Labeling Summary / Package Insert NIOX MINO®
Contents
1. Caution Smoking Chronically reduced levels of FENO have been demonstrated in cigarette smokers in addition to acute effects immediately after cigarette smoking Despite the depressant effect of smoking smokers with asthma still have a raised FENO Subjects should not smoke in the hour before measurements and short and long term active and passive smoking history should be recorded Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page11 of 32 Caution Infection Upper and lower respiratory tract viral infections may lead to increased levels of exhaled NO in asthma Therefore FENO measurements should be deferred until recovery if possible or the infection should be recorded in the chart HIV infection is associated with reduction in exhaled NO Caution Medications and exhaled NO The potential effect of drugs on NO cannot be excluded and so all current medication and time administered should be recorded Exhaled NO falls after treatment with inhaled or oral corticosteroids in subjects with asthma and after inhaled NO synthase inhibitors Leukotriene axis modifiers also reduce FENO NO donor drugs and oral inhaled and intravenous L arginine increase FENO and nasal FENO Even if a certain medication does not affect NO production it might affect the apparent level of NO through other mechanisms such as changes in airway caliber Caution Other factors The manipulation of physiol2. Fractional Exhaled Nitric Oxide FENO Measurement of FENO is an easy non invasive procedure that can be performed in adults and children 29 For the above statements NIOX was used in study 6 16 18 19 24 28 and 29 NIOX MINO was used in study 27 The other referred studies were performed with other NO analyzers 3 2 Product characteristics NIOX MINO is designed as a hand held device for measuring FENO a marker of airway inflammation in exhaled breath from humans NIOX MINO can be used in children 7 17 years and in adults NIOX MINO follows in all essential aspects the American Thoracic Society ATS 2005 equipment recommendations for measurement of exhaled NO NIOX MINO uses an electrochemical sensor technology as analytical method One vital advantage of this technology is that NIOX MINO requires no calibration Built in controls and an External Quality Control Procedure ensure reliability to measured values 4 Training requirements NIOX MINO should only be used as directed in the NIOX MINO User Manual by trained physicians nurses respiratory therapists and laboratory technicians Trained status is achieved only after careful reading of the NIOX MINO User Manual 5 Clinical Limitations NIOX MINO is a Prescription Use Device according to 21 CFR 801 D NIOX MINO cannot be used with infants or by children approximately under age of 7 as it requires patient cooperation The determining factor for age l
3. 25 2 44 0 2 20 0 0005 48 1 p value for statistical significance 7 _ vs baseline Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB pagel4 of 32 Table 4 Subset analysis adults first attempt NIOX MINO Mean Range Standard Error NIOX MINO first reading 35 338 9 e lt 0 0001 0001 102 NIOX a 3 85 3 144 4 3 33 lt 0 ae 102 FEV 6 3 36 4 72 7 1 35 lt 0 0001 101 1 p value for statistical significance of change vs baseline The relationship between the percent change in FENO and the percent change in pre bronchodilator Forced Expiratory Volume FEV post bronchodilator FEV and the total symptom scores Asthma Control Questionnaire ACQ from V1 to V2 was investigated for the Intent to Treat ITT population per tables 2 3 and 4 14 1 2 Results and conclusion 118 out of 133 89 patients experienced a reduction of FENO had also an improvement in symptom score as measured by the ACQ The magnitude of the FENO change and degree of improvement in ACQ are different because the scale and precision of these metrics varies Table 5 Correlation between change in FENO and change in FEV1 and ACQ for NIOX and NIOX MINO in the Intent To Treat ITT population adults and children combined for Study AER 036 NIOX NIOX MINO Change in FEV R square correlation 0 213 0 208 P value 0 0100 0 0120 Change in asthma symptom score ACQ R square co
4. 571 2 Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page32 of 32
5. D496 667 and patents pending NIOX MINO is a registered trademark of Aerocrine AB 21 Revision History Revision Description Status Valid date EPS 000063 00 New document based on EPS 000050 Version for 510k July 2010 NIOX MINO upgrade review EPS 000063 01 Set to valid November 2010 EPS 000063 02 Typographical errors fixed terminology February 2011 updated in accordance with those required for clarifications in the manual EPS 000063 03 Information updated as required by July 2012 606013rd Ed electrical safety certification EPS 000063 04 Changed responsible manufacturer Valid March 2013 address Modified test kit description Removed duplicated cautions Typographical errors fixed Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page29 of 32 22 Bibliography 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Gustafsson L E et al Endogenous nitric oxide is present in the exhaled air of rabbits guinea pigs and humans Biochem Biophys Res Commun 1991 181 2 p 852 7 Alving K E Weitzberg and J M Lundberg Increased amount of nitric oxide in exhaled air of asthmatics Eur Respir J 1993 6 9 p 1368 70 Covar R A et al Relations between exhaled nitric oxide and measures of disease activity among children with mild to moderate asthma J Pediatr 2003 142 5 p 469 75 Salome C M et al Exha
6. Rolla G et al Exhaled nitric oxide in systemic sclerosis relationships with lung involvement and pulmonary hypertension J Rheumatol 2000 27 7 p 1693 8 Kharitonov S A et al Acute and chronic effects of cigarette smoking on exhaled nitric oxide Am J Respir Crit Care Med 1995 152 2 p 609 12 Horvath 1 et al Exhaled nitric oxide and hydrogen peroxide concentrations in asthmatic smokers Respiration 2004 71 5 p 463 8 Terada A et al Exhaled nitric oxide decreases during exercise induced bronchoconstriction in children with asthma Am J Respir Crit Care Med 2001 164 10 Pt 1 p 1879 84 Silkoff P E et al Exhaled nitric oxide after beta2 agonist inhalation and spirometry in asthma Am J Respir Crit Care Med 1999 159 3 p 940 4 Piacentini G L et al Reduction in exhaled nitric oxide immediately after methacholine challenge in asthmatic children Thorax 2002 57 9 p 771 3 Stirling R G et al Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids Asthma and Allergy Group Thorax 1998 53 12 p 1030 4 Payne D N et al Evidence for different subgroups of difficult asthma in children Thorax 2001 56 5 p 345 50 Juniper E F et al Measuring asthma control Clinic questionnaire or daily diary Am J Respir Crit Care Med 2000 162 4 Pt 1 p 1330 4 Olin A
7. 1 05 and an intercept of 3 ppb Determination based on pooled regression analysis from 10 instruments using standard gas reference samples at 7 different concentration levels covering the operating measurement range Precision lt 3 ppb of measured value lt 30 ppb lt 10 of measured value gt 30 ppb Expressed as one standard deviation for replicate measurements with the same instrument using a certified gas concentration of Nitric Oxide reference standard Accuracy 5 ppb or max 10 Expressed as the upper 95 confidence limit based on absolute differences for concentrations lt 50 ppb and relative differences for concentrations gt 50 ppb from certified gas concentration of Nitric Oxide reference standard Method comparison lt 10 ppb for values lt 50 ppb lt 20 for values gt 50 ppb Expressed as the difference between a NIOX MINO FENO value and the corresponding FENO value measured with NIOX instrument from Aerocrine Performance data typical for temperature range 60 to 85 F 16 to 30 C Humidity range 20 60 RH Pressure 14 7 psi 1013 hPa Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB pagel 8 of 32 Table 10 Interfering substances Substance Concentration Expected concentrations in Sensor Interference tested for exhaled breath of healthy equivalent to ppb NO subjects 66 Carbon dioxide CO2 8 lt 4 5 lt 3 ppb
