Asthma
Conditions
Brief summary
The purpose of this study is to test the safety of DULERA. DULERA is a pressurized metered-dose inhaler (MDI) that contains two drugs combined, namely mometasone and formoterol in a single inhaler. Mometasone is an inhaled corticosteroid (ICS), which reduces the inflammation in the airways. Formoterol is a long-acting beta 2 agonist (LABA), which helps to relax the muscles of the airways in the lungs, making it easier to breathe. In combination, mometasone and formoterol are used for the treatment of asthma. This study will evaluate whether participants taking a LABA in combination with an ICS in a single inhaler have a different risk of having serious asthma events (hospitalization, intubation and death) compared to participants taking an ICS alone. The primary safety hypothesis is that the time-to-first serious asthma outcome (SAO) with mometasone furoate/formoterol (MF/F) MDI twice daily (BID) is non-inferior to that with mometasone furoate (MF) MDI BID in adolescents and adults with persistent asthma. If non-inferiority is achieved, the key secondary safety hypothesis of superiority of MF/F over MF will be assessed.
Detailed description
Amendments 2 and 3 are specific to Brazil; all other countries will enroll patients under Amendment 1.
Interventions
DRUGMometasone Furoate/Formoterol MDI 100/5 mcg
two inhalations BID
DRUGMometasone Furoate/Formoterol MDI 200/5 mcg
two inhalations BID
DRUGMometasone Furoate MDI 100 mcg
two inhalations BID
DRUGMometasone Furoate MDI 200 mcg
two inhalations BID
DRUGAlbuterol 90 mcg /salbutamol 100 mcg HFA MDI
use as needed for asthma symptoms
Oral prednisone/prednisolone used only as an emergency rescue medication at the discretion of the investigator
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Persistent asthma for at least 1-year * Must use a daily asthma controller medication for at least 4 weeks prior to randomization, including an inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA) or other adjunctive asthma therapy OR be using a leukotriene receptor antagonist (LTRA), xanthine or short acting beta agonist (SABA) as a monotherapy. * Must be able to discontinue current asthma medication * Must have a history of at least one asthma exacerbation in previous 4 to 52 weeks
Exclusion criteria
* Unstable asthma * Taking high dose ICS with or without other adjunctive therapy who have an Asthma Control Questionnaire 6 (ACQ6) total score ≥ 1.5 * Taking LTRA, xanthine or SABA monotherapy with an ACQ-6 total score \< 1.5 (controlled) * Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), or other significant, non-asthmatic, lung disease * Clinically significant abnormality, illness or disorder of any body or organ system * Significant underlying cardiovascular condition which may contraindicate use of a beta-agonist. * History of smoking greater than 10-pack years * Had an asthma exacerbation within 4 weeks of the Baseline Visit * Had more than 4 asthma exacerbations or 2 hospitalizations within 52 weeks of the randomization visit * Known or suspected hypersensitivity or intolerance to corticosteroids, beta-2 agonists, or any of the (inactive ingredients) excipients present in the medications used in this study * Require the use of chronic systemic steroids, omalizumab, or other monoclonal or polyclonal antibodies * Requires the use of beta-blockers * History of life-threatening asthma, including an asthma episode that required intubation and/or was associated with hypercapnia requiring noninvasive ventilatory support * Lactating, pregnant, or plans to become pregnant during the course of the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-First Serious Asthma Outcomes (SAO): Number of First SAO in the MF/F vs MF Arms | 26 weeks, or 7 days after the last treatment dose, whichever occurred later | The primary safety outcome was the time-to-first SAO (a composite endpoint of adjudicated asthma-related hospitalizations, adjudicated asthma-related intubations, and adjudicated asthma-related deaths). To accomplish this, the number of participants experiencing a first SAO was collected for 26 weeks following initiation of study treatment (or 7 days after the last treatment dose, whichever occurred later). Data generated by this methodology were used to compute a hazard ratio (HR) and 95% confidence interval (CI), modeling the likelihood of a first SAO occurring at any given time in the MF/F arm relative to the MF arm. Although data were sufficient to generate a HR and 95% CI, time-to-first SAO in the overall population could not be accurately reported due to insufficient SAO occurrence. Therefore, the number of first SAO in either arm is reported as a descriptive measure. For each participant, first SAO denotes first event per participant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-First Severe Asthma Exacerbation (SAEX): Number of First SAEX in the MF/F vs MF Arms | 26 weeks, plus 7 days after the last treatment | The key secondary efficacy outcome was time-to-first protocol-defined asthma exacerbation (SAEX). The SAEX were deteriorations of asthma requiring: use of systemic corticosteroids (tablets, suspension, or injection) for \>= 3 consecutive days, in-patient hospitalization \>= 24 hours, or an emergency department (ED) visit \< 24 hours that required systemic corticosteroids in the MF/F MDI BID arm versus the MF MDI BID arm. The number of first SAEX occurred from initiation of study treatment to 7 days after the last treatment (modified intention-to-treat). This outcome was measured as the HR and 95% CI for the number of first SAEX in the MF/F MDI BID arm versus the number of first SAEX in the MF MDI BID arm. Given insufficient data for SAEX events, it was not informative to report the time-to-first SAEX in the overall population. Therefore, the number of first SAEXs in either arm is reported as a descriptive measure. For each participant, first SAEX denotes first event per participant. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of SAO Components in MF/F Participants vs MF Participants | 26 weeks, or 7 days after the last treatment dose, whichever occurred later | To further examine the primary safety outcome, each adjudicated component of the SAO composite endpoint (asthma-related hospitalization, asthma-related intubation and asthma-related death), was tabulated for descriptive purposes only to show the relative contribution of each component to the SAO composite. Hospitalizations were defined as an in-patient stay of \>= 24 hour in a hospital, emergency department or equivalent healthcare facility. Intubation was defined as endotracheal intubation only. |
Participant flow
Recruitment details
11,744 participants were enrolled in the study and 11,729 participants were randomized and received at least one dose of blinded study treatment (defined as the number started). Treatments were Mometasone Furoate/Formoterol (MF/F) metered dose inhaler (MDI) twice daily (BID) and Mometasone Furoate (MF) MDI BID.
Participants by arm
| Arm | Count |
|---|---|
| Mometasone Furoate/Formoterol (MF/F) MDI BID MF/F MDI administered as two puffs of 100/5 mcg or 200/5 mcg, twice daily, with oral inhalation of a pressurized inhalation aerosol | 5,868 |
| Mometasone Furoate (MF) MDI BID MF MDI administered as two puffs of 100 mcg or 200 mcg, twice daily, with oral inhalation of a pressurized inhalation aerosol | 5,861 |
| Total | 11,729 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 4 |
| Overall Study | Invalid informed consent | 1 | 0 |
| Overall Study | Investigational site closure | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Mometasone Furoate/Formoterol (MF/F) MDI BID | Mometasone Furoate (MF) MDI BID | Total |
|---|---|---|---|
| Age, Continuous | 45.3 Years STANDARD_DEVIATION 17.19 | 44.8 Years STANDARD_DEVIATION 17.55 | 45.1 Years STANDARD_DEVIATION 17.37 |
| Sex: Female, Male Female | 3841 Participants | 3875 Participants | 7716 Participants |
| Sex: Female, Male Male | 2027 Participants | 1986 Participants | 4013 Participants |
| Treatment Covariates (MF/F or MF) and ICS Dose Level (100 or 200 mcg, per actuation) MF 200 mcg | 0 Participants | 3601 Participants | 3601 Participants |
| Treatment Covariates (MF/F or MF) and ICS Dose Level (100 or 200 mcg, per actuation) MF 400 mcg | 0 Participants | 2260 Participants | 2260 Participants |
| Treatment Covariates (MF/F or MF) and ICS Dose Level (100 or 200 mcg, per actuation) MF/F 200/10 mcg | 3604 Participants | 0 Participants | 3604 Participants |
| Treatment Covariates (MF/F or MF) and ICS Dose Level (100 or 200 mcg, per actuation) MF/F 400/10 mcg | 2264 Participants | 0 Participants | 2264 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 5,868 | 4 / 5,861 |
| other Total, other adverse events | 67 / 5,868 | 75 / 5,861 |
| serious Total, serious adverse events | 136 / 5,868 | 137 / 5,861 |
Outcome results
Primary
Time-to-First Serious Asthma Outcomes (SAO): Number of First SAO in the MF/F vs MF Arms
The primary safety outcome was the time-to-first SAO (a composite endpoint of adjudicated asthma-related hospitalizations, adjudicated asthma-related intubations, and adjudicated asthma-related deaths). To accomplish this, the number of participants experiencing a first SAO was collected for 26 weeks following initiation of study treatment (or 7 days after the last treatment dose, whichever occurred later). Data generated by this methodology were used to compute a hazard ratio (HR) and 95% confidence interval (CI), modeling the likelihood of a first SAO occurring at any given time in the MF/F arm relative to the MF arm. Although data were sufficient to generate a HR and 95% CI, time-to-first SAO in the overall population could not be accurately reported due to insufficient SAO occurrence. Therefore, the number of first SAO in either arm is reported as a descriptive measure. For each participant, first SAO denotes first event per participant.
