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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo dose | Placebo Comparator | Placebo dose: 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and one actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols |
|
| 90 mcg ProAir HFA | Active Comparator | 90 mcg of ProAir HFA: 1 actuation each from ProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols |
|
| 180 mcg ProAir HFA | Active Comparator | 180 mcg of ProAir HFA: 1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols |
|
| 90 mcg Lupin albuterol HFA MDI | Experimental | 90 mcg of Lupin albuterol HFA MDI product: 1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| methacholine chloride | Other |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Post-dose at Visits 2-6 of the study, a total of approximately 4 weeks. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Investigational Research Center Site #110 | Huntington Beach | California | 92647 | United States | ||
| Investigational Research Center Site #114 |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | PBO-R90-T180-R180-T90 | Subjects received PBO in period 1 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R90 in period 2 (1 actuation each from ProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T180 in period 3 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), R180 in period 4 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T90 in period 5 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Period 1 |
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| 180 mcg Lupin albuterol HFA MDI | Experimental | 180 mcg of Lupin albuterol HFA MDI: 1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols |
|
| placebo ProAir HFA | Drug |
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| ProAir HFA | Drug |
|
| Lupin albuterol HFA MDI | Drug |
|
| placebo Lupin albuterol HFA MDI | Drug |
|
| Mission Viejo |
| California |
| 92691 |
| United States |
| Investigational Research Center Site #113 | Rolling Hills Estates | California | 90274 | United States |
| Investigational Research Center Site #112 | San Diego | California | 92123 | United States |
| Investigational Research Center Site #116 | San Jose | California | 95117 | United States |
| Investigational Research Center Site #106 | Tallahassee | Florida | 32308 | United States |
| Investigational Research Center Site #109 | Baltimore | Maryland | 21236 | United States |
| Investigational Research Center Site #105 | Bethesda | Maryland | 20814 | United States |
| Investigational Research Center Site #103 | North Dartmouth | Massachusetts | 02747 | United States |
| Investigational Research Center Site #108 | St Louis | Missouri | 63141 | United States |
| Investigational Research Center Site #115 | Bellevue | Nebraska | 68123 | United States |
| Investigational Research Center Site #104 | Skillman | New Jersey | 08558 | United States |
| Investigational Research Center Site #102 | Raleigh | North Carolina | 27607 | United States |
| Investigational Research Center Site #111 | Cincinnati | Ohio | 45231 | United States |
| Investigational Research Center Site #118 | Tulsa | Oklahoma | 74136 | United States |
| Investigational Research Center Site #101 | Medford | Oregon | 97504 | United States |
| Investigational Research Center Site #107 | Portland | Oregon | 97202 | United States |
| FG001 | R90-R180-PBO-T90-T180 | Subjects received R90 in period 1 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R180 in period 2 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), PBO in period 3 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T90 in period 4 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), T180 in period 5 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols) |
| FG002 | R180-T90-R90-T180-PBO | Subjects received R180 in period 1 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T90 in period 2 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), R90 in period 3 (1 actuation each from ProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T180 in period 4 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), PBO in period 5 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols) |
| FG003 | T90-T180-R180-PBO-R90 | Subjects received T90 in period 1 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), T180 in period 2 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), R180 in period 3 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), PBO in period 4 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R90 in period 5 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols) |
| FG004 | T180-PBO-T90-R90-R180 | Subjects received T180 in period 1 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), PBO in period 2 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T90 in period 3 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), R90 in period 4 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R180 in period 5 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols) |
| FG005 | T90-R180-T180-R90-PBO | Subjects received T90 in period 1 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), R180 in period 2 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T180 in period 3 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), R90 in period 4 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), PBO in period 5 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols) |
| FG006 | T180-T90-PBO-R180-R90 | Subjects received T180 in period 1 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), T90 in period 2 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), PBO in period 3 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R180 in period 4 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R90 in period 5 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols) |
| FG007 | R90-PBO-R180-T180-T90 | Subjects received R90 in period 1 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), PBO in period 2 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R180 in period 3 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T180 in period 4 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), T90 in period 5 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols) |
| FG008 | R180-R90-T90-PBO-T180 | Subjects received R180 in period 1 (1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), R90 in period 2 (1 actuation each from tProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T90 in period 3 (1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols), PBO in period 4 (1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols), T180 in period 5 (1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols), |
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| NOT COMPLETED |
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| Period 2 |
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| Period 3 |
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| Period 4 |
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| Period 5 |
