Online Data Supplement Effect of CPAP on Airways Reactivity in Asthma: A Randomized Sham-Controlled Clinical Trial

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1 Online Data Supplement Effect of CPAP on Airways Reactivity in Asthma: A Randomized Sham-Controlled Clinical Trial Janet T. Holbrook, PhD, MPH, Elizabeth A. Sugar, PhD, Robert H. Brown, MD, MPH, Lea T. Drye, PhD, Charles G. Irvin, PhD, Alan R. Schwartz, MD, Robert S. Tepper, MD, PhD, Robert A. Wise, MD, Razan Z. Yasin, MHS, Michael F. Busk, MD, MPH, on behalf of the American Lung Association Airways Clinical Research Centers

2 Table of Contents Figure E1: Distribution of pre-bronchodilator percent predicated FEV 1 at baseline... 3 Figure E2: Distribution of Asthma Control (ACT) Scores at Baseline... 4 Figure E3: Distribution of Asthma Symptom Utility Index (ASUI) Scores at Baseline... 5 Figure E4: Distribution of Marks Asthma Quality of Life Scores at Baseline... 6 Table E1: Treatment adherence based on Diary Cards... 7 Table E2: Treatment adherence by response... 8 Table E3: Ratio follow-up compared to baseline PC 20 by adherence... 9 Table E4: Development of moderate or severe symptoms during follow-up Methods E2

3 Figure E1: Distribution of pre-bronchodilator percent predicated FEV1 at baseline E3

4 Figure E2: Distribution of Asthma Control (ACT) Scores at Baseline E4

5 Figure E3: Distribution of Asthma Symptom Utility Index (ASUI) Scores at Baseline E5

6 Figure E4: Distribution of Marks Asthma Quality of Life Scores at Baseline E6

7 Table E1: Treatment adherence based on Diary Cards Treatment Assignment Sham < 1cmH 2O N = 63 5cmH 2O N = 67 10cmH 2O N = 59 P- Value Hours of usage/night, median (Q1, Q3) 5.5 (2.9, 7.3) 5.5 (2.4, 6.6) 4.0 (1.8, 6.2) 0.12 Total hours of usage, median (Q1, Q3) 416 (157, 575) 420 (136, 546) 295 (99, 503) 0.23 Average daily use 4 hours/ night, N (%) 42 (67%) 45 (67%) 31 (53%) 0.17* Difference in total hours (diary card - machine run time), median (Q1, Q3) 5.0 (-28, 85) 42.5 (0, 226) 43.0 (2, 113) 0.02 Kruskal Wallis test for the distribution of total run hours by dose. *Fisher's exact test for difference in proportions. Q1 = first quartile, Q3 = third quartile E7

8 Table E2: Treatment adherence by response Total follow up Nonadherer* Adherer* % Adherer P-value Machine run time Non-responder % Responder % SD cards (not including sham) Non-responder % Responder % Diary Cards Non-responder % Responder % Follow-up in 3 days prior to 12-week visit Diary Cards Non-responder % Responder % Follow-up in 7 days prior to 12-week visit Diary Cards Non-responder % Responder % *Adherence defined as average daily use 4 hours Response defined as the difference in log PC 20 at week 12 and log PC 20 baseline > 2 P-value for difference in adherence between responders and non-responders based on Fisher Test Adhered to CPAP for 3 or 7 days prior to 12-week visit >0.99 E8

9 Table E3: Ratio follow-up compared to baseline PC20 by adherence Adherent* Non-adherent* P-Value with sham P-Value excluding sham Ratio of 12 week follow-up compared to baseline PC 20, median (Q1, Q3) Follow-up in 3 days prior to 12-week visit 2.8 (0.5, 26.3) 2.8 (0.3, 33.1) Follow-up in 7 days prior to 12-week visit 3.4 (0.5, 35.6) 2.8 (0.5, 20.0) * Adherence defined as average daily use 4 hours P-value for differences between adherent and non-adherent E9

