Effect of Positive Airway Pressure on Reducing Airway Reactivity in Patients With Asthma (CPAP)

It is now well established that failure to rhythmically apply strain to airway smooth muscle
leads to change in the biomechanics of the smooth muscle characterized by shortened resting
length and increased sensitivity to pharmacologic constrictors. Patients with asthma have
physiologic airway characteristics that recapitulate this condition - increased airway tone
and increased sensitivity to methacholine. It is our underlying hypothesis that asthma,
although it may be initiated by allergic airway inflammation, is promoted by decreased tidal
force fluctuations during recumbent sleep. If this is true, then treatments that increase
tidal force fluctuations of airways should reverse these abnormalities. One treatment that
increases tidal force fluctuations is continuous positive airway pressure (CPAP). CPAP
prevents a fall in end expiratory lung volume and prevents closure of airways in dependent
regions of the lung thereby permitting the stresses of tidal breathing to apply strain to
airways. Preliminary data in 15 asthmatics showed that 1 week of 10cm H₂O nocturnal CPAP was
associated with a remarkable 2.7-fold increase in the concentration of methacholine causing
a 20% fall in FEV₁ (PC20). The objective of this study is to conduct a randomized,
sham-controlled, multicenter study of 5 and 10 cm H₂O CPAP in order to verify these
findings; to assess the effect of nocturnal CPAP on airways reactivity; to determine the
durability of the effect over 12 weeks; to assess the safety, tolerability and adherence to
this treatment; and to explore if there are clinically meaningful benefits. The study will
be conducted at 18 centers of the American Lung Association-Asthma Clinical Research Centers
(ALA-ACRC) with the Data Coordinating Center (DCC) at Johns Hopkins University.

A substudy of High Resolution Computed Tomography (HRCT) will also be conducted at a subset
of the ACRC clinics. A total of 54 subjects (18 per arm)who are randomized in the main study
will be voluntarily enrolled in the substudy to compare the structural changes in the
airways across treatment groups and to correlate structural changes with the physiological
changes. A total of two visits will be conducted. HRCT Visit 1 will be performed after
randomization in the main CPAP study, and prior to initiation of CPAP. HRCT Visit 2 will be
performed between weeks 10 and 12 of CPAP, at a different day or prior of methacholine
challenge testing.Two CT scans will be performed each at different lung volume at each visit
(Total of 4 scans for the study duration). The first volume will be at Total Lung Capacity
(TLC), followed by another CT scan at Functional Residual Capacity (FRC).

Inclusion criteria

- 15 - 60 years of age at V1

- Physician diagnosis of asthma and on prescribed asthma medication for at least the
past 12 months at V1

- Pre-bronchodilator FEV₁ greater than or equal to 75% predicted at V1 (to minimize the
likelihood that variability in FEV₁ will preclude participants from having
methacholine challenges in follow-up visits)

- Airways reactivity: Methacholine bronchial challenge with PC₂₀ less than or equal 8
mg/mL for FEV₁ at V1

- Stable asthma defined by no change in treatment, ED visit, hospitalization, or urgent
health care visit for asthma for the 8 weeks prior to screening

- Non-smoker for more than 6 months and less than or equal to 10 pack-year history of
smoking

- Ability and willingness to provide informed consent

- If receiving immunotherapy, must have had stable therapy for the 8 weeks prior to
screening

- Spend a minimum of six hours per night in bed on average

- Willingness to sleep 5 days a week on average in the same place for the next 4 months

- For women of child bearing potential; not pregnant, not lactating and agree to
practice and adequate birth control method (abstinence, combination barrier and
spermicide, or hormonal) for the duration of the study

Exclusion criteria

- Weight less than or equal to 66 lbs. (30kg) at V1

- BMI greater than or equal to 35 at V1

- Acute respiratory illness in the month prior to screening

- Systemic corticosteroid therapy during the 3 months preceding screening

- History of sleep apnea by self-report High risk of sleep apnea as assessed by
Multivariable Apnea Prediction (MAP) Index; high risk defined as probability that is
equal to or greater than 20%

- Chronic diseases (other than asthma) that in the opinion of the investigator would
interfere with participation in the trial or put the participant at risk by
participation, e.g. non-skin cancer, chronic diseases of the lung (other than
asthma), chronic heart diseases, endocrine diseases, liver, kidney or nervous system
diseases, or immunodeficiency, any pre-existing conditions that may be
contraindications to positive airway pressure including: severe bullous lung disease,
pneumothorax, pathologically low blood pressure, dehydration, cerebrospinal fluid
leak, recent cranial surgery, trauma, bypassed upper (supraglottic) airway

- Known sleep disorders that are currently under treatment by a sleep specialist

- Known intolerance to methacholine

- Absolute contraindications to methacholine that include: current use of
beta-adrenergic blocking agent, heart attack or stroke in the last 3 months,
uncontrolled hypertension, known aortic aneurysm

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

- Prior use of CPAP for any reason Homelessness, lack of telephone access, or intention
to move within the next 4 months of the trial.

- For blinding purposes, members from the same household cannot participate in the
study at the same time.