8. 16 0 0 14 12 ppb 0 10 1 32 75 ppb Device 1 40 69 6 0 29 7 2 0 39 7 87 Device 2 40 72 4 0 30 3 6 0 37 4 18 Device 3 40 73 2 0 18 2 4 0 24 2 78 Device 4 40 71 7 0 28 4 4 o 0 38 5 06 Device 5 40 77 8 0 32 4 1 0 34 4 63 200 ppb Device 1 40 188 6 0 66 5 7 o 0 33 6 26 Device 2 40 196 0 0 66 2 5 0 23 2 87 Device 3 40 197 3 0 41 1 6 0 15 1 84 Device 4 40 193 4 0 63 3 3 o 0 31 3 82 Device 5 40 209 4 0 98 5 4 o 0 28 5 82 80 for 5 gt 100 000 1 00 2 00 3 00 4 00 2 0 2 4 6 8 0 2 Absolute deviation from nominal ppb Absolute deviation from nominal Number of observations ine oOo Number of observations Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page24 of 32 Nominal 200 ppb 257 De Ss 1 a fi fi Number of observations a i 0 2 4 6 8 10 Absolute deviation from nominal Figure 9a b and c Absolute deviation from nominal at 15 75 and 200 ppb Table 15 deviation from nominal Nominal ppb All observations n Mean SEM 95 UL 15 Deviation from nominal ppb _ 200 0 7 0 05 0 77 75 Deviation from nominal 200 4 3 0 19 4 65 200 Deviation from nominal 200 3 7 0 16 3 95 Climate effects The combined effects of temperature and relative humidity RH were measured at 60 F 72 F and 85 F 16 C 22 C and 30 C and 20 40 60 RH This covers all the conditions within the low and hi
9. C B Bake and K Toren Fraction of exhaled nitric oxide at 50 mL s reference values for adult lifelong never smokers Chest 2007 131 6 p 1852 6 Olivieri M et al Reference values for exhaled nitric oxide reveno study Respir Res 2006 7 p 94 Olivieri M et al Reference values for exhaled nitric oxide in the general population Chest 2008 133 3 p 831 2 Haight R R R L Gordon and S M Brooks The effects of age on exhaled breath nitric oxide levels Lung 2006 184 2 p 113 9 Buchvald F et al Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years J Allergy Clin Immunol 2005 115 6 p 1130 6 Malmberg L P et al Exhaled nitric oxide in healthy nonatopic school age children determinants and height adjusted reference values Pediatr Pulmonol 2006 41 7 p 635 42 Taylor D R et al Factors affecting exhaled nitric oxide measurements the effect of sex Respir Res 2007 8 p 82 Travers J et al Reference ranges for exhaled nitric oxide derived from a random community survey of adults Am J Respir Crit Care Med 2007 176 3 p 238 42 Kovesi T R Kulka and R Dales Exhaled nitric oxide concentration is affected by age height and race in healthy 9 to 12 year old children Chest 2008 133 1 p 169 75 Wong G W et al High levels and gender difference of exhaled nitric oxide in Chinese schoolchildren Clin Exp Allergy 2005 35 7 p 889 93 Levesque M C
10. NIOX MINO EPS 000063 04 Aerocrine AB page12 of 32 inflammatory treatment 6 18 2 24 28 601 Allergen exposure has been shown to influence FENO levels in asthmatics 60 Correlation between symptom improvement and decreasing FENO has been observed 241 Monitoring a patient s FENO levels before and during anti inflammatory therapy can therefore be used for studying the therapeutic effect 62 41 However approximately 18 of subjects in clinical studies with NIOX MINO experienced an improvement in asthma symptoms without a decrease in FENO Note If FENO levels are high despite medication this may indicate non compliance poor inhaler technique or inadequate corticosteroid dosage 20 Continuous high levels of allergen exposure create an overwhelming inflammatory activity There may also be a small number of patients especially those with severe asthma who are unresponsive to steroid treatment 43 44 Any change of anti inflammatory therapy can affect FENO levels and should be recorded Note Changes in airway inflammation measured as FENO levels and lung function parameters may be non synchronous as they have different response times to anti inflammatory treatment 1 14 Clinical Data 14 1 Clinical validation a method comparison study 14 1 1 Study description The study was a multi center device randomized open label prospective single cohort study aimed at demonstrating substantial equivale
11. certified concentration of a nitric oxide reference standard Mixtures of a certified calibration gas of 200 ppb NO in Nz were used yielding concentrations 15 ppb 75 ppb and 200 ppb The gas mixer was connected in line with the NIOX MINO instrument A total of 20 sensors mounted in 20 NIOX MINO instruments were used for accuracy evaluation Three replicate determinations were made at each occasion The temperature and relative humidity were within the claimed operational range for the entire test period For each test occasion the mean NO concentration M for each set of replicates and the absolute deviation of each replicate mean D from the nominal gas concentration G were calculated The mean D the standard deviation and the 95 confidence interval for all instruments were calculated At 50 ppb and higher concentration levels the deviation D is expressed as percentage of the nominal NO concentration Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page23 of 32 The results for the 5 NIOX MINO systems are presented in Table 14 and 15 and Figure 9 a b and c The accuracy was in all test occasions within the technical specification i e 5 ppb or max 10 Table 14 Accuracy Mean Nominal n Mean ppb SEM deviation SEM 95 UL 15 ppb NM_1 40 14 3 0 15 1 0 ppb 0 11 1 13 Device 2 40 15 1 0 09 0 4 ppb 0 06 0 52 Device 3 40 15 4 0 11 0 6 ppb 0 10 0 73 Device4 40 14 9 0 09 0 4 ppb 0 07 0 50 Device5 40
12. ppb for 10 NIOX MINO instruments HC se Postar ost ost o7 post 06 0 At nominal value of 3 ppb the overall mean measured value was 2 ppb 95 CI 2 0 2 3 At nominal value of 5 ppb the overall mean measured value was 3 ppb 95 CI 3 0 3 3 Thus it can be concluded that the lowest detectable level for NIOX MINO is reached at around 3 ppb which is why the specification limit for lowest detectable level is set at 5 ppb Linearity Certified NO in N calibration gas of 200 ppb and 2100 ppb was mixed with nitrogen gas in a gas mixer connected in line with the NIOX MINO instrument with mounted NIOX MINO 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 All NIOX MINO systems were scheduled for testing after keeping them continuously powered up for 0 6 12 and 18 months respectively at ambient conditions i e at room temperature between 60 F 16 C and 85 F 30 C and a relative humidity RH between 20 and 60 non condensing The mean NO concentration for each set of replicates was plotted against the nominal NO concentration and the data subjected to regression analysis applying option confidence intervals for slope The total regression analysis gave a slope of 0 08 and intercept 2 0 and the squared correlation coefficient r was gt 0 998 for all
13. the 10 devices tested The results conclude that NIOX MINO linearity is within the specification of r gt 0 998 Data from the first test occasion at O months is presented in figure 7 above Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page21 of 32 DA So oO J Y 0 984 X 2 035 R square 0 997 3007 Line of identity 2007 Measured NO NIOX MINO 09 ppb T 0 100 200 300 400 Nominal NO gas mix ppb Figure 7 Measurement range and linearity determination plotted for 10 instruments Analytical Precision Analytical precision was determined in house Certified NO in N calibration gas of 200 ppb was mixed with nitrogen gas in a gas mixer connected in line with the NIOX MINO instrument to obtain three NO concentration levels 15 75 and 200 ppb Two replicate determinations of each concentration were made twice a day more than 2 hours apart for 20 days Repeatability is an estimate of variation within one test run in one day Within device precision is an estimate of variation between test runs and days The repeatability and within device precision were calculated for the 5 instruments The results at 15 ppb are expressed as absolute values in ppb The results at the 75 and 200 ppb levels are expressed as percentage of the measured NO concentration Both standard deviation estimates met the precision claim at all three concentration levels The results are presented in Figure 8 and Table
