Asthma
Conditions
Keywords
Asthma, Mometasone, Tiotropium
Brief summary
Because approximately half of all mild-moderately-severe asthma is persistently non-eosinophilic, it is important to determine prospectively if patients who are persistently non-eosinophilic differ in their benefit from inhaled corticosteroid treatment compared to patients who are not persistently non-eosinophilic.
Detailed description
SIENA is a 42-week randomized, stratified, 3-period double-blind placebo-controlled crossover study of patients with symptomatic mild-to-moderate asthma, not already taking an inhaled corticosteroid, in whom the effect of medium-dose inhaled corticosteroid (ICS) will be compared with the effect of placebo and with a long-acting muscarinic antagonist (LMA).
Interventions
DRUGMometasone 220mcg BID
Mometasone is an ICS
DRUGTiotropium Respimat 5mcg QD
Tiotropium is a LMA
DRUGPlacebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Physician-diagnosed asthma for at least previous 12 months. * Able to perform reproducible spirometry. * Baseline FEV1≥70% of predicted. * Asthma confirmed either by: * Beta-agonist reversibility to 4 puffs albuterol ≥ 12% OR * Methacholine PC20 ≤ 16 mg/ml * At least 1 of the following indications for chronic controller therapy: * Asthma Symptoms \> 2 days/week OR * Nocturnal Asthma Symptoms \> 2 nights/month OR * Short-acting beta-agonist use for symptom control \> 2 days/week * For participants ≥18 years of age: Ability to provide informed consent. For participants under 18 years of age: Ability to provide verbal or written assent and ability of parent to provide informed consent. * Willingness, if female and able to conceive, to utilize one medically-acceptable form of contraception.
Exclusion criteria
* Chronic inhaled or oral corticosteroid therapy. * Use of inhaled or oral corticosteroid therapy within 6 weeks. * New allergen immunotherapy within the past 3 months or anticipated changes to an ongoing immunotherapy regimen. * Use of omalizumab within 3 months. * History of: * bladder-neck obstruction, urinary retention or benign prostatic hyperplasia * narrow angle glaucoma * significant cardiovascular disorders and arrhythmias * life-threatening asthma requiring treatment with intubation or mechanical ventilation within the past 5 years * Respiratory tract infection within past 6 weeks. * History of smoking within the past 1 year, or \> 10 pack-years total if ≥ 18 years of age, or \> 5 pack-years total if \< 18 years of age. * Chronic diseases or medical conditions (other than asthma) that could put the participant at risk by participation, e.g. chronic diseases of the lung (other than asthma), heart, liver, kidney, endocrine or nervous system, or immunodeficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | End of 12-week treatment period | This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure | End of 12-week treatment period | Treatment Failure includes: * Awakening from asthma three or more times in a two-week period or on two consecutive nights, or * Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or * Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or * Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or * exercise induces unusual breathlessness |
| Annualized Asthma Control Days | End of 12-week treatment period | Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF \< 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365. |
| Forced Expiratory Volume at One Second (FEV1) Percent of Predicted | End of 12-week treatment period | FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height. |
| Peak Expiratory Flow Rate | End of 12-week treatment period | Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways. |
| Asthma Exacerbations | End of 12-week treatment period | Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: * FEV1 \<50% of baseline on 2 consecutive measurements * FEV1 \<40% of predicted on 2 consecutive measurements * Use of ≥ 16 puffs of as needed β-agonist per 24 hours for a period of 48 hours * Use of oral/parenteral corticosteroid due to asthma |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mometasone Then Tiotropium Then Placebo Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo
Mometasone 220mcg BID: Mometasone is an ICS
Tiotropium Respimat 5mcg QD: Tiotropium is a LMA
Placebo | 49 |
| Mometasone Then Placebo Then Tiotropium Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD
