Bronchial Thermoplasty for Severe Asthmatics Guided by HXe MRI

This study explores the feasibility of using hyperpolarized xenon (HXe) Magnetic Resonance
Imaging (MRI) as a diagnostic imaging agent to prioritize the order of airway treatment by
bronchial thermoplasty, rather than the FDA approved pre-established treatment sequence that
is performed today.

The Alair® Bronchial Thermoplasty System is an FDA approved device clinically proven to be
effective in treating severe asthma patients who are not well controlled with inhaled
corticosteroids and long acting beta agonists. Bronchial thermoplasty (BT) is a procedure
that reduces excessive airway smooth muscle by radio wave ablation, thus decreasing the
ability of the airways to constrict during an asthma attack. The BT procedure is performed in
three separate outpatient treatment sessions, each treating pre-established regions of the
lungs. The sessions are separated by at least three weeks healing time.

MagniXene® is pure xenon gas which is magnetically altered to become a contrast agent for
magnetic resonance imaging of the lungs. The subject inhales the hyperpolarized xenon while
inside the MRI scanner and a highly detailed ventilation map of the lung spaces is acquired
during a short breath-hold. By detecting unventilated regions and airway reactivity using HXe
images, a prioritized scheme for performing bronchial thermoplasty can be elaborated to treat
the most problematic airways within the first BT session. In this study the rest of the
airway will be treated in the following two sessions, such that all the airways are treated
in the end as in the standard procedure.

This study will include approximately 30 patients clinically indicated to undergo bronchial
thermoplasty. Half of the patients will be randomly assigned to receive HXe guided BT, while
the other half will receive standard BT procedure. HXe images and clinical measures of asthma
disease severity, such as Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test
(ACT), morning expiratory peak flow (AM-PEF), pulmonary function tests (PFT), will be
acquired at three time points interleaved with the BT sessions: before BT, 12 weeks after
first session of BT, and 12 weeks after the third session of BT (approximately 36 weeks from
baseline). HXe MRI will be repeated within the same day after bronchodilator treatment of the
patient to establish airways reactivity. Additionally, a three-week follow up for HXe MRI
will allow us to study temporal variability of HXe metrics. A total of six HXe imaging
sessions (distinctive days), each including at least four HXe images will be dedicated to
each patient.

The primary outcome of this study will be to determine to what extent the guided treatment is
not inferior in benefit to the standard full treatment course. The statistical metric will be
the incremental change in the AQLQ score.

Inclusion Criteria (bronchial thermoplasty):

- Males or females age 18 or greater and less than 65.

- Subject has asthma and is taking regular maintenance medication for past 12 months
that includes:

- Inhaled corticosteroid (ICS) at a dosage greater than 1000μg beclomethasone per
day or equivalent, AND long acting ß2-agonist (LABA) at a dosage of ≥100μg per
day Salmeterol or equivalent.

- Other asthma medications such as leukotriene modifiers, or anti-immunoglobulin E
(IgE), are acceptable (Subjects on Xolair® must have been on Xolair for greater
than 1 year).

- Asthma confirmed by: (a) b-agonist reversibility of FEV1 ≥ 12 % following 360mcg
albuterol OR (b) 20% fall in forced expiratory volume in 1 second (PC20-FEV1) after a
challenge with methacholine ≤ 8 mg/ml if not receiving an inhaled corticosteroid (ICS)
or ≤ 16 mg/ml if receiving an ICS.

- FEV1 ≥ 50% predicted pre-bronchodilator.

- Asthma symptoms on at least two days or one night per week over the last 2 weeks.

- Subject is a non-smoker for 1 year or greater (if former smoker, less than 10
pack-years total smoking history).

- Patient has a clinical indication for bronchial thermoplasty as decided by their
treating physician.

- Ability to undergo bronchoscopy in the opinion of the investigator.

Exclusion Criteria (bronchial thermoplasty):

- Asthma exacerbation (ED visit, hospitalization, course of increased systemic steroids,
or urgent health care visit for asthma) during the prior four weeks.

- Asthma exacerbation requiring hospitalization during the prior six weeks.

- Chronic oral steroid therapy greater than 30 mg per day.

- Respiratory tract infection within past 4 weeks

- Subject has a known sensitivity to medications required to perform bronchoscopy (such
as lidocaine, atropine and benzodiazepines).

- Subject is undergoing immunosuppressant therapy (e.g., methotrexate).

- Subject is on anticoagulant medication.

- Subject has bleeding diathesis, platelet dysfunction, and thrombocytopenia with
platelet count less than 125,000/mm2 or known coagulopathy (INR > 1.5).

- Subject has other respiratory diseases including interstitial lung disease, emphysema,
cystic fibrosis, vocal cord dysfunction, mechanical upper airway obstruction,
untreated obstructive sleep apnea, Churg-Strauss syndrome, cardiac dysfunction, and
allergic bronchopulmonary aspergillosis (total IgE of >1000 Units/mL with positive
specific IgE to aspergillus and evidence of central bronchiectasis).

- Subject has segmental atelectasis, lobar consolidation, significant or unstable
pulmonary infiltrate, or pneumothorax, confirmed on x-ray.

- Subject has clinically significant cardiovascular disease, including myocardial
infarction, angina, cardiac dysrhythmia, conduction defect, cardiomyopathy, aortic
aneurysm, or stroke.

- Subject has uncontrolled hypertension (>200mm Hg systolic or >100mm Hg diastolic
pressure).

- Subject uses an internal or external pacemaker or cardiac defibrillator.

- Chronic diseases (other than asthma) that in the opinion of the investigator would
prevent participation in the trial or put the participant at risk by participation,
e.g. chronic diseases of the lung (other than asthma), heart, liver, kidney, or
nervous system, or immunodeficiency

- History of cigarette smoking with > 10 pack years total

- Use of investigative drugs or intervention trials in the 30 days prior to enrollment
or during the duration of the study

- Any condition or compliance issue which in the opinion of the investigator might
interfere with participation in the study

Exclusion Criteria (Magnetic Resonance Imaging):

- Obesity exceeding the scanner capability

- Metal implants or non-removable metal piercings

- Inability to tolerate MRI scanning due to claustrophobia

Exclusion Criteria (HXe inhalation):

- Pregnancy or intention to become pregnant

- Neurological or cardiac comorbidities

- Hemoglobin level below 10 g/dl as determined in a recent (within 12 months)
measurement