Asthma
Conditions
Keywords
Glucocorticosteroids, Dry Powder Inhaler, Bronchodilator, Metered-Dose Inhaler
Brief summary
This study is being conducted to demonstrate the non-inferiority between two inhaled glucocorticosteroids and long-acting bronchodilator combination drugs called mometasone furoate/formoterol fumarate in a metered-dose inhaler (MDI) and fluticasone propionate/salmeterol in a dry powder inhaler (DPI) on lung function. Information on the onset of action, the overall safety, and how the drugs control asthma will also be assessed. The study is approximately 1 year in duration.
Interventions
DRUGMometasone furoate/formoterol (MF/F) MDI
MF/F 200/10 mcg via a metered dose inhaler (MDI) twice daily for 52 weeks.
DRUGFluticasone propionate/salmeterol (F/SC) DPI
Fluticasone propionate 250 mcg and salmeterol 50 mcg fixed dose combination dry powder inhaler taken twice daily for 52 weeks.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participants must have a diagnosis of asthma for at least 12 months' duration. * A participant must have been using a medium daily dose of inhaled glucocorticosteroids (alone or in combination with long-acting beta 2-agonist \[LABA\]) for at least 12 weeks and must have been on a stable regimen for at least 2 weeks prior to Screening. * If there is no inherent harm in changing the participant's current asthma therapy, the participant must be willing to discontinue his/her prescribed inhaled glucocorticosteroid (ICS) or ICS/LABA prior to initiating MF MDI run-in medication. * The diagnosis of asthma must be documented by either demonstrating an increase in absolute forced expiratory volume in 1 second (FEV1) of at least 12% and a volume increase of at least 200 mL within approximately 15 to 20 minutes after administration of 4 inhalations of albuterol/salbutamol or of nebulized short-acting beta 2-agonist (SABA) OR peak expiratory flow (PEF) variability of more than 20% OR a diurnal variation PEF of more than 20% based on the difference between pre-bronchodilator (before taking albuterol/salbutamol) morning value and the post-bronchodilator value (after taking albuterol/salbutamol) from the evening before, expressed as a percentage of the mean daily PEF value on any day during the open-label Run-in Period. * A participant must have a history of \>= 2 asthma-related unscheduled visits to a physician or to an emergency room within the past year AND \>= 3 asthma-related unscheduled visits within the past 2 years. * Prior to randomization participants must have used a total of 12 or more inhalations of SABA rescue medication during the last 10 days of run-in. * Clinical laboratory tests (complete blood counts \[CBC\], blood chemistries, including serum pregnancy for females of child-bearing potential, and urinalysis) conducted at the Screening Visit must be within normal limits or clinically acceptable to the investigator/sponsor before the participant is instructed to start using open-label MF MDI run-in medication. * An electrocardiogram (ECG) performed at the Screening Visit, using a centralized trans-telephonic technology, must be clinically acceptable to the investigator. * A chest x-ray performed at the Screening Visit, or within 12 months prior to the Screening Visit, must be clinically acceptable to the investigator. * A non-pregnant female participant of childbearing potential must be using a medically acceptable, adequate form of birth control. A female participant of childbearing potential must have a negative serum pregnancy test at Screening in order to be considered eligible for enrollment.
Exclusion criteria
* A participant who demonstrates a change in absolute FEV1 of \> 20% at any time between the Screening and Baseline Visits on any 2 consecutive days between the Screening and Baseline visits. * A participant who requires the use of greater than 8 inhalations per day of SABA MDI or 2 or more nebulized treatments per day of 2.5 mg SABA on any 2 consecutive days between the Screening and Baseline Visits. * A participant who experiences a decrease in AM or PM PEF below the Run-in Period stability limit on any 2 consecutive days prior to randomization. The average AM and average PM PEF respective values from the preceding 7 days are added, divided by the number of non-missing values, and multiplied by 0.70 to determine the stability limit. * A participant who experiences a clinical asthma exacerbation: defined as a clinical deterioration of asthma as judged by the clinical investigator between the Screening and Baseline Visits, that results in emergency treatment, hospitalization due to asthma, or treatment with additional, excluded asthma medication (including oral or other systemic corticosteroids, but allowing SABA).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Area Under the Curve From 0 to 12 Hours [AUC](0-12 hr) of the Change From Baseline to the Week 12 Endpoint in Forced Expiratory Volume in One Second (FEV1) | Baseline to Week 12 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Onset-of-action Based on Change From Baseline FEV1 at the 5 Min Pulmonary Function Test (PFT) Assessment on Day 1 | Baseline to 5 minutes post-dose on Day 1 | PFTs, including FEV1, were done on Day 1. Evaluations included 30 min before and immediately before the first dose, the mean of which was Baseline, and at intervals from 5 min to 12 hrs postdose. Onset of action was defined as statistically significant improvement of MF/F over F/SC in Change from Baseline FEV1 at the 5-min postdose evaluation on Day 1. The same series of PFTs were done at Week 12. Change from Baseline to Week 12 evaluations were calculated using the same Day 1 predose scores for Baseline. The Week-12 evaluation consisted of AUC FEV1 scores across the 12-hour postdose interval. |
