Asthma
Conditions
Keywords
bioequivalence
Brief summary
A randomized multiple-dose, placebo-controlled, parallel group design consisting of a 2-week run-in period followed by a 6-week treatment period of the placebo, Test product (Budesonide 80 mcg / Formoterol fumarate dihydrate 4.5 mcg), or Reference product Symbicort® inhalation aerosol.
Detailed description
This is a pivotal trial that will examine therapeutic equivalence of a new generic fixed-dose combination product containing Budesonide 80 mcg / Formoterol fumarate dihydrate 4.5 mcg and reference listed drug (RLD) Symbicort® inhalation aerosol in adult patients with chronic but stable asthma as defined in National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP 3) guidelines. To ensure adequate study sensitivity the test and reference products should both be statistically superior to placebo (p\<0.05) with regard to the bioequivalent study primary endpoints. A secondary study objective is the safety and tolerability of the test compound.
Interventions
Experimental: Treatment 1
DRUGSymbicort
Active Comparator: Treatment 2
DRUGPlacebo
Placebo Comparator: Treatment 3
Sponsors
Kindeva Drug Delivery
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult male or female subjects of non-childbearing or of childbearing potential committed to consistent and correct use of an acceptable method of birth control * Diagnosed with asthma, as defined by the National Asthma Education and Prevention Program (NAEPP),at least 6 months prior to screening * Moderate-to-severe asthma with a pre-bronchodilator FEV1 of \>45% and \<85% of predicted normal, measured at least 6 hours after short-acting β agonist (SABA)and at least 24 hours after the last dose of long-acting β agonist (LABA), at the screening visit and on the day of treatment * \>15% and \>0.20 L reversibility of FEV1 within 30 minutes following 360 mcg of albuterol inhalation (pMDI) * Patients should be stable on their chronic asthma treatment regimen for at least 4 weeks prior to enrollment * Currently non-smoking; having not used tobacco products (i.e., cigarettes, cigars, pipe tobacco) within the past year, and having \< 10 pack-years of historical use * Able to replace current regularly scheduled short-acting β agonists (SABAs) with salbutamol/albuterol inhaler for use only on an as-needed basis for the duration of the study (subjects should be able to withhold all inhaled SABAs for at least 6 hours prior to lung function assessments on study visits) * Willing to discontinue their asthma medications (inhaled corticosteroids and long-acting β agonists) during the run-in period and for the remainder of the study * Willingness to give their written informed consent to participate in the study
Exclusion criteria
* Life-threatening asthma, defined as a history of asthma episodes(s) requiring intubation, and/or associated with hypercapnia, respiratory arrest or hypoxic seizures, asthma-related syncopal episodes(s), or hospitalizations within the past year or during the run-in period * Significant respiratory disease other than asthma (chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc.) * Evidence or history of clinically significant disease or abnormality including congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery disease, myocardial infarction, or cardiac dysrhythmia. In addition, historical or current evidence of significant hematologic, hepatic, neurologic, psychiatric, renal, or other diseases that, in the opinion of the investigator, would put the patient at risk through study participation, or would affect the study analyses if the disease exacerbated during the study * Patients who required systemic corticosteroids (for any reason) within the past 4 weeks * Hypersensitivity to any sympathomimetic drug (e.g., formoterol or albuterol) or any inhaled, intranasal, or systemic corticosteroid therapy * Patients currently receiving β-blockers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serial Forced Expiratory Volume in 1 Second (FEV1) | Day 1 | FEV1 Area calculated over 12 hours (measurements at 0, 1, 2, 3, 4, 6, 8, 12 hours post-dose) on Day 1 of treatment. Because this was a primary endpoint, Per Protocol Population used to calculate this endpoint. |
| Change From Baseline in FEV1 Measured in the Morning at the End of Treatment Visit | Day 1 - Day 49 | Average predose FEV1 at End of Treatment defined as the average of all predose assessments on Day 42 (+/- 7 days). Baseline was defined as the average of 2 predose FEV1 values obtained on Day 1. The endpoint of baseline-adjusted predose FEV1 at end of treatment was calculated as follows: \[FEV1 at end of treatment\] - \[Baseline FEV1\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 6 Weeks | Number of participants reporting at least one adverse event (safety population) |
Countries
United States
Participant flow
Pre-assignment details
Participants (N=1762) were provided a generic placebo pressurized metered dose inhaler (pMDI) device for use during a 2-week Run-in Period for device training. Then, qualified participants (N=1439) were randomly assigned to treatment on a 3:3:1 ratio of generic budesonide/formoterol fumarate dihydrate, Symbicort, or Placebo, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Treatment 1 Generic Budesonide/Formoterol Fumarate Dihydrate (80mcg/4.5mcg) Inhalation Aerosol, two inhalation twice daily, consisting of a 2-week run-in period followed by a 6-week treatment period
Budesonide/Formoterol fumarate dihydrate: Experimental: Treatment 1 | 613 |
| Treatment 2 Symbicort (Budesonide/Formoterol Fumarate Dihydrate) Inhalation Aerosol, two inhalation twice daily, consisting of a 2-week run-in period followed by a 6-week treatment period
Symbicort: Active Comparator: Treatment 2 | 622 |
| Treatment 3 Placebo Inhalation Aerosol, two inhalation twice daily, consisting of a 2-week run-in period followed by a 6-week treatment period
