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Package Insert IDkit:Hp™ for the Exalenz BreathID® System BREATH TEST FOR DETECTION of H. pylori | IDkit HP ONE [Exalenz Bioscience Ltd.] | BioPortfolio

12:19 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

This package insert includes information for conducting the BreathID® H. pylori test for two modes of analysis with two Breath Test Kits:

The following are trademarks of Exalenz Bioscience Ltd.: Exalenz™ , MCS™, IDcircuit™, IDcheck™,  IDkit: Hp™, and  BreathID®

All reference to Exalenz in this document refers to the company Exalenz Bioscience Ltd.

Note: No license, expressed or implied, is granted under any patents of Exalenz Bioscience Ltd.

Breath Test Kit
BreathID® Mode
IDkit: HpTM ONE
H. pylori PATIENT MODE
IDkit: HpTM TWO
H. pylori BAG MODE

The Exalenz BreathID® Breath Test System is intended for use in the qualitative detection of urease associated with Helicobacter pylori (H. pylori) in the human stomach and as an aid in the initial diagnosis and post treatment monitoring of H. pylori infection in adult patients. This test should be used after at least four weeks of H. pylori eradication therapy. For these purposes, the system utilizes Molecular Correlation Spectrometry (MCS™) for the measurement of the ratio of 13CO2 to 12CO2 in breath samples.

The Exalenz BreathID® System is used to detect and monitor H. pylori infection by measuring changes in the CO to CO ratio in a patient’s breath following the ingestion of C-urea.The Exalenz BreathID® Breath Test System consists of the IDkit: Hp™ kits containing 13C-urea tablet, 75 mg for oral solution and 4.3 g Citrica Powder (4g citric acid) for oral solution; the BreathID® device and the IDcheck™ system quality control accessory.The device is for use by trained healthcare professionals and the test kit is to be administered under a physician’s supervision.

Since the initial identification of H. pylori in the early 1980s [1], the management of upper gastrointestinal disease has changed dramatically. “Helicobacter pylori is now recognized as an important pathogen and a casual relationship between H. pylori and chronic active gastritis, duodenal ulcer, and gastric ulcer is well documented” [2]. Currently there are numerous H. pylori detection technologies for upper gastrointestinal disease including biopsy and serum analysis. These technologies depend on two general approaches for obtaining a sample for testing: invasive and non-invasive.The first invasive test method requires an endoscopic gastric biopsy. The tissue collected from the biopsy is then examined in a laboratory by microbiological culture of the organism, direct detection of urease activity in the tissue (for example, the CLOtest®), or by histological examination of stained tissue. Biopsy-based methods present an element of patient risk and discomfort and may provide false negative results due to sampling errors.The second invasive test is a serological test; this requires a blood sample which is used to detect serum antibodies to H. pylori.  The disadvantage of this test is that it is difficult to distinguish between positive active infections and past exposure to infection, and therefore it is not a conclusive indicator of current H. pylori infection. C-urea breath tests provide a non-invasive and non-hazardous analysis of the exhaled breath. The BreathID® test (described in the next section) measures the COand CO components of the exhaled breath before and after the oral ingestion of C-enriched urea.  This establishes the baseline ratio of CO / CO and the post ingestion ratio of CO / CO in order to determine the Delta Over Baseline (change in the CO / CO ratio). (Delta Over Baseline is defined as: {(CO /CO - CO /CO )*1000}/(CO /CO ) where PDB is the standard C/C isotope ratio (=1.1273%). (0) is the base line measurement and (N) is the measurement of interest.)

