Asthma
Conditions
Brief summary
The objectives of this trial are primarily to evaluate the efficacy and safety of BI 655066/ABBV-066 (risankizumab) as compared to placebo over a 24-week treatment period in severe asthma patients. The primary endpoint is time to first asthma worsening during the planned 24 week treatment period for active vs. placebo treated patients on top of standard of care therapy. Upon demonstration of a meaningful clinical response, another important objective is the identification of biomarkers that can be used to target patients who will likely respond to treatment with BI 655066/ABBV-066 (risankizumab).
Interventions
DRUGplacebo
Matching placebo for risankizumab
DRUGrisankizumab
Monoclonal IgG antibody
Sponsors
Boehringer Ingelheim
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Pre-bronchodilator clinic measured forced expiratory volume (FEV1) of =40% and =85% of predicted normal. 2. One year history of asthma diagnosed by a physician, and have FEV1 reversibility of =12% and an absolute change of at least 200 mL after administration of 400 µg salbutamol. 3. Must be on at least medium dose inhaled corticosteroids and at least one other asthma controller medication for at least one year. 4. Must have documented history of two or more severe asthma exacerbations in the last 12 months.
Exclusion criteria
1. Patients with a significant disease other than asthma. 2. Patients who are not able to produce sputum or sputum samples of sufficient quality. 3. Patients who had clinically relevant history of intubation for asthma exacerbation in the past year. 4. Patients diagnosed with any concurrent respiratory disease. 5. Recent history (within 6 months) of myocardial infarction or hospitalized for cardiac failure in the past year. 6. Patients who have undergone thoracotomy with pulmonary resection. 7. Patients who have undergone bronchial thermoplasty or radiotherapy procedure in the past year or have planned procedures during the study. 8. Patients taking oral corticosteroids with a total daily dose of more than 20 mg prednisone (or equivalent) in the past 6 weeks. 9. Pregnant or nursing women. 10. Women of childbearing potential that, if sexually active, is unwilling to use a highly effective method of birth control. 11. Clinically relevant acute infections or chronic infections. 12. Have received any live bacterial or live viral vaccination in the last12 weeks. 13. Have received Bacille Calmette-Guerin (BCG) vaccination in the last 12 months. 14. Have received treatment with ustekinumab (Stelara®). 15. Have received treatment with any other biologics in the last 3 months or within 6 times the half-life of the compound.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Asthma Worsening During the Planned 24 Week Treatment Period | 24 weeks | Time to first asthma worsening during the planned 24 week treatment period: Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.75 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Asthma Worsening During the Planned 24 Week Treatment Period | 24 weeks | Annualized rate of asthma worsening during the planned 24 week treatment period. Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.75 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Mean is Annualized rate. |
| Time to First Severe Asthma Exacerbation During the Planned 24 Week Treatment Period | 24 weeks | Time to first severe asthma exacerbation during the planned 24 week treatment period. Severe asthma exacerbation was defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. |
| Annualized Rate of Severe Asthma Exacerbation During the Planned 24-week Treatment Period | 24 weeks | Annualized rate of severe asthma exacerbation during the planned 24-week treatment period. Severe asthma exacerbation was defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Mean is Annualized rate. |
| Time to First Asthma Worsening During the Planned 24 Week Treatment Period According to Alternative Definition | 24 weeks | Time to first asthma worsening during the planned 24 week treatment period according to alternative definition: Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.5 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. |
| Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24 | Baseline and 24 weeks | Post-bronchodilator forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24. |
| Weekly Asthma Control Questionaire Score at Week 24 | 24 weeks | The score at week 24 is the average of the responses to the five ACQ5 questions for the week preceding the Week 24 visit. The ACQ5 asks patients to rate the severity of their asthma symptoms and the degree to which asthma affected their sleep and other daily activities. The scale for all five ACQ5 questions range from the best possible answer of 0 (No symptoms, None, Never) to the worst possible answer of 6 (very severe, unable to sleep, totally limited). The ACQ5 score can range from 0.0 (best) to 6.0 (worst). |
