MEDICAL SUPPLIES CELLTRION-CTP60-AG-COVID Celltrion DiaTrust COVID-19 AG Rapid Test Instruction Manual

MEDICAL SUPPLIES CELLTRION-CTP60-AG-COVID Celltrion DiaTrust COVID-19 AG

Rapid Test

For use under the Emergency Use Authorization (EUA) only
For in vitro diagnostic use
For Prescription Use only

INTENDED USE

Celltrion DiaTrustTMCOVID-19 Ag Rapid Test is a rapid test based on lateral flow immunoassay intended for the qualitative detection of nucleocapsid and receptor binding domains (RBDs) from the SARS-CoV2 in human nasopharyngeal swab specimens directly collected from individuals who are suspected of COVID-19 by their healthcare provider within the first seven days of symptom onset, or from individuals without symptoms or other epidemiological reasons to suspect COVID-19 when tested twice over two or three days with at least 24 hours and no more than 48 hours between tests. Testing is limited to laboratories certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a, that meet the requirements to perform high complexity, moderate complexity, or waived tests. This test is authorized for use at the Point of Care (POC), i.e., in patient care settings operating under a CLIA Certificate of Waiver, Certificate of Compliance, or Certificate of Accreditation.
The Celltrion DiaTrustTM COVID-19 Ag Rapid Test does not differentiate between SARS-CoV and SARSCoV-2.

Results are for the identification of SARS-CoV-2 nucleocapsid and RBD protein antigen. Antigen is generally detectable in human nasopharyngeal swab specimens during the acute phase of infection. Positive results indicate the presence of viral antigens, but clinical correlation with the patient history and other diagnostic information is necessary to determine infection status. Positive results do not rule out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease. Laboratories within the United States and its territories are required to report all results to the appropriate public health authorities.

Negative results should be treated as presumptive and confirmation with a molecular assay, if necessary, for patient management may be performed. Negative results do not rule out SARS-CoV-2 infection and should not be used as the sole basis for treatment or patient management decisions, including infection control decisions. Negative results should be considered in the context of a patient’s recent exposures, history and the presence of clinical signs and symptoms consistent with COVID-19. For serial testing programs, additional confirmatory testing with a molecular test for negative results may be necessary, if there is a high likelihood of SARS-CoV-2 infection, such as in an individual with a close contact with COVID-19 or with suspected exposure to COVID-19 or in communities with high prevalence of infection. Additional confirmatory testing with a molecular test for positive results may also be necessary, if there is a low likelihood of SARS-CoV-2 infection, such as in individuals without known exposures to SARS-CoV-2 or residing in communities with low prevalence of infection.
The Celltrion DiaTrustTM COVID-19 Ag Rapid Test is intended for use by medical professionals or trained operators who are proficient in performing tests, trained clinical laboratory personnel, or individuals trained in POC settings. In the United States, the Celltrion DiaTrustTM COVID-19 Ag Rapid Test is only for use under the Food and Drug Administration’s Emergency Use Authorization.

SUMMARY AND EXPLANATION

Coronavirus is a group of viruses that belongs to the Family Coronaviridae; a type of RNA virus of 27~32 kb commonly found in birds and mammals including human. Coronavirus is divided into four genera: alpha, beta, gamma and delta. The virus causes illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV).
Coronavirus disease 2019 (COVID-19) is a new strain caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease originated from Wuhan city of China in December 2019. The World Health Organization (WHO) publicly named this virus ‘COVID-19’ and declared it a pandemic and a Public Health Emergency of International Concern. The infection is typically spread from one person to another via direct contact or respiratory droplets from cough or sneeze. Latent period from exposure to onset of symptoms is between one to fourteen days (four to seven days on average). Common symptoms and signs of infection include fever, cough, shortness of breath and breathing difficulties. In severe cases, infections can cause pneumonia, severe acute respiratory syndrome, kidney failure and even death.
Due to the wide variety of symptoms, it is difficult to differentiate COVID-19 from other existing respiratory viruses or bacteria. Diagnosing COVID-19 through isolating the virus or detecting specific genes from the collected respiratory droplet specimens is a challenge in terms of time and accessibility as it requires long hours, well-equipped laboratory and advanced technology which are often not available to many public. The test is designed to detect antigen to SARS-CoV-2, and it will help assess if an individual has COVID-19 antigen within 15 minutes.

