Supplementary Appendix: Step-Down Therapy for Asthma Well- Controlled on Inhaled Corticosteroid and Long-Acting Beta-Agonist: A Randomized Clinical Trial 1
Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: The American Lung Association Airways Clinical Research Centers. Step-Down Therapy for Asthma Well- Controlled on Inhaled Corticosteroid and Long-Acting Beta-Agonist: A Randomized Clinical Trial
Contents
- Members of the American Lung Association Airways Clinical Research Centers
- Eligibility Criteria
- Data Collection Schedule
- Spirometry outcomes by treatment group
- Secondary Outcomes by Treatment Group
- Treatment Emergent Adverse Effects by Treatment Group
American Lung Association Airways Clinical Research Centers
Supplementary Appendix: Step-Down Therapy for Asthma Well- Controlled on Inhaled Corticosteroid and Long-Acting Beta-Agonist: A Randomized Clinical Trial 1
Members of the American Lung Association Airways Clinical Research Centers
Baylor College of Medicine, Houston: Nicola Hanania, MD, FCCP (principal investigator), Marianna Sockrider, MD, Dr PH (co-principal investigator), Harold Farber, MD, Amit Parulekar, MD (co-investigators), Laura Bertrand, RN, RPFT (principal clinic coordinator),Mustafa Atik, MD (coordinator)
Columbia University–New York University Consortium, New York: Joan Reibman, MD (principal investigator), Emily DiMango, MD, Linda Rogers, MD (co-principal investigators), Karen Carapetyan, MA (principal clinic coordinator at New York University), Kristina Rivera, MPH, Melissa Scheuerman, BSc (clinic coordinators at Columbia University)
Former members:Elizabeth Fiorino, MD, Newel Bryce-Robinson
Duke University Medical Center, Durham, N.C.:Loretta G. Que, MD (principal investigator), Deanna Green, MD, (co-principal investigator), Robert Noveck, MD, PhD, Ankoor Shah, MD (co-investigators), Catherine Foss, BS, RRT, CCRC, (principal clinic coordinator)Jessica Ghidorzi (regulatory coordinator), Zongyao Wang, MB, MHS, RAC, CCRC, Stephanie Allen, Sabrena Mervin-Blake, MS, Elise Pangborn, BS,
V. Susan Robertson, BSN, Nicholas Eberlein, BA (coordinators)
Former members: Michael Land, MD, Brian Vickery, MD, Eveline Wu, MD, Denise Jaggers, RN
Hofstra-NSLIJ School of Medicine, Jay & Beth Thalheim Asthma Center, New Hyde Park, N.Y.:Arunabh Talwar, MD (principal investigator), MariaTeresa Santiago, MD, Kalliope Tsirilakis, MD (co-principal investigators), RamonaS. Ramdeo, MSN, FNP-C, RN, RT (principal clinic coordinator), Natalie Rajcooar, BA (coordinator, data entry operator), Maureen Dreyfus (data entry operator)
Former members: Rubin I. Cohen, MD
Illinois Consortium, Chicago: Lewis Smith, MD (principal investigator), James Moy, MD, Edward Naureckas, MD, Mary Nevin, MD (co-principal investigators), Christopher D. Codispoti, MD, Ravi Kalhan, MD (sub-investigators), Jenny Hixon, BS, CCRC (principal clinic coordinator), Abbi Brees, BA, CCRC, Zenobia Gonsalves, Virginia Zagaja, Jennifer Kustwin, Ben Xu, BS, CCRC, Thomas Matthews, MPH, RRT, Lucius Robinson III, Noopur Singh, Jun Fu, PhD, CRC (coordinators), Benjamin Thompson, BA (regulatory specialist)
