COPD
Conditions
Keywords
Long acting muscarinic antagonist, Chronic Bronchitis, Emphysema, Chronic Obstructive Pulmonary Disease, COPD
Brief summary
This study will characterize the dose response of TD-4208 after 7 days of dosing in subjects with Chronic Obstructive Pulmonary Disease (COPD).
Interventions
DRUGTD-4208
DRUGPlacebo
Sponsors
Theravance Biopharma
Mylan Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is a male or female between the ages of 40 and 75 years (inclusive, at randomization). 2. Subject: * Has an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) \<0.7 at screening; and * Has a post-bronchodilator FEV1 at screening of between 30% and 80% (inclusive) of the predicted normal value. 3. Subject demonstrates at screening at least a 120 mL increase in FEV1 within 1 hour of receiving 500 µg of ipratropium bromide from a PARI LC Sprint® nebulizer. 4. Females of non-childbearing potential. All male subjects must agree to use a highly effective method of birth control with partners of childbearing potential during the study and for 1 month after completion of study dosing. 5. Subject (or care giver) is able to properly prepare and administer study medication. 6. Subject is willing and able to give written informed consent to participate.
Exclusion criteria
1. Subject has had a COPD exacerbation or lung infection within 6 weeks before randomization. 2. Subject has had an initiation of treatment, or a change in dose, of an inhaled or oral corticosteroid, or long-acting beta2 agonist (LABA), or long-acting muscarinic antagonist (LAMA) within 4 weeks before the qualifying ipratropium bromide response test. 3. Subject is taking daily maintenance inhaled/systemic corticosteroids (\>1000 μg of fluticasone propionate equivalent or ≥10 mg prednisone). 4. Subject has an uncontrolled hematologic, immunologic, renal, neurologic, hepatic, endocrine, or other disease or condition based on information gathered from the medical history, physical examination, or laboratory findings that might place the subject at undue risk or potentially compromise the results or interpretation of the study. 5. Subject has a history of significant cerebrovascular disease, coronary artery disease, or cardiac arrhythmias. Subject has a history (or family history) of congenital prolonged QTc (corrected QT interval) syndrome or has an abnormal clinically significant electrocardiogram (ECG) at screening, including QTcB (QT interval corrected for heart rate using Bazett's formula) value \>450 msec (males) or \>470 msec (females); or shows evidence of clinically significant rhythm abnormality. 6. Subject has a known hypersensitivity to TD-4208 or similar drug class. 7. Subject has a history of alcoholism or drug abuse within 2 years prior to screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | From baseline to day 7 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cmax | From baseline to day 7 | Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours. |
| Tmax | From baseline to day 7 | Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours. |
| Plasma Half-life | From baseline to day 7 | Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours. |
Countries
New Zealand
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population All subjects received Placebo and 4 of 6 TD-4208 dose levels:
TD-4208 - 22 µg TD-4208 - 44 µg TD-4208 - 88 µg TD-4208 - 175 µg TD-4208 - 350 µg TD-4208 - 700 µg | 62 |
| Total | 62 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 64.2 year STANDARD_DEVIATION 6.8 |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 41 | 12 / 39 | 12 / 40 | 13 / 37 | 8 / 41 | 9 / 37 | 16 / 61 |
| serious Total, serious adverse events | 2 / 42 | 0 / 42 | 0 / 40 | 0 / 41 | 0 / 41 | 0 / 42 | 1 / 62 |
Outcome results
Primary
Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second)
Time frame: From baseline to day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 TD-4208 | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 91.2 FEV1 (mL) | Standard Error 19.21 |
| Dose 2 TD-4208 | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 92.8 FEV1 (mL) | Standard Error 20.25 |
| Dose 3 TD-4208 | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 113.1 FEV1 (mL) | Standard Error 19.55 |
| Dose 4 TD-4208 | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 151.9 FEV1 (mL) | Standard Error 19.99 |
| Dose 5 TD-4208 | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 132.2 FEV1 (mL) | Standard Error 19.02 |
| Dose 6 TD-4208 | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 119.4 FEV1 (mL) | Standard Error 19.54 |
| Placebo | Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second) | 37.8 FEV1 (mL) | Standard Error 16.93 |
Other Pre-specified
Cmax
Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.
Time frame: From baseline to day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 TD-4208 | Cmax | .0125 ng/mL | Standard Deviation 0.00627 |
| Dose 2 TD-4208 | Cmax | .0224 ng/mL | Standard Deviation 0.00864 |
| Dose 3 TD-4208 | Cmax | .0526 ng/mL | Standard Deviation 0.0214 |
| Dose 4 TD-4208 | Cmax | .114 ng/mL | Standard Deviation 0.0488 |
| Dose 5 TD-4208 | Cmax | .243 ng/mL | Standard Deviation 0.104 |
| Dose 6 TD-4208 | Cmax | .577 ng/mL | Standard Deviation 0.261 |
Other Pre-specified
Plasma Half-life
Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.
Time frame: From baseline to day 7
Population: The number of subjects reported for plasma half lives are based on the actual evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 5 TD-4208 | Plasma Half-life | 25.1 hours | Standard Deviation 7.89 |
| Dose 6 TD-4208 | Plasma Half-life | 23.0 hours | Standard Deviation 7.05 |
Other Pre-specified
Tmax
Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours. Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours.
Time frame: From baseline to day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 TD-4208 | Tmax | .233 hours | Standard Deviation 0.217 |
| Dose 2 TD-4208 | Tmax | .233 hours | Standard Deviation 0.2 |
| Dose 3 TD-4208 | Tmax | 0.233 hours | Standard Deviation 0.2 |
| Dose 4 TD-4208 | Tmax | 0.233 hours | Standard Deviation 0.2 |
| Dose 5 TD-4208 | Tmax | 0.233 hours | Standard Deviation 0.217 |
| Dose 6 TD-4208 | Tmax | 0.233 hours | Standard Deviation 0.2 |