14. transmitting equipment and other sources of electrical noise emitters in the health care and home environments such as base stations for radio cellular cordless telephones and land mobile radios amateur radio AM and FM radio broadcast and TV broadcast it is possible that high levels of such interferences due to close proximity or strength of a source may result in disruption of performance of the device If abnormal performance is observed it may be necessary to reorient or relocate NIOX MINO Caution A PC connected to the USB connector has to be certified for one of the standards IEC 60601 1 IEC 61010 1 IEC 60950 or comparable with safety extra low voltage on the USB ports Caution The connected PC should be placed out of reach from the patient Do not simultaneously touch the connected PC and the patient Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page9 of 32 9 Specimen collection and preparation for analysis NIOX MINO provides direct sampling with delayed analysis 100 seconds of sequentially collected and analyzed exhaled air No subsequent specific specimen collection specimen preparation or reagents are required 10 Step by step outline of recommended procedures For details regarding the operation of NIOX MINO read the NIOX MINO User Manual 11 Results The FENO results expressed as parts per billion ppb are presented after a short time about 100 seconds on the displ
15. 12 15 ppb 75 ppb 200 ppb E Repeatability IB Within device precision El Repeatability a Repeatability na E Within device precision I Within device precision 2 x o Q 1 00 o xL a J A S 5 fa O 0 757 a a 7 oO oO 0 504 D a a a a 0 254 0 00 Device Device Figure 8 Precision at levels 15 ppb 75 ppb and 200 ppb Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page22 of 32 Table 12 Precision Repeatability Within device precision NO concentration ppb 15 ppb 75 ppb 200 ppb 15 ppb 75 ppb 200 ppb Claim lt 3 ppb lt 10 lt 10 lt 3 ppb lt 10 lt 10 Serial No NIOX MINO Sensor 9999930 23963 1 2 1 2 1 0 1 3 2 6 2 2 9999907 23961 1 1 1 3 0 8 1 0 2 7 2 2 9999941 21652 1 0 1 2 0 7 1 0 1 8 1 4 9999914 23255 0 8 1 4 0 8 0 8 2 6 2 1 9999945 22711 1 1 1 6 0 8 1 2 3 0 3 2 The results conclude that the repeatability and within device precision are well within specification limit lt 3 ppb of measured value lt 30 ppb lt 10 of measured value gt 30 ppb Both standard deviation estimates for repeatability and within device precision met the precision claim in the labeling at all three concentration levels Clinical Precision Clinical Reproducibility was assessed in a clinical setting evaluating the variability between measurements performed in the same patient by different operators Total 62 subjects were a
16. Aerocrine Labeling Summary Package Insert NIOX MINO According to 21CFR 809 10 b Labeling for In Vitro Diagnostic Devices For USA 1 Proprietary and Established Names NIOX MINO Airway Inflammation Monitor measures the concentration of fractional exhaled nitric oxide FENO in human exhaled breath 2 Intended Use NIOX MINO 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 MINO according to guidelines for NO measurement established by the American Thoracic Society Measurement of FENO by NIOX MINO 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 MINO 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 NIOX MINO should only be used as directed in the NIOX MINO User Manual and the NIOX MINO Quality Control Test User Manual by trained physicians nurses respiratory therapists and laboratory technicians
17. Ethanol 165 ppm 13 1000 ppb lt 3 ppb Ammonia NH3 0 5 ppm 50 500 ppb lt 3 ppb Carbon monoxide CO 50 ppm 0 5 15 ppm lt 3 ppb Isoprene 1 ppm 5 580 ppb lt 3 ppb Hydrogen peroxide H202 1 ppm lt 1 ppb lt 3 ppb Oxygen O2 21 lt 17 lt 3 ppb Hydrogen H2 50 ppm lt 20 ppm lt 3 ppb Hydrogen sulfide H2S 1 ppm 300 500 ppb lt 3 ppb Acetone 10 ppm 1 2 1880 ppb lt 3 ppb Acetonitrile 100 ppb lt 100 ppb lt 3 ppb Acetaldehyde 100 ppb lt 50 ppb lt 3 ppb Nitrogen dioxide NO2 200 ppb Below detectable level lt 10 ppb The gas scrubber in the instrument eliminates interference of Nitrogen Dioxide NOz 16 Operating Conditions Ambient temperature 60 to 85 F 16 to 30 C Atmospheric pressure range 10 to 15 psi 700 hPa to 1060 hPa Humidity 20 60 RH non condensing Ambient NO concentration lt 300 ppb Exhaled flow during FENO measurements at 50 mL s 3 L min 10 BTPS during 10 seconds Body Temperature Pressure Saturated 98 6 F 37 C 14 7 psi 1013 hPa 100 RH 16 1 Calibration The manufacturer performs the calibration for each NIOX MINO Sensor No additional calibration is needed during the sensor lifetime 17 Shelf life 17 1 Life time of instrument The life time is a minimum of 3 years from time of delivery or 3000 measurements whichever comes first The expiry date is shown on the bottom plate and the user is prompted for expir
18. NIOX MINO cannot be used with infants or by children approximately under the age of 7 as measurement requires patient cooperation NIOX MINO should not be used in critical care emergency care or in anesthesiology Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB pagel of 32 3 Summary and Explanation 3 1 Methodology background Nitric Oxide is endogenously produced in the airways and production is increased when there is airway inflammation Exhaled NO is elevated in asthma and correlates with generally accepted clinical markers of airway inflammation such as sputum eosinophils eosinophils in bronchoalveolar lavage and in bronchial biopsies Levels of exhaled NO in patients with asthma correlate with disease activity such as frequency of beta 2 agonists use and day and night time asthma symptoms as measured in clinic visits and or patient diaries Treatment of airway inflammation in asthma with anti inflammatory agents such as inhaled and or oral corticosteroids and or anti leukotrienes reduces levels of NO in exhaled air 8 Exhaled NO measurements can be used for monitoring the effect of anti inflammatory therapy such as inhaled and or oral corticosteroids and or anti leukotrienes but not to monitor the effect of bronchodilators since these primarily relieve the bronchoconstriction and have limited effect on the inflammation Published guidelines allow standardization of the measurement of exhaled NO
19. arison of exhaled nitric oxide to spirometry during emergency treatment of asthma exacerbations with glucocorticoids in children Ann Allergy Asthma Immunol 1999 82 2 p 161 4 Tsai Y G et al A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma J Pediatr 2001 139 3 p 433 7 Bisgaard H L Loland and J A Oj NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast Am J Respir Crit Care Med 1999 160 4 p 1227 31 Zeiger R S et al Response profiles to fluticasone and montelukast in mild to moderate persistent childhood asthma J Allergy Clin Immunol 2006 117 1 p 45 52 Lipworth B J et al Effects of adding a leukotriene antagonist or a long acting beta 2 agonist in asthmatic patients with the glycine 16 beta 2 adrenoceptor genotype Am J Med 2000 109 2 p 114 21 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 8 p 912 30 Alving K C Janson and L Nordvall Performance of a new hand held device for exhaled nitric oxide measurement in adults and children Respir Res 2006 7 p 67 Smith A D et al Use of exhaled nitric oxide measurements to guide treatment in chronic asthma N Engl J Med 2005 352 21 p 2163 73 Labeling Summary NIOX MINO EPS 000063 04 Aer
20. ay The instrument calculates the result based on the calibration settings sensitivity of the Sensor expressed as nA ppb For details regarding the FENO measurement and results please read the NIOX MINO User Manual Caution FENO measurement results are to be interpreted in conjunction to other clinical and laboratory assessments of the patient s condition Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page10 of 32 12 Limitations to the procedure Known patient factors that could interfere with FENO measurement are described in the ATS guidelines To assure correct results when performing FENO measurement with NIOX MINO the following cautions apply Caution Respiratory maneuvers Because spirometric maneuvers have been shown to transiently reduce exhaled NO levels it is recommended that NO measurement be performed before spirometry The same stipulation applies to other taxing respiratory maneuvers unless these can be shown not to influence exhaled NO The FENO maneuver itself and body pletysmography do not appear to affect plateau exhaled NO levels Caution Age sex In adults there is no consistent relationship between exhaled NO level and age but it has been reported that in children FENO increases with age In adults there are conflicting reports regarding the effects of sex menstrual cycle and pregnancy so these patient characteristics should be recorded at the time of mea
