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

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

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

Study Overview

• Status: Completed
• Conditions: Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: GSP304 (tiotropium bromide) Inhalation Solution; Drug: GSP304 Placebo Inhalation Solution; Drug: Spiriva® Respimat® inhalation spray

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Andalusia, Alabama, United States, 36420
      • Glenmark Investigational Site 23
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Glenmark Investigational Site 12
    • Tempe, Arizona, United States, 85283
      • Glenmark Investigational Site 14
  • California
    • Fullerton, California, United States, 92835
      • Glenmark Investigational Site 17
  • Florida
    • Edgewater, Florida, United States, 32132
      • Glenmark Investigational Site 19
    • Miami, Florida, United States, 33144
      • Glenmark Investigational Site 24
    • Miami, Florida, United States, 33186
      • Glenmark Investigational Site 16
    • Miami Lakes, Florida, United States, 33016
      • Glenmark Investigational Site 10
    • Orlando, Florida, United States, 32825
      • Glenmark Investigational Site 6
    • Ormond Beach, Florida, United States, 32124
      • Glenmark Investigational Site 20
    • Vero Beach, Florida, United States, 32960
      • Glenmark Investigational Site 21
    • Winter Park, Florida, United States, 32789
      • Glenmark Investigational Site 13
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Glenmark Investigational Site 18
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Glenmark Investigational Site 9
  • Ohio
    • Columbus, Ohio, United States, 43213
      • Glenmark Investigational Site 5
    • Columbus, Ohio, United States, 43215
      • Glenmark Investigational Site 22
    • Dublin, Ohio, United States, 43016
      • Glenmark Investigational Site 8
  • Oregon
    • Medford, Oregon, United States, 97504-9741
      • Glenmark Investigational Site 11
  • South Carolina
    • Easley, South Carolina, United States, 29640
      • Glenmark Investigational Site 3
    • Greenville, South Carolina, United States, 29615
      • Glenmark Investigational Site 2
    • Greenville, South Carolina, United States, 29615
      • Glenmark Investigational Site 4
    • Rock Hill, South Carolina, United States, 29732
      • Glenmark Investigational Site 1
    • Spartanburg, South Carolina, United States, 29303
      • Glenmark Investigational Site 15
    • Spartanburg, South Carolina, United States, 29303
      • Glenmark Investigational Site 7
  • Texas
    • Tomball, Texas, United States, 77375
      • Glenmark Investigational Site 25

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Test Treatment T1: GSP304 Inhalation Solution	Drug: GSP304 (tiotropium bromide) Inhalation Solution; Once daily (QD) oral inhalation using a nebulizer
EXPERIMENTAL: Test Treatment T2: GSP304 Inhalation Solution	Drug: GSP304 (tiotropium bromide) Inhalation Solution; Once daily (QD) oral inhalation using a nebulizer
EXPERIMENTAL: Test Treatment T3: GSP304 Inhalation Solution	Drug: GSP304 (tiotropium bromide) Inhalation Solution; Once daily (QD) oral inhalation using a nebulizer
PLACEBO_COMPARATOR: Test Treatment T4: GSP304 Placebo Inhalation Solution	Drug: GSP304 Placebo Inhalation Solution; Once daily (QD) oral inhalation using a nebulizer
ACTIVE_COMPARATOR: Test Treatment T5: Spiriva® Respimat® inhalation spray	Drug: Spiriva® Respimat® inhalation spray; Once daily (QD) oral inhalation

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Glenmark Specialty S.A.
• Investigators: Study Director: Cynthia Caracta, MD FCCP, Glenmark Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 24, 2017
• Primary Completion (ACTUAL): July 31, 2017
• Study Completion (ACTUAL): July 31, 2017

Study Registration Dates

• First Submitted: April 10, 2017
• First Submitted That Met QC Criteria: April 17, 2017
• First Posted (ACTUAL): April 18, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 1, 2019
• Last Update Submitted That Met QC Criteria: July 5, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Anticonvulsants; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Pharmaceutical Solutions; Tiotropium Bromide; Bromides
• Other Study ID Numbers: GSP304-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No