. The assay is linear across the range 0.037 pg/mL to 11.326 pg/mL. Lumipulse G pTau 217 Plasma correlated with expected concentrations per the linear regression formula:
y = -0.001293 + 0.9849x; R²: 0.9993
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Lumipulse G β-Amyloid 1-42-N Plasma
Lumipulse G β-Amyloid 1-42-N Plasma on the LUMIPULSE G1200 System demonstrated linearity in a study consistent with the guidelines in CLSI EP06-Ed2. The assay is linear across the range 0.8 pg/mL to 1012.0 pg/mL. Lumipulse G β-Amyloid 1-42-N Plasma correlated with expected concentrations per the linear regression formula:
y = 0.02084 + 1.01x; R²: 0.9997
3. Analytical Specificity/Interference
(i) Interference
Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma on the Lumipulse G1200 System demonstrated an interference of less than ± 10% for each compound shown in the table below, in a study performed in accordance with the CLSI guidelines EP07, 3rd ed. and EP37. To assess test performance in the presence of potentially interfering substances, five pooled human plasma samples with varying pTau 217 (0.079 – 5.179 pg/mL) and β-Amyloid 1-42 (20.2 – 498.6 pg/mL) concentrations were prepared for targeting the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma ratio between 0.00322 – 0.1000. Test samples were created by spiking with potential endogenous and exogenous interfering substances. Control samples were spiked only with the solvent used to create the interfering substances panel. The pTau 217 and β-Amyloid 1-42 in the test samples were measured in three replicates. The percent interference of each analyte was calculated by determining the percent differences between the test and control samples. The following compounds were tested and found not to interfere with the assay.
| Endogenous Interferent | Concentration |
|---|---|
| Free Bilirubin (Unconjugated) | 40 mg/dL |
| Conjugated Bilirubin | 40 mg/dL |
| Hemoglobin | 400 mg/dL |
| Total Protein (Human Serum Albumin (HSA)) | 14 g/dL |
| Triglycerides | 1350 mg/dL |
| Biotin | 3500 ng/mL |
| Human Anti-Mouse Antibodies (HAMA IgG) | 1000 ng/mL |
| Rheumatoid Factor (RF IgM) | 200 IU/mL |
| Immunoglobulin G (IgG) | 2000 mg/dL |
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| Endogenous Interferent | Concentration |
|---|---|
| Immunoglobulin M (IgM) | 300 mg/dL |
| Immunoglobulin A (IgA) | 500 mg/dL |
| Exogenous Interferent | Concentration |
|---|---|
| Acetaminophen | 1324 µmol/L |
| Acetazolamide | 5.7 mg/dL |
| Acetylcysteine | 15.0 mg/dL |
| Acetylsalicylic acid | 3.62 mmol/L |
| Aducanumab (Aduhelm) | 2 mg/mL |
| Alendronate Sodium | 0.04 mg/mL |
| Ampicillin | 215 µmol/L |
| Aripiprazole | 45 mg/L |
| Ascorbic Acid | 342 µmol/L |
| Aspirin | 0.39 mg/mL |
| Atorvastatin | 0.075 mg/dL |
| Bisacodyl | 0.009 mg/mL |
| Caffeine | 556 µmol/L |
| Calcium Dobesilate | 6.0 mg/dL |
| Cefoxitin | 660 mg/dL |
| Cetirizine HCL | 0.435 mg/dL |
| Chloramphenicol | 186 µmol/L |
| Chlorothiazide | 2.7 mg/dL |
| Clopidogrel | 0.045 mg/mL |
| Cyclosporine | 0.18 mg/dL |
| Desipramine HCL | 0.204 mg/dL |
| Diazepam | 3.00 mg/dL |
