Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients With Chronic Obstructive Pulmonary Disease (COPD).

Official Title
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A Dose Ranging, Parallel Group, Active (Spiriva® Respimat®) And Placebo Controlled Study To Assess Relative Bioavailability, Pharmacodynamics And Safety Of Three Doses Of Tiotropium Bromide Inhalation Solution In Subjects With Mild To Moderate Chronic Obstructive Pulmonary Disease

Conditions
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Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: GSP304 (tiotropium bromide) Inhalation Solution
* Drug: GSP304 Placebo Inhalation Solution
* Drug: Spiriva® Respimat® inhalation spray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects ≥40 years and ≤85 years of age at the time of consent. Subject must have a primary diagnosis of mild or moderate COPD defined as post-bronchodilator FEV1/FVC ratio of <70% and FEV1 of ≥50% of predicted normal value as per the NHANES III predicted normal values at screening. Willing to stop all other COPD medications or other medications which will interfere with the study results for the entire duration of the study, except albuterol/salbutamol as needed. Current or ex-smoker with ≥10 pack-year smoking history. Exclusion Criteria: Subjects with a chest x-ray/CT scan that suggests a diagnosis other than COPD (eg, pneumonia, other infection, atelectasis, or pneumothorax or other active/ongoing pulmonary conditions) and taken within 6 months prior to study start. If there is no chest x-ray or CT scan taken within 6 months prior to study start, or if recent results are unavailable for review, a chest x-ray must be performed. Use of oral/parenteral corticosteroids or antibiotics for COPD within 6 weeks or depot corticosteroids within 3 months prior to screening or subject has had a change in dose or type of any medications for COPD within 14 days before screening. Hospitalization for COPD exacerbation or pneumonia within 3 months prior to screening. Subjects with a history of asthma, with the exception of outgrown childhood asthma, defined as transient wheezers outgrown by 5 years of age. Subject has a known history of alpha 1 antitrypsin deficiency-related emphysema. Subject requires nocturnal oxygen or continuous supplemental oxygen therapy. Subject with history of a positive result for HBsAg or HCV antibody. Subject is known to be seropositive for human immunodeficiency virus. Female subject is pregnant or lactating. Subject has a history of allergic reaction to the anti-cholinergic or any components of the study medications.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test Treatment T1: GSP304 Inhalation Solution<br> | Drug: GSP304 (tiotropium bromide) Inhalation Solution<br>* Once daily (QD) oral inhalation using a nebulizer<br>|
| Experimental: Test Treatment T2: GSP304 Inhalation Solution<br> | Drug: GSP304 (tiotropium bromide) Inhalation Solution<br>* Once daily (QD) oral inhalation using a nebulizer<br>|
| Experimental: Test Treatment T3: GSP304 Inhalation Solution<br> | Drug: GSP304 (tiotropium bromide) Inhalation Solution<br>* Once daily (QD) oral inhalation using a nebulizer<br>|
| Placebo Comparator: Test Treatment T4: GSP304 Placebo Inhalation Solution<br> | Drug: GSP304 Placebo Inhalation Solution<br>* Once daily (QD) oral inhalation using a nebulizer<br>|
| Active Comparator: Test Treatment T5: Spiriva® Respimat® inhalation spray<br> | Drug: Spiriva® Respimat® inhalation spray<br>* Once daily (QD) oral inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS | The PK endpoint in plasma to assess the relative bioavailability was peak concentrations of tiotropium during the dosing interval at steady-state (CmaxSS) | Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose. | 
| Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS | The PK endpoint in plasma to assess the relative bioavailability was area under the plasma concentration-time curve of tiotropium over the dosing interval at steady state (AUC0-tauSS) | Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose. | 
| Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes postdose measurements), in comparison with placebo. | 21 days (Pre- dose trough FEV1 is mean FEV1 at -45 mins and -15 mins pre-morning dose at Day 1. Trough FEV1 is mean FEV1 obtained 23 hrs 15 mins and 23 hrs 45 mins post-morning dose of day 21). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of tiotropium excreted in urine over the dosing interval on Day 1 | Day 1 | 
| Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | Day 21 | 
| Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | Descriptive statistics for tiotropium urine PK parameter - Fraction of dose (Fe) of tiotropium excreted in urine over the dosing interval on Day 1 | Day 1 | 
| Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | Descriptive statistics for tiotropium urine PK parameter-Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | Day 21 | 
| Peak Concentrations During the Dosing Interval (Cmax) on Day 1 | Descriptive statistics for tiotropium plasma PK parameters - (Cmax) on Day 1 | Day 1 | 
| Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1 | Descriptive statistics for tiotropium plasma PK parameter - Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1 | Day 1 | 
| Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1 | Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 1 | Day 1 | 
| Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21 | Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 21 | Day 21 | 
| Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21 | Descriptive statistics for tiotropium plasma PK parameter - Average concentration during a dosing interval at steady state (CavSS) on day 21 | Day 21 | 
| Accumulation Ratio Rac(Auc) | Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(auc). Rac(auc) was calculated as AUC0-tauSS/AUC0-tau. | Day 21 | 
| Accumulation Ratio Rac(Cmax) | Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(cmax). Rac(Cmax) was calculated as CmaxSS/Cmax. | Day 21 | 
| Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 1. Change from baseline in peak FEV1 within 12 hours postdose on Day 1 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline. | Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | 
| Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 21. Change from baseline in peak FEV1 within 12 hours postdose on Day 21 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline. | Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | 
| Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 1. | Day 1 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 1. Postdose timing were relative to the end of dosing.The window for 1 hour spirometry and thereafter was ±5 minutes). | 
| Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 21 | Day 21 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 21. Postdose timing were relative to the end of dosing. The window for 1 hour spirometry and thereafter was ±5 minutes). | 
| Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1. | Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | 
| Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 Measured Over 12 Hours on Day 21. | Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). |