Time frame: 26 weeks, or 7 days after the last treatment dose, whichever occurred later
Population: The analyzed population for assessment of the number of first SAO was all participants who received at least one dose of randomized treatment assignment (intention-to-treat principle).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MF/F MDI BID | Time-to-First Serious Asthma Outcomes (SAO): Number of First SAO in the MF/F vs MF Arms | 39 Serious asthma outcomes |
| MF MDI BID | Time-to-First Serious Asthma Outcomes (SAO): Number of First SAO in the MF/F vs MF Arms | 32 Serious asthma outcomes |
Comparison: Pertains only to the First SAO; pooled MF/F treatments and pooled MF treatmentsp-value: 0.41195% CI: [0.76, 1.94]Cox proportional-hazard model
Secondary
Time-to-First Severe Asthma Exacerbation (SAEX): Number of First SAEX in the MF/F vs MF Arms
The key secondary efficacy outcome was time-to-first protocol-defined asthma exacerbation (SAEX). The SAEX were deteriorations of asthma requiring: use of systemic corticosteroids (tablets, suspension, or injection) for \>= 3 consecutive days, in-patient hospitalization \>= 24 hours, or an emergency department (ED) visit \< 24 hours that required systemic corticosteroids in the MF/F MDI BID arm versus the MF MDI BID arm. The number of first SAEX occurred from initiation of study treatment to 7 days after the last treatment (modified intention-to-treat). This outcome was measured as the HR and 95% CI for the number of first SAEX in the MF/F MDI BID arm versus the number of first SAEX in the MF MDI BID arm. Given insufficient data for SAEX events, it was not informative to report the time-to-first SAEX in the overall population. Therefore, the number of first SAEXs in either arm is reported as a descriptive measure. For each participant, first SAEX denotes first event per participant.
Time frame: 26 weeks, plus 7 days after the last treatment
Population: The analyzed population for assessment of the number of first asthma exacerbations was all treated participants who received at least one dose of randomized treatment assignment (intention-to-treat principle).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MF/F MDI BID | Time-to-First Severe Asthma Exacerbation (SAEX): Number of First SAEX in the MF/F vs MF Arms | 708 Asthma exacerbations |
| MF MDI BID | Time-to-First Severe Asthma Exacerbation (SAEX): Number of First SAEX in the MF/F vs MF Arms | 779 Asthma exacerbations |
Comparison: Pertains only to the First SAEX; pooled MF/F treatments and pooled MF treatmentsp-value: 0.02195% CI: [0.8, 0.98]Cox proportional-hazard model
Other Pre-specified
Number of SAO Components in MF/F Participants vs MF Participants
To further examine the primary safety outcome, each adjudicated component of the SAO composite endpoint (asthma-related hospitalization, asthma-related intubation and asthma-related death), was tabulated for descriptive purposes only to show the relative contribution of each component to the SAO composite. Hospitalizations were defined as an in-patient stay of \>= 24 hour in a hospital, emergency department or equivalent healthcare facility. Intubation was defined as endotracheal intubation only.
Time frame: 26 weeks, or 7 days after the last treatment dose, whichever occurred later
Population: The analyzed population for tabulation of the number of SAO components was all participants who received at least one dose of randomized treatment assignment (intention-to-treat principle).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MF/F MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | First SAO | 39 SAO components |
| MF/F MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | Asthma-related hospitalizations | 39 SAO components |
| MF/F MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | Asthma-related intubations | 0 SAO components |
| MF/F MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | Asthma-related deaths | 0 SAO components |
| MF MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | Asthma-related deaths | 0 SAO components |
| MF MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | First SAO | 32 SAO components |
| MF MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | Asthma-related intubations | 0 SAO components |
| MF MDI BID | Number of SAO Components in MF/F Participants vs MF Participants | Asthma-related hospitalizations | 32 SAO components |