Louisiana State University Health Sciences Center-New Orleans, Section of Pulmonary & Critical Care/Allergy & Immunology: Kyle I. Happel, MD (principal investigator), Richard S. Tejedor, MD (co-principal investigator), Marie C. Sandi, FNP-BC (principal clinic coordinator), Connie B. Romaine, NP-C (coordinator), Olivia L. Eusea, Jennifer M. Graham (data system operators)
Former members: Arlene A. Antoine, Callan J. Burzynski
Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College: Allen J. Dozor, MD (principal investigator), Sankaran Krishnan, MD, MPH, Joseph Boyer, MD (co-investigators); Agnes Banquet, MD, Elizabeth de la Riva-Velasco, MD, Diana Lowenthal, MD, Suzette Gjonaj, MD, Cathy Kim, MD, Nadav Traeger, MD, John Welter, MD, Marilyn Scharbach, MD, Subhadra Siegel, MD (study physicians); Meighan M. Gallagher (research manager), LaToya Holness (lead clinic coordinator), Julia Arena (clinic coordinator and laboratory technician)
Former members: Lisa Monchil, RRT, CCRC, Ingrid Gherson, MPH, Aliza Goldstein
National Jewish Health, Denver: Rohit Katial, MD (principal investigator), Flavia Hoyte, MD, Trisha Larson (principal clinic coordinator), Maria Rojas, Holly Currier, RN (coordinators)
Former members:Nina Phillips
Nemours Children’s Clinic–University of Florida Consortium, Jacksonville: Kathryn Blake, PharmD (principal investigator), John Lima, PharmD, Jason Lang, MD, (co-principal investigators), Nancy Archer, RN, BSN (principal clinic coordinator), Edward Mougey, PhD (co-investigator), Angie Price, RN, BSN (coordinator)
Former members: Sandra Budd, BS (coordinator)
The Ohio State University Medical Center/Columbus Children’s Hospital, Columbus: John Mastronarde, MD (principal investigator), Jonathan Parsons, MD (co-investigator), Janice Drake, CCRC (principal clinic coordinator), Joseph Santiago, BS, RRT, CCRC, Rachael Compton, CCRC (coordinators), Samantha Arrowsmith, Sean Stein (data entry operators)
St. Louis Asthma Clinical Research Center: Washington University, St. Louis:Mario Castro, MD, MPH (principal investigator), Leonard Bacharier, MD, Kaharu Sumino, MD (co-principal investigators); Jaime J. Tarsi, RN, MPH (principal clinic coordinator), Brenda Patterson, MSN, RN, FNP (coordinator); Terri Montgomery (data entry operator)
St. Vincent Hospital and Health Care Center, Inc, Indianapolis: Michael Busk, MD, MPH (principal investigator), Debra Weiss (principal clinic coordinator)
Former members: Kimberly Sundblad
Vermont Lung Center at the University of Vermont, Colchester, Vt.: Charles Irvin, PhD (principal investigator), Anne E. Dixon, MD, David A. Kaminsky, MD, Thomas Lahiri, MD (co-principal investigators), Stephanie M. Burns(principalclinic coordinator)
University of Arizona, Tucson: Lynn B. Gerald, PhD, MSPH (principal investigator), James L. Goodwin, PhD, Mark A. Brown, MD, Kenneth S. Knox, MD (co-principal investigators), Tara F. Carr, MD, Cristine E. Berry, MD, MHS, WayneJ. Morgan, MD, Cori L. Daines, MD, Roni Grad, MD, Dima Ezmigna, MBBS, Anunya Hiranratana, MD, Mohammad Alzoubaidi, MD, Janet M. Campion, MD, Wendy Hsu, MD, Afshin R. Sam, MD, Tauseef Afaq, MD, Josh Malo, MD, Candy Wong, MD, Nathaniel Reyes, MD (study physicians), Elizabeth A. Ryan, BS, RRT (principal clinic coordinator), MonicaM. Vasquez, MPH, MEd , Jesus A. Wences, BS, Silvia S. Lopez, RN, Janette Priefert, Valerie R. Bloss, BS (coordinators), Natalie S. Provencio-Dean, Clara S. Ehrman, BS, BSHS, Destinee R. Ogas (data system operators)
