Asthma
Conditions
Keywords
Asthma, Step down therapy, Inhaled corticosteroids, Long-acting beta agonists, Fluticasone Salmeterol
Brief summary
This study is a 56-week, multi-center, blinded, randomized, double-masked parallel group comparative effectiveness study of approaches to stepping down therapy for patients with well-controlled asthma treated with combination ICS and LABA.
Detailed description
Current asthma guidelines recommend stepping down therapy once asthma is controlled for at least 3 months. For patients treated with inhaled corticosteroids (ICS) alone, a dose reduction of 25-50% to a minimal dose that controls disease is recommended. The optimal approach to reducing treatment in patients with asthma treated with combination inhaled corticosteroids and long-acting beta agonists (ICS/LABA) is not clear. The American Lung Association Asthma Clinical Research Center (ALAACRC) is a network of 18 asthma research centers with the goal of performing clinical trials directly relevant to clinical practice. The question of the optimal way to de-escalate therapy in patients with asthma that is well controlled on fixed dose combination ICS/LABA is a key question for practitioners caring for patients with moderate to severe persistent asthma. We propose a 56 week multi-center, prospective, randomized, three-arm parallel group comparative effectiveness study comparing three approaches to care of patients with asthma well-controlled for three months on combination ICS/LABA: reduction of ICS dose and maintenance of LABA, initial discontinuation of LABA with continuation of ICS, and continuation of stable dose ICS/LABA. Our primary goal is to perform a pragmatic study that resembles clinical practice and determine the optimal treatment strategy that results in the lowest rate of treatment failure over 48 weeks of follow-up. Additional exploratory analyses include assessing risk factors for step-down failure, and to assess the duration of time that asthma control is maintained when therapy is de-escalated.
Interventions
DRUGFluticasone/Salmeterol Diskus
Continuation of Fluticasone/Salmeterol Diskus 250/50 ug twice daily
DRUGFluticasone Diskus
Fluticasone Diskus alone 250 ug twice daily without Salmeterol
Sponsors
American Lung Association
GlaxoSmithKline
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* age 12-80 years * physician diagnosed asthma that is well-controlled on moderate dose ICS/LABA based on an Asthma Control Test (ACT) score more than or equal to 20, and the absence of unscheduled visits or use of rescue prednisone for 4 weeks prior to enrollment * pre-bronchodilator FEV1 (forced expiratory volume in 1 second) more than or equal to 70% predicted
Exclusion criteria
* chronic oral steroid therapy * hospitalization or urgent care visit within 4 weeks of the screening visit * lung disease other than asthma including COPD, bronchiectasis, sarcoidosis or other lung disease * less than 10 pack/yr of tobacco use and abstinence for at least 1 yr * history of extensive environmental tobacco exposure or occupational exposure suggestive of possible COPD (chronic obstructive pulmonary disease) per judgment of investigator * post bronchodilator FEV1 less than 70% predicted * near fatal asthma (intubation or ICU admission for asthma) within 2 yrs of enrollment * high risk of near fatal or fatal asthma * history of known premature birth less than 33 weeks or any significant level of respiratory care including prolonged oxygen administration or mechanical ventilation during the neonatal period * unstable cardiac disease (decompensated congestive heart failure, unstable angina, recent myocardial infarction, atrial fibrillation, supraventricular or ventricular tachycardia, congenital heart disease, or severe uncontrolled hypertension) * other major chronic illnesses 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 * drug allergies to any component of study drug or history of adverse reaction to short or long acting beta agonists * for women of child bearing 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure | 48 weeks | Rate of treatment failures assessed by decline in peak flow or FEV1, increased need for beta agonists, requirement for non-scheduled medical care for asthma symptoms, or prednisone taper. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Function- Change in Peak Expiratory Flow | Baseline and 48 weeks | Change in morning peak expiratory flow rate from the patients' daily diary cards, calculated at 48 weeks minus baseline (randomization) |
| Rate of Episodes of Poor Asthma Control | 48 weeks | Rate of episodes of poor asthma control (EPAC) defined by unscheduled medical care, hospitalization, use of oral corticosteroids and/or increased use of rescue medications and/or decrease of 30% or more in morning peak expiratory flow rate |
| Change in Pulmonary Function: FEV1 and FVC | Baseline and 48 weeks | Change in participant's pre-bronchodilator pulmonary function tests (FEV1 and FVC) calculated as 48 weeks minus baseline. |
| Pulmonary Function: Change in FEV1/FVC Ratio | Baseline and 48 weeks | Change in participant's FEV1/FVC ratio calculated as 48 weeks minus baseline. |
Countries
United States
Participant flow
Pre-assignment details
Enrolled participants were enrolled in an 8-week open label treatment run-in and were subsequently randomized only if their asthma remained stable (i.e. an ACT score ≥ 20 at weeks 4 & 8, no unscheduled healthcare encounters, no change in asthma medication, pre-bronchodilator FEV1 ≥ 70% predicted, and limited use of rescue beta-agonist).