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| Exogenous Interferent | Concentration |
|---|---|
| Digoxin | 49.9 nmol/L |
| Donanemab (Kisunla) | 0.84 mg/mL |
| Donepezil (Aricept) | 30 mg/L |
| Doxycycline | 1.8 mg/dL |
| Escitalopram | 0.0192 mg/dL |
| Esomeprazole | 0.69 mg/dL |
| Estradiol | 0.00000075 mg/dL |
| Famotidine | 0.244 mg/dL |
| Furosemide | 1.59 mg/dL |
| Gabapentin | 2.67 mg/dL |
| Galantamine (Reminyl) | 250 mg/L |
| Heparin | 330 units/dL |
| Hydralazine HCl | 1.44 mg/dL |
| Hydrochlorothiazide | 3.79 µmol/L |
| Ibuprofen | 21.9 mg/dL |
| Insulin | 115 mU/L |
| Lactitol | 12 mg/mL |
| Lecanemab (Leqembi) | 0.475 mg/mL |
| Levodopa | 0.5 mg/dL |
| Levothyroxine | 0.0429 mg/dL |
| Lisinopril | 0.0246 mg/dL |
| Loperamide HCl | 0.0090 mg/mL |
| Losartan | 0.06 mg/mL |
| Memantine (Namenda) | 250 mg/L |
| Metformin | 1.2 mg/dL |
| Methyldopa | 2.25 mg/dL |
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| Exogenous Interferent | Concentration |
|---|---|
| Metoprolol | 18.7 µmol/L |
| Minocycline | 0.1 mg/mL |
| Mirtazapine | 0.025 mg/mL |
| Nifedipine | 5.4 mg/dL |
| Phenylbutazone | 32.1mg/dL |
| Prednisone | 0.00950 mg/dL |
| Quetiapine (Seroquel) | 800 mg/L |
| Rifampicin | 4.8 mg/dL |
| Rivastigmine (Exelon) | 45 mg/L |
| Sacubitril Calcium Salt | 0.915 mg/dL |
| Simvastatin | 0.168 mg/dL |
| Spironolactone | 0.0555 mg/dL |
| Sulfasalazine | 7.5 mg/dL |
| Theophylline | 333 µmol/L |
| Tramadol HCl | 0.314 mg/dL |
| Valsartan | 1.17 mg/dL |
| Venlafaxine HCl | 0.135 mg/mL |
| Warfarin | 243 µmol/L |
| Zaleplon | 0.01 mg/mL |
(ii) Cross-reactivity
To assess test performance in the presence of potential cross-reactive pTau and β-amyloid species, human plasma samples with varying pTau 217 concentrations and human plasma samples with varying β-Amyloid 1-42 concentrations targeting the cutoffs and covering the AMI were used in a study consistent with the CLSI guideline EP07. The percent cross-reactivity of each analyte was calculated by comparing measurements of the test and control samples using the equation below:
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% Cross-Reactivity = [Mean Concentration(pg/mL)(Test) − Mean Concentration(pg/mL)(Control)] / Concentration of Cross-Reactant(pg/mL) x 100
The highest observed cross-reactivity values are listed in the table below for each cross-reactive pTau and β-amyloid species.
Lumipulse G pTau 217 Plasma
| Cross-Reactant | Test Concentration (pg/mL) | Highest Observed Cross-Reactivity (%) |
|---|---|---|
| pTau 181 | 100 | 0.050 |
| pTau 205 | 100 | 0.090 |
| pTau 212 | 100 | 0.020 |
| pTau 231 | 100 | 0.040 |
| Total Tau | 100 | 0.040 |
Lumipulse G β-Amyloid 1-42-N Plasma
| Cross-Reactant | Test Concentration (pg/mL) | Highest Observed Cross-Reactivity (%) |
|---|---|---|
| β-Amyloid (3pε) 3-42ᵃ | 10,000 | 0.007 |
| β-amyloid 1-37 | 1,000 | 0.100 |
| β-amyloid 17-42 | 1,000 | 0.000 |
| β-amyloid 1-38 | 1,000 | 0.000 |
| β-amyloid 1-40 | 1,000 | 0.000 |
| β-amyloid 1-43 | 1,000 | 0.200 |
ᵃ 3pε means the N-terminus (the beginning) of the amyloid beta protein has been modified with pyroglutamate.