TEST PRINCIPLE

The Celltrion DiaTrustTM COVID-19 Ag Rapid Test is a lateral flow immunoassay test. The Celltrion DiaTrustTM COVID-19 Ag Rapid Test is designed to detect antigen from the SARS-CoV-2 in human nasopharyngeal swab specimens from patients who are suspected of COVID-19 by their healthcare provider within the first seven days of symptom onset, or from individuals without symptoms or other epidemiological reasons to suspect COVID-19 when tested twice over two or three days with at least 24 hours and no more than 48 hours between tests. The Celltrion DiaTrustTMCOVID-19 Ag Rapid Test is validated for use from direct specimens testing without transport media.
A nitrocellulose membrane strip in the device having a test line and a control line, wherein the test line is pre-coated with anti-mouse monoclonal antibody to SARS-CoV-2 to detect SARS-CoV-2 nucleocapsid and RBDs from the SARS-CoV-2 spike proteins, and the control line is coated with goat anti-mouse IgG. When the extracted swab specimen is dispensed into to the sample well, the specimen migrates towards the conjugate pad, which contains conjugated antibodies with colloidal gold directed against the SARS-CoV-2 antigen. When the sample contains SARS-CoV-2 antigens, an antigen-antibody-conjugate complex is formed. The sample-conjugate complex then passes over the membrane until it reaches the capture zone (test line) Here, the complex is bound to immobilized antibodies and form visible colored band in the test line. The sample then migrates across the membrane along the strip until it reaches the control line where excess conjugate binds and produces a second visible line on the membrane. This control line indicates that the sample has migrated across the membrane as intended and indicates that the test was correctly performed.

MATERIALS PROVIDED

• Test devices packaged individually in aluminum pouch (25 test/box)
• Disposable test tube with 0.3 mL of extraction buffer (25 ea/box)
• Filter cap (25 ea/box)
• Sterilized swabs for specimen collection (25 ea/box)
• Quick reference instruction (1 ea)
• Positive control swab (1 ea/box)
• Negative control swab (1 ea/box)

MATERIALS REQUIRED BUT NOT PROVIDED

• Timer
• Any necessary personal protective equipment

REAGENT STORAGE AND STABILITY
An unopened test device should be stored at 2 -30°C (36 -86°F). The shelf-life of the test device is 10 months and it is stable until the expiration date marked on the label. An opened test device is stable up to 1 hour after released from the aluminum pouch.

SPECIMEN STORAGE AND STABILITY
Nasopharyngeal specimens should be tested immediately after collection. If immediate testing is not possible, specimens should be stored immediately into extraction buffer and may be stored for up to 4 hours until testing. If testing cannot be performed within this time, a new specimen should be collected and tested.

QUALITY CONTROL
An external positive control is needed to confirm that the device performs as intended and that the test procedure is conducted correctly. 0.1 μg/mL of non- infectious recombinant SARS-CoV-2 RBD antigen and 0.1 μg/mL non-infectious recombinant SARS-CoV-2 nucleoprotein antigen is dried onto the swab. This control swab should be tested once with every new lot and shipment, on a daily basis, for each new user, or according to the quality control procedures established for each laboratory.

A sterile swab is included as an external negative control to confirm that the device performs as intended and that the test procedure is conducted correctly. This control swab should be tested once with every new lot and shipment, on a daily basis, for each new user, or according to the quality control procedures established for each laboratory.

A procedural internal control is built in the ‘control line (c)’ of the device and is used to ensure that the applied specimen has migrated well into the device and the test procedure was properly done. It is coated with goat anti- mouse IgG and a colored line will always appear when the test is performed properly.

CHEMICAL HAZARD AND SAFETY INFORMATION

Hazardous ingredients for the extraction buffer

Chemical Name (CAS)| Material Safety Data Sheet| GHS Code for each ingredient| Conc.
---|---|---|---
Sodium Azide (26628-

22-8)

| Material Safety Data Sheet| Acute Tox.2 (oral), H300

Acute Tox.1 (dermal), H310

|

0.09%

The extraction buffer solution in the extraction buffer tube contains a hazardous ingredient as shown in above table. If the extraction buffer solution contacts the skin or eye, immediately wash with plenty of running water. In case the irritation persists, please seek medical advice at: https://www.poison.org/contact-us or 1-800-222-1222

PRECAUTIONS AND WARNINGS

• For use under Emergency Use Authorization Only.
• For in vitro diagnostic use only.
• For prescription use only.
• Read all instructions completely and carefully and follow all instructions. Failure to follow all instructions may result in inaccurate test results. -This product has not been FDA cleared or approved, but has been authorized by FDA under an Emergency Use Authorization (EUA) for use by laboratories certified under the CLIA that meet the requirements to perform high or moderate complexity, or waived tests. This product is authorized for use at the Point of Care (POC), i.e., in patient care settings operating under a CLIA Certificate of Waiver, Certificate of Compliance, or Certificate of Accreditation.
• This product has been authorized only for the detection of proteins from SARS-CoV-2, not for any other viruses or pathogens -The emergency use of this product is only authorized for the duration of the declaration that circumstances exist justifying the authorization of emergency use of in vitro diagnostic tests for detection and/or diagnosis of COVID-19 under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is terminated or the authorization is revoked sooner.
• Use appropriate precautions in the collection, handling and storage of patient samples. Refer to CDC Interim Guidelines for Collection, Handling and Transportation of clinical specimens from persons with Coronavirus Disease 2019 (COVID-19) at https://www.cdc.gov/coronavirus/2019nCoV/lab/guidelines-clinical-specimens.html, and to WHO’s Interim guidance for Laboratory testing for coronavirus disease (COVID-19) in suspected human cases at http://www.who.int/publications-detail/laboratory-testing-for-2019-novel-coronavirus-insuspected-human-cases-20200117, as amended and supplemented. Refer to the WHO website for additional publications.
• Federal Law restricts this device to sale by or on the order of a licensed practitioner (US only).
• Laboratories within the United States and its territories are required to report all results to the appropriate public health laboratories.
• This test has been authorized only for the detection of proteins from SARS-CoV-2, not for any other viruses or pathogens.
• Do not use the test device beyond the expiration date.
• Keep sealed until usage, and once opened use immediately.
• Do not use the test device if the pouch is damaged or the device is seriously broken. -Do not re-use the device.
• Handle all specimens safely as potentially infectious.
• All samples, even after the extraction procedure, and reagents containing biological materials used for the assay must be considered as potentially able to transmit infectious agents; accordingly samples, reagents and the waste must be handled with utmost care and disposed of in compliance with the laboratory guidelines and the statutory provisions in force in each country.
• This test is intended for assessment of coronavirus infection by detecting COVID-19 antigen, but should not be used as a sole criterion for the determination of SARS-CoV-2 infection. Other methods and clinical information (signs and symptoms) should be used and considered for diagnosis.
• Discard Celltrion DiaTrustTM COVID-19 Ag Rapid Test in accordance with local, state and federal regulations or accreditation requirements.