10 Table E4: Development of moderate or severe symptoms during follow-up Cumulative Percent that Developed Symptom by 12 weeks Hazard Ratio (95% CI) P-value Symptom # at Risk* Sham <1cmH 2O Headaches % 13% 15% 5cmH 2O 10cmH 2O 5cmH 2O/ Sham 10cmH 2O/Sham 0.62 ( ) ( ) 0.55 Increased work breathing 171 6% 10% 5% 1.90 ( ) ( ) > 0.99 Acute upper respiratory tract infection % 12% 9% 0.71 ( ) ( ) 0.29 Drying of nose, mouth and/or throat % 12% 9% 1.17 ( ) ( ) 0.60 Nose irritation 174 9% 13% 11% Ear or sinus discomfort % 12% 9% 1.53 ( ) ( ) ( ) ( ) 0.56 Eye irritation 168 9% 7% 6% Congestion, runny nose, sneezing % 36% 20% 0.71 ( ) ( ) 0.96 *Individuals are excluded from the risk set if they presented with or were missing data on the symptom at randomization. In addition, sixteen individuals were excluded due to lack of FU data ( ) ( ) 0.10 Estimates of the proportion with a symptom are based upon Kaplan-Meier estimates of the survival function. The hazard ratio was computed using Cox proportional hazards models. P-values are for the comparison of the 5 or 10 cm H 2O groups to the sham group. # = Number; CI = confidence interval. Symptoms with too few events for analysis: chest pain (N = 3), chest discomfort (N = 9), nose bleeds (N = 5), bloating/gas (N= 9), skin rashes (N = 4). E10

11 Methods The study was conducted at 18 centers of the American Lung Association-Airways Clinical Research Centers Network (ALA-ACRC). All study centers received approval from their respective institutional review boards. An independent Data and Safety Monitoring Board (DSMB) was in charge of assessing the safety of study procedures, and for monitoring the overall conduct of the study. The Steering Committee of the ALA ACRC designed, oversaw and approved the study implementation. All participants provided written informed consents. Participants who were under 18 years of age at the time of screening signed assents according to the local regulatory policies. Randomization and masking: Treatment assignment was randomly allocated in a 1:1:1 ratio with stratification by clinic using a permuted block randomization scheme with concealed allocation. Randomization occurred at visit 2 after the participant met all eligibility criteria. The clinic staff completed a randomization form for each eligible participant and entered it into a web-based randomization system. Eligibility criteria were verified via computer program, which then provided a study treatment assignment number according to an encrypted table on the server; the assignment number corresponded to a specific CPAP study kit and associated supplies (e.g., mask, tubing). In order to blind study team members, we distributed the numbered CPAP devices from the DCC. As a further measure to ensure blinding, we tried to the extent possible to have clinics assign different staff to fit and train participants in the use of the CPAP device, than the staff E11

12 assigned to collect outcome data. Envelopes with treatment assignment were provided to the clinic in the case a treating physician felt it was important to know the treatment assignment. All participants were provided with a wallet card that provided information about the clinical trial and gave the contact numbers of personnel at the clinic. Study treatment Patients were provided a CPAP machine that delivered either < 1 cmh2o (sham), 5cmH2O, or 10cmH2O via a nasal mask that was fitted by a trained research coordinator. ResMed Science Center, ResMed Ltd provided CPAP devices and sham CPAP devices for the trial. CPAP was administered using the ResMed S9 CPAP devices with a heated humidifier. Devices and masks used in this study have received 510(k) clearance for commercial use by ResMed. These included S9 Elite TM and S9 Escape TM CPAP devices, and Swift TM FX, and Mirage TM FX Masks. The CPAP devices themselves were identical to the FDA 510(k) cleared commercial devices with the exception that the CPAP level was adjusted to a pre-set fixed level. For the purposes of blinding, the manufacturer removed the model names (Escape/Elite) from the units, so that both units looked identical. Displays that give information on the level of CPAP were masked by the manufacturer. Access to the device screen for adjustment of settings required additional steps which were not shared by study staff at the clinics. The sham CPAP devices were set to deliver less than 1cmH2O pressure by using a modified mask that allowed for more leak than the unmodified mask. In addition, an internal resistor disc was placed inside the swivel connector that was part of the mask. The swivel connector connects the mask to the tube, which connects to the S9 unit. Factory calibration was done to insure that all delivered CPAP devices were E12

13 within tolerance (+ or - 1cm). Thus the sham device had a similar flow rate and noise level to that of the non-sham devices. All the devices were set to have a ramp up time of 15 minutes. This allowed the pressure to increase slowly and less noticeably. Participants were instructed to use the device on a nightly basis. One common side effect of using CPAP is drying of the nose from the air flow. This was minimized by the use of air that was warmed and humidified. CPAP set-up and education At the screening visit, participants were able to see the CPAP device and wear a demo mask while the device was turned off so they get an idea of how the mask felt on the face. After confirming eligibility and randomization, the participants received standardized instructions on how to set-up and use the device and masks specifically assigned to them. They also received an instruction manual for device and mask set-up, mask and humidifier cleaning, and troubleshooting device and mask-related problems. The coordinator at each clinic demonstrated setting up the device and fitting the mask, and had each participant initiate treatment at the clinical site with them to help resolve any issues with the mask fit or device use. All coordinators working with participants on their CPAP devices were trained and received certification from the DCC on how to properly use the device, fit the masks, and resolve issues with the device or masks. Treatment compliance To reinforce adherence to study treatment, a range of mask sizes and types were provided to the participant to ensure comfortable fits. E13

