Phase 4 COPD and Suboptimal Inspiratory Flow Rate

Study Overview
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Brief Summary
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Study is a randomized, double-blind, double-dummy, parallel-group study evaluating efficacy and safety of revefenacin vs. tiotropium in adults with severe to very severe COPD and suboptimal PIFR.

Official Title
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A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Study Comparing Improvements in Lung Function in Adults With Severe to Very Severe Chronic Obstructive Pulmonary Disease and Suboptimal Inspiratory Flow Rate Following Once-Daily Treatment Over 12 Weeks With Either Revefenacin Inhalation Solution Delivered Via Standard Jet Nebulizer or Tiotropium Delivered Via a Dry Powder Inhaler (Spiriva® HandiHaler®)

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Revefenacin
* Drug: Tiotropium
* Drug: Revefenacin Placebo
* Drug: Tiotropium Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is a male or female 40 years of age or older. Participant is female and is nonpregnant and nonlactating. A woman of childbearing potential must have a documented negative urine pregnancy test at screening. Women are considered not to be of childbearing potential if they have had a total hysterectomy and/or bilateral tubal ligation (documentation for either must be provided before enrollment) or are at least 2 years postmenopausal. During the study and for 30 days after receiving the last dose of study drug, women of childbearing potential and men capable of fathering children must agree to use highly effective birth control measures or agree to abstain from sexual intercourse. A highly effective method of birth control is defined as one that results in a low failure rate (i.e. <1% per year) when used consistently and correctly, such as condom + diaphragm, condom + spermicide, diaphragm + spermicide, or intrauterine device [IUD] with documented failure rate of <1% per year, or oral/injectable/implanted hormonal contraceptives used in combination with an additional barrier method. Participant has a diagnosis of COPD, specifically, a post-ipratropium FEV1/FVC ratio <0.7. Participant has a post ipratropium 30% ≤ FEV1 < 50% of predicted normal (using National Health and Nutrition Examination Survey-predicted equations) and absolute FEV1 > 500 mL, or FEV1 <30% predicted normal and absolute FEV1 > 700 mL. Participant has a PIFR <60 L/min as measured by an In-Check™ device with resistance set to DISKUS at Visit 1A (if not combined with Visit 1B) and < 55 L/min as measured by an In-Check™ device with resistance set to DISKUS at Visit 1B and Visit 2 prior to randomization. Participant is capable of performing reproducible spirometry maneuvers (and plethysmography maneuvers for a subset of participants) as described by current American Thoracic Society (ATS) Guidelines. Participant is an active or former smoker with a cigarette smoking history (or equivalent for cigar or pipe smoking history) of at least 10 pack-years. Participant or legal guardian is willing and able to provide signed and dated informed consent to participate prior to initiation of any study related procedures. Participant is willing and able to adhere to all study assessments/procedures. Care partner assistance is acceptable. Participant is willing and able to adhere to all restrictions during their study participation as follows: Use of recreational drugs Medicinal marijuana Excessive alcohol during the study period Participation in another investigational drug study Donation of ≥500 mL blood (or equivalent) Participant (or care partner) based on the investigator's assessment is able to properly prepare and administer study medication administered from both nebulizer and HandiHaler® according to their respective Instructions for Use. Exclusion Criteria: Participant has a concurrent disease or condition that, in the opinion of the investigator, would interfere with study participation or confound the evaluation of safety and tolerability of the study drug. Participant has a history of reactions or hypersensitivity to inhaled or nebulized anticholinergics. Participant suffers from any medical condition that would preclude the use of inhaled anticholinergics, including narrow-angle glaucoma, symptomatic benign prostatic hyperplasia, bladder neck obstruction, or urinary retention. Participant has Moderate to Severe Hepatic impairment (Child-Pugh B or C) or Severe Renal Insufficiency (i.e. a glomerular filtration rate <30 mL/min/1.72m2). Participant has been hospitalized for COPD or pneumonia within 8 weeks prior to Visit 1. Participant is receiving a LABA or LABA/inhaled corticosteroid (ICS; either QD or BID) at a dose that has been stable for ≤ 30 days prior to screening. Participant has used systemic corticosteroids within 8 weeks of Visit 1. Participant has used antibiotics for respiratory tract infections within 8 weeks of Visit 1, or is using antibiotics prophylactically. Participant received COVID-19 vaccine within 2 weeks prior to Visit 1.

Ages Eligible for Study
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Minimum Age: 40 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Revefenacin<br>Revefenacin DoseA administered with tiotropium placebo | Drug: Revefenacin<br>* Revefenacin DoseA<br>* Other names: Yupelri;Drug: Tiotropium Placebo<br>* Placebo for Tiotropium administered with Revefenacin<br>|
| Active Comparator: Tiotropium<br>Tiotropium DoseB administered with revefenacin placebo | Drug: Tiotropium<br>* Tiotropium DoseB<br>Drug: Revefenacin Placebo<br>* Placebo for Revefenacin administered with Tiotropium<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 | Change from baseline in trough FEV1 | Day 85 following 84 days of dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OTE on FEV1 | Trough Overall treatment effect (OTE) on FEV1 | Day 30 through Day 85 | 
| FEV1 | Change from baseline in Trough FEV1 on Day 30 | Day 30 | 
| FEV1 | Change from baseline in Trough FEV1 on Day 60 | Day 60 | 
| FVC | Change from baseline in Trough FVC | Day 85 | 
| 80-mL improvement in trough FEV1 | Percentage of participants who achieve at least an 80-mL improvement in trough FEV1 | Day 85 | 
| Time to first CompEx | Composite endpoint for exacerbations of COPD event | Baseline through Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Peak Inspiratory Flow Rate, PIFR, Pulmonary Function