| Trough Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24 | Baseline and 24 weeks | Trough forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24. |
Countries
Belgium, Canada, France, Germany, Netherlands, Poland, South Korea, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This was a randomized, double-blind, placebo-controlled, parallel-group multicenter study to assess the efficacy and safety of risankizumab, an IL-23p19 monoclonal antibody, compared to placebo in patients with severe persistent asthma.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| Risankizumab Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20) | 105 |
| Placebo Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20) | 109 |
| Total | 214 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Risankizumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 54.1 Years STANDARD_DEVIATION 11.3 | 53.2 Years STANDARD_DEVIATION 11.9 | 52.3 Years STANDARD_DEVIATION 12.5 |
| Baseline 24 Hour Rescue Medication Use | 3.17 Puff STANDARD_DEVIATION 3.81 | 3.53 Puff STANDARD_DEVIATION 4.34 | 3.89 Puff STANDARD_DEVIATION 4.78 |
| Baseline First 5 questions of the Asthma Control Questionnaire (ACQ5) Score | 2.15 Unit on scale STANDARD_DEVIATION 1.15 | 2.27 Unit on scale STANDARD_DEVIATION 1.17 | 2.39 Unit on scale STANDARD_DEVIATION 1.17 |
| Baseline Morning peak expiratory flow (PEF) | 299.34 Liter/Minute (L/min) STANDARD_DEVIATION 110.5 | 304.54 Liter/Minute (L/min) STANDARD_DEVIATION 112.84 | 309.56 Liter/Minute (L/min) STANDARD_DEVIATION 115.34 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 102 Participants | 208 Participants | 106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Oral corticosteroid (OCS) use at baseline No | 90 Participants | 182 Participants | 92 Participants |
| Oral corticosteroid (OCS) use at baseline Yes | 15 Participants | 32 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 22 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 17 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 84 Participants | 172 Participants | 88 Participants |
| Sex: Female, Male Female | 69 Participants | 133 Participants | 64 Participants |
| Sex: Female, Male Male | 36 Participants | 81 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 105 | 0 / 109 |
| other Total, other adverse events | 84 / 105 | 80 / 109 |
| serious Total, serious adverse events | 14 / 105 | 21 / 109 |
Outcome results
Primary
Time to First Asthma Worsening During the Planned 24 Week Treatment Period
Time to first asthma worsening during the planned 24 week treatment period: Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.75 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Risankizumab | Time to First Asthma Worsening During the Planned 24 Week Treatment Period | 40.00 Days |
| Placebo | Time to First Asthma Worsening During the Planned 24 Week Treatment Period | 85.50 Days |
Comparison: This was analyzed by using a Cox proportional hazards model that included treatment and the stratification factor of OCS use at baseline as fixed effects.p-value: 0.025580% CI: [1.18, 1.81]Cox proportional hazards model
Secondary
Annualized Rate of Asthma Worsening During the Planned 24 Week Treatment Period
Annualized rate of asthma worsening during the planned 24 week treatment period. Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.75 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Mean is Annualized rate.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Risankizumab | Annualized Rate of Asthma Worsening During the Planned 24 Week Treatment Period | 4.8412 Events per patient year | Standard Error 0.577 |
| Placebo | Annualized Rate of Asthma Worsening During the Planned 24 Week Treatment Period | 3.2410 Events per patient year | Standard Error 0.401 |
Comparison: Annualized rate is obtained from fitting a negative binomial regression including logarithm of the exposure as an offset, treatment, and OCS use at baseline as covariate.p-value: 0.006580% CI: [1.2366, 1.8044]Negative binomial regression
Secondary
Annualized Rate of Severe Asthma Exacerbation During the Planned 24-week Treatment Period
Annualized rate of severe asthma exacerbation during the planned 24-week treatment period. Severe asthma exacerbation was defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Mean is Annualized rate.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Risankizumab | Annualized Rate of Severe Asthma Exacerbation During the Planned 24-week Treatment Period | 1.5901 Events per patient year | Standard Error 0.257 |
| Placebo | Annualized Rate of Severe Asthma Exacerbation During the Planned 24-week Treatment Period | 1.4051 Events per patient year | Standard Error 0.228 |
Comparison: Annualized rate is obtained from fitting a negative binomial regression including logarithm of the exposure as an offset, treatment, and OCS use at baseline as covariate.p-value: 0.55580% CI: [0.8652, 1.4803]Negative binomial regression
Secondary
Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24
Post-bronchodilator forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24.