(iii) Assay Reportable Range
Representative data supports the following intervals based on the CLSI guideline EP34 The established measuring intervals for each individual analyte support the calculation of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio result up to 1.0000.
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Lumipulse G pTau217 Plasma
| Analytical Measuring Interval (AMI)ᵃ | 0.047 pg/mL to 10.000 pg/mL |
|---|---|
| Reportable Rangeᵇ | 0.041 pg/mL to 10.000 pg/mL |
Lumipulse G β-Amyloid 1-42-N Plasma
| Analytical Measuring Interval (AMI)ᵃ | 0.8 pg/mL to 500.0 pg/mL |
|---|---|
| Reportable Rangeᵇ | 0.2 pg/mL to 500.0 pg/mL |
ᵃ Analytical Measuring Interval (AMI): The range of values in pg/mL which meets the limits of acceptable performance for linearity, imprecision, and bias. The AMI extends from the lower limit of the linear range to the upper limit of the assay parameter.
ᵇ The Reportable Range: The lower limit of the detection to the upper limit of the assay parameter.
(iv) Traceability, Stability, Expected Values (controls, calibrators, or methods)
(i) Traceability:
The calibrators for use with Lumipulse G pTau 217 are traceable to in-house reference calibrators.
The calibrators for use with Lumipulse G β-Amyloid 1-42 Plasma are traceable to in-house reference calibrators.
(ii) Shelf life:
Current stability of the Lumipulse G pTau 217 Plasma Immunoreaction Cartridges supports up to 9 months at 2-8°C. Current stability of the Lumipulse G β-Amyloid 1-42-N Plasma Immunoreaction Cartridges supports up to 9 months at 2–10°C.
(iii) On-board the LUMIPULSE G1200:
Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma Immunoreaction Cartridges are stored on-board the LUMIPULSE G System for a maximum of 30 days.
(iv) Transport Conditions:
The intermediate study results of the Lumipulse G pTau 217 Plasma reagents were subject to a drop, vibration and inverted transport simulation at 2 stressed conditions: (i) 25°C ± 2°C for 6 hours and (ii) -5°C ± 2°C for 6 hours. 5 pooled human plasma samples with varying pTau 217 concentrations were tested. The test results obtained at stressed conditions (i) and (ii) were compared to the test results at normal storage conditions (2-10°C). The Lumipulse G pTau 217 Plasma reagents are stable at these conditions for 7 months. This study is ongoing.
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To evaluate reagent transport stability, the Lumipulse G β-Amyloid 1-42-N reagents were subject to a drop, vibration and inverted transport simulation at 2 stressed conditions: (i) 25°C ± 2°C for 6 hours and (ii) -5°C ± 2°C for 6 hours. 3 pooled human plasma samples with varying β-Amyloid 1-42 concentrations were tested. The test results obtained at stressed conditions (i) and (ii) were compared to the test results at normal storage conditions (2-10°C). The Lumipulse G β-Amyloid 1-42-N Plasma reagents are stable at these conditions for 12 months.
(v) Detection Limit
Lumipulse G pTau 217 Plasma
The Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) studies were conducted in accordance with the CLSI guideline EP17-A2. The studies were evaluated using three lots of Lumipulse G pTau 217 Plasma on three LUMIPULSE G1200 Systems.
-
LoB
For LoB, a set of four analyte-depleted samples was tested in 10 replicates per run, two runs per day for three days to reach a total of 60 measurements per sample for each reagent lot. The higher value from the three lots was taken for the LoB at 0.025 pg/mL -
LoD
For LoD, a set of five low level samples with target concentrations of pTau 217 between 0.19 – 0.64 pg/mL was tested in 10 replicates per run, two runs per day for three days to reach a total of 60 measurements per sample for each reagent lot. The LoD was calculated using a variance model and the higher value from the three lots was taken for the LoD at 0.0407 pg/mL. -
LoQ
The LoQ was estimated based on the lowest value of the test samples at which the variability was below the 20 %CV. The final LoQ for this assay was defined at 0.0472 pg/mL.