Safety Precautions

• Specimens may be infectious. Use Universal Precautions when performing this assay.
• Use routine laboratory precautions. Do not eat, drink, or smoke in the area where samples are being handled and testing is being conducted. Avoid any contact between hands, eyes or mouth during sample collection and testing.
• Wear personal protective equipment (PPE) in accordance with laboratory and institutional policies, such as laboratory coats, disposable gloves, and eye protection when handling patient samples.
• Wash hands thoroughly after handling specimens and used cartridge.
• Dispose of used test device in a biohazard waste container. Proper handling and disposal methods should be established according to local regulations.
• Avoid splashing or aerosolization of samples or reagents as droplets are a means of transmission of SARS-CoV-2 virus. All drops and spills must be wiped up with an appropriate disinfectant such as a sodium hypochlorite solution with 0.5% active chlorine, and all soiled materials must be disposed of as infectious waste.

TEST PROCEDURE

1. Specimen collection (CDC guideline):
   Use only the swabs provided with the test kit (FA/FANAB01 and Miraclean Technology, Item No. 96000) for specimen collection. Make sure extraction buffer tube and filter cap is also readily available before starting sample collection, as collected swab sample need to be immediately inserted into the extraction buffer tube for sample extraction. After swabbing, immediately insert the swab into extraction buffer tube. Do not leave the sampled swab dry in open air as it may affect the performance of the test.
   Gently and slowly insert a sterile nasal swab through the nostril parallel to the palate (not upwards) until resistance is encountered or the distance is equivalent to that from the ear to the nostril of the patient, indicating contact with the nasopharynx. Swab should reach depth equal to distance from nostrils to outer opening of the ear. Gently rub and roll the swab. Leave swab in place for several seconds to absorb secretions. Slowly remove swab while rotating it. Specimens can be collected from both sides using the same swab, but it is not necessary to collect specimens from both sides if the swab is saturated with fluid from the first collection. If a deviated septum or blockage create difficulty in obtaining the specimen from one nostril, use the same swab to obtain the specimen from the other nostril.
   NOTE: Do not store the swab without extraction buffer. Swabs may be stored in extraction buffer up to 4 hours after collection in room temperature. However, it is highly recommended to perform test immediately after collection for the best results.

2. Test method

   • Prepare an aluminum pouch containing the test device and place it on the testing surface along with the test tube filled with the extraction bufferand filter cap. In case the tests were refrigerated,keep themambient for 30 minutes to let it reachthe room temperature.
   • Release the test device from the aluminum pouch and place it on a flat surface just prior to starting test.
   • Collect the buffer fluid at the bottom of the test tube by shaking it and then peel off the seal of the test tube. Insert the tip of the swab with the patient specimen and move the swab up and down more than 10 times to ensure sufficient sample extraction.
   • Remove the swab while pressing against the sides of the tube to ensure maximum amount of liquid has been squeezed from the swab.
   • Equip the filter cap on the test tube and immediately dispense three drops of sample extracts (100 μL) into the sample well of the device. (If you have dropped the test device after sample application, please discard the device and restart the test using new device.)
   • Read results 15 minutes after applying the sample. Do not read results after 20 minutes. Note: False negative or false positive results could occur if the results are read before 15 minutes or after 20 minutes.

Avoid swabbing and inserting excessive amount of nasopharyngeal specimen into the test tube, as it may block the filter cap when dispensing sample extracts.

INTERPRETATION OF RESULTS

All test controls should be examined prior to interpretation of patient results. If the controls are not valid, the patient results cannot be interpreted.

• Celltrion DiaTrustTM COVID-19 Ag Rapid Test Controls – positive and negative:
  Celltrion DiaTrustTM COVID-19 Ag Rapid Test contains one positive and one negative control to ensure that the test device is working as intended, and the test is correctly performed. A positive control swab will give two colored lines in both test line and control line indicating a positive result.
  If incorrect control results are obtained, do not perform patient tests or report patient results. Contact technical support.

