NIOX VERO AIRWAY INFLAMMATION MONITOR
Device Facts
| Record ID | K133898 |
|---|---|
| Device Name | NIOX VERO AIRWAY INFLAMMATION MONITOR |
| Applicant | Aerocrine AB |
| Product Code | MXA · Clinical Toxicology |
| Decision Date | Nov 6, 2014 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.3080 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
NIOX VERO® measures Nitric Oxide (NO) in human breath. Nitric Oxide is frequently increased in some inflammatory processes such as asthma. The fractional NO concentration in expired breath (FeNO), can be measured by NIOX VERO according to guidelines for NO measurement established by the American Thoracic Society. Measurement of FeNO by NIOX VERO is a quantitative, non-invasive, simple and safe method to measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy, as an indication of the therapeutic effect in patients with elevated FeNO levels. NIOX VERO is suitable for children, approximately 7 - 17 years, and adults 18 years and older. FeNO measurements provide the physician with means of evaluating an asthma patient’s response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. The NIOX VERO is intended for prescription use and should only be used as directed in the NIOX VERO User Manual by trained healthcare professionals. NIOX VERO cannot be used with infants or by children approximately under the age of 7, as measurement requires patient cooperation. NIOX VERO should not be used in critical care, emergency care or in anesthesiology.
Device Story
Portable system for non-invasive, quantitative measurement of fractional exhaled nitric oxide (FeNO) in human breath; used by trained healthcare professionals in clinical settings. Input: patient exhales into device through disposable filter; exhalation flow controlled to 50 ml/s ±5 ml/s at 10-20 cm H2O pressure. Operation: electrochemical sensor detects NO molecules diffusing through membrane; chemical reaction generates electrical current proportional to NO concentration. Output: NO concentration in parts per billion (ppb) displayed after 10-second exhalation and 25-second analysis. Software processes results; optional PC application (NIOX Panel) enables EMR integration. Benefits: provides objective marker of airway inflammation; assists physicians in evaluating patient response to anti-inflammatory therapy. Device includes internal/external quality control procedures; requires daily QC testing for clinical readiness.
Clinical Evidence
Method comparison study (n=112, 109 completed) compared NIOX VERO to NIOX MINO. Weighted Deming regression slope 0.842 (95% CI 0.757, 0.927). Differences in measurements between devices were not clinically significant. Inter-operator variability study (n=122) showed consistent performance across operators. Exogenous substance study (n=12) showed minimal impact of gum, carbonated beverages, or mouthwash on FeNO measurements. No new clinical study was conducted; results from k072816 were deemed applicable.
Technological Characteristics
Portable electrochemical breath NO monitor. Features: electromechanical flow regulator, disposable patient filters, exchangeable handle with NO scrubber. Connectivity: USB for PC communication. Software: Moderate Concern, validated per FDA guidance and IEC 62304. Power: Battery/AC adapter. Sensor: Electrochemical, utilizing temperature/humidity compensation algorithm.
Indications for Use
Indicated for quantitative measurement of fractional exhaled nitric oxide (FeNO) in human breath to evaluate response to anti-inflammatory therapy in asthma patients. Suitable for children (approx. 7-17 years) and adults (18+). Contraindicated for infants, children under 7, and use in critical care, emergency care, or anesthesiology.
Regulatory Classification
Identification
A breath nitric oxide test system is a device intended to measure fractional nitric oxide in human breath. Measurement of changes in fractional nitric oxide concentration in expired breath aids in evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments of asthma. A breath nitric oxide test system combines chemiluminescence detection of nitric oxide with a pneumotachograph, display, and dedicated software.
Special Controls
*Classification.* Class II (special controls). The special control is FDA's guidance entitled “Class II Special Controls Guidance Document: Breath Nitric Oxide Test System.” See § 862.1(d) for the availability of this guidance document.