Former members: Monica T. Varela, LPN, Rosemary J. Weese, RN,Martha Preciado, BA, Katherine Chee, Andrea Paco, BS, Patricia M. Ore Degnan, RN
University of California, San Diego:Stephen Wasserman, MD (principal investigator), Joe Ramsdell, MD, Xavier Soler, MD, PhD (co-principal investigators), Katie Kinninger,RCP (principal clinic coordinator),Paul Ferguson, MS, Amber Martineau (coordinators)
Former members: Tonya Greene, Samang Ung
University of Miami, Miami–University of South Florida, Tampa: Adam Wanner, MD (principal investigator, Miami), RichardF. Lockey, MD, (principal investigator, Tampa), Andreas Schmid, MD, Michael Campos, MD (co-principal investigators, Miami), Monroe King, DO (co-principal investigator, Tampa), Eliana S. Mendes, MD (principal clinic coordinator, Miami), Catherine Renee Smith (principal clinic coordinator, Tampa), Jeaneen Ahmad, Patricia D Rebolledo, Johana Arana, Lilian Cadet, Rebecca McCrery, Sarah M Croker, BA (coordinators)
University of Missouri, Kansas City School of Medicine, Kansas City: GaryA. Salzman, MD (principal investigator), Chitra Dinakar, MD, Asem Abdeljalil, MD, Abid M. Bhat, MD, Ashraf Gohar, MD (co-principal investigators), Patti S. Haney, BSN, CCRC (principal clinic coordinator), Mary R. Reed, RN, BSN, CCRC, Donna Horner, SrLPN, CCRC, Susan Flack, RN, CCRC (coordinators)
University of Virginia, Charlottesville: W. Gerald Teague, MD (principal investigator), Larry Borish, MD (co-principal investigator), Kristin W Wavell, BS, CCRC (principal clinic coordinator), Theresa A. Altherr, BA, CIP (coordinator)
Former members: Donna Wolf, PhD, Denise Thompson-Batt, RRT, CRP
Chairman’s Office University of Alabama, Birmingham: William C. Bailey, MD
Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, Baltimore: Robert Wise, MD (center director), Janet Holbrook, PhD, MPH (deputy director), Joy Saams, RN (principal coordinator), Debra Amend-Libercci, Marie Daniel, RN,AndreaLears, BS, Jill Meinert, Deborah Nowakowski, David Shade, JD, Elizabeth Sugar, PhD,April Thurman
Former members:Ellen Brown, MS, Gwen Leatherman, BSN, MS, RN, Weijiang Shen, MHS, Lucy Wang, BS, Christine Wei, MS, Razan Yasin, MHS
Data and Safety Monitoring Board:Vernon M. Chinchilli, MD (chair), Paul N. Lanken, MD, Donald P. Tashkin, MD.
Project Office, American Lung Association, New York: Elizabeth Lancet, MPH (project officer), NormanH. Edelman, MD (scientific consultant), Susan Rappaport, MPH, Alexandra Sierra, MA. The sponsor had a role in the management and review of the study.
Eligibility Criteria
The goal is to enroll participants whose asthma is well controlled on a moderate dose of combination ICS and LABA therapy. Well controlled will be determined by Asthma Control Test Scores, history of asthma symptoms, and medication as well as lung function.