Placebo: Placebo Comparator: Treatment 3 | 204 |
| Total | 1,439 |
Baseline characteristics
| Characteristic | Treatment 1 | Treatment 2 | Treatment 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 46.3 years STANDARD_DEVIATION 15.02 | 45.5 years STANDARD_DEVIATION 14.44 | 45.5 years STANDARD_DEVIATION 14.78 | 45.8 years STANDARD_DEVIATION 14.73 |
| Body Mass Index | 30.73 kg/m^2 STANDARD_DEVIATION 7.667 | 31.27 kg/m^2 STANDARD_DEVIATION 8.108 | 30.93 kg/m^2 STANDARD_DEVIATION 7.96 | 30.99 kg/m^2 STANDARD_DEVIATION 7.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 153 Participants | 151 Participants | 55 Participants | 359 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 460 Participants | 471 Participants | 149 Participants | 1080 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 6 Participants | 4 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 107 Participants | 112 Participants | 43 Participants | 262 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 9 Participants | 3 Participants | 21 Participants |
| Race (NIH/OMB) White | 490 Participants | 495 Participants | 154 Participants | 1139 Participants |
| Sex: Female, Male Female | 375 Participants | 392 Participants | 137 Participants | 904 Participants |
| Sex: Female, Male Male | 238 Participants | 230 Participants | 67 Participants | 535 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 613 | 0 / 622 | 0 / 204 |
| other Total, other adverse events | 121 / 613 | 138 / 622 | 71 / 204 |
| serious Total, serious adverse events | 4 / 613 | 3 / 622 | 2 / 204 |
Outcome results
Primary
Area Under the Serial Forced Expiratory Volume in 1 Second (FEV1)
FEV1 Area calculated over 12 hours (measurements at 0, 1, 2, 3, 4, 6, 8, 12 hours post-dose) on Day 1 of treatment. Because this was a primary endpoint, Per Protocol Population used to calculate this endpoint.
Time frame: Day 1
Population: Per Protocol Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1 | Area Under the Serial Forced Expiratory Volume in 1 Second (FEV1) | 4.4453 l * hr | Standard Error 0.1552 |
| Treatment 2 | Area Under the Serial Forced Expiratory Volume in 1 Second (FEV1) | 4.2790 l * hr | Standard Error 0.1547 |
| Treatment 3 | Area Under the Serial Forced Expiratory Volume in 1 Second (FEV1) | 1.6876 l * hr | Standard Error 0.2782 |
Comparison: Only Treatments 1 and 2 were compared for equivalence. Treatment 3 (placebo) was subtracted from both Treatments 1 and 2, as this primary endpoint was baseline adjusted.90% CI: [0.958, 1.13]
Primary
Change From Baseline in FEV1 Measured in the Morning at the End of Treatment Visit
Average predose FEV1 at End of Treatment defined as the average of all predose assessments on Day 42 (+/- 7 days). Baseline was defined as the average of 2 predose FEV1 values obtained on Day 1. The endpoint of baseline-adjusted predose FEV1 at end of treatment was calculated as follows: \[FEV1 at end of treatment\] - \[Baseline FEV1\].
Time frame: Day 1 - Day 49
Population: Per Protocol Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1 | Change From Baseline in FEV1 Measured in the Morning at the End of Treatment Visit | 0.3096 liter | Standard Error 0.0162 |
| Treatment 2 | Change From Baseline in FEV1 Measured in the Morning at the End of Treatment Visit | 0.3077 liter | Standard Error 0.0162 |
| Treatment 3 | Change From Baseline in FEV1 Measured in the Morning at the End of Treatment Visit | 0.1236 liter | Standard Error 0.0285 |
Comparison: Treatments 1 and 2 were baseline adjusted by subtracting Treatment 3 (placebo) from each.90% CI: [0.889, 1.14]
Secondary
Number of Participants With Adverse Events
Number of participants reporting at least one adverse event (safety population)
Time frame: 6 Weeks
Population: Safety Population: All enrolled participants who received one dose of a treatment drug. This population was larger than the Per Protocol Population that included only those participants who provided analyzable primary endpoints.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Number of Participants With Adverse Events | Nasopharyngitis | 7 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Chest discomfort | 1 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Bronchitis | 3 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Viral upper respiratory tract infection | 6 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Asthma | 17 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Upper respiratory tract infection | 12 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Cough | 4 Participants |
| Treatment 1 | Number of Participants With Adverse Events | Headache | 4 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Viral upper respiratory tract infection | 4 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Asthma | 24 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Cough | 4 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Upper respiratory tract infection | 15 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Nasopharyngitis | 11 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Bronchitis | 4 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Headache | 8 Participants |
| Treatment 2 | Number of Participants With Adverse Events | Chest discomfort | 0 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Bronchitis | 2 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Cough | 3 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Upper respiratory tract infection | 7 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Chest discomfort | 2 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Headache | 2 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Viral upper respiratory tract infection | 1 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Nasopharyngitis | 4 Participants |
| Treatment 3 | Number of Participants With Adverse Events | Asthma | 39 Participants |
Comparison: Comparison of means, no formal statistical comparison