Predicate Devices
- NIOX MINO® Airway Inflammation Monitor (K101034)
Related Devices
- K072816 — NIOX MINO · Aerocrine AB · Mar 3, 2008
- K182874 — Fenom Pro Nitric Oxide Test · Spirosure, Inc. · Feb 13, 2019
Submission Summary (Full Text)
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION MEMORANDUM INSTRUMENT ONLY TEMPLATE
A. 510(k) Number:
k133898
B. Purpose for Submission:
New Device
C. Manufacturer and Instrument Name:
Aerocrine NIOX VERO
D. Type of Test or Tests Performed:
Quantitative
E. System Descriptions:
1. Device Description:
NIOX VERO is a portable system for the non-invasive, quantitative measurement of the fraction of exhaled nitric oxide (NO) in expired human breath (FeNO).
The NIOX VERO system is comprised of the NIOX VERO unit with AC adapter, a rechargeable battery, an electrochemical NO sensor, disposable patient filters, and an exchangeable handle containing an internal NO scrubber filter. The NIOX Panel is an optional PC application for operation of the NIOX VERO from a PC and access to electronic medical record systems.
For testing, the patient empties their lungs, inhales deeply through the patient filter to total lung capacity and then slowly exhales for 10 seconds. In approximately one minute, the NO concentration is displayed in parts per billion (ppb). Results are processed using dedicated software.
2. Principles of Operation:
Measurement principle is based on American Thoracic Society guidelines (ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005. Am J Respir Crit Care Med. 2005;171:912-930). The last three second fraction of a 10 second exhalation is evaluated for average NO concentration. The exhalation flow is controlled to 50 ml/s ±5 ml/s at an applied pressure of 10 to 20 cm H2O. Sample is evaluated in 25
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seconds (2 ml/sec for 25 seconds). The inhaled air is NO free. NO is measured using electrochemical detection. There is a gas inlet chamber with an electrolyte (sulfuric acid solution) and hardware. The NO molecules diffuse through the membrane and reach the electrolyte. A chemical reaction takes place where one electron for each NO molecule is generated. The current is proportional to the number of converted NO molecules.
3. Modes of Operation:
NIOX VERO is a portable system for the non-invasive, quantitative measurement of the fraction of exhaled nitric oxide (NO) in expired human breath (FeNO) measured in parts per billion (ppb).
The NIOX VERO system is comprised of the NIOX VERO unit with AC adapter, a rechargeable battery, an electrochemical NO sensor, disposable patient filters, and an exchangeable handle containing an internal NO scrubber filter. The NIOX Panel is an optional PC application for operation of the NIOX VERO from a PC and access to electronic medical record systems.
The NIOX VERO unit includes a sampling and gas conditioning system and a man-machine interface (MMI). The instrument controls the inhaled sample appropriately via the electronics and software program. Filtering of inhaled air eliminates contamination from ambient NO levels. A built-in flow control keeps exhalation standardized at 50 ml/s so that it is standardized for all patients. The sample enters an electromechanical sensor and interacts with an electrolyte. A chemical reaction takes place where electrons are generated proportional to the number of NO molecules.
The patient empties their lungs, inhales deeply through the patient filter to total lung capacity and then slowly exhale for 10 seconds. In approximately one minute, the NO concentration is displayed in parts per billion (ppb).
Results are processed using dedicated software. In order to verify the device's performance and reliability of measurements, there are built-in system control procedures and a Quality Control procedure to be performed on a daily basis.
4. Specimen Identification:
There is no mechanism to identify the specimen.
5. Specimen Sampling and Handling:
The user obtains a breath sample by exhaling into the device.
6. Calibration:
The manufacturer performs calibration for each NIOX VERO® Sensor. NIOX VERO sensor is an electrochemical sensor pre-calibrated and pre-programmed for a defined
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number of tests (60, 100, 300, 500, or 1000 tests). The user exchanges the sensor upon expiration. The instrument prompts the user for upcoming exchange prior to sensor expiration and does not allow for measurements with an expired sensor. No additional calibration is needed during the lifetime of the sensor.
## 7. Quality Control:
NIOX VERO provides internal controls as well as an External Quality Control program for the user to verify the reliability of measurements.