Inclusion criteria for open label stable phase
Gender and age:
- Males and females, age 12 years or older
Asthma:
- Physician diagnosed asthma that is well controlled:
- On fixed, moderate dose, combination ICS/LABA
Fluticasone/Salmeterol Diskus – 250/50 mcg, 1 puff 2x daily
Fluticasone/Salmeterol HFA – 115/21 mcg, 2 puffs 2x daily
Budesonide/Formoterol – 160/4.5 mcg, 2 puffs 2x daily
Mometasone/Formoterol – 100/5 mcg, 2 puffs 2x daily or 200/5mcg, 1 puff 2x daily
Or a combination of moderate dose ICS + long-acting beta agonist:
▪Moderate dose ICS (total daily dose)
○Fluticasone HFA – >264 mcg to 480 mcg/day
○Fluticasone Diskus – >300 mcg to 500 mcg/day
○Mometasone – 400 mcg/day
○Beclamethasone – >240 mcg to 480 mcg/day
○Ciclesonide – 320 mcg/day
○Budesonide – >600 mcg to 1200 mcg/day
plus:
▪Long-acting beta agonist
○Salmeterol Diskus – 50 mcg every 12 hours
○Formoterol – 12 mcg every 12 hours
- Asthma Control Test (ACT) score greater than or equal to 20
- In the 9 months prior to enrollment, no more than one hospitalization for asthma
- In the 4 weeks prior to enrollment:
No unscheduled doctor/ED/hospital visits for asthma
No use of rescue prednisone (oral or IV)
- Pre-BD FEV1 greater than or equal to 70% predicted
Pregnancy
- Females of childbearing potential: not pregnant, not lactating and agree to practice an adequate birth control method (abstinence, combination barrier and spermicide, or hormonal) for the duration of the study
Smoking
- Less than 10 pack-year history of tobacco use
and:
- Abstinence from smoking for more than 1 year
Exclusion criteria for open label stable phase
Poor asthma control:
- Near fatal asthma (intubation or ICU admission for asthma) within 2 years of enrollment
- High risk of near fatal or fatal asthma as defined by one or more of the following criteria:
More than 2 hospitalizations for asthma in the previous year
More than 3 ED visits for asthma in previous year
Hospitalization for asthma in past month
Use of more than 2 canisters of inhaled short-acting beta2-agonist in past month
- Hospitalization or urgent care visit within 4 weeks of the screening visit
Smoking:
- History of extensive environmental tobacco exposure or occupational exposure suggestive of possible COPD per judgment of investigator
Other major chronic illnesses:
- Conditions which in the judgment of the study physician would interfere with participation in the study e.g. including but not limited to uncontrolled diabetes, uncontrolled HIV infection or other immune system disorder, hyperthyroidism, seizure disorders, renal failure, liver disease, non–skin cancer, unstable psychiatric illness
- Recent active substance abuse (in past 6 months)
- Lung disease other than asthma including COPD, bronchiectasis, sarcoidosis or other lung disease
- History of known premature birth less than 33 weeks or any significant level of respiratory care including prolonged O2 administration or mechanical ventilation during the neonatal period
- Unstable cardiac disease (decompensated CHF, unstable angina, recent MI, atrial fibrillation, supraventricular or ventricular tachycardia, congenital heart disease, or severe uncontrolled hypertension)
Medication use:
- Chronic oral steroid therapy
- Xolair (Omalizumab) therapy in the previous 6 months
- Tiotropium (Spiriva)
“Drug” allergy:
- Drug allergies to any component of study drug or history of adverse reaction to short or long acting beta agonists
Participation in clinical trial:
- Participation in another clinical trial within the past 30 days
Eligibility for randomization
Inclusion criteria for randomization:
- Continues to meet all eligibility criteria for enrollment
- Successful completion of the fluticasone/salmeterol stable phase:
No unscheduled visits, no ED visits, and no hospitalizations for asthma
No change in asthma medication for entire 8 week stable phase period
Rescue beta-agonist use less than 16 puffs per week (excluding use as a pre-medication for exercise) and not to exceed more than 10 puffs per day on 2 consecutive days. One nebulizer use is equivalent to 2 puffs of beta-agonist.