21. 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 Nitrogen Dioxide was the only detected significant interferent see section 15 Specific Performance Characteristics When using NIOX MINO the patient first inhales through a mouthpiece connected to a scrubber that eliminates Nitric Oxide Nitrogen Dioxide and also other contaminants from the ambient air Interference of exogenous substances A clinical study was performed with purpose to investigate the influence of exogenous substances chewing gum carbonated beverage and mouthwash on FENO measured with NIOX MINO The primary endpoint was the difference between baseline FENO and FENO measured directly after one and two hours after exposure to each exogenous substance The subjects were healthy volunteers between 20 and 65 years of age 10 20 planned 11 analyzed The result showed that there are no statistically detectable changes in the FENO levels from baseline to 0 minutes 1 or 2 hours assessments for chewing gum carbonated beverage and mouth wash Student s T test for the difference between baseline FENO and FENO measured one and two hours after exposure to these exogenous substances were calculated The largest systematic change was observed for chewing gum though not significant which demonstrated a decrease in the clinically observed difference with le
22. cal verification with human samples in a clinical setting The study was a randomized single center study to determine the agreement and repeatability of the NIOX Flex Nitric Oxide Monitoring system and the hand held NIOX MINO 09 device Measurements were performed in a routine clinical setting on patients visiting pediatric and lung physiology clinics The measurements were supervised by nurses and physicians on the clinics In total 73 subjects 37 children 36 adults were included in the study The subjects represented diagnosed asthmatics n 73 with a FENO range of 4 1 161 5 ppb male n 38 and female n 35 between 7 and 65 years of age The test subjects performed measurements in both the modified NIOX MINO and the predicate device NIOX Flex which is known to have a higher accuracy Agreement between the two devices was then calculated using Deming Regression Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page26 of 32 Boys A Girls 150 7 Men x Women 100 7 NIOXMINO 09 Deming Y 0 68 0 94 X Regr Y 0 12 0 92 X 50 74 y R square 96 T T T T 0 50 100 150 NIOX Flex Figure 10 Deming regression clinical comparison between NIOX MINO and NIOX Flex Table 18 Parameter estimates for linear regression analyses Estimate 95 Confidence Interval Intercept 0 116 1 942 1 711 Slope 0 920 0 875 0 965 Table 19 Parameter estimates fo
23. ce was observed between Caucasians Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page15 of 32 and African Americans with respect to correlation coefficients r 0 975 vs r 0 982 p 0 378 Significance test based on Fisher Z transform See Table 7 Table 7 Subgroup analysis com aring Caucasians and African Americans Parameter African Americans Caucasians Entire group n 33 n 76 n 109 Correlation analysis R 0 97 0 98 0 98 p value lt 0 0001 lt 0 0001 lt 0 0001 Regression analysis Slope 95 Cl 1 09 1 00 1 18 1 02 0 97 1 06 1 05 1 01 1 09 Intercept 95 Cl 2 06 5 83 1 70 0 48 1 83 0 87 1 09 2 50 0 31 Tolerance limit analysis Proportion of patients within 0 97 0 99 0 98 tolerance limits Lower limit of 95 CI 0 92 0 96 0 96 14 3 Other clinical performance studies Chemilumenescence is established as a highly selective and sensitive method for detecting Nitric Oxide in ppb levels Aerocrine s 510 k cleared product NIOX Nitric Oxide monitoring system is based on chemilumenescence technique Several studies have been performed with the aim to evaluate NIOX MINO compared to NIOX and to show the performance of NIOX MINO in various clinical settings 3 61 1 Many of the comparisons have been published in peer review journals Table 8 and other presented at scientific meetings The outcome is very homogenou
24. d NIOX showed substantially similar performance in FENO with minor non significant differences between the type of device used 37 3 and 35 5 reduction in FENO respectively The reduction in FENO from Visit 1 to follow up visit 2 following corticosteroid treatment was highly significant for both devices The patients well being which was followed with the validated Asthma Control Questionnaire ACQ also showed a significant improvement in the same range 39 7 as the improvement of FENO values These data improvement in FENO and ACQ were in accordance with the spirometry that also showed a significant improvement although the magnitude of the improvement using this method was less obvious 6 9 Table 2 below shows a summary of the primary and secondary outcome data for the Intent to Treat ITT population Tables 3 and 4 show subgroup analyses for children and adults respectively Table 2 Mean change between visit 1 and 2 for the two devices NIOX MINO versus predicate NIOX and change in clinical well being and spirometry Mean change Standard Error of Mean p value NIOX MINO first reading 91 4 118 2 lt 0 0001 NIOX lt 0 0001 151 151 ACQ 151 FEV 36 7 72 7 1 15 lt 0 0001 149 1 p value for statistical significance ee aes vs baseline Table 3 Subset analysis children first attempt NIOX MINO Mean Range Standard Error change a of Mean p value n NOR HINO Tata g AQ a FEV
25. d and a steady top light is shown as long as the pressure is maintained A standard exhalation sampling is performed during 10 seconds As the exhaled NO levels are flow dependent NIOX MINO cues mean exhalation rate for a valid measurement to be within be 50 5 mL sec BTPS in accordance with the ATS guidelines With exhalation pressure within the specified limits 10 20 cm H20 the built in NIOX MINO dynamic flow controller ensures a flow rate of 50 mL sec Figure 5 graphical interaction image for correct exhalation If the pressure from the patient is lower than 12 cm H20 a low intermittent sound is heard and a flickering top light is shown If the pressure exceeds 18 cm H20 a high intermittent sound is heard and a flickering top light is shown On the display a pressure controlled graphical interaction image is shown Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB paged of 32 Figure 6 graphical interaction image for too hard exhalation and too low exhalation The patient can see the display during his her exhalation by using a mirror The patient is thereby guided to maintain the pressure within the specified limits Exhalation pressures outside the specified 10 20 cm H2O limitation render an Alert message is shown on the display A three second adaptation time period outside the specified pressure range is allowed in the beginning of the exhalation The results are processed using dedicated software expressed as the NO conce
26. et al Determinants of exhaled nitric oxide levels in healthy nonsmoking African American adults J Allergy Clin Immunol 2008 121 2 p 396 402 e3 Malmberg L P et al Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma Thorax 2003 58 6 p 494 9 Smith A D et al Diagnosing asthma comparisons between exhaled nitric oxide measurements and conventional tests Am J Respir Crit Care Med 2004 169 4 p 473 8 Taylor D R et al Exhaled nitric oxide measurements clinical application and interpretation Thorax 2006 61 9 p 817 27 Piacentini G L et al Allergen avoidance is associated with a fall in exhaled nitric oxide in asthmatic children J Allergy Clin Immunol 1999 104 6 p 1323 4 Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page31 of 32 61 Khalili B P B Boggs and S L Bahna Reliability of a new hand held device for the measurement of exhaled nitric oxide Allergy 2007 62 10 p 1171 4 62 McGill C G Malik and S W Turner Validation of a hand held exhaled nitric oxide analyzer for use in children Pediatr Pulmonol 2006 41 11 p 1053 7 63 Menzies D A Nair and B J Lipworth Portable exhaled nitric oxide measurement Comparison with the gold standard technique Chest 2007 131 2 p 410 4 64 Chen W et al Niox and Niox Mino comparison of exhaled NO in grass pollen allergic adult volunteers Allergy 2007 62 5 p