The Exalenz BreathID® non-invasive breath test is a diagnostic test that analyzes a breath sample before and after ingestion of C-enriched urea; it is used to identify those patients with H. pylori infection.The Exalenz BreathID® breath test is performed as follows: a 75 mg C-urea tablet and 4.3 g Citrica Powder are dissolved in water, and the resulting solution is ingested by the patient. The presence of the Citrica creates an acidic environment in the stomach and also delays the transfer of the ingested solution to the duodenum. These two characteristics facilitate the decomposition of the urea by H. pylori, if present. Thus, in the presence of urease associated with gastric H. pylori, C-urea is decomposed to CO and NH according to the following equation: 2 C-urea + 2 HO ----------> H. pylori urease----------> 2 CO+ 2 NH The CO is absorbed into the blood and then exhaled in the breath. Absorption and distribution of CO is fast. Therefore, the cleavage of urea by the H. pylori urease that produces the CO occurs immediately after the solution is ingested and enables immediate detection of increased CO in the exhaled breath of H. pylori-positive patients.In the case of H. pylori-negative patients, the C-urea does not produce CO in the stomach because there are no human enzymes that can decompose the urea in the stomach.

The diagnostic drug component of the kits is C-enriched urea prepared as a tablet. The tablet should be dissolved with Citrica Powder in a glass of water, providing a clear, colorless solution for oral administration.The 75 mg C-urea component is supplied as a tablet in a sealed pouch. The 4.3 g of Citrica Powder (4 g citric acid [3,4,5], aspartame, and Tutti Frutti flavoring) is supplied in a separate sealed pouch.

An average adult body normally contains about 9.0 grams of urea, which is a product of protein metabolism. Urea in the body is referred to as a natural isotopic abundance urea since it is composed of 98.9% C-urea and 1.1% C-urea.

Greater than or equal to 99% of the carbon molecules in the supplied tablet are in the form of C; a stable, naturally occurring, non-radioactive isotope of carbon. C-urea is the diamide of 13C carbonic acid and is highly soluble in water (1 gram per ml at 25C). It has the following chemical formula: CHNO.

The BreathID® device can be operated in two pre-selected modes of testing. These are the PATIENT MODE and the BAG MODE as described below. PATIENT MODE The test begins with the selection of the PATIENT MODE and with the collection of a baseline breath sample. The patient breathes normally while the BreathID® device collects samples through the IDcircuit™ nasal cannula. The IDcircuit™ extracts moisture and patient secretions from the breath samples to provide accurate CO readings, and the device measures the CO / CO ratio of the baseline measurement. The patient then ingests a test drink consisting of C-urea tablet 75 mg and 4.3 g of citric Powder (4g citric acid). While the patient continues to breathe normally, the BreathID® device continually and non-invasively samples the patient’s breath (via the cannula) and measures the changes in the CO / CO ratio versus the original baseline sample. These changes are displayed as a graph on the large display screen while the test continues. The graph shows multiple points that allow the physician to identify the change in the DOB of the CO / CO ratio in response to the administered C-urea. Once the BreathID® device has collected enough data to determine whether or not a patient is H. pylori-positive, (i.e. the graph passes the threshold unambiguously), it automatically ends the test and prints out the results. BAG MODE The test begins with the collection of normally exhaled breath of the patient into a baseline breath collection bag, which is then sealed. This sample provides the baseline isotope ratio reading. Next, the patient ingests the test drink consisting of dissolved of C-urea tablet, 75 mg and 4.3 g of Citrica Powder (4g citric acid), as in the PATIENT MODE. After 20 minutes, the patient exhales into a post-ingestion breath collection bag, which is subsequently sealed. The test is performed on the BreathID® device. After selecting BAG MODE, the baseline and then the post-ingestion breath collection bags are connected to the BreathID® device, one after the other. Each bag is separately sampled by the BreathID® device to determine the CO / CO ratio. The values of the ratios obtained are compared in order to determine the Delta Over Baseline (change in the CO / CO ratio between the baseline and the post-ingestion measurements). Once the BreathID® completes measuring the bags, it automatically displays and prints the results. This enables the physician to determine whether a patient is positive or negative for H. pylori, based on whether or not the graph passed the threshold line.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. The following components of the test kits have expiration dates: the C-urea tablet and the Citrica Powder. Do not use either of these components beyond the expiration date stated on the respective labels.

Remind the patient that the Citrica contains 84 mg of phenylalanine per packet of Citrica. Phenylketonurics restrict dietary phenylalanine.The patient should have fasted at least one hour before administering the solution.The patient should not have taken antimicrobials, proton pump inhibitors or bismuth preparations within two weeks prior to administering the test.