Lumipulse G β-Amyloid 1-42-N Plasma
The Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) studies were conducted in accordance with the CLSI guideline EP17-A2. The studies were evaluated using three lots of Lumipulse G β-Amyloid 1-42-N Plasma on three LUMIPULSE G1200 Systems.
- LoB
For LoB, a set of four analyte-depleted samples was tested in 10 replicates per run, two runs per day for three days to reach a total of 60 measurements per
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sample for each reagent lot. The higher value from the three lots was taken for the LoB at 0.128 pg/mL
-
LoD
For LoD, a set of five low level samples with target concentrations of β-Amyloid 1-42 between 0.2 – 0.6 pg/mL was tested in 10 replicates per run, two runs per day for three days to reach a total of 60 measurements per sample for each reagent lot. The LoD was calculated using a variance model and the higher value from the three lots was taken for the LoD at 0.2074 pg/mL. -
LOQ
The LoQ was estimated based on the lowest value of the test samples at which the variability was below the 20 %CV. The final LoQ for this assay was defined as at 0.8 pg/mL.
(vi) High Dose Hook Effect
Lumipulse G pTau217 Plasma
High dose hook effect is a phenomenon whereby very high-level specimens may read within the dynamic range of the assay. For Lumipulse G pTau 217 Plasma on the LUMIPULSE G1200 System, no high dose hook effect was observed for samples containing approximately 610 pg/mL of pTau 217.
Lumipulse G β-Amyloid 1-42-N Plasma
High dose hook effect is a phenomenon whereby very high-level specimens may read within the dynamic range of the assay. For Lumipulse G β-Amyloid 1-42-N Plasma on the LUMIPULSE G1200 System, no high dose hook effect was observed for samples containing approximately 2,200 pg/mL of β-Amyloid 1-42.
(vii) Assay Cut-off
The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio assay cutoffs were determined by analyzing banked K2EDTA plasma samples from the following sources:
- Patient samples collected from the screening period of the clinical phase III studies (MissionAD) of elenbecestat (E2609-G000-301–ClinicalTrials.gov Identifier: NCT02956486 and E2609-G000-302–ClinicalTrials.gov Identifier: NCT03036280).
- Plasma samples collected from subjects enrolled in BioFINDER-2 (ClinicalTrials.gov Identifier: NCT03174938)
- Plasma samples collected from subjects enrolled in BIOCARD (http://grantome.com/grant/NIH/U19-AG033655-06)
A total of 208 samples were tested on the Lumipulse G1200 utilizing the Lumipulse G pTau 217 and Lumipulse G β-Amyloid 1-42-N plasma assays. Subjects' clinical data included signs and symptoms of cognitive decline, amyloid
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PET with FDA-cleared tracer and/or FDA-cleared amyloid CSF ratio information. These subjects are distinct from the subjects evaluated in the pivotal clinical validation study (see Section C. Clinical Studies below). The 208 patients are comprised of 12 patients with AD dementia, 150 with mild cognitive impairment (MCI), 7 with subjective cognitive decline (SCD) and 39 with other causes of cognitive decline. The procedures of plasma collection, processing and handling were conducted according to the tube manufacturer's instructions. Amyloid positivity was derived from either a positive amyloid PET and/or a positive amyloid CSF ratio. The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio assay cutoffs were calculated based on agreement with amyloid status. The resulting agreement rates are shown below with the specific cutoffs.
| Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio | PET and/or CSF | Total (n) | Frequency (%) | Predictive Value (PV)% (95% CIᵃ) | Likelihood Ratio (95% CIᵇ) | |
|---|---|---|---|---|---|---|
| Pos (n) | Neg (n) | |||||
| Positive (Ratio ≥ 0.00738) | 88 | 5 | 93 | 44.7% | 94.6% (88.7%, 97.6%) | 14.51 (6.49, 33.90) |
| Indeterminate (0.00371 ≤ Ratio ≤ 0.00737) | 20 | 22 | 42 | 20.2% | 47.6% (34.7%, 60.9%) | 0.75 (0.44, 1.28) |
| Negative (Ratio ≤ 0.00370) | 6 | 67 | 73 | 35.1% | 4.3% (3.9%, 16.0%) | 0.07 (0.03, 0.15) |
| Total | 114 | 94 | 208 | Prevalence=54.8% |
ᵃ 95%CIs are calculated based on 95%CI of corresponding likelihood ratio.