The External Quality Control program consists of two parts: One positive control from a qualified staff member with a stable $\mathrm{Fe}_{\mathrm{NO}}$ value providing a normal biological $\mathrm{Fe}_{\mathrm{NO}}$ sample and a negative control consisting of a NO free gas sample automatically generated from ambient air. The process consists of performing 3 QC measurements one per day within 7 days. A mean is calculated from the 3 measurements that must be between 5-40 ppb to establish the baseline. The following QC measurement on the 4th day must be within +/- 10 ppb from the mean value of the initial 3 measurements and the NO scrubber result < 5ppb. Then the QC has passed and the instrument is ready for clinical use. A moving mean is calculated when the QC tester performs a QC measurement following 7 days. A QC test must be performed each day of use. If the QC tester does not perform a QC test in 30 days, the qualification is suspended and the QC tester needs to re-qualify.
## 8. Software:
FDA has reviewed applicant’s Hazard Analysis and Software Development processes for this line of product types:
Yes ☐ X ☐ or No ☐
## F. Regulatory Information:
1. Regulation section:
21 CFR 862.3080, Breath nitric oxide test system
2. Classification:
Class II
3. Product code:
MXA
4. Panel:
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Clinical Chemistry (75)
G. Intended Use:
1. Indication(s) for Use:
NIOX VERO® measures Nitric Oxide (NO) in human breath. Nitric Oxide is frequently increased in some inflammatory processes such as asthma. The fractional NO concentration in expired breath (FeNO), can be measured by NIOX VERO according to guidelines for NO measurement established by the American Thoracic Society.
Measurement of FeNO by NIOX VERO is a quantitative, non-invasive, simple and safe method to measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy, as an indication of the therapeutic effect in patients with elevated FeNO levels. NIOX VERO is suitable for children, approximately 7 - 17 years, and adults 18 years and older.
FeNO measurements provide the physician with means of evaluating an asthma patient’s response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. The NIOX VERO is intended for prescription use and should only be used as directed in the NIOX VERO User Manual by trained healthcare professionals. NIOX VERO cannot be used with infants or by children approximately under the age of 7, as measurement requires patient cooperation. NIOX VERO should not be used in critical care, emergency care or in anesthesiology.
2. Special Conditions for Use Statement(s):
NIOX VERO should only be operated by trained healthcare professionals and only after careful reading of the NIOX VERO User Manual.
The device should not be used with infants or by children under age of 7, or any patient who cannot cooperate with any necessary requirements of test performance.
The device should not be used in critical care, emergency care or in anaesthesiology.
Subjects should not smoke in the hour before measurements, and short- and long-term active and passive smoking history should be recorded. In addition, subjects should refrain from eating and drinking for 1 hour before exhaled NO measurement. Alcohol ingestion reduces FENO in patients with asthma and healthy subjects FENO.
It is prudent, where possible, to perform serial NO measurements in the same period of the day and to always record the time.
For prescription use only.
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H. Substantial Equivalence Information:
1. Predicate Device Name(s) and 510(k) numbers:
NIOX MINO Airway Inflammation Monitor, k101034
2. Comparison with Predicate Device:
| Similarities | | |
| --- | --- | --- |
| Item | Device: NIOX VERO | Predicate: NIOX MINO |
| Intended Use/ Indications for Use | To measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy, as an indication of the therapeutic effect in patients with elevated FeNO levels. NIOX VERO is suitable for children, approximately 7 - 17 years, and adults 18 years and older.
FeNO measurements provide the physician with means of evaluating an asthma patient’s response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. The NIOX VERO is intended for prescription use and should only be used as directed in the NIOX VERO User Manual by trained healthcare professionals. | Same |
| Measurement Principle | Measurement principle is based on ATS guidelines.
