(88 days)
No reference devices were used in this submission.
No
The device description and performance studies focus on a standard immunoturbidimetric assay and statistical analysis of quantitative results, with no mention of AI or ML.
No
therapeutic devices are used for treatment, while this device is used for diagnosis.
Yes
The device is explicitly stated "As an aid in the diagnosis of protein S deficiency." This indicates its role in the diagnostic process.
No
The device is a reagent kit used with a specific analyzer (Sysmex® CS-5100) to perform an immunoturbidimetric assay. This involves physical components (reagents, particles) and a hardware analyzer, not just software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states it's for the "quantitative determination of free protein S antigen in human plasma collected from venous blood samples" and is used "as an aid in the diagnosis of protein S deficiency". This clearly indicates it's used to test human samples in vitro (outside the body) to provide information for diagnosis.
- Device Description: The description details an "immunoturbidimetric assay" that uses reagents to react with components in the plasma sample. This is a typical method for in vitro diagnostic tests.
- Sample Type: The device is designed to analyze "human plasma collected from venous blood samples". This is a biological sample taken from the human body for in vitro analysis.
All these points align with the definition of an In Vitro Diagnostic device, which is a medical device used to examine specimens from the human body to provide information for diagnosis, monitoring, or screening.
N/A
Intended Use / Indications for Use
For the quantitative determination of free protein S antigen in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the Sysmex® CS-5100 analyzer.
As an aid in the diagnosis of protein S deficiency in patients who are suspected of free protein S deficiency. The performance of this device has not been established in neonate and pediatric patient populations.
Product codes (comma separated list FDA assigned to the subject device)
GGP
Device Description
The INNOVANCE® Free PS Ag assay is an immunoturbidimetric assay. The reagent kit consists of two components. One component (Reagent) contains polystyrene particles coated with two different monoclonal antibodies both specific for free protein S. This latex reagent aggregates when mixed with samples containing free protein S. The degree of aggregation is directly proportional to the concentration of free protein S in the test sample and is detected turbidimetrically via the increase in turbidity.
Protein S is a vitamin K-dependent plasma protein that is mainly synthesized by the liver. During blood coagulation, protein S exhibits an essential anticoagulant function by acting as a cofactor of activated protein C (APC). In the presence of calcium, protein S forms a complex with APC that binds to phospholipid surfaces and accelerates the APC-catalyzed proteolytic inactivation of the factors Va and VIIIa. Protein S circulates in human blood with a half-life of about 2 days at a plasma concentration of about 25 mg/L. Approximately 60% of the protein is non-covalently bound to C4b-binding protein (C4BP), a regulator of the classical complement pathway. The remaining approx. 40% of the total protein S fraction, i.e. free protein S, represent the physiologically active form that primarily exhibits APC-cofactor activity. Inherited or acquired deficiency of protein S is associated with an increased risk of venous thromboembolism.
Inherited protein S deficiencies are classified into three types:
- type I is defined by a reduction in both total and free protein S levels (quantitative defect).
- . type II is rare and characterized by a decreased protein S activity but normal levels of total and free protein S (qualitative defect),
- . type III corresponds to normal levels of total protein S but low levels of free protein S (quantitative defect).
Homozygous and heterozygous deficiencies of protein S are rare and commonly lead to purpura fulminans in neonates.
Acquired protein S deficiencies, indicated by decreased free protein S levels, may be caused by:
- hepatic disorders
- . nephrotic syndrome
- oral anticoagulation with vitamin K antagonists
- L-asparaginase treatment
- . pregnancy
- oral contraceptives
- . estrogen therapy
- . viral infections
- disseminated intravascular coagulation
- . elevated plasma levels of C4BP in an acute-phase reaction.
Newborns may also have decreased levels of free protein S.
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 performance of this device has not been established in neonate and pediatric patient populations.
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Non-Clinical Studies:
- Measuring Interval (Limit of Quantitation and Linearity): LoQ study in accordance with CLSI document EP17-A2 using five independent low-analyte plasma pools (7.68 to 7.91% of norm). Linearity study across 10 to 150% of norm with 11 different dilutions (7 to 183% of norm) in accordance with CLSI document EP06-A.