ACT score greater than or equal to 20 at V1, V2 and V3
Pre-BD FEV1 greater than or equal to 70% predicted
- Demonstrated adherence:
Completed at least 10 days of the last 14 days of diary card entries
Received treatment with Fluticasone/Salmeterol 250/50 for at least 21 days of the last 28 days (treatment = at least one dose for the day)
Data Collection Schedule
Visit / V1 / V2 / V3* / V4** / V5 / V6 / V7 / V8 / V9 / V10 / V11 / V12Time Window (weeks) / -10 to -6 / -6 to -2 / *** / 3-9 / 9-15 / 15-21 / 21-27 / 27-33 / 33-39 / 39-45 / 45-51
Target (week) / -8 / -4 / 0 / 3 / 6 / 12 / 18 / 24 / 30 / 36 / 42 / 48
Consent / •
Eligibility evaluation / • / •
Randomization / •
ACT / • / • / • / • / • / • / • / • / • / • / • / •
ASUI / • / • / • / • / • / • / • / • / • / •
Marks AQLQ (adult) or CHSA-Child / • / • / • / • / • / • / • / • / • / •
FQ / •
EQ-5D / • / • / • / • / • / •
Pregnancy test / • / •
Blood (DNA, allergy) / •
Vital signs / • / • / • / •
Physical Exam / • / • / • / •
Baseline/Interval asthma/medical history / • / • / • / • / • / • / • / • / • / • / • / •
AE screen / • / • / • / • / • / • / • / • / • / • / •
eNO / • / • / • / • / • / • / • / • / • / • / • / •
Spirometry –
Pre- and Post-BD / • / • / • / • / • / • / • / • / • / • / •
Treatment distribution / • / • / • / • / • / • / • / • / • / •
Adherence counseling / • / • / • / • / • / • / • / • / • / • / •
Diary/PEF/AAP / • / • / • / • / • / • / • / • / • / •
Return diary / • / • / • / • / • / • / • / • / • / •
* Randomization
** Phone visit
*** Conducted between V3 and V5
Minimum of one week required between each visit after V3
(AAP) LASST Asthma Action Plan
(ACT) Asthma Control Test
(ASUI) Asthma Symptom Utility Index
(BD) Bronchodilator
(CHSA) Children’s Health Survey for Asthma-Child version
(EQ-5D) EQ-5D 5 level / (eNO) Exhaled Nitric Oxide
(FQ) Asthma in Females Questionnaire
(Marks AQLQ) Marks Asthma Quality of Life Questionnaire
(PEF) Peak Expiratory Flow
(V#) Visit number
Spirometry outcomes by treatment group
Supplemental Figure 1. Comparison of the change in post-bronchodilator pulmonary function from randomization to 48 weeks by treatment group.
Supplemental Table 1 Spirometry Outcomes by Treatment Group. Change from randomization (RZ) to 48 week follow-up visit
Secondary Outcomes by Treatment Group
Supplemental Table 2. Model-based estimates of mean change from baseline to 48 weeks for asthma scores, quality of life and laboratory markers by treatment group.
Outcomes / Secondary OutcomesEstimated Δ from
RZ to 48 weeks
(Standard Error)* / Treatment Comparisons:
Difference in Δ from
RZ to 48 weeks
(95% Confidence Interval)*
Stable
-
ICS/
LABA / Reduced-
ICS/
LABA / LABA
-
step-off / Reduced ICS/LABA
-
Stable
ICS/LABA / LABA-
step-off
-
Stable ICS/LABA / LABA-
step-off
-
Reduced ICS/LABA
Questionnaires
Asthma Control Test Score (↑)(range: 5 to 25) / -0.23 (0.17) / 0.06 (0.22) / -0.38 (0.23) / 0.29
(-0.27, 0.84) / -0.14
(-0.71, 0.42) / -0.43
(-1.05, 0.19)
Asthma Symptom Utility Index (↑)(range: 0 to 1) / -0.004
(0.01) / 0.002
(0.01) / -0.02
(0.01) / 0.01
(-0.02, 0.03) / -0.02
