COPD
Conditions
Keywords
Revefenacin, Long-acting muscarinic receptor antagonist(LAMA)
Brief summary
This study is a phase III clinical study to assess the efficacy and safety of Revefenacin inhalation solution 175 mcg administered once daily via nebulization for 12 weeks compared to placebo in a population of Chinese subjects with moderate to very severe COPD.
Detailed description
This will be a multi-center, randomized, double blind, placebo-controlled, parallel group study, randomizing approximately 320 male or female moderate-very severe COPD subjects. Subjects will receive study drug for 12 weeks. Treatments to be received during the study will include one of the following, administered using a centrally-provided, standard jet nebulizer and compressor via a mouthpiece: A. Revefenacin inhalation solution 175 mcg Quaque die (QD). B. Placebo inhalation solution QD. Subjects will have approximately 6 clinic visits (encompassing a screening period of up to 30 days and a treatment period of 12 weeks), and a follow-up telephone call 1-2 weeks after the End of Treatment (EoT) visit.
Interventions
DRUGRevefenacin 175 mcg in 3 ML Inhalation Solution
Revefenacin
DRUGPlacebo inhalation solution QD
Placebo
Sponsors
Mylan Pharma UK Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Multicenter, randomized, double-blind, placebo-control, parallel group study
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Key inclusion criteria include: * Males and females of Chinese ethnicity, at least 40 years of age. Females may be of either childbearing or non-childbearing potential. All females of childbearing potential must be using an acceptable, highly effective method of contraception and have a negative pregnancy test at screening. * A clinical diagnosis for at least 6 months prior to screening of COPD according to Global Initiative for Chronic Obstructive Lung Disease(GOLD) guidelines. * Subject is capable of performing reproducible spirometry maneuvers as described by current American Thoracic Society/European Respiratory Society (ATS/ERS) Guidelines and has a post-ipratropium (500 mcg nebulized) Forced Expiratory Volume in 1 second(FEV1)/Forced Vital Capacity(FVC) ratio \<0.7 at Visit 2. * Subject has moderate to very severe COPD with a post-ipratropium (500 mcg nebulized) FEV1 less than 80% of predicted normal (using the Global Lung Function Initiative reference range; ) and an absolute FEV1 \>700 mL at Visit 2 * Current smoker or ex-smoker, with a history of at least 10 pack-years of tobacco smoking. Ex-smokers must have stopped smoking \>6 months prior to Visit 1.
Exclusion criteria
* Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough FEV1 on Day 85 | Baseline and Day 85 | Change from Baseline (Day 1, pre-dose) trough FEV1 on Day 85 |
| Trough FEV1 on Day 85 - Sensitivity Analysis With Missing Data Imputed | Baseline, Day 29, Day 57 and Day 85 | Sensitivity analysis results of change from baseline in trough FEV1 (mL) on Day 85 with missing data imputed by last observation carried forward |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak FEV1 (0-2h) on Day 85 | Day 1 (baseline) and Day 85, from 45 minutes before dosing to 2 hours after dosing | Baseline FEV1 was defined as the average of the -45 and -15 minute measurements prior to dosing of study drug on Day 1. Peak FEV1 (0-2h) was defined as the highest post dose FEV1 value within 2 hours after the dosing. |
| Trough FVC on Day 85 | Baseline and Day 85 | Change from baseline (Day 1, pre-dose) trough Forced Vital Capacity (FVC) on Day 85 |
| Number (%) of SGRQ Responders on Day 85 | Day 85 | Number of subjects with a decrease from baseline of ≥4 units in SGRQ total score (which was defined as a responder) on Day 85 |
| Change From Baseline in SGRQ Total Score on Day 85 | Day 1 (baseline) and Day 85 | Change from Baseline in the St George's Respiratory Questionnaire (SGRQ) Total Score on Day 85. Scores range from 0 to 100, with higher scores indicating more health limitations. A reduction of 4 or more points is considered to be a clinically meaningful improvement |
| Change From Baseline in Peak FEV1 (0-2h) on Day 1 | Day 1, from 45 minutes before dosing to 2 hours after dosing | Baseline FEV1 was defined as the average of the -45 and -15 minute measurements prior to dosing of study drug on Day 1. Peak FEV1 (0-2h) was defined as the highest post dose FEV1 value within 2 hours after the dosing. |