Sampling principle
The last three second fraction of a 10 seconds exhalation is evaluated for | Same |
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| Similarities | | |
| --- | --- | --- |
| Item | Device: NIOX VERO | Predicate: NIOX MINO |
| | average NO concentration. The exhalation flow is controlled to 50 ml/s ±5 ml/s at an applied pressure of 10 to 20 cm H2O. The inhaled air is NO free. Electrochemical detection, NO concentration derived from proportional electrical current. | |
| Measurement range | 5 - 300 ppb | Same |
| Detection level | 5 ppb | Same |
| Differences | | |
| --- | --- | --- |
| Item | Device: NIOX VERO | Predicate: NIOX MINO |
| Buffer chamber capacity | Buffer chamber capacity 50 mls. | Buffer chamber capacity 150 mls. |
| Patient Filter Case Material | Plastic material is K-resin | Plastic material ABS. |
| Temperature control/monitoring | The measured sensor temperature is input to a compensation software algorithm to adjust the Nitric Oxide value. | Sensor temperature stabilized to 22.5°C |
| Instrument Lifetime | 5.5 years or 15,000 measurements plus QC measurements | 3.5 years or 3000 measurements plus QC measurements |
| Sample analysis time | Sample is evaluated in 25 seconds (2 ml/sec for 25 seconds). | Sample is evaluated in 50 seconds (1 ml/sec for 50 seconds). |
| Power supply | External AC/DC power supply and internal lithium battery. | External AC/DC power supply only |
| Ambient temperature (operating condition) | +10 to +35°C | +16 to +30°C |
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| Differences | | |
| --- | --- | --- |
| Item | Device: NIOX VERO | Predicate: NIOX MINO |
| Humidity
(non-condensing)
(operating condition) | 20 to 80% RH | 20 to 60% RH |
I. Special Control/Guidance Document Referenced (if applicable):
- AAMI 62304:2006: Medical device software - Software life cycle processes
- IEC 62366: Medical devices - Application of usability engineering to medical devices
- CLSI EP 7-A2: Interference Testing in Clinical Chemistry; Approved Guideline
- CLSI EP9-A2 1995: Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline
- CLSI EP5-A2: Evaluation of Precision Performance of Clinical Chemistry Devices; Approved Guideline
- ISO 10993-1: Biological Evaluation of Medical Devices - Part 1: Guidance on Selection of Tests
- AAMI 10993-5:1993: Biological evaluation of medical devices -- Part 5: Tests for cytotoxicity: in vitro methods
- AAMI 10993-10:1995: Biological evaluation of medical devices -- Part 10: Tests for irritation and sensitization -- Maximization sensitization test
- ISO 14971:2000: Medical devices - Application of risk management to medical devices
- IEC 60601-1: Medical electrical equipment - Part 1: General requirements for safety
- AAMI 14155:2011: Clinical investigation of medical devices for human subjects - Good clinical practice
- IEC 60601-1-2: Medical Electrical Equipment - Part 1: General Requirements for Safety; Electromagnetic Compatibility - Requirements and Tests
- CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures, Approved Guideline
J. Performance Characteristics:
1. Analytical Performance:
a. Accuracy:
A method comparison study was performed, to compare performance of the NIOX VERO to the predicate device (NIOX MINO). A total of 112 male and female subjects (48 Children and 64 Adults) aged 7 to 78 years with either physician diagnosed asthma or under evaluation for a diagnosis of asthma were enrolled and 109 subjects completed the study.
The first NIOX VERO $\mathrm{Fe_{NO}}$ measurement was compared to the first NIOX MINO
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$\mathrm{Fe_{NO}}$ measurement. Analysis of the relationship between the NIOX VERO and the NIOX MINO showed the slope of the Weighted Deming regression analysis was 0.842 (95% CI 0.757, 0.927) and the intercept was -0.472 (95% CI -1.999, 1.055).
Exhaled nitric oxide is recognized by the American Thoracic Society as a marker of airway inflammation and is recommended (in conjunction with other clinical attributes) in the diagnosis of airway inflammation and in determining response to corticosteroid therapy. In the clinical setting, the utility of FeNO is the shift (upward or downward) or lack thereof, rather than a specific percentage change in the FeNO value. Therefore, when comparing the change in nitric oxide values between clinical visits, the difference in measurements between the NIOX VERO and the NIOX MINO was not clinically significant.
See section J.2. for additional clinical supportive data.
# b. Precision/Reproducibility:
The precision was tested based on CLSI EP5-A2. Certified NO of 200 ppb and 2100 ppb in nitrogen calibration gas was used. Data was collected over 20 operating days, two runs per day, with duplicate determinations for each concentration, using the concentrations 15, 75 and 200 ppb. The repeatability and within-device precision over 20 days were determined for each concentration. Five NIOX VERO sensors, continually mounted in 5 NIOX VERO instruments, respectively, were used in these tests. All NIOX VERO instruments were tested and stored at ambient room conditions. The NIOX VERO instruments were continuously powered during the test period.
