Effect of Positive Airway Pressure on Reducing Airway Reactivity in Patients With Asthma (CPAP)
Effect of Positive Airway Pressure on Reducing Airway Reactivity in Patients With Asthma (CPAP)
The CPAP trial is a 3-arm parallel design randomized sham-controlled trial. Participants are
 randomly assigned in equal allocation to one of three treatments: CPAP 10 cm water (H₂O)
 (high) vs. CPAP 5 cm H₂O (medium) vs. CPAP Sham (less than 1 cm H₂O, Low). The treatment
 period is 12 weeks with airways reactivity assessed at baseline, 6 and 12 weeks of treatment
 and after a 2 week washout.
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 forced expiratory volume in 1 second (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 concentration of
 methacholine causing a 20% fall in forced expiratory volume in 1 second (PC ₂₀) less
 than or equal to 8 mg/mL at V1

 -  Stable asthma defined by no change in treatment, emergency department (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.