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All randomized patients who received a dose of any of the study medications.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | The study was conducted in 17 study centers in the United States of America (USA) | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. | 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. | Posted | Least Squares Mean | Standard Error | log(mg/mL) | Post-dose at Visits 2-6 of the study, a total of approximately 4 weeks. |
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All AE/SAEs (including treatment-emergent AEs) were assessed throughout the study visits and followed to resolution/satisfaction. AEs were recorded starting after the patient had signed the informed consent form and assessed at all visits. Each AE was evaluated for date/time of onset, duration, intensity, and causal relationship with the investigational product or other factors. (5 months) First Patient Screened: 12-Apr 2016 & Last Patient Visit: 12 Aug 2016
An AE was defined as any untoward medical occurrence in a clinical trial patient administered a medicinal product and which did not necessarily have a causal relationship with the treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo Dose | Placebo dose: 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols and one actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols methacholine chloride placebo ProAir HFA placebo Lupin albuterol HFA MDI | 0 | 89 | 0 | 89 | 3 | 89 |
| EG001 | 90 mcg ProAir HFA | 90 mcg of ProAir HFA: 1 actuation each from ProAir HFA inhalation aerosol and the placebo ProAir HFA inhalation aerosol and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols methacholine chloride placebo ProAir HFA ProAir HFA placebo Lupin albuterol HFA MDI | 0 | 90 | 0 | 90 | 4 | 90 |
| EG002 | 180 mcg ProAir HFA | 180 mcg of ProAir HFA: 1 actuation each from 2 different ProAir HFA inhalation aerosols and 1 actuation each from 2 different placebo Lupin albuterol HFA MDI inhalation aerosols methacholine chloride ProAir HFA placebo Lupin albuterol HFA MDI | 0 | 89 | 0 | 89 | 1 | 89 |
| EG003 | 90 mcg Lupin Albuterol HFA MDI | 90 mcg of Lupin albuterol HFA MDI product: 1 actuation each from the Lupin albuterol HFA MDI inhalation aerosol and the placebo Lupin albuterol HFA MDI inhalation aerosol and 1 actuation each from 2 different placebo ProAir HFA inhalation aerosols methacholine chloride placebo ProAir HFA Lupin albuterol HFA MDI placebo Lupin albuterol HFA MDI | 0 | 88 | 0 | 88 | 8 | 88 |
| EG004 | 180 mcg Lupin Albuterol HFA MDI | 180 mcg of Lupin albuterol HFA MDI: 1 actuation each from 2 different Lupin albuterol HFA MDI inhalation aerosols and 1 actuation each from 2 different placebo ProAir HFA product inhalation aerosols methacholine chloride placebo ProAir HFA Lupin albuterol HFA MDI | 0 | 89 | 0 | 89 | 1 | 89 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | MedDRA (18.0) | Systematic Assessment |
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| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA (18.0) | Systematic Assessment |
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| Abdominal Pain Upper | Gastrointestinal disorders | MedDRA (18.0) | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (18.0) | Systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA (18.0) | Systematic Assessment |
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| Abdominal Discomfort | Gastrointestinal disorders | MedDRA (18.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (18.0) | Systematic Assessment |
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| Herpes Zoster | Infections and infestations | MedDRA (18.0) | Systematic Assessment |
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| Heart Rate Increased | Investigations | MedDRA (18.0) | Systematic Assessment |
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| Tension Headache | Nervous system disorders | MedDRA (18.0) | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA (18.0) | Systematic Assessment |
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| Tremor | Nervous system disorders | MedDRA (18.0) | Systematic Assessment |
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| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (18.0) | Systematic Assessment |
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| Arthropod Bite | Injury, poisoning and procedural complications | MedDRA (18.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mark Lepore | Lupin Research Inc | (443) 740-9323 | marklepore@lupin.com |
| ID | Term |
|---|---|
| D016210 | Methacholine Chloride |
| D000420 | Albuterol |
| ID | Term |
|---|---|
| D008688 | Methacholine Compounds |
| D050337 | Trimethyl Ammonium Compounds |
| D000644 | Quaternary Ammonium Compounds |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D009861 | Onium Compounds |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
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| Adverse Event |
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| Asian |
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| American Indian/Alaska Native |
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| Native Hawaiian/Other Pacific Islander |
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| Other |
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| Brief Mixed Models Analysis | For this model, the dependent variable was log2(PC20FEV1) values where PC20FEV1 was measured in mg/mL | <0.0001 | Fixed effects of dose, week, and sequence and the random effect of the patient was carried out to ensure that the overall treatment effect was significant at p<0.05. | Least Square Means Differences | 3.824 | Standard Error of the Mean | 0.238 | 2-Sided | 95 | 3.384 | 4.263 | Superiority |
| Brief Mixed Models Analysis | For this model, the dependent variable was log2(PC20FEV1) values where PC20FEV1 was measured in mg/mL. | <0.0001 | Fixed effects of dose, week, and sequence and the random effect of the patient was carried out to ensure that the overall treatment effect was significant at p<0.05. | Least Square Means Differences | 3.320 | Standard Error of the Mean | 0.241 | 2-Sided | 95 | 2.876 | 3.764 | Superiority |
| Brief Mixed Models Analysis | For this model, the dependent variable was log2(PC20FEV1) values where PC20FEV1 was measured in mg/mL | <0.0001 | Fixed effects of dose, week, and sequence and the random effect of the patient was carried out to ensure that the overall treatment effect was significant at p<0.05. | Least Square Means Differences | 3.872 | Standard Error of the Mean | 0.240 | 2-Sided | 95 | 3.430 | 4.315 | Superiority |
| 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. | Frel | 1.15 | Standard Error of the Mean | 0.17 | 2-Sided | 90 | 0.93 | 1.48 | Frel is the relative bioavailability of the test versus reference product. The CI was a bias corrected and accelerated CI based on a bootstrapping procedure. The FDA acceptable CI was between 0.67 and 1.50. | Equivalence | A blinded interim analysis was performed after 60 patients completed all treatment visits which determined that 80 subjects would be sufficient to complete the study with 90% power. |