Countries
China
Participant flow
Recruitment details
258 subjects were randomized, of which 257 received randomized study treatment. The one subject who was not treated was randomized in error
Participants by arm
| Arm | Count |
|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. Revefenacin inhalation solution 175 mcg in 3 mL administered once daily by nebulizer for 12 weeks | 129 |
| Placebo Inhalation Solution QD. Placebo inhalation solution in 3 mL administered once daily by nebulizer for 12 weeks | 128 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 15 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Public health emergency (COVID-19) restrictions | 2 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 7 |
Baseline characteristics
| Characteristic | Placebo Inhalation Solution QD. | Revefenacin Inhalation Solution 175 mcg QD. | Total |
|---|---|---|---|
| Age, Continuous | 67.7 Years STANDARD_DEVIATION 6.8 | 67.6 Years STANDARD_DEVIATION 6.18 | 67.6 Years STANDARD_DEVIATION 6.48 |
| Age, Customized Age group <65 years | 37 Participants | 36 Participants | 73 Participants |
| Age, Customized Age group >=65 years | 91 Participants | 93 Participants | 184 Participants |
| Body Mass Index (BMI) | 23.44 kg/m^2 STANDARD_DEVIATION 3.106 | 22.92 kg/m^2 STANDARD_DEVIATION 3.559 | 23.18 kg/m^2 STANDARD_DEVIATION 3.345 |
| Concomitant inhaled corticosteroid use No | 40 Participants | 44 Participants | 84 Participants |
| Concomitant inhaled corticosteroid use Yes | 88 Participants | 85 Participants | 173 Participants |
| Concomitant long acting beta agonist use No | 41 Participants | 42 Participants | 83 Participants |
| Concomitant long acting beta agonist use Yes | 87 Participants | 87 Participants | 174 Participants |
| Race/Ethnicity, Customized Race Asian - Chinese | 128 Participants | 129 Participants | 257 Participants |
| Race/Ethnicity, Customized Race Asian - Not Chinese | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 128 participants | 129 participants | 257 participants |
| Reversibility to ipratropium No | 71 Participants | 70 Participants | 141 Participants |
| Reversibility to ipratropium Yes | 57 Participants | 59 Participants | 116 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 122 Participants | 122 Participants | 244 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 129 | 0 / 128 |
| other Total, other adverse events | 58 / 129 | 60 / 128 |
| serious Total, serious adverse events | 14 / 129 | 11 / 128 |
Outcome results
Primary
Trough FEV1 on Day 85
Change from Baseline (Day 1, pre-dose) trough FEV1 on Day 85
Time frame: Baseline and Day 85
Population: The Analysis Population was all subjects in the Full Analysis Set who had evaluable data for the respective endpoint. Missing data was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Trough FEV1 on Day 85 | 55.12 mL | Standard Error 23.974 |
| Placebo Inhalation Solution QD. | Trough FEV1 on Day 85 | -95.78 mL | Standard Error 24.504 |
p-value: <0.000195% CI: [104.145, 197.671]Mixed Models Analysis
Primary
Trough FEV1 on Day 85 - Sensitivity Analysis With Missing Data Imputed
Sensitivity analysis results of change from baseline in trough FEV1 (mL) on Day 85 with missing data imputed by last observation carried forward
Time frame: Baseline, Day 29, Day 57 and Day 85
Population: Full analysis set (missing data for Day 85 was imputed from Day 29 or Day 57 data by Last Observation Carried Forward)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Trough FEV1 on Day 85 - Sensitivity Analysis With Missing Data Imputed | 52.05 mL | Standard Error 27.036 |
| Placebo Inhalation Solution QD. | Trough FEV1 on Day 85 - Sensitivity Analysis With Missing Data Imputed | -92.30 mL | Standard Error 27.502 |
p-value: <0.000195% CI: [102.61, 186.088]Mixed Models Analysis
Secondary
Change From Baseline in Peak FEV1 (0-2h) on Day 1
Baseline FEV1 was defined as the average of the -45 and -15 minute measurements prior to dosing of study drug on Day 1. Peak FEV1 (0-2h) was defined as the highest post dose FEV1 value within 2 hours after the dosing.