ᵇ 95%CIs are calculated using an asymptotic method for ratios of two independent binomial proportions.
| pTau 217/β-Amyloid 1-42 | Interpretation |
|---|---|
| Result ≤ 0.00370 = Negative | A negative result is consistent with patients who are unlikely to have amyloid pathology. These patients should be investigated for other causes of cognitive decline. |
| Result ≥ 0.00738 = Positive | A positive result is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of AD or other cognitive disorders. |
| 0.00371 ≤ Result ≤ 0.00737 = Indeterminate | An indeterminate result is consistent with patients who are uncertain to have amyloid pathology. These patients should be considered for further testing. |
B. Comparison Studies
1. Method Comparison with Predicate Device
Refer to Section C on Clinical Studies below
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2. Matrix Comparison
Not applicable
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C. Clinical Studies
Evaluation of Patients Presenting with Cognitive Decline
A clinical study of 499 patients was conducted to evaluate performance of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio. The study patient population (N=499) was between the ages of 52 and 93 years with Amyloid positivity confirmed by historic amyloid PET with an FDA-cleared tracer or FDA-cleared amyloid CSF ratio. Polaris-AD (AriBio) patient samples used for testing were collected from the screening period of the clinical phase III study of AR1001. Skåne University Hospital Memory Clinic, Malmö, Sweden plasma samples used in the study were collected from subjects enrolled in BioFINDER-2. Bio-Hermes-001 samples obtained from Global Alzheimer's Platform Foundation were used in this study. University of Wisconsin Plasma samples from subjects enrolled in Wisconsin Registry for Alzheimer's Prevention (WRAP) were also used in this study.
The 499 patients were categorized into four diagnostic groups: 1.2% (6/499) other cognitive diagnoses, 9.8% (49/499) subjective cognitive decline (SCD), 30.9% (154/499) MCI, and 58.1% (290/499) AD patients. No other neurological diseases were included in this cohort. The demographic and clinical characteristics of patients are presented according to diagnostic groups, PET scan or CSF result in the table below:
| Diagnostic Groups | Adjudicated PET Read | CSF Ratio | Amyloid Status | TOTAL | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| AD | MCI | SCD | Other | Positive | Negative | Positive | Negative | Positive | Negative | ||
| Total N | 290 | 154 | 49 | 6 | 66 | 86 | 189 | 158 | 255 | 244 | 499 |
| Sex | |||||||||||
| Male | 135 (46.6%) | 81 (52.6%) | 21 (42.9%) | 3 (50.0%) | 22 (33.3%) | 27 (31.4%) | 102 (54.0%) | 89 (56.3%) | 124 (48.6%) | 116 (47.5%) | 240 (48.1%) |
| Female | 155 (53.4%) | 73 (47.4%) | 28 (57.1%) | 3 (50.0%) | 44 (66.7%) | 59 (68.6%) | 87 (46.0%) | 69 (43.7%) | 131 (51.4%) | 128 (52.5%) | 259 (51.9%) |