Mometasone 220mcg BID: Mometasone is an ICS
Tiotropium Respimat 5mcg QD: Tiotropium is a LMA
Placebo | 48 |
| Placebo Then Mometasone Then Tiotropium Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD
Mometasone 220mcg BID: Mometasone is an ICS
Tiotropium Respimat 5mcg QD: Tiotropium is a LMA
Placebo | 50 |
| Placebo Then Tiotropium Then Mometasone Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID
Mometasone 220mcg BID: Mometasone is an ICS
Tiotropium Respimat 5mcg QD: Tiotropium is a LMA
Placebo | 51 |
| Tiotropium Then Placebo Then Mometasone Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID
Mometasone 220mcg BID: Mometasone is an ICS
Tiotropium Respimat 5mcg QD: Tiotropium is a LMA
Placebo | 47 |
| Tiotropium Then Mometasone Then Placebo Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo
Mometasone 220mcg BID: Mometasone is an ICS
Tiotropium Respimat 5mcg QD: Tiotropium is a LMA
Placebo | 50 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 2 | 3 | 2 | 3 | 4 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 6 | 6 | 4 | 5 | 8 |
Baseline characteristics
| Characteristic | Mometasone Then Placebo Then Tiotropium | Placebo Then Mometasone Then Tiotropium | Mometasone Then Tiotropium Then Placebo | Placebo Then Tiotropium Then Mometasone | Tiotropium Then Placebo Then Mometasone | Tiotropium Then Mometasone Then Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 32.6 years STANDARD_DEVIATION 13.8 | 33.2 years STANDARD_DEVIATION 13.9 | 32.3 years STANDARD_DEVIATION 15.3 | 30.0 years STANDARD_DEVIATION 14.8 | 30.8 years STANDARD_DEVIATION 12.5 | 28.2 years STANDARD_DEVIATION 12.9 | 31.2 years STANDARD_DEVIATION 13.9 |
| Asthma Control Test | 21.2 units on a scale STANDARD_DEVIATION 2.5 | 21.1 units on a scale STANDARD_DEVIATION 2.7 | 21.3 units on a scale STANDARD_DEVIATION 2.3 | 20.9 units on a scale STANDARD_DEVIATION 2.2 | 20.9 units on a scale STANDARD_DEVIATION 2.8 | 21.1 units on a scale STANDARD_DEVIATION 2.5 | 21.1 units on a scale STANDARD_DEVIATION 2.5 |
| Blood differential count - Percent eosinophils | 4.0 percentage of cells | 3.0 percentage of cells | 2.3 percentage of cells | 3.2 percentage of cells | 3.0 percentage of cells | 2.8 percentage of cells | 3.0 percentage of cells |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 6 Participants | 7 Participants | 7 Participants | 7 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 46 Participants | 43 Participants | 44 Participants | 40 Participants | 43 Participants | 260 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Forced expiratory volume at one second (FEV1) Percent of Predicted | 91.5 percentage of predicted FEV1 STANDARD_DEVIATION 11.2 | 92.0 percentage of predicted FEV1 STANDARD_DEVIATION 11.8 | 90.6 percentage of predicted FEV1 STANDARD_DEVIATION 11.5 | 93.8 percentage of predicted FEV1 STANDARD_DEVIATION 12.4 | 91.7 percentage of predicted FEV1 STANDARD_DEVIATION 13.6 | 91.6 percentage of predicted FEV1 STANDARD_DEVIATION 12.5 | 91.9 percentage of predicted FEV1 STANDARD_DEVIATION 12.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 15 Participants | 13 Participants | 16 Participants | 14 Participants | 16 Participants | 88 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 33 Participants | 34 Participants | 31 Participants | 32 Participants | 30 Participants | 192 Participants |
| Region of Enrollment United States | 48 participants | 50 participants | 49 participants | 51 participants | 47 participants | 50 participants | 295 participants |
| Sex: Female, Male Female | 30 Participants | 32 Participants | 29 Participants | 33 Participants | 27 Participants | 33 Participants | 184 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 20 Participants | 18 Participants | 20 Participants | 17 Participants | 111 Participants |
| Sputum differential count - Percent eosinophils | 0.4 percentage of cells | 0.4 percentage of cells | 0.1 percentage of cells | 0.2 percentage of cells | 0.2 percentage of cells | 0.2 percentage of cells | 0.2 percentage of cells |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 276 | 0 / 275 | 0 / 271 |
| other Total, other adverse events | 45 / 276 | 47 / 275 | 38 / 271 |
| serious Total, serious adverse events | 0 / 276 | 6 / 275 | 2 / 271 |
Outcome results
Primary
Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1.
This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response.
