Asthma
Conditions
Brief summary
To investigate the effectiveness and safety of BI 671800 given in the morning (AM), evening (PM) or twice daily (b.i.d.) compared too placebo as add on therapy to inhaled corticosteroid in symptomatic asthma patients.
Interventions
DRUGBI 671800
BI 671800
DRUGPlacebo
Placebo matching BI 671800
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent consistent with International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP) (ICH-GCP) 2. Three month history of reversible (12% with 200 mL) asthma according to \[Global Initiative for Asthma (GINA)\] with following spirometry at randomization:forced expiratory volume in 1 second (FEV1) 60%-85%. 3. Stable inhaled corticosteroid (ICS) dose 3 months prior to screening. 4. Diagnosis of asthma prior to 40 years. 5. Asthma Control Questionnaire (ACQ) at least 1.5 at randomization. 6. Male or female, 18 to 65 years. 7. Non-smokers or ex-smokers ( less than 10 pack year history) with negative cotinine screen. 8. Able to perform pulmonary function test (PFT).
Exclusion criteria
1. Significant diseases other than asthma or allergic rhinitis. 2. Hepatic transaminases or total bilirubin greater than 1.5 upper limit of normal (ULN). 3. Hospitalizations for asthma or asthma related intubation within 3 months. 4. Uncontrolled asthma on ICS + another controller. 5. Respiratory tract infection or exacerbation within 4 weeks. 6. FEV1 less than 40%, more than 12 puffs of short acting beta agonists (SABA) on more than two consecutive days or asthma exacerbation during the run-in period. 7. Participation in another interventional study. 8. Pregnant or nursing women. 9. Women of child bearing potential nor using appropriate methods of birth control as defined by protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Trough Forced Expiratory Volume in One Second (FEV1) Percent Predicted After 4 Weeks of Treatment | At baseline and 4 weeks | Trough FEV1 percent (%) predicted was defined as the mean of the morning and the evening FEV1 % predicted daily trough value at the end of the dosing interval. For the morning (evening) measurements, when FEV1 % predicted was available at both 25 minutes and 10 minutes prior to morning (evening) test-drug inhalation, morning (evening) trough FEV1 % predicted was the mean of these two morning (evening) pre-inhalation measurements. Trough FEV1 % predicted change from baseline after 4 weeks of treatment was defined as the change from baseline in the mean of the morning and the evening trough FEV1 % predicted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Asthma Control Questionnaire (ACQ) Mean Score After Four Weeks of Treatment | At baseline and 4 weeks | The Asthma Control Questionnaire (ACQ) consists of 6 patient self-evaluated questions and 1 by clinical staff with each question in 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of less than or equal to 0.75 indicate well-controlled asthma, scores between 0.76 and less than 1.5 indicate partly controlled asthma, and a score greater than or equal to 1.5 indicates uncontrolled asthma. |
Countries
United States
Participant flow
Recruitment details
This randomised, double-blind, placebo-controlled, cross-over study was to investigate efficacy and safety of 3×4-week treatment periods of oral BI 671800 Ethylenediamine 200 milligram (mg) twice or 400 mg once daily administered in the morning or evening, in symptomatic asthma patients on inhaled fluticasone propionate Metered Dose Inhaler.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Overall Population All of the enrolled participants that were randomized to one of the treatment sequences for 3 × 4-week treatment periods and treated with at least one dose of study drug. | 108 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Period 1 | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 1 | Met exclusion criteria | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 3 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 3 | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 3 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Population |
|---|---|
| Age, Continuous | 41.1 Years STANDARD_DEVIATION 12.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 97 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 89 Participants |
| Sex: Female, Male Female | 58 Participants |
| Sex: Female, Male Male | 50 Participants |
| Trough forced expiratory volume in one second (FEV1) percent predicted | 72.816 Percentage of predicted trough FEV1 STANDARD_DEVIATION 7.5759 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 104 | 0 / 70 | 0 / 68 | 0 / 67 |
| other Total, other adverse events | 4 / 104 | 3 / 70 | 5 / 68 | 2 / 67 |
| serious Total, serious adverse events | 0 / 104 | 0 / 70 | 0 / 68 | 0 / 67 |
Outcome results
Primary
Change From Baseline of Trough Forced Expiratory Volume in One Second (FEV1) Percent Predicted After 4 Weeks of Treatment
Trough FEV1 percent (%) predicted was defined as the mean of the morning and the evening FEV1 % predicted daily trough value at the end of the dosing interval. For the morning (evening) measurements, when FEV1 % predicted was available at both 25 minutes and 10 minutes prior to morning (evening) test-drug inhalation, morning (evening) trough FEV1 % predicted was the mean of these two morning (evening) pre-inhalation measurements. Trough FEV1 % predicted change from baseline after 4 weeks of treatment was defined as the change from baseline in the mean of the morning and the evening trough FEV1 % predicted.