(-0.05, 0.01) / -0.02
(-0.05, 0.01)
EQ-5D-5L
(↑)(range: -0.109 to 1) / -0.001
(0.007) / -0.003
(0.007) / 0.0001
(0.010) / -0.002
(-0.023, 0.019) / 0.001
(-0.023, 0.026) / 0.003
(-0.021, 0.028)
Mark’s AQLQ: age 18†
(↓)(range: 0-80) / 0.35
(0.51) / 0.47
(0.78) / 1.89
(0.85) / 0.12
(-1.72, 1.96) / 1.54
(-0.41, 3.49) / 1.42
(-0.85, 3.69)
CHSA: ages 12-17†
(↑)(range: 0 to 100)
Physical health / 0.76
(1.41) / 3.96
(1.47) / 1.85
(1.64) / 3.21
(-0.79, 7.20) / 1.10
(-3.15, 5.34) / -2.11
(-6.43, 2.21)
Child activities / 0.22
(1.60) / 1.68
(1.09) / -2.50
(1.59) / 1.46
(-2.34, 5.26) / -2.72
(-7.15, 1.71) / -4.18‡
(-7.97, -0.40)
Emotional health / 2.13
(2.35) / 0.71
(1.35) / 1.24
(0.90) / -1.43
(-6.73, 3.88) / -0.90
(-5.83, 4.03) / 0.53
(-2.65, 3.70)
Laboratory Measurement
FeNO (ppb) / 3.52
(1.52) / 4.38
(1.47) / 6.16
(1.88) / 0.86
(-3.28, 5.00) / 2.64
(-2.11, 7.39) / 1.78
(-2.91, 6.46)
* Parameter estimates are calculated using generalized estimating equations with robust standard errors. The models use a saturated mean structure and a variety of covariance structures (unstructured: ACT;Toeplitz: ASUI, EQ-5D-5L, Mark’s, CHSA physical health; exchangeable: CHSA child activities and emotional health, FeNO).
† Age is based upon the age of enrollment as opposed to randomization.
‡ p = 0.030.
↑ = Higher values indicate less severe disease. ↓ Lower values indicate less severe disease.
Δ = change; AQLQ = Asthma Quality of Life Questionnaire; CHSA = Children’s Health Survey for Asthma; EQ-5D-5L = Euroqual questionnaire; FeNO = Exhaled Nitric Oxide.
Minimal Clinically Important Difference: ACT = 3.0, ASUI = 0.09, EQ5D = 0.074, Marks AQLQ = 3.3-7.3, CHSA = not known, FeNO = not known
Treatment Emergent Adverse Effects by Treatment Group
Supplemental Table 2: Treatment emergent moderate or severe symptoms by treatment groups
Symptoms* / Number at Risk† / Cumulative Proportion at 48 weeks§Stable-ICS/LABA / Reduced-ICS/LABA / LABA-step-off
Skin bruising / 441 / 9% / 6% / 7%
Upper respiratory infection / 433 / 34% / 26% / 35%
Sore throat / 435 / 20% / 28% / 26%
Hoarseness / 432 / 21% / 26% / 16%‡
Chest pain / 444 / 8% / 12% / 13%
Cough / 423 / 40% / 44% / 45%
Musculoskeletal pain / 420 / 26% / 20% / 20%
Headache / 414 / 29% / 22% / 31%
Increased/irregular heartbeat / 446 / 4% / 0.7% / 4%
Restlessness or nervousness / 444 / 13% / 11% / 9%
Runny nose/congestion / 383 / 49% / 46% / 46%
Nausea/vomiting / 445 / 12% / 13% / 8%
* Only symptoms with 10 or more events are summarized. Seven individuals experienced moderate or severe tremors and thrush during follow-up.
† Individuals were at risk if they did not have moderate or severe symptoms at randomization and had follow-up available.
§ The cumulative proportion is estimated using Kaplan-Meier techniques to account for variable follow-up.
‡ The LABA-step-off group had significantly fewer individuals develop moderate or severe hoarseness as compared to the reduced-ICS/LABA group (HR: 0.54, P = 0.027). All other differences were not statistically significant.
American Lung Association Airways Clinical Research Centers