• Examination and interpretation of patient specimen results:
  Assessment of Celltrion DiaTrustTM COVID-19 Ag Rapid Test results should be performed after the positive and negative controls have been examined and determined to be valid and acceptable. If the controls are not valid, the patient results cannot be interpreted.

  • Negative result: If no colored line appears in the test line (T) and a colored line is present on the control region (C), then the result is negative.
  • Note: A negative result is presumptive and confirmation with a molecular assay, if necessary, for patient management may be performed.
  • For serial testing programs, additional confirmatory testing with a molecular test for negative results may be necessary after second negative result for asymptomatic patients, if there is a high likelihood of SARS-CoV-2 infection, such in an individual with as a close contract with COVID-19 or with suspected exposure to COVID-19 or in communities with high prevalence of infection. Additional confirmatory testing with a molecular test for positive results may also be necessary, if there is a low likelihood of SARS-CoV-2 infection, such as in individuals without known exposures to SARS-CoV-2 or residing in communities with low prevalence of infection.

Note: Positive results do not rule out co-infections with other pathogens.
Invalid result: If there is no colored line in the control region (C), the result is invalid.

LIMITATIONS OF THE PROCEDURE

Limitations

• Failure to follow the test procedure may adversely affect test performance and/or invalidate the test result.
• The performance of this device has not been assessed in a population vaccinated against COVID-19.
• This test detects both viable (live) and non-viable, SARS-CoV, and SARS-CoV-2. Test performance depends on the amount of virus (antigen) in the sample and may or may not correlate with viral culture results performed on the same sample.
• Performance has not been established for use with specimens other than nasopharyngeal swabs. Other specimen types have not been evaluated and should not be used with this assay.
• Test results should be considered in the context of all available clinical and diagnostic information, including patient history and other test results.
• The performance of this test was established based on the evaluation of a limited number of clinical specimens collected between 5th Feb 2021 and 25th Feb 2021. The clinical performance has not been established in all circulating variants but is anticipated to be reflective of the prevalent variants in circulation at the time and location of the clinical evaluation. Performance at the time of testing may vary depending on the variants circulating, including newly emerging strains of SARS-CoV-2 and their prevalence, which change over time.
• The clinical performance of this test has not been evaluated in patients without signs and symptoms of respiratory infection or other reasons to suspect COVID-19 infection, or for serial testing when tested twice over two or three days with at least 24 hours and no more than 48 hours between tests. A clinical study to support use in these individuals will be completed.
• A false negative test result may occur if the level of antigen in a sample is below the detection limit of the test or if the sample was collected or transported improperly.
• Negative results should be treated as presumptive and confirmation with a molecular assay, if necessary, for patient management may be performed.
• Negative test results are not intended to rule in other non-SARS-CoV-2 viral or bacterial infections.
• The results obtained with this test should only be interpreted in conjunction with clinical findings, and the results from other laboratory tests and evaluations. This is especially important if the patient has had recent exposure to COVID-19, or clinical presentation indicates that COVID-19 is likely and diagnostic tests for other causes of illness (e.g., other respiratory illness) are negative. In this case, direct testing for the SARS-CoV-2 virus (e.g. PCR testing) should be considered.
• Positive results do not rule out co-infections with other pathogens.
• Positive test results do not differentiate between SARS-CoV-2 and SARS-CoV.
• If the differentiation of specific coronaviruses and strains is needed, additional testing, in consultation with state or local public health departments, is required.
• The amount of antigen in a sample may decrease as the duration of illness increases. Specimens collected after seven days are more likely to be negative compared to RTPCR.

CONDITIONS OF AUTHORIZATION FOR THE LABORATORY

The Celltrion DiaTrustTM COVID-19 Ag Rapid Test Letter of Authorization, along with the authorized Fact Sheet for Healthcare Providers, the authorized Fact Sheet for Patients, and authorized labeling are available on the FDA website: https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19 -emergency-use-authorizations-medicaldevices/vitro-diagnostics-euas. However, to assist clinical laboratories using the DiaTrustTM COVID-19 Ag Rapid Test (“your product” in the conditions below), the relevant Conditions of Authorization are listed below:

• Authorized laboratories* using your product must include, with test result reports, all Fact Sheets. Under exigent circumstances, other appropriate methods for disseminat ing these Fact Sheets may be used, which may include mass media.
• Authorized laboratories using your product must use your product as outlined in the “Celltrion DiaTrustTM COVID-19 Ag Rapid Test” Instructions for Use. Deviations from the authorized procedures, including the authorized instruments, authorized clinical specimen types, authorized control materials, authorized other ancillary reagents and authorized materials required to use your product are not permitted.
• Authorized laboratories that receive your product must notify the relevant public health authorities of their intent to run your product prior to initiating tests.
• Authorized laboratories using your product must have a process in place for reporting test results to healthcare providers and relevant public health authorities, as appropriate.
• Authorized laboratories must collect information on the performance of your product and report to DMD/OHT7-OIR/OPEQ/CDRH (via email: [email protected]), Humasis Co., Ltd. (via email: [email protected] or via phone: +82-31-8085-6284) and Celltrion USA, Inc. (via email: [email protected] or via phone: 201-499-1844) any suspected occurrence of false positive or false negative results and significant deviations from the established performance characteristics of your product of which they become aware.
• All operators using your product must be appropriately trained in performing and interpreting the results of your product. Use appropriate personal protective equipment when handling this kit, and use your product in accordance with the labeling.
• Celltrion USA, Inc., Humasis Co., Ltd., and authorized laboratories using your product must ensure that any records associated with this EUA are maintained until otherwise notified by the FDA. Such records will be made available to the FDA for inspection upon request.
  The letter of authorization refers to, “Laboratories certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a, that meet requirements to perform high, moderate or waived complexity tests. This test is authorized for use at the Point of Care (POC) i.e. in patient care settings operating under CLIA Certificate of Waiver, Certificate of Compliance, or Certificate of Accreditation” as “authorized laboratories.”

PERFORMANCE CHARACTERISTICS

Limit of detection (LoD)
LoD studies determine the lowest detectable concentration of SARS-CoV-2. The LoD was determined by limiting dilution studies using SARS-CoV-2 virus inactivated by beta-Propiolactone (BPL).
Negative sample was prepared by collecting nasopharyngeal swab samples from healthy donors (negative clinical matrix) eluted in PBS.
The positive standard materials are prepared with the six different concentrations of SARS-CoV-2 inactivated virus (Conc. 6.3 × 105 TCID50/mL, NMC-nCoV02 #24) that is serially diluted in PBS and negative clinical matrix.
The diluted positive standard materials are applied to the swab tip with 100 μL of approximate absorption volume. The extraction buffer tubes are prepared and each swab samples are inserted into each extraction buffer tubes. The swab was moved up and down inside the tube 10 times and taken out by pressing to remove the extracted liquid. The filter cap was equipped onto the test tube, then three drops of extracts (100 μL) was dispensed into the sample inlet. The result was read 15 minutes after applying the sample.
Serial dilutions of the inactivated SARS-CoV-2 were tested in 5 replicates. The lowest concentration at which all 5replicates were positive was treated as the tentative LoD for each test. Based on this testing, the tentative LoD was3.2 × 101 TCID50/mL.
The LoD of each test was then confirmed by testing 20 replicates with concentrations near the tentative limit of detection. The final LoD of Celltrion DiaTrustTM COVID-19 Ag Rapid Test was determined to be the lowest concentration resulting in positive detection more than 95% of the time, which is at least 19 out of 20 replicates.
In conclusion, the limit of detection (LoD) of CelltrionDiaTrustTMCOVID-19Ag Rapid Testfor NPswab is 3.2× 101 TCID50/mL.

Cross-reactivity (Analytical specificity) and 3) Microbial Interference Studies Wet-testing:
The study was performed to evaluate the cross-reactivity of the Celltrion DiaTrustTM COVID-19 Ag Rapid Test.
Nasopharyngeal swab sample from healthy donors (negative clinical matrix) were collected and eluted in extraction buffer to be used as a negative standard material. For each test, the diluted sample was added to a sterile nasal swab before conducting the test according to the instruction for use. Positive standard materials(NMC-nCoV02 #24, 6.3 ×105 TCID50/mL) were spiked into negative sample and were diluted to make low concentration level (6.3 × 101 TCID50/mL, approx.2xLOD) for testing.
Potential cross-reactive organisms listed in the below table were prepared at the concentration of 105 PFU/mL or higher for viruses and 106 CFU/mL or higher for bacteria. They were spiked into the negative and low positive samples and were testedin 3 replicates. A total of 31 pathogens listed in the below tableshowed no cross-reactivitywith the Celltrion DiaTrustTMCOVID-19 Ag Rapid Test.

List of organisms

|

Testing conc.

| Test result
---|---|---
Negative

(No. of negative/ No. of replicates)

| Low Positive

(No. of positive/ No. of replicates)

Other high priority pathogens from the same virus family

| Coronavirus OC43| 4.4 × 107 PFU/mL| 3/3| 3/3
Coronavirus 229E| 3 × 106 PFU/mL| 3/3| 3/3
Coronavirus NL63| 1 × 105 TCID50/mL| 3/3| 3/3
MERS-coronavirus| 1.183 × 105

TCID50/mL

| 3/3| 3/3

List of organisms

|

Testing conc.

| Test result
---|---|---
Negative

(No. of

negative/ No. of replicates)

| Low Positive

(No. of positive/

No. of replicates)