The repeatability and within-device precision were calculated for the 5 instruments. The results at the 15 ppb level is expressed as ppb, and at 75 and 200 ppb as percentage of the measured NO concentration (Table 1). The repeatability and within-device precision were additionally tested using concentrations of 5, 25, 75, and 200 ppb to include more concentrations across the measurement range of the device (Table 2).
| Precision (Table 1) | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Repeatability | | | Within-device precision | | |
| NO concentration, ppb | 15 ppb | 75 ppb | 200 ppb | 15 ppb | 75 ppb | 200 ppb |
| Serial No. NIOX VERO/Sensor | SD[ppb] | CV[%] | CV[%] | SD[ppb] | CV[%] | CV[%] |
| 112 / 2921 | 0.6 | 1.5 | 0.9 | 1.5 | 1.7 | 1.0 |
| 114 / 2938 | 1.7 | 1.3 | 1.3 | 2.0 | 3.7 | 2.2 |
| 102 / 2941 | 1.4 | 1.3 | 0.9 | 1.9 | 2.9 | 1.7 |
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| 119 / 2936 | 2.0 | 1.5 | 1.6 | 2.4 | 4.5 | 2.7 |
| --- | --- | --- | --- | --- | --- | --- |
| 129 / 2934 | 1.1 | 1.6 | 0.6 | 1.6 | 2.7 | 1.0 |
| Precision (Table 2) | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Repeatability | | | | Within-device precision | | | |
| NO concentration, ppb | 5 ppb | 25 ppb | 75 ppb | 200 ppb | 5 ppb | 25 ppb | 75 ppb | 200 ppb |
| Serial No. NIOX VERO/Sensor | SD[ppb] | SD[ppb] | CV[%] | CV[%] | SD[ppb] | SD[ppb] | CV[%] | CV[%] |
| 735/4847 | 0.74 | 0.58 | 1.4 | 1.9 | 0.83 | 0.63 | 1.5 | 1.7 |
| 741/4848 | 0.44 | 0.51 | 1.1 | 1.0 | 0.63 | 0.59 | 1.3 | 1.0 |
| 748/4849 | 0.55 | 0.51 | 1.1 | 1.0 | 0.63 | 0.65 | 1.4 | 1.1 |
| 755/4850 | 0.42 | 0.46 | 1.0 | 0.8 | 0.55 | 0.56 | 1.3 | 0.9 |
| 762/4859 | 0.47 | 0.50 | 0.7 | 0.5 | 0.49 | 0.55 | 1.2 | 0.8 |
# Clinical Precision:
A multi-center, single visit, point-of-care, inter-operator variability study was conducted to determine the repeatability of $\mathrm{Fe_{NO}}$ measured with the NIOX VERO® device when three consecutive valid $\mathrm{Fe_{NO}}$ measurements were obtained in a single subject by three different NIOX VERO® operators using the same NIOX VERO® device. Fractional Exhaled Nitric Oxide $(\mathrm{Fe_{NO}})$ levels in this study were assessed for a total of 122 subjects at 3 different sites by a total of 43 different operators.
The table below shows the agreement among operators for NIOX VERO measurement at six different measurement ranges.
| Median concentration | N | Within Subject Mean SD (ppb) | 95% CI for SD [1] | Within Subject Mean CV (%) | 95% CI for CV [1] |
| --- | --- | --- | --- | --- | --- |
| 0<=10 | 39 | 0.56 | 0.39, 0.73 | 7.86% | 5.59%, 10.27% |
| 10<=20 | 31 | 1.12 | 0.92, 1.34 | 8.19% | 6.89%, 9.64% |
| 20<=30 | 8 | 1.13 | 0.77, 1.53 | 4.78% | 3.11%, 6.76% |
| 30<=40 | 9 | 1.32 | 0.89, 1.77 | 3.94% | 2.63%, 5.38% |
| 40<=50 | 5 | 1.91 | 1.04, 2.90 | 4.24% | 2.28%, 6.62% |
| >=50 | 30 | 3.79 | 2.82, 4.83 | 4.85% | 3.63%, 6.22% |
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c. Linearity:
Certified NO at 200 ppb and 2000 ppb in nitrogen calibration gas was mixed with nitrogen gas in a gas mixer, connected in-line with the NIOX VERO instrument, (with mounted NIOX VERO sensors), to obtain 7 NO concentration levels (3, 5, 25, 100, 200, 300 and 330 ppb). Five replicate determinations of the concentrations at 3 and 5 ppb, and three replicate determinations on the other intervals were made.
