A Study to Explore the Utility of Fractional Exhaled Nitric Oxide (FeNO) Compared With Methacholine Challenge (MCC) Testing in the Assessment of Patients With Suspected But Undiagnosed Asthma

INTRODUCTION

Overview:

The measurement of exhaled nitric oxide (FeNO) is the only clinical test for measuring
airway inflammation that can be performed consistently and accurately in clinical practice
at the point-of-care. Airway inflammation is now recognized as the central mechanism in the
pathogenesis of asthma. The measurement of FeNO with the NIOX MINO® device provides a rapid,
noninvasive, and inexpensive tool to assess airway inflammation in inflammatory airway
diseases such as asthma. The test is easy to perform and requires minimal training for the
operator to conduct the test.

Role of Exhaled Nitric Oxide (FeNO):

FeNO has evolved as a predictive and prognostic biomarker for airway inflammation. Nitric
oxide (NO) gas is produced in the epithelial cells of the bronchial wall as an intrinsic
part of the inflammatory process.

Measuring the amount of FeNO is useful in the initial assessment of patients with chronic
cough or non-specific respiratory symptoms suggestive of asthma, and for the management of
patients with established asthma who are receiving corticosteroid treatment.

Intended Use:

NIOX MINO® measures Nitric Oxide (NO) in human breath. Nitric Oxide is frequently increased
in inflammatory processes such as asthma. The fractional NO concentration in expired breath
(FeNO) can be measured by NIOX MINO® with assurance that such measurements are repeatable
and according to guidelines for NO measurement established by the American Thoracic Society.

Rationale for Study:

The burden of asthma in the U.S. is significant and growing. In addition, it has been
established that asthma is both over- and under- diagnosed. Equally concerning is the fact
that nearly 75% of these misdiagnosed patients are receiving anti-asthma treatments. Data
such as these point out the need for a simple, inexpensive and reliable way to establish the
diagnosis of asthma.

Presently, the assessment of patients with suspected but undiagnosed asthma is to perform
Methacholine Challenge (MCC) testing to evaluate airway hyperresponsiveness. However, MCC,
testing is difficult, time-consuming, and costly and also involves some level of risk to the
patient. Nonetheless, there is some evidence that FeNO testing may be able to identify the
patients who actually have asthma among those with suspected but undiagnosed asthma who have
normal pulmonary function tests, thus potentially eliminating the need for MCC testing in
many patients.

CLINICAL INVESTIGATION OBJECTIVES To explore the utility of FeNO compared with MCC in
assessing patients with suspected but undiagnosed asthma.

CLINICAL INVESTIGATION PLAN

This is an exploratory, multi-center, single-visit, outpatient study. Approximately 50
subjects will participate in the study during an (approximately 8-16 week study enrollment
period:

- Demographics

- Physical Characteristics

- Smoking history (cigarettes only)

- FeNO

- Spirometry

- Asthma and Allergy Specialists MCC Test Procedure

Subject discharge from the study:

Once all information has been collected and all procedures have been performed, the subject
will be discharged from the clinic and their study participation will be complete

Medical device:

The NIOX MINO® was initially cleared by the FDA on March 4, 2008 as a new hand-held device
for the measurement of exhaled Nitric Oxide, a marker of eosinophilic airway inflammation.
The most recent clearance by the FDA was on September 2, 2010 for Instrument (09-1100),
which will be used in this study. NIOX MINO® can be used in children 7-17 years of age and
in adults 18 years of age or older in the initial assessment and management of asthma.

The NIOX MINO® is a 10 second test based on exhaled breath measured at a 50 ml/second flow
rate. Results are provided at the point of care within 2 minutes after the successful
completion of the breath test. The test cannot be influenced by patient effort or variations
in the clinician's test technique.

Definitions:

Adverse event: Any incident where the use of a medical device (including in vitro
diagnostics) is suspected to have resulted in an adverse outcome in a patient.

Serious Injury means injury or illness that:

- Is life-threatening

- Results in permanent impairment of a body function or permanent damage to a body
structure, or

- Necessitates medical or surgical intervention to preclude permanent impairment of a
body function or permanent damage to a body structure.

Malfunction: the failure of a device to meet its performance specifications or otherwise
perform as intended.

Caused or contributed: the death or serous injury was or may have been attributed to a
medical device, or that the medical device was or may have been a factor in a death or
serious injury, including events occurring as a result of:

- Failure

- Malfunction

- Improper or inadequate design

- Manufacture

- Labeling

- User error

Inclusion Criteria:

- Subjects with suspected but undiagnosed asthma that are scheduled to undergo MCC
testing as part of the routine evaluation of suspected asthma.

Exclusion Criteria:

- Concurrent Conditions or Disease:

- current diagnosis of asthma, COPD, or other chronic respiratory disease

- upper or lower respiratory infection (including the common cold) that has not
resolved within 4 weeks prior to the MCC test

Medication Use:

- scheduled use of asthma and allergy medication(s) should be discontinued at least 48
hours prior to MCC testing

- rescue medications should be discontinued at least 8 hour prior to MCC testing

Smoking:

- smoking should be avoided for at least 8 hours prior to MCC testing

Exercise:

- exercise or outdoor activity should be avoided for at least 2 hours prior to testing

Vaccinations:

-vaccinations should be avoided at least 2 weeks prior to MCC testing

Study participation outside of the protocol:

-subjects currently enrolled in studies of investigational or non-investigational drugs or
medical devices and/or who participated in these studies within 30 days prior to this
study are excluded