Phase 4 COPD and Suboptimal Inspiratory Flow Rate (PIFR-2)

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®)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Revefenacin; Drug: Tiotropium Placebo; Drug: Tiotropium; Drug: Revefenacin Placebo

• Study Type: Interventional
• Enrollment (Actual): 404
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Jasper, Alabama, United States, 35501
      • Theravance Biopharma Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Theravance Biopharma Investigational Site
    • Tucson, Arizona, United States, 85715
      • Theravance Biopharma Investigational Site
  • California
    • Newport Beach, California, United States, 92663
      • Theravance Biopharma Investigational Site
    • San Diego, California, United States, 92120
      • Theravance Biopharma Investigational Site
    • Stockton, California, United States, 95207
      • Theravance Biopharma Investigational Site
    • Upland, California, United States, 91786
      • Theravance Biopharma Investigational Site
  • Colorado
    • Lakewood, Colorado, United States, 80228
      • Theravance Biopharma Investigational Site
  • Florida
    • Brandon, Florida, United States, 33511
      • Theravance Biopharma Investigational Site
    • Clearwater, Florida, United States, 33756
      • Theravance Biopharma Investigational Site
    • Clearwater, Florida, United States, 33765
      • Theravance Biopharma Investigational Site
    • Clearwater, Florida, United States, 33765
      • Theravance Biopharma Investigational Site site 2
    • Daytona Beach, Florida, United States, 32117
      • Theravance Biopharma Investigational Site
    • Leesburg, Florida, United States, 34748
      • Theravance Biopharma Investigational Site
    • Miami, Florida, United States, 33155
      • Theravance Biopharma Investigational Site
    • Miami, Florida, United States, 33186
      • Theravance Biopharma Investigational Site
    • Orlando, Florida, United States, 32825
      • Theravance Biopharma Investigational Site
    • Ormond Beach, Florida, United States, 32174
      • Theravance Biopharma Investigational Site
    • Sarasota, Florida, United States, 34239
      • Theravance Biopharma Investigational Site
    • Tampa, Florida, United States, 33606
      • Theravance Biopharma Investigational Site
    • Winter Park, Florida, United States, 32789
      • Theravance Biopharma Investigational Site
  • Illinois
    • Chicago Ridge, Illinois, United States, 60415
      • Theravance Biopharma Investigational Site
    • River Forest, Illinois, United States, 60305
      • Theravance Biopharma Investigational Site
  • Indiana
    • Hammond, Indiana, United States, 46324
      • Theravance Biopharma Investigational Site
    • Valparaiso, Indiana, United States, 46383
      • Theravance Biopharma Investigational Site
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Theravance Biopharma Investigational Site
    • Columbia, Maryland, United States, 21046
      • Theravance Biopharma Investigational Site
    • Oxon Hill, Maryland, United States, 20745
      • Theravance Biopharma Investigational Site
    • Towson, Maryland, United States, 21286
      • Theravance Biopharma Investigational Site
  • Massachusetts
    • North Dartmouth, Massachusetts, United States, 02747
      • Theravance Biopharma Investigational Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48336
      • Theravance Biopharma Investigational Site
  • Missouri
    • Saint Charles, Missouri, United States, 63301
      • Theravance Biopharma Investigational Site
    • Saint Louis, Missouri, United States, 63141
      • Theravance Biopharma Investigational Site
  • Montana
    • Missoula, Montana, United States, 59808
      • Theravance Biopharma Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Theravance Biopharma Investigational Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108
      • Theravance Biopharma Investigational Site
  • New York
    • Bronxville, New York, United States, 10708
      • Theravance Biopharma Investigational Site
    • Schenectady, New York, United States, 12308
      • Theravance Biopharma Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Theravance Biopharma Investigational Site
    • Hickory, North Carolina, United States, 28601
      • Theravance Biopharma Investigational Site
    • Huntersville, North Carolina, United States, 28078
      • Theravance Biopharma Investigational Site
    • Kernersville, North Carolina, United States, 27284
      • Theravance Biopharma Investigational Site
    • Monroe, North Carolina, United States, 28112
      • Theravance Biopharma Investigational Site
    • Raleigh, North Carolina, United States, 27607
      • Theravance Biopharma Investigational Site
    • Winston-Salem, North Carolina, United States, 27103
      • Theravance Biopharma Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Theravance Biopharma Investigational Site
    • Cincinnati, Ohio, United States, 45236
      • Theravance Biopharma Investigational Site
    • Columbus, Ohio, United States, 43215
      • Theravance Biopharma Investigational Site
    • Columbus, Ohio, United States, 43235
      • Theravance Biopharma Investigational Site
    • Marion, Ohio, United States, 43302
      • Theravance Biopharma Investigational Site
  • Oregon
    • Grants Pass, Oregon, United States, 97527
      • Theravance Biopharma Investigational Site
    • Medford, Oregon, United States, 97504
      • Theravance Biopharma Investigational Site
    • Portland, Oregon, United States, 97202
      • Theravance Biopharma Investigational Site
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Theravance Biopharma Investigational Site
    • Columbia, South Carolina, United States, 29204
      • Theravance Biopharma Investigational Site
    • Gaffney, South Carolina, United States, 29340
      • Theravance Biopharma Investigational Site
    • Greenville, South Carolina, United States, 29615
      • Theravance Biopharma Investigational Site
    • Lexington, South Carolina, United States, 29072
      • Theravance Biopharma Investigational Site
    • North Charleston, South Carolina, United States, 29406
      • Theravance Biopharma Investigational Site
    • Rock Hill, South Carolina, United States, 29732
      • Theravance Biopharma Investigational Site
    • Spartanburg, South Carolina, United States, 29303
      • Theravance Biopharma Investigational Site
    • Spartanburg, South Carolina, United States, 29303
      • Theravance Biopharma Investigational Site #2
    • Union, South Carolina, United States, 29379
      • Theravance Biopharma Investigational Site
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Theravance Biopharma Investigational Site
    • Johnson City, Tennessee, United States, 37601
      • Theravance Biopharma Investigational Site
    • Knoxville, Tennessee, United States, 37909
      • Theravance Biopharma Investigational Site
  • Texas
    • Kerrville, Texas, United States, 78028
      • Theravance Biopharma Investigational Site
    • McAllen, Texas, United States, 78503
      • Theravance Biopharma Investigational Site
    • San Antonio, Texas, United States, 78229
      • Theravance Biopharma Investigational Site
    • Sherman, Texas, United States, 75092
      • Theravance Biopharma Investigational Site
    • Webster, Texas, United States, 77598
      • Theravance Biopharma Investigational Site
  • Utah
    • Roy, Utah, United States, 84067
      • Theravance Biopharma Investigational Site
    • West Valley City, Utah, United States, 84120
      • Theravance Biopharma Investigational Site
  • Virginia
    • Abingdon, Virginia, United States, 24210
      • Theravance Biopharma Investigational Site
  • Washington
    • Spokane, Washington, United States, 99204
      • Theravance Biopharma Investigational Site
  • Wisconsin
    • Cudahy, Wisconsin, United States, 53110
      • Theravance Biopharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participant is a male or female 40 years of age or older.
2. 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.