27. evices of 7 2 ppb The difference between the devices remained unaltered during the time of the test Median repeatability was 1 3 ppb Intra assay coefficient of variability was 33 3 Correlation between NIOX and NIOX MINO was excellent NIOX MINO gave higher values than NIOX Alving et al 7 Aerocrine sponsored study 71 Subjects healthy controls and atopic patients with and without asthma performed three exhalations in each device NIOX and NIOX MINO Median intra subject difference was 1 2 ppb the NIOX MINO readings were generally higher The median intra subject difference between NIOX and the first approved measurement with NIOX MINO was 2 0 ppb The median repeatability for NIOX and NIOX MINO was 1 1 and 1 2 resp Hemmingson et al 8 Aerocrine internal study 19 healthy adult volunteers performed three measurements on NIOX and NIOX MINO consecutive days Publication of Aerocrine internal study The average disagreement was 0 5 ppb and the mean SD 3 8 ppb Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB pagel7 of 32 15 Specific Performance Characteristics Table 9 Performance Specification Performance Parameter NIOX MINO Limits Measurement range 5 300 ppb Lowest Detection Limit 5 ppb FENO measurement time lt 2 min Temperature lt 30 minutes Stabilization time Linearity Squared correlation coefficient r gt 0 998 slope 0 95
28. f 32 Figure 1 NIOX MINO instrument NIOX MINO is a hand held instrument for exhaled NO analysis applying the FENO method The instrument is intended for use together with a Power Supply Unit NIOX Filter NIOX MINO Sensor and optional NIOX MINO Data Management PC application Figure 2 NIOX Filter NIOX filter is a single use bacterial and viral filter which is attached to the sample inlet to prevent contamination of the instrument and between patients Figure 3 NIOX MINO Sensor Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page4 of 32 NIOX MINO Sensor is an electrochemical sensor pre calibrated and pre programmed for a defined number of tests 50 100 300 500 or 1000 tests The user may easily change it after the measurements have been used up The instrument will also alert the user to sensor expiration two weeks prior to the expiration date and will not allow for measurements with an expired sensor Figure 4 NIOX MINO Scrubber NIOX MINO Scrubber is an exchangeable NO scrubber for elimination of ambient NO in the patient sample 7 2 Operating principles The patient should empty the lungs and then inhale through the NIOX Filter mouthpiece NO free air to total lung capacity TLC in order to trigger the measurement procedure The pressure parameters are controlled by both visible and audible feedback in order to guide the patient in performing a valid exhalation maneuver A continuous sound is hear
29. gh temperature and humidity ranges Measures were taken at 15 ppb 75 ppb and at 200 ppb with standard reference gas mixtures of NO in N2 see table 16 and table 17 The mean absolute difference from nominal NO concentration obtained at each test occasion is shown in Table 16 and 17 The results at NO concentrations below 50 ppb are presented in ppb and results above 50 ppb are presented as percentage of nominal NO concentration The deviations are within the technical specification i e 5 ppb for the level 15 ppb and max 10 for the levels 75 and 200 ppb at 95 confidence interval Table 16 absolute difference from nominal concentration 15 ppb Test Number Temp C RH Nom Conc ppb Average Dev ppb Stdv ppb Conf Int ppb UCL ppb Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page25 of 32 Table 17 relative difference from nominal concentrations 75 and 200 ppb Test Number 1 2 3 4 5 6 7 Temp C 19 25 23 23 23 25 30 RH 40 50 27 40 60 26 60 Nom Conc ppb 75 200 75 200 75 200 75 200 75 200 75 200 75 200 Average Dev 8 7 6 8 8 0 3 7 6 7 5 5 5 7 5 1 6 9 5 2 6 8 5 1 6 4 5 4 Stdv 2 7 2 3 4 4 2 2 22 2 0 2 4 2 1 2 5 2 0 4 2 2 7 3 3 2 6 Conf Int 1 7 1 4 2 7 1 3 1 3 1 3 1 5 1 3 1 5 i2 2 6 TZ 2 0 1 6 UCL 10 3 8 2 10 7 5 0 8 0 6 7 7 2 6 4 8 5 6 4 9 4 6 8 8 4 7 0 Method Comparison Method comparison between NIOX MINO and NIOX Flex was performed as clini
30. hed 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 mL s 93 Analysis of the variation seen in such studies suggests that 97 of healthy individuals have FENO levels of less than 35 ppb lt 25 ppb in children The lower values reported in children indicate an age dependence of FENO levels It has been shown that FENO levels increase with age in children 5 Studies have shown that males have higher FENO levels than females 4 48 521 FENO values increase with age 49 Ethnic differences in healthy FENO levels have been observed Asian schoolchildren especially boys could have up to 15 ppb higher FENO levels than Caucasians while Asian girls had on average elevated FENO levels to a lesser extent African American children and adults seems to have a couple of ppb higher average healthy FENO levels than Caucasians 4 53 94561 It is established that asthma is associated with higher than normal levels of FENO gt 29 43 57 581 However FENO levels in asthma patients vary greatly depending upon the extent of their airway inflammation Literature data suggest that patients with asthma usually have FENO levels in the range 25 80 ppb 18 19 24 29 59 although higher levels may occur in some patients Values at the lower end of the range are usually seen in patients receiving anti Labeling Summary
31. how a significant decrease in FENO value despite a significant change in Asthma Control Questionnaire ACQ For NIOX the figure was 28 out of 147 subjects 19 In a previous study performed with NIOX 11 out of 62 patients 18 showed no decrease in FENO after anti inflammatory treatment and 9 out of 62 15 showed no decrease in FENO despite improvement in asthma symptoms The medical explanation behind a lack of FENO change has not been explicitly evaluated 6 Risks to Health There are no known direct risks to patient health However failure of the test to perform as indicated or erroneous interpretation of results may lead to improper patient management Therefore use of FENO measurement results to adjust a treatment regimen without consideration of other clinical factors could pose a risk 7 Test Principle 7 1 System description and functions List of materials provided NIOX MINO instrument including Power Supply Unit NIOX MINO User Manual incorporating a NIOX MINO QC Manual NIOX MINO Scrubber NIOX MINO QC plug USB stick with Visual Incentive Test kits including NIOX MINO Sensor for 50 100 300 500 or 1000 tests NIOX Filter disposable patient filters box of 50 100 3x100 5 x 100 or 10 x 100 filters Accessories NIOX MINO Data Management Program Optional PC application NIOX MINO scrubber spare part for regular exchange Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page3 o
32. imitation is based on a patient s ability to understand and execute the instructions given Diseases associated with elevated levels of FENO are aside from asthma airway viral infections allergic rhinitis systemic lupus erythematosus and liver cirrhosis Another factor that may increase FENO levels is recent intake of nitrate rich diet Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page2 of 32 Diseases associated with decreased levels of FENO are cystic fibrosis primary ciliary dyskinesia and pulmonary hypertension Smoking reduce exhaled NO values however elevated FENO levels in smokers still indicate ongoing eosinophilic inflammation 31 Other factors that may decrease FENO levels transiently are physical exercise spirometric maneuvers and bronchoconstriction 1 Other factors that may affect the level of exhaled NO upwards or downwards are more extensively reviewed in section 12 Limitations of the procedure The fact that no change in FENO is encountered for some patients despite anti inflammatory treatment could be due to non compliance poor inhaler technique or inadequate corticosteroid dosage There may also be a small number of patients especially those with severe asthma who are unresponsive to steroid treatment 44 In the multi center device randomized open label prospective study performed with NIOX MINO described in section 14 26 out of 147 of the subjects 18 did not s