| Age (Years) | |||||||||||
| 52 - 65 | 56 (19.3%) | 34 (22.1%) | 12 (24.5%) | 2 (33.3%) | 6 (9.1%) | 27 (31.4%) | 24 (12.7%) | 47 (29.7%) | 30 (11.8%) | 74 (30.3%) | 104 (20.8%) |
| 66 - 70 | 48 (16.6%) | 39 (25.3%) | 12 (24.5%) | 0 (0.0%) | 7 (10.6%) | 17 (19.8%) | 36 (19.0%) | 39 (24.7%) | 43 (16.9%) | 56 (23.0%) | 99 (19.8%) |
| 71 - 75 | 83 (28.6%) | 29 (18.8%) | 8 (16.3%) | 0 (0.0%) | 17 (25.8%) | 17 (19.8%) | 54 (28.6%) | 32 (20.3%) | 71 (27.8%) | 49 (20.1%) | 120 (24.0%) |
| 76 - 80 | 74 (25.5%) | 34 (22.1%) | 14 (28.6%) | 2 (33.3%) | 23 (34.8%) | 12 (14.0%) | 54 (28.6%) | 35 (22.2%) | 77 (30.2%) | 47 (19.3%) | 124 (24.8%) |
| 81 - 93 | 29 (10.0%) | 18 (11.7%) | 3 (6.1%) | 2 (33.3%) | 13 (19.7%) | 13 (15.1%) | 21 (11.1%) | 5 (3.2%) | 34 (13.3%) | 18 (7.4%) | 52 (10.4%) |
| Average | 72 | 72 | 71 | 74 | 75 | 71 | 73 | 70 | 74 | 70 | 72 |
| Median | 73 | 71 | 72 | 78 | 76 | 70 | 74 | 69 | 74 | 69 | 72 |
| Min - Max | 55 - 89 | 56 - 93 | 52 - 88 | 60 - 85 | 64 - 84 | 60 - 85 | 57 - 93 | 52 - 88 | 57 - 93 | 52 - 88 | 52 - 93 |
| Race | |||||||||||
| White | 243 (83.8%) | 131 (85.1%) | 43 (87.8%) | 6 (100%) | 49 (74.2%) | 57 (66.3%) | 177 (93.7%) | 140 (88.6%) | 226 (88.6%) | 197 (80.7%) | 423 (84.8%) |
| Asian | 7 (2.4%) | 3 (1.9%) | 0 (0.0%) | 0 (0.0%) | 3 (4.5%) | 4 (4.7%) | 1 (0.5%) | 2 (1.3%) | 4 (1.6%) | 6 (2.5%) | 10 (2.0%) |
| Black | 37 (12.8%) | 18 (11.7%) | 5 (10.2%) | 0 (0.0%) | 14 (21.2%) | 21 (24.4%) | 10 (5.3%) | 15 (9.5%) | 24 (9.4%) | 36 (14.8%) | 60 (12.0%) |
| Other* | 3 (1.0%) | 2 (1.3%) | 1 (2.0%) | 0 (0.0%) | 0 (0.0%) | 4 (4.7%) | 1 (0.5%) | 1 (0.6%) | 1 (0.4%) | 5 (2.0%) | 6 (1.2%) |
| MMSE | |||||||||||
| 13 | 40 (13.8%) | 76 (49.4%) | 34 (69.4%) | 3 (50.0%) | 42 (63.6%) | 63 (73.3%) | 25 (13.2%) | 23 (14.6%) | 67 (26.3%) | 86 (35.2%) | 153 (30.7%) |
| Unknown | 222 (76.6%) | 46 (29.9%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 143 (75.7%) | 125 (79.1%) | 143 (56.1%) | 125 (51.2%) | 268 (53.7%) |
- Including Hawaiian / Pacific Islander
The study population consisted of 48.1% (240/499) males with a mean age of 72 years (range 55-93) years with a median age of 73 years, and 51.9% females (259/499) with a mean age of 72 years (range 52-86) years with a median 72 years. The study subjects were mainly white patients (84.8%, 423/499). The pre-clinical AD diagnostic groups (SCD and MCI) were 40.7% (203/499) and the PET+, CSF+, and PET+ or CSF+ were found in 13.2% (66/499), 35.7% (178/499), and 2.4% (12/499) of the study population, respectively.
Patients with AD also presented with a positive PET scan or CSF positive result more frequently than MCI patients, who in turn presented with a positive PET scan or CSF more frequently than those with SCD. The prevalence of amyloid positivity among AD was 58.6% (170/290) compared to 40.9% (63/154) and 38.8% (19/49) among those with MCI and SCD, respectively.