MaterialsA single BreathID®  IDkit: Hp™ ONE is provided to perform the Breath Test in the PATIENT MODE.Each IDkit: Hp™ ONE for the Exalenz BreathID® Breath Test System contains:

SystemCheck One SystemCheck accessory is supplied for every 25 units of BreathID® kits, IDkit: Hp™ ONE. The SystemCheck accessory supplied with the BreathID® kits provides quality control for the BreathID® system as described in the Quality Control section. The SystemCheck has an expiration date and shouldn't be used beyond this date as stated on the label.

Materials Needed But Not Provided:

Step-by-Step Procedure for the PATIENT MODEFor more detailed information regarding the step-by-step procedure, on screen instructions, and device operation, refer to the BreathID® Operator’s Manual.For performing the BreathID® H. pylori test in PATIENT MODE, use the IDkit: Hp™ ONE single-use kit.

Materials A single BreathID® IDkit: Hp™ TWO is provided to perform the Breath Test in the BAG MODE. Each Exalenz IDkit: Hp™ TWO for the Exalenz BreathID®  Breath Test System contains:

SystemCheck One SystemCheck accessory is supplied for every 25 units of BreathID® IDkit: Hp™ TWO. The SystemCheck accessory supplied with IDkit: Hp™ TWO provides quality control for the BreathID® System, as described in the Quality Control section. The SystemCheck has an expiration date and shouldn't be used beyond this date as stated on the label. Materials Needed But Not Provided:

Step-by-Step Procedure of the BAG MODE For detailed information regarding the step-by-step procedure, on screen instructions, and device operation, refer to the BreathID® Operator’s Manual. For performing the BreathID® H. pylori test in the BAG MODE, use the IDkit: Hp™ TWO single-use kit.

The BreathID® device is an instrument for measuring changes in the ratio of CO to CO in the patient’s exhalation. Since the BreathID®is not a laboratory device, no field laboratory quality control procedures are required. The BreathID® device undergoes rigorous quality assurance procedures before leaving the manufacturer.However, to ensure correct functioning of the BreathID® in the field, an accessory labeled SystemCheck is provided for every 25 units of IDkit: Hp™. The BreathID® will automatically display a request to perform a SystemCheck™ after 25 tests are completed. The BreathID® device will not continue to function unless the SystemCheck accessory is used as directed.The SystemCheck quality control is accomplished by introducing a single-use cartridge that contains a known concentration of CO into the device after every 25 breath tests. This procedure confirms that the BreathID® System is functional and is performing within specifications.Complete operating information including appropriate quality control activities is provided in the BreathID® Operator’s Manual.

The calibration stability of the BreathID® system is ensured by the Exalenz proprietary CO and CO Isotope Specific InfraRed (ISIR) lamps. The physical process underlying gas discharge emissions supports this stability. The emissions are caused by molecular rotation-vibration transitions, each generating a spectral line at a specific wavelength, uniquely defined to an accuracy of better than 0.01 Å (Angstrom). Five gas samples of known concentration and isotope ratio are used to adjust the absorption cell calibration curves, aiming to attain identical isotope ratios over the collection range of CO concentrations.  This will ensure accurate readings in both negative and positive samples.In addition, quality checks as described above in the Quality Control section are performed by the BreathID® device after every 25 tests in order to ensure that the BreathID® System performs within established limits, and calibration is performed if required. Refer to the BreathID® Operator’s Manual for a complete description of the SystemCheck and calibration procedure.

The ratio of CO to CO in breath samples is determined by Molecular Correlation Spectrometry (MCS™), which is utilized by the BreathID® device software.

The results of the BreathID® test are provided as Delta Over Baseline. Delta Over Baseline is the difference between the Delta value (based on a ratio of CO / CO) in the test specimen and the corresponding baseline sample. There are no calculations required by the user.