Other high priority organisms

| Human adenovirus 1| 7 × 107 PFU/mL| 3/3| 3/3
Human adenovirus 3| 2.4 × 106 PFU/mL| 3/3| 3/3
Human adenovirus 5| 4.0 × 107 PFU/mL| 3/3| 3/3
Human adenovirus 7| 2.0 × 108 PFU/mL| 3/3| 3/3
Respiratory syncytial virus A| 8.0 × 105 PFU/mL| 3/3| 3/3
Respiratory syncytial virus B| 2.4 × 106 PFU/mL| 3/3| 3/3
Parainfluenza 1| 2.8 × 105 PFU/mL| 3/3| 3/3
Parainfluenza 2| 2 × 107 PFU/mL| 3/3| 3/3
Parainfluenza 3| 8 × 105 PFU/mL| 3/3| 3/3
Parainfluenza 4a| 1.3 × 108 PFU/mL| 3/3| 3/3
Rhinovirus 1| 1.4 × 105 PFU/mL| 3/3| 3/3
Metapneumovirus| 6 × 105 PFU/mL| 3/3| 3/3
Human enterovirus| 1 × 105 PFU/mL| 3/3| 3/3
Influenza A H1N1| 2 × 105 PFU/mL| 3/3| 3/3
Influenza A H3N2| 4.9 × 106 PFU/mL| 3/3| 3/3
Influenza B| 1 × 106 PFU/mL| 3/3| 3/3
Mycoplasma pneumonia

(whole organism)

| 1 × 107 CFU/mL| 3/3| 3/3
Streptococcus pyogenes| 1 × 106 CFU/mL| 3/3| 3/3
Bordetella pertussis| 1 × 106 CFU/mL| 3/3| 3/3
Streptococcus pneumoniae| 1 × 106 CFU/mL| 3/3| 3/3
Legionella pneumophila| 1 × 106 CFU/mL| 3/3| 3/3
Haemophilusinfluenzae| 1 × 106 CFU/mL| 3/3| 3/3
Candida albicans| 1 × 106 CFU/mL| 3/3| 3/3
Chlamydiapneumoniae| 2.0 × 107 TCID50/mL| 3/3| 3/3
Pooled human nasal wash| 100%| 3/3| 3/3
Staphylococcus epidermidis| 1 × 106 CFU/mL| 3/3| 3/3
Staphylococcus aureus| 1 × 106 CFU/mL| 3/3| 3/3

Human coronavirus HKU1 spike protein at the concentration of 10 μg/mL was spiked into negative and positive samples. It was tested in 3 replicates using the Celltrion DiaTrustTM COVID-19 Ag Rapid Test, and no cross-reactivity was observed.
In-silico : To estimate the likelihood of cross-reactivity with SARS- CoV-2 virus in the presence of organisms that were not available for wet testing,in silico analysis using the Basic Local Alignment Search Tool (BLAST) managed by the National Center for Biotechnology Information (NCBI) was used to assess the degree of protein sequence homology.
Human coronavirus HKU1: 12% homology was found between SARS-CoV-2 Receptor Binding Domain spike proteins and HKU1 spike protein, and 32% homology was found between SARS-CoV-2 Nucleocapsid protein and HKU1 Nucleocapsid protein. Therefore, cross-reactivity is highly unlikely but cannot be ruled out.
Pneumocystis jirovecii: No sequence homology was found between SARS-CoV-2 RBD spike protein / nucleocapsid protein and P. jirovecii. Therefore, there is no cross-reactivity.
Mycobacterium tuberculosis: There was 45.6% homology across 9% of the whole sequence between
M.tuberculosis and SARS-CoV-2 RBD spike protein. No similarity was found between M. tuberculosis and SARS-CoV-2 NP. Therefore,cross-reactivity is highly unlikely but cannot be ruled out.
SARS-CoV: 72% homology was found between SARS-CoV-2 Receptor Binding Domain spike proteins and SARS-CoV spike protein, and 96% homology was found between SARS-CoV-2 Nucleocapsid protein and SARS-CoV Nucleocapsid protein. Therefore, cross-reactivity is highly likely.
Note: The Celltrion DiaTrustTM COVID-19 Ag Rapid Test does not differentiate between SARS-CoV and SARS-CoV-2.

Endogenous interference substances study:
Testing to evaluate interference of the Celltrion DiaTrustTM COVID-19 Ag Rapid Test was performed.
Extraction buffer was used as negative sample. Positive standard materials were spiked into negative sample and werediluted toprepare alow concentration level (6.3 × 101TCID50/mL, approx. 2xLoD) for testing.
Potential interfering substances were added to the negative and positive samples and were tested using the Celltrion DiaTrustTM COVID-19 Ag Rapid Test in 3 replicates. The test results demonstrated that 41 interfering substances (table below) did not affect the performance of Celltrion’s DiaTrustTM COVID-19 Ag Rapid Test.