Time frame: Baseline and 24 weeks
Population: FAS: All randomized patients who received at least one dose of treatment. One patient not included in the analysis due to missing baseline value and one patient not included in the analysis due to missing on-treatment data. Number of patients with either baseline or on-treatment data at the respective week and does not require having both.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Risankizumab | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24 | -0.097 Liter (L) | Standard Error 0.032 |
| Placebo | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24 | -0.030 Liter (L) | Standard Error 0.032 |
Comparison: The adjusted mean (SE) are obtained from fitting a mixed effect repeated measures (MMRM) model including treatment, OCS use at baseline, test day, treatment-by-test day interaction, baseline, and baseline-by-test day interaction as covariates patient as a random effect.p-value: 0.137780% CI: [-0.126, -0.009]Mixed Models Analysis
Secondary
Time to First Asthma Worsening During the Planned 24 Week Treatment Period According to Alternative Definition
Time to first asthma worsening during the planned 24 week treatment period according to alternative definition: Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.5 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Risankizumab | Time to First Asthma Worsening During the Planned 24 Week Treatment Period According to Alternative Definition | 20.00 Days |
| Placebo | Time to First Asthma Worsening During the Planned 24 Week Treatment Period According to Alternative Definition | 37.00 Days |
Comparison: This was analyzed by using a Cox proportional hazards model that included treatment and the stratification factor of OCS use at baseline as fixed effects.p-value: 0.013180% CI: [1.2, 1.79]Cox proportional hazards model
Secondary
Time to First Severe Asthma Exacerbation During the Planned 24 Week Treatment Period
Time to first severe asthma exacerbation during the planned 24 week treatment period. Severe asthma exacerbation was defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment. NA = not estimable due to an insufficient numbers of patient with an event
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Risankizumab | Time to First Severe Asthma Exacerbation During the Planned 24 Week Treatment Period | NA Days |
| Placebo | Time to First Severe Asthma Exacerbation During the Planned 24 Week Treatment Period | NA Days |
Comparison: Time to first event is obtained from fitting a Cox proportional-hazards model including treatment, and OCS use at baseline as covariatep-value: 0.461980% CI: [0.88, 1.57]Cox proportional hazards model
Secondary
Trough Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24
Trough forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24.
Time frame: Baseline and 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment. One patient not included in the analysis due to missing baseline value. Number of patients with either baseline or on-treatment data at the respective week and does not require having both.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Risankizumab | Trough Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24 | -0.052 Liter (L) | Standard Error 0.036 |
| Placebo | Trough Forced Expiratory Volume in 1 Second (FEV1) In-clinic Change From Baseline at Week 24 | -0.013 Liter (L) | Standard Error 0.035 |
Comparison: The adjusted mean (SE) are obtained from fitting a mixed effect repeated measures (MMRM) model including treatment, OCS use at baseline, test day, treatment-by-test day interaction, baseline, and baseline-by-test day interaction as covariates patient as a random effect.p-value: 0.442380% CI: [-0.104, 0.026]Mixed Models Analysis
Secondary
Weekly Asthma Control Questionaire Score at Week 24
The score at week 24 is the average of the responses to the five ACQ5 questions for the week preceding the Week 24 visit. The ACQ5 asks patients to rate the severity of their asthma symptoms and the degree to which asthma affected their sleep and other daily activities. The scale for all five ACQ5 questions range from the best possible answer of 0 (No symptoms, None, Never) to the worst possible answer of 6 (very severe, unable to sleep, totally limited). The ACQ5 score can range from 0.0 (best) to 6.0 (worst).
Time frame: 24 weeks
Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment. Ten patients excluded from the analysis due to missing data at week 24.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Risankizumab | Weekly Asthma Control Questionaire Score at Week 24 | 1.857 Unit on Scale | Standard Error 0.099 |
| Placebo | Weekly Asthma Control Questionaire Score at Week 24 | 1.708 Unit on Scale | Standard Error 0.099 |
Comparison: The adjusted mean (SE) are obtained from fitting an analysis of covariance (ANCOVA) model separately for each week including treatment, OCS use at baseline, and baseline as covariates. The weekly averages of daily measurements are calculated before fitting the model.p-value: 0.198580% CI: [0, 0.297]ANCOVA