- Specificity: Interference studies according to CLSI document EP07-A2 for endogenous (hemoglobin, unconjugated bilirubin, conjugated bilirubin, platelets, cholesterol, fibrinogen) and exogenous interferents (Dalteparin sodium, Danaparoid sodium, Enoxaparin sodium, Unfractionated heparin, Acarbose, Acetyl salicylic acid, Amiodarone hydrochloride, Amitriptyline, Amoxicillin, Apixaban, Argatroban, Atorvastatin calcium salt trihydrate, Bisoprolol fumarate, Bivalidrudin trifluoro acetate salt, Carbamazepin, Carbapanem (Imipenem monohydrat), Ciprofloxacin, Citalopram x HBr, Clarithromycin, Clopidogrel hydrogensulfate, Dabigatran, Dalteparin sodium, Danaparoid sodium, Diclofenac sodium salt, Digoxin, Enoxaparin sodium, Estrogene, Etilefrine hydrochloride, Folic acid, Fondaparinux sodium salt, Furosemide solution, Ibuprofen sodium salt, Ketoconazole, L-Asparaginase, Lisinopril Dihydrat, Metformin hydrochloride, N-Acetyl-4-aminophenol, Pantoprazole sodium sesquihydrate, Phenobarbital, Prasugrel, Progesteron, Ramipril, Rivaroxaban, Ticagrelor, Torasemid, Unfractionated heparin, sodium salt, Valproic acid, Valsartan, Verapamil hydrochloride, Warfarin). Also investigated Harvoni® (ledipasvir and sofosbuvir), Zepatier® (elbasvir and grazoprevir), Epivir-HBV® (lamivudine), Edurant® (rilpivirine), Aptivus® (tipranavir) and Isentress® (raltegravir).
Clinical Studies:
- Reference Interval: Conducted at three clinical study sites in the United States with ostensibly healthy subjects aged ≥ 18 years. N=149 males (72.8 – 138.8 % of norm), N=151 females (65.8 – 146.7 % of norm).
- Frozen versus Fresh Samples (Bridging Study): N=66 fresh individual plasma samples covering 10 to 150% of norm measured on Sysmex® CS-5100 analyzer, then frozen and re-measured. Analyzed by Passing-Bablok regression and Bland Altman analysis. Slope = 0.98, Intercept = 1.50 % of norm, r = 0.999, r2 = 0.998.
- Precision / Reproducibility:
- Multi-center study (Reproducibility) at two U.S. sites and one German site for 20 days with 2 runs/day, 2 replicates/run (20x2x2). Overall CV (Combined Sites) between 2.10 - 4.08%.
- Internal precision study at Siemens company site (Germany) for 5 days with 2 runs/day, 4 replicates/run (5x2x4) using three different analyzers and operators. Overall CV (Combined Instruments) between 1.15 - 4.86%.
- Method comparison: Three external sites in the United States. Proposed device (INNOVANCE® Free PS Ag on Sysmex® CS-5100 analyzer) compared to predicate device (STA® Liatest® Free Protein S on STA-R Evolution® Expert Series Hemostasis System). N=350 total samples (119 from Site 1, 119 from Site 2, 112 from Site 3). Samples included clinical demand (304), congenital Protein S deficiency from commercial vendor (31), and no clinical demand (15).
- Sites Combined: y=0.95x + 4.92, r=0.940 (r2=0.883).
- 1st Site: y=0.85x - 6.34, r=0.941 (r2=0.886).
- 2nd Site: y=0.95x - 5.70, r=0.962 (r2=0.926).
- 3rd Site: y=1.00x + 3.31, r=0.949 (r2=0.900).
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Not Found. The study focuses on precision, linearity, interference, and agreement with the predicate device, not diagnostic performance metrics like sensitivity or specificity relative to a disease state.
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.
STA®-Liatest® Free Protein S (K010963)
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.
No reference devices were used in this submission.
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
§ 864.7290 Factor deficiency test.
(a)
Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).(b)
Classification. Class II (performance standards).
