Impact of FeNO Measured With the NIOX MINO® Device in Identifying Asthma Among Patients With Prolonged Respiratory Symptoms

Overall Aim:

To better understand the diagnostic process for prolonged respiratory events and determine the potential role of FeNO in assessing the possibility of asthma as the symptoms etiology.

Study Objectives:

The specific objectives of this study are to:

* Determine the frequency of ICS prescription for the treatment of non-specific lower respiratory symptoms.
* Determine the frequency of asthma diagnosis as an etiology for the non-specific lower respiratory symptoms.
* Explore the value of FeNO in identifying asthma as the etiology of the non-specific lower respiratory symptoms.

Number of Subjects:

It is anticipated that up to approximately 3,000 patients will be asked to complete the brief screening questionnaire that will be used to identify up to approximately 280 eligible patients who meet the study inclusion/exclusion criteria during a (approximately) 4 to 6 week study enrollment period.

Reference Product: NIOX MINO®

Duration of the participants involvement in the investigation: Single Visit

Performance assessments:

Fractional Exhaled Nitric Oxide (FeNO) Measurements will be performed using the NIOX MINO® device according to "Instructions for NO measurements" which will be provided to each Investigative site prior to patient enrollment.

Safety Assessments:

The Investigator is responsible for the detection, reporting, and documentation of events meeting the definition of an Adverse Event (AE) and/or Serious Injuries as provided in this clinical investigation plan from the time of informed consent/assent and during the study period.

Criteria for Evaluation:

The relationship(s) between FeNO and both the diagnosis of asthma and prescription of ICS will be explored by correlation, measures of concordance and logistic modeling.

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 asthma. The test is easy to perform and requires minimal training for the operator to conduct the test.

Burden of Disease:

The burden of asthma in the U.S. is significant and growing. In May 2011, the Centers for Disease Control and Prevention (CDC) reported that the prevalence of asthma has increased by 12.3% from 2001 to 2009 and affects approximately 24.6 million Americans, including 9.6% of the pediatric population. In 2008, at least one half (52.6%) of persons with asthma in the U.S. reported having an asthma attack in the preceding 12 months. In 2007, there were 1.75 million asthma-related emergency department visits and 456,000 asthma hospitalizations.

Initial assessment and diagnosis of asthma and ongoing management of asthma patients remain key challenges. The traditional approaches for diagnosing and management of asthma include family history evaluation, symptom assessment and airflow measures (e.g. spirometry). However, these approaches do not effectively incorporate measurement of inflammation into diagnosis and management approaches.

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 symptoms suggestive of asthma, and for the management of patients on corticosteroid treatment. Exhaled nitric oxide increases when there is eosinophilic airway inflammation. Changes in FeNO precede changes in symptoms that are observed with increased and decreased airway inflammation. The measurement of FeNO is easily and rapidly accomplished, providing an objective, interpretable value that cannot be influenced by patient effort or variations in the clinician's test technique. FeNO measurement is a well-established and scientifically documented procedure with over 2000 publications on its use.

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 with assurance that such measurements are repeatable and 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.

Rationale for the Study:

The current study will generate information to characterize patients seeking health care in a Primary Care Clinic presenting with non-specific lower respiratory symptoms such as cough, wheeze, and/or shortness of breath that are associated with asthma but may be labeled as more acute respiratory conditions, e.g. infections. Results from this study may be used to estimate the number of patients required to demonstrate meaningful changes in non-specific lower respiratory symptoms in future studies and may also support the usefulness of FeNO in the Primary Care setting.

CLINICAL INVESTIGATION OBJECTIVES:

Overall Aim:

To better understand the diagnostic process for prolonged respiratory events and determine the potential role of FeNO in assessing the possibility of asthma as the symptoms etiology.

Study Objectives:

The specific objectives of this study are to:

* Determine the frequency of ICS prescription for the treatment of non-specific lower respiratory symptoms.
* Determine the frequency of asthma diagnosis as an etiology for the non-specific lower respiratory symptoms.
* Explore the value of FeNO in identifying asthma as the etiology of the non-specific lower respiratory symptoms.

CLINICAL INVESTIGATION PLAN:

Overall Clinical Investigation Design and Plan-Description:

An observational, multicenter, single-visit study to collect information on patients utilizing a Primary Care Clinic to seek health care for the assessment, treatment, and management of non-specific lower respiratory symptoms such as cough, wheeze, and/or shortness of breath. All patients seeking care at the clinic for any medical condition will be asked to complete a brief screening questionnaire designed to capture a self-assessment of non-specific lower respiratory symptoms. Patients with non-specific lower respiratory symptoms such as cough, wheeze, and/or shortness of breath who meet the inclusion/exclusion criteria for this study may be invited to participate in the study.

Visit and Procedures:

Subjects meeting Inclusion and Exclusion Criteria and who express interest in study participation will be asked to provide the following documentation and information: Informed Consent/Assent; Baseline Characteristics; Medical History

FeNO Measurement: A single blinded FeNO measurement will be obtained.

Patient Discharge from the Study: Once all information has been collected and procedures performed, the patient will be discharged from the clinic and their study participation will be complete.

Medical Record Review: Patient's medical record and administrative data will be reviewed before study close-out to assess the number of previous similar episodes each patient has had during the previous two (2) years.

Selection of Population:

Population Characteristics: Males and females, seven (7) to 65 years of age. It is anticipated that up to approximately 3,000 patients from multiple primary care clinics will complete the brief screening questionnaire that will be used to identify up to approximately 280 eligible patients who meet the study inclusion/exclusion criteria during a (approximately) 4 to 6 week study enrollment period.

Medical Device:

The NIOX MINO® was 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 NIOX MINO® is a 10 second test based on exhaled breath measured at a 50 ml/second flow rate. In this study the results will not be displayed, but will remain blinded to the investigator.

PERFORMANCE AND SAFETY ASSESSMENT:

Clinical performance assessments: Investigators should use their judgment to determine if study candidates will be able to successfully perform assessment of FeNO using the NIOX MINO®.

Clinical safety assessments: The Investigator is responsible for the detection, reporting, and documentation of events meeting the definition of an Adverse Event (AE) and/or Serious Injury as provided in this clinical investigation plan from the time of informed consent/assent and during the study period.

Adverse events:

* 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:

  1. Is life-threatening, or
  2. Results in permanent impairment of a body function or permanent damage to a body structure, or
  3. 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 serious 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:

  1. Failure
  2. Malfunction
  3. Improper or inadequate design
  4. Manufacture
  5. Labeling
  6. User error

Eligibility Criteria:
Inclusion Criteria:

* Symptoms: Must have non-specific lower respiratory symptoms, such as cough, wheeze, and/or shortness of breath
* Age: Seven (7) to 65 years, inclusive
* Sex: Males and Females
* Ability to successfully perform assessment of FeNO: Investigators should use their judgment to determine if study candidates will be able to successfully perform assessment of FeNO using the NIOX MINO®.

Exclusion Criteria:

* Diagnosis: No previous or current diagnosis of asthma or chronic obstructive pulmonary disease (COPD).
* Medications: No use of inhaled or oral corticosteroids within 7 days prior to the visit.
* Study Participation Outside of This Protocol: Patients 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.