33. led nitric oxide measurements in a population sample of young adults Am J Respir Crit Care Med 1999 159 3 p 911 6 Zietkowski Z et al Comparison of exhaled nitric oxide measurement with conventional tests in steroid naive asthma patients J Investig Allergol Clin Immunol 2006 16 4 p 239 46 Strunk R C et al Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children J Allergy Clin Immunol 2003 112 5 p 883 92 Berry M A et al The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation an observational study in adults with asthma Clin Exp Allergy 2005 35 9 p 1175 9 Malmberg L P et al Determinants of increased exhaled nitric oxide in patients with suspected asthma Allergy 2005 60 4 p 464 8 Warke T J et al Exhaled nitric oxide correlates with airway eosinophils in childhood asthma Thorax 2002 57 5 p 383 7 Lex C et al Airway eosinophilia in children with severe asthma predictive values of noninvasive tests Am J Respir Crit Care Med 2006 174 12 p 1286 91 Payne D N et al Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma after treatment with oral prednisolone Am J Respir Crit Care Med 2001 164 8 Pt 1 p 1376 81 van den Toorn L M et al Airway inflammation is present during clinical remission of atopic asthma Am J Respir Crit Ca
34. mary NIOX MINO EPS 000063 04 Aerocrine AB pages of 32 Caution Do not touch or clean the white sensor membrane Caution Be careful when opening the sensor can The inside of the opening has sharp edges Caution Best performance is achieved if the ambient conditions are stable Refer to the Operating conditions section in the NIOX MINO User Manual Keep the instrument away from windows sunshine radiators stoves or open fire in order to avoid unstable conditions When transporting the instrument from one location to another a prolonged stabilization period before measurement might be required Refer to the recommended transportation conditions in the transport and storage section in the NIOX MINO User Manual Always use the NIOX MINO Bag for transportation Keep the NIOX MINO with mounted sensor connected to the power outlet whenever possible Caution Elevated ambient Nitrogen Dioxide NO3 may interfere with FENO measurement therefore ensure that the patient inhales correctly according to instruction solely through the NIOX filter Caution NIOX MINO has been tested and found to comply with the limits for medical devices according EN IEC 60601 1 Safety requirements for medical electrical systems and electromagnetic compatibility These limits are designed to provide protection against harmful interference in a typical medical installation However because of the increased use of radio frequency
35. nce between NIOX MINO and NIOX when measuring the change of FENO that often occurs after 2 weeks of corticosteroid therapy compared to their baseline levels Symptomatic asthmatic males and females from 7 years of age performed two valid FENO measurements at each visit with NIOX MINO and predicate device NIOX respectively with a limit of six exhalation attempts per subject and per device The order of the FENO 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 were recruited 147 individuals performed valid measurements on both visits and were evaluable per protocol Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page13 of 32 Table 1 Demographics in method comparison study Adults Children Total N 105 N 51 N 156 Gender n Male 53 50 5 31 60 8 84 53 8 Female 52 49 5 20 39 2 72 46 2 Ethnic origin n Caucasian 100 95 2 42 82 4 142 91 0 African 2 1 9 2 3 9 4 2 6 Hispanic 1 2 0 1 0 6 Asian 2 1 9 4 7 8 6 3 8 Other 1 1 0 2 3 9 3 1 9 Age years Mean SD 42 9 14 9 12 3 2 9 32 9 19 0 Median 42 0 13 0 30 0 Range 18 to 70 7 to 17 7 to 70 n 105 51 156 NIOX MINO an
36. ntration in parts per billion ppb and are presented on the display 1 minute 40 seconds after the exhalation 7 3 Operating and maintenance instructions For details regarding the operational and maintenance procedures please refer to NIOX MINO User Manual 7 4 Quality Control procedures NIOX MINO provides built in internal controls as well as an External Quality Control procedure for the user to verify the reliability of measurements The External Quality control procedure should be performed daily and is prompted for by the instrument An asterisk is displayed by every presented measurement result if the external Quality Control procedure has not been successfully performed The Quality Control Procedure consists of a sequential positive and negative control 1 The positive control is performed using exhaled breath samples from one or more qualified staff members The qualified staff member should have an expected FENO value within the range 5 40 ppb The staff member performs a standard exhalation test and the instrument should display a result that is close to the persons normal measurement result 10 ppb The measurement result is calculated as the mean value from three measurements performed on three sequential days This reference value is updated on a regular basis 2 The negative control consists of a NO free sample of ambient air scrubbed through the exchangeable NO scrubber The result is compared with sample genera
37. ocrine AB page30 of 32 29 30 3T 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Kharitonov S A et al Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children Eur Respir J 2003 21 3 p 433 8 Hemmingsson T D Linnarsson and R Gambert Novel hand held device for exhaled nitric oxide analysis in research and clinical applications J Clin Monit Comput 2004 18 5 6 p 379 87 Murphy A W et al Respiratory nitric oxide levels in experimental human influenza Chest 1998 114 2 p 452 6 Henriksen A H et al Exhaled and nasal NO levels in allergic rhinitis relation to sensitization pollen season and bronchial hyperresponsiveness Eur Respir J 1999 13 2 p 301 6 Rolla G et al Increased nitric oxide in exhaled air of patients with systemic lupus erythematosus J Rheumatol 1997 24 6 p 1066 71 Soderman C et al Endogenous nitric oxide in exhaled air from patients with liver cirrhosis Scand J Gastroenterol 1997 32 6 p 591 7 Olin A C et al Increased nitric oxide in exhaled air after intake of a nitrate rich meal Respir Med 2001 95 2 p 153 8 Narang l et al Nitric oxide in chronic airway inflammation in children diagnostic use and pathophysiological significance Thorax 2002 57 7 p 586 9
38. ogic parameters has been shown to affect FENO Changing pulmonary blood flow has no effect in humans but hypoxia decreases exhaled NO and this may occur in subjects at high altitude particularly those prone to high altitude pulmonary oedema The application of positive end expiratory pressure has been shown to increase FENO in animals but airway pressure in humans does not affect exhaled NO plateau levels according to most reports although one study suggests the opposite Many studies have examined the effect of exercise on FENO During exercise according to one report FENO falls whereas NO output increases and this effect may last up to 1 hour Others have reported that FENO remains stable after exercise It would seem prudent to avoid strenuous exercise for 1 hour before the measurement Caution Ethnic differences in healthy FENO levels have been observed In schoolchildren Asian boys could have 6 15 ppb higher FENO levels than Caucasians boys By contrast Asian girls have elevated FENO levels to a lesser extent African Americans children seem to have slightly higher healthy FENO levels than Caucasians 17 ppb versus 12 ppb In African American adults slightly higher average healthy FENO levels than Caucasians 20 ppb versus 17 18 ppb have been observed 13 Expected Values Given that physiological and environmental factors can affect FENO levels in clinical practice healthy FENO levels need to be establis
39. r the Deming regression analyses Estimate 95 Confidence Interval Intercept 0 677 4 196 1 765 Slope 0 938 0 829 1 081 Table 20 Number and proportion of subjects within tolerance limits Number of subjects in analysis 73 Number within tolerance limits 71 Proportion within tolerance limits 0 973 lower limit of a 95 Cl 0 905 The results show that clinically acceptable agreement exists between the stationary device NIOX Flex and the hand held device NIOX MINO 09 when applied in patients with asthma aged 6 years and up The intrasubject repeatability in the hand held device is excellent The results from this study indicate that NIOX MINO 09 and NIOX Flex can be used interchangeably Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page27 of 32 Interference of analytically determined interfering substances Sensor interference levels was tested in a laboratory setting The substances and concentrations tested are summarized in Table 10 above 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