For the 10 devices tested, the regression analysis gave slopes of 0.95 to 1.05 and intercept ±3 ppb. The squared correlation coefficient r² was > 0.998 for all the 10 devices tested. Results indicate linearity within the 5-30 ppb measuring range.
Effects of Temperature and Relative Humidity
Variations due to climate conditions were evaluated by test measurements at three NO concentration levels (15, 75, and 200 ppb). Combinations within the claimed operational range, i.e. temperature 10-35°C and relative humidity (RH) 20-80%, were tested. Five replicate determinations of each concentration were made for each climate.
5 NIOX VERO sensors, continually mounted in 5 NIOX VERO instruments, respectively, were used in these tests.
The obtained upper 95% confidence limit was within 5ppb (for 15ppb) or max 10% (for 75 and 200 ppb) on all test occasions.
d. Carryover:
Not applicable.
e. Interfering Substances:
Sensor interference levels were tested in a laboratory setting. The substances and concentrations tested are summarized in the table below. Substances were selected based on their oxidizing potential, which could interfere with the electrochemical signal from NO detection. The concentrations were in the same range or higher than expected concentration of each substance in exhaled breath. The interference is calculated in relation to highest NO level in the measurement range, i.e. 300 ppb. The applicable concentration of each substance was generated, the gas stream was fed to the sensor by a gas-mixer, and the sensor signal was measured. All tests were performed at normal ambient conditions: Temperature between 20 and 24 °C, relative humidity between 45 and 55%.
Interference was defined as an incremental change of at least 3.0 ppb NO. No interferents met that definition; however nitrogen dioxide and hydrogen sulfide are noted as interferents in the device labeling since incremental changes noted for these substances was near 3.0 ppb NO. The table below provides interference information
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for all tested substances and is also included in the device labeling.
| Substance | Concentration tested | Concentration expected in exhaled breath | Sensor Interference, equivalent to ppb NO |
| --- | --- | --- | --- |
| Acetaldehyde | 1000 ppm | 100 ppb | Non-detectable |
| Acetone | 100 ppm | 10 ppb | Non-detectable |
| Acetonitrile | 500 ppm | 100 ppb | Non-detectable |
| Ammonia | 100 ppm, balance air | 0.5 ppb | Non-detectable |
| Carbon Dioxide | 5 Vol. %, balance air | 8 % | Non-detectable |
| Carbon Monoxide | 250 ppm, balance nitrogen | 50 ppm | Non-detectable |
| Ethanol | 1000 ppm, balance nitrogen | 165 ppm | Non-detectable |
| Hydrogen | 500 ppm, balance nitrogen | 50 ppm | Non-detectable |
| Hydrogen Peroxide | 500 ppm, balance air | 1 ppm | Non-detectable |
| Hydrogen Sulfide | 1 ppm, balance nitrogen | 1 ppm | 2.0 ppb |
| Isoprene | 1000 ppm, balance air | 1 ppm | Non-detectable |
| Nitrogen Dioxide | 9.2 ppb, balance nitrogen | 200 ppb | 2.5 ppb |
| Oxygen | 100 Vol. % | 21 % | Non-detectable |
# Interference of exogenous substances
A clinical study was performed to investigate the influence of exogenous substances (chewing gum, carbonated beverage and mouthwash) on $\mathrm{Fe_{NO}}$ measured with NIOX VERO. The primary endpoint was the difference between baseline $\mathrm{Fe_{NO}}$ and $\mathrm{Fe_{NO}}$ measured directly after, one and two hours after exposure to each exogenous substance. A total of 12 subjects were tested. The Paired Student's t-test was used to compare the time points to baseline following each exposure.
The results of this study show that there is little or no effect of these exogenous substances on the measurement of exhaled nitric oxide. The differences that were seen were all within the performance characteristics of the NIOX VERO.