Participants by arm
| Arm | Count |
|---|---|
| Stable ICS-LABA Continuation of Fluticasone/Salmeterol Diskus 250/50 ug twice daily
Fluticasone/Salmeterol Diskus: Continuation of Fluticasone/Salmeterol Diskus 250/50 ug twice daily | 151 |
| Reduced ICS/LABA Reduced dose Fluticasone/Salmeterol Diskus 100/50 ug twice daily
Fluticasone/Salmeterol Diskus: Reduced dose Fluticasone/Salmeterol Diskus 100/50 ug twice daily | 149 |
| LABA Step Off Fluticasone Diskus alone 250 ug twice daily without Salmeterol
Fluticasone Diskus: Fluticasone Diskus alone 250 ug twice daily without Salmeterol | 155 |
| Total | 455 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 11 | 18 | 20 |
Baseline characteristics
| Characteristic | Stable ICS-LABA | Reduced ICS/LABA | LABA Step Off | Total |
|---|---|---|---|---|
| Age, Continuous | 36 years | 33 years | 35 years | 35 years |
| Age, Customized <18 | 31 participants | 39 participants | 30 participants | 100 participants |
| Age, Customized >=18 | 120 participants | 110 participants | 125 participants | 355 participants |
| Age of Asthma Onset | 7 years | 7 years | 7 years | 7 years |
| Asthma characteristics Daily anti-leukotriene use | 32 participants | 30 participants | 30 participants | 92 participants |
| Asthma characteristics Daily short-acting beta agonist use | 7 participants | 12 participants | 10 participants | 29 participants |
| Asthma characteristics Hospitalized for asthma in past year | 5 participants | 3 participants | 6 participants | 14 participants |
| Asthma characteristics Oral steroids in past year | 44 participants | 36 participants | 42 participants | 122 participants |
| Asthma Control Test Score | 23 units on a scale | 23 units on a scale | 23 units on a scale | 23 units on a scale |
| Asthma Symptom Utility Index | 0.95 units on a scale | 0.94 units on a scale | 0.98 units on a scale | 0.95 units on a scale |
| Atopy (phadiatop ≥ 0.35 kUA/l) | 115 participants | 123 participants | 114 participants | 352 participants |
| Children's Health Survey for Asthma - Child Version Activity | 100 units on a scale | 100 units on a scale | 100 units on a scale | 100 units on a scale |
| Children's Health Survey for Asthma - Child Version Emotional | 93 units on a scale | 95 units on a scale | 93 units on a scale | 93 units on a scale |
| Children's Health Survey for Asthma - Child Version Physical | 93 units on a scale | 93 units on a scale | 96 units on a scale | 93 units on a scale |
| eNO (exhaled nitric oxide) | 18.5 parts per billion | 17.5 parts per billion | 16.5 parts per billion | 17.5 parts per billion |
| Euroqual EQ-5D-5L | 1.00 units on a scale | 1.00 units on a scale | 1.00 units on a scale | 1.00 units on a scale |
| Marks AQLQ | 4.0 units on a scale | 5.0 units on a scale | 4.0 units on a scale | 4.0 units on a scale |
| Other conditions, based upon self-report Allergic rhinitis | 85 participants | 73 participants | 88 participants | 246 participants |
| Other conditions, based upon self-report Allergies worsen asthma | 123 participants | 113 participants | 122 participants | 358 participants |
| Other conditions, based upon self-report Eczema | 35 participants | 28 participants | 26 participants | 89 participants |