Time frame: Day 1, from 45 minutes before dosing to 2 hours after dosing
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Change From Baseline in Peak FEV1 (0-2h) on Day 1 | 234.2 mL | Standard Error 21.55 |
| Placebo Inhalation Solution QD. | Change From Baseline in Peak FEV1 (0-2h) on Day 1 | 128.4 mL | Standard Error 21.92 |
p-value: <0.000195% CI: [72.6, 139.12]ANCOVA
Secondary
Change From Baseline in Peak FEV1 (0-2h) on Day 85
Baseline FEV1 was defined as the average of the -45 and -15 minute measurements prior to dosing of study drug on Day 1. Peak FEV1 (0-2h) was defined as the highest post dose FEV1 value within 2 hours after the dosing.
Time frame: Day 1 (baseline) and Day 85, from 45 minutes before dosing to 2 hours after dosing
Population: The Analysis Population was all subjects in the Full Analysis Set who had evaluable data for the respective endpoint. Missing data was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Change From Baseline in Peak FEV1 (0-2h) on Day 85 | 199.0 mL | Standard Error 32.72 |
| Placebo Inhalation Solution QD. | Change From Baseline in Peak FEV1 (0-2h) on Day 85 | 44.2 mL | Standard Error 33.62 |
p-value: <0.000195% CI: [98.86, 210.78]ANCOVA
Secondary
Change From Baseline in SGRQ Total Score on Day 85
Change from Baseline in the St George's Respiratory Questionnaire (SGRQ) Total Score on Day 85. Scores range from 0 to 100, with higher scores indicating more health limitations. A reduction of 4 or more points is considered to be a clinically meaningful improvement
Time frame: Day 1 (baseline) and Day 85
Population: The Analysis Population was all subjects in the Full Analysis Set who had evaluable data for the respective endpoint. Missing data was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Change From Baseline in SGRQ Total Score on Day 85 | -4.8 Score on a scale | Standard Error 2.17 |
| Placebo Inhalation Solution QD. | Change From Baseline in SGRQ Total Score on Day 85 | 0.2 Score on a scale | Standard Error 2.2 |
p-value: 0.006495% CI: [-8.49, -1.4]ANCOVA
Secondary
Number (%) of SGRQ Responders on Day 85
Number of subjects with a decrease from baseline of ≥4 units in SGRQ total score (which was defined as a responder) on Day 85
Time frame: Day 85
Population: The Analysis Population was all subjects in the Full Analysis Set who had evaluable data for the respective endpoint. Missing data was not imputed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Number (%) of SGRQ Responders on Day 85 | 58 Participants |
| Placebo Inhalation Solution QD. | Number (%) of SGRQ Responders on Day 85 | 45 Participants |
p-value: 0.014495% CI: [1.16, 3.84]Regression, Logistic
Secondary
Trough FVC on Day 85
Change from baseline (Day 1, pre-dose) trough Forced Vital Capacity (FVC) on Day 85
Time frame: Baseline and Day 85
Population: The Analysis Population was all subjects in the Full Analysis Set who had evaluable data for the respective endpoint. Missing data was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Revefenacin Inhalation Solution 175 mcg QD. | Trough FVC on Day 85 | 97.92 mL | Standard Error 41.833 |
| Placebo Inhalation Solution QD. | Trough FVC on Day 85 | -189.83 mL | Standard Error 42.801 |
p-value: <0.000195% CI: [211.933, 363.57]Mixed Models Analysis