Mild Persistent Asthma
Conditions
Brief summary
The purpose of this study is to demonstrate the pharmacodynamic bioequivalence of the test product to the reference product, using bronchoprovocation (methacholine challenge testing) in adult patients with stable mild asthma.
Detailed description
A Multicenter, Double-Blind, Double-Dummy, Placebo-Controlled, 5-Treatment, Randomized, Crossover Study to Demonstrate the Pharmacodynamic Bioequivalence of Test and Reference Metered Dose Inhalers containing Albuterol Sulfate using Bronchoprovocation in Adult Patients with Stable Mild Asthma
Interventions
Sponsors
Lupin, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and non-pregnant female subjects (18-65 years of age) * Stable mild asthmatics based on National Asthma Education and Prevention Program (NAEPP) guidelines. * Forced Expiratory Volume in 1 second ( FEV1) ≥ 80% of predicted. Airway responsiveness to methacholine demonstrated by a pre-albuterol dose (baseline) PC20 ≤ 8 mg/ml. * Nonsmokers for at least 1 year prior to the study and a maximum smoking history of five pack-years (the equivalent of one pack per day for five years). * Written informed consent.
Exclusion criteria
* Conditions which could alter airway reactivity to methacholine (e.g., pneumonia, upper respiratory tract infection, lower respiratory tract, viral bronchitis and/or sinobronchitis) within six weeks preceding the screening visit. * History of seasonal asthma exacerbations, in which case the patient should be studied outside of the relevant allergen season. * History of cystic fibrosis, bronchiectasis or other respiratory diseases. * History of cardiovascular, renal, neurologic, liver or endocrine dysfunction, or chronic condition that could put the safety of the patient at risk during the study or affect the efficacy and safety analyses during the study. * Treatment in an emergency room, urgent care center, or hospitalization for acute asthmatic symptoms within the past 6 months or need for daily oral corticosteroids within past 3 months. * Known intolerance or hypersensitivity to any component of the albuterol metered dose inhaler (MDI).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo | Post-dose at Visits 2-6 of the study, a total of approximately 4 weeks. | The primary efficacy endpoint was the postdose PC20 following administration of differing doses of albuterol (or placebo) by inhalation. The 20% reduction in FEV1 was determined relative to the saline stage FEV1 measured before albuterol or placebo administration. Additionally, an analysis of superiority to placebo was performed for the T and R products prior to the BE determination. In this study the ITT and PP populations were identical. |
Countries
United States
Participant flow
Recruitment details
Male/female patients 18-65 years of age, inclusive, with a diagnosis of asthma and at least a 6-month history of stable mild asthma as defined by the NAEPP EPR-3 guidelines were recruited and enrolled at 17 different centers in the USA. First subject was screened on April 12th, 2016 and the last patient was completed the study on August 12th, 2016.
Pre-assignment details
Of the 217 patients enrolled in the study, 126 failed screening or were randomization failures, largely due to failure to meet the inclusion and exclusion criteria. 91 Subjects were randomized to treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Safety Population All randomized patients who received a dose of any of the randomized study medications. Patient baseline characteristics are not designated by treatment arms due to the crossover design of the study (treatment groups are not mutually exclusive). | 91 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 2 | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Safety Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants |
| Age, Continuous | 41.1 years STANDARD_DEVIATION 11.96 |
| Race/Ethnicity, Customized American Indian/Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black/African American | 25 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 88 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 63 Participants |
| Region of Enrollment United States | 91 participants |
| Sex: Female, Male Female | 54 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 89 | 0 / 90 | 0 / 89 | 0 / 88 | 0 / 89 |
| other Total, other adverse events | 3 / 89 | 4 / 90 | 1 / 89 | 8 / 88 | 1 / 89 |
| serious Total, serious adverse events | 0 / 89 | 0 / 90 | 0 / 89 | 0 / 88 | 0 / 89 |
Outcome results
Primary
Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo
The primary efficacy endpoint was the postdose PC20 following administration of differing doses of albuterol (or placebo) by inhalation. The 20% reduction in FEV1 was determined relative to the saline stage FEV1 measured before albuterol or placebo administration. Additionally, an analysis of superiority to placebo was performed for the T and R products prior to the BE determination. In this study the ITT and PP populations were identical.
Time frame: Post-dose at Visits 2-6 of the study, a total of approximately 4 weeks.
Population: Intent-to-Treat population included all randomized patients who completed at least 2 treatment periods with valid PC20 FEV1 measurements.Treatment was assigned based upon treatment to which patients had been randomized regardless of which treatment they actually received. This was primary population for comparisons of T and R products to placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Dose | Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo | 0.608 log(mg/mL) | Standard Error 0.239 |
| 90 mcg ProAir HFA | Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo | 3.779 log(mg/mL) | Standard Error 0.238 |
| 180 mcg ProAir HFA | Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo | 4.432 log(mg/mL) | Standard Error 0.238 |
| 90 mcg Lupin Albuterol HFA MDI | Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo | 3.928 log(mg/mL) | Standard Error 0.241 |
| 180 mcg Lupin Albuterol HFA MDI | Post-dose PC20 Concentration After Receiving Differing Doses of Test, Reference, or Placebo | 4.481 log(mg/mL) | Standard Error 0.24 |
p-value: <0.000195% CI: [2.732, 3.61]Brief Mixed Models Analysis
p-value: <0.000195% CI: [3.384, 4.263]Brief Mixed Models Analysis
p-value: <0.000195% CI: [2.876, 3.764]Brief Mixed Models Analysis
p-value: <0.000195% CI: [3.43, 4.315]Brief Mixed Models Analysis
Comparison: An Emax model was developed and the 90% confidence interval of Frel was a bias corrected accelerated confidence interval based on a bootstrapping procedure. The bootstrapping procedure used for this analysis was residual resampling. The Per-Protocol population was the primary population for bioequivalence analysis. Patients in the PP population must have completed at least 2 treatment periods with valid PC20FEV1 measurements and had no major protocol deviations within those intervals.90% CI: [0.93, 1.48]