| Other conditions, based upon self-report Food allergies | 33 participants | 40 participants | 34 participants | 107 participants |
| Other conditions, based upon self-report Sinusitis | 50 participants | 41 participants | 34 participants | 125 participants |
| Pre-bronchodilator peak flow | 420 Liters per minute | 430 Liters per minute | 430 Liters per minute | 430 Liters per minute |
| Pulmonary function measures Post-bronchodilator FEV1 | 2.88 Liters | 2.96 Liters | 2.93 Liters | 2.92 Liters |
| Pulmonary function measures Post-bronchodilator FVC | 3.59 Liters | 3.72 Liters | 3.65 Liters | 3.62 Liters |
| Pulmonary function measures Pre-bronchodilator FEV1 | 2.82 Liters | 2.86 Liters | 2.82 Liters | 2.83 Liters |
| Pulmonary function measures Pre-bronchodilator FVC | 3.54 Liters | 3.62 Liters | 3.65 Liters | 3.62 Liters |
| Pulmonary function measures, percent predicted Pre-bronchodilator FEV1 | 91 percent predicted | 91 percent predicted | 92 percent predicted | 91 percent predicted |
| Pulmonary function measures, percent predicted Pre-bronchodilator FVC | 98 percent predicted | 100 percent predicted | 98 percent predicted | 99 percent predicted |
| Pulmonary function measures, percent predicted Pre-bronchodilator peak flow | 96 percent predicted | 100 percent predicted | 98 percent predicted | 98 percent predicted |
| Race/Ethnicity, Customized Black | 52 participants | 48 participants | 51 participants | 151 participants |
| Race/Ethnicity, Customized Hispanic | 19 participants | 23 participants | 24 participants | 66 participants |
| Race/Ethnicity, Customized Other | 8 participants | 4 participants | 5 participants | 17 participants |
| Race/Ethnicity, Customized White | 72 participants | 74 participants | 75 participants | 221 participants |
| Region of Enrollment United States | 151 participants | 149 participants | 155 participants | 455 participants |
| Sex: Female, Male Female | 96 Participants | 88 Participants | 103 Participants | 287 Participants |
| Sex: Female, Male Male | 55 Participants | 61 Participants | 52 Participants | 168 Participants |
| Smoke exposure Former smoker | 23 participants | 25 participants | 14 participants | 62 participants |
| Smoke exposure Secondhand smoke home/work | 18 participants | 21 participants | 17 participants | 56 participants |
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 | 110 / 151 | 102 / 149 | 100 / 155 |
| serious Total, serious adverse events | 7 / 151 | 3 / 149 | 15 / 155 |
Outcome results
Primary
Treatment Failure
Rate of treatment failures assessed by decline in peak flow or FEV1, increased need for beta agonists, requirement for non-scheduled medical care for asthma symptoms, or prednisone taper.
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stable ICS-LABA | Treatment Failure | 38 participants |
| Reduced ICS/LABA | Treatment Failure | 39 participants |
| LABA Step Off | Treatment Failure | 45 participants |
95.3% CI: [0.69, 1.65]
Secondary
Change in Pulmonary Function: FEV1 and FVC
Change in participant's pre-bronchodilator pulmonary function tests (FEV1 and FVC) calculated as 48 weeks minus baseline.