14 Adherence was monitored by reviewing usage patterns recorded on the CPAP machine. Adherence was encouraged with a phone call several days after initiating treatment, a clinic visit after one week of randomization, and review of individual s adherence using recorded information about usage patterns. Coordinators were trained to troubleshoot problems with mask fitting or sino-nasal symptoms associated with CPAP. Adherence was measured based on the total run time that the machine was operating. Study schema and data collection schedule The study included 6 clinic visits and one phone call. After randomization, participants were instructed to use the device for 12 weeks, follow-up clinic visits were scheduled for weeks 1, 6, and 12, and after a 2 week washout. 2 week 12 week treatment period CPAP 10 cmh2o 2 week CPAP 5 cmh2o CPAP less than 1 cmh2o (sham) Randomize V1 V2 V3 V4 V5 V6 V7 1 day 1 wk 6 wks 12 wks 14 wks E14

15 Data collection schedule E15

16 Methacholine challenge testing Methacholine Challenge Testing: Modified ATS guidelines were followed for pre-bronchodilator spirometry and methacholine challenge testing using the 5 breath dosimeter technique [1]. Spirometry reference values were those of Hankinson et al from NHANES[2]. 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. Pre-bronchodilator spirometry and methacholine challenge testing were performed at baseline, 6 weeks, 12 weeks, and 14 weeks. Results were computed as the logarithmic interpolated concentration that causes a 20% fall (PC20). Methacholine challenge tests were carried out according to ATS and institutional guidelines at each participating clinical center by studycertified technicians. Consistency of testing was enforced by the use of identical spirometers (Koko, nspire Health, Longmont, CO.), customized testing and reporting software, dosimeters, calibrated nebulizers, and central review and certification of technicians. Other procedures: Visits also included an interval medical history, exhaled nitric oxide (FeNO) (NIOX MINO, Aerocrine, Solna, Sweden) following ATS/ERS guidelines[3], and asthma control and asthma quality of life questionnaires (see details below). At randomization (visit 2) and select follow-up visits, blood was collected (visits 6 and 7), and sleep questionnaires were administered (see E16

17 details below). Side-effects and symptoms were assessed by the questionnaire and open-ended questions at each visit. Outcome measures Rates of Episodes of Poor Asthma Control (EPAC) were defined from diary cards by one of the following: > 30% decrease in morning Peak Expiratory Flow (PEF) (from personal best) for 2 consecutive days (definite yellow zone event), addition of oral corticosteroid to treat asthma symptoms, unscheduled contact with a health care provider (ED, physician office, hospital) for asthma symptoms, increased use of bronchodilator rescue medication over baseline by 4 or more puffs of metered dose inhaler or 2 or more nebulizer treatments on one day[4]. Data Analysis: Data from one clinical site (15 patients) were excluded from the analysis because of data irregularities. A sensitivity analysis was performed using multiple imputation to impute missing PC20 values for missing values due to missed visits, visits at which staff were not able to perform methacholine challenge, and visits at which participants did not decline at the highest dose. The analyses of secondary outcomes (FEV₁, asthma diary data, asthma control, quality of life, and inflammatory biomarkers) were similar to those used for the primary outcome. GEE with a saturated mean model and an exchangeable or unstructured covariance matrix were used. The rates of episodes of poor asthma control (EPACs) were compared using negative binomial regression. Kaplan-Meier estimates of the survival function were used to estimate the cumulative proportion developing moderate or severe symptoms during follow-up, excluding E17

18 those with the symptoms at randomization. Cox proportional hazards were used to compare the hazards of developing symptoms between the treatment and sham arms. Subgroup analyses comparing the treatment effects for adherers vs non-adherers was assessed using GEE modeling with the addition of interaction terms for adherence. The data were analyzed at the Data Coordinating Center (DCC) at Johns Hopkins University. Analyses were performed using SAS (SAS/STAT User s Guide, Version 9.2, SAS, Inc, Cary NC), STATA (StataCorp. 2013, Stata Statistical Software, Release 13, College Station, TX) and R (The R Project for Statistical Computing, Version , available at: References 1. Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July Am J Respir Crit Care Med, (1): p Hankinson JL, Odencrantz JR,Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med, (1): p ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, Am. J. Respir. Crit. Care Med., (8): p American Lung Association Asthma Clinical Research C, Mastronarde JG, Anthonisen NR, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med, (15): p E18