40. re Med 2001 164 11 p 2107 13 Meyts I M Proesmans and K De Boeck Exhaled nitric oxide corresponds with office evaluation of asthma control Pediatr Pulmonol 2003 36 4 p 283 9 Delgado Corcoran C et al Exhaled nitric oxide reflects asthma severity and asthma control Pediatr Crit Care Med 2004 5 1 p 48 52 Reid D W et al Exhaled nitric oxide continues to reflect airway hyperresponsiveness and disease activity in inhaled corticosteroid treated adult asthmatic patients Respirology 2003 8 4 p 479 86 Silkoff P E et al The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma J Allergy Clin Immunol 2004 114 5 p 1241 56 Massaro A F et al Expired nitric oxide levels during treatment of acute asthma Am J Respir Crit Care Med 1995 152 2 p 800 3 Sorkness C A et al Long term comparison of 3 controller regimens for mild moderate persistent childhood asthma the Pediatric Asthma Controller Trial Allergy Clin Immunol 2007 119 1 p 64 72 Smith A D et al Exhaled nitric oxide a predictor of steroid response Am J Respir Crit Care Med 2005 172 4 p 453 9 Silkoff P E et al Dose response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients Chest 2001 119 5 p 1322 8 Lanz M J D Y Leung and C W White Comp
41. rrelation 0 274 0 244 P value 0 0008 0 0029 This table indicates as seen in the literature 74 441 that FEV1 spirometry and symptom score ACQ are different metrics and not directly linear correlated with FENO as we observed in both NIOX MINO and NIOX as observed in the Intent to Treat population 156 subjects 14 1 3 Subgroup analysis gender sex A significant difference between males and females for the proportion of patients within tolerance limits was observed see Table 6 This indicates that sex could be a confounder when comparing measurements from NIOX MINO and NIOX As between men and women in this study 92 of the men and 77 of the women were within the tolerance limits For subjects with a FENO value below 50 ppb mean of NIOX and NIOX MINO the tolerance limit was defined as 10 ppb For subjects with a FENO above 50 ppb the tolerance limit was defined as 20 Table 6 Tolerance limit percentages for individual sexes Number of Subjects PP First NIOX MINO trial Total n within limits Females 70 54 77 Males 77 1 92 Fishers exact test p 0 01 14 2 Ethnicity Another clinical study has been performed comparing NIOX MINO and NIOX by Khalili et al 6 with 110 subjects wherein 32 were African Americans A subgroup analysis comparing Caucasians and African Americans was performed on data from this study and no statistical significant differen
42. s a strong correlation between NIOX and NIOX MINO r 0 98 e Intra subject FENO difference between the three NIOX MINOs revealed no significant difference between measurements p 0 59 The mean intra subject FENO difference between NIOX and NIOX MINO was 0 5ppb McGill et al 1621 independent study 55 children 33 asthmatics Mean FENO values were higher for NIOX compared to NIOX MINO mean diff 3 9 ppb Difference was greater at higher FENO values Median CVs were 11 8 for NIOX and 7 4 for NIOX MINO Measurements of FENO were consistent Menzies et al independent study Chen et all independent study 101 asthmatic patients and 50 healthy volunteers Three measurements were performed with NIOX and one with NIOX MINO 27 adults allergic to grass pollen Three consecutive measurements were made with NIOX and NIOX MINO Measurements were performed before and immediately after a challenge and at 3 6 and 24 hours 52 Healthy adult volunteers 10 volunteers were performing 5 consecutive measurements on the same day The values obtained with NIOX MINO are directly comparable with NIOX device Readings with NIOX MINO were slightly higher 1 2 ppb There was a strong correlation between NIOX and NIOX MINO r 0 94 0 99 p lt 0 0001 general correlation 0 98 There was a statistically significant difference between the devices p lt 0 0001 There was a median intra subject difference between the d
43. s and can be summarized as follows e Measurements of FENO were consistent with both NIOX and NIOX MINO with repeatability well over 90 for both devices e There is a strong correlation between measurements performed in NIOX and NIOX MINO with a correlation coefficient at or above 0 92 e CVs are similar for NIOX and NIOX MINO in general below 10 e The frequency of success rate with NIOX and NIOX MINO are similar e In both asthmatic patients and healthy volunteers the values obtained with NIOX MINO correlated well with the values obtained with NIOX e The absolute values obtained with NIOX and NIOX MINO departs more from one another at higher levels above 50 ppb the range within which the clinical signal was obvious in both instruments Small differences usually in the 2 4 ppb range are seen in a number of studies with however consistency in the clinical signal used for response to anti inflammatory therapy Hence NIOX MINO performance is equivalent to NIOX and both devices are suitable for clinical evaluation of airway inflammation according to Intended Use Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB pagel 6 of 32 Table 8 PUBLISHED STUDIES EVALUATING THE USE OF NIOX MINO Reference Khalili et al 6 Independent study Time and number of individuals 110 patients aged 6 86 years presenting to an allergy and asthma clinic performed measurements on NIOX and three NIOX MINOs Outcome e There wa
44. s phones might interfere with the instrument and should therefore be kept away from the instrument Interference could make it impossible to perform a measurement Caution Make sure that you use the required measurement mode otherwise incorrect exhaled NO results might be obtained Caution Use of substances containing alcohol close to NIOX MINO may cause erroneous measurement results Caution Do not reuse the NIOX Filters Caution The NIOX MINO instrument might produce some heat during normal operation the temperature could increase up to 10 F above the ambient temperature Make sure that the base ventilation slots are not blocked Do not place the instrument on a bed sofa carpet or other soft surface Caution A maximum of 10 measurements hour can be performed during continuous use However it will be possible to perform 20 measurements per hour if the instrument is allowed to rest for a minimum of 30 minutes after that Caution The NIOX MINO Sensor shall be kept in its original unopened package before installation Caution The NIOX MINO Sensor shall be kept in its original unopened package before installation For transportation and storage conditions refer to the corresponding section in this manual Caution Keep the NIOX MINO sensor out of reach of children Caution The NIOX MINO Sensor is sensitive to changes in ambient temperature and humidity Labeling Sum
45. sor contains chemicals that could be harmful if swallowed Warning Touch only the grey cap when exchanging the sensor Warning Do not clean the sensor Cleaning of the Sensor with ethanol or similar disinfectant might destabilize it for a non predicable time period Warning Keep the sensor out of water Ensure that no liquid is spilled or dripped on the sensor Warning The NO scrubber contains potassium permanganate and should be disposed of as hazardous waste in accordance with the local waste disposal regulations Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page7 of 32 Warning When selecting an accessory for your NIOX MINO please keep in mind that an accessory not recommended by Aerocrine may result in loss of performance damage to your NIOX MINO fire electric shock injury or damage to other property The product warranty does not cover product failure or damage resulting from use with non approved accessories Aerocrine takes no responsibility for health and safety problems or other problems caused by the use of accessories not approved by Aerocrine Warning No modification of the NIOX MINO instrument or the Sensor is allowed The following cautions apply in the handling and operation of NIOX MINO Caution Measurement results are to be used as an adjunct to established clinical and laboratory assessments in asthma Caution Mobile phones and cordles