Time frame: Baseline and 48 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stable ICS-LABA | Change in Pulmonary Function: FEV1 and FVC | Pre-bronchodilator FEV1 | -0.02 Liters |
| Stable ICS-LABA | Change in Pulmonary Function: FEV1 and FVC | Pre-bronchodilator FVC | -0.01 Liters |
| Reduced ICS/LABA | Change in Pulmonary Function: FEV1 and FVC | Pre-bronchodilator FVC | -0.04 Liters |
| Reduced ICS/LABA | Change in Pulmonary Function: FEV1 and FVC | Pre-bronchodilator FEV1 | -0.07 Liters |
| LABA Step Off | Change in Pulmonary Function: FEV1 and FVC | Pre-bronchodilator FEV1 | -0.13 Liters |
| LABA Step Off | Change in Pulmonary Function: FEV1 and FVC | Pre-bronchodilator FVC | -0.09 Liters |
Comparison: Comparing change in pre-bronchodilator FEV1p-value: 0.15Kruskal-Wallis
Comparison: Comparing change in pre-bronchodilator FEV1p-value: <0.001Kruskal-Wallis
Comparison: Comparing change in pre-bronchodilator FEV1p-value: 0.027Kruskal-Wallis
Comparison: Comparison of change in pre-bronchodilator FVCp-value: 0.4Kruskal-Wallis
Comparison: Comparison of change in pre-bronchodilator FVCp-value: 0.032Kruskal-Wallis
Comparison: Comparison of change in pre-bronchodilator FVCp-value: 0.21Kruskal-Wallis
Secondary
Pulmonary Function: Change in FEV1/FVC Ratio
Change in participant's FEV1/FVC ratio calculated as 48 weeks minus baseline.
Time frame: Baseline and 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stable ICS-LABA | Pulmonary Function: Change in FEV1/FVC Ratio | -0.002 ratio |
| Reduced ICS/LABA | Pulmonary Function: Change in FEV1/FVC Ratio | -0.009 ratio |
| LABA Step Off | Pulmonary Function: Change in FEV1/FVC Ratio | -0.02 ratio |
Comparison: Comparison of change in FEV1/FVC ratiop-value: 0.14Kruskal-Wallis
Comparison: Comparison of change in FEV1/FVC ratiop-value: <0.001Kruskal-Wallis
Comparison: Comparison of change in FEV1/FVC ratiop-value: 0.031Kruskal-Wallis
Secondary
Pulmonary Function- Change in Peak Expiratory Flow
Change in morning peak expiratory flow rate from the patients' daily diary cards, calculated at 48 weeks minus baseline (randomization)
Time frame: Baseline and 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stable ICS-LABA | Pulmonary Function- Change in Peak Expiratory Flow | -0.08 Liters per minute |
| Reduced ICS/LABA | Pulmonary Function- Change in Peak Expiratory Flow | 4.40 Liters per minute |
| LABA Step Off | Pulmonary Function- Change in Peak Expiratory Flow | -14.16 Liters per minute |
p-value: 0.43Kruskal-Wallis
p-value: 0.022Kruskal-Wallis
p-value: 0.002Kruskal-Wallis
Secondary
Rate of Episodes of Poor Asthma Control
Rate of episodes of poor asthma control (EPAC) defined by unscheduled medical care, hospitalization, use of oral corticosteroids and/or increased use of rescue medications and/or decrease of 30% or more in morning peak expiratory flow rate
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stable ICS-LABA | Rate of Episodes of Poor Asthma Control | 183 Episodes of poor asthma control |
| Reduced ICS/LABA | Rate of Episodes of Poor Asthma Control | 164 Episodes of poor asthma control |
| LABA Step Off | Rate of Episodes of Poor Asthma Control | 219 Episodes of poor asthma control |
95% CI: [0.63, 1.41]
95% CI: [0.8, 1.73]
95% CI: [0.83, 1.81]