No.

|

Interfering substances

| Testing conc.|

Negative

| Negative + Interfering

substances

| Low positive| Low pos. + Interfering

substances

---|---|---|---|---|---|---
1| Whole blood| 4%| 3/3| 3/3| 3/3| 3/3
2| Mucin| 0.5%| 3/3| 3/3| 3/3| 3/3
3| Chloraseptic| 1.5 mg/mL| 3/3| 3/3| 3/3| 3/3
4| NeilMed NasoGel| 5% v/v| 3/3| 3/3| 3/3| 3/3
5| CVS Nasal drops| 15% v/v| 3/3| 3/3| 3/3| 3/3
6| Afrin (Oxymetazoline)| 15% v/v| 3/3| 3/3| 3/3| 3/3
7| Sodium cromoglycate

(CVS nasal spray, Cromolyn)

| 15% v/v| 3/3| 3/3| 3/3| 3/3
8| Zicam| 15% v/v| 3/3| 3/3| 3/3| 3/3
9| Homeopathic (Alkalol)| 1:10

dilution

| 3/3| 3/3| 3/3| 3/3
10| Sore throat Phenol Spray| 15% v/v| 3/3| 3/3| 3/3| 3/3
11| Tobramycin| 5 μg/mL| 3/3| 3/3| 3/3| 3/3
12| Mupirocin| 10 mg/mL| 3/3| 3/3| 3/3| 3/3
13| Fluticasone Propionate| 5% v/v| 3/3| 3/3| 3/3| 3/3
14| Tamiflu (Oseltamivir Phosphate)| 5 mg/mL| 3/3| 3/3| 3/3| 3/3
15| Albumin, human| 3000| 3/3| 3/3| 3/3| 3/3

No.

|

Interfering substances

| Testing conc.|

Negative

| Negative + Interfering

substances

| Low positive| Low pos. + Interfering

substances

---|---|---|---|---|---|---
| | mg/dL| | | |
16| Bilirubin| 500 μmol/L| 3/3| 3/3| 3/3| 3/3
17| Hemoglobin| 500 mg/dL| 3/3| 3/3| 3/3| 3/3
18| Cholesterol| 20 μmol/L| 3/3| 3/3| 3/3| 3/3
19| Triglyceride| 1000

mg/dL

| 3/3| 3/3| 3/3| 3/3
20| Biotin| 0.75

mg/mL

| 3/3| 3/3| 3/3| 3/3
21| Sodium citrate| 25 mg/mL| 3/3| 3/3| 3/3| 3/3
22| Heparin| 100 U/mL| 3/3| 3/3| 3/3| 3/3
23| EDTA| 5 μmol/L| 3/3| 3/3| 3/3| 3/3
24| K3-EDTA| 20 mg/mL| 3/3| 3/3| 3/3| 3/3
25| Diphenhydramine hydrochloride| 5 mg/mL| 3/3| 3/3| 3/3| 3/3
26| Acetaminophen| 199 μmol/L| 3/3| 3/3| 3/3| 3/3
27| Acetylsalicylic acid| 3.62

mmol/L

| 3/3| 3/3| 3/3| 3/3
28| Ibuprofen| 2.425

mmol/L

| 3/3| 3/3| 3/3| 3/3
29| Olopatadine hydrochloride| 5 mg/mL| 3/3| 3/3| 3/3| 3/3

30

| Hanmi Ko-and-Cool Nasal Spray (Chlorpheniramine Maleate 250 mg/ 100 mL, Xylometazoline

Hydrochloride 0.1 g/100 mL)

|

10%(v/v)

|

3/3*

|

3/3*

|

3/3**

|

3/3**

31

| Samchundang Narista-S Nasal

Spray (Chlorpheniramine Maleate 2.5 mg/mL, Dipotassium Glycyrrhizinate 3 mg/mL, Naphazoline

Hydrochloride 0.5 mg/mL)

|

10%(v/v)

|

3/3*

|

3/3*

|

3/3**

|

3/3**

32| Sodium chloride| 20 mg/mL| 3/3| 3/3| 3/3| 3/3
33| Zanamivir| 5 mg/mL| 3/3| 3/3| 3/3| 3/3
34| Oseltamivir| 10 mg/mL| 3/3| 3/3| 3/3| 3/3
35| Artemether-lumefantrine| 50 μmol/L| 3/3| 3/3| 3/3| 3/3
36| Doxycycline hyclate| 70 μmol/L| 3/3| 3/3| 3/3| 3/3
37| Quinine| 150 μmol/L| 3/3| 3/3| 3/3| 3/3
38| Lamivudine| 1 mg/mL| 3/3| 3/3| 3/3| 3/3
39| Erythromycin| 81.6

μmol/L

| 3/3| 3/3| 3/3| 3/3
40| Ciprofloxacin| 30.2

μmol/L

| 3/3| 3/3| 3/3| 3/3
41| Rheumatoid factor positive

plasma

| 10%(v/v)| 3/3| 3/3| 3/3| 3/3

High-dose Hook effect
Pooled nasopharyngeal specimens was used as clinical matrix, and SARS-CoV-2 virus inactivated by beta-Propiolactone (BPL) was spiked to make various high concentration levels of SARS-CoV-2 antigens. Prepared samples of each concentration levels were tested using Celltrion DiaTrustTM COVID-19 Ag Rapid Test in 3 replicates following instructions.
No high-dose hook effectwasobserved up to6.3×105TCID50/mL, approx.20,000xLoD.