To estimate the clinical performance characteristics of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio, the test result was compared to the amyloid PET or CSF result for each patient in the table below:
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| Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio | PET or CSF | Total (n) | |
|---|---|---|---|
| Positive (n) | Negative (n) | ||
| Positive (Ratio ≥ 0.00738) | 201 | 18 | 219 |
| Indeterminate (0.00371 ≤ Ratio ≤ 0.00737) | 49 | 49 | 98 |
| Negative (Ratio ≤ 0.00370) | 5 | 177 | 182 |
| Total | 255 | 244 | 499 |
The performance of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio test is described by PET or CSF-positive predictive value (indicated as Predictive Value, PV) and frequency of test results of the tested samples (indicated as Frequency of Results, FR) for positive, indeterminate and negative test results and it is summarized in the table below:
| Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio | PET or CSF | Total (n) | Frequency (%) (95% CI) | Predictive value (PV)% (95% CI)ᵃ | Likelihood Ratio (95% CI)ᵇ | |
|---|---|---|---|---|---|---|
| Pos (n) | Neg (n) | |||||
| Positive (Ratio ≥ 0.00738) | 201 | 18 | 219 | 43.9% | 91.8% (87.8%, 94.6%) | 10.68 (6.90, 16.79) |
| Indeterminate (0.00371 ≤ Ratio ≤ 0.00737) | 49 | 49 | 98 | 19.6% | 50.0% (41.3%, 58.8%) | 0.96 (0.67, 1.36) |
| Negative (Ratio ≤ 0.00370) | 5 | 177 | 182 | 36.5% | 2.7% (1.2%, 6.1%) | 0.03 (0.01, 0.06) |
| Total | 255 | 244 | 499 | Prevalence = 51.1% |
ᵃ 95% CIs are calculated based on 95%CI of corresponding likelihood ratio.
ᵇ 95% CIs are calculated using an asymptotic method for ratios of two independent binomial proportions.
D. Clinical Cutoff:
- Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio ≤ 0.00370
- Negative
- Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio ≥ 0.00738
- Positive
- Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio between 0.00371 and 0.00737
- Indeterminate
E. Reference Interval/Expected Values
A reference interval study was performed in accordance with the CLSI guideline EP28-A3c. A total of 240 evaluable human plasma samples with clinical information obtained from research biobanks or commercial vendors, and real-world data from the US Department of Veterans Affairs and the University of Nevada. The test samples were collected from 115 males and 125 females aged 51 to 84 years old (mean of 68 years and median of 68 years).cognitively normal individuals. The results in the table below show that 17.9% have a positive Lumipulse G pTau 217/β-Amyloid 1-42
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Plasma Ratio test result, 31.7% have an intermediate Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio test result, and 50.4% have a negative Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio test result across the age groups. The number of cognitively normal subjects who tested positive at a ratio of ≥ 0.00738 with Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio increased with age.
Cognitively Normal
| Age Group (years) | All | Age 51-65 | Age 66-70 | Age 71-75 | Age 76-80 | Age 81-84 |
|---|---|---|---|---|---|---|
| N | 240 | 90 | 68 | 44 | 28 | 10 |
| Mean (SD) | 0.00603 (0.01055) | 0.00342 (0.0312) | 0.00695 (0.01673) | 0.00791 (0.01045) | 0.00729 (0.00430) | 0.01138 (0.00844) |
| Median | 0.00366 | 0.00274 | 0.00373 | 0.00495 | 0.00680 | 0.00983 |