The cutoff point is the level (threshold) used to discriminate betweeny H. pylori-infected and uninfected individuals.The Delta Over Baseline cutoff point was determined to be five in a controlled study of 186 adult asymptomatic and symptomatic patients (101 infected and 85 uninfected). The study was conducted in Israel using a local reference standard called the Isotope Ratio Mass Spectrometer (IRMS). The cutoff point was evaluated by determining the BreathID® test result (DOB) threshold at which positive and negative patients, as determined by the Isotope Ratio Mass Spectrometer, were best distinguished. Figure 3 shows the BreathID® cutoff point graphically, which distinguishes H. pylori-positive and negative patients.

The cutoff point was confirmed in a controlled pivotal clinical study where 300 subjects were enrolled. The study consisted of a pre-therapy and post-therapy phase. Patients enrolled in the pre-therapy phase had dyspeptic symptoms, active peptic ulcer disease, or a past history of peptic ulcer disease.  To be eligible for the post therapy phase, H. pylori-positive patients had to be treated for infection four weeks prior to enrollment (some patients participated in both the pre-therapy and post-therapy phases). In the pre-therapy phase, 47 patients were found to be infected and 253 were found to be uninfected. Congruent results obtained by rapid urease test and histological examination of biopsy tissue were used as the reference standard. In the post-therapy phase, 22 patients were infected and 50 were uninfected. The reference standard was a positive finding by endoscopic test (rapid urease or histology) or Meretek UBT®. For more details, refer to the Performance Characteristics section. Figure 4 shows the BreathID® Delta Over Baseline results.

Interpretation of Results A BreathID® test result of greater than 5 Delta Over Baseline is interpreted as diagnostically positive, indicating the presence of urease associated with H. pylori. A BreathID® test result of less than or equal to 5 Delta Over Baseline is interpreted as diagnostically negative, indicating the absence of urease associated with H. pylori.The 5 Delta Over Baseline cutoff point applies to both initial diagnosis and post treatment monitoring of H. pylori infection.For more details, refer to the Performance Characteristics section.

Potentially interfering substances typically found in a patient’s breath were tested using the BreathID® System to determine their effect on the test results. The potential sources tested were:

There was no observation that these substances had any significant influence on the outcome of the test.

Tests were conducted to evaluate the reproducibility and repeatability of results when measurements are made by different technicians and/or using different BreathID® devices, or when testing is done on different days.

Four different accurate gas isotope mixtures were prepared with Delta Over Baseline values of 0, 2.5, 6.5, and 24 in a bench study. Three operators were asked to operate each of three BreathID® devices, in order to measure the Delta Over Baseline values for samples from each of the four batches. The results demonstrated that the standard deviation and overall reproducibility were stable over different batches for both the operator and the devices. The overall reproducibility standard deviation was 0.77, which is less than the natural variability of the Delta Over Baseline measurement.

Three patients (one H. pylori-negative and two H. pylori-positive) were measured on three different days. From this limited observation, it was assumed that positive and negative subjects maintained their classification with no ambiguity when measured on different occasions. Based on this observed trend and in combination with the reproducibility results, it was concluded that the system is very consistent.

The relationship between pre- and post-therapy BreathID® test results in patients enrolled in the clinical study was examined. Of the 13 patients who were positive pre-therapy and negative post-therapy and the three patients who were positive pre- and post-therapy, none had a borderline result post-therapy. The post-therapy negative patients were close to 0 Delta Over Baseline and the post-therapy positive patients were well above the 5 Delta Over Baseline threshold, again supporting the system coherency.

Experimental DesignThe data presented here was collected from a prospective, open-label clinical trial, designed to assess the sensitivity and specificity of the BreathID® test compared to other methods in determining the status of gastrointestinal infection with H. pylori (pre-therapy phase). In addition, the clinical trial was designed to evaluate the ability of the BreathID® system to monitor the efficacy of therapy for H. pylori (post-therapy phase).There were 315 adult pre-therapy patients at two United States hospitals in the study. There were 77 post–therapy patients who were positive for infection and who had undergone eradication therapy at least four weeks previously. Nineteen of these post-therapy patients participated in the pre-therapy phase as well.Patients were evaluated by at least two of four diagnostic methods:

Results The results are presented in two-way contingency tables.The exact binomial distribution was used to calculate the lower and upper limits of the 95% confidence intervals of the performance statistic. Pre-Therapy Table 1 and Table 2 compare the BreathID® to rapid urease tests and histological exams, respectively. In Table 3, the BreathID® outcome is compared to congruent results from the two endoscopy biopsy-based methods (rapid urease test and histological exam). Table 1: Comparison of BreathID® Test to Rapid Urease Test (Clotest®)

*Four patients out of the 315 were missing either the rapid urease test or BreathID®test results and therefore were not included in the table.Relative sensitivity: 100% [95% CI (94.2, 100)]Relative specificity: 99.2% [95% CI (97.3, 99.9)] Table 2: Comparison of BreathID® Test to Histology Pre-Therapy

*Nine patients out of the 315 were missing either histology or BreathID® test results and therefore were not included in the table.Relative sensitivity: 95.9% [95% CI (86.0, 99.5)]Relative specificity: 97.7% [95% CI (95.0, 99.1] Table 3: Comparison of BreathID® Test to Congruent Endoscopic Tests (CLOtest® and histological exam) Pre-Therapy

*H. pylori positive is defined as positive rapid urea test and positive histology. H. pylori negative is defined as negative rapid urea test and negative histology.Sensitivity**: 100% [95% CI (92.5, 100)]Specificity**: 99.2% [95% CI (97.2, 99.9)]**These calculations of sensitivity and specificity do not include 15 patients. In five of these patients, results obtained from the rapid urease test and histology did not match, and in 10 of these patients, at least one of the three tests was missing. Post Therapy Table 4 compares the BreathID® to congruent results from the two biopsy-based methods (rapid urease test and histological exam) or urea breath test (Meretek UBT®). Table 4: Comparison of BreathID® Test to Endoscopic Tests or Meretek

*H. pylori positive is defined as at least one positive on either of the endoscopic tests or Meretek UBT®.Percent agreement with positive patients: 95.5%Percent agreement with negative patients: 100%

BreathID® Test
 CLOtest® Positive
Negative
Total
Positive
50
0
50
Negative
2
259
261
Total
52
259
311*
BreathID® Test
Histology
Positive
Negative
Total
Positive
47
2
49
Negative
6
251
257
Total
53
253
306*
BreathID® Test
Congruent Endoscopic Tests* Positive
Negative
Total
Positive
47
0
47
Negative
2
251
253
Total
49
251
300
BreathID® Test
Endoscopic Tests of Meretek UBT®* Positive
Negative
Total
Positive
21
1
22
Negative
0
50
50
Total
21
51
72

The two sampling modes of the BreathID® are PATIENT MODE sampling (using the continuous measuring of patient's breath before and after ingestion of the test solution*) and BAG MODE sampling (using two breath collection bags to sample patient's breath before and after ingestion of the test solution*). These sampling modes are described in the Procedure section of this Package Insert.

The BreathID® outcome capabilities of these two sampling modes were evaluated and compared in a series of bench tests using accurate gases and in one clinical study, as described below.*Containing 75 mg C-urea tablet and 4.3 g Citrica Powder. Non-clinical validation (bench tests)

Objectives:

Methodology:

In addition (in protocol 2), three collection bags were filled from three sources of 0, 9.5 and 15.5 to complete a set of nine bags. This was repeated twice more, so a total of 27 collection bags were collected in time "0." One set of nine collection bags was tested at time "0" and the other two sets were kept at different temperatures for seven days. One set was kept at 2º-8º Celsius and the second set was kept between 40-50º Celsius. After seven days, the collection bags were tested in the same device. This was done to demonstrate reproducibility. Criteria for evaluation:The accuracy and precision of the two modes were evaluated. The mean differences between the DOB as obtained by the device and the true values and their standard deviations were calculated. Mean differences should be near zero if the measurement is accurate. Statistical methods:Accuracy was assessed by comparing the measurement to its corresponding known value. Mean differences and 95% confidence intervals were calculated. The standard deviation of the mean difference and its 95% confidence interval were presented as an additional measure of accuracy versus the known constants.Repeatability expresses the precision under the same operating conditions over a short interval of time. Reproducibility expresses the precision between different operating conditions. The 95% confidence intervals for repeatability were calculated using a random effects analysis of variance model using the PROC MIXED procedure. The confidence interval of the reproducibility was calculated with bootstrap methodology using 10,000 simulated samples. Results:The overall accuracy of the BAG MODE was 0.11 (95% CI: [-0.91 – 1.13]). This value is similar to the overall accuracy of the PATIENT MODE -0.06 (95% CI: [-0.61 – 0.48]). The repeatability and reproducibility of the measurements assessed with the BAG MODE and PATIENT MODE are similar. Repeatability was 1.07 (95% CI: [0.87 - 1.38]) versus 0.97 (95% CI:[ 0.70 - 1.66])  and reproducibility 1.22 (95% CI:[ 0.70 -1.66]) versus 1.05 (95% CI:[ 0.73 -1.38]), respectively. Again, this demonstrates similar results for both modes.Assessment of the BAG MODE measurements has shown that the overall mean change in DOB measured after seven days is 0.02 (SD=1.21), irrespective of DOB of gas samples; subsequently, it can be reproduced after seven days in storage.Also, the results of the BAG MODE were found to be within the system specification. Conclusion:The data provided by these non-clinical experiments demonstrates the overall high agreement between the PATIENT MODE and the BAG MODE performances and the accuracy of the BAG MODE values. Furthermore, the non-clinical testing portrays the high level of precision, repeatability, and reproducibility of the BAG MODE results. Clinical ValidationObjectives:To show that the BAG MODE results in human subjects are in very high agreement with the results of the PATIENT MODE. Methodology:Validation of the BAG MODE included a clinical study comparing the BAG MODE and the PATIENT MODE applied on the same subjects, which were administered with the test solution of C-urea and Citrica as per Clinical protocol number# 4B-CV-409. For evaluation of the BAG MODE, 48 subjects were enrolled in this study. Statistical methods:The overall percent agreement between the diagnoses was calculated with a 95% exact confidence interval, sensitivity and specificity of the BAG MODE versus the PATIENT MODE, with their respective exact 95%. A Pearson correlation coefficient between measurements of DOB in both modes was calculated. The mean and standard deviation of the difference between the DOB measurements was calculated together with a 95% confidence interval. A linear regression model was fitted to the DOB value obtained by both modes. The slope and intercept together with their respective 95% confidence intervals were calculated. In addition, a Bland-Altman plot of the mean versus the difference were calculated, and the 95% limits of agreement were calculated together with their respective confidence intervals. Results:The overall agreement percentage is 100% (48/48) with a 95% exact binomial CI: [92.6%-100%] sensitivity of the BAG MODE versus the PATIENT MODE. Method diagnosis is 100% (95% exact binomial CI:[87.66%-100%]) and specificity is 100% (95% exact binomial CI:[83.16%-100%]). Conclusion:The clinical outcome results obtained by the BAG MODE are essentially the same as those obtained by the PATIENT MODE. Therefore, the two collection modes are considered equivalent and can be used interchangeably for assessing the presence of H. pylori infection with the BreathID® System.

The above sections of the performance validations of all aspects of the BreathID® System show unequivocally that the BreathID® System can be used with its kits and two sampling modes to determine the DOB (change in the CO / CO ratio between the baseline and the post-ingestion measurements) and therefore to imply the presence of H. pylori in humans when the DOB is above 5.

REPRESENTATIVE PACKAGING See How Supplied section for a complete list of available packages of the IDkit:Hp™ for the Exalenz BreathID® System.

Case containing 25 kits of IDkit:Hp™ ONE

Kit label for IDkit:Hp™ ONE

Box containing 5 kits of IDkit:Hp™ TWO

Kit label for IDkit:Hp™ TWO

Citrica pouch

Urea blister pack

Manufacturer

Exalenz Bioscience Ltd.

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