Asthma
Conditions
Keywords
Asthma, fluticasone, salmeterol, CRC749, Diskus, Advair, FEV1, MGR001
Brief summary
The purpose of this study is to determine whether MGR001 is equivalent to Advair Diskus when administered by inhalation in adult asthma patients
Interventions
DRUGMGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate)
Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device
DRUGAdvair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate)
Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device
DRUGPlacebo
Placebo administered via the CRC749 and Diskus devices
Sponsors
Mylan Pharma UK Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria include: * Male or female subjects aged ≥18 years. Females may be of either childbearing or non-childbearing potential * Physician diagnosed history of asthma for at least 12 weeks prior to screening * pre-bronchodilator FEV1 60-85% at screening and other specified visits * Post-bronchodilator reversibility \>/=12% * Non-smokers and prior smokers with no history of smoking within the past 12 months prior to screening and a total smoking history of ≤10 pack-years * Subjects able to discontinue asthma medications for the duration of the study and be maintained using albuterol as required * Body mass index between 18-40 kg/m2 inclusive Key
Exclusion criteria
include: * Presence or recent history of any other active, severe, progressive, and/or uncontrolled clinical disease, eg, poorly controlled Type 1 or 2 diabetes, seizure disorder or epilepsy, cerebrovascular accident, significant cardiac conduction abnormalities * Respiratory conditions other than asthma and allergic rhinitis, including but not limited to: severe nasal polyposis or chronic rhinosinusitis, chronic obstructive pulmonary disease, bronchiectasis, Churg-Strauss Disease, lung resection, pulmonary fibrosis (primary or secondary), pulmonary hypertension, cystic fibrosis, sarcoidosis * History of life-threatening asthma, defined as a history of asthma episode(s) requiring intubation, and/or associated with hypercapnia; respiratory arrest or hypoxic seizures, asthma related syncopal episode(s) * In patient hospitalization (not including ER visits) for an asthma exacerbation within the past year or during the run in period * An asthma exacerbation requiring change in asthma therapy or oral/IV corticosteroids in the 3 months prior to screening * History of seasonally unstable asthma where the season will coincide with the subject's participation in the study * Use of prescription or non-prescription drugs, including beta blockers, tricyclic antidepressants, oral decongestants, benzodiazepines, digitalis, phenothiazines, monoamine oxidase inhibitors, etc * Suspected hypersensitivity to the study drugs (including lactose) or severe milk protein allergy * Clinically significant abnormalities in the screening ECG * Evidence of alcohol or drug abuse or dependency within 6 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity) | 0-12 hours after dosing on Day 1 | The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo |
| Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence) | 0-12 hours after dosing on Day 1 | The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures |
| FEV1 Trough Value (Assay Sensitivity) | Day 1 and Day 29 | Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of \[prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1\]. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo. |
| FEV1 Trough Value (Bioequivalence) | Day 1 and Day 29 | Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of \[prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1\] |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MGR001 MGR001 administered two times per day by inhalation throughout the study
MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device | 512 |
| Advair Diskus Advair Diskus administered two times per day by inhalation throughout the study
Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device | 512 |
| Placebo Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study
Placebo: Placebo administered via the CRC749 and Diskus devices | 103 |
| Total | 1,127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 | 4 |
| Overall Study | Lost to Follow-up | 3 | 5 | 1 |
| Overall Study | Randomized in error (not treated) | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 3 | 0 |
Baseline characteristics
| Characteristic | MGR001 | Advair Diskus | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 14.08 | 42.5 years STANDARD_DEVIATION 14.21 | 43.5 years STANDARD_DEVIATION 13.85 | 42.6 years STANDARD_DEVIATION 14.11 |
| Body Mass Index (BMI) | 29.38 kg/m^2 STANDARD_DEVIATION 6.026 | 29.12 kg/m^2 STANDARD_DEVIATION 5.886 | 29.37 kg/m^2 STANDARD_DEVIATION 5.89 | 29.26 kg/m^2 STANDARD_DEVIATION 5.947 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 102 Participants | 92 Participants | 24 Participants | 218 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 410 Participants | 420 Participants | 79 Participants | 909 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 11 Participants | 1 Participants | 23 Participants |
| Race (NIH/OMB) Black or African American | 92 Participants | 98 Participants | 22 Participants | 212 Participants |
| Race (NIH/OMB) More than one race | 30 Participants | 31 Participants | 6 Participants | 67 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 378 Participants | 372 Participants | 73 Participants | 823 Participants |
| Region of Enrollment United States | 512 participants | 512 participants | 103 participants | 1127 participants |
| Sex: Female, Male Female | 306 Participants | 309 Participants | 64 Participants | 679 Participants |
| Sex: Female, Male Male | 206 Participants | 203 Participants | 39 Participants | 448 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 512 | 0 / 512 | 0 / 103 |
| other Total, other adverse events | 39 / 512 | 51 / 512 | 10 / 103 |
| serious Total, serious adverse events | 0 / 512 | 0 / 512 | 0 / 103 |
Outcome results
Primary
FEV1 Trough Value (Assay Sensitivity)
Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of \[prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1\]. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo.
Time frame: Day 1 and Day 29
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGR001 | FEV1 Trough Value (Assay Sensitivity) | 0.2927 L | Standard Error 0.0162 |
| Advair Diskus | FEV1 Trough Value (Assay Sensitivity) | 0.2720 L | Standard Error 0.0161 |
| Placebo | FEV1 Trough Value (Assay Sensitivity) | 0.0575 L | Standard Error 0.0353 |
Comparison: MGR001 (Test) vs Placebop-value: <0.0001ANCOVA
Comparison: Advair Diskus (Reference) vs Placebop-value: <0.0001ANCOVA
Primary
FEV1 Trough Value (Bioequivalence)
Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of \[prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1\]
Time frame: Day 1 and Day 29
Population: Per Protocol Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGR001 | FEV1 Trough Value (Bioequivalence) | 0.2911 L | Standard Error 0.0163 |
| Advair Diskus | FEV1 Trough Value (Bioequivalence) | 0.2728 L | Standard Error 0.0162 |
| Placebo | FEV1 Trough Value (Bioequivalence) | 0.0574 L | Standard Error 0.0355 |
Comparison: Equivalence of MGR001 and Advair Diskus is established if the ratio of the LS means and 90% confidence interval are wholly contained within the interval 0.80-1.25 (i.e., 80%-125%).90% CI: [0.938, 1.22]
Primary
Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity)
The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo
Time frame: 0-12 hours after dosing on Day 1
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGR001 | Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity) | 3.9534 L*hr | Standard Error 0.1609 |
| Advair Diskus | Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity) | 3.4964 L*hr | Standard Error 0.1595 |
| Placebo | Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity) | 0.8191 L*hr | Standard Error 0.3477 |
Comparison: MGR001 (Test) vs Placebop-value: <0.0001ANCOVA
Comparison: Advair Diskus (Reference) vs Placebop-value: <0.0001ANCOVA
Primary
Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence)
The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures
Time frame: 0-12 hours after dosing on Day 1
Population: Per Protocol Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MGR001 | Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence) | 3.9734 L*hr | Standard Error 0.1704 |
| Advair Diskus | Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence) | 3.5411 L*hr | Standard Error 0.1593 |
| Placebo | Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence) | 0.8400 L*hr | Standard Error 0.2983 |
Comparison: Equivalence of MGR001 and Advair Diskus is established if the ratio of the LS means and 90% confidence interval are wholly contained within the interval 0.80-1.25 (i.e., 80%-125%).90% CI: [1.016, 1.237]