SARS-CoV-2 inactivated virus ( 6.3  105 TCID50/mL )

TCID 50 /mL (concentration)

| Test results (No. of positives/ No. of replicates)
Lot 1| Lot 2
3.2 x 101 [1xLoD]| 3/3| 3/3
1.3 x 102 [4xLoD]| 3/3| 3/3
1.5 x 104 [500xLoD]| 3/3| 3/3
6.3 x 105 [20,000xLoD]| 3/3| 3/3

Specimen stability
Nasopharyngeal swab samples were collected from healthy donors and were used as negative sample. Positive materials were prepared usingthe SARS-CoV-2 inactivated virus(NMC-nCoV02 #24, 6.3×105 TCID50/mL) diluted to low positive concentration (6.3 × 101 TCID50/mL, approx. 2xLoD) in negative sample, and 20 μL of the prepared low positive materials were coated on the swab to be used as positive sample.
Prepared negative and positive samples were mixed in extraction buffer and capped as per the instructions for use and stored in room temperature (30°C) for various time periods; immediately, and 1, 2, 3, 4, 6 hours after preparation. Samples of each conditions were tested in 5 replicates for negative samples and 10 replicates for low positive samples following the instructions, using randomly selected samples of the Celltrion DiaTrustTMCOVID-19 Ag RapidTest.
Test results showed that collected nasopharyngeal swab specimen in extraction buffer is stable for testing up to 4 hours after collection in room temperature. However, it is highly recommended to perform test immediately after collection for the best results.

Time periods after storage in room temperature

| Test result
---|---
Negative

(No. of negative/ No. of replicates)

| Low Positive

(No. of positive/ No. of replicates)

Immediately| 5/5| 10/10
1 hour| 5/5| 10/10
2 hours| 5/5| 10/10
3 hours| 5/5| 10/10
4 hours| 5/5| 10/10
6 hours| 5/5| 8/10

Clinical evaluation
The clinical evaluation of the Celltrion DiaTrustTM COVID-19 Ag Rapid Test was evaluated by testing a total of 133 prospectively collected direct nasopharyngeal swab samples, consisted of 30 positive and 103 negative samples from suspected COVID-19 patients in United States within 7 days of symptom onset. Direct nasopharyngeal swabs were collected from each patient, eluted in the extraction buffer and tested with the device immediately. Results of each samples were confirmed by a high-sensitivity FDA authorized RT-PCR assay.
According to the test results, clinical performance results of the Celltrion DiaTrustTM COVID-19 Ag Rapid Test was as follows:

Test result

| RT-PCR|

Total

---|---|---
Positive| Negative

Celltrion DiaTrustTM COVID-19 Ag Rapid Test

| Positive| 28| 1| 29
Negative| 2| 102| 104
Total| 30| 103| 133
Parameter| Proportion (%)| 95% Confidence Interval
---|---|---
Sensitivity| 28/30 (93.33%)| 78.7 – 98.2%
Specificity| 102/103 (99.03%)| 94.7 – 99.8%
Positive Predictive Value| 28/29 (96.55%)| 82.8 – 99.4%
Negative Predictive Value| 102/104 (98.08%)| 93.3 – 99.5%
Prevalence| 22.56%| 16.3 – 30.4%

Day Since Symptom Onset

|

Cumulative RT-PCR (+)

| Cumulative Celltrion DiaTrust TM COVID- 19 Ag Rapid Test Positive (+)|

PPA

|

95% Confidential interval

---|---|---|---|---
1| 3| 3| 100.0%| 43.9%| 100%
2| 9| 9| 100.0%| 70.1%| 100%
3| 15| 14| 93.33%| 70.2%| 98.8%
4| 24| 23| 95.83%| 79.8%| 99.3%
5| 26| 25| 96.15%| 81.1%| 99.3%
6| 27| 26| 96.30%| 81.7%| 99.3%
7| 30| 28| 93.33%| 78.7%| 98.2%

Patient demographics are available for the 30 samples used in the analysis of patients with symptom onset within the previous seven (7) days. The table below shows the positive results broken down by age of patient.

Age Group

| Celltrion DiaTrust TM COVID-19 Ag Rapid Test
---|---
Total number| Positive| Prevalence
≤5 Years of Age| 0| 0| N/A
6-21 Years of Age| 1| 1| 100%
22-59 Years of Age| 25| 24| 96%
≥60 Years of Age| 4| 3| 75%

Celltrion DiaTrustTM COVID-19 Ag Rapid Test was demonstrated at near patient or Point of Care (POC) testing that non-laboratory personnel can perform the test accurately in the intended use environment. In addition, the robust use of Celltrion DiaTrustTM COVID-19 Ag Rapid Test for near patient or Point of Care (POC) testing was demonstrated by nine (9) Flex studies.
The performance of this test has not yet been clinically validated for use in patients without signs and symptoms of respiratory infection or for serial screening applications and performance may differ in these populations.
ASSISTANCE
If you have any questions regarding the use of this product or if you want to report a test system problem, please contact Humasis Co., Ltd. (via email: [email protected], via phone: +82-31-80856284) or Celltrion USA, Inc. (via email: [email protected], or via phone: 201-499-1844). Test system problems may also be reported to the FDA through the MedWatch medical products reporting program (phone: 800.FDA.1088; fax: 800.FDA.0178; http://www.fda.gov/medwatch).

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