0
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
September 7, 2018
Siemens Healthcare Diagnostics Products GmbH Petra Dissmann Regulatory Affairs Manager Emil-von-Behring Strasse 76 35041 Marburg, Germany
Re: K181525
Trade/Device Name: INNOVANCE Free PS Ag Regulation Number: 21 CFR 864.7290 Regulation Name: Factor deficiency test Regulatory Class: Class II Product Code: GGP Dated: June 6, 2018 Received: June 11, 2018
Dear Petra Dissmann:
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 mav, 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 avare that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located 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.
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
1
requirements, including, but not limited to: registration and listing (21 CFR Part 807): labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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 comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely.
Leonthena R. Carrington -S
Lea Carrington Director Division of Immunology and Hematology 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) K181525
Device Name INNOVANCE® Free PS Ag
Indications for Use (Describe)
For the quantitative determination of free protein S antigen in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the Sysmex® CS-5100 analyzer.
As an aid in the diagnosis of protein S deficiency in patients who are suspected of free protein S deficiency. The performance of this device has not been established in neonate and pediatric patient populations.
| 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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3
510(k) Summary
This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of 21 CFR §807.92 and follows the FDA guidance 'The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]', issued July 28, 2014.
1. Submitter
Siemens Healthcare Diagnostics Products GmbH
| Emil-von-Behring-Str. 76 | |
|---|---|
| 35041 Marburg, Germany | |
| Contact Person: | Dr. Petra M. Dissmann |
| Email: | petra.dissmann@siemens-healthineers.com |
| Phone: | + 49 172 369 245 9 |
| Facsimile: | + 49 642 139 497 7 |
| Date Prepared: | July 19, 2018 |
| 2. Device | |
| Name of Device: | INNOVANCE® Free PS Ag (K181525) |
| Common or Usual Name: | Test, qualitative and quantitative factor deficiency |
| Classification Name: | Factor deficiency test |
| (21 CFR 864.7290) | |
| Regulatory Class: | Class II |
| Product Code: | GGP |
| 510(k) Review Panel | Hematology |
| 3. Predicate Device | |
| Name of Device: | STA®-Liatest® Free Protein S (K010963) |
| Common or Usual Name: | Test, qualitative and quantitative factor deficiency |
| Classification Name: | Factor deficiency test |
| (21 CFR 864.7290) | |
| Regulatory Class: | Class II |
| Product Code: | GGP |
| 510(k) Review Panel | Hematology |
Two recalls associated with the predicate reagent were found on the FDA Medical Device Recalls database. However, the recalls were specific to assignment ranges of specific production lots. These lots were not used in the generation of data for this 510(k); they have no bearing on the content of this premarket notification. No reference devices were used in this submission.
4
4. Device Description / Test Principle
The INNOVANCE® Free PS Ag assay is an immunoturbidimetric assay. The reagent kit consists of two components. One component (Reagent) contains polystyrene particles coated with two different monoclonal antibodies both specific for free protein S. This latex reagent aggregates when mixed with samples containing free protein S. The degree of aggregation is directly proportional to the concentration of free protein S in the test sample and is detected turbidimetrically via the increase in turbidity.
Protein S is a vitamin K-dependent plasma protein that is mainly synthesized by the liver. During blood coagulation, protein S exhibits an essential anticoagulant function by acting as a cofactor of activated protein C (APC). In the presence of calcium, protein S forms a complex with APC that binds to phospholipid surfaces and accelerates the APC-catalyzed proteolytic inactivation of the factors Va and VIIIa. Protein S circulates in human blood with a half-life of about 2 days at a plasma concentration of about 25 mg/L. Approximately 60% of the protein is non-covalently bound to C4b-binding protein (C4BP), a regulator of the classical complement pathway. The remaining approx. 40% of the total protein S fraction, i.e. free protein S, represent the physiologically active form that primarily exhibits APC-cofactor activity. Inherited or acquired deficiency of protein S is associated with an increased risk of venous thromboembolism.
Inherited protein S deficiencies are classified into three types:
- type I is defined by a reduction in both total and free protein S levels (quantitative defect).