Time frame: At baseline and 4 weeks
Population: Full analysis set (FAS): All patients randomized, treated with at least one dose of blinded study drug, with a baseline Forced expiratory volume in one second (FEV1) value and at least one on-treatment trough FEV1 value. The FAS is the basis for the intention-to-treat analysis. Participants with non-missing endpoint measurements were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (A) | Change From Baseline of Trough Forced Expiratory Volume in One Second (FEV1) Percent Predicted After 4 Weeks of Treatment | 0.128 Percentage of predicted trough FEV1 | Standard Error 0.536 |
| BI 671800 400mg AM QD (B) | Change From Baseline of Trough Forced Expiratory Volume in One Second (FEV1) Percent Predicted After 4 Weeks of Treatment | 0.409 Percentage of predicted trough FEV1 | Standard Error 0.612 |
| BI 671800 400mg PM QD (C) | Change From Baseline of Trough Forced Expiratory Volume in One Second (FEV1) Percent Predicted After 4 Weeks of Treatment | 0.798 Percentage of predicted trough FEV1 | Standard Error 0.626 |
| BI 671800 200mg BID (D) | Change From Baseline of Trough Forced Expiratory Volume in One Second (FEV1) Percent Predicted After 4 Weeks of Treatment | 0.211 Percentage of predicted trough FEV1 | Standard Error 0.626 |
Comparison: Restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM) with terms for baseline, treatment and period as fixed effects and patient as a random effect was used. A compound symmetry covariance structure was used.p-value: 0.447395% CI: [-1.147, 1.313]Mixed effect model
Comparison: Restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM) with terms for baseline, treatment and period as fixed effects and patient as a random effect was used. A compound symmetry covariance structure was used.p-value: 0.142695% CI: [-0.563, 1.903]Mixed effect model
Comparison: Restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM) with terms for baseline, treatment and period as fixed effects and patient as a random effect was used. A compound symmetry covariance structure was used.p-value: 0.323195% CI: [-0.924, 1.486]Mixed effect model
Secondary
Change From Baseline in Asthma Control Questionnaire (ACQ) Mean Score After Four Weeks of Treatment
The Asthma Control Questionnaire (ACQ) consists of 6 patient self-evaluated questions and 1 by clinical staff with each question in 7-point scale. The items are equally weighted and the ACQ score is the mean of 7 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of less than or equal to 0.75 indicate well-controlled asthma, scores between 0.76 and less than 1.5 indicate partly controlled asthma, and a score greater than or equal to 1.5 indicates uncontrolled asthma.
Time frame: At baseline and 4 weeks
Population: Full analysis set (FAS): All patients randomized, treated with at least one dose of blinded study drug, with a baseline Forced expiratory volume in one second (FEV1) value and at least one on-treatment trough FEV1 value. The FAS is the basis for the intention-to-treat analysis. Participants with non-missing endpoint measurements were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (A) | Change From Baseline in Asthma Control Questionnaire (ACQ) Mean Score After Four Weeks of Treatment | -0.595 Score on a scale | Standard Error 0.059 |
| BI 671800 400mg AM QD (B) | Change From Baseline in Asthma Control Questionnaire (ACQ) Mean Score After Four Weeks of Treatment | -0.688 Score on a scale | Standard Error 0.066 |
| BI 671800 400mg PM QD (C) | Change From Baseline in Asthma Control Questionnaire (ACQ) Mean Score After Four Weeks of Treatment | -0.621 Score on a scale | Standard Error 0.068 |
| BI 671800 200mg BID (D) | Change From Baseline in Asthma Control Questionnaire (ACQ) Mean Score After Four Weeks of Treatment | -0.651 Score on a scale | Standard Error 0.068 |
Comparison: Restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM) with terms for baseline, treatment and period as fixed effects and patient as a random effect was used. A autoregressive covariance structure was used.p-value: 0.187995% CI: [-0.18, 0.068]Mixed effect model
Comparison: Restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM) with terms for baseline, treatment and period as fixed effects and patient as a random effect was used. A autoregressive covariance structure was used.p-value: 0.338495% CI: [-0.151, 0.098]Mixed effect model
Comparison: Restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM) with terms for baseline, treatment and period as fixed effects and patient as a random effect was used. A autoregressive covariance structure was used.p-value: 0.06795% CI: [-0.214, 0.029]Mixed effect model