Asthma
Conditions
Brief summary
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.
Detailed description
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).
Interventions
DEVICEContinuous Positive Airway Pressure device (Resmed, Swift, Mirage)
Continuous Positive Airway Pressure device (Resmed, Swift, Mirage): Participants will be randomized to one of three pre-set CPAP pressures: less than 1 cm water (H₂O), 5 cm H₂O or 10 cm H₂O. They will be instructed to use the CPAP device every night for 12 weeks. Methacholine airways reactivity will be measured at the end of these 12 weeks and again after a 2-week washout period, 14 weeks after randomization.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
American Lung Association Asthma Clinical Research Centers
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Methacholine Reactivity | 12 weeks after randomization | The primary outcome measure was the change in provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV₁) (PC20) from baseline to 12 weeks. Modified American Thoracic Society guidelines were followed for pre-bronchodilator spirometry and methacholine challenge testing using the 5 breath dosimeter technique. Up to eleven doses, each a doubling concentration of methacholine (Provocholine™), were inhaled starting at 0.03 mg/mL until a 20% or greater fall in FEV₁ occurred; the maximum dose was 32 mg/mL. Breaths each of doubling concentrations of methacholine were inhaled from a calibrated DeVilbiss™ 646 nebulizer. |
Countries
United States
Participant flow
Pre-assignment details
209 individuals were enrolled in the study. 15 of those participants were excluded from data analysis due to significant data irregularities at one clinical site
Participants by arm
| Arm | Count |
|---|---|
| CPAP Less Than 1 cm H₂O Continuous Positive Airway Pressure device (Resmed, Swift, Mirage): Participants will be randomized to one of three pre-set CPAP pressures: less than 1 cm water (H₂O), 5 cm H₂O or 10 cm H₂O. They will be instructed to use the CPAP device every night for 12 weeks. Methacholine airways reactivity will be measured at the end of these 12 weeks and again after a 2-week washout period, 14 weeks after randomization. | 66 |
| CPAP 5cm H₂O Continuous Positive Airway Pressure device (Resmed, Swift, Mirage): Participants will be randomized to one of three pre-set CPAP pressures: less than 1 cm water (H₂O), 5 cm H₂O or 10 cm H₂O. They will be instructed to use the CPAP device every night for 12 weeks. Methacholine airways reactivity will be measured at the end of these 12 weeks and again after a 2-week washout period, 14 weeks after randomization. | 69 |
| CPAP 10cm H₂O Continuous Positive Airway Pressure device (Resmed, Swift, Mirage): Participants will be randomized to one of three pre-set CPAP pressures: less than 1 cm water (H₂O), 5 cm H₂O or 10 cm H₂O. They will be instructed to use the CPAP device every night for 12 weeks. Methacholine airways reactivity will be measured at the end of these 12 weeks and again after a 2-week washout period, 14 weeks after randomization. | 59 |
| Total | 194 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Trial Period | Adverse Event | 0 | 1 | 0 |
| Trial Period | Failed to hold medication | 0 | 0 | 1 |
| Trial Period | Missed visit | 11 | 9 | 8 |
| Trial Period | Out-of-window visit | 0 | 2 | 0 |
| Trial Period | Pre-diluent FEV₁ predicted <70% | 1 | 1 | 1 |
| Trial Period | Pregnancy | 1 | 0 | 0 |
| Washout Period | Pregnancy | 1 | 0 | 0 |
| Washout Period | Protocol Violation | 0 | 1 | 0 |
| Washout Period | Safety | 2 | 5 | 0 |
Baseline characteristics
| Characteristic | CPAP Less Than 1 cm H₂O | CPAP 5cm H₂O | CPAP 10cm H₂O | Total |
|---|---|---|---|---|
| Age, Continuous | 33 years | 31 years | 25 years | 31 years |
| Asthma Control Test (ACT) Score | 21 units on a scale | 22 units on a scale | 22 units on a scale | 22 units on a scale |
| Asthma Symptom Utility Index (ASUI) Score | 0.89 units on a scale | 0.94 units on a scale | 0.92 units on a scale | 0.92 units on a scale |
| BMI | 25.8 kg/m^2 | 26.2 kg/m^2 | 24.1 kg/m^2 | 25.7 kg/m^2 |
| Daily use of anti-leukotriene | 8 participants | 9 participants | 5 participants | 22 participants |
| Daily use of combined inhaled corticosteroid/long acting beta agonist (ICS/LABA) | 18 participants | 23 participants | 13 participants | 54 participants |
| Daily use of inhaled corticosteroid (ICS) | 11 participants | 10 participants | 10 participants | 31 participants |
| FEV₁ | 2.9 L | 3.1 L | 3.0 L | 3.1 L |
| Forced vital capacity (FVC) | 3.9 L | 4.2 L | 3.9 L | 4.1 L |
| Former smoker | 12 participants | 6 participants | 5 participants | 23 participants |
| Marks Asthma Quality of Life | 9 units on a scale | 7 units on a scale | 6 units on a scale | 7 units on a scale |
| PC20 | 1.06 mg/mL | 0.96 mg/mL | 0.89 mg/mL | 0.98 mg/mL |
| Percent-predicted FEV₁ | 90.0 percent | 90.9 percent | 91.8 percent | 90.6 percent |
| Region of Enrollment United States | 66 participants | 69 participants | 59 participants | 194 participants |
| Sex: Female, Male Female | 42 Participants | 35 Participants | 36 Participants | 113 Participants |
| Sex: Female, Male Male | 24 Participants | 34 Participants | 23 Participants | 81 Participants |
| Sinonasal Questionnaire (SNQ-6) | 0.8 units on a scale | 0.8 units on a scale | 0.8 units on a scale | 0.8 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 58 | 35 / 62 | 25 / 57 |
| serious Total, serious adverse events | 1 / 66 | 1 / 69 | 0 / 59 |
Outcome results
Primary
Methacholine Reactivity
The primary outcome measure was the change in provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV₁) (PC20) from baseline to 12 weeks. Modified American Thoracic Society guidelines were followed for pre-bronchodilator spirometry and methacholine challenge testing using the 5 breath dosimeter technique. Up to eleven doses, each a doubling concentration of methacholine (Provocholine™), were inhaled starting at 0.03 mg/mL until a 20% or greater fall in FEV₁ occurred; the maximum dose was 32 mg/mL. Breaths each of doubling concentrations of methacholine were inhaled from a calibrated DeVilbiss™ 646 nebulizer.
Time frame: 12 weeks after randomization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| CPAP Less Than 1 cm H2O | Methacholine Reactivity | PC20, post-washout (14 weeks) | 1.60 mg/mL |
| CPAP Less Than 1 cm H2O | Methacholine Reactivity | PC20, 12-week | 2.13 mg/mL |
| CPAP 5cm H2O | Methacholine Reactivity | PC20, 12-week | 1.48 mg/mL |
| CPAP 5cm H2O | Methacholine Reactivity | PC20, post-washout (14 weeks) | 1.37 mg/mL |
| CPAP 10cm H2O | Methacholine Reactivity | PC20, 12-week | 1.44 mg/mL |
| CPAP 10cm H2O | Methacholine Reactivity | PC20, post-washout (14 weeks) | 1.27 mg/mL |
Comparison: Both the 5 and 10cm groups were compared to the control group, \<1cm H₂Op-value: 0.5195% CI: [0.44, 1.5]Regression, Linear
p-value: 0.5795% CI: [0.47, 1.52]Regression, Linear