- . type II is rare and characterized by a decreased protein S activity but normal levels of total and free protein S (qualitative defect),
- . type III corresponds to normal levels of total protein S but low levels of free protein S (quantitative defect).
Homozygous and heterozygous deficiencies of protein S are rare and commonly lead to purpura fulminans in neonates.
Acquired protein S deficiencies, indicated by decreased free protein S levels, may be caused by:
- hepatic disorders
- . nephrotic syndrome
- oral anticoagulation with vitamin K antagonists
- L-asparaginase treatment
- . pregnancy
- oral contraceptives
- . estrogen therapy
- . viral infections
- disseminated intravascular coagulation
- . elevated plasma levels of C4BP in an acute-phase reaction.
Newborns may also have decreased levels of free protein S.
5
5. Intended Use / Indications for Use
For the quantitative determination of free protein S antigen in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the Sysmex® CS-5100 analyzer.
As an aid in the diagnosis of protein S deficiency in patients who are suspected of free protein S deficiency.
The performance of this device has not been established in neonate and pediatric patient populations.
6. Comparison of Technological Characteristics with the Predicate Device
- A) Assay
| Similarities between INNOVANCE® Free PS Ag and STA®-Liatest® Free Protein S | |||
|---|---|---|---|
| Item | Proposed Device | ||
| INNOVANCE® Free PS Ag | Predicate Device (K010963) | ||
| STA®-Liatest® Free Protein S | |||
| Intended Use | For the quantitative determination | ||
| of free protein S antigen in human | |||
| plasma collected from venous | |||
| blood samples in 3.2% sodium | |||
| citrate tubes on the SYSMEX CS | |||
| -5100 analyzer. | The STA®-Liatest® Free Protein S kits | ||
| are intended for use on STA-R® and | |||
| STA Compact® for the antigenic assay | |||
| of free protein S in plasma by the | |||
| immune-turbidimetric method. | |||
| Indications for | |||
| Use | As an aid in the diagnosis of protein S | ||
| deficiency in patients who are | |||
| suspected of free protein S deficiency. | |||
| The performance of this device has not | |||
| been established in neonate and | |||
| pediatric patient populations. | Not specified in package insert | ||
| Test Principle | Immuno-turbidimetry | Same | |
| Protein S type | |||
| detected | |||
| (specificity) | Free protein S | Same | |
| Sample Type | Human plasma, | ||
| 3.2% sodium citrate | Same |
6
| Similarities between INNOVANCE® Free PS Ag and STA®-Liatest® Free Protein S | ||
|---|---|---|
| Item | Proposed Device | |
| INNOVANCE® Free PS Ag | Predicate Device (K010963) | |
| STA®-Liatest® Free Protein S | ||
| Control Level | 2 Control levels | |
| (sold separately from the assay): | 2 Control levels | |
| (sold separately from the assay): | ||
| Control Plasma N | ||
| (K042333, normal range) | STA®-Liatest® Control N | |
| (normal range) | ||
| Control Plasma P | ||
| (K042209, pathological range) | STA®-Liatest® Control P | |
| (pathological range) | ||
| Units | % of norm | Same |
| Storage | Until expiration date printed on each vial | |
| and carton at 2 – 8°C | Until expiration date indicated on the | |
| box label, when stored at | ||
| 2 – 8°C | ||
| Measuring | ||
| Interval | 10 - 150% of norm | Same |
| Composition | Liquid | |
| [polystyrene particles (latex) coated with | ||
| two different monoclonal antibodies | ||
| both specific for free protein S] | Liquid | |
| (latex microparticles coated by covalent | ||
| bonding with monoclonal antibodies | ||
| specific for free protein S) | ||
| Stability / Shelf | ||
| Life | 12 months according to 510(k) data | Not specified in package insert |
| Stability Once | ||
| Opened | 8 weeks at 2 – 8°C | Not specified in package insert |
| Differences between INNOVANCE® Free PS Ag and STA®-Liatest® Free Protein S | ||
|---|---|---|
| Item | Proposed Device | |
| INNOVANCE® Free PS Ag | Predicate Device (K010963) | |
| STA®-Liatest® Free Protein S | ||
| Buffer | Buffered saline solution containing | |
| heterophilic blocking reagent for minimizing | ||
| interferences by heterophilic antibodies and | ||
| rheumatoid factors. | HEPES buffer | |
| On Board Stability | 96 hours | 32 hours (in original vials) |
| 5 days (with STA® - mini | ||
| Reducer and the perforated cap | ||
| High Dose Hook | ||
| Effect | The INNOVANCE® Free PS Ag assay | |
| on the SYSMEX® CS-5100 system | ||
| shows no high dose hook effect up to | ||
| 588% of norm free protein S. | No dose-hook effect has been | |
| observed with free protein S | ||
| levels up to 200%. |
.
