Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD
Brief summary
The purpose of this study is to show bioequivalence of test product to reference product based on baseline-adjusted forced expiratory volume in one second (FEV1).
Interventions
Double-Blind: Single dose of test product 18 mcg of test product Open-Label: once daily administration of test product (tiotropium bromide inhalation powder) 18 mcg administered by test dry powder inhaler.
DRUGPlacebo
Single dose of placebo inhalation powder administered by test and reference dry powder inhalers.
DRUGReference Product (Spiriva®)
Reference product (Spiriva®) 18 mcg.
Sponsors
Lupin, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
Double-blind, double-dummy, placebo controlled
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and non-pregnant female subjects (40 years of age and older). * Patients with diagnosis of COPD according to the GOLD guidelines. * Post-bronchodilator FEV1 \<80% of the predicted value at the screening visit. * Post-bronchodilator FEV1/FVC ratio ≤0.70 at the screening visit. * Current or former smokers (e.g., with history of = 10 pack-years). * Written informed consent.
Exclusion criteria
* Known respiratory disorder other than COPD including, but not limited to the following: alpha-1 antitrypsin deficiency, cystic fibrosis, significant asthma, active bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, pulmonary edema, or interstitial lung disease. * History of allergy or hypersensitivity to anticholinergic/muscarinic receptor antagonist agents, beta-2 adrenergic agonists, lactose/milk proteins, or known hypersensitivity to any of the proposed ingredients or components of the delivery system. * Hospitalization for COPD or pneumonia within 12 weeks prior to the screening visit. * Treatment for COPD exacerbation within 12 weeks prior to the screening visit. * Viral or bacterial upper or lower respiratory tract infection, sinusitis, sinus infection, rhinitis, pharyngitis, middle ear infection, urinary tract infection, or illness within 6 weeks prior to the screening visit. * Abnormal and significant ECG finding prior to the screening, during the run-in and treatment periods.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose | 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks | To show clinical bioequivalence in the efficacy of the test product as a single dose versus reference product based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication. |
| Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo | 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks | This measure is to demonstrate that test product as a single dose and reference product are superior to placebo based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication. |
Countries
United States
Participant flow
Pre-assignment details
Of the 377 participants randomized to treatment groups, three subjects did not receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| Safety Population The safety analysis population included all patients who received at least one dose of any one of the randomized investigational products and for whom data had been collected after randomization. Patient baseline characteristics are not designated by treatment arms due to the crossover design of the study (treatment groups are not mutually exclusive). | 374 |
| Total | 374 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 2 (Open-label Extension) | COPD exacerbation | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 2 (Open-label Extension) | Per study team | 1 | 0 | 0 | 0 | 0 | 0 |
| Part 2 (Open-label Extension) | Prohibited Medication | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 (Open-label Extension) | Withdrawal by Subject | 1 | 0 | 1 | 0 | 0 | 0 |
| Period 2 (Visit 3) | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Period 2 (Visit 3) | COPD Exacerbation | 1 | 1 | 0 | 0 | 0 | 1 |
| Period 2 (Visit 3) | Did not meet continuation criteria | 2 | 3 | 3 | 4 | 3 | 7 |
| Period 2 (Visit 3) | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 2 (Visit 3) | Withdrawal by Subject | 0 | 2 | 0 | 0 | 1 | 0 |
| Period 3 (Visit 04) | Did not meet continuation criteria | 6 | 0 | 2 | 0 | 2 | 3 |
| Period 3 (Visit 04) | Withdrawal by Subject | 0 | 2 | 1 | 0 | 1 | 0 |
| Washout Period 1 | Adverse Event | 1 | 1 | 0 | 0 | 0 | 1 |
| Washout Period 1 | COPD Exacerbation | 1 | 1 | 1 | 0 | 1 | 1 |
| Washout Period 1 | Principal Investigator Discretion | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Period 1 | Subject Noncompliance | 1 | 0 | 0 | 0 | 1 | 0 |
| Washout Period 1 | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 0 |
| Washout Period 2 | Adverse Event | 0 | 0 | 0 | 1 | 1 | 0 |
| Washout Period 2 | COPD Exacerbation | 1 | 1 | 0 | 0 | 1 | 0 |
| Washout Period 2 | Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Washout Period 2 | Subject Non-compliance | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Period 2 | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Safety Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 164 Participants |
| Age, Categorical Between 18 and 65 years | 210 Participants |
| Age, Continuous | 63.5 years STANDARD_DEVIATION 8.47 |
| Baseline Height | 168.72 centimeters STANDARD_DEVIATION 9.927 |
| Baseline Weight | 82.710 kilograms STANDARD_DEVIATION 25.452 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 367 Participants |
| Race/Ethnicity, Customized Race American Indian/Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants |
| Race/Ethnicity, Customized Race Black/African American | 19 Participants |
| Race/Ethnicity, Customized Race White | 350 Participants |
| Region of Enrollment United States | 374 Participants |
| Sex: Female, Male Female | 195 Participants |
| Sex: Female, Male Male | 179 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 337 | 0 / 343 | 0 / 329 |
| other Total, other adverse events | 0 / 337 | 0 / 343 | 0 / 329 |
| serious Total, serious adverse events | 0 / 337 | 0 / 343 | 0 / 329 |
Outcome results
Primary
Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose
To show clinical bioequivalence in the efficacy of the test product as a single dose versus reference product based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication.
Time frame: 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks
Population: Per-Protocol population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Test Product (Tiotropium Bromide Inhalation Powder) | Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose | 2.5644 L*hour | Standard Error 0.323 |
| Reference Product (Spiriva®) | Baseline Adjusted Mean Change in FEV1 AUC0-24h Post Dose | 2.7370 L*hour | Standard Error 0.322 |
Comparison: A blinded interim analysis was performed after 241 subjects had been randomized with measurable AUC data, which estimated 238 patients would be needed to demonstrate BE with 90% power. Therefore, it was planned that approximately 378 patients would be randomized to allow for a potential 30% loss/withdrawal from the PP population.90% CI: [0.834, 1.047]
Primary
Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo
This measure is to demonstrate that test product as a single dose and reference product are superior to placebo based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication.
Time frame: 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks
Population: Intention-To-Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Test Product (Tiotropium Bromide Inhalation Powder) | Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo | 2.90 L*hour | Standard Error 0.197 |
| Reference Product (Spiriva®) | Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo | 3.03 L*hour | Standard Error 0.196 |
| Placebo | Difference in Baseline Adjusted FEV1 AUC0-24h for Comparison of Lupin Tiotropium Bromide Inhalation Powder (Test) and Spiriva (Reference) to Placebo | -0.40 L*hour | Standard Error 0.199 |
p-value: <0.00195% CI: [2.9386, 3.646]Mixed Models Analysis
p-value: <0.00195% CI: [3.0718, 3.7797]Mixed Models Analysis