Phase 4 COPD and Suboptimal Inspiratory Flow Rate | NCT05165485

Status Module

Name	Class
Viatris Inc.	INDUSTRY

Label	Type	Description	Intervention Names
Revefenacin	Experimental	Revefenacin administered with Tiotropium Placebo	Drug: Revefenacin Drug: Tiotropium Placebo
Tiotropium	Active Comparator	Tiotropium administered with Revefenacin Placebo	Drug: Tiotropium Drug: Revefenacin Placebo

Name	Type	Description	Arm Group Labels	Other Names
Revefenacin	Drug	Revefenacin 175 mcg administered once daily for 84 days via nebulization	Revefenacin

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

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

Eligibility Module

Eligibility Criteria

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/1.72m^2).
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.

Name	Affiliation	Role
Medical Monitor	Theravance Biopharma	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Theravance Biopharma Investigational Site		Jasper	Alabama	35501	United States
Theravance Biopharma Investigational Site

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
FG001	Revefenacin

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED	A total of 23 enrolled participants from 2 sites are excluded from the Participant Flow table and all analysis populations due to data integrity concerns.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Feb 27, 2023	Nov 12, 2024

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

FEV1

Change from baseline in forced expiratory volume in one second (FEV1) at trough on Day 85

All participants who received study treatment

Posted

Least Squares Mean

Standard Error

Baseline, Day 85 following 84 days of dosing

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Units	Counts
Participants	OG000191 OG001189

Title

Denominators

Categories

Title	Measurements
	OG000101± 17 OG00178± 17

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The null hypothesis was that the Revefenacin - Tiotropium Least Squares Mean Difference was zero and the alternative hypothesis was that it was nonzero.	Mixed Models Analysis	Denominator degrees of freedom were approximated by the Kenward and Roger (1997) method.	0.22	The familywise type 1 error rate is controlled at 0.05 by testing the primary and secondary endpoint hypotheses in sequence, stopping after the first failure to reject the null hypothesis.	Mean Difference (Net)	-23			2-Sided	95	-61	14			Revefenacin - Tiotropium Least Squares Mean Difference

Secondary

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.

All participants who received study treatment

Posted

Least Squares Mean

Standard Error

Baseline, Day 30, Day 60, Day 85

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Units	Counts
Participants	OG000

Secondary

FEV1

Change from baseline in FEV1 at trough on Day 30

All participants who received study treatment

Posted

Least Squares Mean

Standard Error

Baseline, Day 30

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Units	Counts
Participants	OG000

Secondary

FEV1

Change from baseline in FEV1 at trough on Day 60

All participants who received study treatment

Posted

Least Squares Mean

Standard Error

Baseline, Day 60

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Units	Counts
Participants	OG000

Secondary

FVC

Change from baseline in forced vital capacity (FVC) at trough on Day 85

All participants who received study treatment

Posted

Least Squares Mean

Standard Error

Baseline, Day 85

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Units	Counts
Participants	OG000

Secondary

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.

All participants who received study treatment

Posted

Count of Participants

Participants

Baseline, Day 85

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Units	Counts
Participants	OG000

Secondary

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.

All participants who received study treatment and were evaluable for rescue medication use (i.e., were not using nebulized albuterol for rescue or albuterol 4 times daily for maintenance)

Posted

Count of Participants

Participants

Date of first dose through date of last dose + 7 days

ID	Title	Description
OG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
OG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Atrial fibrillation	Cardiac disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Cardiac arrest	Cardiac disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0013 affected189 at risk
Chronic left ventricular failure	Cardiac disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Supraventricular tachycardia	Cardiac disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Colitis	Gastrointestinal disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Gastric ulcer	Gastrointestinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Incarcerated inguinal hernia	Gastrointestinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
COVID-19	Infections and infestations	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0012 affected189 at risk
COVID-19 pneumonia	Infections and infestations	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Pneumonia	Infections and infestations	MedDRA (26.1)	Systematic Assessment	EG0002 affected191 at risk EG0012 affected189 at risk
Pneumonia legionella	Infections and infestations	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Urosepsis	Infections and infestations	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA (26.1)	Systematic Assessment	EG0002 affected191 at risk EG0011 affected189 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	EG0004 affected191 at risk EG0014 affected189 at risk
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	EG0001 affected191 at risk EG0010 affected189 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	EG0000 affected191 at risk EG0011 affected189 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA (26.1)	Systematic Assessment		EG0004 affected191 at risk EG0012 affected189 at risk
COVID-19	Infections and infestations	MedDRA (26.1)	Systematic Assessment		EG0001 affected191 at risk EG0013 affected189 at risk
Cellulitis	Infections and infestations	MedDRA (26.1)	Systematic Assessment		EG0001 affected191 at risk EG0013 affected189 at risk
Nasopharyngitis	Infections and infestations	MedDRA (26.1)	Systematic Assessment		EG0002 affected191 at risk EG0013 affected189 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (26.1)	Systematic Assessment		EG0002 affected191 at risk EG0013 affected189 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (26.1)	Systematic Assessment		EG0002 affected191 at risk EG0014 affected189 at risk
Headache	Nervous system disorders	MedDRA (26.1)	Systematic Assessment		EG0005 affected191 at risk EG0012 affected189 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (26.1)	Systematic Assessment	Treatment-emergent COPD exacerbations were coded to this preferred term.	EG00022 affected191 at risk EG00122 affected189 at risk

ID	Term
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
C583570	revefenacin
D000069447	Tiotropium Bromide

ID	Term
D012602	Scopolamine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds
D009930	Organic Chemicals
D000470	Alkaloids
D006571	Heterocyclic Compounds
D019086	Bridged Bicyclo Compounds, Heterocyclic
D006572	Heterocyclic Compounds, Bridged-Ring

ID	Title	Description
BG000	Tiotropium	Active Tiotropium and Placebo for Revefenacin. Tiotropium: Tiotropium administered via Spiriva HandiHaler® device. Placebo for Revefenacin: Placebo administered as double blind, double dummy via nebulization.
BG001	Revefenacin	Active Revefenacin and Placebo for Tiotropium. Revefenacin: Revefenacin administered via nebulization. Placebo for Tiotropium: Placebo administered as double blind, double dummy via HandiHaler® device.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Tiotropium	Tiotropium administered with Revefenacin Placebo Tiotropium: Tiotropium 18 mcg administered once daily for 84 days via Spiriva HandiHaler® Revefenacin Placebo: Placebo for Revefenacin administered once daily for 84 days via nebulization	0	191	15	191	33	191
EG001	Revefenacin	Revefenacin administered with Tiotropium Placebo Revefenacin: Revefenacin 175 mcg administered once daily for 84 days via nebulization Tiotropium Placebo: Placebo for Tiotropium administered once daily for 84 days via Spiriva HandiHaler®	0	189	16	189	38	189