| Change From Baseline in Asthma Control Questionnaire (ACQ) Total Score at Week 12 Endpoint | Baseline to Week 12 | The Asthma Control Questionnaire (ACQ) by Juniper et al. is a mean of 7 equally weighted composite scores; each scaled from 0=best case scenario to 6=worst case scenario on an integer scale. Composites include the following: How Often Woken by Asthma, How Bad Were Asthma Symptoms When You Woke, Activity Limitations, Shortness of Breath, Wheezing, Average Daily Short-Acting Beta 2-Agonist (SABA) Puffs, and physician-evaluated lung function. With the exception of physician-evaluated lung function collected at the visit, evaluations were over the last week recall period. |
| The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Baseline to Week 12 | For each day of the evaluation period, symptoms were collected in the morning for the night's evaluation, and in the evening for the day's evaluation. Symptoms included coughing, wheezing, and difficulty breathing, each integer-scaled from 0=none to 3=severe. A symptom-free Day/Night is defined as a combined score of 0 across the morning and evening evaluations. The proportion of 0 scores across the Baseline period, and across the 12-week treatment period, is calculated to determine the overall proportion of symptom-free Days/Nights for each of these periods. |
Participant flow
Pre-assignment details
In order to standardize treatment prior to randomization, participants entered a 2- to 4-week open-label Run-in period where they received MF MDI 200 mcg BID. Participants who continued to meet eligibility criteria at the completion of the Run-in Period were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| MF/F MDI 200/10 mcg BID Mometasone furoate 200 mcg and formoterol 10 mcg (MF/F) fixed dose combination taken twice daily (BID) via a metered-dose inhaler (MDI). | 371 |
| F/SC DPI 250/50 mcg BID Fluticasone propionate/salmeterol (F/SC) 250/50 mcg Dry Powder Inhaler (DPI) BID | 351 |
| Total | 722 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative | 266 | 257 |
| Overall Study | Adverse Event | 8 | 6 |
| Overall Study | Did not meet protocol eligibility | 16 | 21 |
| Overall Study | Lack of Efficacy | 40 | 34 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Noncompliance with protocol | 13 | 7 |
| Overall Study | Withdrawal by Subject | 5 | 8 |
Baseline characteristics
| Characteristic | MF/F MDI 200/10 mcg BID | F/SC DPI 250/50 mcg BID | Total |
|---|---|---|---|
| Age, Customized 12 to <18 years | 22 participants | 18 participants | 40 participants |
| Age, Customized 18 to <65 years | 321 participants | 308 participants | 629 participants |
| Age, Customized >=65 years | 28 participants | 25 participants | 53 participants |
| Sex: Female, Male Female | 239 Participants | 220 Participants | 459 Participants |
| Sex: Female, Male Male | 132 Participants | 131 Participants | 263 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 | 43 / 983 | 85 / 371 | 77 / 351 |
| serious Total, serious adverse events | 0 / 983 | 6 / 371 | 8 / 351 |
Outcome results
Primary
The Area Under the Curve From 0 to 12 Hours [AUC](0-12 hr) of the Change From Baseline to the Week 12 Endpoint in Forced Expiratory Volume in One Second (FEV1)
Time frame: Baseline to Week 12
Population: Efficacy analyses were based on randomized subjects with Baseline and any post-baseline data (intent-to-treat principle). The standard deviation is pooled. Least Squares Mean scores are obtained from an analysis of covariance model correcting for treatment, site effects, and the Baseline FEV1 (liters) as a covariate.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MF/F MDI 200/10 mcg BID | The Area Under the Curve From 0 to 12 Hours [AUC](0-12 hr) of the Change From Baseline to the Week 12 Endpoint in Forced Expiratory Volume in One Second (FEV1) | 3.43 Liter x hour | Standard Deviation 3.83 |
| F/SC DPI 250/50 mcg BID | The Area Under the Curve From 0 to 12 Hours [AUC](0-12 hr) of the Change From Baseline to the Week 12 Endpoint in Forced Expiratory Volume in One Second (FEV1) | 3.24 Liter x hour | Standard Deviation 3.83 |
Secondary
Change From Baseline in Asthma Control Questionnaire (ACQ) Total Score at Week 12 Endpoint
The Asthma Control Questionnaire (ACQ) by Juniper et al. is a mean of 7 equally weighted composite scores; each scaled from 0=best case scenario to 6=worst case scenario on an integer scale. Composites include the following: How Often Woken by Asthma, How Bad Were Asthma Symptoms When You Woke, Activity Limitations, Shortness of Breath, Wheezing, Average Daily Short-Acting Beta 2-Agonist (SABA) Puffs, and physician-evaluated lung function. With the exception of physician-evaluated lung function collected at the visit, evaluations were over the last week recall period.