Time frame: End of 12-week treatment period
Population: For each pairwise comparison (mometasone vs. placebo and tiotropium vs. placebo), participants were required to complete both of the relevant treatment periods in order to be included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eosinophil Low | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Mometesone equal to placebo | 46 Participants |
| Eosinophil Low | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Placebo superior to tiotropium | 52 Participants |
| Eosinophil Low | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Tiotropium equal to placebo | 49 Participants |
| Eosinophil Low | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Mometesone superior to placebo | 74 Participants |
| Eosinophil Low | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Placebo superior to mometasone | 56 Participants |
| Eosinophil Low | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Tiotropium superior to placebo | 80 Participants |
| Eosinophil High | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Placebo superior to mometasone | 12 Participants |
| Eosinophil High | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Mometesone equal to placebo | 20 Participants |
| Eosinophil High | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Tiotropium superior to placebo | 25 Participants |
| Eosinophil High | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Mometesone superior to placebo | 35 Participants |
| Eosinophil High | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Placebo superior to tiotropium | 19 Participants |
| Eosinophil High | Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | Tiotropium equal to placebo | 18 Participants |
Comparison: The null hypothesis was that, among those participants for which either mometasone is not equal to placebo, the proportion for which mometasone is superior to placebo is equal to the proportion for which placebo is superior to mometasone. The trial was designed to provide power of 0.85 for a 0.20 difference between the proportions being compared at a significance level of 0.025.p-value: 0.14exact binomial test
Comparison: The null hypothesis was that, among those participants for which either tiotropium is not equal to placebo, the proportion for which tiotropium is superior to placebo is equal to the proportion for which placebo is superior to tiotropium. The trial was designed to provide power of 0.85 for a 0.20 difference between the proportions being compared at a significance level of 0.025.p-value: 0.029exact binomial test
Comparison: The null hypothesis was that, among those participants for which either mometasone is not equal to placebo, the proportion for which mometasone is superior to placebo is equal to the proportion for which placebo is superior to mometasone. This was an exploratory analysis and there were no power considerations.p-value: 0.001exact binomial test
Comparison: The null hypothesis was that, among those participants for which either tiotropium is not equal to placebo, the proportion for which tiotropium is superior to placebo is equal to the proportion for which placebo is superior to tiotropium. This was an exploratory analysis and there were no power considerations.p-value: 0.45exact binomial test
Secondary
Annualized Asthma Control Days
Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF \< 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365.
Time frame: End of 12-week treatment period
Population: participants who completed the treatment period with data to evaluate asthma control days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eosinophil Low | Annualized Asthma Control Days | 179 days | Standard Deviation 137 |
| Eosinophil High | Annualized Asthma Control Days | 186 days | Standard Deviation 141 |
| Tiotropium Respimat 5mcg QD | Annualized Asthma Control Days | 176 days | Standard Deviation 139 |
Secondary
Asthma Exacerbations
Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: * FEV1 \<50% of baseline on 2 consecutive measurements * FEV1 \<40% of predicted on 2 consecutive measurements * Use of ≥ 16 puffs of as needed β-agonist per 24 hours for a period of 48 hours * Use of oral/parenteral corticosteroid due to asthma
Time frame: End of 12-week treatment period
Population: participants who completed the treatment period with data to evaluate exacerbations
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eosinophil Low | Asthma Exacerbations | 1 Participants |
| Eosinophil High | Asthma Exacerbations | 3 Participants |
| Tiotropium Respimat 5mcg QD | Asthma Exacerbations | 5 Participants |
Secondary
Forced Expiratory Volume at One Second (FEV1) Percent of Predicted
FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height.
Time frame: End of 12-week treatment period
Population: participants who completed the treatment period and were able to provide FEV1 measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eosinophil Low | Forced Expiratory Volume at One Second (FEV1) Percent of Predicted | 92 percentage of predicted FEV1 | Standard Deviation 14 |
| Eosinophil High | Forced Expiratory Volume at One Second (FEV1) Percent of Predicted | 94 percentage of predicted FEV1 | Standard Deviation 13 |
| Tiotropium Respimat 5mcg QD | Forced Expiratory Volume at One Second (FEV1) Percent of Predicted | 95 percentage of predicted FEV1 | Standard Deviation 14 |
Secondary
Peak Expiratory Flow Rate
Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways.
Time frame: End of 12-week treatment period
Population: participants who completed the treatment period and were able to provide FEV1 measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eosinophil Low | Peak Expiratory Flow Rate | 476 liters per minute | Standard Deviation 117 |
| Eosinophil High | Peak Expiratory Flow Rate | 485 liters per minute | Standard Deviation 117 |
| Tiotropium Respimat 5mcg QD | Peak Expiratory Flow Rate | 497 liters per minute | Standard Deviation 117 |
Secondary
Treatment Failure
Treatment Failure includes: * Awakening from asthma three or more times in a two-week period or on two consecutive nights, or * Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or * Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or * Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or * exercise induces unusual breathlessness
Time frame: End of 12-week treatment period
Population: participants who completed the treatment period with data to evaluate treatment failure outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eosinophil Low | Treatment Failure | 29 Participants |
| Eosinophil High | Treatment Failure | 29 Participants |
| Tiotropium Respimat 5mcg QD | Treatment Failure | 35 Participants |