3. 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.

4. Participant has a diagnosis of COPD, specifically, a post-ipratropium FEV1/FVC ratio <0.7.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Participant is willing and able to adhere to all study assessments/procedures. Care partner assistance is acceptable.

11. 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)
12. 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:

1. 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.
2. Participant has a history of reactions or hypersensitivity to inhaled or nebulized anticholinergics.
3. 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.
4. 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/1.72m^2).
5. Participant has been hospitalized for COPD or pneumonia within 8 weeks prior to Visit 1.
6. 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.
7. Participant has used systemic corticosteroids within 8 weeks of Visit 1.
8. Participant has used antibiotics for respiratory tract infections within 8 weeks of Visit 1, or is using antibiotics prophylactically.
9. Participant received COVID-19 vaccine within 2 weeks prior to Visit 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Revefenacin; Revefenacin administered with Tiotropium Placebo	Drug: Revefenacin; Revefenacin 175 mcg administered once daily for 84 days via nebulization; Other Names: TD-4208; Yupelri®; Drug: Tiotropium Placebo; Placebo for Tiotropium administered once daily for 84 days via Spiriva HandiHaler®
Active Comparator: Tiotropium; Tiotropium administered with Revefenacin Placebo	Drug: Tiotropium; Tiotropium 18 mcg administered once daily for 84 days via Spiriva HandiHaler®; Other Names: Spiriva®; Drug: Revefenacin Placebo; Placebo for Revefenacin administered once daily for 84 days via nebulization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1	Change from baseline in forced expiratory volume in one second (FEV1) at trough on Day 85	Baseline, 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. Overall is defined as the average change from baseline at trough across Day 30, Day 60, and Day 85.	Baseline, Day 30, Day 60, Day 85
FEV1	Change from baseline in FEV1 at trough on Day 30	Baseline, Day 30
FEV1	Change from baseline in FEV1 at trough on Day 60	Baseline, Day 60
FVC	Change from baseline in forced vital capacity (FVC) at trough on Day 85	Baseline, Day 85
80-mL Increase in FEV1 at Trough on Day 85	Participants with an 80-mL or greater change from baseline FEV1 at trough were counted as responders. Participants with change from baseline FEV1 < 80 mL and participants with change from baseline FEV1 not obtained were counted as nonresponders.	Baseline, Day 85
First Occurrence of CompEx Event	Count of participants experiencing events and time from first dose to first occurrence of a composite endpoint for exacerbations of COPD (CompEx) event were evaluated. The statistical analysis is a Cox proportional hazards model analysis of time to first event and the Revefenacin / Tiotropium hazard ratio is calculated and reported. Data are reported as the numbers of subjects with events and the hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table. CompEx events are a composite of moderate or severe COPD exacerbation, premature termination from the study for any reason other than Sponsor decision, and clinically relevant deterioration in COPD. Clinically relevant deterioration events are defined as increases in COPD symptoms meeting specified criteria based on participant diary data.	Date of first dose through date of last dose + 7 days

Collaborators and Investigators

• Sponsor: Theravance Biopharma
• Collaborators: Viatris Inc.
• Investigators: Study Director: Medical Monitor, Theravance Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2022
• Primary Completion (Actual): November 13, 2023
• Study Completion (Actual): November 20, 2023

Study Registration Dates

• First Submitted: December 7, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 21, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 17, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: COPD; Pulmonary Function; Peak Inspiratory Flow Rate; PIFR
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Respiratory Aspiration; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Cholinergic Antagonists; Cholinergic Agents; Parasympatholytics; Tiotropium Bromide
• Other Study ID Numbers: 0180

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

Drug and device information, study documents

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