46. ss of than one ppb see table 21 Though with chewing gum the peak difference appeared to be an hour vs baseline mean difference in parts of ppb no analytical conclusion can be drawn from these exquisitely small figures The differences are within the NIOX MINO technical specification Table 21 Student s t test of difference between baseline FENO and FENO measured immediately after 1 and 2 hours after exposure to chewing gum Difference No of Mean Standard t value p value observations difference deviation ppb immediately after vs baseline 11 0 36 1 86 0 65 0 5310 1 hour vs baseline 11 0 91 1 51 1 99 0 0744 2 hour vs baseline 11 0 18 2 18 0 28 0 7880 Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page28 of 32 Manufacturer Information Representative in North America Aerocrine Inc 5151 McCrimmon Parkway Suite 260 Morrisville NC 27560 Phone 866 275 6469 Fax 877 329 6469 All questions regarding technical and application support in North America region Phone 866 275 6469 E mail service us aerocrine com Responsible Manufacturer Aerocrine AB R sundav gen 18 8 floor PO Box 1024 SE 171 21 Solna Sweden Phone 46 8 629 07 80 Fax 46 8 629 07 81 www aerocrine com US Patent 5 447 165 5 922 610 6 038 913 6 063 027 6 099 480 6 149 606 6 183 416 6 511 425 6 626 844 6 723 056 6 733 463 6 761 185 7 014 692 7 270 638 D448 693 D457 231 D492 035
47. ssessed Three operators each took two completed measurements in the same subject in a point of care setting The order of the three operators used was randomized and the subject was attempt to perform two completed measurement with each operator i e a total of six completed FENO measurements per subject with the NIOX MINO within a maximum of 18 attempts per subject Table 13 shows the agreement among operators for first NIOX MINO measurement at four different measurement ranges Table 13 agreement between operators at different measurement ranges n Within sd 95 Cl for sd Within CV 95 Cl for CV Median 0 10 1 0 58 ppb Not possible to calculate 5 59 Not possible to calculate Median 10 20 6 1 ppb 0 61 ppb 1 39 ppb 6 06 3 78 15 02 Median 20 30 16 1 98 ppb 1 27 ppb 2 7 ppb 7 91 5 83 12 3 Median 30 40 20 1 95 ppb 1 37 ppb 2 52 ppb 5 4 4 1 7 89 Median 40 50 5 2 43 ppb 1 ppb 3 85 ppb 5 51 3 3 16 02 Median 50 12 3 74 ppb 2 45 ppb 5 03 ppb 6 26 4 43 10 67 Within the patients with a median of 50 there were two subjects who had a very large variation One had a CV of 75 and one had 38 This row presents data excluding these two subjects The standard deviation was based on the individual FENO values Accuracy Analytical accuracy is the deviation of the measured value from a known nominal value i e the
48. surement Caution Airway caliber It has been demonstrated that FENO levels may vary with the degree of airway obstruction or after bronchodilatation perhaps because of a mechanical effect on NO output Depending on the setting it may be prudent to record the time of last bronchodilator administration and some measure of airway caliber such as FEV 261 Caution Food and beverages Patients should refrain from eating and drinking before NO analysis An increase in FENO has been found after the ingestion of nitrate or nitrate containing foods such as lettuce with a maximum effect 2 hours after ingestion and drinking of water and ingestion of caffeine may lead to transiently altered FENO levels It is possible that a mouthwash may reduce the effect of nitrate containing foods Until more is known it is prudent when possible to refrain from eating and drinking for 1 hour before exhaled NO measurement and to question patients about recent food intake Alcohol ingestion reduces FENO in patients with asthma and healthy subjects FENO Caution Circadian rhythm Although FENO levels are higher in nocturnal asthma there was no circadian rhythm in two studies but another study did report a circadian pattern so it is uncertain whether measurements need to be standardized for time of day It is however prudent where possible to perform serial NO measurements in the same period of the day and to always record the time
49. ted from the zero scrubber used for baseline control The result should be lt 5 ppb Please refer to the Quality Control section in NIOX MINO User Manual for further details on the Quality Control procedure Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page6 of 32 8 Hazards The following warnings apply in the handling and operation of NIOX MINO Warning Handle the NIOX MINO instrument as stated in the User Manual Aerocrine accepts no responsibility for damaged equipment or faulty results if the equipment is not used according to the User Manual Warning Do not use a damaged NIOX MINO instrument or damaged components Warning Use only the Power Supply unit provided Warning Keep the instrument out of water Ensure that no liquid is spilled or dripped on the instrument Warning Do not heat or dispose the instrument or sensor in fire Please refer to the Disposal of used expired products section of the User Manual Warning Take care not to drop the instrument or subject it to strong impact Warning It is recommended not to use NIOX MINO in the proximity of areas where volatile substances such as organic fluids or disinfectants are being used Special attention should be paid to aerosols and disinfection baths either open vessels or ultrasonic baths Warning NIOX MINO should not be used adjacent to or stacked with other equipment Warning The NIOX MINO Sen
50. y parameters via the device display The NIOX MINO instrument stops functioning when expired 17 2 Life time of NIOX MINO sensor The life time of the sensor is a maximum of 12 months when mounted in the instrument or expiration date as stated on the sensor whichever comes first When there is less than 10 of the number of the measurements left or less than 2 weeks of use remaining a message is displayed The expiry date is also shown on the sensor label 17 3 Shelf life NIOX Filter The shelf life for NIOX Filter in unopened primary package is 3 years NIOX Filter is for single use and must be replaced for every new patient and measurement occasion 17 4 Shelf life of NIOX MINO NO Scrubber The shelf life for NIOX MINO NO Scrubber is 2 years in unopened package Once inserted the NIOX MINO Scrubber expires after 1 year or after 1000 measurements A message is displayed when it is time to exchange the scrubber Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB pagel9 of 32 18 Routine Maintenance Please refer to NIOX MINO User Manual 19 Periodic Service No periodic service is performed 20 Evaluation methods performance data The following provides a summary of performed tests with protocol design data results and conclusion FENO_measurement time The time from end of exhalation until the result is presented on the screen was measured The FENO measurement time were determined to 1 30 s Temperature stabili
51. zation time The time from power up until the system is ready for use was measured The temperature stabilization time were determined to lt 30 min Measurement range The measurement range was determined in a laboratory setting using mixtures of standard reference NO gas Certified NO in N calibration gas of 200 ppb and 2100 ppb was mixed with nitrogen gas in a gas mixer connected in line with the NIOX MINO instrument with mounted NIOX MINO 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 10 NIOX MINO sensors continually mounted in 10 NIOX MINO instruments respectively were used in these tests 5 ppb was the lowest detectable level and 300 ppb the highest detectable level See figure 7 under section Linearity Lowest detection limit Lowest detection limit was determined in a laboratory setting using mixtures of standard reference NO gas and N2 gas below and above the detection limit at 3 and 5 ppb Three replicate determinations of each concentration were made at each occasion 5 NIOX MINO sensors continually mounted in 5 NIOX MINO instruments respectively were used in these tests Measured data at 3 ppb and 5 ppb are presented in table 11 Labeling Summary NIOX MINO EPS 000063 04 Aerocrine AB page20 of 32 Table 11 Measured data at nominal 3 ppb and 5
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