Time frame: Baseline to Week 12
Population: Efficacy analyses were based on randomized subjects with Baseline and any postbaseline data (intent-to-treat principle).~The standard deviation is pooled. Least Squares Mean scores are obtained from an analysis of covariance model correcting for treatment, site effects, and the Baseline ACQ score as a covariate.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MF/F MDI 200/10 mcg BID | Change From Baseline in Asthma Control Questionnaire (ACQ) Total Score at Week 12 Endpoint | -0.65 Scores on a scale | Standard Deviation 0.61 |
| F/SC DPI 250/50 mcg BID | Change From Baseline in Asthma Control Questionnaire (ACQ) Total Score at Week 12 Endpoint | -0.65 Scores on a scale | Standard Deviation 0.61 |
Secondary
Onset-of-action Based on Change From Baseline FEV1 at the 5 Min Pulmonary Function Test (PFT) Assessment on Day 1
PFTs, including FEV1, were done on Day 1. Evaluations included 30 min before and immediately before the first dose, the mean of which was Baseline, and at intervals from 5 min to 12 hrs postdose. Onset of action was defined as statistically significant improvement of MF/F over F/SC in Change from Baseline FEV1 at the 5-min postdose evaluation on Day 1. The same series of PFTs were done at Week 12. Change from Baseline to Week 12 evaluations were calculated using the same Day 1 predose scores for Baseline. The Week-12 evaluation consisted of AUC FEV1 scores across the 12-hour postdose interval.
Time frame: Baseline to 5 minutes post-dose on Day 1
Population: Participants with data at Day One 5 minutes post-dose.~The standard deviation is pooled. Least Squares Mean scores are obtained from an analysis of covariance model correcting for treatment, site effects, and the Baseline FEV1 (liters) as a covariate.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MF/F MDI 200/10 mcg BID | Onset-of-action Based on Change From Baseline FEV1 at the 5 Min Pulmonary Function Test (PFT) Assessment on Day 1 | 0.20 Liters | Standard Deviation 0.2 |
| F/SC DPI 250/50 mcg BID | Onset-of-action Based on Change From Baseline FEV1 at the 5 Min Pulmonary Function Test (PFT) Assessment on Day 1 | 0.09 Liters | Standard Deviation 0.2 |
Secondary
The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period.
For each day of the evaluation period, symptoms were collected in the morning for the night's evaluation, and in the evening for the day's evaluation. Symptoms included coughing, wheezing, and difficulty breathing, each integer-scaled from 0=none to 3=severe. A symptom-free Day/Night is defined as a combined score of 0 across the morning and evening evaluations. The proportion of 0 scores across the Baseline period, and across the 12-week treatment period, is calculated to determine the overall proportion of symptom-free Days/Nights for each of these periods.
Time frame: Baseline to Week 12
Population: Efficacy analyses were based on randomized subjects with Baseline and any post-baseline data (intent-to-treat principle).~The standard deviation is pooled. Least Squares Mean scores are obtained from an analysis of covariance model correcting for treatment, site effects, and the Baseline proportion of symptom-free days/nights as a covariate.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MF/F MDI 200/10 mcg BID | The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Baseline (over the last week prior to first dose) | 0.19 Proportion of symptom-free days/nights | Standard Deviation 0.28 |
| MF/F MDI 200/10 mcg BID | The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Actual proportion over the 12-wk treatment period | 0.42 Proportion of symptom-free days/nights | Standard Deviation 0.32 |
| MF/F MDI 200/10 mcg BID | The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Change from Baseline to over the 12-wk tx period | 0.24 Proportion of symptom-free days/nights | Standard Deviation 0.32 |
| F/SC DPI 250/50 mcg BID | The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Change from Baseline to over the 12-wk tx period | 0.25 Proportion of symptom-free days/nights | Standard Deviation 0.32 |
| F/SC DPI 250/50 mcg BID | The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Baseline (over the last week prior to first dose) | 0.18 Proportion of symptom-free days/nights | Standard Deviation 0.28 |
| F/SC DPI 250/50 mcg BID | The Proportion of Symptom-free Days and Nights (Combined) Over the 12-week Treatment Period. | Actual proportion over the 12-wk treatment period | 0.43 Proportion of symptom-free days/nights | Standard Deviation 0.32 |