| Range | 0.00087 - 0.13815 | 0.00156 - 0.02930 | 0.00087 - 0.13815 | 0.00181 - 0.06356 | 0.00187 - 0.01928 | 0.00284 - 0.02734 |
| Reference Interval (2.5th Percentile, 97.5th Percentile) | 0.00179, 0.02609 | 0.00173, 0.01033 | 0.00154, 0.05694 | 0.00184, 0.05982 | N/A, N/A | N/A, N/A |
| % (N) Ratio ≤ 0.00370 | 50.4% | 74.4% | 50.0% | 31.8% | 14.3% | 20.0% |
| % (N) Ratio (0.00371 – 0.0.00737) | 31.7% | 23.3% | 32.4% | 45.5% | 39.3% | 20.0% |
| % (N) Ratio ≥ 0.00738 | 17.9% | 2.2% | 17.6% | 22.7% | 46.4% | 60.0% |
Cognitively Normal
| White | Black | Other | |
|---|---|---|---|
| N | 216 | 18 | 6 |
| Mean (SD) | 0.00625 (0.01106) | 0.00432 (0.00326) | 0.00300 (0.00099) |
| Median | 0.00378 | 0.00304 | 0.00306 |
| Range | 0.00173 - 0.13815 | 0.00087 - 0.01199 | 0.00156 - 0.00444 |
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| White | Black | Other | |
|---|---|---|---|
| Reference Interval (2.5th Percentile, 97.5th Percentile) | 0.00180, 0.02683 | N/A, N/A | N/A, N/A |
| % (N) Ratio ≤ 0.00370 | 48.6% | 61.1% | 83.3% |
| % (N) Ratio (0.00371 – 0.0.00737) | 32.9% | 22.2% | 16.7% |
| % (N) Ratio ≥ 0.00738 | 18.5% | 16.7% | 0.0% |
The expected values for non-AD and other neurological conditions were investigated. A total of 296 evaluable human plasma samples with clinical information obtained from research biobanks or commercial vendors were included in analyzing expected values. The test samples were collected from individuals 22 years and older who presented with a diagnosis of non-AD dementia and other neurological conditions. The test results are summarized in the tables below:
Disease Conditions
| All Conditions Combined | Brain Hemorrhage or Ischemia* | Frontotemporal Dementia* | Lewy Body Dementia* | |
|---|---|---|---|---|
| N | 269 | 24 | 41 | 39 |
| Mean (SD) | 0.02814 (0.04592) | 0.02655 (0.04174) | 0.02699 (0.02857) | 0.03958 (0.03851) |
| Median | 0.00992 | 0.01610 | 0.01360 | 0.02642 |
| Range | 0.00173 - 0.45182 | 0.00173 - 0.20909 | 0.00222 - 0.11113 | 0.00295 - 0.17443 |
| Reference Interval (2.5th Percentile, 97.5th Percentile) | 0.00211, 0.17086 | N/A, N/A | 0.00223, 0.10979 | 0.00295, 0.17443 |
| % (N) Ratio ≤ 0.00370 | 23.0% | 12.5% | 12.2% | 5.1% |
| % (N) Ratio (0.00371 – 0.0.00737) | 21.2% | 16.7% | 22.0% | 10.3% |
| % (N) Ratio ≥ 0.00738 | 55.8% | 70.8% | 65.9% | 84.6% |
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Disease Conditions
| Multiple Sclerosis | Parkinson's Disease | Stroke* | Traumatic Brain Injury* | Vascular Dementia | |
|---|---|---|---|---|---|
| N | 39 | 40 | 33 | 30 | 23 |
| Mean (SD) | 0.00578 (0.00672) | 0.01032 (0.01203) | 0.03958 (0.05044) | 0.06593 (0.09111) | 0.01564 (0.02891) |
| Median | 0.00367 | 0.00592 | 0.01851 | 0.03739 | 0.00421 |
| Range | 0.00175 - 0.03238 | 0.00242 - 0.04729 | 0.00213 - 0.22429 | 0.00235 - 0.45182 | 0.00174 - 0.13606 |
| Reference Interval (2.5th Percentile, 97.5th Percentile) | 0.00175, 0.03238 | 0.00242, 0.04725 | N/A, N/A | N/A, N/A | N/A, N/A |
| % (N) Ratio ≤ 0.00370 | 51.3% | 32.5% | 12.1% | 20.0% | 39.1% |
| % (N) Ratio (0.00371 – 0.0.00737) | 33.3% | 30.0% | 18.2% | 6.7% | 30.4% |
| % (N) Ratio ≥ 0.00738 | 15.4% | 37.5% | 69.7% | 73.3% | 30.4% |
*Note: Observed expected values were high due to pTau 217 being elevated for individuals for these conditions.
VIII. PROPOSED LABELING
The labeling supports the finding of substantial equivalence for this device.
IX. CONCLUSION
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.