Study to Evaluate the Treatment Effect of PT003 on Cardiovascular Hemodynamics in Subjects With Moderate to Severe COPD

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, single-center, chronic-dosing (7 days), two-period, two-treatment, cross-over study to evaluate the treatment effect of PT003 compared with that of Placebo MDI on Cardiovascular Hemodynamics following chronic-dosing (7 days) in subjects with moderate to severe COPD.

Official Title
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A Randomized, Phase IIIb, Two-period , Double-blind, Two-treatment, Chronic-dosing (7 Days), Single-center Crossover Study to Evaluate the Treatment Effect of PT003 on Cardiovascular Hemodynamics in Subjects With Moderate to Severe Chronic Obstructive Pulmonary Disease, Compared With Placebo

Conditions
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COPD

Intervention / Treatment
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* Drug: GFF MDI (PT003)
* Drug: Placebo MDI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 40 years of age and no older than 80 at Visit 1. Women of non-child bearing potential,or negative serum pregnancy test at Screening, and agrees to acceptable contraceptive methods used consistently and correctly from Screening until 14 days after final visit Evidence of lung hyperinflation Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) Current or former smokers with a history of at least 10 pack-years of cigarette smoking. Pre- and Post-bronchodilator FEV1/FVC ratio must be <0.70 Post-bronchodilator FEV1 must be ≥30% to <65% predicted normal value, calculated using NHANES III reference equations. Exclusion Criteria: Significant diseases or conditions other than COPD which, in the opinion of the Investigator, may put the patient at risk Women who are pregnant or lactating or are planning to become pregnant during the course of the study Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma or other active pulmonary disease Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Screening Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Screening or during the Screening Period Subjects who have clinically significant uncontrolled hypertension. Subjects with symptomatic prostatic hypertrophy that is clinically significant and not adequately controlled with appropriate therapy, in the opinion of the Investigator. Subjects with bladder neck obstruction or urinary retention that is clinically significant in the opinion of the Investigator. Subjects with a calculated creatinine clearance ≤30 mL/minute using Chronic Kidney Disease Epidemiology Collaboration. (CKD-EPI) formula at Screening and on repeat testing prior to Visit 2. Subjects with abnormal liver function tests defined as AST, ALT, or total bilirubin ≥ 1.5 times upper limit of normal at Screening and on repeat testing prior to Visit 2 Subjects who have cancer that has not been in complete remission for at least five years. Subjects with a diagnosis of glaucoma, who in the opinion of the Investigator, have not been adequately treated. Subjects with a clinically significant ECG Subjects who were previously enrolled in any previous PT001, PT003, or PT005 study conducted or sponsored by Pearl.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GFF MDI (PT003)<br>Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI) | Drug: GFF MDI (PT003)<br>* Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI)<br>|
| Placebo Comparator: Placebo MDI<br>Placebo Metered Dose Inhaler (MDI) for Glycopyrronium and Formoterol Fumarate Inhalation Aerosol | Drug: Placebo MDI<br>* Placebo Metered Dose Inhaler (MDI) for Glycopyrronium and Formoterol Fumarate Inhalation Aerosol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Right Ventricular End Diastolic Volume Index (RVEDVi) at 2-3 Hours Post-dose on Day 8 | Assessment of right ventricular (RV) volume was performed using magnetic resonance imaging (MRI) using RV end diastolic volume (RVEDV), 2-3 hours after dosing on Day 8 of each treatment period. RVEDV was normalized to body surface area (BSA) to provide the indexed counterpart (RVEDVi). Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Aortic Left Ventricular Stroke Volume (LVSV) at 2-3 Hours Post-dose on Day 8 | Assessment of LVSV was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Right Ventricular Stroke Volume (RVSV) at 2-3 Hours Post-dose on Day 8 | Assessment of RVSV, phase contrast from pulmonic valve, was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Pulmonary Artery Velocity at 2-3 Hours Post-dose on Day 8 | Assessment of Pulmonary Artery Velocity was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVi) at 2-3 Hours Post-dose on Day 8 | Assessment of left ventricular (LV) volume was performed using MRI using LV end diastolic volume (LVEDV), 2-3 hours after dosing of Day 8 of each treatment period. LVEDV was normalized to BSA to provide the indexed counterpart (LVEDVi). Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Cardiac Output at 2-3 Hours Post-dose on Day 8 | Assessment of cardiac output was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at 30 and 60 Minutes Post-dose on Day 8 | Assessment of PVR was performed by impedance cardiography at 30 and 60 minutes after dosing on Day 8 of each treatment period. Baseline for was defined as the average of the subject values obtained pre-dose on Day 1 of each treatment period. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Pulmonary Artery/Aortic Diameter Ratio (PA:A) at 2-3 Hours Post-dose on Day 8 | Assessment of PA:A was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Left Atrial End Diastolic Volume (LAEDV) at 2-3 Hours Post-dose on Day 8 | Assessment of LAEDV was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Left Atrial End Systolic Volume (LAESV) at 2-3 Hours Post-dose on Day 8 | Assessment of LAESV was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Left Atrial Ejection Fraction (LAEF) at 2-3 Hours Post-dose on Day 8 | Assessment of LAEF was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVi) at 2-3 Hours Post-dose on Day 8 | Assessment of LV volume was performed using MRI using LV end systolic volume (LVESV), 2-3 hours after dosing on Day 8 of each treatment period. LVESV was normalized to BSA to provide the indexed counterpart (LVESVi). Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Right Ventricular End Systolic Volume Index (RVESVi) at 2-3 Hours Post-dose on Day 8 | Assessment of RV volume was performed using MRI using RV end systolic volume (RVESV), 2-3 hours after dosing on Day 8 of each treatment period. RVESV was normalized to BSA to provide the indexed counterpart (RVESVi). Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Pulsatility Index Aorta (PIAo) at 2-3 Hours Post-dose on Day 8 | Assessment of PIAo was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. | 
| Change From Baseline in Pulmonary Artery Pulsatility Index (PAPi) at 2-3 Hours Post-dose on Day 8 | Assessment of PAPi was performed using MRI, 2-3 hours after dosing on Day 8 of each treatment period. Baseline was defined as the pre-dose value on Day 1 of treatment period 1. | Baseline and Day 8 of either treatment period 1 or 2, as applicable. |