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| Difference from Baseline (BL) (ppb) | Gum | | Carbonated Beverage | | Mouthwash | |
| --- | --- | --- | --- | --- | --- | --- |
| | Mean | 95% CI | Mean | 95% CI | Mean | 95% CI |
| 0 hr –BL | -1.08 | -2.25, 0.08 | -2.08 | -3.91, -0.26 | 1.08 | -1.30, 3.47 |
| 1 hr – BL | 0.33 | -1.06, 1.72 | -0.17 | -2.00, 1.67 | 2.58 | -0.13, 5.30 |
| 2 hr – BL | -0.25 | -1.71, 1.21 | -0.08 | -1.37, 1.20 | 2.25 | 0.53, 3.97 |
ATS guidelines recommend that no food or beverage be consumed, and no smoking be done for at least one hour before taking an $\mathrm{Fe_{NO}}$ measurement. This recommendation would be in line with the results from this study where the differences mostly occurred in the 0-1 hr time frame, where the differences from baseline was determined to be -1.08, 0.33, and -0.25, for chewing gum, carbonated beverage, and mouthwash, respectively.
# 2. Other Supportive Instrument Performance Data Not Covered Above:
# Other clinical supportive data:
A clinical study was not conducted with the NIOX VERO device. In 2007, a multicenter device randomized open-label prospective single-cohort study was conducted to demonstrate substantial equivalence between NIOX MINO® and predicate device (NIOX®) when measuring the change of $\mathrm{FE}_{\mathrm{NO}}$ that often occurs after 2 weeks of corticosteroid therapy compared to their baseline levels (See k072816). Symptomatic asthmatic males and females, performed two valid $\mathrm{FE}_{\mathrm{NO}}$ measurements at each visit, with NIOX MINO and NIOX respectively, with a limit of six exhalation attempts per subject in each device. The order of the $\mathrm{FE}_{\mathrm{NO}}$ measurement on NIOX MINO versus NIOX was randomized. At every visit and for every patient, spirometry was performed and asthma symptoms were recorded using Asthma Control Questionnaire® (ACQ). In total, 156 subjects were included, 105 adults 18 - 70 years old and 51 children 7 - 17 years old. Results from this study, in conjunction with the new method comparison study described above, were determined to be applicable to the candidate device, the NIOX VERO. See k072816 for more details.
Traceability, Stability, Expected values (controls, calibrators, or methods):
The instrument is manufacturer calibrated. NIOX VERO does not require calibration by the user. A replaceable sensor is used which is pre-programmed and pre-calibrated for a defined number of tests. The life time of NIOX VERO instrument is set to 5.5 years. The number of possible tests is 15000. The sensor life time is limited to 12 months in unopened packaging following manufacture, for 6 months from initial installation into NIOX VERO, or for the defined number of tests (60, 100, 300, 500 or 1000), whichever comes first. The shelf life for NIOX Filter in unopened primary package is 2 years. NIOX Filter is for single use and must be replaced for every new patient and measurement occasion. Stability information to support all claims was reviewed and deemed acceptable.
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Detection limit:
The lowest detection limit was determined in a laboratory setting, using mixtures of standard reference NO gas and nitrogen gas below and above the detection limit, at 3 and 5 ppb. Five replicate determinations of each concentration were made. 10 NIOX VERO sensors, continually mounted in 10 NIOX VERO instruments, respectively, were used in these tests. The mean and confidence limit at 3 ppb (mean 3.5 ppb, 95% CI: 3.3,3.7) and 5 ppb (8.2 ppb, 95% CI: 7.9, 8.5) support the claimed detection limit of 5 ppb.
Expected values/Reference range:
The expected values are provided from the literature. In the labeling the sponsor states, “Given that physiological and environmental factors can affect $\mathrm{Fe_{NO}}$, $\mathrm{Fe_{NO}}$ levels in clinical practice need to be established on an individual basis. However, most healthy individuals will have NO levels in the range 5-35 ppb (children slightly lower, 5-25 ppb) when measured at $50~\mathrm{ml/s}$.” (ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005. Am J Respir Crit Care Med. 2005;171:912-930.)
K. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.
L. Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
