Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, Peak Inspiratory Flow Rate, PIFR, Pulmonary Function
Brief summary
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.
Interventions
DRUGRevefenacin
Revefenacin 175 mcg administered once daily for 84 days via nebulization
DRUGTiotropium
Tiotropium 18 mcg administered once daily for 84 days via Spiriva HandiHaler®
DRUGRevefenacin Placebo
Placebo for Revefenacin administered once daily for 84 days via nebulization
Placebo for Tiotropium administered once daily for 84 days via Spiriva HandiHaler®
Sponsors
Viatris Inc.
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 | Baseline, Day 85 following 84 days of dosing | Change from baseline in forced expiratory volume in one second (FEV1) at trough on Day 85 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OTE on FEV1 | Baseline, Day 30, Day 60, Day 85 | 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. |
| FEV1 | Baseline, Day 30 | Change from baseline in FEV1 at trough on Day 30 |
| FVC | Baseline, Day 85 | Change from baseline in forced vital capacity (FVC) at trough on Day 85 |
| 80-mL Increase in FEV1 at Trough on Day 85 | Baseline, 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. |
| First Occurrence of CompEx Event | Date of first dose through date of last dose + 7 days | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 191 |
| 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. | 189 |
| Total | 380 |
Baseline characteristics
| Characteristic | Tiotropium | Revefenacin | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 67 years | 66 years |
| Age, Customized 40 to 64 years old | 81 Participants | 79 Participants | 160 Participants |
| Age, Customized 65 years old and over | 110 Participants | 110 Participants | 220 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 176 Participants | 172 Participants | 348 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 10 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 14 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 175 Participants | 171 Participants | 346 Participants |
| Region of Enrollment United States | 191 Participants | 189 Participants | 380 Participants |
| Sex: Female, Male Female | 86 Participants | 90 Participants | 176 Participants |
| Sex: Female, Male Male | 105 Participants | 99 Participants | 204 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 191 | 0 / 189 |
| other Total, other adverse events | 33 / 191 | 38 / 189 |
| serious Total, serious adverse events | 15 / 191 | 16 / 189 |
Outcome results
Primary
FEV1
Change from baseline in forced expiratory volume in one second (FEV1) at trough on Day 85
Time frame: Baseline, Day 85 following 84 days of dosing
Population: All participants who received study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium | FEV1 | 101 mL | Standard Error 17 |
| Revefenacin | FEV1 | 78 mL | Standard Error 17 |
Comparison: The null hypothesis was that the Revefenacin - Tiotropium Least Squares Mean Difference was zero and the alternative hypothesis was that it was nonzero.p-value: 0.2295% CI: [-61, 14]Mixed Models Analysis
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.
Time frame: Baseline, Day 85
Population: All participants who received study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tiotropium | 80-mL Increase in FEV1 at Trough on Day 85 | 83 Participants |
| Revefenacin | 80-mL Increase in FEV1 at Trough on Day 85 | 63 Participants |
Comparison: The null hypothesis was that the Revefenacin / Tiotropium responder Odds Ratio was equal to 1 and the alternative hypothesis was that it was not equal to 1.95% CI: [0.39, 0.92]Regression, Logistic
Secondary
FEV1
Change from baseline in FEV1 at trough on Day 60
Time frame: Baseline, Day 60
Population: All participants who received study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium | FEV1 | 79 mL | Standard Error 17 |
| Revefenacin | FEV1 | 73 mL | Standard Error 17 |
Comparison: The null hypothesis was that the Revefenacin - Tiotropium Least Squares Mean Difference was zero and the alternative hypothesis was that it was nonzero.95% CI: [-40, 29]Mixed Models Analysis
Secondary
FEV1
Change from baseline in FEV1 at trough on Day 30
Time frame: Baseline, Day 30
Population: All participants who received study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium | FEV1 | 81 mL | Standard Error 16 |
| Revefenacin | FEV1 | 83 mL | Standard Error 16 |
Comparison: The null hypothesis was that the Revefenacin - Tiotropium Least Squares Mean Difference was zero and the alternative hypothesis was that it was nonzero.95% CI: [-29, 32]Mixed Models Analysis
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.
Time frame: Date of first dose through date of last dose + 7 days
Population: 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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tiotropium | First Occurrence of CompEx Event | 56 Participants |
| Revefenacin | First Occurrence of CompEx Event | 58 Participants |
Comparison: The null hypothesis was that the Revefenacin / Tiotropium CompEx Event Hazard Ratio was equal to 1 and the alternative hypothesis was that it was not equal to 1.95% CI: [0.69, 1.45]Regression, Cox
Secondary
FVC
Change from baseline in forced vital capacity (FVC) at trough on Day 85
Time frame: Baseline, Day 85
Population: All participants who received study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium | FVC | 198 mL | Standard Error 35 |
| Revefenacin | FVC | 156 mL | Standard Error 35 |
Comparison: The null hypothesis was that the Revefenacin - Tiotropium Least Squares Mean Difference was zero and the alternative hypothesis was that it was nonzero.95% CI: [-118, 35]Mixed Models Analysis
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.
Time frame: Baseline, Day 30, Day 60, Day 85
Population: All participants who received study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium | OTE on FEV1 | 87 mL | Standard Error 15 |
| Revefenacin | OTE on FEV1 | 78 mL | Standard Error 15 |
Comparison: The OTE is defined as the average of the Day 30, Day 60, and Day 85 Revefenacin - Tiotropium Least Squares Mean differences. The null hypothesis was that the OTE Revefenacin - Tiotropium Least Squares Mean Difference was zero and the alternative hypothesis was that it was nonzero.95% CI: [-38, 20]Mixed Models Analysis