Use of FeNO to Identify Eosinophilic Inflammation in Patients Age 40 Years and Above With Chronic Obstructive Airways Disease

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 and its symptoms. 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.

Burden of Disease:

Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of diseases
characterized by chronic airflow obstruction that interferes with normal breathing . The
Centers for Disease Control and Prevention (CDC) reported that in the year 2005,
approximately one in 20 deaths in the United States had COPD as the underlying cause.

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.

COPD can coexist with asthma. However, the exact role of FeNO in patients with established
COPD remains to be the defined. While COPD airway inflammation is usually associated with
increased neutrophils, some patients with COPD may have features of asthma such as a mixed
inflammatory pattern with increased eosinophils. However, many patients have difficulty
expectorating sputum and/or can only produce poor quality sputum samples which are not
adequate to accurately quantify eosinophilic cells. Since FeNO can be measured easily and
reliably, it may be useful in evaluating airway inflammation in COPD and thus predicting
steroid responsiveness in COPD.

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:

While there have been a number of preliminary studies on FeNO in COPD, literature defining
the role of FeNO in patients with established COPD is minimal. The purpose of the current
study, therefore is to characterize FeNO levels that may be indicative of eosinophilic
airway inflammation in patients with chronic obstructive airways disease. This data may be
useful in determining whether or not FeNO can predict improvement in FEV1 following ICS
treatment

CLINICAL INVESTIGATION OBJECTIVES To characterize FeNO levels that may be indicative of
eosinophilic airway inflammation in patients with chronic obstructive airways disease.

CLINICAL INVESTIGATION PLAN

This is a pilot, observational, multi-center, single-visit, outpatient study. Subjects
meeting all of the Inclusion Criteria and none of the Exclusion Criteria, and who express
interest in study participation, will be asked to provide the following documentation and
information:

- Informed Consent

- Demographics

- Baseline Characteristics

- FeNO:

- Subjects will receive training by the study staff on use of the NIOX MINO® device to
perform FeNO Measurements

- Spirometry

- Severity of COPD

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

Selection of investigation population:

Male and female subjects, age 40 years and above, inclusive, with chronic obstructive
pulmonary disease (COPD) including chronic bronchitis and emphysema and/or a mixed diagnosis
of asthma/COPD will be recruited. A subject should be withdrawn from the clinical
investigation if, in the opinion of the Investigator, it is medically necessary, or if it is
the expressed wish of the subject.

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:

- Diagnosis: Chronic obstructive pulmonary disease (COPD) including chronic bronchitis
and emphysema, and/or a mixed diagnosis of asthma/COPD.

Exclusion Criteria:

- Concurrent Conditions or Disease: Subjects with other chronic obstructive lung
diseases including but not limited to cystic fibrosis (CF), bronchiectasis,
obliterative bronchiolitis, ciliary dyskinesia, post-viral bronchial hyperresponsive
syndrome, vocal cord dysfunction, rhinosinusitis, non-eosinophilic asthma, and
reactive airways dysfunction syndrome are excluded. In addition, subjects with
pneumothorax, fractured rib(s), or signs of cardiac instability including but not
limited to a recent myocardial infarction, unstable angina, unstable vital signs, or
acute shortness of breath, chest tightness or chest pain are excluded.

- Study Participation Outside of This 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.