7
B) Calibrator
Г
| Comparison between Calibrators | |||
|---|---|---|---|
| Item | Proposed Device | ||
| INNOVANCE® Free PS Ag | Predicate Device (K010963) | ||
| STA®-Liatest® Free Protein S | |||
| Intended Use | Standard Human Plasma is used for | ||
| the calibration of the following | |||
| coagulation and fibrinolysis tests: |
- Prothrombin time (PT)
- Fibrinogen (Clauss method)
- Coagulation factors II, V, VII,
VIII, IX, X, XI, XII and VWF - Inhibitors: Antithrombin III,
protein C, protein S, a2-antiplasmin - Plasminogen
The percentage values given in the
enclosed table of values relate to a
pool of fresh citrated human plasma,
which by definition, exhibits 100 %
of norm for all the factors.
Coagulation factors and inhibitors for
which a WHO Standard is available
are referenced to this standard and
the values are given in International
Units (IU). | Unknown | |
| Matrix | Normal human plasma (lyophilized) | Unknown | |
| Directly traceable to
WHO Standard | Yes | Information given in the instructions
for use of the predicate:
Kit reagents are pre-calibrated
against a secondary standard of the
03/228 International Standard for
free protein S established in 2006. | |
| Calibration Curve | Standard Human Plasma (K023141,
calibrator sold separately from the
assay) is diluted automatically by the
instrument used. The respective
levels are defined by the actual
concentration of free protein S in the
Standard Human Plasma lot as
provided in the enclosed Table of
Analytical Values, and by the
system-specific dilution settings
for calibration (6-point-calibration
curve on the Sysmex® CS-5100). | Information given in the instructions
for use of the predicate:
To enter the calibration curve on the
analyzer, the barcode printed on the
Assay Value insert has to be scanned
with the instrument barcode reader.
The calibration curve is validated
subsequently after the two control
levels are determined on the
analyzer. | |
| Comparison between Calibrators | | | |
| Item | Proposed Device
INNOVANCE® Free PS Ag | Predicate Device (K010963)
STA®-Liatest® Free Protein S | |
| Stability / Shelf Life | 12 month according to 510(k) data | Unknown | |
| On Board Stability | Because calibrators are intended to
be used immediately, Siemens does
not claim the on-board stability of
Standard Human Plasma in the
labeling. | Unknown | |
| Stability after
Reconstitution | 4 hours stored at 15 to 25 °C and 4
weeks stored at -20 °C | Unknown | |
8
The above described differences do not raise new questions as to safety and effectiveness of the new device.
7. Performance Data
The following performance data were provided in support of the substantial equivalence determination.
7.1. Non-Clinical Studies
7.1.1. Measuring Interval (Limit of Quantitation and Linearity)
The measuring interval of the application was established with respect to the results of the limit of quantitation (LoQ) and the linearity study.
The LoQ study was carried out in accordance with the CLSI document EP17-A2 'Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition', chapter 6. The verification of the LoO was performed with five independent low-analyte plasma pools. Normal plasma pools were diluted with commercial protein S deficient plasma. The free protein S concentrations of these plasma pools were determined with INNOVANCE® Free PS Ag on the Sysmex® CS-5100 analyzer to be between 7.68 to 7.91% of norm.
The LoO candidate (